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Bibliografia: Chen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. Paediatr Drugs. 2015;17(4):273-81. Harrington J, Palmert M R. Definition, etiology, and evaluation of precocious puberty. En UpToDate. Hoppin A G, Martin K, Ed. 2018. Available at: http://www.UpToDate.com/ Bereket A. A Critical Appraisal of the Effect of Gonadotropin-Releasing Hormon Analog Treatment on Adult Height of Girls with Central Precocious Puberty. J Clin Res Pediatr Endocrinol. 2017 30;9(Suppl 2):33-48.

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HHS Public Access Author manuscript

Author Manuscript Paediatr Drugs. Author manuscript; available in PMC 2018 March 27. Published in final edited form as: Paediatr Drugs. 2015 August ; 17(4): 273–281. doi:10.1007/s40272-015-0130-8.

Central Precocious Puberty: Update on Diagnosis and Treatment

Melinda Chen1 and Erica A. Eugster1 1Section of Pediatric Endocrinology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, 705 Riley Hospital Drive, Room # 5960, Indianapolis, IN 46202, USA

Author Manuscript Abstract Central precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ∼50 % of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is go-nadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional Author Manuscript investigation.

1 Introduction Central precocious puberty (CPP) refers to premature activation of the hypothalamic– pituitary–gonadal (HPG) axis, resulting in early development of secondary sexual characteristics. Although the exact threshold defining “normal” pubertal timing has been disputed, commonly used cutoffs to define CPP are 8 years of age for females (7.5 years for Hispanics and African Americans) and 9 years of age for males [1]. The earliest clinical manifestation of central puberty in girls is usually breast development (thelarche), followed by pubic hair (pub-arche). The pubertal growth spurt typically occurs during Tanner stage II–III, with the first menstrual period, known as menarche, usually occurring at Tanner stage Author Manuscript IV. In boys, the initial clinical sign of central puberty is testicular enlargement and the pubertal growth spurt happens later than in girls [2, 3].

Although the precise mechanisms triggering the onset of puberty are unclear, the earliest known biochemical change during puberty is increased production of kisspeptin in the hypothalamus. While kisspeptin itself has several proposed stimulatory and inhibitory signals, which have not yet been clearly elucidated, it has been shown that increased

Correspondence to: Melinda Chen. Conflict of interest Dr. Chen has no conflicts of interest to disclose. Dr. Eugster participates in clinical trials investigating treatment of CPP, funded by Endo Pharmaceuticals. No sources of funding were used to support the writing of this article.

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kisspeptin production results in increased gonadotropin-releasing hormone (GnRH) release. Author Manuscript Thus, a rise in kisspeptin is widely acknowledged as the seminal event that initiates HPG axis activation during puberty [2]. Inhibition of the GnRH pulse generator decreases first during sleep, resulting in an increase of nighttime luteinizing hormone (LH) pulse amplitude during early and mid-puberty. As puberty progresses, LH pulse amplitude increases during daytime hours as well, and estrogen and testosterone levels rise accordingly.

2 Etiology CPP, for unknown reasons, is found predominantly in girls. In an observational study of the incidence of CPP in Spain, females were approximately ten times more likely to be affected than males [4], and other sources have cited a female-to-male ratio as high as 20:1 [5]. In addition, the etiology of CPP differs between the genders. While the majority of girls will

Author Manuscript have idiopathic CPP, boys are more likely to have a pathological source [1, 6]. Risk factors for CPP include a history of international adoption, as well as congenital or acquired central nervous system insults, such as hypothalamic hamartoma, septo-optic dysplasia, tumor, trauma, infection, or ischemia. Several genetic syndromes, including neurofibromatosis type 1, tuberous sclerosis, and Sturge–Weber syndrome, are associated with CPP [2]. Apart from recognized genetic syndromes, anywhere from 5.2 to 27.5 % of cases have been reported to be familial [7, 8].

Specific genetic causes of CPP have been described relatively recently. A substitution mutation in the G-protein coupled kisspeptin receptor gene KISS1R (formerly known as GPR54) was found in a patient with CPP and was associated with delayed degradation of the ligand–receptor complex within the cell membrane. This was further linked to an extended period of downstream signaling, postulated to result in increased amplitude of GnRH Author Manuscript pulsatility [9]. An additional KISS1R polymorphism in the promoter region has been described in Chinese girls with CPP, though a detailed knowledge of whether or how this variant impacts the expression or function of the gene is as yet unknown [10].

A mutation in KISS1, encoding the ligand kisspeptin, has also been described within an amino-terminal sequence associated with protein degradation [11]. The mutated li-gand– receptor complex similarly demonstrates resistance to degradation. However, the low population frequency associated with this mutation suggests that it is a relatively uncommon cause of CPP.

More recently, ten separate heterozygous mutations in MKRN3, encoding makorin RING- finger protein 3, have been found in association with both sporadic and familial CPP [12–

Author Manuscript 14]. MKRN3 is a paternally expressed imprinted gene located within the region typically affected in Prader–Willi syndrome. Although the exact function of MKRN3 in humans is as yet unknown, studies in mice have illustrated that mkrn3 mRNA is expressed in the hypothalamic arcuate nucleus, and that a decline in mkrn3 expression is temporally correlated with the rise in kiss1 expression. Other studies have postulated that down- regulation of MKRN3 is permissive for increased GnRH pulses during puberty [13]. Thus, deficiency of this protein would be expected to result in a loss of inhibition of HPG axis activation. These mutations are thought to result in loss of function of the abnormal gene

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product. In familial cases, all affected subjects have inherited mutations from their fathers. Author Manuscript Interestingly, there was an almost equal gender distribution of CPP among affected family members [12].

Other molecular defects have been identified with less clear or weaker associations. These include single nucleotide polymorphisms (SNPs) in the FSHB gene and the LHB gene, though the resulting molecular mechanisms that cause CPP have not been identified [15]. Mutations in the Y1 subtype receptor for neuropeptide Y (NPY) could theoretically cause precocious puberty, as NPY is thought to be an inhibitor of pulsatile GnRH secretion. However, the only currently described mutation has not correlated well with an effect on function or with CPP [16]. Additional studies have investigated genes involved in hypothalamic hamartomas and have identified several with increased expression in patients with CPP [17]. LIN28B, which is postulated to have a role in determining the timing of

Author Manuscript pubertal development, has also been proposed as a genetic target in CPP. However, its exact role in humans is not yet clear. In addition, study findings have been contradictory, and no clinically significant mutations have yet been observed that cause a functional deficit at a molecular level [18, 19].

3 Diagnosis 3.1 Clinical Features On initial examination of the child with CPP, bilateral testicular enlargement (≥4 cc in volume) will be apparent in males, in contrast to patients with peripheral forms of precocious puberty. Girls usually present with both breast development and pubic hair, in contrast to nonpathological entities such as premature thelarche or premature adrenarche.

Author Manuscript Other signs of pathological precocious puberty include a rapid tempo of progression and linear growth acceleration. Bone age will typically be advanced, though this is certainly not exclusive to CPP and may be seen to a milder degree in numerous other conditions [2].

3.2 Biochemical Features A GnRH stimulation test has long been considered the gold standard for the diagnosis of CPP. However, lack of availability of synthetic GnRH in the USA has led to the use of GnRH analogs (GnRHa) for this purpose instead. While precise cutoffs are difficult to establish, a peak stimulated LH of >∼8 mIU/mL after GnRH and >∼5 IU/L after GnRHa are considered indicative of CPP [2, 20]. An LH/FSH [luteinizing hormone/follicle-stimulating hormone] ratio of ≥2 is also consistent with CPP. However, the results should always be interpreted in light of the specific assay performed and the available sensitivity limits. An

Author Manuscript alternative diagnostic approach has been measurement of basal ultrasensitive LH, which is typically <0.3 IU/L in prepubertal children. However, basal ultrasensitive LH is often prepubertal in early CPP and thus may be falsely reassuring [1]. Measurement of basal or stimulated sex steroids, while never sufficient alone, can be helpful in evaluation of suspected CPP. This is particularly true of testosterone, whereas random estradiol levels are often unmeasurable even when advanced pubertal development is present. Even if the laboratory evaluation is unremarkable, patients should continue to be monitored over time and retested as indicated if clinical suspicion is high [1, 2, 20].

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Author Manuscript 4 Imaging Pelvic ultrasound has been found to be a useful adjunct to support the diagnosis of CPP over other forms of puberty in girls, especially in equivocal situations. Uterine and ovarian dimensions have a stronger association with bone age than with chronological age and are correlated with CPP up to the age of 8 years [21]. While proposed cutoffs for uterine and ovarian volumes exist, these have been somewhat variable, and other studies have suggested a considerable overlap between patients with and without CPP, making reliable parameters difficult to establish. For those who present for evaluation after the age of 8 years, ultrasound parameters become even more difficult to interpret, as there is an even greater overlap in uterine and ovarian dimensions between prepubertal and early pubertal girls [21–24]. The finding of small ovarian follicles on a pelvic ultrasound is normal even in prepubertal girls [25]. Clinicians should further keep in mind that ultrasound results may be technician

Author Manuscript dependent.

The role of brain magnetic resonance imaging (MRI) in the evaluation of patients with CPP has been debated. Boys are more likely to have a pathological cause, making diagnostic imaging for intracranial pathology an essential tool in their evaluation [6]. However, controversy exists regarding recommendations in girls. When female CPP patients without neurological symptoms are screened with MRI, the incidence of positive findings is approximately 15 % [26, 27]. However, some of the abnormalities that are found may be incidental and unrelated to the CPP. In one study, 86 % of 182 girls had normal MRIs, 11 % had mild abnormalities believed to be unrelated to CPP, and 3 % had hamartomas, leading the authors to conclude that routine screening was not indicated in this population, particularly in girls older than 6 years [26]. This is in contrast to a prior study of 67 girls, in

Author Manuscript whom six of ten with MRI findings had hamartomas, while the remainder were diagnosed with an astrocytoma, teratoma, arachnoid cyst, and pineal cyst. Three of the ten had lesions requiring surgical intervention, leading the authors to conclude that MRI should be part of routine evaluation in CPP regardless of age [27]. Investigations into clinical and biochemical features of patients with intracranial pathology have suggested that younger age at onset, more rapid tempo, and higher levels of sex steroids or gonadotropins are predictive features. However, these overlap to such an extent that no specific cutoff has been identified that can be used to determine whether or not to obtain an MRI in any individual patient. For this reason, many institutions include a brain MRI as a universal part of the evaluation in all children diagnosed with CPP [26–29].

5 Treatment

Author Manuscript The primary goal of CPP treatment is to preserve final adult height. However, it should be recognized that some patients will have a nonprogressive or slowly progressive form of CPP, and these patients can achieve normal adult height without any intervention [20]. Therefore, a period of observation is usually appropriate prior to starting treatment. In patients who do show progression of CPP, there is significant variability in the degree of height gained after discontinuation of treatment, even among patients with the same bone age [30–32]. Numerous studies have demonstrated that the greatest gain in final height is achieved in girls with onset of puberty before 6 years of age, although girls with onset between 6 and 8 years

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of age may still reap some benefit from treatment. In contrast, girls aged ≥8 years have not Author Manuscript been found to benefit from intervention in terms of height. Thus, treatment in this age group is usually not indicated. An additional issue is that outcomes of treatment are typically defined as the difference between predicted adult height at baseline and the actual height achieved. Unfortunately, height prediction methods are notoriously flawed [33] and have often been found to overpredict height in the setting of early puberty. Therefore, it is impossible to predict the precise amount of additional height that will be gained by an individual patient as a result of putting puberty on hold. While preliminary evidence suggests that electronic methods of bone age assessment may be more accurate, there is minimal information available thus far about their use in precocious puberty [34]. Evidence regarding treatment benefit in males is more limited, as they comprise a relatively small proportion of patients with CPP. The existing data suggest a significant improvement in final height after treatment of CPP in boys [35], though the same measurement and prediction Author Manuscript limitations exist.

Concerns about psychosocial functioning are often used as a justification for treatment of CPP. However, the existing data regarding the psychological aspects of CPP are limited and inconsistent. Insufficient controls and methodological problems render many studies difficult to interpret, compounded by the use of several different assessments, which make comparisons difficult. The current data do not consistently support problems in regard to body image, self-esteem, or sexual behavior in patients with CPP. Differences, where found, tend to be modest and suggest that patients with CPP may engage in psychosexual behaviors only slightly earlier than children with on-time puberty. The prevalence of psychopathology does not seem to differ from that in the general population [36]. Similarly, one study of girls with CPP and their mothers at the time of diagnosis found no difference in psychological

Author Manuscript distress as compared with girls who had early normal puberty, even prior to treatment [37]. At this point, there is no consensus regarding whether CPP is associated with psychological distress and/or whether treatment ameliorates these problems, and more data in this area are needed [20].

GnRHa are well established as a standard of care for the treatment of CPP worldwide. While numerous delivery systems and routes of administration exist, depot intramuscular injections or sustained-release preparations have been most widely used. These drugs are believed to work by providing a steady concentration of GnRH activity instead of the pulsatile variation in levels characteristic of native GnRH release, which results in paradoxical down-regulation and suppression of the HPG axis. Monthly depot leuprolide acetate has been the most common form of injection therapy used in the USA. Although extended-release 3-monthly

Author Manuscript depot leuprolide preparations have been available in Europe and elsewhere for many years, they have been approved by the US Food and Drug Administration (FDA) only recently and are available in 11.25 and 30 mg dosage forms. Although patients on 11.25 mg 3-monthly injections have consistently been shown to have higher stimulated LH and FSH levels than patients receiving 7.5 mg monthly injections or 22.5 mg 3-monthly injections, this has not been accompanied by significant differences in sex steroid levels or clinical parameters [38, 39]. Additional information about these preparations has been derived from a phase III open- label study involving patients receiving 3-monthly depot leuprolide acetate at 11.25 and 30 mg doses for 36 months [40]. Of 72 patients, only two discontinued therapy prior to 36

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months because of treatment failure, while 20 discontinued therapy to undergo age- Author Manuscript appropriate puberty and 24 continued to receive 3-monthly depot leuprolide for the full study period. As in previous studies, LH escape was seen in a minority of patients on stimulation testing, but this did not correlate with clinical features suggesting lack of suppression. Thus, 3-monthly depot leuprolide seems to be both safe and effective for long- term use [38–40].

Adverse effects are similar for 1- and 3-monthly depot injections and include local reactions and pain at the injection site. Sterile abscess formation has been reported after administration of long-acting injection formulations. Although children who experience sterile abscess formation from long-acting preparations have subsequently been treated successfully with daily leuprolide, there are reported cases in the adult literature of resistance to GnRHa following sterile abscesses [41]. Author Manuscript A popular alternative approach to depot GnRHa injections is the histrelin implant, which was approved by the FDA in 2007. This nonbiodegradable implant is made of a flexible hydrogel containing 50 mg of the potent GnRHa histrelin and is placed subcutaneously, usually in the inner aspect of the upper arm. The initial histrelin implant was first developed for treatment of metastatic prostate cancer, where it was found to successfully suppress LH and testosterone levels for up to 1 year. The implant was later reformulated to release histrelin at a higher dose of 65 lg/day for use in children with CPP. An initial pilot study in 11 girls previously treated with depot triptorelin showed satisfactory maintenance of LH and FSH suppression on stimulation tests. This was accompanied by clinical evidence of pubertal suppression, including regression of breast development, a decrease in growth velocity, and a decline in bone age advancement over 15 months. In addition to satisfactory

Author Manuscript clinical benefit, parents reported less discomfort and lifestyle interference overall than with monthly injections [42]. Following this initial report, a phase III study in 36 patients with CPP demonstrated profound suppression of the HPG axis within 1 month of implantation whether subjects were naïve or previously treated with a GnRHa [43]. The long-term extension phase of this study has now been completed and demonstrated significant improvements in predicted adult height after up to 6 years of sequential annual histrelin implants [44]. Reassuringly, body mass index (BMI) z-scores remained normal throughout the treatment interval.

A significant refinement of the histrelin implant as a therapeutic option has been the recognition that a single implant lasts at least 2 years. Given the known rate of release of 65 mcg of histrelin per day, a 50 mg implant should theoretically last 2 years. That this is indeed the case was demonstrated in a prospective study in 33 children with CPP in whom a Author Manuscript single implant was left in place for 2 years. Peak stimulated LH levels at 12 and 24 months were equivalent, and clinical indices of CPP improved progressively. Use of a single implant for 2 years has the potential to significantly decrease costs and numbers of surgical procedures in children treated with this modality [45].

The most common adverse event associated with the histrelin implant is breakage and/or difficulty with localization of the device. These events occur only during explantation and have been noted to take place in 15–39 % of procedures, with a higher likelihood of

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breakage when the implant is left in place for 2 years [44–47]. Additional reported adverse Author Manuscript events include local reactions, which are, for the most part, minor and self-limited. Sterile abscess formation [41], keloids [44], site infection [45], and implant extrusion [42] have rarely been reported. Placement and removal of the implant requires a minor surgical procedure. This is typically accomplished in an outpatient setting, using local anesthesia with the addition of conscious sedation if necessary [47]. In rare cases of difficulty with implant localization, ultrasound has proved to be a useful modality. Characteristics of the most frequently used GnRHa are summarized in Table 1.

6 Adjunctive Treatments 6.1 Nonaromatizable Anabolic Steroids Oxandrolone has been used to improve growth in patients for other indications. The exact Author Manuscript mechanism has not been elucidated, but a stimulatory effect on the growth plate has been postulated. A small nonrandomized study of ten patients receiving oxandrolone in addition to GnRHa for severe deceleration of growth velocity during treatment for CPP suggested that this combination might improve adult height, compared with GnRHa alone. However, larger randomized studies have not been performed [48].

6.2 Growth Hormone Small and nonrandomized studies have demonstrated a significant improvement in final adult height over pre-treated predicted adult height in patients treated with GnRHa and growth hormone (GH) as compared with patients treated with GnRHa alone. However, larger randomized studies are currently lacking, and routine use of GH in this setting is not recommended [49]. Author Manuscript

6.3 Aromatase Inhibitors Aromatase inhibitors have the potential to attenuate estrogenic effects on skeletal maturation and to delay epiphyseal fusion. A small randomized study suggested slower bone age advancement and improved adult height in Chinese boys with CPP receiving letrozole [50]. However, in general, the experience with these compounds in CPP has been very limited.

7 Monitoring Children who are being treated for CPP should receive regular follow-up during which pubertal progression or suppression can be followed and documented. Tanner staging, determination of growth velocity, and assessment of skeletal maturation via bone age

Author Manuscript radiographs are all important indices of suppression. Whether laboratory testing should be routinely included during follow-up is controversial. While several different strategies for biochemical testing exist, no gold standard for how best to monitor children undergoing treatment for CPP has been established. A GnRH- or leuprolide-stimulated peak LH should be <4 IU/L in adequately suppressed children, and random serum gonadotropin levels should theoretically be in the prepubertal range (ultrasensitive LH <0.3 IU/L). However, random ultrasensitive LH levels have been noted to be elevated above prepubertal levels in children who are well suppressed on GnRHa therapy across all forms of treatment, including

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the histrelin implant [51, 52]. Therefore, the utility of measuring random LH levels in Author Manuscript children undergoing treatment for CPP is highly questionable.

8 Resumption of the Native Hypothalamic–Pituitary–Gonadal Axis In studies following patients beyond discontinuation of treatment, the mean time from cessation of injectable depot GnRHa to menses has been found to be 1.5 ± 0.5 years. Some studies have found a slightly shorter time to menses in girls who experienced menarche before treatment than in those who did not. Although less is known about boys, the existing data suggest that clinicians can expect advancement of the Tanner stage within 6 months of discontinuation of treatment [52].

Because use of the histrelin implant is more recent, the data are somewhat more limited but

Author Manuscript thus far seem to indicate similar results, with the average time from explantation to menarche being 12.75 (95 % confidence interval 9.6–15.9) months, with a range of 2–36 months. Likewise, in males, resumption of pubertal progression was seen on examination within 1 year. A negative trend has been noted between the total duration of GnRHa therapy and the time to menarche, whereas the age at explantation and the time to menarche were significantly inversely correlated [53].

9 Outcomes Girls with CPP have been found to have a higher BMI than their peers at diagnosis. However, this observation is confounded by the natural increase in BMI during puberty. Indeed, some authors have found that while BMI increases in general during treatment, the overall BMI standard deviation score (SDS) does not change. When BMI is evaluated after Author Manuscript GnRHa treatment has been completed, there does not appear to be an adverse effect of treatment on BMI in girls with CPP, nor does there appear to be a large impact of CPP itself on BMI at adult height [31, 54, 55].

Results regarding the incidence of polycystic ovary syndrome (PCOS) in GnRHa-treated patients have been quite variable and contradictory, with some authors finding markedly increased rates of PCOS and other authors finding little or no difference. These results are even more difficult to interpret, as multiple criteria for the diagnosis of PCOS exist. Currently, no consensus exists on whether CPP or treatment with GnRHa results in an increased risk of PCOS [2, 54, 56].

Although bone mineral density (BMD) has been seen to be slightly reduced during treatment in girls, these changes do not appear to be sustained. This decrease is thought to be Author Manuscript secondary to suppression of ovarian function. However, after treatment is discontinued and ovarian activity resumes, BMD is regained, and so girls are not significantly different from their peers without CPP, according to evaluation at adult height [31].

10 Reproductive Function and Fertility Limited information exists regarding the long-term effects of treatment for CPP on endocrine and reproductive function. In one study of 49 females receiving monthly depot

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leuprolide, 20 were followed to adulthood (age 18–26 years). Of these, 80 % reported Author Manuscript regular menstrual cycles. Seven of 20 women reported a total of 12 pregnancies, with six live births, five spontaneous or elective terminations, one ongoing pregnancy, and no reports of stillbirth [52]. Though achievement of short-term treatment goals and resumption of puberty seem to be similar in girls treated with 3-monthly leuprolide and the histrelin implant, it remains to be seen whether similar long-term results can be expected. In addition, long-term data are notably lacking for all forms of treatment with regard to fertility and endocrine function beyond the third decade, as well as the timing of menopause.

11 Future Directions Although multiple preparations now exist for GnRHa treatment of CPP, further options are under investigation or may be considered. A 6-month formulation of triptorelin, for example,

Author Manuscript is currently under investigation, providing the potential for even less frequent dosing for those who do not wish to undergo a procedure for the histrelin implant [57].

Other targets for therapy could also be considered. Because GnRH agonists work by stimulation of receptors, leading to desensitization, there is an initial period of increased stimulation, leading to an LH flare, which sometimes precipitates vaginal bleeding in girls with advanced pubertal development before suppression takes place. A GnRH antagonist, however, would theoretically forego this initial phase by disrupting LH pulsatility without an initial flare. Kisspeptin agonists and antagonists, by acting upstream of GnRH, would be expected to have effects similar to those of GnRH agonist and antagonist therapies, respectively. However, since kisspeptin analogs would not work directly at the gonadotropin receptor, they would have the additional theoretical benefit of interrupting pulsatile GnRH and gonadotropin secretion without lowering gonadotropin release below basal secretory Author Manuscript levels. Therefore, sex steroid levels under treatment with these agents could be expected to more closely mimic normal physiology [58]. Though use of kisspeptin antagonists in humans has not yet been studied, animal studies have suggested that kisspeptin analogs are able to cross the blood–brain barrier and suppress puberty [58].

Because existing biochemical markers can be unreliable, monitoring of treatment is also a worthwhile area of research. Markers under investigation include free alpha-subunit (FAS), which rises with suppression of the HPG axis. Though GnRHa levels decrease gradually with discontinuation of depot intramuscular injections, FAS levels are seen to acutely decrease within days of histrelin implant removal, preceding LH, FSH, and estradiol rises by weeks. In one case, elevated FAS levels beyond the expected time period were attributable to retained histrelin implant fragments and fell only after all fragments had been removed, Author Manuscript highlighting the utility of FAS as a target for relatively rapid assessment of HPG axis recovery. A short “rebound” elevation in FAS can be seen in patients 3–8 weeks after histrelin implant removal. This effect is short lived and self limited, although the reasons for it are unclear [59].

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Author Manuscript 12 Conclusion CPP is seen most often in girls and is associated with a multitude of conditions. A substantial proportion (over a quarter) of cases are familial, and genetic causes have begun to be elucidated. The diagnosis is based on a combination of clinical and biochemical factors. Treatment with a GnRHa provides the greatest potential benefit for patients who are younger at the time of onset of CPP. Multiple treatment options are available, and more recent options have the benefit of less frequent dosing, with potential for improved compliance. Though several adjunctive treatments have been proposed, evidence supporting these treatments is generally sparse in CPP, and thus they cannot be recommended for routine use. Biochemical markers, bone age, and growth velocity should be followed during treatment to ensure efficacy. The available evidence shows that GnRHa are safe and effective, and long-term data suggest that reproductive function is satisfactory after

Author Manuscript discontinuation of treatment. However, long-term data, particularly regarding the newer formulations, are still lacking. Continued pharmacological and molecular genetic investigation and rigorously conducted prospective studies will continue to enhance knowledge and optimize treatment in children with CPP.

Acknowledgments

None.

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10. Luan X, Yu H, Wei X, Zhou Y, Wang W, Li P, et al. GPR54 polymorphisms in Chinese girls with Author Manuscript central precocious puberty. Neuroendocrinology. 2007; 86(2):77–83. DOI: 10.1159/000107511 [PubMed: 17700012] 11. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010; 95(5):2276–80. DOI: 10.1210/jc.2009-2421 [PubMed: 20237166] 12. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013; 368(26):2467–75. DOI: 10.1056/NEJMoa1302160 [PubMed: 23738509] 13. Macedo DB, Abreu AP, Reis AC, Montenegro LR, Dauber A, Beneduzzi D, et al. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab. 2014; 99(6):E1097–103. DOI: 10.1210/jc.2013-3126 [PubMed: 24628548] 14. Settas N, Dacou-Voutetakis C, Karantza M, Kanaka-Gantenbein C, Chrousos GP, Voutetakis A. Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. J Clin Endocrinol Metab. 2014; 99(4):E647–51. DOI: 10.1210/jc.2013-4084 Author Manuscript [PubMed: 24438377] 15. Zhao Y, Chen T, Zhou Y, Li K, Xiao J. An association study between the genetic polymorphisms within GnRHI, LHbeta and FSHbeta genes and central precocious puberty in Chinese girls. Neurosci Lett. 2010; 486(3):188–92. DOI: 10.1016/j.neulet.2010.09.049 [PubMed: 20869425] 16. Freitas KC, Ryan G, Brito VN, Tao YX, Costa EM, Mendonca BB, et al. Molecular analysis of the neuropeptide Y1 receptor gene in human idiopathic gonadotropin-dependent precocious puberty and isolated hypogonadotropic hypogonadism. Fertil Steril. 2007; 87(3):627–34. DOI: 10.1016/ j.fertnstert.2006.07.1519 [PubMed: 17140570] 17. Parent AS, Matagne V, Westphal M, Heger S, Ojeda S, Jung H. Gene expression profiling of hypothalamic hamartomas: a search for genes associated with central precocious puberty. Horm Res. 2008; 69(2):114–23. DOI: 10.1159/000111815 [PubMed: 18059092] 18. Park SW, Lee ST, Sohn YB, Cho SY, Kim SH, Kim SJ, et al. LIN28B polymorphisms are associated with central precocious puberty and early puberty in girls. Korean J Pediatr. 2012; 55(10):388–92. DOI: 10.3345/kjp.2012.55.10.388 [PubMed: 23133486]

Author Manuscript 19. Silveira-Neto AP, Leal LF, Emerman AB, Henderson KD, Piskounova E, Henderson BE, et al. Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty. Horm Res Paediatr. 2012; 78(3):144–50. DOI: 10.1159/000342212 [PubMed: 22964795] 20. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR, et al. Group E-LGACC. Consensus statement on the use of gonado-tropin-releasing hormone analogs in children. Pediatrics. 2009; 123(4):e752–62. DOI: 10.1542/peds.2008-1783 [PubMed: 19332438] 21. Eksioglu AS, Yilmaz S, Cetinkaya S, Cinar G, Yildiz YT, Aycan Z. Value of pelvic sonography in the diagnosis of various forms of precocious puberty in girls. J Clin Ultrasound. 2013; 41(2):84– 93. DOI: 10.1002/jcu.22004 [PubMed: 23124596] 22. Badouraki M, Christoforidis A, Economou I, Dimitriadis AS, Katzos G. Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls. Ultrasound Obstetr Gynecol. 2008; 32(6):819–27. DOI: 10.1002/uog.6148 23. de Vries L, Horev G, Schwartz M, Phillip M. Ultrasonographic and clinical parameters for early differentiation between precocious puberty and premature thelarche. Eur J Endocrinol. 2006; Author Manuscript 154(6):891–8. DOI: 10.1530/eje.1.02151 [PubMed: 16728550] 24. Herter LD, Golendziner E, Flores JAM, Moretto M, Di Domenico K, Becker E, et al. Ovarian and uterine findings in pelvic sonography: comparison between prepubertal girls, girls with isolated thelarche, and girls with central precocious puberty. J Ultrasound Med. 2002; 21(11):1237–46. [PubMed: 12418765] 25. Pienkowski C, Cartault A, Carfagna L, Ernoult P, Vial J, Lemasson F, et al. Ovarian cysts in prepubertal girls. Endocr Dev. 2012; 22:101–11. DOI: 10.1159/000326627 [PubMed: 22846524] 26. Pedicelli S, Alessio P, Scire G, Cappa M, Cianfarani S. Routine screening by brain magnetic resonance imaging is not indicated in every girl with onset of puberty between the ages of 6 and 8

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years. J Clin Endocrinol Metab. 2014; 99(12):4455–61. DOI: 10.1210/jc.2014-2702 [PubMed: Author Manuscript 25238205] 27. Ng SM. Cranial MRI scans are indicated in all girls with central precocious puberty. Arch Dis Child. 2003; 88(5):414–8. DOI: 10.1136/adc.88.5.414 [PubMed: 12716713] 28. Chalumeau M, Hadjiathanasiou CG, Ng SM, Cassio A, Mul D, Cisternino M, et al. Selecting girls with precocious puberty for brain imaging: validation of European evidence-based diagnosis rule. J Pediatr. 2003; 143(4):445–50. DOI: 10.1067/s0022-3476(03)00328-7 [PubMed: 14571217] 29. Mogensen SS, Aksglaede L, Mouritsen A, Sorensen K, Main KM, Gideon P, et al. Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty. PloS One. 2012; 7(1):e29829.doi: 10.1371/journal.pone.0029829 [PubMed: 22253792] 30. Carel JC, Roger M, Ispas S, Tondu F, Lahlou N, Blumberg J, et al. Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. French Study Group of Decapeptyl in Precocious Puberty. J Clin Endocrinol Metab. 1999; 84(6):1973–8. DOI: 10.1210/jcem.84.6.5647 [PubMed: 10372696]

Author Manuscript 31. Pasquino AM, Pucarelli I, Accardo F, Demiraj V, Segni M, Di Nardo R. Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function. J Clin Endocrinol Metab. 2008; 93(1):190–5. DOI: 10.1210/jc.2007-1216 [PubMed: 17940112] 32. Lazar L, Padoa A, Phillip M. Growth pattern and final height after cessation of gonadotropin- suppressive therapy in girls with central sexual precocity. J Clin Endocrinol Metab. 2007; 92(9): 3483–9. DOI: 10.1210/jc.2007-0321 [PubMed: 17579199] 33. Carel JC, Lahlou N, Roger M, Chaussain JL. Precocious puberty and statural growth. Hum Reprod Update. 2004; 10(2):135–47. DOI: 10.1093/humupd/dmh012 [PubMed: 15073143] 34. Thodberg HH. Clinical review: an automated method for determination of bone age. J Clin Endocrinol Metab. 2009; 94(7):2239–44. DOI: 10.1210/jc.2008-2474 [PubMed: 19401365] 35. Mul D, Bertelloni S, Carel JC, Saggese G, Chaussain JL, Oostdijk W. Effect of gonadotropin- releasing hormone agonist treatment in boys with central precocious puberty: final height results. Horm Res. 2002; 58(1):1–7. DOI: 10.1159/000063209 Author Manuscript 36. Walvoord EC, Mazur T. Behavioral problems and idiopathic central precocious puberty: fact or fiction? Pediatr Endocrinol Rev. 2007; 4(S3):306–12. 37. Schoelwer MJ, Donahue KL, Bryk K, Didrick P, Berenbaum SA, Eugster EA. Psychological assessment of mothers and their daughters at the time of diagnosis of precocious puberty. Int J Pediatr Endocrinol. 2015; 2015(1):5.doi: 10.1186/s13633-015-0001-7 [PubMed: 25780366] 38. Badaru A, Wilson DM, Bachrach LK, Fechner P, Gandrud LM, Durham E, et al. Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab. 2006; 91(5):1862–7. DOI: 10.1210/jc.2005-1500 [PubMed: 16449344] 39. Fuld K, Chi C, Neely EK. A randomized trial of 1- and 3-month depot leuprolide doses in the treatment of central precocious puberty. J Pediatr. 2011; 159(6):982–7.e1. doi:10.1016/j.jpeds. 2011.05.036. [PubMed: 21798557] 40. Lee PA, Klein K, Mauras N, Lev-Vaisler T, Bacher P. 36-month treatment experience of two doses of leuprolide acetate 3-month depot for children with central precocious puberty. J Clin En-

Author Manuscript docrinol Metab. 2014; 99(9):3153–9. DOI: 10.1210/jc.2013-4471 41. Miller BS, Shukla AR. Sterile abscess formation in response to two separate branded long-acting gonadotropin-releasing hormone agonists. Clin Ther. 2010; 32(10):1749–51. DOI: 10.1016/ j.clinthera.2010.09.009 [PubMed: 21194598] 42. Hirsch HJ, Gillis D, Strich D, Chertin B, Farkas A, Lindenberg T, et al. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics. 2005; 116(6):e798–802. DOI: 10.1542/ peds.2005-0538 [PubMed: 16322137] 43. Eugster EA, Clarke W, Kletter GB, Lee PA, Neely EK, Reiter EO, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin En-docrinol Metab. 2007; 92(5):1697–704. DOI: 10.1210/jc.2006-2479

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44. Silverman, LA., Neely, EK., Kletter, GB., Lewis, K., Chitra, S., Terleckyj, O., Eugster, EA. J Clin Author Manuscript Endocrinol Metab. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: a final report of a phase 3 multicenter trial. Epub 2015 Mar 24 45. Lewis KA, Goldyn AK, West KW, Eugster EA. A single histrelin implant is effective for 2 years for treatment of central precocious puberty. J Pediatr. 2013; 163(4):1214–6. DOI: 10.1016/j.jpeds. 2013.05.033 [PubMed: 23809043] 46. Rahhal S, Clarke WL, Kletter GB, Lee PA, Neely EK, Reiter EO, et al. Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty. Int J Pediatr Endocrinol. 2009; 2009:812517.doi: 10.1155/2009/812517 [PubMed: 19956699] 47. Davis JS, Alkhoury F, Burnweit C. Surgical and anesthetic considerations in histrelin capsule implantation for the treatment of precocious puberty. J Pediatr Surg. 2014; 49(5):807–10. DOI: 10.1016/j.jpedsurg.2014.02.067 [PubMed: 24851775] 48. Vottero A, Pedori S, Verna M, Pagano B, Cappa M, Loche S, et al. Final height in girls with central idiopathic precocious puberty treated with gonadotropin-releasing hormone analog and oxandrolone. J Clin Endocrinol Metab. 2006; 91(4):1284–7. DOI: 10.1210/jc.2005-1693 Author Manuscript [PubMed: 16449342] 49. Pucarelli I, Segni M, Ortore M, Arcadi E, Pasquino AM. Effects of combined gonadotropin- releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab. 2003; 16(7):1005–10. [PubMed: 14513877] 50. Zhao X, Zhang Q. Clinical efficacy of letrozole in boys with idiopathic central precocious puberty. Chin J Contemp Pediatr. 2014; 16(4):397–400. DOI: 10.7499/j.issn.1008-8830.2014.04.018 51. Lewis KA, Eugster EA. Random luteinizing hormone often remains pubertal in children treated with the histrelin implant for central precocious puberty. J Pediatr. 2013; 162(3):562–5. DOI: 10.1016/j.jpeds.2012.08.038 [PubMed: 23040793] 52. Neely EK, Lee PA, Bloch CA, Larsen L, Yang D, Mattia-Goldberg C, et al. Leuprolide acetate 1- month depot for central precocious puberty: hormonal suppression and recovery. Int J Pediatr Endocrinol. 2010; 2010:398639.doi: 10.1155/2010/398639 [PubMed: 21437000] 53. Fisher MM, Lemay D, Eugster EA. Resumption of puberty in girls and boys following removal of the histrelin implant. J Pediatr. 2014; 164(4):912–6.e1. DOI: 10.1016/j.jpeds.2013.12.009 Author Manuscript [PubMed: 24433825] 54. Magiakou MA, Manousaki D, Papadaki M, Hadjidakis D, Le-vidou G, Vakaki M, et al. The efficacy and safety of go-nadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J Clin Endocrinol Metab. 2010; 95(1): 109–17. DOI: 10.1210/jc.2009-0793 [PubMed: 19897682] 55. Poomthavorn P, Suphasit R, Mahachoklertwattana P. Adult height, body mass index and time of menarche of girls with id-iopathic central precocious puberty after gonadotropin-releasing hormone analogue treatment. Gynecol Endocrinol. 2011; 27(8):524–8. DOI: 10.3109/09513590.2010.507289 [PubMed: 21501002] 56. Franceschi R, Gaudino R, Marcolongo A, Gallo MC, Rossi L, Antoniazzi F, et al. Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty. Fertil Steril. 2010; 93(4):1185–91. DOI: 10.1016/j.fertnstert.2008.11.016 [PubMed: 19135667] 57. Dajani, T., Reiner, B., Salem, G., Shea, H., Rappaport, M., Alzohaili, O., Van Meter, Q., Domek, D., Bethin, K., Kaplowitz, P., Klein, K., Merritt, D., Rose, S., Kletter, G., Aisenberg, J., Brenner, D., Rogers, D., Silverman, L., Lee, P., Gomez, R., Cassorla, F., Yang, J., Eugster, E., Flores, O., Author Manuscript Wright, N. ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD): 2014. Efficacy, safety, and pharmacokinetics (PK) of triptorelin 6-month formulation in patients with central precocious puberty. https://clinicaltrials.gov/ct2/show/NCT01467882 58. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012; 92(3):1235–316. DOI: 10.1152/physrev.00037.2010 [PubMed: 22811428] 59. Hirsch HJ, Lahlou N, Gillis D, Strich D, Rosenberg-Hagen B, Chertin B, et al. Free alpha-subunit is the most sensitive marker of gonadotropin recovery after treatment of central precocious puberty with the histrelin implant. J Clin Endocrinol Metab. 2010; 95(6):2841–4. DOI: 10.1210/jc. 2009-2078 [PubMed: 20339028]

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Author Manuscript Key Points Molecular genetic etiologies of central precocious puberty (CPP) are beginning to be elucidated. Evaluation of CPP should be based on a combination of clinical and biochemical factors, as each parameter has specific limitations. The gold-standard treatment for CPP is gonadotropin-releasing hormone (GnRH) analogs (GnRHa). GnRHa provide sustained high concentrations of GnRH, resulting in downregulation of the hypothalamic–pituitary–gonadal axis. Multiple formulations of GnRHa exist. Although minor differences in

Author Manuscript gonadotropin levels are observed, all available GnRHa appear to be equally effective in terms of clinical parameters. Long-term outcomes of children treated with GnRHa for CPP are reassuring with regard to fertility, body mass index, and bone mineral density. Author Manuscript Author Manuscript

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Chen and Eugster Page 15 Author Manuscript Disadvantages Frequent injections Frequent injections Conscious or general sedation may be required; implant removal breakage makes difficult Advantages Less frequent dosing Less frequent dosing Infrequent replacement; minimal opportunity for noncompliance Author Manuscript Table 1 Table Adverse effects Adverse Local reactions; pain at injection site; sterile abscess Local reactions; pain at injection site; sterile abscess Discomfort at implant site; local reactions; sterile abscess; implant extrusion Author Manuscript Dose 7.5 mg 11.25 mg 15 mg 11.25 mg 30 mg 3.75 mg 11.25 mg 50 mg implants (65 mcg/ day) Frequency Monthly 3-monthly Monthly 3-monthly 1–2 years Administration Intramuscular Intramuscular Subcutaneous Author Manuscript Characteristics of the most frequently prescribed gonadotropin-releasing hormone analogs for the treatment of central precocious puberty of central precocious the treatment hormone analogs for gonadotropin-releasing prescribed Characteristics of the most frequently Treatment Leuprolide acetate Triptorelin (available (available Triptorelin only in Europe) Histrelin implant

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Definition, etiology, and evaluation of precocious puberty

Authors: Jennifer Harrington, MBBS, PhD, Mark R Palmert, MD, PhD Section Editors: Peter J Snyder, MD, William F Crowley, Jr, MD, Mitchell E Geffner, MD Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2018. | This topic last updated: Sep 04, 2018.

INTRODUCTION — Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD) earlier than population norms. The cause of precocious puberty may range from a variant of normal development (eg, isolated premature adrenarche or isolated premature thelarche) to pathologic conditions with significant risk of morbidity and even death (eg, malignant germ-cell tumor and astrocytoma).

The clinician faced with a child who presents with early development of secondary sexual characteristics should consider the following questions:

● Is the child too young to have reached the pubertal milestone in question? – To answer this question, the clinician needs to know the normal ages for pubertal milestones and how to separate normal from abnormal development.

● What is causing the early development? – To answer this question, the physician ascertains whether the development of secondary sexual characteristics is attributable to androgen and/or estrogen effects, and whether the source of sex hormone is centrally mediated through the hypothalamic-pituitary-gonadal axis, from an autonomous peripheral origin, or has an exogenous basis.

● Is therapy indicated, and, if so, what therapy?

The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of precocious puberty is discussed separately. (See "Treatment of precocious puberty".)

DEFINITION — Precocious puberty is traditionally defined as the onset of secondary sexual characteristics before the age of eight years in girls and nine years in boys [1]. These limits are chosen to be 2 to 2.5 standard deviations (SD) below the mean age of onset of puberty. In most populations, attainment of pubertal milestones approximates a normal distribution, with a mean age of onset of puberty of about 10.5 years in girls and 11.5 years in boys (figure 1A-B) and an SD of approximately one year [1-9].

NORMAL PUBERTAL DEVELOPMENT — The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during the first week of life. It then becomes more active again during infancy, with peak activity between one and three months of age [10]. This state yields sex steroid levels comparable with those seen in early-to-mid puberty, but without peripheral effects. In boys, gonadotropin concentrations then decrease to prepubertal levels by six to nine months of age. In girls, luteinizing hormone (LH) levels decrease at approximately the same time as in boys, but the follicle-stimulating hormone (FSH) concentrations can remain elevated into the second year of life. This hypothalamic-pituitary-gonadal activity during infancy is known as the "mini puberty of infancy"; its biological relevance is unknown.

The neonatal stage is followed by a long period of pre-puberty, which is a state of active suppression of the hypothalamic-pituitary- gonadal axis. Puberty occurs when there is reactivation of the hypothalamic-pituitary-gonadal axis. The physiologic and genetic mechanisms that affect timing of pubertal maturation are discussed separately. (See "Normal puberty", section on 'Sequence of pubertal maturation'.)

In 1969 and 1970, Marshall and Tanner defined the standards of normal pubertal development in children and adolescents, known as sexual maturity ratings or "Tanner stages" (picture 1A-C) [2,3]. These studies reported that the first sign of puberty in English girls was breast development at an average age of 11 years (thelarche), followed by pubic hair growth (pubarche), and then menarche. In English boys, the first sign was testicular enlargement at an average age of 11.5 years followed by penile growth and pubic hair growth. (See "Normal puberty".)

Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest that children, especially overweight children, are entering puberty at a younger age than previously [4-9,11]. In addition, there are racial differences, with puberty occurring earlier in African-American children compared with non-Hispanic Caucasian and Hispanic children. These data and the proposed explanations for the trends are discussed separately. (See "Normal puberty", section on 'Trends in pubertal timing'.)

EPIDEMIOLOGY — Using the traditional definition of precocious puberty as the development of secondary sexual characteristics https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 1/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate before age eight in girls and nine in boys (2 to 2.5 standard deviations [SD] below the average age of pubertal onset in healthy children), one would expect that the prevalence rate should be around 2 percent, or 2 in every 100 children. However, population studies looking at the prevalence rates of precocious puberty yield markedly different rates depending on the population studied:

● In a population-based United States study, breast and/or pubic hair development was present at age eight in 48 percent of African-American girls and 15 percent of White girls [11]. At seven years of age, the proportions were 27 percent and 7 percent, respectively.

● In a population-based study of data from Danish national registries from 1993 to 2001, the incidence of precocious puberty was 20 per 10,000 girls and less than 5 per 10,000 boys [12]. The diagnostic age limit utilized in this study was eight years for girls and nine for boys. About half the patients had central precocious puberty (CPP) and the remainder were isolated premature thelarche or adrenarche, or early normal pubertal development. (See "Premature adrenarche".)

These observations suggest that the definition of precocious puberty is problematic, at least in girls, and that selection of children for evaluation should not only depend on age but also clinical features, race/ethnicity, and presence/absence of obesity [13]. (See 'Definition' above and 'Threshold for evaluation' below.)

There is a strong female predominance of children with precocious puberty. In a retrospective review of 104 consecutive children referred for evaluation of precocious puberty, 87 percent were female [14].

THRESHOLD FOR EVALUATION — We suggest careful evaluation of children presenting with signs of secondary sexual development younger than the age of eight years in girls or nine years in boys. The level of concern and extent of evaluation should increase with younger age at presentation. Given the trend towards earlier pubertal development, in girls who are between the ages of seven and eight, a comprehensive history and physical examination and clinical follow-up may be sufficient if the clinical evaluation does not raise any additional concerns [15]. (See 'Epidemiology' above and 'Evaluation' below.)

A more controversial approach was suggested in 1999 by the Lawson Wilkins Pediatric Endocrine Society (LWPES), which recommended that evaluation for a pathologic cause of precocious puberty be reserved for Caucasian girls who have breast and/or pubic hair development before seven years of age and for African-American girls who have these findings before six years of age [16]. This recommendation was based on a study describing the first signs of pubertal development among approximately 18,000 girls in the United States and Puerto Rico, among whom development occurred at a younger age than had been previously reported (figure 2) [11]. The study did not distinguish between girls with isolated thelarche or adrenarche from those with true precocious puberty. This same study reported an average age at menarche of approximately 12.5 years, which was not substantially earlier than had been reported in the 1940s [17].

This LWPES recommendation is controversial because of concerns that lowering the age threshold for evaluation of precocious puberty will result in failure to identify some children with pathologic disease [18,19]. As an example, a retrospective review of 223 girls referred to a tertiary center for evaluation of pubertal development before eight years of age found that utilization of the LWPES guidelines would have resulted in failure to identify a substantial number of patients with treatable disease [19]. Twelve percent of these girls were ultimately diagnosed with an endocrinopathy that was amenable to early intervention, including congenital adrenal hyperplasia, McCune-Albright syndrome, pituitary adenoma, and neurofibromatosis.

CLASSIFICATION — Precocious puberty can be classified based upon the underlying pathologic process (algorithm 1).

● Central precocious puberty – Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. CPP is characterized by sequential maturation of breasts and pubic hair in girls, and of testicular and penile enlargement and pubic hair in boys. In these patients, the sexual characteristics are appropriate for the child's gender (isosexual). CPP is pathologic in up to 40 to 75 percent of cases in boys [20,21], compared with 10 to 20 percent in girls [22-24] (table 1) (See 'Causes of central precocious puberty (CPP)' below.)

● Peripheral precocity – Peripheral precocity (also known as peripheral precocious puberty, gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) from the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropin from a germ cell tumor (eg, human chorionic gonadotropin, hCG) (table 2). The term precocity is used instead of puberty here because true puberty requires activation of the hypothalamic-pituitary-gonadal (HPG) axis, as occurs in CPP. Peripheral precocity may be appropriate for the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys (contrasexual). (See 'Causes of peripheral precocity' below.)

● Benign or non-progressive pubertal variants – Benign pubertal variants include isolated breast development in girls (premature thelarche), or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) in boys or girls that result from early activation of the hypothalamic pituitary adrenal axis as confirmed by mildly elevated levels of dehydroepiandrosterone sulfate (DHEAS) for age (premature adrenarche) (table 3). Both of these disorders can be a variant of normal puberty. However, repeat evaluations are warranted in these children to be certain that the diagnosis is correct. (See 'Types of benign or non-progressive pubertal variants' below.)

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate CAUSES OF CENTRAL PRECOCIOUS PUBERTY (CPP) — Central precocious puberty (CPP, also known as gonadotropin- dependent precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early, the pattern and timing of pubertal events is usually normal. These children have accelerated linear growth for age, advanced bone age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation of the pituitary response to endogenous GnRH, produces a prepubertal hormonal state, and stops the progression of secondary sexual development, accelerated growth, and undue bone age advancement. (See "Treatment of precocious puberty", section on 'Treatment for CPP'.)

Idiopathic — CPP is idiopathic in 80 to 90 percent of cases of girls, but in only 25 to 60 percent of boys [20-24].

CNS lesions — Although CPP is idiopathic in up to 90 percent of girls and 60 percent of boys, some cases are caused by lesions of the central nervous system (CNS), a condition often referred to as neurogenic CPP (table 1). Contrast-enhanced magnetic resonance imaging (MRI) is therefore recommended, even in the absence of clinically evident neurologic abnormalities [20,22,24]. The low prevalence of CNS lesions in girls with the onset of puberty that begins after age six years raises the question if all girls in this age group need imaging [23].

Many different types of intracranial disturbances can cause precocious puberty, including the following:

● Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with gelastic (laughing or crying) and other types of seizures [25]. They are the most frequent type of CNS tumor to cause precocious puberty in very young children, although in most cases, the mechanism by which these tumors lead to CPP is unknown.

● Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas [26], ependymomas, pinealomas, and optic and hypothalamic gliomas [22]. Sexual precocity in patients with neurofibromatosis is usually, but not always, associated with an optic glioma [27]. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

● CNS irradiation – Precocious puberty caused by CNS irradiation is commonly associated with growth hormone (GH) deficiency [28]. In this setting, regardless of height velocity, the GH axis should be evaluated. If testing shows GH deficiency, such patients should be treated with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Growth hormone (GH) deficiency'.)

● Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS inflammatory disease, and congenital midline defects, such as optic nerve hypoplasia. (See "Congenital anomalies and acquired abnormalities of the optic nerve", section on 'Hypoplasia'.)

Genetics — Specific genetic mutations have been associated with CPP, although each appears to be present in only a minority of cases:

● Gain-of-function mutations in the Kisspeptin 1 gene (KISS1) [29] and its G protein-coupled receptor KISS1R (formerly known as GPR54) [30] have been implicated in the pathogenesis of some cases of CPP, while loss-of function mutations in KISS1R can cause hypogonadotropic hypogonadism. These observations suggest that KISS1/KISS1R is essential for gonadotropin-releasing hormone physiology and for initiation of puberty [31].

● CPP also can be caused by loss-of-function mutations in MKRN3 (makorin ring finger protein 3), an imprinted gene in the Prader-Willi syndrome critical region (15q11-q13). The decline of hypothalamic MKRN3 gene expression in mice [32] and serum protein levels in girls prior to the onset of puberty [33] suggest that MKRN3 is one of the factors involved in repressing pubertal initiation. Thus, loss of function mutations in this gene would lead to diminished inhibition and early onset of puberty. Paternally- inherited loss of function mutations in MKRN3 have been demonstrated to be associated with up to 46 percent of familial cases of CPP [32,34,35].

● A loss-of-function mutation in another gene, DLK1 (Delta-like 1 homolog), leads to undetectable serum concentrations of the DLK1 protein and has been associated with isolated CPP in five members of one family [36]. DLK1 is a paternally expressed gene, mostly in adrenal, pituitary, and ovarian tissue. No definitive mechanistic link between DLK1 function and pubertal development has been determined to date, but polymorphisms in this gene as well as in MKRN3 are associated with variation in the age of menarche in large genome-wide association studies providing further evidence of a mechanistic link [37].

Previous excess sex steroid exposure — Children who have been exposed to high serum levels of sex steroid (eg, those with McCune Albright Syndrome and poorly controlled congenital adrenal hyperplasia) may sometimes develop superimposed CPP, either from the priming effect of the peripheral precocity-derived sex steroid on the hypothalamus, or in response to the sudden lowering of the sex steroid levels following improved control of the sexual precocity [38-40]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Monitoring and dose adjustment' and 'McCune- Albright syndrome' below.)

Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are associated with elevated levels of LH and/or follicle-stimulating hormone (FSH) [41,42]. https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 3/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate CAUSES OF PERIPHERAL PRECOCITY — Peripheral precocity (also known as peripheral precocious puberty or gonadotropin- independent precocious puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from the gonads or adrenal glands, or from exogenous sources (table 2). Further characterization is based upon whether the sexual characteristics are appropriate for the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys (contrasexual). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are suppressed (in the prepubertal range) and do not increase substantially with gonadotropin-releasing hormone (GnRH) stimulation.

The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is ineffective, in contrast to patients with central precocious puberty (CPP). (See "Treatment of precocious puberty", section on 'Treatment for peripheral precocity'.)

In the following discussion, the causes of peripheral precocity are described based upon sex.

Girls

Ovarian cysts — A large functioning follicular cyst of the ovaries is the most common cause of peripheral precocity in girls [43]. Affected patients often present with breast development, followed by an episode of vaginal bleeding, which occurs due to estrogen withdrawal once the cyst has regressed. These cysts may appear and regress spontaneously, so conservative management is usually appropriate [44]. Large cysts may predispose to ovarian torsion.

Ovarian tumors — Ovarian tumors are a rare cause of peripheral precocity in girls. Granulosa cell tumors, the most common type, typically present as isosexual precocity; Sertoli/Leydig cell tumors (arrhenoblastoma), pure Leydig cell tumors, and gonadoblastoma may make androgens and cause contrasexual precocity [45-47]. (See "Sex cord-stromal tumors of the ovary: Granulosa-stromal cell tumors", section on 'Granulosa cell tumor'.)

Boys

Leydig cell tumors — Leydig cell tumor should be considered in any boy with asymmetric testicular enlargement. Even if a distinct mass cannot be palpated and none is evident on ultrasonography, the larger testis should be biopsied if it enlarges during follow-up. These testosterone-secreting tumors are almost always benign and are readily cured by surgical removal [48]. Radical orchiectomy is the most common procedure; however, successful treatment by direct enucleation of the tumor with sparing of the remainder of the testis has been reported [49]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)

Human chorionic gonadotropin (hCG)-secreting germ cell tumors — Germ-cell tumors secrete hCG, which in boys activates LH receptors on the Leydig cells, resulting in increased testosterone production [50]. The increase in testicular size (usually only to an early pubertal size) is less than expected for the serum testosterone concentration and degree of pubertal development. This is because most of the testis is made up of tubular elements whose maturation depends upon FSH. In girls, hCG-secreting tumors do not lead to precocious puberty because activation of both FSH and LH receptors is needed for estrogen biosynthesis.

These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting sites of embryonic germ cells before their coalescence in the gonadal ridge [50]. The histology of hCG-secreting tumors ranges from dysgerminoma, which respond readily to therapy, to the more malignant embryonal cell carcinoma and choriocarcinoma. All males with anterior mediastinal germinomas should have a karyotype because these tumors may be associated with Klinefelter syndrome. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors", section on 'Germ cell tumors'.)

Familial male-limited precocious puberty — This rare disorder (also known as testotoxicosis) is caused by an activating mutation in the LH receptor gene, which results in premature Leydig cell maturation and testosterone secretion [51]. Although inherited as an autosomal dominant disorder, girls are not affected clinically because (similar to hCG-secreting germ tumors) activation of both the LH and FSH receptors is required for estrogen biosynthesis [52]. Also similar to hCG-secreting tumors, the increase in testicular size is usually only to an early pubertal size. Affected boys typically present between one to four years of age.

Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on 'Familial male-limited precocious puberty'.)

Both girls and boys — The following causes of peripheral precocity can occur in either girls or boys. Physical changes either may be isosexual or contrasexual depending on the sex of the child and the type of sex hormone produced. Excess estrogen will cause feminization, while excess androgen will result in virilization.

Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally present with precocious puberty. In girls, findings include early breast development, galactorrhea, and recurrent vaginal bleeding, while affected boys present with premature testicular enlargement [53-55]. Historically this has been referred to as the "overlap" or Van Wyk-Grumbach syndrome [56]. The signs of pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and adolescence".)

A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin (TSH) concentrations, given that both TSH and FSH share a common alpha subunit [57].

https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 4/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate Exogenous sex steroids — Feminization, including gynecomastia in boys, has been attributed to excess estrogen exposure from creams, ointments, and sprays. Caretakers using these topical estrogens to treat menopausal symptoms may inadvertently expose children to the hormones [58,59]. Other possible sources of estrogen exposure include contamination of food with hormones, phytoestrogens (eg, in soy), and folk remedies such as lavender oil and tea tree oil [60,61]. A food source was suspected for local "epidemics" of early thelarche in Italy and Puerto Rico during the 1980s, but no single causative substance was found in food samples [62-64]. Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing creams [65,66].

Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors and enzymatic defects in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Boys who have an adrenal cause for their precocity will not have testicular enlargement (testes will be <4 mL testicular volume or <2.5 cm in diameter). (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Premature pubarche may be the presenting feature of an inherited disorder of adrenal steroid metabolism, including 21-hydroxylase deficiency, 11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate dehydrogenase deficiency, and PAPSS2 deficiency. (See "Uncommon congenital adrenal hyperplasias".)

Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen and estrogen, the latter because of intra-adrenal aromatization of androgen (or production of enough androgen that is peripherally aromatized to estrogen), causing both male and female pubertal changes [67]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

McCune-Albright syndrome — McCune-Albright Syndrome (MAS) is a rare disorder defined as the triad of peripheral precocious puberty, irregular café-au-lait ("Coast of Maine") skin pigmentation (picture 2), and fibrous dysplasia of bone (image 1) [68]. MAS should be considered in girls with recurrent formation of follicular cysts and cyclic menses [69]. The skin manifestations and bone lesions may increase over time. In girls presenting with vaginal bleeding, the ovarian enlargement has often been mistaken for an ovarian tumor, leading to unnecessary oophorectomy [70]. Girls presenting with premature vaginal bleeding should therefore be evaluated for features of McCune-Albright syndrome to avoid this potential mistake.

The clinical phenotype varies markedly, depending on which tissues are affected by the mutation, but precocious puberty is the most commonly reported manifestation [71]. As in other forms of peripheral precocity, the sequence of pubertal progression may be abnormal, in that vaginal bleeding often precedes significant breast development [72]. Prolonged exposure to elevated levels of sex steroids may cause accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious puberty is typically peripheral precocity, a secondary component of CPP may develop because of sex steroid withdrawal leading to activation of the hypothalamic-pituitary-gonadal axis [73] (see 'Previous excess sex steroid exposure' above). In boys with MAS, while sexual precocity is less common, there is a high prevalence of testicular pathology on ultrasound, including hyper-and hypoechoic lesions (most likely representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [74].

Patients with MAS have a somatic (postzygotic) mutation of the alpha subunit of the Gs protein that activates adenylyl cyclase [75-77]. This mutation leads to continued stimulation of endocrine function (eg, precocious puberty, thyrotoxicosis, gigantism or acromegaly, Cushing syndrome, and hypophosphatemic rickets) in various combinations. Mutations can be found in other non-endocrine organs (liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and cardiac arrhythmias, respectively. A heightened risk of malignancy has also been reported [78]. Germline occurrences of this mutation would presumably be lethal [75,77,79,80].

Treatment of MAS is described in a separate topic review. (See "Treatment of precocious puberty", section on 'McCune-Albright syndrome'.)

TYPES OF BENIGN OR NON-PROGRESSIVE PUBERTAL VARIANTS — Early pubertal development fits into this category when the early development of secondary sexual characteristics does not herald underlying pathology and is not followed by progressive development (table 3). However, monitoring for evidence of pubertal progression is important, as some children presenting with an apparent benign pubertal variant will instead turn out to have a different disorder. As examples, thelarche may be the initial presenting feature of central precocious puberty (CPP), or progressive pubic hair development may herald a form of peripheral precocity.

Premature thelarche — Most cases of premature thelarche are idiopathic and present under two years of age (and may even start at birth). Many cases will remit spontaneously, and most others do not progress. However, follow-up is warranted because premature thelarche can represent the initial presentation of true CPP in 10 to 20 percent of children referred to pediatric endocrine units [81- 83].

Key features of premature thelarche are:

● Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage 3

● Absence of other secondary sexual characteristics

● Normal height velocity for age (not accelerated)

● Normal or near-normal bone age https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 5/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one should be cautious in interpreting these levels in children under the age of two years because elevations can be seen as part of the normal transient "mini- puberty of infancy," and CPP can be diagnosed inappropriately (See 'Normal pubertal development' above.)

Toddlers and children — Premature thelarche occurs in two peaks: one during the first two years of life and the other at six to eight years of age [83], with potentially different underlying pathophysiology accountable for each of these peaks. Postulated mechanisms include transient activation of the hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH) secretion [84]. In infants, soy-based formulas have been implicated, although the evidence is weak and may represent only a slower waning of breast tissue during infancy [85-87]. Use of lavender oil, tea tree oil, or hair care products that contain placental extract has also been implicated in some cases of premature thelarche [60]. In most instances, no cause can be found.

In most cases, premature thelarche requires only reassurance. However, the patient should be examined for other signs of pubertal development, and growth data should be plotted; an accelerated height velocity may be indicative of progressive puberty and requires further evaluation. To identify patients with progressive puberty, patients should be monitored for several months for evidence of pubertal progression. (See 'Evaluation' below.)

Neonates — Breast hypertrophy can occur in neonates of both sexes, and is sometimes quite prominent. It is caused by stimulation from maternal hormones and usually resolves spontaneously within a few weeks or months. The breast development may also be associated with galactorrhea ("witch's milk"), which also resolves spontaneously [88]. While in most cases neonatal thelarche disappears over the first months of life, failure to do so almost never has any pathologic significance. (See "Breast masses in children and adolescents", section on 'Neonates and infants'.).

Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or axillary hair (pubarche) prior to the age of eight years in girls and nine years in boys, in conjunction with a mild elevation in serum dehydroepiandrosterone sulfate (DHEAS) for age. It is more common in girls, African-American and Hispanic females, and individuals with obesity and insulin resistance [15]. Premature adrenarche is considered a variant of normal development, but may be a risk factor for later development of polycystic ovary disease in girls. (See "Premature adrenarche" and "Definition, clinical features and differential diagnosis of polycystic ovary syndrome in adolescents".)

In the child presenting with isolated adrenarche, monitoring for the development of other secondary sexual characteristics (breast or testicular enlargement) is important to ensure that the child's presentation is not the first feature of CPP or a form of peripheral precocity. Premature adrenarche can be associated with mild growth acceleration and advance in bone age. In children with progressive virilization or with a more advanced bone age (>2 standard deviations [SD] beyond chronological age), further investigation for other causes of early pubertal development should be considered. (See "Premature adrenarche", section on 'Evaluation of premature pubarche'.)

Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with isolated genital hair, usually finer in texture than typical pubic hair and located along the labia or over the scrotum (rather than on the pubic symphysis) [89-91]. The steroid profile of these infants demonstrates normal or mildly elevated DHEAS concentrations for age. Unlike premature adrenarche, the condition is transient and the hair typically disappears within 6 to 24 months [92]. In the absence of progressive development of further genital hair or other secondary sexual characteristics during follow-up, extensive evaluation is not needed.

Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the presence of isolated, self- limited vaginal bleeding in the absence of other secondary sexual characteristics [93]. The underlying etiology is unknown but potential mechanisms include increased endometrial sensitivity to circulating estrogens or transient stimulation of the HPG axis [94]. Pelvic ultrasonography is normal and gonadotropins are pre-pubertal. Genital or vaginal trauma, infection, and sexual abuse should be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses such as recurrent functional ovarian cysts or McCune Albright Syndrome should be considered. (See 'McCune-Albright syndrome' above.)

Non-progressive or intermittently progressive precocious puberty — A subgroup of patients presenting with what clinically appears to be CPP (often with evidence of both gonadarche and pubarche) will either have stabilization or very slow progression in their pubertal signs [95]. The bone age is typically not as advanced compared with children with true CPP, and serum LH concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated and a FSH-predominant response is typically seen if gonadotropin-releasing hormone agonist (GnRHa) stimulation testing is performed. Monitoring for evidence of pubertal progression is important to distinguish these children from those with true CPP. In children with non-progressive precocious puberty, treatment with a GnRHa is not needed because their adult height is not affected (ie, their final height untreated is concordant with their midparental height) [95,96].

EVALUATION

Guiding principles — The evaluation for precocious puberty focuses on answering the following questions:

● Who should be evaluated? – Evaluation is warranted in children presenting with signs of secondary sexual development younger than the age of eight (girls) or nine (boys) years. The concern and extent of evaluation should increase with decreasing age at presentation. In girls who are between the ages of seven and eight, a comprehensive history and physical examination may be sufficient if this examination does not raise any additional concerns. https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 6/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate ● Is the cause of precocity central or peripheral? – The sequence of pubertal development in children with central precocious puberty (CPP) recapitulates normal pubertal development but at an earlier age (figure 1A-B). By contrast, individuals with peripheral precocity have a peripheral source of gonadal hormones and are more likely to display deviations from the normal sequence and/or pace of puberty. As an example, a girl who progresses to menstrual bleeding within one year of the onset of breast development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP [97,98].

● How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and duration of sex steroid action.

• A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests either CPP or peripheral precocity with high concentrations of sex steroids (table 4). Pubertal progression would be considered slow if there is minimal or no change in stage of breast, pubic hair, or genital development during six or more months of observation. Height velocity is considered accelerated if it is more than the 95th percentile for age (figure 3A-B).

• By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally advanced) suggests a benign pubertal variant with low concentrations of sex steroids, rather than true CPP or peripheral precocity.

● Is the precocity because of excess androgen or estrogen? – Are the secondary sexual characteristics virilizing or feminizing? Isolated contrasexual development (isolated virilization in girls or isolated feminization in boys) excludes central etiologies. While in girls the most common cause of virilization is due to excess adrenal androgens, a rare ovarian cause of virilization is ovarian arrhenoblastoma (Sertoli-Leydig cell tumor) [99]. Conversely, a rare testicular cause of feminization is a feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [100]. (See "Sex cord-stromal tumors of the ovary: Sertoli-stromal cell tumors", section on 'Clinical features' and "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)

Initial evaluation — The evaluation of a patient suspected to have precocious puberty begins with a history and physical examination. In most cases, radiographic measurement of bone age is performed to determine whether there is a corresponding increase in epiphysial maturation.

● Medical history – The history focuses on when the initial pubertal changes were first noted, as well as the timing of pubertal onset in the parents and siblings. In addition, other questions are directed toward evidence of linear growth acceleration, headaches, changes in behavior or vision, seizures, or abdominal pain (indicative of either a central nervous system [CNS] or ovarian process) and previous history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids (medicinal or cosmetic sources) or compounds with sex-steroid-like properties should always be explored [58].

● Physical examination – This includes height, weight, and height velocity (cm/year). Children with benign forms of precocious puberty do not usually display the early growth acceleration pattern that is seen among those with progressive forms of precocious puberty [101]. The physical examination should include assessment of visual fields (a defect suggests the possibility of a CNS mass) and examination for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome) (picture 2). (See 'McCune-Albright syndrome' above.)

● Pubertal staging – Secondary sexual development should be assessed to determine the sexual maturity rating (Tanner stage) of pubertal development. This means staging breast development in girls (picture 1A), genital development in boys, and pubic hair development in both sexes (picture 1B-C). In girls, the diameter of glandular breast tissue (by direct palpation including compression to differentiate from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In boys, measurements are made of the testicular volume (figure 4) [102]. Penile size (stretched length of the non-erect penis, measuring from the pubic bone to tip of glans, excluding the foreskin) is rarely used for monitoring of pubertal progress because penile growth is not an early event in puberty, accurate measurement is difficult and may be awkward for the adolescent boy, and the "pubertal threshold" for penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of testicular volume are critical to determine whether further radiologic or laboratory testing is necessary. (See "Normal puberty", section on 'Sexual maturity rating (Tanner stages)' and "Normal puberty", section on 'Sequence of pubertal maturation'.)

● Bone age – In patients with early development of secondary sexual characteristics confirmed by physical examination, evaluation of skeletal maturation by radiographic assessment of bone age can help with both the differential diagnosis and assessment of whether there may be an impact on final height. However, in patients presenting with typical features indicative of either isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

A significant advance in the bone age (greater than approximately 2 standard deviations [SD] beyond chronological age) is more likely to be indicative of either CPP or peripheral precocity, rather than a benign pubertal variant. A significantly advanced bone age does not, however, exclude a diagnosis of a benign pubertal variant. As an example, up to 30 percent of children with benign premature adrenarche have bone ages more than two years in advance of their chronological age [103]. (See 'Types of benign or non-progressive pubertal variants' above.)

Initial laboratory evaluation — If there is evidence of progressive development of secondary sexual characteristics, further evaluation is needed to determine its cause, whether therapy is needed, and, if so, which treatment is appropriate. https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 7/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either estradiol and/or testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and table 4).

Basal serum LH — A good initial screening test to identify activation of the hypothalamic-pituitary-gonadal axis is measurement of basal LH concentration (ideally in the morning), using sensitive immunochemiluminescence assays with a lower limit of detection of ≤0.1 mIU/mL (where mIU = milli-International Units) [104]. Results are interpreted as follows:

● LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant such as premature thelarche.

● LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can identify children with progressive CPP with high sensitivity and specificity [105,106].

● LH concentrations are less informative in the evaluation of children with non-progressive or intermittently progressive precocious puberty. While such children typically have basal LH concentrations <0.2 to 0.3 mIU/mL, levels can be in the early pubertal range in some children. Additional clinical characteristics such as lack of progression in secondary sexual characteristics or low LH/FSH ratio post-gonadotropin stimulation test can help to differentiate these children from those with progressive CPP. (See 'Serum LH concentrations after GnRH agonist stimulation' below.)

Care should be used in the interpretation of LH levels in girls under the age of two years, as gonadotropin concentrations may be elevated at this age in association with the "mini-puberty of infancy" and CPP can be misdiagnosed during this phase of development [10,107].

An emerging approach is to identify cases of progressive CPP using first-morning urinary gonadotropin levels. These early results need further validation, but this could be an important alternative diagnostic strategy in the future [108,109].

Basal serum FSH — Basal FSH concentrations have limited diagnostic utility in distinguishing children with CPP from those with benign pubertal variants. FSH concentrations are often higher in children with CPP compared with benign pubertal variants, but there is substantial overlap between these groups of children [104,105]. Like LH, FSH concentrations are typically suppressed in children with peripheral precocity.

Serum estradiol — Very high concentrations of estradiol, with associated suppression of gonadotropins, are generally indicative of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol immunoassays, however, have poor ability to discriminate at the lower limits of the assay between prepubertal and early pubertal concentrations [110]. More sensitive methods of estimating estradiol concentrations, such as tandem mass spectrometry, distinguish better between pre-pubertal and pubertal estradiol concentrations [111], and should be ordered exclusively. However, further studies are still needed to clarify threshold concentrations.

Serum testosterone — Elevated testosterone concentrations are indicative of testicular testosterone production in boys, or of adrenal testosterone production or exogenous exposure in both sexes. Very high concentrations, with associated suppression of gonadotropins, are generally indicative of peripheral precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone sulfate [DHEAS]) may be necessary to help discriminate between adrenal and testicular sources of the androgens. In children with CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal testosterone concentrations, but tandem mass spectroscopy methods are more discriminative [112] (similar to the estradiol assays discussed above), so these should be ordered whenever available.

Subsequent laboratory testing — Subsequent laboratory testing depends on the results of the tests outlined above (basal LH, FSH, and estrogen or testosterone), and on the patient's clinical characteristics:

Serum LH concentrations after GnRH agonist stimulation — In children in whom the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test may help differentiate those with CPP from those with a benign pubertal variant. This test consists of measurement of serum LH concentrations before and after administration of GnRH. GnRH is not available in the United States; a GnRH agonist may be used instead because of the initial stimulatory effect on the hypothalamic-pituitary-gonadal (HPG) axis following a single dose of a GnRH agonist.

A common protocol is as follows:

● Blood is sampled at baseline for LH, FSH, and either estradiol in girls or testosterone in boys.

● The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide acetate at a dose of 20 mcg/kg.

● LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [113-115]. Other protocols employ sampling every 30 minutes for up to two hours [113,116] or testing of estradiol or testosterone 24 hours later [117,118].

The results are interpreted as follows: https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 8/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate ● Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP has not been established, and varies somewhat among assays. For most LH assays, a value of 3.3 to 5 mIU/mL defines the upper limit of normal for stimulated LH values in prepubertal children [113,119]. Stimulated LH concentrations above this normal range suggest CPP.

● Peak stimulated LH/FSH ratio – Children with progressive CPP tend to have a more prominent LH increase post-stimulation, and higher peak LH/FSH ratios, compared with those with non- or intermittently progressive precocious puberty [117,120]. While a definite diagnostic threshold has not been well defined, a peak LH/FSH ratio >0.66 is typically seen with CPP, whereas a ratio <0.66 suggests non-progressive precocious puberty [120].

● Stimulated estradiol / testosterone – Children with progressive CPP tend to have higher stimulated serum estradiol and testosterone concentrations when measured 24 hours after administration of GnRH or GnRH agonist [117,118]. However, the disadvantage of requiring venipunctures on two consecutive days as well as the lack of consistent published diagnostic thresholds limits the clinical utility of these measurements.

As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in girls under the age of two years, as both basal and stimulated LH levels can be elevated as part of the normal hormonal changes associated with the mini-puberty of infancy [107].

Serum adrenal steroids — In children with precocious pubarche, measurement of adrenal steroids may be necessary to help distinguish between peripheral precocity and benign premature adrenarche. Children with premature adrenarche can have mild elevation in adrenal hormones, with DHEAS concentrations of 40 to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35 ng/dL (1.2 nmol/L) [121]. (See "Premature adrenarche", section on 'Hormonal measurements at baseline'.)

Concentrations above these thresholds warrant further investigation for causes of peripheral precocity, such as non-classical congenital adrenal hyperplasia and virilizing adrenal tumors. In children with suspected non-classical congenital adrenal hyperplasia (CAH) secondary to 21- hydroxylase deficiency who have an early morning 17-hydroxyprogesterone (17-OHP) concentration between 82 ng/dL (2.5 nmol/L) and 200 ng/dL (6 nmol/L), follow-up adrenocorticotropic hormone (ACTH) stimulation testing should be performed. A 17-OHP value >200 ng/dL has a high sensitivity and specificity for non-classical CAH [122,123], although an ACTH stimulation test may still be needed to confirm the diagnosis. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Other biochemical tests — In boys, human chorionic gonadotropin (hCG) should be measured to evaluate for the possibility of an hCG-secreting tumor. If a tumor is found in the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter syndrome because of its association with mediastinal germinoma [50]. A thyroid-stimulating hormone (TSH) concentration should be measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity.

Imaging

● Central precocious puberty

• Brain magnetic resonance imaging (MRI) – We recommend performing a contrast-enhanced brain MRI for all boys with CPP, and for girls with onset of secondary sexual characteristics before six years of age, because of higher rates of CNS abnormalities in these groups of patients (see 'CNS lesions' above). In our practice, we usually do not perform MRI for girls with CPP onset between seven and eight years of age if there is no clinical evidence of CNS pathology and if there is a family history of earlier pubertal onset, or if the child has an increased body mass index (BMI).

In girls with CPP onset after their sixth birthday, there is ongoing debate about the utility of brain imaging in this age group because of conflicting data about the risk for CNS pathology: In a meta-analysis, the prevalence of intracranial lesions was 3 percent among girls presenting with CPP after six years of age, compared with 25 percent among those presenting before six years [124]. These findings are in contrast to a study of girls with precocious puberty that was not included in this part of the meta-analysis, in which 13 of 208 girls (6.3 percent) had related MRI brain abnormalities, all of whom had onset of CPP after the age of six years [22]. A younger age of onset of pubertal signs and higher basal LH and estradiol concentrations have been proposed as predictive features for intracranial pathology [22,23,125]. Because these features and clinical suspicion have been shown to have variable sensitivity to detect girls with abnormal brain MRIs, some have recommended imaging for all girls with CPP [22,24].

• Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help differentiate between CPP and benign pubertal variants, especially when the evaluation remains equivocal. Girls with CPP have greater uterine and ovarian volumes compared with girls who are prepubertal or those with premature thelarche [126-129]. Diagnostic thresholds for uterine and ovarian volumes have been proposed; however, these are variable and some studies have suggested that there is considerable overlap between patients with and without CPP [126,127].

● Peripheral precocity

• In girls with progressive peripheral precocity, a pelvic ultrasound can be performed to help identify the presence of an ovarian cyst or tumor. For suspected adrenal pathology, for example when there is rapid virilization, an adrenal ultrasound should be strongly considered. https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 9/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate • Ultrasound examination of the testes can be performed in boys with peripheral precocity to evaluate for the possibility of a Leydig-cell tumor.

• In children where an adrenal tumor is suspected (due to evidence of progressive virilization and elevated serum adrenal androgens, eg, DHEAS), an abdominal ultrasound and/or computerized tomography (CT) abdomen should be performed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Early puberty (The Basics)")

SUMMARY

● Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard deviations (SD) earlier than the average age (figure 1A-B). (See 'Definition' above.)

● Because of the trend of earlier pubertal development, there is controversy about the lower age limit for normal pubertal development. Nonetheless, we recommend evaluation in children presenting with secondary sexual development younger than eight years in girls or nine years in boys (figure 2). (See 'Definition' above and 'Evaluation' above.)

● The etiology of precocious puberty is classified by the underlying pathogenesis into three categories (see 'Classification' above):

• Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-gonadal axis. CPP is pathologic in up to 40 to 75 percent of boys and 10 to 20 percent of girls (table 1). (See 'Causes of central precocious puberty (CPP)' above.)

• Peripheral precocity is caused by secretion of sex hormones either from the gonads or adrenal glands, ectopic human chorionic gonadotropin (hCG) production by a germ cell tumor, or by exogenous sources of sex steroids, and is independent from the hypothalamic-pituitary-gonadal axis (table 2). (See 'Causes of peripheral precocity' above.)

• Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic hair development (premature pubarche/adrenarche), benign pre-pubertal vaginal bleeding, and non-progressive precocious puberty (table 3). These patterns are usually a variant of normal puberty and require no intervention. If the finding is isolated breast development or isolated pubarche, and there is no evidence of pubertal progression or accelerated growth, laboratory evaluation may not be necessary. However, close follow-up is recommended because some of these patients will turn out to have progressive precocity. (See 'Types of benign or non-progressive pubertal variants' above.)

● The first step in the laboratory evaluation of progressive development of precocious secondary sexual characteristics is to measure basal luteinizing hormone (LH), follicle stimulating hormone (FSH), and either estradiol or testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and table 4). A good initial screening test to distinguish CPP from benign pubertal variants is measurement of a basal LH concentration (see 'Basal serum LH' above):

• In CPP, basal LH levels are often elevated into the pubertal range (greater than 0.2 to 0.3 mIU/mL, depending on the assay).

• LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant such as premature thelarche.

● If the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test can be performed to help distinguish CPP from a benign pubertal variant. Children with CPP have a pubertal (heightened) LH response to GnRH stimulation (table 4). (See 'Serum LH concentrations after GnRH agonist stimulation' above.)

● Recommendations for imaging depends on the type of precocious puberty (see 'Imaging' above):

• All boys with CPP should have brain imaging because of the high prevalence of central nervous system (CNS) lesions in this https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 10/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate group. While all girls with onset of CPP below the age of six years should also have a contrast-enhanced brain magnetic resonance imaging (MRI), there is ongoing controversy about the need for more routine imaging of girls between the ages of six and eight years.

• Boys with peripheral precocity may warrant an ultrasound examination of the testes to evaluate for the possibility of a Leydig-cell tumor. Girls with peripheral precocity may warrant a pelvic ultrasound performed to help identify the presence of an ovarian cyst or tumor. In both sexes, ultrasound of the adrenal glands may be indicated if adrenal pathology is suspected, and should be performed if there is suspicion for an adrenal tumor.

• Other than a bone age, no further imaging is usually required for children with benign or non-progressive pubertal variants.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Paul Saenger, MD, MACE, who contributed to an earlier version of this topic review.

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate of McCune-Albright syndrome--a European Collaborative Study. J Clin Endocrinol Metab 2004; 89:2107. 78. Chanson P, Salenave S, Orcel P. McCune-Albright syndrome in adulthood. Pediatr Endocrinol Rev 2007; 4 Suppl 4:453. 79. Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A 1992; 89:5152. 80. Grant DB, Martinez L. The McCune-Albright syndrome without typical skin pigmentation. Acta Paediatr Scand 1983; 72:477. 81. Pasquino AM, Pucarelli I, Passeri F, et al. Progression of premature thelarche to central precocious puberty. J Pediatr 1995; 126:11. 82. Zhu SY, Du ML, Huang TT. An analysis of predictive factors for the conversion from premature thelarche into complete central precocious puberty. J Pediatr Endocrinol Metab 2008; 21:533. 83. de Vries L, Guz-Mark A, Lazar L, et al. Premature thelarche: age at presentation affects clinical course but not clinical characteristics or risk to progress to precocious puberty. J Pediatr 2010; 156:466. 84. Crofton PM, Evans NE, Wardhaugh B, et al. Evidence for increased ovarian follicular activity in girls with premature thelarche. Clin Endocrinol (Oxf) 2005; 62:205. 85. Zung A, Glaser T, Kerem Z, Zadik Z. Breast development in the first 2 years of life: an association with soy-based infant formulas. J Pediatr Gastroenterol Nutr 2008; 46:191. 86. Mendez MA, Anthony MS, Arab L. Soy-based formulae and infant growth and development: a review. J Nutr 2002; 132:2127. 87. Freni-Titulaer LW, Cordero JF, Haddock L, et al. Premature thelarche in Puerto Rico. A search for environmental factors. Am J Dis Child 1986; 140:1263. 88. Madlon-Kay DJ. 'Witch's milk'. Galactorrhea in the newborn. Am J Dis Child 1986; 140:252. 89. Nebesio TD, Eugster EA. Pubic hair of infancy: endocrinopathy or enigma? Pediatrics 2006; 117:951. 90. Kaplowitz PB, Mehra R. Clinical characteristics of children referred for signs of early puberty before age 3. J Pediatr Endocrinol Metab 2015; 28:1139. 91. Janus D, Wojcik M, Tyrawa K, Starzyk J. Transient isolated scrotal hair development in infancy. Clin Pediatr (Phila) 2013; 52:628. 92. Kaplowitz P, Soldin SJ. Steroid profiles in serum by liquid chromatography-tandem mass spectrometry in infants with genital hair. J Pediatr Endocrinol Metab 2007; 20:597. 93. Ejaz S, Lane A, Wilson T. Outcome of Isolated Premature Menarche: A Retrospective and Follow-Up Study. Horm Res Paediatr 2015; 84:217. 94. Nella AA, Kaplowitz PB, Ramnitz MS, Nandagopal R. Benign vaginal bleeding in 24 prepubertal patients: clinical, biochemical and imaging features. J Pediatr Endocrinol Metab 2014; 27:821. 95. Palmert MR, Malin HV, Boepple PA. Unsustained or slowly progressive puberty in young girls: initial presentation and long-term follow-up of 20 untreated patients. J Clin Endocrinol Metab 1999; 84:415. 96. Lazar L, Pertzelan A, Weintrob N, et al. Sexual precocity in boys: accelerated versus slowly progressive puberty gonadotropin- suppressive therapy and final height. J Clin Endocrinol Metab 2001; 86:4127. 97. Heller ME, Dewhurst J, Grant DB. Premature menarche without other evidence of precocious puberty. Arch Dis Child 1979; 54:472. 98. Hill NC, Oppenheimer LW, Morton KE. The aetiology of vaginal bleeding in children. A 20-year review. Br J Obstet Gynaecol 1989; 96:467. 99. Cabrera-Cantú F, Urrutia-Osorio M, Valdez-Arellano F, et al. Sertoli-Leydig cell tumor in a 12-year-old girl: a review article and case report. Arch Gynecol Obstet 2014; 290:791. 100. Alikasifoglu A, Gonc EN, Akcoren Z, et al. Feminizing Sertoli cell tumor associated with Peutz-Jeghers syndrome. J Pediatr Endocrinol Metab 2002; 15:449. 101. Papadimitriou A, Beri D, Tsialla A, et al. Early growth acceleration in girls with idiopathic precocious puberty. J Pediatr 2006; 149:43. 102. Joustra SD, van der Plas EM, Goede J, et al. New reference charts for testicular volume in Dutch children and adolescents allow the calculation of standard deviation scores. Acta Paediatr 2015; 104:e271. 103. DeSalvo DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign. J Pediatr Endocrinol Metab 2013; 26:215. 104. Neely EK, Hintz RL, Wilson DM, et al. Normal ranges for immunochemiluminometric gonadotropin assays. J Pediatr 1995; 127:40. 105. Harrington J, Palmert MR, Hamilton J. Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of precocious puberty. Arch Dis Child 2014; 99:15. 106. Houk CP, Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 14/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate puberty in girls. Pediatrics 2009; 123:e1059. 107. Bizzarri C, Spadoni GL, Bottaro G, et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. J Clin Endocrinol Metab 2014; 99:433. 108. Zung A, Burundukov E, Ulman M, et al. The diagnostic value of first-voided urinary LH compared with GNRH-stimulated gonadotropins in differentiating slowly progressive from rapidly progressive precocious puberty in girls. Eur J Endocrinol 2014; 170:749. 109. Lucaccioni L, McNeilly J, Mason A, et al. The measurement of urinary gonadotropins for assessment and management of pubertal disorder. Hormones (Athens) 2016; 15:377. 110. Bay K, Andersson AM, Skakkebaek NE. Estradiol levels in prepubertal boys and girls--analytical challenges. Int J Androl 2004; 27:266. 111. Rosenfield RL, Bordini B, Yu C. Comparison of detection of normal puberty in girls by a hormonal sleep test and a gonadotropin-releasing hormone agonist test. J Clin Endocrinol Metab 2013; 98:1591. 112. Lee PA, Gollenberg AL, Hediger ML, et al. Luteinizing hormone, testosterone and inhibin B levels in the peripubertal period and racial/ethnic differences among boys aged 6-11 years: analyses from NHANES III, 1988-1994. Clin Endocrinol (Oxf) 2010; 73:744. 113. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009; 123:e752. 114. Houk CP, Kunselman AR, Lee PA. The diagnostic value of a brief GnRH analogue stimulation test in girls with central precocious puberty: a single 30-minute post-stimulation LH sample is adequate. J Pediatr Endocrinol Metab 2008; 21:1113. 115. Kandemir N, Demirbilek H, Özön ZA, et al. GnRH stimulation test in precocious puberty: single sample is adequate for diagnosis and dose adjustment. J Clin Res Pediatr Endocrinol 2011; 3:12. 116. Chi CH, Durham E, Neely EK. Pharmacodynamics of aqueous leuprolide acetate stimulation testing in girls: correlation between clinical diagnosis and time of peak luteinizing hormone level. J Pediatr 2012; 161:757. 117. Carretto F, Salinas-Vert I, Granada-Yvern ML, et al. The usefulness of the leuprolide stimulation test as a diagnostic method of idiopathic central precocious puberty in girls. Horm Metab Res 2014; 46:959. 118. Sathasivam A, Garibaldi L, Shapiro S, et al. Leuprolide stimulation testing for the evaluation of early female sexual maturation. Clin Endocrinol (Oxf) 2010; 73:375. 119. Resende EA, Lara BH, Reis JD, et al. Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children. J Clin Endocrinol Metab 2007; 92:1424. 120. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251. 121. Rosenfield RL. Clinical review: Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:787. 122. Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol (Oxf) 2015; 82:543. 123. Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab 2009; 94:2835. 124. Cantas-Orsdemir S, Garb JL, Allen HF. Prevalence of cranial MRI findings in girls with central precocious puberty: a systematic review and meta-analysis. J Pediatr Endocrinol Metab 2018; 31:701. 125. Chalumeau M, Chemaitilly W, Trivin C, et al. Central precocious puberty in girls: an evidence-based diagnosis tree to predict central nervous system abnormalities. Pediatrics 2002; 109:61. 126. Eksioglu AS, Yilmaz S, Cetinkaya S, et al. Value of pelvic sonography in the diagnosis of various forms of precocious puberty in girls. J Clin Ultrasound 2013; 41:84. 127. Sathasivam A, Rosenberg HK, Shapiro S, et al. Pelvic ultrasonography in the evaluation of central precocious puberty: comparison with leuprolide stimulation test. J Pediatr 2011; 159:490. 128. de Vries L, Horev G, Schwartz M, Phillip M. Ultrasonographic and clinical parameters for early differentiation between precocious puberty and premature thelarche. Eur J Endocrinol 2006; 154:891. 129. Badouraki M, Christoforidis A, Economou I, et al. Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls. Ultrasound Obstet Gynecol 2008; 32:819.

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Sequence of puberty in girls

Sequence of events in girls w ith average timing of pubertal development in the United States. The median age for achieving each milestone is younger for African American girls (dashed vertical line) compared w ith Caucasian girls (dotted vertical line). The median length of time betw een the onset of puberty (breast Tanner stage 2) and menarche is 2.6 years, and the 95 th percentile is 4.5 years.

SMR: sexual maturity rating (also known as Tanner stage).

Data from: Biro FM, Huang B, Lucky AW, et al. Pubertal correlates in black and white US girls. J Pediatr 2006; 148:234, and from: Tanner JM, Davies PS. J Pediatr 1985; 107:317.

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Sequence of puberty in boys

Sequence of pubertal events in boys w ith average timing of pubertal development in the United States.

Data from: 1. Biro FM et al, Pubertal staging in boys. J Pediatr 1995; 127:100. 2. Karpati AM et al, Stature and pubertal stage assessment in American boys: the 1988-1994 Third National Health and Nutrition Examination Survey. J Adolesc Health 2002; 30:205-12. 3. Dore E et al. Gender differences in peak muscle performance during growth. Int J Sports Med 2005; 26:274. 4. Neu CM et al. Influence of puberty on muscle development at the forearm. Amer J Physiol Endocrin Metab 2002; 283:E103. 5. Tanner et al. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985; 107:317.

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Sexual maturity rating (Tanner staging) of breast development in girls

Stages in breast development in girls. Stage 1: Prepubertal, w ith no palpable breast tissue. Stage 2: Development of a breast bud, w ith elevation of the papilla and enlargement of the areolar diameter. Stage 3: Enlargement of the breast, w ithout separation of areolar contour from the breast. Stage 4: The areola and papilla project above the breast, forming a secondary mound. Stage 5: Recession of the areo la to match the contour of the breast; the papilla projects beyond the contour of the areola and breast.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

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Sexual maturity rating (Tanner staging) of pubic hair and external genitalia development in boys

Stages of pubic hair development in boys: Stage 1: Prepubertal, w ith no pubic hair. Stage 2: Sparse, straight pubic hair along the base of the penis. Stage 3: Hair is darker, coarser, and curlier, extending over the mid- pubis. Stage 4: Hair is adult-like in appearance, but does not extend to thighs. Stage 5: Hair is adult in appearance, extending from thigh to thigh. Stages of external genitalia development in boys: Stage 1: Prepubertal. Stage 2: Enlargement of testes and scrotum; scrotal skin reddens and changes in texture. Stage 3: Enlargement of penis (length at first); further grow th of testes. Stage 4: Increased size of penis w ith grow th in breadth and development of glans; testes and scrotum larger, scrotal skin darker. Stage 5: Adult genitalia.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

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Sexual maturity rating (Tanner staging) of pubic hair development in girls

Stages of development in pubic hair in girls. Stage 1: Prepubertal w ith no pubic hair. Stage 2: Sparse, straight hair along the lateral vulva. Stage 3: Hair is darker, coarser, and curlier, extending over the mid-pubis. Stage 4: Hair is adult-like in appearance, but does not extend to the thighs. Stage 5: Hair is adult in appearance, extending from thigh to thigh.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

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Timing of puberty in Caucasian and African American girls in the United States

In this study, the first signs of puberty occurred at a younger age than had been previously reported; the mean age of onset w as earlier for African American versus Caucasian girls.

Data from Herman-Giddens, ME, Slora, EJ, Wasserman, RC, et al, Pediatrics 1997; 99:505.

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Etiology and mechanisms of precocious puberty

GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

From: Harrington J, Palmert MR, Hamilton J. Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of precocious puberty. Arch Dis Child 2014; 99:15. Reproduced with permission from BMJ Publishing Group Ltd. Copyright © 2014.

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Central (gonadotropin-dependent) precocious puberty

Etiology Clinical features Bone age Additional evaluation

Idiopathic Early progressive pubertal ↑↑ Increased ovarian and uterine (80 to 90% of girls with C PP, development, but proceeds in normal volumes on ultrasound may help and 25 to 60% of boys with sequence. differentiate girls with C PP from those C PP) with premature thelarche. C ontrast enhanced MRI to rule out Secondary to CNS lesions Early progressive pubertal ↑↑ C NS abnormality. (eg, hypothalamic hamartomas, development, but proceeds in normal other C NS tumors and lesions, sequence. cranial radiation) C entral precocious puberty secondary to a C NS lesion occurs more commonly in boys and younger children.

Post early exposure to sex History of treatment of peripheral ↑↑ Basal and stimulated LH concentrations steroids precocity. are pubertal. (after treatment for peripheral Progressive pubertal development with precocity) breast development in girls and testicular enlargement in boys.

Central precocious puberty is characterized by basal LH concentrations >0.2 to 0.3 mIU/L, and/or stimulated LH concentration post GnRH or GnRHa of >3.3 to 5.0 mIU/L.

↑↑: significantly advanced for chronological age (eg, ≥ 2 standard deviations); C PP: central precocious puberty; C NS: central nervous system; LH: luteinizing hormone; MRI: magnetic resonance imaging; GnRH: gonadotropin-releasing hormone; GnRHa: gonadotropin- releasing hormone agonist.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

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Peripheral precocity (gonadotropin-independent precocious puberty)

Bone Etiology Clinical features Additional evaluation age

Girls only

Ovarian cysts Breast development and/or vaginal bleeding. ↑ to ↑↑ Pelvic ultrasound may visualize the cyst, Occasionally presents with ovarian torsion although in some cases the cyst may have and abdominal pain. involuted by the time of the study. Vaginal bleeding is indicative of estrogen withdrawal. Recurrent ovarian cysts suggest McC une Albright Syndrome.

Ovarian tumor Development of either isosexual or ↑↑ Pelvic ultrasound contrasexual sexual precocity, depending of tumor type.

Boys only

Leydig cell tumor Asymmetrical enlargement of the testes. ↑↑ Pubertal testosterone concentrations. Testicular ultrasound aids in diagnosis.

hC G-secreting germ Symmetric testicular enlargement to an early ↑↑ These tumors may occur in gonads, brain, cell tumors pubertal size, but testes remain smaller than liver, retroperitoneum, or mediastinum. expected for degree of pubertal development. When a tumor is identified in the anterior Peripheral precocity is seen only in boys, mediastinum, a karyotype must be performed because hC G only activates LH receptors because of an association of this finding with (estrogen biosynthesis in the ovaries requires Klinefelter syndrome. both FSH and LH receptor activation).

Familial male-limited Symmetric testicular enlargement to an early ↑↑ Genetic testing for mutations of the LH precocious puberty pubertal size, but testes remain smaller than receptor gene (LHC GR). expected for degree of pubertal development; spermatogenesis may occur. Familial: Male-limited autosomal dominant trait. Peripheral precocity is seen only in boys, because there is only activation of the LH receptors (ovarian estrogen biosynthesis requires both FSH and LH receptor activation).

Girls and boys

Exogenous sex Estrogen preparations cause feminization, ↑ to ↑↑ C linical history explores use of exogenous steroids (estradiol and while topical androgens cause virilization in sex steroids and folk remedies by caretakers. testosterone creams) both sexes.

McC une-Albright In girls, may present with recurrent episodes ↑ to ↑↑ Ultrasound: Ovaries enlarged, with follicular syndrome of breast development, regression and cysts. In boys, testicular ultrasound can (girls>boys) vaginal bleeding. In boys, sexual precocity demonstrate hyper-and hypoechoic lesions less common. (most likely representing areas of leydig cell Skin: Multiple irregular-edged café-au-lait hyperplasia), microlithiasis and focal spots. calcifications. Bone: Polyostotic fibrous dysplasia. May have other hyperactive endocrine disorders: ie, thyrotoxicosis, glucocorticoid excess and/or gigantism.

Primary Girls: vaginal bleeding, breast development ↓ Elevated TSH hypothyroidism and galactorrhea. Boys: testicular enlargement. Other clinical features of hypothyroidism such as short stature.

C ongenital adrenal Boys have prepubertal testes with enlarged ↑↑ Sex hormone levels vary depending on the hyperplasia phallus and pubic hair development. Girls with adrenal enzyme block. An early morning 17- (untreated) "nonclassic" C AH may present with early OHP >200 ng/dL (6 nmol/L) has a high pubic and/or axillary hair, and other signs of sensitivity and specificity for congenital androgen excess. adrenal hyperplasia secondary to 21 hydroxylase deficiency. AC TH stimulation test is recommended to confirm the diagnosis of C AH if the 17-OHP level is intermediate (eg, between 200 and 1500 ng/dL). After therapy with glucocorticoids, C PP may develop.

Virilizing adrenal Boys: pubic and/or axillary hair and penile ↑↑ High DHEA or DHEAS, androstenedione and tumor growth with pre-pubertal testes. testosterone. Girls: pubic and/or axillary hair, other C T and/or ultrasound of adrenal glands to significant signs of androgen excess (acne locate tumor. and clitoromegaly). https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 24/33

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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate May present with signs of glucocorticoid excess. May be associated with hereditary cancer syndromes.

Peripheral precocity is characterized by low or suppressed gonadotropin concentrations w ith elevated sex hormone levels. Pubertal status should be monitored for six months after treatment, because treatment of peripheral precocity can trigger central precocious puberty (CPP).

↑: advanced for chronological age; ↓: delayed for chronological age; hC G: human chorionic gonadotropin; LH: luteinizing hormone; FSH: follicle-stimulating hormone; LHC GR: luteinizing hormone/choriogonadotropin receptor; C PP: central precocious puberty; TSH: thyroid- stimulating hormone; C AH: congenital adrenal hyperplasia; 17-OHP: 17-hydroxyprogesterone; AC TH: adrenocorticotropic hormone; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; C T: computed tomography.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

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Types of benign pubertal variants

Etiology Clinical Features Bone Age Additional Evaluation

Premature Isolated pubarche. Gonads are prepubertal ↑ to ↑↑* Further investigations needed only if there is adrenarche in size and there is no breast development in significant progressive virilization, to help (boys or girls) girls. Typical age of onset four to eight exclude peripheral precocity. years. Mild elevation in DHEAS for chronological age Seen more commonly in African-American (but appropriate for bone age). and Hispanic girls and in children with obesity Prepubertal concentrations of 17- and insulin resistance. hydroxyprogesterone and testosterone.

Premature thelarche Isolated breast development with normal Normal No further evaluation needed in most cases, (girls) growth velocity. (prepubertal) unless evidence of pubertal progression. Most commonly seen in girls less than three Basal LH concentrations typically <0.2 to 0.3 years of age. mIU/L.¶

Non-progressive or Development of gonadarche (breast or Normal to ↑ Basal LH concentrations typically <0.2 to 0.3 intermittently testicular enlargement) with pubarche (pubic mIU/L, although can be in early pubertal progressive and/or axillary hair), with either no range in some children. precocious puberty progression or intermittent slow progression Lower stimulated LH/FSH ratio compared with (boys or girls) in clinical pubertal signs. children with progressive central precocious puberty.Δ Patients with non-progressive precocious puberty do not need treatment with GnRH agonist, because final height untreated is concordant with mid-parental height.

If further evaluation is needed and performed, patients w ith benign pubertal variants typically have pre-pubertal basal LH concentrations (<0.2 to 0.3 mIU/L) and/or stimulated LH concentration post GnRHa of <3.3 to 5.0 mIU/L.

↑: elevated for chronological age; DHEAS: dehydroepiandrosterone sulfate; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone. * Up to 30% of children with premature adrenarche can have a bone age more than two years advanced than their chronological age.[1] ¶ Interpretation of basal LH and stimulated LH concentrations can be difficult in girls younger than two years of age because normal gonadotropin concentrations can be elevated as part of the mini-puberty of infancy.[2] Δ A peak LH/FSH ratio <0.66 suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with central precocious puberty.[3]

1. DeSalvo, DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign. J Pediatr Endocrinolo Metab 2013; 26: 215. 2. Bizzarri C, Spadoni G, Bottaro G et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. JCEM 2014; 99:433. 3. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251.

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Café-au-lait spots in McCune-Albright syndrome

(A) A typical lesion on the face, chest, and arm of a five-year-old girl w ith McCune-Albright syndrome, w hich demonstrates jagged "coast of Maine" borders and the tendency for the lesions to both respect the midline and follow the developmental lines of Blaschko (a configuration of skin lesions characterized by arcs on the upper chest, S shapes on the abdomen, and V shapes over the posterior midline, caused by patterns of X-chromosome inactivation). (B) Typical lesions that are often found on the nape of the neck and crease of the buttocks are show n (arrow s).

Reproduced from: Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis 2008; 3:12. Copyright ©2008 BioMed Central Ltd.

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Radiographic appearance of fibrous dysplasia in McCune-Albright syndrome

A) A proximal femur w ith typical ground glass appearance and shepherd's crook deformity characteristic of fibrous dysplasia (FD) in a 10-year-old child. B) The appearance of FD in the femur of an untreated 40-year-old man demonstrates the tendency for FD to appear more sclerotic w ith time. C) The typical ground glass appearance of FD in the craniofacial region on a CT image of a 10-year-old child is sh ow n. The w hite arrow s indicate the optic nerves, w hich are typically encased w ith FD. D) A CT image in a 40-year-old w oman demonstrates the typical appearance of craniofacial FD in an older person, w ith mixed solid and "cystic" lesions. The Hounsfield Unit measurements of "cystic" lesions are quite useful in distinguishing soft tissue "cystic" lesions from true fluid-filled cysts, w hich are much more u ncommon and tend to behave aggressively w ith rapid expansion and compression of vital structures. E-G) Bone Scintigraphy in FD. Representative 99Tc- MDP bone scans w hich show tracer uptake at affected skeletal sites, and the associated skeletal disease burden score are show n. E) A 50-year-old w oman w ith monostotic FD confined to a single focus involving contiguous bones in the craniofacial region. F) A 42-year-old man w ith polyostotic FD show s the tendency for FD to be predominantly (but not exclusively) unilateral, and to involve the skull base and proximal femur. G) A 16-year-old boy w ith McCune-Albright syndrome and involvement of virtually all skeletal sites (panostotic) is show n.

Reproduced from: Dumitrescu, CE, Collins, MT. McCune-Albright syndrome. Orphanet J Rare Dis 2008; 3:12. Copyright ©2008 BioMed Central Ltd.

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Clinical characteristics of forms of early pubertal development

Nonprogressive Central precocious Peripheral precocity precocious puberty puberty (CPP)

Physical examination: No progression in Tanner Progression to next pubertal Progression Advancement through staging during 3 to 6 months of stage in 3 to 6 months pubertal stages (Tanner observation stage)

Growth velocity Normal for bone age Accelerated (>6 cm per year)* Accelerated*

Bone age Normal to mildly advanced Advanced for height age Advanced for height age

Serum estradiol PrepubertalΔ Prepubertal to pubertal Increased in ovarian causes of concentration (girls)¶ peripheral precocity, or with exogenous estrogen exposure

Serum testosterone PrepubertalΔ Prepubertal to pubertal Pubertal and increasing concentration (boys, or girls with virilization)¶

Basal (unstimulated) serum PrepubertalΔ◊ Pubertal◊ Suppressed or prepubertal◊ LH concentration ¶

GnRH (or GnRHa) LH peak in the prepubertal LH peak elevated (in the No change from baseline, or LH stimulation test¶ range Δ§ pubertal range)§ peak in the prepubertal range Lower stimulated LH to FSH Higher stimulated LH to FSH ratio ¥ ratio ¥

C PP: central precocious puberty (also known as gonadotropin-dependent precocious puberty); LH: luteinizing hormone; GnRH: gonadotropin- releasing hormone; GnRHa: gonadotropin-releasing hormone agonist; FSH: follicle-stimulating hormone. * UNLESS the patient has concomitant growth hormone deficiency (as in the case of a neurogenic form of C PP), or has already passed his or her peak height velocity at the time of evaluation, in which case growth velocity may be normal or decreased for chronological age. ¶ Using most commercially available immunoassays, serum concentrations of gonadal steroids have poor sensitivity to differentiate between prepubertal and early pubertal concentrations. Δ In most cases these levels will be prepubertal, however in children with intermittently progressive C PP, these levels may reach pubertal concentrations during times of active development. ◊ Using ultrasensitive assays with detection limit of LH <0.1 mIU/L, prepubertal basal LH concentrations are <0.2 to 0.3 mIU/L. § In most laboratories, the upper limit of normal for LH after GnRH stimulation is 3.3 to 5.0 mIU/mL. Stimulated LH concentrations above this normal range suggests C PP. ¥ A peak stimulated LH/FSH ratio <0.66 usually suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with C PP.[1]

Reference: 1. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251. Courtesy of Drs. Mark Palmert and Jennifer Harrington.

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Height velocity in American boys

Height velocity by age for American boys. The main set of curves (black lines) is centered on the population w ith average timing of peak grow th velocity (around 13.5 years for boys) and show an approximate trajectory for individual children w ith this average pubertal timing. The tw o other curves outline a trajectory (50 th percentile) for a child w ith 'early' (solid blue) or 'late' (solid orange) timing of peak grow th velocity. Other height velocity curves (not show n here) have been developed that reflect population averages; those curves are substantially flatter than the trajectory follow ed by any individual patient [1]. Those curves are based on data from a more recent and ethnically diverse population of children, and are valuable for understanding overall grow th patterns in the population, but are less appropriate for evalua tion of the grow th of an individual patient.

SD: standard deviations.

Reference: 1. Kelly A, Winer KK, Kalkwarf H, et al. Age-based reference ranges for annual height velocity in US children. J Clin Endocrinol Metab 2014; 99:2104. Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985 Elsevier.

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Height velocity in American girls

Height velocity by age for American girls. The main set of curves (black lines) is centered on the population w ith average timing of peak grow th velocity (around 11.5 years for girls), and show an approximate trajectory for individual children w ith this average pubertal timing. The tw o other curves outline a trajectory (50 th percentile) for a child w ith 'early' (solid blue) or 'late' (solid orange) timing of peak grow th velocity. Other height velocity curves (not show n here) have been developed that reflect population averages; those curves are substantially flatter than the trajectory follow ed by any individual patient [1]. Those curves are based on data from a more recent and ethnically diverse population of children, and are valuable for understanding overall grow th patterns in the population, but are less appropriate for evalua tion of the grow th of an individual patient.

SD: standard deviations.

Reference: 1. Kelly A, Winer KK, Kalkwarf H, et al. Age-based reference ranges for annual height velocity in US children. J Clin Endocrinol Metab 2014; 99:2104. Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985 Elsevier.

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Reference chart for testicular volume

Reference chart of testicular volume measured w ith an orchidometer, based upon data from 769 healthy Dutch boys aged 6 months to 19 years.[1]

Reference: 1. Joustra S, van der Plas E, Goede J, et al. New reference charts for testicular volume in Dutch children and adolescents allow calculation of standard deviation scores. Acta Paediatrica 2015; 104:e271. Reproduced with permission. Copyright ©2015 TNO.

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Contributor Disclosures

Jennifer Harrington, MBBS, PhD Nothing to disclose Mark R Palmert, MD, PhD Nothing to disclose Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism (Testosterone gel)]; Novo Nordisk [Growth hormone (Somatropin)]; Novartis [Cushing's (LCI699)]; Cortendo [Cushing's]. Consultant/Advisory Boards: AbbVie [Hypogonadism (Testosterone gel)]; Novartis [Cushing's (LCI699)]; Pfizer [Acromegaly (Pegvisomant)]; Watson [Testosterone (Testosterone gel)]. William F Crowley, Jr, MD Consultant/Advisory Boards: Juniper Pharmaceuticals [Endocrinology (Vaginal progesterone)]; Quest Diagnostics [Reproductive endocrinology]. Other Financial Interest: Stock ownership: Juniper Pharmaceuticals [Endocrinology (Transvaginal ring delivery systems)]. Mitchell E Geffner, MD Consultant/Advisory Boards: Daiichi-Sankyo [Type 2 diabetes (Colesevelam)]; NovoNordisk [Growth (Somatropin)]; Nutritional Growth Solutions [Growth]; Pfizer [Growth (Somatropin)]. Spruce Biosciences [congenital adrenal hyperplasia]. Other Financial Interest: McGraw-Hill [Pediatric endocrinology (Textbook royalties)]. Alison G Hoppin, MD Nothing to disclose Kathryn A Martin, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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REVIEW DO I: 10.4274/jcrpe.2017.S004 J Clin Res Pediatr Endocrinol 2017;9(Suppl 2):33-48

A Critical Appraisal of the Effect of Gonadotropin-Releasing Hormon Analog Treatment on Adult Height of Girls with Central Precocious Puberty

Abdullah Bereket

Marmara University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, İstanbul, Turkey

Abstract Central precocious puberty (CPP) is a diagnosis that pediatric endocrinologists worldwide increasingly make in girls of age 6-8 years and is mostly idiopathic. Part of the reason for increasing referral and diagnosis is the perception among the doctors as well as the patients that treatment of CPP with long-acting gonadotropin-releasing hormon analogues (GnRHa) promote height of the child. Although, the timing and the tempo of puberty does influence statural growth and achieved adult height, the extent of this effect is variable depending on several factors and is modest in most cases. Studies investigating GnRHa treatment in girls with idiopathic CPP demonstrate that treatment is able to restore adult height compromised by precocious puberty. However, reports on untreated girls with precocious puberty demonstrate that some of these girls achieve their target height without treatment as well, thus, blurring the net effect of GnRHa treatment on height in girls with CPP. Clinical studies on treatment of girls with idiopathic CPP on adult stature suffers from the solid evidence-base due mainly to the lack of well-designed randomized controlled studies and our insufficiencies of predicting adult height of a child with narrow precision. This is particularly true for girls in whom age of pubertal onset is close to physiological age of puberty, which are the majority of cases treated with GnRHa nowadays. Heterogeneous nature of pubertal tempo (progressive vs. nonprogressive) leading to different height outcomes also complicates the interpretation of the results in both treated and untreated cases. This review will attemp to summarize and critically appraise available data in the field. Keywords: Central precocious puberty, gonadotropin-releasing hormon analogues, treatment, final height, adult height, growth, triptoreli, leuprolide

Introduction Although the majority of the studies in the field suggests beneficial effects of treatment, there have been ongoing Gonadotropin-releasing hormone analogues (GnRHa) are uncertainties about the achievement of both aims of the the treatment of choice for nearly four decades in children treatment due to methodological limitations of the present with central precocious puberty (CPP) (1). Treatment studies. This review wil focus on the effect of GnRHa effectively suppresses hypothalamo-pituitary-gonadal axis, treatment on height outcome in girls with CPP. which results in arresting early and accelerated activation Uncertainties about the benefits of GnRH analog treatment of sex hormone synthesis, progression of secondary on growth of children with CPP comes from the fact that sexual characteristics and undue maturation of the skeletal there is no randomised controlled study on this respect. development, thus meeting the aims of the treatment, Some of the studies in this field compare treatment group which are 1) to prevent potential psycological problems with a historical control groups which are reported decades related to early pubertal development, and 2) to restore ago, include limited number of subjects and heterogeneous genetic growth potential otherwise compromised by sex- with respect to nuances of pubertal development. Some hormone-driven premature closure of bone growth plates. studies have their own untreated control group (but not

Address for Correspondence: Abdullah Bereket MD, Conflict of interest: None declared Marmara University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, İstanbul, Turkey Received: 20.12.2017 Phone: +90 532 285 88 30 E-mail: [email protected] ORCID ID: orcid.org/0000-0002-6584-9043 Accepted: 22.12.2017 ©Copyright 2017 by Turkish Pediatric Endocrinology and Diabetes Society The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.

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Bereket A. J Clin Res Pediatr Endocrinol Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty 2017;9(Suppl 2):33-48 randomised) which brings biases to the interpretation of Height Outcome in Girls with Precocious Puberty without the data. Finally, many studies are comparing the achieved Treatment adult height with predicted adult height (PAH) at initiation of Historical series of untreated patients (Table 1) reported treatment which suffers from the limitations of our ability to mean heights of 152 cm in girls and 156 cm in boys, a loss assess bone age (BA) and predict adult height precisely, and of ~10 cm in girls and 20 cm in boys (9,10,11,12,13,14). disregard the genetic height potential of the child. However, these data should be interpreted very cautiously. The Relationship Between Height and Timing of Puberty First of all, those data come from a limited number of patients from the 1950s and 1960s with cases that are It has been known for a long time that physiological very severe and early onset CPP, with cases due to organic variations in the time of pubertal development has an reasons constituting the great part of it. Thus, more severe effect on statural height. Shangold et al (2) evaluated the relationship between recalled menarcheal age and than the average patient treated today. In fact, in most of adult height, in 425 women. After exclusion of those in these historical series, there was a negative correlation whom menarche occurred after age 16, the overall linear between the age of onset of precocious puberty and adult regression equation for the remaining 416 patients, height height, confirming the poor height prognosis of the most = 153.95 + 0 .7353 x (age of menarche), was significant. severe and early cases. Furthermore, some of the untreated Average height in women who had menarche at age 9 was patients with organic CPP may have had growth limitation 159.5±6.5 whereas those with menarche at age 11-13 yrs due to factors associated with their central nervous system was 163 cm. Overall the data suggested that menarcheal age disorder, such as growth hormone (GH) deficiency. Secondly, significantly correlates with adult height as an independent these were not large series, especially for the figure of boys variable (2). which derived from total of 38 untreated boys in total of four studies (9,10,11,12). Lastly, these studies do not take A large longitudinal study on American girls also evaluated into account the secular increase in height. the effect of timing of spontaneous puberty on height was indicated a higher adult height in girls with late (>12.9 In one of the early studies, Paul et al (11) compared their years) versus early (<11.7 years) age at menarche. The treated patients with untreated subjects from the literature median difference was of 2.6 and 1.7 cm in white and (9,10,13,14). The final height of treated females was black girls respectively (3). A recent Korean study of 4218 160.5±6.6 cm whereas matched untreated historical post-menarcheal girls between the ages of 16 and 18 years females had a height of 152.7±8.6 cm (difference of reported mean heights of early (9.9±0.2 years), average treated vs. untreated 7.8 cm). Although treated girls’ mean (12.5±0.9 years) and late (15.1±0.3 years) menarche final height was still -1 standard deviation (SD) below mean groups as 160.4±5.2 cm, 161.8±4.9 cm, 162.3±4.7 cm midparental TH, this was better compared to untreated ones respectively p=0.001) (4). who had height -2.4 SD below TH. Further classification of In contrast to above studies, a recent longitudinal study Table 1. Historical data of untreated children with from Thailand followed 104 girls with breast development precocious puberty at 7.0-9.0 years. Despite the average age at menarche Reference No. of patients Mean final height ± SD (cm) was early (10.2±0.9), their near final height obtained at (female/male) Females Males 12.6±0.4 years was 154.0±4.9 cm, which was similar to their average target height (TH) of 153.1±4.8 cm (5). Thamdrup (9) 26/18 151.3±8.8 155.4±8.3 It can be concluded from above mentioned studies that Sigurjonsdottir 40/11 152.7±8.0 156.0±7.3 and Hayles (10) “early” puberty within the currently accepted physiological range has “if any” a very small (2-4 cm) effect on adult Paul et al (11) 8/4 153.8±6.8 159.6±8.7 height reached, an observation consistent with none to very small height gain achieved in GnRH analog treatment of girls Bovier-Lapierre et 4/5 150±6.2 156±6.3 al (12) with “early” puberty (6,7,8). However, “truely” precocious puberty starting at a very young age is expected to result in Lee (14) 15/0 155.3±9.6 - more loss in height potential depending on the age at start and the tempo of puberty. Precise estimation of the height Werder et al (13) 4/0 150.9±5.0 - loss caused by precocious puberty is difficult to estimate because of the scarcity and imperfections of data in that Total: 107 F/38 M respect. SD: standard deviation

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J Clin Res Pediatr Endocrinol Bereket A. 2017;9(Suppl 2):33-48 Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty the patients according to age revealed that untreated girls these series were seen before the introduction of computed who were <5 years of age had a mean final/near final tomography it is quite possible that some who had a small height of 150.2±7.6 cm whereas those treated reached intracranial lesion, for example a small hypothalamic 164.3±7.7 (difference of treated vs. untreated 14.1 cm). hamartoma, were included in this untreated “seemingly” Untreated girls who were >5 years of age had a mean final idiopathic CPP groups. height of 153.4±8.4 cm whereas those treated reached Nevertheless, those studies with untreated control groups 157.6±6.6 (difference of treated vs. untreated 4.2 cm). (Table 2) (11,15), as well as later studies without control Kletter and Kelch (15) reviewed this matter in 1994. They groups (Table 3) (16,17), confirmed that age is an important found more modest height gains in treated girls compared determinant of treatment outcome and that earlier the to untreated girls (6.5 cm and 0.5 cm in <6 yrs and >6 age of onset of CPP, the worst is the height outcome if left yrs respectively). However, when they compared patients untreated. Thus, earlier the onset of treatment, height gain with their TH, the effect of GnRHa treatment on height was achieved by the GnRHa treatment is bigger. much less (only 2.7 cm in whom puberty started before However, unlike historical untreated cohorts mentioned 6 years of age and no height gain in those >6 yrs). The above, some studies afterwards reported final height of authors concluded that treatment with GnRH agonist analog untreated girls with CPP demonstrated less, or no decrease does not significantly alter the final adult height of girls with in height compared to their TH. Bar et al (18) reported final idiopathic CPP whose age at diagnosis is greater than 6 height data of 20 and near final of 7, girls with idipathic years. CPP. The appearance of breast tissue occurred at 5.6±1.6 The obvious difference between the conclusion of these years; the first evaluation was performed at 7.0±2.4 years. studies might arise from the heterogeneity of the subjects Six children were less than 6 years of age at the time of the in regard to TH, and the tempo of puberty in the subjects initial evaluation. Although the mean BA was 8.4±3 years, (both treated and untreated). As most untreated patients in one third of the girls had a BA at least 2 years (range, 2 to 3.7

Table 2. Adult heights (cm) of treated and untreated (historical) girls with central precocious puberty according to the age of onset

Untreated <5 yr Untreated >5 yr Treated >5 yr Treated <5 yr (n=11) (n=41) (n=75) (n=15) Paul et al (11) Final height 150.2±7.6 164.3±7.7 153.4±8.4 157.6±6.6 Height difference: 14.1 cm Height difference: 4.2 cm Untreated <6 yr Treated <6 yr Untreated >6 yr Treated >6 yr (n=10) (n=17) (n=54) (n=114) FH 153.9±3.8 160.4±1.8 157.0±0.9 157.5±0.6 Kletter and Height difference: 6.5 cm Height difference: 0.5 cm Kelch (15) TH 160.7±1.7 164.5±1.4 159.0±0.9 161.4±0.6 FH-TH -6.8 cm -4.1 cm -2 cm -3.9 cm

Net height gain from treatment: 2.7 cm Net height gain from treatment: -1.9 cm

FH: final height, TH: target height

Table 3. Effect of age of onset of treatment on height (studies with no control group)

CA at onset BA at onset <6 yr >6 yr

<6 yr >6 yr <6 yr >6 yr PAH TH FH PAH TH FH Partsch et al 5.0±0.4 7.8±0.2 8.4±0.5 10.4±0.3 152.1±2.2 162.4± 1.08 161.6±1.43 157.7±1.8 165.3±1.43 159.4±1.75 (16) Lazar et 6.4±1.2 7.5±0.6 11.3±0.4 11.3±0.3 154.6±6.6 159.3±5.0 162.8±5.0 157.8±5.2 153.7±6.7 157.9±5.1 al (17)

CA: chronological age, BA: bone age

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Bereket A. J Clin Res Pediatr Endocrinol Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty 2017;9(Suppl 2):33-48 years) greater than their chronologic age. The mean age of GnRH). Thus, at that time, these girls were not considered menarche was 10.5 years which was 4.9±2.4 years (range, candidates for long term pituitary-gonadal suppression 3 to 13 years) after thelarche. Despite that, adult height was with a GnRH agonist. Seventy percent of those patients normal in 90% of girls (mean, 161.4±7.7 cm). Although experienced cessation of their early pubertal development, parental heights were not available in this study, mean final whereas the remainder reported a slowly progressive course. height of the untreated girls with ICCP were only slightly Those with a slowly progressive course were significantly less than healthy average American women 163.8 cm. older than those with an unsustained course [mean age of In another study, untreated control group consisted of 10 thelarche, 6.1 vs. 3.4 yr; age of pubarche, 6.0 vs. 4.0 yr. They girls with idiopathic precocious puberty who, at their parents’ also had more advanced skeletal maturation (BA, 10.2 vs. request, were not treated. Mean age at the onset of pubertal 7.3 yr; at the time of evaluation. Both groups, however, had signs was 6.05±0.3 years. There was no significant difference similar outcomes with respect to linear growth and young between final height of treated (152.4±1.4 cm) and untreated adult reproductive function. On the average, the study (149.5±2.0 cm) girls. Final height was significantly lower patients reached their genetic targets for final height (mean than TH in both treated (with ciproteron) (155.1±0.9 cm; and final height, 165.5±2.2 cm; mean genetic TH, 164.0±1.1 untreated (156.4±1.3 patients, but the mean height of treated cm; p 5 NS). The average age of menarche was 11.0±0.4 yr. patients is nearer to TH than that of untreated ones (19). Léger et al (22) also followed 9 patients (mean age 6.5 years, In a similar study, Kauli et al (20) reported final height of range 4.8-7.7 years) with a slowly progressing variant of CPP 28 untreated girls with ICCP. Fourteen of them had a slow without treatment; final height (161.8±4.6 cm) was similar course of puberty and reached final height of 160.2±7.1 to the pre-treatment predicted height (163.1±-6.2 cm) and (their TH was 159.5±6.6 cm); the other half (14/28) had an was not significantly different from TH (161.0±5.9 cm). accelerated course of puberty with a final height well below Table 4 summarizes height outcome of girls with untreated TH (final height 150.8±4.3, TH 159.2±5.9 cm) and in most CPP (slowly progressive, milder, or older onset) patients in cases (14/28) below the height SD score (SDS) of both parents. different series. Final height-TH ranged between -6.8 cm to Obvious differences in the height outcome of untreated 1.6 cm. On average, final height was -4.4 cm shorter than patients in different studies (historical cohorts versus more TH in six studies (15,18,19,20,23,24) but similar to TH in recent cohorts) reflect the heterogeneity of the patients in the remaining seven studies (20,21,22,25,26,27,28). Thus, regard to pubertal hormonal activation. As in Kauli et al’s (20) it can be concluded that the different height outcome of study, it has been shown in several series that in a subgoup girls with untreated idiopathic CPP in various studies are of the girls presenting with what appears to be idiopathic due to the fact that natural course of precocious puberty CPP, will either have stabilization or very slow progression differs from one subject to another, i.e. some are more in their pubertal signs. Progression of hormonal activation progressive hence have unfavorable outcome whereas some is somewhat slower in these girls and the final heights are are slowly progressive hence favorable outcome in regards not compromised. The BA is typically not as advanced to final height. compared with children with true CPP, and serum lutenizing hormone (LH) concentrations are within the pre- or early- Identification of Girls with Progressive Central Precocious Puberty pubertal range, indicating that the hypothalamic-pituitary- There is not enough data about the ratio of progressive gonadal axis is not fully activated. GnRH stimulation test in vs. nonprogressive precocious puberty among girls who these children demonstrate a follicle-stimulating hormone develop breast development before 8 years of age. Kaplowitz (FSH) dominant response. These children are considered to (29) reported 9% of true precocious puberty in 104 children have slowly progressive form of CPP. referred for any signs of early puberty, whereas this ratio Palmert et al (21) reported 12-yr follow-up of 20 patients who was higher (47%) in another US study of 223 girls referred initially presented with unsustained or slowly progressive for precocious puberty between ages 7 and 8 (white girls) or puberty by the presence of one or more of the following 6 and 8 (black girls) (30). Mogensen et al (31) reported nearly findings: menses, pubic hair, accelerated growth velocity, 20% true precocious puberty, among 449 girls referred and/or BA greater than 2 SD above chronological age. None for early pubertal signs. All of these cohorts included all of the 20 patients had a pubertal response to exogenous variants of early pubertal development including premature GnRH; (by that time with an radioimmunoassay LH increase thelarche, premature adrenarche and early normal variants of less than 25 IU/L above baseline and a peak FSH greater (those >age 8 yrs). However, we have recently reviewed 236 than or equal to the peak LH in response to exogenous girls who presented with breast development between ages

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4-8 years (thus excluding premature adrenarche, thelarche As distinguishing progressive form of CPP from nonprogressive variant etc.). 59% of these girls were eventually diagnosed forms is important for therapeutic decision-making, the with true precocious puberty and given GnRHa treatment Consensus Conference Group has recommended that progressive (32). This was nearly 34% in Mogensen et al’s (31) series pubertal development be documented for 3-6 months before after exclusion of other variants. starting GnRHa treatment This observational period may not be necessary if the child is at or past Tanner stage 3 (breast), Although the mechanism of why puberty is nonprogressive particularly with advanced skeletal maturation (1). in certain girls is unknown, some clinical features have been proposed to help identifying those who will likely to progress In addition to above mentioned anthropometric and clinical rapidly, although specifity and sensitivity of these criteria criteria, we should be aware of certain risk groups in whom varies greatly (33,34,35,36,37,38,39,40) (Table 5). Along precocious puberty is likely to be progressive. These are, with clinical and anthropometric criteria, GnRH-stimulated family history for precocious puberty, being born small LH levels of 5 IU/L have been suggested to mark the beginning for gestational age (SGA), and adopted children. One has of puberty using one modern immunochemiluminometric to carefully follow these children when they develop breast assays (34,35). Stimulated LH limit of 5 IU/L to define CPP development early, as they likely to have progressive was found to have specificity of (77%), and sensitivity of precocious puberty. Familial forms of precocious puberty (95%) (36). In one study, randomly measured LH values tend to be more progressive than those of sporadic ones. of 0.3 IU per liter and above were reported to be 100% Comparison of 43 familial cases among the total cohort of specific for peak values above 5 IU per liter (37). However, in 156 (147 girls and 9 boys) cases of idiopathic CPP, it was young children (2-4 years) gonadotropin levels are normally found that the familial group had lower maternal age at high and therefore LH (basal or peak) should be carefully menarche than the sporadic group (mean, 11.47 +/- 1.96 vs. interpreted in this age group (38). In the consensus report 12.66 +/- 1.18 yr; p=0.0001) and more advanced puberty on the use of GnRHa treatment, mentioned values for at admission (Tanner stage 2, 56.5% vs. 78.1%; p=0.006). uterine length range from 3.4 to 4.0 cm (1). The cutoffs Segregation analysis suggested autosomal dominant for a pubertal ovarian volume range between 1 and 3 mL transmission with incomplete, sex-dependent penetrance (volume: length x width x height x 0.5233) (39). A uterine (41). Similarly reviewing case histories of familial CPP due volume greater than 2.0 mL has been reported to have 89% to MKRN mutations reveal early and progressive nature of sensitivity and specificity for precocious puberty (40). puberty in these girls (42).

Table 4. Final height of girls with untreated central precocious puberty (slowly progressive, milder, or older onset) patients in different series n CA BA Age of TH FH Difference menarche (FH-TH) cm Bar et al (18) 20 5.6 (7.0)# 8.4 10.5 163.8* 161.4 -2.4 Kauli et al (20) 14^ - - - 159.5±6.6 160.2±7.1 0.7 14 159.2± 5.9 150.8±4.3 -8.4 Antoniazzi et al (23) 10 7.2±0.9 9.6±2.2 - 156.4±1.3 149.6±6.3 -6.8 Cisternino et al (19) 10 6.1 - - 156.4 152.4 -4.0 Palmert et al (21)^ 16 5.5 7.9 11 164.0 165.5 1.5 Brauner et al (25)^ 15 7.9 9.4 10.4 161.0 162.0 1.0 Bertelloni et al (26)^ 9 6.5 161.0 161.8 0.8 Léger et al (22)^ 17 7.4 9.2 11.9 161.3 160.7 0.7 Allali et al (27) 52 8.0 9.1 - 161.4 163 1.6 Kletter and Kelch (15) 66 7.6±0.24 10.1±0.29 - 159.3±1.1 156.5±0.9 -2.8 Magiakou et al (28) 14 7.9 10.75 - 161.2 161.5 0.3 Balanli et al (24) 16 7.5±2.0 10.9±2.8 10.0 156.5±5.2 154.5±7.2 -2.0 (9.0±2.1)# #CA at the time of bone age determination is given in parenthesis *Parental heights were not available. The height given is average healthy American women ^Patients were slowly progressing variants and or who had height prognosis above 155 cm thus treatment was not given FH: final height, TH: target height, CA: chronological age, BA: bone age

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Table 5. Criteria for identifying girls who are likely to identification of rapidly progressing forms of CPP with have progressive precocious puberty compromised PAH, who are thought to benefit most Progression of breast staging in less than 3-6 months from the treatment in respect to height. Periodical BA Growth velocity >6 cm/year evaluation is also a part of monitoring treatment efficacy, as deceleration of BA maturation is expected as a result of Bone age advancement of more than 1.5-2 years treatment. However, BA assessment is affected by a great PAH below target height and decline in PAH during follow-up intra-observer variance, especially around BA of 8-10 years. Uterine volume >2.0 mL, long diameter >35 mm, presence of endometrial echo Nowadays, the majority of girls who are being treated with Ovarian volume >2-3 mL GnRHa are those between the ages of 6 and 8 years with their BA in the range of 8-10 years. Peak LH >5.0 mIU/L at GnRH test, peak LH/FSH ratio >0.66 Basal LH >0.3 mIU/L, detectable basal E2 Although there are several methods for evaluation of BA, the PAH: predicted adult height, LH: lutenizing hormone, GnRH: gonadotropin- most commonly used method by pediatric endocrinologists releasing hormon, FSH: follicle-stimulating hormone, E2: estradiol is the Greulich-Pyle (GP) method. The GP method is an SGA-born girls are another special group of children in regard atlas method in which BA is evaluated by comparing to puberty. Although being born SGA and having catch-up the radiograph of the patient with the nearest standard growth is clearly associated with premature pubarche and radiograph in the atlas. Its simplicity, speed and precision exagerated premature adrenarche, these children also have made this method the most commonly used standard of accelerated skeletal maturation and tend to have early (not reference for skeletal maturation worldwide. However, the GP necessarily precocious) but fast puberty resulting in short method was developed using radiographs of upper-middle stature (43). class Caucasian children in Cleveland, Ohio, United States, and the radiographs were obtained between 1931 and 1942 Finally the risk of developing precocious puberty was (48). One has to take the potential insufficiencies of this significantly increased in adopted girls and in these girls evaluation into account when evaluating children of today pubertal process usually continue progressively resulting in and children from various populations of different ethnic early menarche, rapid progression of BA and compromised background. Furthermore, these BA methods are based on adult height (44,45,46). manual BA determination, the assessment is necessarily Bone Age-Based Treatment Decision subjective and thus, have certain degree of inter-observer and intraobserver difference. In a study, three second year Some authors suggested predicted height-based decisions radiology registrars performed both Tanner-Whitehouse 2 regarding GnRHa treatment of girls with CPP. Adan et al (47) (TW2) and GP assessments on each of the BA films. The used the criteria for treatment as; a PAH <155 cm and/or a average spread (the difference between the highest and the LH/FSH peaks ratio of >0.6. Treatment group had greater lowest of the three results) of BA readings was 0.74 years breast development and BA advances (2.0±0.2 years) and higher plasma estradiol concentrations than the group left for TW2 method, and 0.96 years for the GP method (49). untreated. Treated group achieved adult height of 159.5 cm, 3 Bull et al (50) investigated 362 consecutive “BA” radiographs cm taller than predicted height (156 cm), whereas untreated of the left hand and distal radius performed in a large patients reached an adult height of 162,7 cm, 1.4 cm shorter provincial teaching hospital. Data were analysed using the than predicted height of 164.1 cm. Similarly, Léger et al (22) “method comparison” statistical technique. Ten per cent of based treatment decision on BA and LH peak. They did not the radiographs were re-analysed to assess intra-observer give treatment in those BA advancement is less than 2 years variation. The 95% confidence interval for the difference and peak LH <6 mIU/mL at the initial evaluation. However between the two methods was 2.28 to -1.52 years. Intra- they decided to begin treatment in girls whose PAH declined observer variation was greater for the GP method than during treatment, and were able to achieve a final height for the TW2 method (95% confidence limit, -2.46 to 2.18 better than PAH and surpassing the TH (22). versus -1.41 to 1.43). Thus, BA advancement, and as closely related to it, PAH There is now, a recently developed an automated system have major determinants in decision making in regard to of BA measurement using computerized image analysis GnRHa treatment. based on both GP and TW2. The use of this automated system was validated in healthy children and in children Handicaps in Bone Age Assessment with various endocrine disorders. It has been shown that BA assessment is one of the key parameters in the automated systems have a better precision and accuracy management of patient with CPP as it allows the compared to radiologists’ reading (51). However, still, there

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J Clin Res Pediatr Endocrinol Bereket A. 2017;9(Suppl 2):33-48 Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty are differences in the interpretation of BA, which are big subjects, final height-PAH-average was significantly higher enough to influence clinical decision-making. In a recent than final height-PAH-accelerated (28). Thus it appears that study using an automated BA reading the BA difference using advanced column for height prediction gives a better between the most advanced and most retarded individual estimation of final height to be reached. bones exceeded 2.0 years. The BA mean differences Height Outcome in Studies with Gonadotropin-Releasing Hormone between the most advanced and most retarded individual Analogues Treatment of Progressive Central Precocious Puberty bones were 2.58 and 2.25 years for the automated method (Table 6) and GP atlas methods, respectively (52). GnRHa treatment has been a standart of care in girls with Predicting Height in Girls with ICCP progressive CPP for nearly four decades now. GnRHa Height prognosis of the child i.e. “PAH” is of major treatment decreases gonadotrophins, estradiol and the importance in clinical decision making in girls with CPP. growth velocity and decelerates the skeletal advancement. Several alghoritms based on current height and BA to Linear growth gradually decrease to a rate which is normal estimate adult height are available but none of them have for a prepubertal child (~5 cm/year) during the first or been fully validated. Predicting adult height with accuracy second year of treatment, sometimes further deceleration is hampered by the problems in the accuracy of BA happens in the following years (57,58). Bone maturation determination as well as problems of methodology in height also slows down beginning from the 6 months of treatment, prediction methods themselves. Bayley-Pinneau method averaging 0.5+0.2 BA year/year (59). Similar values have is the most commonly used method for estimating adult been recorded in other reports (60,61,62). This decrease in height in children have been validated for height prediction bone maturation is progressive and does not occur before in normal children (53). Bayley-Pinneau method estimates six months of treatment (63). As a result of the progressive adult height as a percentage of current height, based on BA normalization of BA, and continued linear growth, treatment and its relationship to chronological age. It has a wide 95% provides increase in PAH despite the decreased growth confidence interval of about 6 cm below to 6 cm above velocity, although it is difficult to predict precisely the effect the predicted value, a range which is large enough to mask of GnRHa treatment on height gain of these patients, due or blunt small losses or gains in height that occurs due to to handicaps discussed above. Reviewing the available 28 precocious puberty or its treatment. The prediction equation studies on GnRHa treatment of CPP (7,15,16,17,20,22,23, differs for children whose BA is similar, retarded or advanced 28,47,54,55,56,59,60,61,62,63,64,65,66,67,68,69,70,71, in comparison to chronological age (retarded, average and 72,73,74) (Table 6) and our own experience (75) demonstrate advanced columns in the Bayley-Pinneau height prediction that the mean age at onset of pubertal development table). Since children with precocious puberty has advanced ranged 3-8 years, usually younger and more severe cases BA, “advanced column” is used to predict height in girls in older studies, older and milder cases in recent studies. with CPP. However, it has been shown in several studies that Nevertheless, in most series, the age of treatment initiation in untreated girls with precocious puberty, Bayley-Pinneau was around 7 years, (5.4-8.7 years) with again recent method tend to overrestimate final height by 3.7-5.9 cm in studies tend to be a year later around 7.5-8 years. Mean BA different studies (18,20,23). was around 10 years (8.9-12.5 years) at the beginning of treatment and most series report mean treatment durations To overcome this systematic error it has been proposed around 3.0 years. Mean chronological age at the end of that “average column” should be used instead of advanced treatment was around 11.1 (9.4-12.7) years of age with a column (20). This approach might correct the systematic mean BA of 12.4 (11.9-13.6) years. At the achievement of error but is unlikely to increase the precision. Studies final height all studies except two (69,73) reported final reporting PAH in GnRHa treated girls by both advanced height better than PAH (ranging 2.0-10.5 cm). On average, and average column demonstrates that final height is closer final height was ~4.0 cm higher than height predicted at to PAH calculated with the advanced column than that of the time of initiation of GnRHa treatment. the average column (20,26,28,54,55,56). A recent study, when PAH was calculated using the average standards of Comparison of final height of treated patients with their GP, the median delta final height-PAH was 6.96 and 3.34 TH eliminates the handicaps of predicting adult heigt thus cm in GnRHa-treated and nontreated subjects, respectively, allows perhaps a better estimation of the effect of GnRHa whereas when the accelerated standards were used, the treatment on height. When compared to TH, in most studies differences were less (1.7 and 1.2 cm, p:NS). Final height-PAH- (nineteen studies), final height was 0.4 to 5.2 cm shorter average and final height-PAH-accelerated were comparable than TH (15,16,20,28,47,54,60,61,62,63,64,65,66,67, among the nontreated subjects but among GnRHa-treated 68,69,70,71,74) but 0.4-4.2 cm taller in the remaining nine

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Bereket A. J Clin Res Pediatr Endocrinol Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty 2017;9(Suppl 2):33-48 studies (17,22,23,55,56,59,72,73,75). On average, final Height SDS at the onset (7,17,33,54,56,62,67) and at height was ~1 cm shorter than TH. termination of treatment (7,17,54,56,59,67,73), as well as higher TH (7,17,65,67,72) have also been positively However, one should also be aware that, even with associated with adult height, supporting that influence of comparison with TH is not free of biases. Calculation of genetic factors on height is dominant among other factors. midparental TH assumes equal contribution of each parents heights to the offsprings height, thus neglects the effect of Naturally, BA at the end of treatment, is associated with dominant genes from one parent. Although TH correlates final height, as it determines posttreatment residual growth well with the offsprings height on a population level, it may potential (7,59,71). Although data are scarce in this respect, not correlate well with individual subject. This is especially stopping treatment at a BA of 12-12.5 years (7) or even true for children whose parents are discordant for height. <11.5 years (26) seemed to be associated with best height Finally, in a limited number of studies when adult height outcome, while continuing treatment after a BA ≥13 years of treated patients were compared with untreated study negatively impacted on statural growth (7). Three factors subjects, mean difference ranged from -3.0 to +11 cm) explained 66% of adult height variance: BA advance before (20,23,28,75). Again, height gain was highly variable among treatment, height at the end of treatment and height gain studies depending on sample characteristics including the after interruption of treatment (33). progression of pubertal development. It should be bear in In summary, among the factors associated with the height mind, that the treatment effect also might be overestimated outcome, height SDS and TH reflecting genetic potential, are since most of the studies describe observed cases and always associated with positive outcome, BA advance and none of them comprise an intention-to-treat analysis. It is delay in treatment are negative factors. This highlights the possible that the patients who interrupt the treatment early importance of rapid recognition, evaluation and treatment and are not followed to adult height might have a poorer of patients with true precocious puberty. However, one has height outcome than those who continued to the end. to balance this with careful follow-up in some girls to not Finally, predicted height values obtained during treatment treat those with slow progression unnecessarily. are often overestimated in comparison to the adult height eventually achieved by the patient (7,33). In terms of effcicacy of treatment, various GnRHa appeared similar as regards to height outcome (26,62,71,74), except Factors Influencing Height Outcome for a study (69) demonstrating slightly better adult height As mentioned earlier, and seen in the Table 2 data of historical SDS in patients treated with leuprolide depot compared to untreated girls with CPP demonstrated that earlier the age triptorelin depot. of onset of puberty, worse the height prognosis. In line with Optimal Age of Discontinuation of Gonadotropin-Releasing that, evaluation of treatment series also show that younger Hormone Agonist Treatment in Girls with Central Precocious age of onset of CPP and hence, younger age of initiation of Puberty treatment (which also means longer duration of treatment) Data is also missing on this respect. In the literature, (Table is associated with bigger height gain, although a few 6) the mean age at interruption of treatment ranges 9.4 to studies refute that showing no correlation between height 12.7 averaging around age 11 year and BA ranging from 11.9 gain and age at puberty onset or initiation of treatment to 13.6 averaging 12.5 years. BA at the end of treatment (20,59). Greater effectivenesss of GnRHa treatment on correlates negatively with height gain after treatment. Carel younger girls who are destined to poorer height prognosis et al (33) using multivariate analysis estimated that an 11 without treatment, proves further that GnRH treatment is year old girl, growing 4 cm and gaining 0.5 BA year per an effective strategy to preserve diminished height potential year, could loose 2.6 cm of adult height if treatment was in these children. discontinued 1 year later. Opposite results were found by BA advance at start of treatment and at the end, is Klein et al (62) who found a positive correlation between age negatively associated with height outcome (7,47,54,65,73). at discontinuation of treatment and adult height (r=0.25, BA/statural age ratio at the onset of treatment and adult p=0.03), suggesting that prolonging the treatment could height is negatively associated with outcome suggesting increase height. Obviously, this discrepancy only can be that treatment is not capable of restoring a full adult height solved with a formal controlled trial (i.e. randomizing potential if started after a certain critical advancement girls between “early” and “late” age at discontinuation of BA. Kauli et al (20) demonstrated that therapy is more of treatment). However, such a trial would be difficult beneficial if started before BA exceeds 12 years. to perform since patients and the parents prefer to stop

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J Clin Res Pediatr Endocrinol Bereket A. 2017;9(Suppl 2):33-48 Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty FH-PH 2.0 3.4 3.0 7.3 4.6 3.2 4.7 5.7 2.9 4.9 5.7 9.6 1.7 10.5 14.5 6.8 6.4 FH-TH -3.9 -4.1 -3.9 -7.1 1.9 -3.8 -5.2 1.0 -2.0 -2.9 0.4 -3.4 -0.8 -5.9 -3.9 -2.4 NA -4.9 FH 157.9±0.6 160.4±1.8 157.5±0.6 161.6±7.0 159.6±6.3 Unt 155.5±7.5 158.1±5.2 158.5±5.3 161.1±5.9 160.6±8.0 158.4±5.8 160.2±6.7 160.6±8.0 161.6±1.43 159.4±1.75 159.8±7.6 162.1±7.0 157.9±7.6 149.8±6.9 PH 155.9 158.2±7.4 AD: 156.6±6.7 152.3±6.0 AV: 153.5±7.2 155.2±4.7 156.4±6.3 154.9±9.6 155.5±7.0 155.3±5.6 154.9±9.6 152.1±2.22 157.7±1.80 149.3±9.6 NA 151.1±8.6 143.4±8.3 TH 161.8±0.7 164.5±1.4 161.4±0.6 168.7±6.4 157.7±5.7 Unt 159.3±6.1 163.3±6.2 160.1±4.4 163.6±6.2 161.5±6.9 159.8±4.6 164 162.4±1.08 165.3±1.43 163.7±5.6 164.5±5.9 NA 154.7±6.1 BA at ET BA 12.5 12.5±0.7 12.6±0.8 12.2±0.8 12.4±0.8 11.8±0.5 12.6±0.2 12.8±1.1 12.0±0.5 CA at ET CA 11.1 11.5±0.5 11.3±0.7 11.2±1.0 11.0±1.1 11.0±1.0 10.8±0.6 11.1±1.1 11.1±1.0 10.2±2.5 BA at onset BA 10.9±0.1 9.4±0.6 11.2±0.1 10.8 12.5±0.7 Unt 10.2±1.3 9.6±1.6 10.3±0.9 10.1±1.5 9.3±2.5 9.8±1.4 11.1±0.4 9.3±0.3 10.0±2.7 10.1±1.6 CA at onset CA 7.6±0.13 4.7±0.3 <6 years 8.1±0.1 >6 years 7.7 8.3±1.5 Unt 7.8±1.0 6.2±1.8 7.3±1.1 7.5±1.3 6.2±2.0 7.0±1.3 8.7±0.4 6.2±0.3 <6 years 5.0±0.35 >6 years 7.8+0.18 5.4±1.9 6.5±1.8 n 131 31 48 28 14 22 58 50 71 9 52 80 <6 yr >6 yr 30 Table 6. Height outcome in studies with gonadotrophin‐releasing hormone agonists treatment of progressive idiopathic central precocious puberty precocious idiopathic central of progressive agonists treatment hormone in studies with gonadotrophin‐releasing 6. Height outcome Table (ref Author no), year Kletter and (15), Keltch 1994 Oostdijk et al Oostdijk (60), 1996 Kauli et al (20), Kauli 1997 (AD-AV) Bertelloni et al (26), 1998 Galluzzi et al 1998 (61), Carel et al (59), Carel 1999 Heger et al (64), 1999 Arrigo et al (7), 1999 Léger et al Léger (22), 2000 Partsch et al Partsch (16), 2000 Klein et al (62), 2001 Bajpai et al (65), 2002 (AV)

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Bereket A. J Clin Res Pediatr Endocrinol Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty 2017;9(Suppl 2):33-48 3.5 0 3.4 9.6 8.2 0.1 5.6 9.8 3.7 8.0 4.5 0.4 7.0 5.1 3.3 7.8 3.0 -1.7 -0.4 -0.7 3.1 4.2 2.2 -2.2 -1.0 -0.25 -1.3 2.8 160.6±5.7 Unt 149.6±6.3 159.5±5.3 154.5±5.7 156.3±4.3 162.8±5.0 157.9±5.1 159.8±5.3 155.3±6.9 163.0±7.6 Ht SDS L group: -1.5±0.7 T group: -0.9±0.5 158.5 Unt 161.5 162.5 158.6±5.2 156.0±7.8 AD: 154.5±7.1 151.1±7.3 AV: 146.7±4.8 154.6±6.6 153.7±6.7 AD: 154.2±5.2 150.0±5.1 AV: AD: 151.6±9.7 147.3±9.0 AV: 158.5±6.8 Ht SDS L group: -1.0±0.6 T group: -0.6±0.6 AD: 158.16 AV:151.53 Unt AD: 160.2 154.3 AV: 157.4 AD: 155.3±6.7 150.8±5.5 AV: 157.6±5.9 Unt 156.4±1.3 161.2±4.6 154.9±4.6 157.0±4.5 159.3±5.0 157.8±5.2 157.6±4.7 157.5±4.5 164.0±5.7 Ht SDS L group: -0.2±0.3 0.1±0.2 T group: 158.75 cm Unt 161.2 163.8 155.8±4.1 12.1±0.8 12.2±0.7 12.0±0.8 13.6±0.6 12.1±0.5 12.4±0.5 13.1±0.5 12.4±0.9 12.4±0.9 L group: L group: 12.3±0.9 T group: 12.0±0.7 13.3±0.5 11.0±0.9 11.0±0.9 10.8±0.7 11.6±1.4 12.7±0.9 11.3±0.4 11.3±0.3 12.6±1.0 10.7±0.8 10.9±1.2 Lgroup: Lgroup: 10.6±1.1 T group: 9.4±1.2 11.8±1.0 9.8±1.0 Unt 9.6±2.2 10.3±1.3 10.2±1.5 11.5±1.3 8.9 10 11.1±1.6 10.6±2.2 10.1±2.2 L group: L group: 10.5±1.3 T group: 10.2±1.3 10.0 Unt 10.75 10.2±2.13 11.1±1.7 7.6±0.5 Unt 7.2±0.9 7.9±1.3 7.7±2.2 8.0±1.5 <6 years 6.4±1.2 <6 years 7.5±0.6 >6 years 8.4±1.5 7.3±2.0 7.2±2.0 L group: 7.6±0.7 L group: 7.4±0.8 T group: 7.92 Unt 7.95 7.3±1.9 8.5±1.0 15 10 43 63 11 60 87 45 26 47 33 14 29 47 Table 6. Continue Table et Antoniazzi al (23), 2000 Adan et al (47), Adan 2002 Tanaka et al Tanaka (54), 2005 (AD-AV) Tung et al (66), Tung 2007 Lazar et al Lazar (17), 2007 Pasquino et Pasquino al (55), 2008 (AD-AV) Brito et al (67), Brito 2008 (AD-AV) Nabhan et al (68), 2009 (P) Massart et al (69), 2009 Magiakou et Magiakou al (28), 2010 (AD-AV) Lee et al (70), et al (70), Lee 2 011 Poomthavorn Poomthavorn et al (56), 2011 (AD-AV)

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J Clin Res Pediatr Endocrinol Bereket A. 2017;9(Suppl 2):33-48 Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty

treatment when the girl has reached an age that peers of the patients have already started 2.7 4.3 3.8 6.0 -1.8 2.1 7.2 2.7 7.9 puberty which is usually around age 11 year. Could the BA be a useful parameter to decide -0.9 1.0 0.5 1.6 Unt: -1.9 1.5 -2.6 -0.3 when to stop treatment? Although the optimal age for treatment interruption is not clearly defined by international guidelines, it has been proposed that the best heights are achieved when treatment is discontinued at around 12-12.5 years in girls (7,76) However, in girls 157.9±1.7 161±2.0 160.4±4.2 160.6 Unt: 158.1 159.8±1.2 157.1±4.9 158.1±6.6 around the age of 11 years with previous advance in BA and a long-standing treatment with GnRH agonists, BA often is approximately 12 years with little variation and is therefore of little help to orient decisions. Furthermore, 155.2±1.9 156.8±2.6 156.6±4.0 154.6 161.6±0.9 AD: 155.0±3.5 149.9±3.5 AV: AD: 155.4±5.9 150.2±5.3 AV: reduction of growth velocity, commonly observed around this age, due to the increasing dependence of growth on sex steroids (77) with time, necessitates stopping treatment. Treatment of Gonadotropin-Releasing Hormone Analogues Combined with Growth Hormone 160.8±0.8 160.1±1.0 159.9±3.5 159.0 Unt: 160.0 158.3±0.9 159.7±3.8 158.4±5.0 Treatment (Table 7) The growth velocity in some CPP patients decreases below the normal for prepubertal children during GnRHa therapy. Subnormal

11.9±0.5 growth velocity during GnRHa therapy may be associated with a decrease in GH and insulin-like growth factor 1 secretion due to suppression of gonadal steroids (77). Therefore, some studies 10.6 11.7 10.6±0.8 investigated in girls with precocious puberty and poor predicted height, whether adding GH to GnRHa treatment is associated with a better height outcome (78,79,80,81,82,83,84). Data is even more limited and biased about 10.0±0.3 10.4±0.4 10.2±1.6 9.66±1.4 Unt: 10.0±1.5 9.2±0.3 10.6±0.9 10.6±0.9 10.4±0.9 this type of approach. In short, it can be stated that at present, studies are insufficient to make definite conclusions about the height outcomes of GnRHa plus GH treatment. Lanes and Gunczler (78) treated 15 short children (boys and girls) entering into normally timed puberty T group: 8.4±0.3 T group: HIS impt group: 8.7±0.3 8.7±0.8 7.76±1.2 Unt: 8.08±0.8 8.1±0.2 Three monthly: Three 7.9±0.6 Monthly: 8.0±0.6 with both GnRHa and GH and compared them with an identical number of untreated children. 23 11 59 48 52 17 13 12 In their study, no relevant height gain was observed after 2.5 years of treatment. Pasquino et al (79) and Pucarelli et al (80) on the other hand, showed differences of about 6-8 cm of height gain on girls with CPP Table 6. Continue Table Gillis et al (71), (AV) 2013 depot, Unt: T: triptorelin initiation, FH: final height, height at treatment height, PH: predicted target TH: midparental end of treatment, ET: bone age, BA: age, chronological CA: n: number of subjects, AD: PH calculated according tables, average to PH calculated according AV: score, deviation implant, Ht SDS: height standard HIS impt: histrelin L: leuprolide, NA: not available, group, control untreated J adult stature. for predicting table E, Richman R. A condensed by “Post to the model proposed used, P: PH calculated according were tables bone age; if not specified, advanced advanced for tables to 1981;98:440-442” Pediatr IN: intranasal age in years, in centimeters, Height is expressed when available. deviation as mean ± standard presented are All values Jung et al (72), 2014 Atay et al (75), Atay 2014 Liang et al (73), 2015 Bertelloni et al (74), 2015 (AD-AV) treated with GnRHa plus GH, compared to

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Bereket A. J Clin Res Pediatr Endocrinol Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty 2017;9(Suppl 2):33-48 -0.6 3.8 1.6 5.0 0.5 1.2 FH- TH 2.3±2.9 AD 8.2±4.8 AV 1.6±1.2 7.9±1.1 3.8 4.7 FH-PAH -1.0±3.6 5.2±3.7 3.3±3.5 8.2±3.4 155.8±6.9 158.9±5.4 156.6±5.7 161.2±4.8 157.1±2.5 160.6±1.3 160.4±4.2 159.3±5.33 FH 155.0±5.6 155.0±5.5 NA 153.9±3.8 AD 149.6±4.0 AV 156.2±4.5 AD 150±4.5 AV 155.5±2.0 152.7±1.7 156.6±4.0 154.6±2.55 PAH 156.0±5.7 AD 149.8±5.6 AV AD 151.7±5.0 146.8±4.8 AV 157.2 ±6.0 157.4±4.8 155.5±2.1 155.6±2.0 159.9±3.5 158.1±3.31 TH NA NA NA 10.7±1.2 12.1±0.8 10.4±0.3 10.6±0.4& 12.0±0.2# 10.2±1.6 10.5±0.86 BA at onset BA 10.7±1.1 11.6±0.8 8.2±0.83 8.4±0.78 7.9±0.8 9.9±1.3 7.6±0.2 7.9±0.6 10.0±0.5# 8.7±0.8 8.8±0.59 CA at onset CA 9.6±0.9 9.6±0.9 22 24 18 17 10 10 59 23 Subjects (n) 12 14 2-4 years 2-4 years 4.9 5.1 (total) 2 years Duration Duration of therapy (year) 3 years /day, i.m. /day, 2 Triptorelin 3.75 Triptorelin i.m. mg/28 days, + GH 4 Triptorelin IU/m Buserelin 300 mg/6 Buserelin IN 2-4 times daily, years + GH Buserelin 0.033 mg/kg/week Trip 100 mg/kg/21 mg/kg/21 100 Trip i.m. days, + GH Triptorelin 0.3 mg/kg/week Triptorelin, 100 mg/ 100 Triptorelin, days kg/q 21 + GH Triptorelin 0.3 mg/kg/week of (after 2-3 years GnRH therapy) GnRHa* 75-150 µg/ kg q 28 days GnRHA + GH 0.25 mg/kg per week Treatment GnRHa GnRHa + GH GnRHa GnRHa + GH GnRHa GnRHa + GH GnRHa GnRHa + GH GnRH GnRHa + GH Comparison Mul et al (81), Mul et al (81), 2005 Tuvemo et al Tuvemo (82), 2004 Pucarelli et al Pucarelli (80), 2003 Pasquino et Pasquino al (79), 1999 Jung et al (83), 2014 Table 7. Studies investigating gonadotrophin‐releasing hormone analog plus growth hormone treatment on final height of girls with central on final height of girls with central treatment hormone analog plus growth hormone gonadotrophin‐releasing 7. Studies investigating Table puberty precocious (ref), Author year hormone therapy #at the beginning of growth hormone agonists therapy, hormone analog not specified, and at the beginning of gonadotrophin‐releasing *Gonadotrophin‐releasing GnRH: tables, average to initiation calculated according height at treatment predicted AV: bone age, advanced for tables to initiation calculated according height at treatment AD: predicted height, FH: final target TH: midparental bone age, BA: age, chronological CA: hormone, GH: growth hormone agonists, GnRHa: gonadotrophin‐releasing hormone, gonadotrophin‐releasing IN: intranasal NA: not available, adult height, i.m.: intramuscular, predicted PAH:

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J Clin Res Pediatr Endocrinol Bereket A. 2017;9(Suppl 2):33-48 Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty

GnRHa alone. In their first report, the gain in centimeters, of the before mentioned methodological handicaps of (calculated between pretreatment PAH (152.7±1.7 cm) accurately predicting adult height. Furthermore, the number and final height (160.6±1.3 cm), was 7.9±1.1 in patients of treated patients are much less, and most likely involves treated with GH plus GnRHa, whereas in patients treated selection biase as those who have poor height potential or with GnRHa alone, the gain between pretreatment PAH attenuated growth velocity might tend to choose or given the (155.5±1.7) and final height (157.1±2.5 cm) was just combined GnRHa GH treatment. Finally, since GH treatment 1.6 cm ± 1.2. The difference between the gain obtained requires the consideration of cost, economic status may in the groups is significant, in favor of combination group be another affecting factor to select the patients treated (p<0.001) (79). However, the same group reported four with GnRHa plus GH. Cost-effectiveness of combined GH years later a larger number of patients with a longer follow- treatment in patients with CPP has also to be elucidated. up period that, adult height versus pre-treatment PAH was Ethics 6 cm greater in combination treatment than that of GnRHa alone but concluded that true efficacy of the addition Peer-review: Internally peer-reviewed. of GH to GnRHa therapy is still questionable (80). They Financial Disclosure: The author declared that this study recommended caution regarding such an invasive and received no financial support. expensive treatment, outside a research setting. It should also be taken into account that, in the above studies, References the treatment period was not standardized, and the authors 1. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR; ESPE-LWPES treated a selected group of patients, i.e. those whose height GnRH Analogs Consensus Conference Group, Antoniazzi F, Berenbaum velocity decreased to value

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11 . Paul D, Conte FA, Grumbach MM, Kaplan SL. Long-term effect of 28. Magiakou MA, Manousaki D, Papadaki M, Hadjidakis D, Levidou G, gonadotropin-releasing hormone agonist therapy on final and near-final Vakaki M, Papaefstathiou A, Lalioti N, Kanaka-Gantenbein C, Piaditis height in 26 children with true precocious puberty treated at a median G, Chrousos GP, Dacou-Voutetakis C. The efficacy and safety of age of less than 5 years. J Clin Endocrinol Metab 1995;80:546-551. gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J Clin 12. Bovier-Lapierre M, Sempe M, David M. Aspects eatiologiques, Endocrinol Metab 2010;95:109-117. Epub 2009 Nov 6 cliniques et biologiques des puberteas preacoces d`origine centrale. Peadiatrie 1972;6:587-609. 29. Kaplowitz P. Clinical characteristics of 104 children referred for evaluation of precocious puberty. J Clin Endocrinol Metab 13. Werder EA, Mürset G, Zachmann M, Brook CG, Prader A. Treatment of 2004;89:3644-3650. precocious puberty with cyproterone acetate. Pediatr Res 1974;8:248- 256. 30. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age 8 benign? Pediatrics 2003;111:47-51. 14. Lee PA. Medroxyprogesterone therapy for sexual precocity in girls. Am J Dis Child 1981;135:443-445. 31. Mogensen SS, Aksglaede L, Mouritsen A, Sørensen K, Main KM, Gideon P, Juul A. Diagnostic work-up of 449 consecutive girls who 15. Kletter GB, Kelch RP. Clinical review 60: Effects of gonadotropin- were referred to be evaluated for precocious puberty. J Clin Endocrinol releasing hormone analog therapy on adult stature in precocious Metab 2011;96:1393-1401. Epub 2011 Feb 23 puberty. J Clin Endocrinol Metab 1994;79:331-334. 32. Acar Ü. Clinical and laboratory characteristics of girls who admitted for 16. Partsch CJ, Heger S, Sippell WG. Treatment of central precocious precocious puberty. Specialisation thesis. In: Bereket A (ed). 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Assessment of basal and gonadotropin-releasing hormone- stimulated gonadotropins by immunochemiluminometric and 19. Cisternino M, Arrigo T, Pasquino AM, Tinelli C, Antoniazzi F, Beduschi immunofluorometric assays in normal children. J Clin Endocrinol L, Bindi G, Borrelli P, De Sanctis V, Farello G, Galluzzi F, Gargantini L, Lo Metab 2007;92:1424-1429. Epub 2007 Feb 6 Presti D, Sposito M, Tatò L. Etiology and age incidence of precocious puberty in girls: a multicentric study. J Pediatr Endocrinol Metab 36. Giabicani E, Allali S, Durand A, Sommet J, Couto-Silva AC, Brauner R. 2000;13:695-701. Presentation of 493 consecutive girls with idiopathic central precocious puberty: a single-center study. PLoS One 2013;8:e70931. 20. Kauli R, Galatzer A, Kornreich L, Lazar L, Pertzelan A, Laron Z. Final height of girls with central precocious puberty, untreated versus treated 37. Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler GB Jr. with cyproterone acetate or GnRH analogue. A comparative study with Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to re-evaluation of predictions by the Bayley-Pinneau method. Horm Res luteinizing hormone-releasing hormone. J Clin Endocrinol Metab 1997;47:54-61. 1988;67:474-479. 21. Palmert MR, Malin HV, Boepple PA. Unsustained or slowly progressive 38. Bizzarri C, Spadoni GL, Bottaro G, Montanari G, Giannone G, Cappa M, puberty in young girls: initial presentation and long-term follow-up of Cianfarani S. The response to gonadotropin releasing hormone (GnRH) 20 untreated patients. J Clin Endocrinol Metab 1999;84:415-423. stimulation test does not predict the progression to true precocious 22. Léger J, Reynaud R, Czernichow P. Do all girls with apparent idiopathic puberty in girls with onset of premature thelarche in the first three precocious puberty require gonadotropin-releasing hormone agonist years of life. J Clin Endocrinol Metab 2014;99:433-439. Epub 2013 Dec treatment? J Pediatr 2000;137:819-825. 2 23. Antoniazzi F, Arrigo T, Cisternino M, Galluzzi F, Bertelloni S, Pasquino 39. Haber HP, Wollmann HA, Ranke MB. Pelvic ultrasonography: early AM, Borrelli P, Osio D, Mengarda F, De Luca F, Tatò L. End results in differentiation between isolated premature thelarche and central central precocious puberty with GnRH analog treatment: the data precocious puberty. Eur J Pediatr 1995;154:182186. of the Italian Study Group for Physiopathology of Puberty. J Pediatr 40. de Vries L, Horev G, Schwartz M, Phillip M. Ultrasonographic and Endocrinol Metab 2000;13:773-780. clinical parameters for early differentiation between precocious 24. Balanli E, Guran T, Turan S, Atay Z, Bereket A. Final height in girls with puberty and premature thelarche. Eur J Endocrinol 2006;154:891-898. idiopathic precocious puberty treated with leuprolide: dose-titration 41. de Vries L, Kauschansky A, Shohat M, Phillip M. Familial central approach. Horm Res 2009;72(Suppl 3):123. precocious puberty suggests autosomal dominant inheritance. J Clin 25. Brauner R, Adan L, Malandry F, Zantleifer D. Adult height in girls Endocrinol Metab 2004;89:1794-1800. with idiopathic true precocious puberty. J Clin Endocrinol Metab 42. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, 1994;79:415-420. Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui 26. Bertelloni S, Baroncelli GI, Sorrentino MC, Perri G, Saggese G. Effect CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, of central precocious puberty and gonadotropin-releasing hormone Hirschhorn JN, Latronico AC, Kaiser UB. Central precocious puberty analogue treatment on peak bone mass and final height in females. caused by mutations in the imprinted gene MKRN3. N Engl J Med Eur J Pediatr 1998;157:363-367. 2013;368:2467-2475. Epub 2013 Jun 5 27. 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Tanaka T, Niimi H, Matsuo N, Fujieda K, Tachibana K, Ohyama K, gonadotropin-releasing hormone analogs. J Clin Endocrinol Metab Satoh M & Kugu K. Results of long-term follow-up after treatment 2008;93:2662-2669. Epub 2008 May 6 of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. The TAP- 68. Nabhan ZM, Feezle LK, Kunselman AR, Johnson NB, Lee PA. Normal 144-SR Japanese Study Group on Central Precocious Puberty. J Clin adult height among girls treated for central precocious puberty with Endocrinol Metab 2005;90:1371-1376. Epub 2004 Dec 14 gonadotropin-releasing hormone analog therapy. J Pediatr Endocrinol Metab 2009;22:309-316. 55. Pasquino AM, Pucarelli I, Accardo F, Demiraj V, Segni M, Di Nardo R. Long-term observation of 87 girls with idiopathic central precocious 69. Massart F, Federico G, Harrell JC, Saggese G. Growth outcome during puberty treated with gonadotropin-releasing hormone analogs: GnRH agonist treatments for slowly progressive central precocious impact on adult height, body mass index, bone mineral content, and puberty. Neuroendocrinology 2009;90:307-314. Epub 2009 Jul 30 reproductive function. J Clin Endocrinol Metab 2008;93:190-195. Epub 70. Lee PA, Neely EK, Fuqua J, Yang D, Larsen LM, Mattia-Goldberg C, 2007 Oct 16 Chwalisz K. Efficacy of Leuprolide Acetate 1-Month Depot for Central 56. Poomthavorn P, Suphasit R, Mahachoklertwattana P. Adult height, Precocious Puberty (CPP): Growth Outcomes During a Prospective, body mass index and time of menarche of girls with idiopathic central Longitudinal Study. Int J Pediatr Endocrinol 2011;2011:7. Epub 2011 Jul precocious puberty after gonadotropin-releasing hormone analogue 12 treatment. Gynecol Endocrinol 2011;27:524-528. Epub 2011 Apr 18 71. Gillis D, Karavani G, Hirsch HJ, Strich D. Time to menarche and final 57. Mansfield MJ, Rudlin CR, Crigler JF Jr, Karol KA, Crawford JD, Boepple height after histrelin implant treatment for central precocious puberty. PA, Crowley WF Jr. Changes in growth and serum growth hormone J Pediatr 2013;163:532-536. Epub 2013 Feb 26 and plasma somatomedin-C levels during suppression of gonadal 72. Jung MK, Song KC, Kwon AR, Chae HW, Kim DH, Kim HS. Adult height sex steroid secretion in girls with central precocious puberty. J Clin in girls with central precocious puberty treated with gonadotropin- Endocrinol Metab 1988;66:3-9. releasing hormone agonist with or without growth hormone. Ann 58. Roger,M, Chaussain JL, Berlier P, Bost M, Canlorbe P, Colle M, Francois Pediatr Endocrinol Metab 2014;19:214-219. R, Garandeau P, Lahlou N, Morel Y, Schally AV. Long term treatment 73. Liang Y, Wei H, Li J, Hou L, Zhang J, Wu W, Ying Y, Luo X. Effect of of male and female precocious puberty by periodic administration GnRHa 3.75 mg subcutaneously every 6 weeks on adult height in girls of a long-acting preparation of D-Trp6-luteinizing hormone-releasing with idiopathic central precocious puberty. J Pediatr Endocrinol Metab hormone microcapsules. J Clin Endocrinol Metab 1986;62:670-677. 2015;28:839-846. 59. Carel JC, Roger M, Ispas S, Tondu F, Lahlou N, Blumberg J, Chaussain 74. Bertelloni S, Massart F, Einaudi S, Wasniewska M, Miccoli M, Baroncelli JL. Final height after long-term treatment with triptorelin slow release GI. Central Precocious Puberty: Adult Height in Girls Treated with for central precocious puberty: importance of statural growth after Quarterly or Monthly Gonadotropin-Releasing Hormone Analog interruption of treatment. French study group of Decapeptyl in Triptorelin. Horm Res Paediatr 2015;84:396-400. Epub 2015 Nov 4

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75. Atay Z, Abali S, Guran T, Haliloglu B, Baş S, Turan S, Bereket A. Final hormone therapy on adult height in precocious puberty: a further Height in Girls with Idiopathic Central Precocious Puberty Treated contribution. J Pediatr Endocrinol Metab 2003;16:1005-1010. with GNRH Analog: Comparison with Untreated Controls . Horm Res Paediatr 2014;82(Suppl 1):443. 81. Mul D, Oostdijk W, Waelkens JJ, Drop SL. Final height after treatment of early puberty in short adopted girls with gonadotrophin releasing 76. Lazar L, Phillip M. Pubertal disorders and bone maturation. Endocrinol hormone agonist with or without growth hormone. Clin Endocrinol Metab Clin North Am 2012;41:805-825. (Oxf) 2005;63:185-190. 77. Mansfield MJ, Rudlin CR, Crigler JF Jr, Karol KA, Crawford JD, Boepple PA, Crowley WF Jr. Changes in growth and serum growth hormone 82. Tuvemo T, Jonsson B, Gustafsson J, Albertsson-Wikland K, Aronson AS, and plasma somatomedin-C levels during suppression of gonadal Häger A, Ivarson S, Kriström B, Marcus C, Nilsson KO, Westgren U, sex steroid secretion in girls with central precocious puberty. J Clin Westphal O, Aman J, Proos LA. Final height after combined growth Endocrinol Metab 1988;66:3-9. hormone and GnRH analogue treatment in adopted girls with early 78. Lanes R, Gunczler P. Final height after combined growth hormone and puberty. Acta Paediatr 2004;93:1456-1462. gonadotrophin-releasing hormone analogue therapy in short healthy 83. Jung MK, Song KC, Kwon AR, Chae HW, Kim DH, Kim HS. Adult height children entering into normally timed puberty. Clin Endocrinol (Oxf) in girls with central precocious puberty treated with gonadotropin- 1998;49:197-202. releasing hormone agonist with or without growth hormone. Ann 79. Pasquino AM, Pucarelli I, Segni M, Matrunola M, Cerroni F. Adult height Pediatr Endocrinol Metab 2014;19:214-219. in girls with central precocious puberty treated with gonadotropin- releasing hormone analogues and growth hormone. J Clin Endocrinol 84. Liu S, Liu Q, Cheng X, Luo Y, Wen Y. Effects and safety of combination Metab 1999;84:449-452. therapy with gonadotropin-releasing hormone analogue and growth 80. Pucarelli I, Segni M, Ortore M, Arcadi E, Pasquino AM. Effects of hormone in girls with idiopathic central precocious puberty: a meta- combined gonadotropin-releasing hormone agonist and growth analysis. J Endocrinol Invest 2016;39:1167-1178. Epub 2016 May 25

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Bibliografia: Harrington J., MBBS. Definition, etiology, and evaluation of precocious puberty. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on Oct 26, 2018.) Guillén LS y Argente J. Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos. An Pediatr (Barc). 2012;76(4):229.e1-229.e10

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Official reprint from UpToDate® www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Definition, etiology, and evaluation of precocious puberty

Authors: Jennifer Harrington, MBBS, PhD, Mark R Palmert, MD, PhD Section Editors: Peter J Snyder, MD, William F Crowley, Jr, MD, Mitchell E Geffner, MD Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2018. | This topic last updated: Sep 04, 2018.

INTRODUCTION — Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD) earlier than population norms. The cause of precocious puberty may range from a variant of normal development (eg, isolated premature adrenarche or isolated premature thelarche) to pathologic conditions with significant risk of morbidity and even death (eg, malignant germ-cell tumor and astrocytoma).

The clinician faced with a child who presents with early development of secondary sexual characteristics should consider the following questions:

● Is the child too young to have reached the pubertal milestone in question? – To answer this question, the clinician needs to know the normal ages for pubertal milestones and how to separate normal from abnormal development.

● What is causing the early development? – To answer this question, the physician ascertains whether the development of secondary sexual characteristics is attributable to androgen and/or estrogen effects, and whether the source of sex hormone is centrally mediated through the hypothalamic-pituitary-gonadal axis, from an autonomous peripheral origin, or has an exogenous basis.

● Is therapy indicated, and, if so, what therapy?

The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of precocious puberty is discussed separately. (See "Treatment of precocious puberty".)

DEFINITION — Precocious puberty is traditionally defined as the onset of secondary sexual characteristics before the age of eight years in girls and nine years in boys [1]. These limits are chosen to be 2 to 2.5 standard deviations (SD) below the mean age of onset of puberty. In most populations, attainment of pubertal milestones approximates a normal distribution, with a mean age of onset of puberty of about 10.5 years in girls and 11.5 years in boys (figure 1A-B) and an SD of approximately one year [1-9].

NORMAL PUBERTAL DEVELOPMENT — The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during the first week of life. It then becomes more active again during infancy, with peak activity between one and three months of age [10]. This state yields sex steroid levels comparable with those seen in early-to-mid puberty, but without peripheral effects. In boys, gonadotropin concentrations then decrease to prepubertal levels by six to nine months of age. In girls, luteinizing hormone (LH) levels decrease at approximately the same time as in boys, but the follicle-stimulating hormone (FSH) concentrations can remain elevated into the second year of life. This hypothalamic-pituitary-gonadal activity during infancy is known as the "mini puberty of infancy"; its biological relevance is unknown.

The neonatal stage is followed by a long period of pre-puberty, which is a state of active suppression of the hypothalamic-pituitary- gonadal axis. Puberty occurs when there is reactivation of the hypothalamic-pituitary-gonadal axis. The physiologic and genetic mechanisms that affect timing of pubertal maturation are discussed separately. (See "Normal puberty", section on 'Sequence of pubertal maturation'.)

In 1969 and 1970, Marshall and Tanner defined the standards of normal pubertal development in children and adolescents, known as sexual maturity ratings or "Tanner stages" (picture 1A-C) [2,3]. These studies reported that the first sign of puberty in English girls was breast development at an average age of 11 years (thelarche), followed by pubic hair growth (pubarche), and then menarche. In English boys, the first sign was testicular enlargement at an average age of 11.5 years followed by penile growth and pubic hair growth. (See "Normal puberty".)

Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest that children, especially overweight children, are entering puberty at a younger age than previously [4-9,11]. In addition, there are racial differences, with puberty occurring earlier in African-American children compared with non-Hispanic Caucasian and Hispanic children. These data and the proposed explanations for the trends are discussed separately. (See "Normal puberty", section on 'Trends in pubertal timing'.)

EPIDEMIOLOGY — Using the traditional definition of precocious puberty as the development of secondary sexual characteristics before age eight in girls and nine in boys (2 to 2.5 standard deviations [SD] below the average age of pubertal onset in healthy

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children), one would expect that the prevalence rate should be around 2 percent, or 2 in every 100 children. However, population studies looking at the prevalence rates of precocious puberty yield markedly different rates depending on the population studied:

● In a population-based United States study, breast and/or pubic hair development was present at age eight in 48 percent of African-American girls and 15 percent of White girls [11]. At seven years of age, the proportions were 27 percent and 7 percent, respectively.

● In a population-based study of data from Danish national registries from 1993 to 2001, the incidence of precocious puberty was 20 per 10,000 girls and less than 5 per 10,000 boys [12]. The diagnostic age limit utilized in this study was eight years for girls and nine for boys. About half the patients had central precocious puberty (CPP) and the remainder were isolated premature thelarche or adrenarche, or early normal pubertal development. (See "Premature adrenarche".)

These observations suggest that the definition of precocious puberty is problematic, at least in girls, and that selection of children for evaluation should not only depend on age but also clinical features, race/ethnicity, and presence/absence of obesity [13]. (See 'Definition' above and 'Threshold for evaluation' below.)

There is a strong female predominance of children with precocious puberty. In a retrospective review of 104 consecutive children referred for evaluation of precocious puberty, 87 percent were female [14].

THRESHOLD FOR EVALUATION — We suggest careful evaluation of children presenting with signs of secondary sexual development younger than the age of eight years in girls or nine years in boys. The level of concern and extent of evaluation should increase with younger age at presentation. Given the trend towards earlier pubertal development, in girls who are between the ages of seven and eight, a comprehensive history and physical examination and clinical follow-up may be sufficient if the clinical evaluation does not raise any additional concerns [15]. (See 'Epidemiology' above and 'Evaluation' below.)

A more controversial approach was suggested in 1999 by the Lawson Wilkins Pediatric Endocrine Society (LWPES), which recommended that evaluation for a pathologic cause of precocious puberty be reserved for Caucasian girls who have breast and/or pubic hair development before seven years of age and for African-American girls who have these findings before six years of age [16]. This recommendation was based on a study describing the first signs of pubertal development among approximately 18,000 girls in the United States and Puerto Rico, among whom development occurred at a younger age than had been previously reported (figure 2) [11]. The study did not distinguish between girls with isolated thelarche or adrenarche from those with true precocious puberty. This same study reported an average age at menarche of approximately 12.5 years, which was not substantially earlier than had been reported in the 1940s [17].

This LWPES recommendation is controversial because of concerns that lowering the age threshold for evaluation of precocious puberty will result in failure to identify some children with pathologic disease [18,19]. As an example, a retrospective review of 223 girls referred to a tertiary center for evaluation of pubertal development before eight years of age found that utilization of the LWPES guidelines would have resulted in failure to identify a substantial number of patients with treatable disease [19]. Twelve percent of these girls were ultimately diagnosed with an endocrinopathy that was amenable to early intervention, including congenital adrenal hyperplasia, McCune-Albright syndrome, pituitary adenoma, and neurofibromatosis.

CLASSIFICATION — Precocious puberty can be classified based upon the underlying pathologic process (algorithm 1).

● Central precocious puberty – Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. CPP is characterized by sequential maturation of breasts and pubic hair in girls, and of testicular and penile enlargement and pubic hair in boys. In these patients, the sexual characteristics are appropriate for the child's gender (isosexual). CPP is pathologic in up to 40 to 75 percent of cases in boys [20,21], compared with 10 to 20 percent in girls [22-24] (table 1) (See 'Causes of central precocious puberty (CPP)' below.)

● Peripheral precocity – Peripheral precocity (also known as peripheral precocious puberty, gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) from the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropin from a germ cell tumor (eg, human chorionic gonadotropin, hCG) (table 2). The term precocity is used instead of puberty here because true puberty requires activation of the hypothalamic-pituitary-gonadal (HPG) axis, as occurs in CPP. Peripheral precocity may be appropriate for the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys (contrasexual). (See 'Causes of peripheral precocity' below.)

● Benign or non-progressive pubertal variants – Benign pubertal variants include isolated breast development in girls (premature thelarche), or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) in boys or girls that result from early activation of the hypothalamic pituitary adrenal axis as confirmed by mildly elevated levels of dehydroepiandrosterone sulfate (DHEAS) for age (premature adrenarche) (table 3). Both of these disorders can be a variant of normal puberty. However, repeat evaluations are warranted in these children to be certain that the diagnosis is correct. (See 'Types of benign or non-progressive pubertal variants' below.)

CAUSES OF CENTRAL PRECOCIOUS PUBERTY (CPP) — Central precocious puberty (CPP, also known as gonadotropin- dependent precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early, the pattern and timing of pubertal events is usually normal. These children have accelerated linear growth for age, advanced bone age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

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CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation of the pituitary response to endogenous GnRH, produces a prepubertal hormonal state, and stops the progression of secondary sexual development, accelerated growth, and undue bone age advancement. (See "Treatment of precocious puberty", section on 'Treatment for CPP'.)

Idiopathic — CPP is idiopathic in 80 to 90 percent of cases of girls, but in only 25 to 60 percent of boys [20-24].

CNS lesions — Although CPP is idiopathic in up to 90 percent of girls and 60 percent of boys, some cases are caused by lesions of the central nervous system (CNS), a condition often referred to as neurogenic CPP (table 1). Contrast-enhanced magnetic resonance imaging (MRI) is therefore recommended, even in the absence of clinically evident neurologic abnormalities [20,22,24]. The low prevalence of CNS lesions in girls with the onset of puberty that begins after age six years raises the question if all girls in this age group need imaging [23].

Many different types of intracranial disturbances can cause precocious puberty, including the following:

● Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with gelastic (laughing or crying) and other types of seizures [25]. They are the most frequent type of CNS tumor to cause precocious puberty in very young children, although in most cases, the mechanism by which these tumors lead to CPP is unknown.

● Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas [26], ependymomas, pinealomas, and optic and hypothalamic gliomas [22]. Sexual precocity in patients with neurofibromatosis is usually, but not always, associated with an optic glioma [27]. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

● CNS irradiation – Precocious puberty caused by CNS irradiation is commonly associated with growth hormone (GH) deficiency [28]. In this setting, regardless of height velocity, the GH axis should be evaluated. If testing shows GH deficiency, such patients should be treated with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Growth hormone (GH) deficiency'.)

● Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS inflammatory disease, and congenital midline defects, such as optic nerve hypoplasia. (See "Congenital anomalies and acquired abnormalities of the optic nerve", section on 'Hypoplasia'.)

Genetics — Specific genetic mutations have been associated with CPP, although each appears to be present in only a minority of cases:

● Gain-of-function mutations in the Kisspeptin 1 gene (KISS1) [29] and its G protein-coupled receptor KISS1R (formerly known as GPR54) [30] have been implicated in the pathogenesis of some cases of CPP, while loss-of function mutations in KISS1R can cause hypogonadotropic hypogonadism. These observations suggest that KISS1/KISS1R is essential for gonadotropin- releasing hormone physiology and for initiation of puberty [31].

● CPP also can be caused by loss-of-function mutations in MKRN3 (makorin ring finger protein 3), an imprinted gene in the Prader-Willi syndrome critical region (15q11-q13). The decline of hypothalamic MKRN3 gene expression in mice [32] and serum protein levels in girls prior to the onset of puberty [33] suggest that MKRN3 is one of the factors involved in repressing pubertal initiation. Thus, loss of function mutations in this gene would lead to diminished inhibition and early onset of puberty. Paternally- inherited loss of function mutations in MKRN3 have been demonstrated to be associated with up to 46 percent of familial cases of CPP [32,34,35].

● A loss-of-function mutation in another gene, DLK1 (Delta-like 1 homolog), leads to undetectable serum concentrations of the DLK1 protein and has been associated with isolated CPP in five members of one family [36]. DLK1 is a paternally expressed gene, mostly in adrenal, pituitary, and ovarian tissue. No definitive mechanistic link between DLK1 function and pubertal development has been determined to date, but polymorphisms in this gene as well as in MKRN3 are associated with variation in the age of menarche in large genome-wide association studies providing further evidence of a mechanistic link [37].

Previous excess sex steroid exposure — Children who have been exposed to high serum levels of sex steroid (eg, those with McCune Albright Syndrome and poorly controlled congenital adrenal hyperplasia) may sometimes develop superimposed CPP, either from the priming effect of the peripheral precocity-derived sex steroid on the hypothalamus, or in response to the sudden lowering of the sex steroid levels following improved control of the sexual precocity [38-40]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Monitoring therapy' and 'McCune-Albright syndrome' below.)

Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are associated with elevated levels of LH and/or follicle-stimulating hormone (FSH) [41,42].

CAUSES OF PERIPHERAL PRECOCITY — Peripheral precocity (also known as peripheral precocious puberty or gonadotropin- independent precocious puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from the gonads or adrenal glands, or from exogenous sources (table 2). Further characterization is based upon whether the sexual characteristics are appropriate for the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys (contrasexual). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are suppressed (in the prepubertal range) and do not increase substantially with gonadotropin-releasing hormone (GnRH) stimulation.

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The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is ineffective, in contrast to patients with central precocious puberty (CPP). (See "Treatment of precocious puberty", section on 'Treatment for peripheral precocity'.)

In the following discussion, the causes of peripheral precocity are described based upon sex.

Girls

Ovarian cysts — A large functioning follicular cyst of the ovaries is the most common cause of peripheral precocity in girls [43]. Affected patients often present with breast development, followed by an episode of vaginal bleeding, which occurs due to estrogen withdrawal once the cyst has regressed. These cysts may appear and regress spontaneously, so conservative management is usually appropriate [44]. Large cysts may predispose to ovarian torsion.

Ovarian tumors — Ovarian tumors are a rare cause of peripheral precocity in girls. Granulosa cell tumors, the most common type, typically present as isosexual precocity; Sertoli/Leydig cell tumors (arrhenoblastoma), pure Leydig cell tumors, and gonadoblastoma may make androgens and cause contrasexual precocity [45-47]. (See "Sex cord-stromal tumors of the ovary: Granulosa-stromal cell tumors", section on 'Granulosa cell tumor'.)

Boys

Leydig cell tumors — Leydig cell tumor should be considered in any boy with asymmetric testicular enlargement. Even if a distinct mass cannot be palpated and none is evident on ultrasonography, the larger testis should be biopsied if it enlarges during follow-up. These testosterone-secreting tumors are almost always benign and are readily cured by surgical removal [48]. Radical orchiectomy is the most common procedure; however, successful treatment by direct enucleation of the tumor with sparing of the remainder of the testis has been reported [49]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)

Human chorionic gonadotropin (hCG)-secreting germ cell tumors — Germ-cell tumors secrete hCG, which in boys activates LH receptors on the Leydig cells, resulting in increased testosterone production [50]. The increase in testicular size (usually only to an early pubertal size) is less than expected for the serum testosterone concentration and degree of pubertal development. This is because most of the testis is made up of tubular elements whose maturation depends upon FSH. In girls, hCG-secreting tumors do not lead to precocious puberty because activation of both FSH and LH receptors is needed for estrogen biosynthesis.

These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting sites of embryonic germ cells before their coalescence in the gonadal ridge [50]. The histology of hCG-secreting tumors ranges from dysgerminoma, which respond readily to therapy, to the more malignant embryonal cell carcinoma and choriocarcinoma. All males with anterior mediastinal germinomas should have a karyotype because these tumors may be associated with Klinefelter syndrome. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors", section on 'Germ cell tumors'.)

Familial male-limited precocious puberty — This rare disorder (also known as testotoxicosis) is caused by an activating mutation in the LH receptor gene, which results in premature Leydig cell maturation and testosterone secretion [51]. Although inherited as an autosomal dominant disorder, girls are not affected clinically because (similar to hCG-secreting germ tumors) activation of both the LH and FSH receptors is required for estrogen biosynthesis [52]. Also similar to hCG-secreting tumors, the increase in testicular size is usually only to an early pubertal size. Affected boys typically present between one to four years of age.

Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on 'Familial male-limited precocious puberty'.)

Both girls and boys — The following causes of peripheral precocity can occur in either girls or boys. Physical changes either may be isosexual or contrasexual depending on the sex of the child and the type of sex hormone produced. Excess estrogen will cause feminization, while excess androgen will result in virilization.

Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally present with precocious puberty. In girls, findings include early breast development, galactorrhea, and recurrent vaginal bleeding, while affected boys present with premature testicular enlargement [53-55]. Historically this has been referred to as the "overlap" or Van Wyk-Grumbach syndrome [56]. The signs of pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and adolescence".)

A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin (TSH) concentrations, given that both TSH and FSH share a common alpha subunit [57].

Exogenous sex steroids — Feminization, including gynecomastia in boys, has been attributed to excess estrogen exposure from creams, ointments, and sprays. Caretakers using these topical estrogens to treat menopausal symptoms may inadvertently expose children to the hormones [58,59]. Other possible sources of estrogen exposure include contamination of food with hormones, phytoestrogens (eg, in soy), and folk remedies such as lavender oil and tea tree oil [60,61]. A food source was suspected for local "epidemics" of early thelarche in Italy and Puerto Rico during the 1980s, but no single causative substance was found in food samples [62-64]. Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing creams [65,66].

Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors and enzymatic defects in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Boys who have an adrenal cause for their precocity will not have

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testicular enlargement (testes will be <4 mL testicular volume or <2.5 cm in diameter). (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Premature pubarche may be the presenting feature of an inherited disorder of adrenal steroid metabolism, including 21-hydroxylase deficiency, 11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate dehydrogenase deficiency, and PAPSS2 deficiency. (See "Uncommon congenital adrenal hyperplasias".)

Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen and estrogen, the latter because of intra-adrenal aromatization of androgen (or production of enough androgen that is peripherally aromatized to estrogen), causing both male and female pubertal changes [67]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

McCune-Albright syndrome — McCune-Albright Syndrome (MAS) is a rare disorder defined as the triad of peripheral precocious puberty, irregular café-au-lait ("Coast of Maine") skin pigmentation (picture 2), and fibrous dysplasia of bone (image 1) [68]. MAS should be considered in girls with recurrent formation of follicular cysts and cyclic menses [69]. The skin manifestations and bone lesions may increase over time. In girls presenting with vaginal bleeding, the ovarian enlargement has often been mistaken for an ovarian tumor, leading to unnecessary oophorectomy [70]. Girls presenting with premature vaginal bleeding should therefore be evaluated for features of McCune-Albright syndrome to avoid this potential mistake.

The clinical phenotype varies markedly, depending on which tissues are affected by the mutation, but precocious puberty is the most commonly reported manifestation [71]. As in other forms of peripheral precocity, the sequence of pubertal progression may be abnormal, in that vaginal bleeding often precedes significant breast development [72]. Prolonged exposure to elevated levels of sex steroids may cause accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious puberty is typically peripheral precocity, a secondary component of CPP may develop because of sex steroid withdrawal leading to activation of the hypothalamic-pituitary-gonadal axis [73] (see 'Previous excess sex steroid exposure' above). In boys with MAS, while sexual precocity is less common, there is a high prevalence of testicular pathology on ultrasound, including hyper-and hypoechoic lesions (most likely representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [74].

Patients with MAS have a somatic (postzygotic) mutation of the alpha subunit of the Gs protein that activates adenylyl cyclase [75- 77]. This mutation leads to continued stimulation of endocrine function (eg, precocious puberty, thyrotoxicosis, gigantism or acromegaly, Cushing syndrome, and hypophosphatemic rickets) in various combinations. Mutations can be found in other non- endocrine organs (liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and cardiac arrhythmias, respectively. A heightened risk of malignancy has also been reported [78]. Germline occurrences of this mutation would presumably be lethal [75,77,79,80].

Treatment of MAS is described in a separate topic review. (See "Treatment of precocious puberty", section on 'McCune-Albright syndrome'.)

TYPES OF BENIGN OR NON-PROGRESSIVE PUBERTAL VARIANTS — Early pubertal development fits into this category when the early development of secondary sexual characteristics does not herald underlying pathology and is not followed by progressive development (table 3). However, monitoring for evidence of pubertal progression is important, as some children presenting with an apparent benign pubertal variant will instead turn out to have a different disorder. As examples, thelarche may be the initial presenting feature of central precocious puberty (CPP), or progressive pubic hair development may herald a form of peripheral precocity.

Premature thelarche — Most cases of premature thelarche are idiopathic and present under two years of age (and may even start at birth). Many cases will remit spontaneously, and most others do not progress. However, follow-up is warranted because premature thelarche can represent the initial presentation of true CPP in 10 to 20 percent of children referred to pediatric endocrine units [81-83].

Key features of premature thelarche are:

● Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage 3

● Absence of other secondary sexual characteristics

● Normal height velocity for age (not accelerated)

● Normal or near-normal bone age

Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one should be cautious in interpreting these levels in children under the age of two years because elevations can be seen as part of the normal transient "mini- puberty of infancy," and CPP can be diagnosed inappropriately (See 'Normal pubertal development' above.)

Toddlers and children — Premature thelarche occurs in two peaks: one during the first two years of life and the other at six to eight years of age [83], with potentially different underlying pathophysiology accountable for each of these peaks. Postulated mechanisms include transient activation of the hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH) secretion [84]. In infants, soy-based formulas have been implicated, although the evidence is weak and may represent only a slower waning of breast tissue during infancy [85-87]. Use of lavender oil, tea tree oil, or hair care products that contain placental extract has also been implicated in some cases of premature thelarche [60]. In most instances, no cause can be found.

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In most cases, premature thelarche requires only reassurance. However, the patient should be examined for other signs of pubertal development, and growth data should be plotted; an accelerated height velocity may be indicative of progressive puberty and requires further evaluation. To identify patients with progressive puberty, patients should be monitored for several months for evidence of pubertal progression. (See 'Evaluation' below.)

Neonates — Breast hypertrophy can occur in neonates of both sexes, and is sometimes quite prominent. It is caused by stimulation from maternal hormones and usually resolves spontaneously within a few weeks or months. The breast development may also be associated with galactorrhea ("witch's milk"), which also resolves spontaneously [88]. While in most cases neonatal thelarche disappears over the first months of life, failure to do so almost never has any pathologic significance. (See "Breast masses in children and adolescents", section on 'Neonates and infants'.).

Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or axillary hair (pubarche) prior to the age of eight years in girls and nine years in boys, in conjunction with a mild elevation in serum dehydroepiandrosterone sulfate (DHEAS) for age. It is more common in girls, African-American and Hispanic females, and individuals with obesity and insulin resistance [15]. Premature adrenarche is considered a variant of normal development, but may be a risk factor for later development of polycystic ovary disease in girls. (See "Premature adrenarche" and "Definition, clinical features and differential diagnosis of polycystic ovary syndrome in adolescents".)

In the child presenting with isolated adrenarche, monitoring for the development of other secondary sexual characteristics (breast or testicular enlargement) is important to ensure that the child's presentation is not the first feature of CPP or a form of peripheral precocity. Premature adrenarche can be associated with mild growth acceleration and advance in bone age. In children with progressive virilization or with a more advanced bone age (>2 standard deviations [SD] beyond chronological age), further investigation for other causes of early pubertal development should be considered. (See "Premature adrenarche", section on 'Evaluation of premature pubarche'.)

Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with isolated genital hair, usually finer in texture than typical pubic hair and located along the labia or over the scrotum (rather than on the pubic symphysis) [89-91]. The steroid profile of these infants demonstrates normal or mildly elevated DHEAS concentrations for age. Unlike premature adrenarche, the condition is transient and the hair typically disappears within 6 to 24 months [92]. In the absence of progressive development of further genital hair or other secondary sexual characteristics during follow-up, extensive evaluation is not needed.

Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the presence of isolated, self- limited vaginal bleeding in the absence of other secondary sexual characteristics [93]. The underlying etiology is unknown but potential mechanisms include increased endometrial sensitivity to circulating estrogens or transient stimulation of the HPG axis [94]. Pelvic ultrasonography is normal and gonadotropins are pre-pubertal. Genital or vaginal trauma, infection, and sexual abuse should be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses such as recurrent functional ovarian cysts or McCune Albright Syndrome should be considered. (See 'McCune-Albright syndrome' above.)

Non-progressive or intermittently progressive precocious puberty — A subgroup of patients presenting with what clinically appears to be CPP (often with evidence of both gonadarche and pubarche) will either have stabilization or very slow progression in their pubertal signs [95]. The bone age is typically not as advanced compared with children with true CPP, and serum LH concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated and a FSH-predominant response is typically seen if gonadotropin-releasing hormone agonist (GnRHa) stimulation testing is performed. Monitoring for evidence of pubertal progression is important to distinguish these children from those with true CPP. In children with non-progressive precocious puberty, treatment with a GnRHa is not needed because their adult height is not affected (ie, their final height untreated is concordant with their midparental height) [95,96].

EVALUATION

Guiding principles — The evaluation for precocious puberty focuses on answering the following questions:

● Who should be evaluated? – Evaluation is warranted in children presenting with signs of secondary sexual development younger than the age of eight (girls) or nine (boys) years. The concern and extent of evaluation should increase with decreasing age at presentation. In girls who are between the ages of seven and eight, a comprehensive history and physical examination may be sufficient if this examination does not raise any additional concerns.

● Is the cause of precocity central or peripheral? – The sequence of pubertal development in children with central precocious puberty (CPP) recapitulates normal pubertal development but at an earlier age (figure 1A-B). By contrast, individuals with peripheral precocity have a peripheral source of gonadal hormones and are more likely to display deviations from the normal sequence and/or pace of puberty. As an example, a girl who progresses to menstrual bleeding within one year of the onset of breast development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP [97,98].

● How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and duration of sex steroid action.

• A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests either CPP or peripheral precocity with high concentrations of sex steroids (table 4). Pubertal progression would be considered slow if there is minimal or no change in stage of breast, pubic hair, or genital development during six or more months of observation. Height velocity is considered accelerated if it is more than the 95th percentile for age (figure 3A-B).

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• By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally advanced) suggests a benign pubertal variant with low concentrations of sex steroids, rather than true CPP or peripheral precocity.

● Is the precocity because of excess androgen or estrogen? – Are the secondary sexual characteristics virilizing or feminizing? Isolated contrasexual development (isolated virilization in girls or isolated feminization in boys) excludes central etiologies. While in girls the most common cause of virilization is due to excess adrenal androgens, a rare ovarian cause of virilization is ovarian arrhenoblastoma (Sertoli-Leydig cell tumor) [99]. Conversely, a rare testicular cause of feminization is a feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [100]. (See "Sex cord-stromal tumors of the ovary: Sertoli-stromal cell tumors", section on 'Clinical features' and "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)

Initial evaluation — The evaluation of a patient suspected to have precocious puberty begins with a history and physical examination. In most cases, radiographic measurement of bone age is performed to determine whether there is a corresponding increase in epiphysial maturation.

● Medical history – The history focuses on when the initial pubertal changes were first noted, as well as the timing of pubertal onset in the parents and siblings. In addition, other questions are directed toward evidence of linear growth acceleration, headaches, changes in behavior or vision, seizures, or abdominal pain (indicative of either a central nervous system [CNS] or ovarian process) and previous history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids (medicinal or cosmetic sources) or compounds with sex-steroid-like properties should always be explored [58].

● Physical examination – This includes height, weight, and height velocity (cm/year). Children with benign forms of precocious puberty do not usually display the early growth acceleration pattern that is seen among those with progressive forms of precocious puberty [101]. The physical examination should include assessment of visual fields (a defect suggests the possibility of a CNS mass) and examination for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome) (picture 2). (See 'McCune-Albright syndrome' above.)

● Pubertal staging – Secondary sexual development should be assessed to determine the sexual maturity rating (Tanner stage) of pubertal development. This means staging breast development in girls (picture 1A), genital development in boys, and pubic hair development in both sexes (picture 1B-C). In girls, the diameter of glandular breast tissue (by direct palpation including compression to differentiate from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In boys, measurements are made of the testicular volume (figure 4) [102]. Penile size (stretched length of the non-erect penis, measuring from the pubic bone to tip of glans, excluding the foreskin) is rarely used for monitoring of pubertal progress because penile growth is not an early event in puberty, accurate measurement is difficult and may be awkward for the adolescent boy, and the "pubertal threshold" for penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of testicular volume are critical to determine whether further radiologic or laboratory testing is necessary. (See "Normal puberty", section on 'Sexual maturity rating (Tanner stages)' and "Normal puberty", section on 'Sequence of pubertal maturation'.)

● Bone age – In patients with early development of secondary sexual characteristics confirmed by physical examination, evaluation of skeletal maturation by radiographic assessment of bone age can help with both the differential diagnosis and assessment of whether there may be an impact on final height. However, in patients presenting with typical features indicative of either isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

A significant advance in the bone age (greater than approximately 2 standard deviations [SD] beyond chronological age) is more likely to be indicative of either CPP or peripheral precocity, rather than a benign pubertal variant. A significantly advanced bone age does not, however, exclude a diagnosis of a benign pubertal variant. As an example, up to 30 percent of children with benign premature adrenarche have bone ages more than two years in advance of their chronological age [103]. (See 'Types of benign or non-progressive pubertal variants' above.)

Initial laboratory evaluation — If there is evidence of progressive development of secondary sexual characteristics, further evaluation is needed to determine its cause, whether therapy is needed, and, if so, which treatment is appropriate.

The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either estradiol and/or testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and table 4).

Basal serum LH — A good initial screening test to identify activation of the hypothalamic-pituitary-gonadal axis is measurement of basal LH concentration (ideally in the morning), using sensitive immunochemiluminescence assays with a lower limit of detection of ≤0.1 mIU/mL (where mIU = milli-International Units) [104]. Results are interpreted as follows:

● LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant such as premature thelarche.

● LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can identify children with progressive CPP with high sensitivity and specificity [105,106].

● LH concentrations are less informative in the evaluation of children with non-progressive or intermittently progressive precocious puberty. While such children typically have basal LH concentrations <0.2 to 0.3 mIU/mL, levels can be in the early pubertal

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range in some children. Additional clinical characteristics such as lack of progression in secondary sexual characteristics or low LH/FSH ratio post-gonadotropin stimulation test can help to differentiate these children from those with progressive CPP. (See 'Serum LH concentrations after GnRH agonist stimulation' below.)

Care should be used in the interpretation of LH levels in girls under the age of two years, as gonadotropin concentrations may be elevated at this age in association with the "mini-puberty of infancy" and CPP can be misdiagnosed during this phase of development [10,107].

An emerging approach is to identify cases of progressive CPP using first-morning urinary gonadotropin levels. These early results need further validation, but this could be an important alternative diagnostic strategy in the future [108,109].

Basal serum FSH — Basal FSH concentrations have limited diagnostic utility in distinguishing children with CPP from those with benign pubertal variants. FSH concentrations are often higher in children with CPP compared with benign pubertal variants, but there is substantial overlap between these groups of children [104,105]. Like LH, FSH concentrations are typically suppressed in children with peripheral precocity.

Serum estradiol — Very high concentrations of estradiol, with associated suppression of gonadotropins, are generally indicative of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol immunoassays, however, have poor ability to discriminate at the lower limits of the assay between prepubertal and early pubertal concentrations [110]. More sensitive methods of estimating estradiol concentrations, such as tandem mass spectrometry, distinguish better between pre-pubertal and pubertal estradiol concentrations [111], and should be ordered exclusively. However, further studies are still needed to clarify threshold concentrations.

Serum testosterone — Elevated testosterone concentrations are indicative of testicular testosterone production in boys, or of adrenal testosterone production or exogenous exposure in both sexes. Very high concentrations, with associated suppression of gonadotropins, are generally indicative of peripheral precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone sulfate [DHEAS]) may be necessary to help discriminate between adrenal and testicular sources of the androgens. In children with CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal testosterone concentrations, but tandem mass spectroscopy methods are more discriminative [112] (similar to the estradiol assays discussed above), so these should be ordered whenever available.

Subsequent laboratory testing — Subsequent laboratory testing depends on the results of the tests outlined above (basal LH, FSH, and estrogen or testosterone), and on the patient's clinical characteristics:

Serum LH concentrations after GnRH agonist stimulation — In children in whom the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test may help differentiate those with CPP from those with a benign pubertal variant. This test consists of measurement of serum LH concentrations before and after administration of GnRH. GnRH is not available in the United States; a GnRH agonist may be used instead because of the initial stimulatory effect on the hypothalamic-pituitary-gonadal (HPG) axis following a single dose of a GnRH agonist.

A common protocol is as follows:

● Blood is sampled at baseline for LH, FSH, and either estradiol in girls or testosterone in boys.

● The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide acetate at a dose of 20 mcg/kg.

● LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [113-115]. Other protocols employ sampling every 30 minutes for up to two hours [113,116] or testing of estradiol or testosterone 24 hours later [117,118].

The results are interpreted as follows:

● Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP has not been established, and varies somewhat among assays. For most LH assays, a value of 3.3 to 5 mIU/mL defines the upper limit of normal for stimulated LH values in prepubertal children [113,119]. Stimulated LH concentrations above this normal range suggest CPP.

● Peak stimulated LH/FSH ratio – Children with progressive CPP tend to have a more prominent LH increase post-stimulation, and higher peak LH/FSH ratios, compared with those with non- or intermittently progressive precocious puberty [117,120]. While a definite diagnostic threshold has not been well defined, a peak LH/FSH ratio >0.66 is typically seen with CPP, whereas a ratio <0.66 suggests non-progressive precocious puberty [120].

● Stimulated estradiol / testosterone – Children with progressive CPP tend to have higher stimulated serum estradiol and testosterone concentrations when measured 24 hours after administration of GnRH or GnRH agonist [117,118]. However, the disadvantage of requiring venipunctures on two consecutive days as well as the lack of consistent published diagnostic thresholds limits the clinical utility of these measurements.

As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in girls under the age of two years, as both basal and stimulated LH levels can be elevated as part of the normal hormonal changes associated with the mini-puberty of infancy [107].

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Serum adrenal steroids — In children with precocious pubarche, measurement of adrenal steroids may be necessary to help distinguish between peripheral precocity and benign premature adrenarche. Children with premature adrenarche can have mild elevation in adrenal hormones, with DHEAS concentrations of 40 to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35 ng/dL (1.2 nmol/L) [121]. (See "Premature adrenarche", section on 'Hormonal measurements at baseline'.)

Concentrations above these thresholds warrant further investigation for causes of peripheral precocity, such as non-classical congenital adrenal hyperplasia and virilizing adrenal tumors. In children with suspected non-classical congenital adrenal hyperplasia (CAH) secondary to 21- hydroxylase deficiency who have an early morning 17-hydroxyprogesterone (17-OHP) concentration between 82 ng/dL (2.5 nmol/L) and 200 ng/dL (6 nmol/L), follow-up adrenocorticotropic hormone (ACTH) stimulation testing should be performed. A 17-OHP value >200 ng/dL has a high sensitivity and specificity for non-classical CAH [122,123], although an ACTH stimulation test may still be needed to confirm the diagnosis. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Other biochemical tests — In boys, human chorionic gonadotropin (hCG) should be measured to evaluate for the possibility of an hCG-secreting tumor. If a tumor is found in the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter syndrome because of its association with mediastinal germinoma [50]. A thyroid-stimulating hormone (TSH) concentration should be measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity.

Imaging

● Central precocious puberty

• Brain magnetic resonance imaging (MRI) – We recommend performing a contrast-enhanced brain MRI for all boys with CPP, and for girls with onset of secondary sexual characteristics before six years of age, because of higher rates of CNS abnormalities in these groups of patients (see 'CNS lesions' above). In our practice, we usually do not perform MRI for girls with CPP onset between seven and eight years of age if there is no clinical evidence of CNS pathology and if there is a family history of earlier pubertal onset, or if the child has an increased body mass index (BMI).

In girls with CPP onset after their sixth birthday, there is ongoing debate about the utility of brain imaging in this age group because of conflicting data about the risk for CNS pathology: In a meta-analysis, the prevalence of intracranial lesions was 3 percent among girls presenting with CPP after six years of age, compared with 25 percent among those presenting before six years [124]. These findings are in contrast to a study of girls with precocious puberty that was not included in this part of the meta-analysis, in which 13 of 208 girls (6.3 percent) had related MRI brain abnormalities, all of whom had onset of CPP after the age of six years [22]. A younger age of onset of pubertal signs and higher basal LH and estradiol concentrations have been proposed as predictive features for intracranial pathology [22,23,125]. Because these features and clinical suspicion have been shown to have variable sensitivity to detect girls with abnormal brain MRIs, some have recommended imaging for all girls with CPP [22,24].

• Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help differentiate between CPP and benign pubertal variants, especially when the evaluation remains equivocal. Girls with CPP have greater uterine and ovarian volumes compared with girls who are prepubertal or those with premature thelarche [126-129]. Diagnostic thresholds for uterine and ovarian volumes have been proposed; however, these are variable and some studies have suggested that there is considerable overlap between patients with and without CPP [126,127].

● Peripheral precocity

• In girls with progressive peripheral precocity, a pelvic ultrasound can be performed to help identify the presence of an ovarian cyst or tumor. For suspected adrenal pathology, for example when there is rapid virilization, an adrenal ultrasound should be strongly considered.

• Ultrasound examination of the testes can be performed in boys with peripheral precocity to evaluate for the possibility of a Leydig-cell tumor.

• In children where an adrenal tumor is suspected (due to evidence of progressive virilization and elevated serum adrenal androgens, eg, DHEAS), an abdominal ultrasound and/or computerized tomography (CT) abdomen should be performed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Puberty and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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● Basics topic (see "Patient education: Early puberty (The Basics)")

SUMMARY

● Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard deviations (SD) earlier than the average age (figure 1A-B). (See 'Definition' above.)

● Because of the trend of earlier pubertal development, there is controversy about the lower age limit for normal pubertal development. Nonetheless, we recommend evaluation in children presenting with secondary sexual development younger than eight years in girls or nine years in boys (figure 2). (See 'Definition' above and 'Evaluation' above.)

● The etiology of precocious puberty is classified by the underlying pathogenesis into three categories (see 'Classification' above):

• Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-gonadal axis. CPP is pathologic in up to 40 to 75 percent of boys and 10 to 20 percent of girls (table 1). (See 'Causes of central precocious puberty (CPP)' above.)

• Peripheral precocity is caused by secretion of sex hormones either from the gonads or adrenal glands, ectopic human chorionic gonadotropin (hCG) production by a germ cell tumor, or by exogenous sources of sex steroids, and is independent from the hypothalamic-pituitary-gonadal axis (table 2). (See 'Causes of peripheral precocity' above.)

• Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic hair development (premature pubarche/adrenarche), benign pre-pubertal vaginal bleeding, and non-progressive precocious puberty (table 3). These patterns are usually a variant of normal puberty and require no intervention. If the finding is isolated breast development or isolated pubarche, and there is no evidence of pubertal progression or accelerated growth, laboratory evaluation may not be necessary. However, close follow-up is recommended because some of these patients will turn out to have progressive precocity. (See 'Types of benign or non-progressive pubertal variants' above.)

● The first step in the laboratory evaluation of progressive development of precocious secondary sexual characteristics is to measure basal luteinizing hormone (LH), follicle stimulating hormone (FSH), and either estradiol or testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and table 4). A good initial screening test to distinguish CPP from benign pubertal variants is measurement of a basal LH concentration (see 'Basal serum LH' above):

• In CPP, basal LH levels are often elevated into the pubertal range (greater than 0.2 to 0.3 mIU/mL, depending on the assay).

• LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant such as premature thelarche.

● If the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test can be performed to help distinguish CPP from a benign pubertal variant. Children with CPP have a pubertal (heightened) LH response to GnRH stimulation (table 4). (See 'Serum LH concentrations after GnRH agonist stimulation' above.)

● Recommendations for imaging depends on the type of precocious puberty (see 'Imaging' above):

• All boys with CPP should have brain imaging because of the high prevalence of central nervous system (CNS) lesions in this group. While all girls with onset of CPP below the age of six years should also have a contrast-enhanced brain magnetic resonance imaging (MRI), there is ongoing controversy about the need for more routine imaging of girls between the ages of six and eight years.

• Boys with peripheral precocity may warrant an ultrasound examination of the testes to evaluate for the possibility of a Leydig-cell tumor. Girls with peripheral precocity may warrant a pelvic ultrasound performed to help identify the presence of an ovarian cyst or tumor. In both sexes, ultrasound of the adrenal glands may be indicated if adrenal pathology is suspected, and should be performed if there is suspicion for an adrenal tumor.

• Other than a bone age, no further imaging is usually required for children with benign or non-progressive pubertal variants.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Paul Saenger, MD, MACE, who contributed to an earlier version of this topic review.

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REFERENCES

1. Boepple PA, Crowley WF Jr. Precocious puberty. In: Reproductive Endocrinology, Surgery, and Technology, Adashi EY, Rock JA, Rosenwaks Z (Eds), Lippincott-Raven, Philadelphia 1996. Vol 1, p.989. 2. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44:291.

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Central (gonadotropin-dependent) precocious puberty

Etiology Clinical features Bone age Additional evaluation

Idiopathic Early progressive pubertal development, ↑↑ Increased ovarian and uterine volumes (80 to 90% of girls with CPP, and but proceeds in normal sequence. on ultrasound may help differentiate girls 25 to 60% of boys with CPP) with CPP from those with premature thelarche. Secondary to CNS lesions Early progressive pubertal development, ↑↑ Contrast enhanced MRI to rule out CNS but proceeds in normal sequence. (eg, hypothalamic hamartomas, abnormality. other CNS tumors and lesions, Central precocious puberty secondary to cranial radiation) a CNS lesion occurs more commonly in boys and younger children.

Post early exposure to sex History of treatment of peripheral ↑↑ Basal and stimulated LH concentrations steroids precocity. are pubertal. (after treatment for peripheral Progressive pubertal development with precocity) breast development in girls and testicular enlargement in boys.

Central precocious puberty is characterized by basal LH concentrations >0.2 to 0.3 mIU/L, and/or stimulated LH concentration post GnRH or GnRHa of >3.3 to 5.0 mIU/L.

↑↑: significantly advanced for chronological age (eg, ≥ 2 standard deviations); CPP: central precocious puberty; CNS: central nervous system; LH: luteinizing hormone; MRI: magnetic resonance imaging; GnRH: gonadotropin-releasing hormone; GnRHa: gonadotropin-releasing hormone agonist.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

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Peripheral precocity (gonadotropin-independent precocious puberty)

Bone Etiology Clinical features Additional evaluation age

Girls only

Ovarian cysts Breast development and/or vaginal bleeding. ↑ to ↑↑ Pelvic ultrasound may visualize the cyst, Occasionally presents with ovarian torsion and although in some cases the cyst may have abdominal pain. involuted by the time of the study. Vaginal bleeding is indicative of estrogen withdrawal. Recurrent ovarian cysts suggest McCune Albright Syndrome.

Ovarian tumor Development of either isosexual or contrasexual ↑↑ Pelvic ultrasound sexual precocity, depending of tumor type.

Boys only

Leydig cell tumor Asymmetrical enlargement of the testes. ↑↑ Pubertal testosterone concentrations. Testicular ultrasound aids in diagnosis.

hCG-secreting germ Symmetric testicular enlargement to an early ↑↑ These tumors may occur in gonads, brain, liver, cell tumors pubertal size, but testes remain smaller than retroperitoneum, or mediastinum. expected for degree of pubertal development. When a tumor is identified in the anterior Peripheral precocity is seen only in boys, mediastinum, a karyotype must be performed because hCG only activates LH receptors because of an association of this finding with (estrogen biosynthesis in the ovaries requires Klinefelter syndrome. both FSH and LH receptor activation).

Familial male-limited Symmetric testicular enlargement to an early ↑↑ Genetic testing for mutations of the LH receptor precocious puberty pubertal size, but testes remain smaller than gene (LHCGR). expected for degree of pubertal development; spermatogenesis may occur. Familial: Male-limited autosomal dominant trait. Peripheral precocity is seen only in boys, because there is only activation of the LH receptors (ovarian estrogen biosynthesis requires both FSH and LH receptor activation).

Girls and boys

Exogenous sex steroids Estrogen preparations cause feminization, while ↑ to ↑↑ Clinical history explores use of exogenous sex (estradiol and topical androgens cause virilization in both steroids and folk remedies by caretakers. testosterone creams) sexes.

McCune-Albright In girls, may present with recurrent episodes of ↑ to ↑↑ Ultrasound: Ovaries enlarged, with follicular syndrome breast development, regression and vaginal cysts. In boys, testicular ultrasound can (girls>boys) bleeding. In boys, sexual precocity less demonstrate hyper-and hypoechoic lesions common. (most likely representing areas of leydig cell Skin: Multiple irregular-edged café-au-lait spots. hyperplasia), microlithiasis and focal calcifications. Bone: Polyostotic fibrous dysplasia. May have other hyperactive endocrine disorders: ie, thyrotoxicosis, glucocorticoid excess and/or gigantism.

Primary hypothyroidism Girls: vaginal bleeding, breast development and ↓ Elevated TSH galactorrhea. Boys: testicular enlargement. Other clinical features of hypothyroidism such as short stature.

Congenital adrenal Boys have prepubertal testes with enlarged ↑↑ Sex hormone levels vary depending on the hyperplasia phallus and pubic hair development. Girls with adrenal enzyme block. An early morning 17- (untreated) "nonclassic" CAH may present with early pubic OHP >200 ng/dL (6 nmol/L) has a high and/or axillary hair, and other signs of androgen sensitivity and specificity for congenital adrenal excess. hyperplasia secondary to 21 hydroxylase deficiency. ACTH stimulation test is recommended to confirm the diagnosis of CAH if the 17-OHP level is intermediate (eg, between 200 and 1500 ng/dL). After therapy with glucocorticoids, CPP may develop.

Virilizing adrenal tumor Boys: pubic and/or axillary hair and penile ↑↑ High DHEA or DHEAS, androstenedione and growth with pre-pubertal testes. testosterone. Girls: pubic and/or axillary hair, other significant CT and/or ultrasound of adrenal glands to locate signs of androgen excess (acne and tumor. clitoromegaly). May present with signs of glucocorticoid excess. May be associated with hereditary cancer syndromes.

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Types of benign pubertal variants

Etiology Clinical Features Bone Age Additional Evaluation

Premature adrenarche Isolated pubarche. Gonads are prepubertal in ↑ to ↑↑* Further investigations needed only if there is (boys or girls) size and there is no breast development in girls. significant progressive virilization, to help Typical age of onset four to eight years. exclude peripheral precocity. Seen more commonly in African-American and Mild elevation in DHEAS for chronological age Hispanic girls and in children with obesity and (but appropriate for bone age). insulin resistance. Prepubertal concentrations of 17- hydroxyprogesterone and testosterone.

Premature thelarche Isolated breast development with normal Normal No further evaluation needed in most cases, (girls) growth velocity. (prepubertal) unless evidence of pubertal progression. Most commonly seen in girls less than three Basal LH concentrations typically <0.2 to 0.3 years of age. mIU/L. ¶

Non-progressive or Development of gonadarche (breast or Normal to ↑ Basal LH concentrations typically <0.2 to 0.3 intermittently testicular enlargement) with pubarche (pubic mIU/L, although can be in early pubertal range progressive precocious and/or axillary hair), with either no progression in some children. puberty or intermittent slow progression in clinical Lower stimulated LH/FSH ratio compared with (boys or girls) pubertal signs. children with progressive central precocious puberty. Δ Patients with non-progressive precocious puberty do not need treatment with GnRH agonist, because final height untreated is concordant with mid-parental height.

If further evaluation is needed and performed, patients with benign pubertal variants typically have pre-pubertal basal LH concentrations (<0.2 to 0.3 mIU/L) and/or stimulated LH concentration post GnRHa of <3.3 to 5.0 mIU/L.

↑: elevated for chronological age; DHEAS: dehydroepiandrosterone sulfate; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone. * Up to 30% of children with premature adrenarche can have a bone age more than two years advanced than their chronological age.[1] ¶ Interpretation of basal LH and stimulated LH concentrations can be difficult in girls younger than two years of age because normal gonadotropin concentrations can be elevated as part of the mini-puberty of infancy.[2] Δ A peak LH/FSH ratio <0.66 suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with central precocious puberty. [3]

1. DeSalvo, DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign. J Pediatr Endocrinolo Metab 2013; 26: 215. 2. Bizzarri C, Spadoni G, Bottaro G et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. JCEM 2014; 99:433. 3. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251.

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Clinical characteristics of forms of early pubertal development

Nonprogressive Central precocious Peripheral precocity precocious puberty puberty (CPP)

Physical examination: No progression in Tanner staging Progression to next pubertal Progression Advancement through during 3 to 6 months of stage in 3 to 6 months pubertal stages (Tanner observation stage)

Growth velocity Normal for bone age Accelerated (>6 cm per year)* Accelerated*

Bone age Normal to mildly advanced Advanced for height age Advanced for height age

Serum estradiol concentration Prepubertal Δ Prepubertal to pubertal Increased in ovarian causes of (girls) ¶ peripheral precocity, or with exogenous estrogen exposure

Serum testosterone Prepubertal Δ Prepubertal to pubertal Pubertal and increasing concentration (boys, or girls with virilization) ¶

Basal (unstimulated) serum Prepubertal Δ◊ Pubertal ◊ Suppressed or prepubertal ◊ LH concentration ¶

GnRH (or GnRHa) stimulation LH peak in the prepubertal LH peak elevated (in the pubertal No change from baseline, or LH test ¶ range Δ§ range) § peak in the prepubertal range Lower stimulated LH to FSH Higher stimulated LH to FSH ratio ¥ ratio ¥

CPP: central precocious puberty (also known as gonadotropin-dependent precocious puberty); LH: luteinizing hormone; GnRH: gonadotropin- releasing hormone; GnRHa: gonadotropin-releasing hormone agonist; FSH: follicle-stimulating hormone. * UNLESS the patient has concomitant growth hormone deficiency (as in the case of a neurogenic form of CPP), or has already passed his or her peak height velocity at the time of evaluation, in which case growth velocity may be normal or decreased for chronological age. ¶ Using most commercially available immunoassays, serum concentrations of gonadal steroids have poor sensitivity to differentiate between prepubertal and early pubertal concentrations. Δ In most cases these levels will be prepubertal, however in children with intermittently progressive CPP, these levels may reach pubertal concentrations during times of active development. ◊ Using ultrasensitive assays with detection limit of LH <0.1 mIU/L, prepubertal basal LH concentrations are <0.2 to 0.3 mIU/L. § In most laboratories, the upper limit of normal for LH after GnRH stimulation is 3.3 to 5.0 mIU/mL. Stimulated LH concentrations above this normal range suggests CPP. ¥ A peak stimulated LH/FSH ratio <0.66 usually suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with CPP.[1]

Reference: 1. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251. Courtesy of Drs. Mark Palmert and Jennifer Harrington.

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An Pediatr (Barc). 2012;76(4):229.e1---229.e10

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ARTÍCULO ESPECIAL Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos

L. Soriano Guillén a y J. Argente b,∗

a Unidad de Endocrinología Infantil, Servicio de Pediatría, Laboratorio de Endocrinología, Instituto de Investigación Biomédica-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Espana˜ b Servicios de Pediatría y Endocrinología, Hospital Infantil Universitario Nino˜ Jesús, Departamento de Pediatría, Universidad Autónoma de Madrid, CIBER Fisiopatología de la obesidad y nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Espana˜

Recibido el 12 de septiembre de 2011; aceptado el 14 de septiembre de 2011 Disponible en Internet el 25 de noviembre de 2011

PALABRAS CLAVE Resumen La pubertad precoz periférica (PPP) es el resultado de la aparición anormalmente Pubertad precoz precoz de la pubertad, debido al aumento de esteroides sexuales sin evidenciarse activación periférica; del eje hipotálamo-hipófiso-gonadal. Es una patología mucho más infrecuente que la pubertad Síndrome de precoz central (PPC) y es secundaria a trastornos de origen genético o a patologías adquiridas McCune-Albright; muy heterogéneas. Testotoxicosis En los últimos anos,˜ los avances moleculares han contribuido notablemente en el conoci- miento de la fisiopatología de algunos de estos trastornos, muy en particular, en el síndrome de McCune-Albright y la testotoxicosis. Asimismo, las técnicas de imagen y de cuantificación hor- monal han permitido mejorar el diagnóstico precoz de trastornos adquiridos, especialmente, patología tumoral causante de PPP. Desafortunadamente, los avances médicos objetivados en el diagnóstico no se han visto refle- jados en el tratamiento médico del síndrome de McCune-Albright y la testotoxicosis. A pesar de haber probado diversas opciones terapéuticas en ambos trastornos, a día de hoy, los resultados son muy desalentadores, especialmente en el síndrome de McCune-Albright. A nuestro enten- der, este fracaso se sustenta en la ausencia de ensayos clínicos bien disenados˜ con la inclusión de un número adecuado de pacientes seguidos hasta el final de su crecimiento. © 2011 Asociación Española de Pediatría. Publicado por Elsevier España, S.L. Todos los derechos reservados.

KEYWORDS Peripheral precocious puberty: clinical, diagnostic and therapeutical principles McCune-Albright syndrome; Abstract Peripheral precocious puberty (PPP) is the result of the presence of precocious Peripheral precocious puberty due to the increase of sex steroids with no evidence of activation of the hypothalamic- puberty; pituitary-gonadal axis. It is much less common than central precocious puberty (CPP) and it is Testotoxicosis secondary to either genetic disorders or very heterogeneous acquired diseases.

∗ Autor para correspondencia. Correo electrónico: [email protected] (J. Argente).

1695-4033/$ – see front matter © 2011 Asociación Española de Pediatría. Publicado por Elsevier España, S.L. Todos los derechos reservados. doi:10.1016/j.anpedi.2011.09.014

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229.e2 L. Soriano Guillén, J. Argente

In recent years, molecular advances have made remarkable progress in understanding the pathophysiology of some of these disorders, most notably in McCune-Albright syndrome and testotoxicosis. In addition, new imaging techniques and better hormone assays have improved the early diagnosis of acquired disorders, particularly tumour disease causing PPP. Unfortunately, medical advances in the diagnosis of these disorders have not been reflected in the medical treatment of McCune-Albright syndrome and testotoxicosis. Despite having tried various treatment options in both disorders, the results are very disappointing, especially in patients with McCune-Albright syndrome. To our knowledge, this failure is based on the absence of well-designed clinical trials that include an adequate number of patients followed up until the end of their growth. © 2011 Asociación Española de Pediatría. Published by Elsevier España, S.L. All rights reserved.

Introducción Genética

El término pubertad precoz periférica (PPP) se utiliza La forma congénita más frecuente de PPP es la hiperplasia para designar aquellos cuadros clínicos de pubertad pre- suprarrenal congénita en el varón, ya que produce un exceso coz (aparición de caracteres sexuales junto a adelanto de de andrógenos y, secundariamente, aparición de caracteres la maduración ósea y aceleración del crecimiento antes de sexuales masculinos de manera precoz. En este trabajo, nos los 8 anos˜ en ninasy9a˜ nos˜ en ninos)˜ que no son mediados por centraremos en otros trastornos genéticos causantes de PPP. el eje hipotálamo-hipófiso-gonadal; es decir, aquellas situa- ciones en las que no hay elevación de gonadotropinas1 --- 4 . Síndrome de McCune-Albright A diferencia de lo que ocurre con la pubertad precoz cen- Desde la descripción inicial de McCune y Albright en 19366,7 tral (PPC)5, no hay datos epidemiológicos generales sobre hasta el momento actual, el conocimiento de la fisiopa- PPP. Tampoco existen datos de incidencia y prevalencia tología y las bases moleculares de este síndrome se han de algunos trastornos específicos como el síndrome de desarrollado extraordinariamente. De manera que, aunque McCune Albright (SMA) y la testotoxicosis. tradicionalmente se describía la tríada clásica de PPP, man- chas café con leche y displasia fibrosa ósea (figs. 1 y 2), en la actualidad, se considera un síndrome heterogéneo con un amplio espectro de manifestaciones endocrinas y no Etiopatogenia endocrinas8-10. Este cuadro clínico se produce por una mutación somá- Mucho más infrecuente que la PPC, puede ser de origen tica activante de la subunidad ␣ de la proteína G (20q13.2), genético o adquirido (véase tabla 1). primordial en la senalización˜ intracelular de células endo- crinas y de otros tejidos11. En la mayoría de las ocasiones, se trata de una mutación sin sentido ocasionada por una susti- tución de una arginina en posición 201 por una histidina. Con menor frecuencia podemos encontrar una serina, leucina o Tabla 1 Clasificación etiológica de la pubertad precoz glicina sustituida por una histidina. Por otra parte, es preciso periférica resenar˜ que aquellas mutaciones que aparecen en etapas precoces de la embriogénesis presentan una distribución Nino˜ Genética muy amplia en distintos tejidos, constituyendo un fenotipo más severo, mientras que las mutaciones que ocurren más Variantes de LHR (testotoxicosis) tardíamente en el desarrollo afectan a menor número de Hiperplasia suprarrenal congénita tejidos y, por consiguiente, presentan un fenotipo más leve Mutación gen DAX1 12 Adquirida o incompleto . Por tanto, la expresividad clínica es muy Tumor testicular/suprarrenal heterogénea y, en ocasiones, no es fácil encontrar la triada clásica ni descubrir la mutación en sangre periférica, lo que Tumores productores de ␤-HCG 8-10 Esteroides sexuales exógenos puede complicar el diagnóstico . La presencia de pubertad precoz es la anomalía endo- Nina˜ crina más frecuente asociada a este síndrome, apareciendo Genética entre los2y6anos.˜ Este cuadro se caracteriza por aparición Síndrome de McCune-Albright (muy raro en ninos)˜ de telarquia fluctuante junto con episodios cíclicos de san- Adquirida grado vaginal y aceleración de la velocidad de crecimiento. Quiste ovárico Es preciso resenar˜ que en este síndrome no es habitual Tumor ovárico/suprarrenal una progresión puberal normal; es decir, pueden aparecer Esteroides sexuales exógenos episodios repetitivos de sangrado vaginal sin un desarrollo Nino/ni˜ na˜ mamario importante. Estos episodios cíclicos son fruto de la Hipotiroidismo primario (excepcional) alteración de la subunidad ␣ de la proteína G que resulta en una activación del ovario, formando quistes productores

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Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos 229.e3

Figura 1 Manchas café con leche de gran tamano˜ (cara interna de muslo izquierdo y dorso) de una ninade7a˜ nos˜ y 6 meses de edad, afecta de síndrome de McCune-Albright.

de estrógenos. De esta forma, la resolución espontánea de acromegalia, hiperplasia adrenal autónoma y osteomalacia estos quistes produce una caída de los estrógenos seguida hipofosfatémica8-10. de episodios de sangrado vaginal8. La manifestación clínica no endocrina más frecuente La evolución natural de esta entidad es muy variable, del SMA es la displasia ósea, que condiciona una morbi- alternando periodos asintomáticos con otros de frecuen- mortalidad considerable por la presencia de dolores óseos tes sangrados vaginales. Así, en los episodios de sangrado importantes y por el incremento notable del riesgo de frac- vaginal abundante será necesario descartar la presencia de turas patológicas y de transformación sarcomatosa maligna. quistes ováricos de gran tamano˜ que puedan producir tor- No obstante, en los últimos anos˜ se está mejorando nota- sión ovárica. Por otra parte, estas ninas˜ presentan un mal blemente la calidad de vida de estos pacientes gracias al pronóstico de talla ya que desarrollan una aceleración pro- empleo de bifosfonatos8. gresiva del crecimiento con una fusión precoz de las epífisis. Los ninos˜ afectos de SMA pueden presentar macroorqui- De manera infrecuente pueden desarrollar otros trastor- dismo sin otros signos clínicos ni biológicos de pubertad nos endocrinos, como hipercortisolismo, hipertiroidismo, precoz. Este hecho es debido a mutaciones de la subunidad

Figura 2 Radiografías antero-posteriores de fémur derecho (distintos ángulos) de ninade7a˜ nos˜ afectada de síndrome de McCune- Albright. Se puede apreciar una fractura patológica subtrocantérea sobre lesión típica de displasia fibrosa ósea (de unos 4 × 2 cm).

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229.e4 L. Soriano Guillén, J. Argente

␣ de la proteína G que se presentan únicamente en las Por tanto, las mutaciones del gen DAX1 tienen un efecto dual células de Sertoli, produciendo una hipertrofia de estas. De sobre el desarrollo puberal: PPP en la infancia e hipogona- forma infrecuente, menos del 15% de las ocasiones, los ninos˜ dismo en la etapa adulta16, habiéndose descrito, finalmente, con SMA asocian PPP.Esta expresividad clínica tan diferente un efecto de mini-pubertad con aumento testicular17. observada en ninos˜ y ninas˜ parece que pudiera estar rela- cionada con un fenómeno de imprinting, de tal forma que Adquirida si la mutación se expresa en células de Sertoli conduce a macroorquidismo, mientras que si lo hace en las células de Leydig se expresaría como PPP8,9. La PPP adquirida es secundaria al aumento de esteroides sexuales exógenos o endógenos. Aunque es infrecuente, se han descrito sujetos que han presentado caracteres sexuales Testotoxicosis o pubertad precoz familiar del varón secundarios de forma precoz tras la ingesta de anticoncep- Es una forma de PPP isosexual e independiente de la acti- tivos orales o esteroides anabolizantes, así como tras el vación de LHRH, que acontece únicamente en varones y es contacto, a través de la piel, con preparados que contienen producida por elevación de los niveles de testosterona de estrógenos o testosterona10. forma autónoma, condicionando la aparición de caracteres De causa endógena, en los varones hay que descartar sexuales secundarios en los varones afectos de forma muy tumores secretores de andrógenos originados en el testículo precoz (entre el primer y cuarto ano˜ de vida), con incre- (tumores de células de Leydig) y en la glándula suprarrenal. mento de la velocidad de crecimiento y aceleración de la 13 Por otro lado, en las ninas˜ con signos de PPP es menester maduración ósea . descartar tumores secretores de estrógenos localizados en Esta perturbación precoz de la síntesis de testosterona ovario (fig. 3) o en glándula suprarrenal, sin olvidar la posi- es producida por una mutación activante del receptor de LH ble presencia de quistes ováricos funcionales benignos como que se hereda de forma dominante, aunque pueden existir causa de hiperestrogenismo10,18-20. de novo 14 mutaciones , afectando únicamente a varones . Los tumores germinales productores de gonadotropina La testotoxicosis puede producir trastornos psicológicos coriónica humana (HCG) son capaces de producir PPP en los en el nino˜ afectado, derivados de la activación muy precoz varones ya que la HCG tiene un efecto similar a la hormona de la pubertad, así como virilización rápida, cierre pre- luteinizante sobre el testículo, estimulando la síntesis de maturo epifisario y talla baja adulta. Por otro lado, estos testosterona. Estos tumores se localizan fundamentalmente pacientes pertenecen al grupo de PPP, pero a diferencia del en hígado, cerebro, mediastino y gónadas. Por el contrario, resto de entidades causantes de PPP en el varón, en este en las ninas,˜ estos tumores no son causantes de pubertad caso existe aumento de tamano˜ testicular bilateral, lo que precoz porque la presencia aislada de LH, sin un aumento puede hacer sospechar una PPC. No obstante, la ausencia concomitante de FSH, es insuficiente para desarrollar clínica de elevación de LH tras test de estimulación junto a los de este tipo10,18-20. antecedentes familiares, deben orientarnos a este cuadro clínico13,15. Evaluación diagnóstica Hipoplasia suprarrenal congénita por mutación del gen DAX1 (dosage-sensitive sex reversal, adrenal congenital Anamnesis hypoplasia, critical region on X chromosome) Los ninos˜ con mutaciones en DAX1 presentan insuficiencia Debe interrogarse sobre la aparición cronológica de los dife- suprarrenal por hipoplasia de estas glándulas y, típicamente, rentes caracteres sexuales. en la etapa adulta desarrollan hipogonadismo hipogonado- Debe valorarse la existencia o no de aceleración de cre- tropo. Sin embargo, hay casos descritos de PPP en la primera cimiento en las gráficas de talla para edad y sexo. infancia. Este hecho parece estar relacionado con los niveles Debe preguntarse sobre la existencia de síntomas de tan elevados de ACTH existentes que pudieran actuar sobre hipertensión intracraneal (cefalea, vómitos, disminución de la célula de Leydig, estimulando la síntesis de testosterona. la agudeza visual).

Figura 3 A) Lactante de 18 meses de edad que, en el momento del diagnóstico, presenta aceleración del crecimiento desde hace 5 meses (talla en +5 SDS), acompanada˜ de telarquia bilateral y sangrado vaginal. Nótense la telarquia y el incremento de pigmentación areolar bilaterales. B) Pieza de ovario izquierdo. El estudio anatomo-patológico reveló que existía un luteoma.

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Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos 229.e5

Debe conocerse la posibilidad de haber ingerido fármacos --- T4 libre y TSH: para descartar hipotiroidismo primario, que contengan esteroides sexuales. causa excepcional de pubertad precoz. Debe demandarse información a los padres acerca de su talla (cálculo de talla diana) y de su desarrollo pube- Por otra parte, disponemos de una serie de pruebas de ral, incluyendo también abuelos, tíos y hermanos del caso imagen de enorme utilidad para el diagnóstico diferencial índice3,4,18-20. de las distintas formas de pubertad precoz3,4,18-21:

Examen físico --- Cálculo de la edad ósea mediante radiografía de mano- muneca˜ izquierda: en los casos de pubertad precoz hay paralelamente aceleración de la edad ósea, en compara- Ante cualquier paciente con sospecha de PPP será preciso ción con las variantes de la normalidad. No obstante, en recoger las siguientes variables 3,4,18-20. casos de reciente diagnóstico de PPP, la edad ósea puede ser similar a la edad cronológica. --- Peso, talla, velocidad de crecimiento, índice de masa cor- --- Ecografía testicular: se realizará siempre que haya sos- poral. pecha de pubertad precoz en el varón que presenta --- Presión arterial, frecuencia cardiaca. asimetría testicular. Asimismo en situaciones de sospe- --- Acné, vello corporal, estrías. cha de pubertad precoz con elevación de testosterona y --- Presencia de bocio. volumen testicular inferior a 4 ml. --- Palpación abdominal (tumor suprarrenal, hepático, ová- --- Ecografía abdominal: de utilidad para valorar área rico) (fig. 3). suprarrenal, tanto en sospecha de tumores virilizantes --- Estadio puberal de Tanner. en el varón, como en ninas˜ con sospecha de pubertad --- Palpación y medición de testículos para descartar asime- precoz periférica por un tumor productor de estróge- tría testicular. nos. Asimismo se realizará cuando haya indicios de tumor --- Manchas café con leche (fig. 1). hepático productor de ␤-HCG. --- Ecografía pélvica: se realizará en todos los casos de Pruebas complementarias pubertad precoz. Por un lado, permite descartar patolo- gía causante de PPP (tumores ováricos, quistes ováricos) y, por otro, valora la existencia de signos de impregnación La determinación de gonadotropinas basales y tras estímulo estrogénica. con LHRH (100 ␮g/m2 iv) es primordial para el diagnóstico --- RM craneal: de obligada realización en todos los casos de diferencial entre PPC y PPP. Si bien no existe unanimidad PPC, tanto en ninos˜ como ninas.˜ También se efectuará en en la comunidad científica internacional sobre el punto de casos de PPP en el nino˜ por sospecha de tumor productor corte de LH para definir PPC y PPP, la mayoría de autores lo de ␤-HCG extragonadal no hepático. sitúan entre5y8U/l3,4,21. --- Serie ósea: para excluir la presencia de displasia fibrosa Además del estudio de gonadotropinas basales y tras asociada a SMA. estímulo, existen otras determinaciones sanguíneas que ser- virán de complemento en el diagnóstico diferencial de PPP3,4,18-20; son las que siguen: Finalmente, ante una sospecha clínica elevada, procedere- mos al estudio genético: --- Testosterona: sus niveles séricos son de utilidad para el --- Estudio del gen del receptor de LH (LHR) en la testotoxi- diagnóstico de pubertad precoz en el nino.˜ Así, valores cosis. por encima de 0,5 ng/ml se consideran en rango puberal. --- Estudio del gen DAX1 ante la sospecha de una hipoplasia --- 1 7 - ␤-estradiol: escasa sensibilidad, ya que valores nor- suprarrenal congénita. males, no descartan pubertad precoz; sin embargo, se --- Estudio gen la subunidad ␣ de la proteína G: la renta- encuentra muy elevada en presencia de tumores ováricos bilidad en sangre periférica es modesta. Por lo que es y suprarrenales productores de estrógenos, así como ante de interés efectuar el estudio en tejidos afectos (ovario, quistes ováricos aislados o asociados a SMA. hueso). --- DHEA-S, androstendiona ( 4) y 17-OH-progesterona: úti- les en el nino˜ con sospecha de pubertad precoz. Si encontramos cifras de DHEA-S por encima de 700 ␮g/dl en Diagnóstico diferencial un nino˜ en edad prepuberal, es altamente sugerente de tumor suprarrenal. Elevaciones moderadas, tras prueba Telarquia prematura aislada de imagen normal, nos obligan a descartar una hiperplasia suprarrenal de presentación tardía. Desarrollo mamario uni o bilateral antes de los 8 anos˜ de --- ␤-HCG (fracción ␤ de gonadotropina coriónica humana): edad, sin evidencia de otros signos de pubertad precoz tales de utilidad como marcador tumoral en casos de pubertad como: aceleración del crecimiento, edad ósea incrementada precoz periférica con tamano˜ testicular menor de 4 ml en y aparición de vello púbico y/o axilar. Es una entidad relati- el que no se encuentra alteración testicular ni suprarrenal vamente frecuente, con una incidencia de hasta 21,2 casos (cuando se trata de tumores germinales extragonadales: por 100.000/ano.˜ En la mayoría de ocasiones (hasta un 60%) hígado, mediastino, cerebro). Los tumores germinales aparece antes de los 2 anos˜ de edad y tiende a la regresión testiculares productores de ␤-HCG producen asimetría espontánea (entre 6 mesesa6anos).˜ El otro pico de presen- testicular (a veces tamano˜ testicular > 4 ml). tación es entre los5y7anos,˜ y es en estas situaciones donde

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229.e6 L. Soriano Guillén, J. Argente

se han descrito mayor porcentaje de telarquias exageradas Tratamiento y mayor prevalencia de pacientes (hasta un 14% según las series) que pueden progresar a un cuadro clínico de PPC. Ante procesos adquiridos de PPP,se procederá, si es posible, A día de hoy, la etiología de este trastorno es desco- a resolver la causa (quistes, tumores, esteroides exógenos). nocida, aunque se barajan varias hipótesis: a) activación Una atención especial merece el tratamiento del SMA y transitoria parcial del eje hipotálamo-hipofisario-gonadal, de la Testotoxicosis (tablas 2---4). con aumento de niveles séricos de FSH; b) fallo de la involución folicular con o sin formación ovárica quística; c) sensibilidad excesiva del tejido mamario a la misma Síndrome de McCune-Albright cantidad de estrógenos; d) contaminantes ambientales o productos alimentarios con actividad estrogénica; e) posi- Los objetivos del tratamiento en este tipo de pacientes bles formas incompletas de SMA (en particular, formas muy serán evitar trastornos psicológicos derivados de un ade- floridas de telarquia prematura)22,23. lanto puberal, frenar los sangrados cíclicos y conseguir un buen pronóstico de talla final. A día de hoy, desafortunada- mente, no existe ningún tratamiento que haya demostrado Menarquia prematura aislada cumplir dichos objetivos en este tipo de pacientes, debido a varias razones: a) inexistencia de ensayos clínicos aleatori- Proceso de sangrado vaginal periódico en ninas˜ de edades zados; b) estudios piloto, sin grupo control, con un número comprendidas entre1y9anos,˜ sin acompanarse˜ de otros muy reducido de pacientes; c) ausencia de datos de talla signos de desarrollo sexual secundario. De etiología desco- adulta, y d) en muchas ocasiones, es necesario asociar aná- nocida, aunque se especula con las mismas teorías que en el logos de GnRH al presentar secundariamente una activación caso de la telarquia prematura. Se trata de un diagnóstico central de la pubertad (PP mixta)3,4,10,25. de exclusión donde previamente deben descartarse otras Para el tratamiento de esta entidad, clásicamente, se entidades que cursan con sangrado periódico: síndrome de han utilizado dos grupos terapéuticos: inhibidores de la aro- McCune-Albright, procesos tumorales vaginales o uterinos, matasa e inhibidores del receptor de estrógenos (véase la enfermedad inflamatoria pélvica, cuerpo extrano˜ en vagina tabla 2). Así, a mediados de los anos˜ ochenta, aparecie- o exposición a estrógenos exógenos22---24. ron datos prometedores en 5 ninas˜ tratadas con un inhibidor

Tabla 2 Fármacos utilizados en el tratamiento del síndrome de McCune-Albright Fármaco Ano˜ publicación Diseno/tama˜ no˜ Duración Eficacia Efectos (referencia muestral estudio secundarios bibliográfica) Testolactona 199327 Estudio piloto 3anos˜ Dudosa Dolor abdominal (40 mg/kg/día) 12 ninas˜ Frecuente activación Cefalea central de la Diarrea pubertad Hipertransaminasemia Incumplimiento terapéutico frecuente Fadrozol (240- 200328 Estudio piloto 2-3 anos˜ Ineficaz Dolor abdominal 480 ␮g/kg/día) 16 ninas˜ Frecuente activación Inhibición de la central de la síntesis de cortisol pubertad y aldosterona Tamoxifeno 200331 Estudio piloto 1ano˜ Disminución Aumento de (20 mg/día) 28 ninas˜ significativa de tamano˜ uterino y sangrado vaginal ovárico durante el Desaceleración de la tratamiento velocidad de crecimiento y de la maduración ósea Letrozol (1,5- 200729 Estudio piloto 1-3 anos˜ Disminución Aumento de 2 mg/m2/día) 9 ninas˜ significativa de tamano˜ ovárico sangrado vaginal Incremento de Desaceleración de la quistes ováricos velocidad de Una nina˜ presentó crecimiento y de la rotura de quiste maduración ósea ovárico tras 2 anos˜ de tratamiento Anastrozol 200830 Estudio piloto 1ano˜ Ineficaz Bien tolerado (1 mg/día) 28 ninas˜

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Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos 229.e7 Efectos secundarios Hipertransaminasemia transitoria en un paciente No descritos No descritos No descritos Ginecomastia en 6 pacientes. Dolor de mamas en 2Elevación pacientes. transitoria de transaminasas en un paciente. Dolor muscular en un paciente Testolactona: dolor abdominal, cefalea, diarrea, hipertransaminemia Espironolactona: cefalea, hipercaliemia, molestias intestinales, cefalea No descritos No descritos Talla adulta acorde con tallaNingún genética caso de activación centralla de pubertad Eficacia modesta: menos de unalcanza 50% talla adulta acorde congenética. talla El 40% presenta activación centralla de pubertad Eficacia modesta: menos de unalcanza 50% talla adulta acorde congenética talla El 40% presenta activación centralla de pubertad No hay datos de tallaReducción adulta significativa de VC y madurez ósea Necesidad de análogos de GnRHde en los 1 casos Reducción muy modesta de VC Reducción moderada de la maduración ósea El 43% precisa asociar análogosGnRH de No hay datos sobre tallaDesaceleración adulta de la velocidad de crecimiento Estabilización de la edad ósea El 100% presenta activación central de la pubertad No hay datos de tallaReducción adulta significativa de VC ymadurez de ósea No hay datos de tallaReducción adulta significativa de VC y madurez ósea Necesidad de análogos de GnRHlos en 2 casos ˜ no de ˜ ˜ nos nos ˜ nos ˜ ˜ ˜ nos nos nos Duración estudio Eficacia 6a 5-9 a 5a8a 5a8a Paciente 1: 44 meses Paciente 2: 17 meses 4a 5a Evaluación del primer a terapia ˜ no ˜ nos ˜ no/tama ˜ ˜ ˜ ˜ nos nos nos nos Estudio descriptivo 10 ni Estudio descriptivo 5 ni Estudio descriptivo 5 ni Estudio descriptivo 5 ni Estudio descriptivo 2 casos Estudio descriptivo 2 ni Estudio descriptivo 2 casos Estudio piloto en fase II en 14 pacientes Dise muestral 33 15 34 34 35 36 37 38 ˜ no publicación 2008 2008 A (referencia bibliográfica) 1999 2008 2006 2005 2010 2010 /día) /día) 2 2 Fármacos utilizados en el tratamiento de testotoxicosis (5,7 mg/kg/día) + testolactona (40 mg/kg/día) (10 mg/kg/día) (70 mg/m + anastrozol (1 mg/día) + ciproterona (70 mg/m (15-20 mg/kg/día) + letrozol (2,5 mg/día) o anastrozol (1 mg/día) 50 o 100 mg/día) + anastrozol (0,5 o 1 mg/día) Tabla 3 Fármaco Espironolactona Ketoconazol Ciproterona Bicalutamida (50 mg/día) Anastrozol (1 mg/día) Ketoconazol Bicalutamida (50 mg/día) Bicalutamida (12,5, 25,

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229.e8 L. Soriano Guillén, J. Argente

de aromatasa de primera generación, la testolactona26; sin en estas pacientes. En este sentido, parece que la tendencia embargo, el seguimiento a largo plazo de este mismo grupo actual ante la presencia de un quiste en una nina˜ o adoles- de pacientes mostró que los sangrados vaginales no se dete- cente es considerar la realización de punción-aspiración del nían y persistía la recurrencia de quistes ováricos, con el mismo, mediante laparoscopia, cuando supere un volumen riesgo de torsión que esto supone. Además, el cumplimiento de 20 ml (3,2 cm de diámetro) y, muy especialmente, cuando terapéutico no era el adecuado debido a la ingente cantidad supere 75 ml (5,2 cm de diámetro) dado el enorme riesgo de de pastillas diarias que debían tomar27. Con posterioridad, torsión ovárica existente32. Estas consideraciones podrían se disenó˜ un nuevo estudio piloto en 16 pacientes con fadro- ser perfectamente aplicables a ninas˜ afectas de SMA, donde zol (inhibidor de segunda generación) obteniendo, de igual el riesgo de torsión es todavía mayor. forma que con testolactona, unos resultados desalentado- res junto a un efecto inhibidor dependiente de la dosis de la síntesis de cortisol y aldosterona28. Testotoxicosis Más recientemente, aparecieron los inhibidores de ter- cera generación: letrozol y anastrozol. En un estudio de Los objetivos del tratamiento son similares a los del grupo 9 pacientes con SMA tratadas con letrozol durante 12 a anterior y, al igual que en el SMA, carecemos de ensayos 36 meses se mostró una desaceleración de la velocidad de clínicos aleatorizados que hayan evaluado la eficacia real crecimiento, una disminución de la edad ósea, así como de las distintas opciones terapéuticas utilizadas. Además, una reducción en el número de sangrados vaginales. No disponemos de pocos datos a talla adulta y, en muchas oca- obstante, durante el estudio se objetivó un aumento del siones, ha sido necesaria la asociación de análogos de GnRH tamano˜ ovárico, así como un incremento de la formación (véase la tabla 3). de quistes ováricos, con un caso descrito de rotura de un En esta situación, debemos actuar sobre el exceso de quiste tras 2 anos˜ de tratamiento29. Teniendo en cuenta andrógenos existente, inhibiendo su síntesis o bloqueando estas últimas observaciones, habrá que esperar nuevos datos su acción. De esta forma, tradicionalmente se han planteado en mayor número de pacientes con un periodo de estu- dos formas de tratamiento9,10: a) inhibir la síntesis de testos- dio más prolongado. Respecto al anastrozol, recientemente terona mediante la utilización de ketoconazol, y b) bloquear se ha constatado su ineficacia en el tratamiento de la el receptor de andrógenos e inhibir la síntesis de estrógenos, PPP30. que son los esteroides sexuales que actúan directamente El otro fármaco utilizado en el tratamiento médico de sobre las epífisis y producen un cierre prematuro de estas. estas pacientes ha sido el tamoxifeno, un inhibidor del Actualmente, disponemos de datos de talla adulta en receptor de estrógenos. Los datos preliminares, tras un 5 pacientes tratados con ketoconazol. En este grupo de ano˜ de tratamiento, de un estudio piloto con tamoxifeno ninos˜ afectados de testotoxicosis, la talla final media fue publicado en 200331 parecían alentadores, a pesar de haber de 173 cm (talla diana: 175 cm), el tratamiento fue bien objetivado aumento de tamano˜ uterino y ovárico durante tolerado y ninguno de los ninos˜ incluidos presentó una acti- el período de estudio. Sin embargo, llama la atención que vación central precoz de la pubertad15. Por el contrario, no desde el ano˜ 2003 no se hayan comunicado nuevos datos. disponemos de datos de talla adulta del tratamiento que Por otra parte, no existe un consenso firme en cuanto a combina testolactona y espironolactona. Únicamente apa- la actitud terapéutica ante la presencia de quistes ováricos recieron datos preliminares a los 6 anos˜ de seguimiento,

Tabla 4 Dosis y coste de distintos fármacos utilizados en el tratamiento de la pubertad precoz periférica Mecanismo de acción Dosis habituales Intervalo de dosis Coste mensual (h)/presentación (mg) aproximado (euros)a Ketoconazol Inhibidor enzima p450 15-20 mg/kg/día 8/200 84 Espironolactona Antiandrógeno débil 2-5 mg/kg/día 12/100 51 Ciproterona Progestágeno con acción 70 mg/m2/día 24/50 41 antiandrogénica Bicalutamida Potente antiandrógeno 2 mg/kg/día 24/50 96 no esteroideo Testolactona Inhibidor de aromatasa 20-40 mg/kg/día 6/50 1528 de primera generación Anastrozol Inhibidor de aromatasa 1 mg/día 24/1 282 de tercera generación Letrozol Inhibidor de aromatasa 2,5 mg/día 24/2,5 293 de tercera generación Tamoxifeno Bloqueante del receptor 20 mg/día 24/20 8 de estrógenos Triptorelina Análogo de GnRH 80-120 (g/kg/mes) Mensual/presentación: 162 3,75 mg/1 ml a Cálculo basado en una dosis para 30 kg, 130 cm y superficie corporal de 1 m2 (peso y talla media de un ninode9a˜ nos).˜ Adaptado de Lenz et al37.

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Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos 229.e9

objetivando desaceleración de la velocidad de crecimiento estudios iniciados y conocer datos a talla adulta, evaluando y del adelanto puberal; sin embargo, todos los pacientes los posibles efectos secundarios del tratamiento instaurado desarrollaron PPC y precisaron la asociación de análogos de a más largo plazo. A la espera de conocer los resultados GnRH33. Por otra parte, este régimen de tratamiento pre- de estas investigaciones, será preciso individualizar cada senta el inconveniente de que su monitorización se realiza paciente y pautar el tratamiento del que se disponga de más mediante parámetros clínicos (velocidad de crecimiento, experiencia, teniendo en cuenta su tolerancia, así como su maduración ósea y estadio puberal), ya que no hay cambios coste (grado de recomendación y nivel de evidencia cientí- en los niveles de testosterona. fica CIII). También se ha utilizado un progestágeno bloqueador del receptor de andrógenos (ciproterona) como única terapia de Tratamiento de testotoxicosis testotoxicosis, siendo bien tolerado, aunque con modestos resultados en cuanto a talla final y con activación central de la pubertad de forma precoz en un 40% de los pacientes. No hay evidencia científica suficiente para recomendar En este mismo trabajo, aparecen datos de talla adulta en terapia con ketoconazol en este síndrome (grado de reco- ninos˜ tratados con ketoconazol siendo la eficacia similar a mendación y nivel de evidencia científica AI). No obstante, la ciproterona y con el mismo porcentaje de casos de PPC a nuestro entender, presenta una serie de ventajas sobre secundaria34. Esta modesta eficacia de testolactona puede el resto de fármacos utilizados hasta el momento: a) datos ser debida a que la dosis utilizada ha sido notablemente a talla adulta; b) bien tolerado, ocasionalmente produce inferior a la empleada en estudios previos15. hipertransaminasemia transitoria a las dosis utilizadas; c) es Con posterioridad, han ido surgiendo distintas modalida- muy infrecuente la aparición de PPC durante esta terapia; des terapéuticas que han asociado un inhibidor de aromatasa d) control de la eficacia del tratamiento no sólo mediante el de tercera generación con bloqueadores del receptor de seguimiento de la velocidad de crecimiento y la regresión de andrógenos35-37. Estos trabajos tienen en común el escaso caracteres sexuales, sino también con los niveles circulantes número de pacientes y la ausencia de datos a talla adulta. de testosterona, y e) bajo coste (grado de recomendación y En la misma línea, el estudio piloto en fase II BATT38 incluye nivel de evidencia científica CIII). a 14 pacientes a los que se les pauta tratamiento con un anti- andrógeno no esteroideo muy potente (bicalutamida) a dosis Conflicto de intereses progresivas, junto con un inhibidor de aromatasa de tercera generación (anastrozol). Los resultados preliminares de este Los autores declaran no tener ningún conflicto de intereses. estudio, tras un ano˜ de tratamiento, son muy modestos y no exentos de efectos secundarios (véase la tabla 3). Finalmente, es preciso resenar˜ que tanto en el SMA como Bibliografía en la testotoxicosis deberemos tener en cuenta no sólo la eficacia y los posibles efectos secundarios de la terapia a 1. Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari instaurar, sino también la manera de dosificar los fármacos J, Bourguignon JP. The timing of normal puberty and the (los comprimidos son difíciles de ingerir, más aún, si es cada age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev. 6 horas) y el coste de los mismos (tabla 4). Así, por ejemplo, 2003;66:8---93. un paciente afecto de testotoxicosis, de unos 30 kg de peso, 2. Cartault A, Edouard T,Pienkowski C, Tauber M. Normal puberty. que reciba terapia con bicalutamida y anastrozol y que, a su Rev Prat. 2008;58:1311---6. vez, necesite terapia con análogos de GnRH (fenómeno de 3. Soriano Guillén L, Argente J. Fundamentos clínicos y escape frecuente con esta terapia), estará gastando aproxi- diagnóstico-terapéuticos de la pubertad precoz central y peri- madamente 540 euros mensuales. férica. Rev Esp Ped. 2009;65:445---61. 4. Soriano Guillén L, Argente J. Pubertad precoz central: epi- demiología, etiología, diagnóstico y tratamiento. An Pediatr Áreas de controversia y perspectivas futuras (Barc). 2011;74:336.e1---13. 5. Soriano-Guillén L, Corripio R, Labarta JI, Canete˜ R, Diagnóstico del síndrome de McCune-Albright Castro-Feijóo L, Espino R, et al. Central Precocious Puberty in children living in Spain: Incidence, Prevalence, and influence Será preciso continuar investigando aquellos pacientes con of adoption and immigration. J Clin Endocrinol Metab. fenotipo no clásico (falta de todos los criterios), en especial, 2010;95:4305---13. aquellos sujetos con telarquia prematura exagerada y test 6. Albright F, Butler A, Hampton A, Smith P. Syndrome characte- rized by osteitis fibrosa disseminata, areas of pigmentation and de LHRH prepuberal. Para ello, será primordial el avance en endocrine dysfunction, with precocious puberty in females. N los conocimientos moleculares asociados a este trastorno y, Engl J Med. 1936;216:727---46. muy en particular, en la búsqueda de métodos diagnósticos 7. McCune D. Osteitis fibrosa cystica: the case of a nine year old que puedan evitar la necesidad de estudios en tejidos como girl who exhibits precocious puberty, multiple pigmentation of hueso y/o ovario. the skin and hyperthyroidism. Am J Dis Child. 1936;52:743---4. 8. Zacharin M. The spectrum of McCune Albright syndrome. Tratamiento del síndrome McCune-Albright Pediatr Endocrinol Rev. 2007;4:412---8. 9. Haddad N, Eugster EA. An update on the treatment of pre- cocious puberty in McCune-Albright and testotoxicosis. J Ped No hay evidencia científica suficiente para recomendar nin- Endocrinol Metab. 2007;20:653---61. guna terapia en este síndrome (grado de recomendación y 10. Eugster EA. Peripheral precocious puberty: causes and current nivel de evidencia científica AI). Es preciso continuar con los management. Horm Res. 2009;71 Suppl 1:64---7.

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229.e10 L. Soriano Guillén, J. Argente

11. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, 26. Feuillan PP, Foster CM, Pescovitz OH, Hench KD, Shawker T, Spiegel AM. Activating mutations of the stimulatory G pro- Dwyer A, et al. Treatment of precocious puberty in the McCune- tein in the McCune-Albright syndrome. N Engl J Med. Albright syndrome with the aromatase inhibitor testolactone. 1991;325:1688---95. N Engl J Med. 1986;315:1115---9. 12. Lietman SA, Schwindinger WF, Levine MA. Genetic and mole- 27. Feuillan PP,Jones J, Cutler Jr GB. Long-term testolactone the- cular aspects of McCune-Albright syndrome. Pediatr Endocrinol rapy for precocious puberty in girls with the McCune-Albright Rev. 2007;4 Suppl 4:380---5. syndrome. J Clin Endocrinol Metab. 1993;77:647---51. 13. Rosenthal SM, Grumbach MM, Kaplan SL. Gonadotropin- 28. Nunez SB, Calis K, Cutler Jr GB, Jones J, Feuillan PP. Lack independent familial sexual precocity with premature Leydig of efficacy of fadrozole in treating precocious puberty in girls and germinal cell maturation (familial testotoxicosis): effects with the McCune-Albright syndrome. J Clin Endocrinol Metab. of a potent luteinizing hormone-releasing factor agonist and 2003;88:5730---3. medroxyprogesterone acetate therapy in four cases. J Clin 29. Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT. Endocrinol Metab. 1983;57:571---9. Letrozole treatment of precocious puberty in girls with the 14. Shenker A, Laue L, Kosugi S, Merendino Jr JJ, Minegishi T, McCune-Albright syndrome: a pilot study. J Clin Endocrinol Cutler Jr GB. A constitutively activating mutation of the lutei- Metab. 2007;92:2100---6. nizing hormone receptor in familial male precocious puberty. 30. Mieszczak J, Lowe ES, Plourde P, Eugster EA. The aromatase Nature. 1993;365:652---4. inhibitor anastrozole is ineffective in the treatment of preco- 15. Soriano-Guillén L, Lahlou N, Ghauvet G, Roger M, Chaussain JL, cious puberty in girls with McCune-Albright syndrome. J Clin Carel JC. Adult height after ketoconazole treatment in patients Endocrinol Metab. 2008;93:2751---4. with familial male-limited precocious puberty. J Clin Endocri- 31. Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, nol Metab. 2005;90:147---51. Pescovitz OH. Tamoxifen treatment for precocious puberty 16. Domenice S, Latronico AC, Brito VN, Arnhold IJ, Kok in McCune-Albright syndrome: a multicenter trial. J Pediatr. F, Mendonca BB. Adrenocorticotropin-dependent precocious 2003;143:60---6. puberty of testicular origin in a boy with X-linked adrenal hypo- 32. Linam LE, Darolia R, Naffaa LN, Breech LL, O’hara SM, plasia congenita due to a novel mutation in the DAX1 gene. J Hillard PJ, et al. US findings of anexal torsion in children and Clin Endocrinol Metab. 2001;86:4068---71. adolescents: size really does matter. Pediatr Radiol. 2007;37: 17. Argente J, Ozisik G, Pozo J, Munoz˜ MT, Soriano-Guillén 1013---9. L, Jameson JL. A novel single base deletion at codon 434 33. Leschek EW, Jones J, Barnes KM, Hill SC, Cutler Jr GB. Six- (1301delT) of the DAX1 gene associated with prepubertal testis year results of spironolactone and testolactone treatment of enlargement. Mol Genet Metab. 2003;78:79---81. familial male-limited precocious puberty with addition of des- 18. Dattani MT, Hindmarsh PC. Normal and abnormal puberty. En: lorelin after central puberty onset. J Clin Endocrinol Metab. Brook CH, Clayton P, Brown R, editores. Clinical Pediatric 1999;84:175---8. Endocrinology. 5th ed. Oxford: Blackwell publishing; 2005. p. 34. Almeida MQ, Brito VN, Lins TS, Guerra-Junior G, de Castro M, 183---211. Antonini SR, et al. Long-term treatment of familial male- 19. Lee PA, Houk CP.Puberty and its disorders. En: Lifshitz F,editor. limited precocious puberty (testotoxicosis) with cyproterone Pediatric Endocrinology, vol. 2, 5th ed. New York: Informa acetate or ketoconazole. Clin Endocrinol (Oxf). 2008;69: Healthcare; 2007. p. 273---305. 93---8. 20. Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders 35. Kreher NC, Pescovitz OH, Delameter P, Tiulpakov A, in the female. En: Sperling MA, editor. Pediatric Endocrinology. Hochberg Z. Treatment of familial male-limited precocious 3rd ed. Philadelphia: Saunders Elsevier; 2008. p. 530---610. puberty with bicalutamide and anastrozole. J Pediatr. 21. Carel JC, Léger J. Precocious puberty. N Engl J Med. 2006;149:416---20. 2008;358:2366---77. 36. Eyssette-Guerreau S, Pinto G, Sultan A, Le Merrer M, Sultan C, 22. Diamantopoulos S, Bao Y. Gynecomastia and premature thelar- Polak M. Effectiveness of anastrozole and cyproterone acetate che: a guide for practicioners. Pediatr Rev. 2007;28:57---68. in two brothers with familial male precocious puberty. J Pediatr 23. Codner E, Roman R. Premature thelarche from phenotype to Endocrinol Metab. 2008;2:995---1002. genotype. Ped Endocrinol Rev. 2008;5:760---5. 37. Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS, 24. Brito VN, Latronico AC, Arnhold IJ, Mendoc¸a BB. Update on Pescovitz OH, et al. Bicalutamide and third-generation aroma- the etiology, diagnosis and therapeutic management of sexual tase inhibitors in testotoxicosis. Pediatrics. 2010;126:728---33. precocity. Arq Bras Endocrinol Metab. 2008;52:18---31. 38. Reiter EO, Mauras N, McCormick K, Kulshresrhtha B, Amrhein J, 25. Shulman DI, Francis GL, Palmert MR, Eugster EA. Use of De Luca F, et al. Bicalutamide plus anastrozole for the treat- aromatase inhibitors in children and adolescents with disor- ment of gonadotropin-independent precocious puberty in boys ders of growth and adolescent development. Pediatrics. with testotoxicosis: a phase II, open-label pilot study (BATT). 2008;121:975---83. J Pediatr Endocrinol Metab. 2010;23:999---1009.

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Bibliografia: Delayed Puberty, Mark R. Palmert, M.D., Ph.D., and Leo Dunkel, M.D., Ph.D., N Engl J Med 366;5, february 2, 2012 Approach to the patient with delayed puberty, William F Crowley Jr, Nelly Pitteloud, in www.uptodate.com, topic last updated: Jul 23, 2018 link: Approach to the patient with delayed puberty Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism), Nelly Pitteloud, William F Crowley Jr, Ravikumar Balasubramanian MBBS, in www.uptodate.com, last updated: Nov 21, 2017. link: Causes of delayed puberty

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Delayed Puberty

Mark R. Palmert, M.D., Ph.D., and Leo Dunkel, M.D., Ph.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations.

A 14-year-old boy with an unremarkable medical history presents because of lack of pubertal development. He has always been relatively short, but his growth velocity is slowing as compared with that of his peers. His height is 146 cm (57.5 in., <3rd percentile for age), and his weight is 37 kg (82 lb, 3rd percentile). His father, who is 168 cm (66.1 in.) tall, continued to grow until his second year in college; his mother is 153 cm (60.2 in.) tall and began menstruating at the age of 14.0 years. The patient’s target height on the basis of the parental heights is 167 cm (65.8 in.). The physical examination reveals Tanner stage 1 pubic hair and prepubertal-sized testes. How should the boy be evaluated and treated?

The Clinical Problem

Puberty leads to sexual maturation and reproductive capability. It requires an intact From the Division of Endocrinology, the hypothalamic–pituitary–gonadal (HPG) axis and is heralded by the reemergence of Hospital for Sick Children, and the De- partments of Pediatrics and Physiology, gonadotropin-releasing hormone (GnRH) secretion from its relative quiescence University of Toronto — both in Toronto during childhood. GnRH stimulates the secretion of luteinizing hormone and fol- (M.R.P.); and the Centre for Endocrinolo- licle-stimulating hormone (FSH), which then stimulate gonadal maturation and gy, William Harvey Research Institute, Barts and the London School of Medi- sex-steroid production. Much is known about components of the HPG axis, but the cine and Dentistry, Queen Mary Univer- factors that trigger pubertal onset remain elusive. It is not understood why one boy sity of London, London (L.D.). Address begins puberty at the age of 10 years and another at the age of 14 years. reprint requests to Dr. Palmert at the Hospital for Sick Children, 555 University Delayed puberty is defined as the absence of testicular enlargement in boys or Ave., Toronto, ON M5G 1X8, Canada, or breast development in girls at an age that is 2 to 2.5 SD later than the population at [email protected]; or to Dr. mean (traditionally, the age of 14 years in boys and 13 years in girls). However, Dunkel at the Centre for Endocrinology, William Harvey Research Institute, Barts 1-3 because of a downward trend in pubertal timing in the United States and other and the London School of Medicine and countries4,5 and differences in pubertal timing among racial and ethnic groups, Dentistry, Queen Mary University of Lon- some observers have advocated for updated definitions with younger age cutoffs don, Charterhouse Sq., London EC1M 6BQ, United Kingdom, or at l.dunkel@ for the general population or perhaps for particular countries or racial or ethnic qmul.ac.uk. groups. Development of pubic hair is usually not considered in the definition be- cause pubarche may result from maturation of the adrenal glands (adrenarche), N Engl J Med 2012;366:443-53. Copyright © 2012 Massachusetts Medical Society. and the onset of pubic hair can be independent of HPG-axis activation. Late puberty can affect psychosocial well-being, and patients, families, and practitioners are often concerned that it may affect adult stature. Adult height can be affected but on average is only slightly below the genetic target.6 Many adoles- An audio version cents present with delayed puberty combined with relative familial short stature, of this article compounding these concerns and leading to more subspecialty referrals than ei- is available at ther condition alone. NEJM.org Delayed puberty in boys usually represents an extreme of the normal spectrum of pubertal timing, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP). In one large series, approximately 65% of boys and 30% of girls with delayed puberty had CDGP.7 However, because the data were

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key clinical points delayed puberty • Delayed puberty is diagnosed when there is no testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the mean age at which these events occur in the population (traditionally, 14 years in boys and 13 years in girls). • Constitutional delay of growth and puberty (CDGP) is the single most common cause of delayed puberty in both sexes, but it can be diagnosed only after underlying conditions have been ruled out. • The cause of CDGP is unknown, but most patients with CDGP have a family history of delayed puberty. • Management of CDGP may involve expectant observation or therapy with low-dose sex steroids. • When treatment is given, the goals are to induce the appearance of secondary sexual characteristics or the acceleration of growth and to mitigate psychosocial difficulties associated with pubertal delay and short stature. • The routine use of growth hormone, anabolic steroids, or aromatase inhibitors is not currently recommended.

obtained from a tertiary referral center, these delayed development among family members percentages may underestimate the frequency of (e.g., the average age at menarche among moth- CDGP encountered by primary care providers. ers is 14.3 years, as compared with a mean of The evaluation and treatment of boys with CDGP 12.7 years among controls9) or evidence of true is the main focus of this review, but consider- CDGP. The investigation of patients with the ation is given to other causes of delayed puberty Kallmann syndrome and isolated hypogonado- and issues specific to girls. tropic hypogonadism has led to the identifica- Although CDGP represents the single most tion of genes that play critical roles in the de- common cause of delayed puberty in both sexes, velopment and regulation of the HPG axis, but it can be diagnosed only after underlying condi- mutations that have been identified in such tions have been ruled out. The differential diag- genes do not cause CDGP, except in rare in- nosis of CDGP can be divided into three main stances.11,12 However, the genes causing 60 to categories7: hypergonadotropic hypogonadism 70% of cases of the Kallmann syndrome and (characterized by elevated levels of luteinizing isolated hypogonadotropic hypogonadism re- hormone and FSH owing to the lack of negative main unknown.13 Loci have also been identi - feedback from the gonads), permanent hypogo- fied that are associated with the age of men- nadotropic hypogonadism (characterized by low arche in the general population,14-18 but these levels of luteinizing hormone and FSH owing to particular loci have likewise not been associ- hypothalamic or pituitary disorders), and transient ated with CDGP.19 hypogonadotropic hypogonadism (functional hy- pogonadotropic hypogonadism), in which puber- Strategies and Evidence tal delay is caused by delayed maturation of the HPG axis secondary to an underlying condition First-Line Evaluation (Table 1, and Table 1 in the Supplementary Ap - Ruling Out Underlying Disorders pendix, available with the full text of this article The aim of initial evaluation is to rule out at NEJM.org). underlying disorders causing delayed puberty The cause of CDGP is unknown, but it has a (Table 2, and Table 2 in the Supplementary Ap- strong genetic basis. It has been estimated that pendix).20-28 Pubertal development is assessed 50 to 80% of variation in the timing of puberty clinically and biochemically, providing infor- in humans is due to genetic factors,8 and 50 to mation that is important for counseling and 75% of patients with CDGP have a family his- predicting further pubertal development. Even- tory of delayed puberty.9,10 The inheritance of tual normal progression of puberty verifies the CDGP is variable but most often is consistent diagnosis of CDGP, whereas absent or slow with an autosomal dominant pattern, with or development or cessation of development after without complete penetrance. CDGP is not sex- onset is consistent with permanent hypogo- specific and is characterized by either relatively nadism.

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Table 1. Frequency and Common Causes of Delayed Puberty Other Than Constitutional Delay of Growth and Puberty.*

Hypergonadotropic Permanent Hypogonadotropic Functional Hypogonadotropic Delayed Puberty Hypogonadism Hypogonadism Hypogonadism Frequency (%) Boys 5–10 10 20 Girls 25 20 20 Common causes Turner’s syndrome, gonadal dysgen- Tumors or infiltrative diseases of the Systemic illness (inflammatory bowel esis, chemotherapy or radiation central nervous system, GnRH disease, celiac disease, anorexia therapy deficiency (isolated hypogonado- nervosa or bulimia), hypothyroid- tropic hypogonadism, Kallmann’s ism, excessive exercise syndrome), combined pituitary- hormone deficiency, chemothera- py or radiation therapy

* For a more comprehensive listing of causes of delayed puberty, see Table 1 in the Supplementary Appendix. GnRH denotes gonadotropin- releasing hormone.

Family History have an increased likelihood of having an under- A family history, including childhood growth lying condition delaying HPG-axis activation. patterns and age at pubertal onset of the parents, Conversely, in boys, unlike girls, being overweight should be obtained. Delayed puberty in a parent can be associated with later pubertal develop- or sibling followed by spontaneous onset of pu- ment.20,21 The most widely used pubertal rating berty suggests CDGP. However, if pubertal devel- system is Tanner staging31,32 (Fig. 3). In boys, the opment was induced by sex steroids in family presence of Tanner stage 2 genitalia marks the members, isolated hypogonadotropic hypogonad- onset of pubertal development and is character- ism is also possible, since reversal of hypogonad- ized by enlargement of the scrotum and testes ism is noted after the discontinuation of sex ste- and by a change in the texture and color of the roids in about 10% of patients with isolated scrotal skin. Testicular volume should be mea- hypogonadotropic hypogonadism.29,30 sured, with a volume of more than 3 ml indicating Patients and their parents should be ques- the initiation of central puberty. In patients with tioned about a history or symptoms of chronic CDGP, both adrenarche and hormonal activation disease, with emphasis on specific disorders (e.g., of the gonads often occur later than average, but celiac disease, thyroid disease, and anorexia) that in isolated hypogonadotropic hypogonadism, may cause temporary delay of puberty (functional adrenarche usually occurs at a normal age.7,33 hypogonadotropic hypogonadism), as well as medication use, nutritional status, and psycho- Bone-Age Radiography social functioning. Delayed cognitive develop- The bone age should be reviewed by a practitio- ment associated with obesity or dysmorphic ner who is experienced in interpreting such ra- features may suggest an underlying genetic syn- diographs. A delay in bone age is characteristic drome. Bilateral cryptorchidism or a small penis but not diagnostic of CDGP and also may occur at birth and hyposmia or anosmia may suggest in patients with chronic illness, hypogonado- hypogonadotropic hypogonadism. A history of tropic hypogonadism, or gonadal failure. Adult chemotherapy or radiotherapy may indicate pri- height prediction is an important part of coun- mary gonadal failure (Fig. 1). seling if short stature is a component of the pre- sentation, and practitioners should be aware that Physical Examination the Bayley–Pinneau tables overestimate adult Previous height and weight measurements should height in patients with CDGP if bone age is de- be obtained and plotted so that longitudinal layed by more than 2 years (Table 2, and Table 2 growth can be carefully assessed (Fig. 2). Delayed in the Supplementary Appendix). puberty is often associated with short stature and slow growth for age although the height and Hormone Measurements and Brain Imaging growth rate are within the prepubertal normal Pubertal onset is characterized by the accentua- range. Children who are underweight for height tion of diurnal secretion of gonadotropin and

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testosterone (in boys) and estrogen (in girls) be- cians routinely perform brain imaging, a reason- fore apparent phenotypic changes. Basal levels of able strategy is to defer such evaluation until the luteinizing hormone and FSH are low in patients age of 15 years, at which point many patients with with CDGP or hypogonadotropic hypogonadism, CDGP will have spontaneously begun puberty and whereas such levels are usually elevated in those will require no further evaluation. Full neuro- with gonadal failure. Serum levels of insulin-like endocrine testing is warranted in patients with growth factor 1 (IGF-1) can be helpful in the hypothalamic–pituitary tumors causing hypogo- evaluation of growth hormone deficiency but nadotropic hypogonadism, since they may have must be interpreted carefully because levels are additional pituitary-hormone deficiencies. often low for chronologic age but within the nor- mal range for bone age. Thyroid-function tests Second-Line Evaluation are routinely obtained. Brain magnetic resonance Most patients will not have an apparent alterna- imaging (MRI) is indicated when there are signs tive cause for delayed puberty on initial evalua- or symptoms to suggest a lesion in the central tion, suggesting CDGP as the likely diagnosis. nervous system. Otherwise, although some clini- However, no test can reliably distinguish CDGP

Table 2. Investigations for Delayed Puberty.*

Variable Interpretation First-line Growth rate In early adolescence in both sexes, an annual growth rate of less than 3 cm is suggestive of a dis- ease specifically inhibiting growth (e.g., growth hormone deficiency, hypercortisolism, and hy- pothyroidism), but such rates can also be seen in CDGP. Boys with delayed puberty who are overweight tend to have height and predicted adult height consistent with their genetic height potential.20,21 Tanner stages In girls, Tanner stage 2 breast development is usually the first physical marker of puberty. In boys, a testicular volume of >3 ml is a more reliable indicator of the onset of puberty than Tanner stage 2 genital development. Testis volume in boys A testicular volume of >3 ml (≥2.5 cm in length) indicates central puberty. Most healthy boys with a testicular volume of ³3 ml will have a further increase in testicular volume or pubic-hair stage, or both, at repeated examination 6 mo later.22 Bone age A bone-age delay of >2 yr has arbitrarily been used as a criterion for CDGP but is nonspecific. A bone-age delay of 4 years has been associated with a mean overprediction of adult height of 8 cm. In children with short stature who have no bone-age delay, adult height is usually under- estimated by the Bayley–Pinneau tables.23 Biochemical analyses To rule out chronic disorders, common tests include complete blood count, erythrocyte sedimenta- tion rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, and free thyroxine. Additional testing may be necessary on the basis of family history and symptoms and signs, including screening for celiac disease and inflammatory bowel disease. Serum luteinizing hormone At low levels, values obtained on immunochemiluminometric (ICMA) assays are at least 50% lower than those obtained on immunofluorometric (IFMA) assays.24 Values of <0.1 IU per liter are not specific for hypogonadotropic hypogonadism. Values of >0.2 IU per liter on ICMA or >0.6 IU per liter on IFMA are specific but not sensitive for the initiation of central puberty; some adoles- cents in early puberty have lower values.24 In delayed puberty, elevated values suggest primary hypogonadism. In general, luteinizing hormone is a better marker of pubertal initiation than follicle-stimulating hormone. Serum follicle-stimulating hormone At low levels, values obtained on ICMA are approximately 50% lower than those obtained on IFMA. Values of <0.2 IU per liter on ICMA or <1.0 IU per liter on IFMA suggest hypogonadotropic hy- pogonadism but are not diagnostic.24,25 In delayed puberty, a value above the upper limit of the normal range for the assay is a sensitive and specific marker of primary gonadal failure. Serum insulin-like growth factor 1 Measurement is used to screen for growth hormone deficiency. An increase in the level during follow- up or during or after treatment with sex steroids makes the diagnosis of growth hormone defi- ciency less likely. Growth hormone provocation tests are needed to diagnose growth hormone deficiency. Serum testosterone in boys A morning value of 20 ng per deciliter (0.7 nmol per liter) often predicts the appearance of pubertal signs within 12 to 15 mo.26

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Table 2. (Continued.)

Variable Interpretation Second-line Gonadotropin-releasing hormone test† A predominant response of luteinizing hormone over follicle-stimulating hormone after stimulation or peak luteinizing hormone levels of 5 to 8 IU per liter (depending on the assay) suggests the onset of central puberty. However, patients with CDGP or hypogonadotropic hypogonadism may have a prepubertal response. Human chorionic gonadotropin test† Peak testosterone levels are lower in patients with hypogonadotropic hypogonadism than in those with CDGP.27 Serum inhibin B† Prepubertal boys with a baseline inhibin B level of >35 pg per milliliter have a higher likelihood of CDGP.28 In boys, unmeasurable inhibin B indicates primary germinal failure. Serum prolactin Elevated levels may indicate hypothalamic–pituitary tumors causing hypogonadotropic hypogonad- ism. In such cases, additional pituitary-hormone deficiencies may be present. Measurement of macroprolactin (a physiologically inactive form of prolactin) is recommended in patients with unexplained hyperprolactinemia. Brain magnetic resonance imaging Imaging is performed to rule out underlying disorders of the central nervous system. Imaging in patients with the Kallmann syndrome commonly shows olfactory-bulb and sulcus aplasia or hypoplasia and thus may help differentiate the Kallmann syndrome from hypogonadotropic hypogonadism in patients with an apparently normal or difficult-to-evaluate sense of smell. Genetic testing Genotyping for known monogenic causes is currently a research procedure and not warranted in routine clinical practice.

* For a more comprehensive listing of investigations, see Table 2 in the Supplementary Appendix. CDGP denotes constitutional delay of growth and puberty. † These tests are used to try to differentiate CDGP from isolated hypogonadotropic hypogonadism. However, validation in larger, independent studies is needed before the use of such tests can be fully endorsed. Often, clinical follow-up is needed to confirm the diagnosis; no endog- enous puberty by the age of 18 years is diagnostic of isolated hypogonadotropic hypogonadism.

from isolated hypogonadotropic hypogonadism, Growth hormone secretion in the basal state, so the diagnosis of CDGP cannot be made with as well as after provocative testing, may be de- certitude. Observation usually resolves this conun- creased in patients with CDGP. If concern about drum; isolated hypogonadotropic hypogonadism growth is sufficient to warrant stimulation test- is diagnosed if endogenous puberty has not be- ing of growth hormone, sex-steroid priming with gun by the age of 18 years. Several tests have estrogen or testosterone is necessary for reliable been proposed to distinguish CDGP from isolated results in patients with delayed puberty; estro- hypogonadotropic hypogonadism (Table 2, and gen stimulates endogenous growth-hormone se- Table 2 in the Supplementary Appendix). If basal cretion, and sex-steroid priming facilitates sepa- gonadotropin levels are inconclusive, stimulation ration of true growth hormone deficiency from by GnRH or a GnRH agonist may be helpful.24,25 the physiologic low growth hormone secretion Stimulated levels of luteinizing hormone in the that stems from low estrogen levels. If a patient pubertal range indicate that the HPG axis has has a normal growth rate, growth hormone been reactivated and that secondary sexual devel- provocation testing is not necessary, whereas low opment is likely to occur within 1 year. However, IGF-1 levels together with reduced growth veloc- the GnRH test alone often cannot differentiate ity warrant testing. CDGP from isolated hypogonadotropic hypogo- nadism because prepubertal values may be ob- Treatment served in isolated hypogonadotropic hypogonad- Patients with CDGP ism or in patients with CDGP in whom the HPG The options for management of CDGP include axis has not yet been activated. Recent data sug- expectant observation or therapy with low-dose gest that baseline levels of inhibin B may facili- testosterone (in boys) or estrogen (in girls) (Table tate discrimination between these conditions,28 3, and Table 3 in the Supplementary Appendix). but replication is needed before this or other If puberty has started, clinically or biochemical- tests can be routinely adopted. ly, and stature is not a major concern, reassur-

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Delayed Puberty

First-Line Family history of delayed puberty Evaluation History of chronic disease, cryptorchidism, anosmia, anorexia, radiotherapy, or chemotherapy

First-line investigations: growth rate, Tanner stage, testis volume Tests: biochemical analyses, bone-age radiography, basal serum LH, FSH, IGF-1, thyrotropin, free thyroxine, and testosterone (in boys)

Low or normal serum LH and Elevated FSH FSH for early Tanner stages

Growth rate in prepubertal Growth rate below prepubertal range range

Working GnRH deficiency or CDGP Functional hypogonadotropic Hypergonadotropic hypogonadism Diagnosis (65% of boys, 30% of girls) hypogonadism (secondary (5–10% of boys, 25% of girls) to a chronic disease, anorexia) (20% of boys, 20% of girls) Permanent hypogonadotropic hypogonadism or hypopitui- tarism (10% of boys, 20% of girls)

GnRH test Examine further for chronic Examine further for underlying cause: Second-Line hCG stimulation test disease: MRI, prolactin karyotype, serum inhibin B (in boys) Evaluation Serum inhibin B (if CDGP is Olfactory-function test not evident) Genetic testing MRI

Low BMI Normal BMI High BMI

Second-Line GI disorder Hypothyreosis Glucocorticoid excess Diagnosis Underfeeding Hyperprolactinemia (iatrogenic, Anorexia GH deficiency Cushing’s disease) Multiple pituitary hor- Hypothyroidism mone deficiency

Intervention Follow up Treat underlying cause Treat with sex steroids Evaluate the need for the induction of secondary sex characteristics

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Figure 1 (facing page). Algorithm for the Evaluation Age (yr) of a Patient with Delayed Puberty. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 in cm cm in Percentages of patients with delayed puberty with vari- 76 76 190 190 ous conditions are from Sedlmeyer and Palmert.7 Percent- 74 95 74 185 90 185 ages do not add up to 100% because of rounding and 72 75 72 180 180 70 70 because a small percentage of patients have disorders 50 Stature 175 175 68 25 68 that cannot be classified with the use of this algorithm. 170 170 66 10 66 Target BMI denotes body-mass index, CDGP constitutional delay 165 5 165 64 64 height of growth and puberty, FSH follicle-stimulating hormone, 160 160 62 62 GH growth hormone, GI gastrointestinal, GnRH gonado- 155 155 60 60 tropin-releasing hormone, hCG human chorionic gonado- 150 150 58 tropin, IGF-1 insulin-like growth factor 1, LH luteinizing 145 56 hormone, and MRI magnetic resonance imaging. 140 105 230

Stature 54 135 100 220 52 130 95 95 210 50 125 90 200 ance with realistic adult height prediction is fre- 90 48 190 120 85 quently sufficient. If therapy is initiated, it is 46 180 115 80 75 44 170 usually to assuage psychosocial difficulties that 110 75 42 160 may derive from negative interactions with peers, 105 50 70 150 40 100 65 decreased self-esteem, and anxiety about growth 25 140 38 95 60 130 10 Weight rate or body habitus. 36 90 5 55 120 Numerous studies of treatment of CDGP in 34 85 50 110 boys have been reported. Although some random- 32 80 45 100 30 ized, controlled trials have been performed with 40 90 80 35 35 80 small numbers of subjects, studies have been 70 70 30 30 60 60 largely observational and have involved treat- 25 25 50 50 ment with short courses of low-dose andro- 20 20 Weight 40 40 34-36 15 15 gens. The data suggest that treatment leads 30 30 10 10 to increased growth velocity and sexual matura- lb kg kg lb 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 tion and positively affects psychosocial well-being, Age (yr) without significant side effects, rapid advance- ment of bone age, or reduced adult height. Figure 2. Linear Growth in Delayed Puberty. Similar data are not available for girls, but simi- In children with delayed puberty (data points), linear growth progresses lar outcomes are likely as long as therapy is initi- with a normal preadolescent height velocity (>3 cm per year). Height rela- ated with appropriately low doses of estrogen. tive to that of peers (height percentile) may decrease slightly before the usual adolescent age range, but this effect is accentuated when the child For a subset of patients with CDGP, short with delayed puberty does not undergo a growth spurt in concert with his stature can be more worrisome than delayed or her peers. Consequently, the height percentile decreases in the early teen- puberty, and indeed CDGP is considered by some age years. In children with constitutional delay of growth and puberty, a late observers to be a subgroup of idiopathic short growth spurt will facilitate subsequent catch-up growth, but adult heights stature. Although the Food and Drug Adminis- are often slightly shorter than expected on the basis of parental heights. tration has approved the use of growth hormone for the treatment of idiopathic short stature and tors could prolong linear growth and potentially height that is 2.25 SD below average for age, this increase adult height. In controlled trials in boys therapy has at best a modest effect on adult with short stature or delayed puberty, aromatase height in adolescents with CDGP, and its use in inhibitors delayed bone maturation and appeared CDGP is not recommended. to increase adult height.37,38 However, the amount In boys with CDGP and short stature, another of height gained as well as the optimal timing, potential therapeutic approach is aromatase inhi- dose, and duration of therapy with aromatase bition, but this treatment requires further study inhibitors remain uncertain.39 Moreover, poten- before it should be incorporated into routine tially adverse effects, especially impaired devel- practice.37,38 Aromatase inhibitors block the con- opment of trabecular bone and vertebral-body version of androgens to estrogens; because es- deformities, which were observed in boys with trogen is the predominant hormone needed for idiopathic short stature who were treated with epiphyseal closure, the use of aromatase inhibi- letrozole,40 must be considered.

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Permanent Hypogonadism A Breast Development and Pubic Hair In boys and girls with hypogonadotropic hypo- gonadism, initial sex-steroid therapy is the same as that for CDGP, but doses are gradually increased to full adult replacement levels during a period of approximately 3 years (Table 3). In hypogonadotropic hypogonadism, exogenous testosterone does not induce testicular growth or spermatogenesis and exogenous estrogen does not induce ovulation, and the induction of Stage 1 Stage 2 fertility in both sexes requires treatment with pulsatile GnRH42-45 or exogenous gonadotro- pins.44 In girls with hypogonadotropic hypo- gonadism, treatment with estrogen needs to be combined with progestin for endometrial cy- cling.

Areas of Uncertainty

Further research is needed to establish appro- priate age cutoffs for delayed puberty in differ- ent racial and ethnic groups and to better un- derstand the physiological basis of CDGP. Suggested causes of CDGP include increased to- Stage 1 Stage 2 tal energy expenditure46 and increased insulin 47 B Genital Development and Pubic Hair sensitivity, but no definitive cause has been identified. Studies should carefully assess the Stage 1 Stage 2 psychosocial distress among children with de- layed puberty, whether this distress has long- term sequelae, and what effect sex-steroid sup- plementation has on these outcomes. It remains unclear whether adult bone mass is adversely affected by pubertal delay48 and whether this represents a medical reason to initiate sex-steroid replacement. Distinguishing between CDGP and isolated hypogonadotropic hypogonadism re- mains difficult in many cases, and further as- Figure 3. Tanner Stages in the Assessment of Delayed sessment of the role of inhibin B or other mark- Puberty. ers for this purpose is needed. Randomized trials Delayed puberty is often associated with short stature and slow growth for age although the growth rate is are needed to compare different estrogen for- within the prepubertal normal range. Physical markers mulations, routes of administration (oral vs. of puberty can also be delayed. In girls (Panel A), breast transdermal), and drug regimens to determine development from Tanner stage 1 (preadolescent) to optimal therapy for girls with delayed puberty. stage 2 (appearance of the breast bud) should tradi- Studies are needed to identify genes that cause tionally take place between 8 and 13 years of age, and in boys the development of genital Tanner stage 1 (pre- CDGP, which would also elucidate factors that adolescent) to stage 2 (enlargement of the testes and regulate the timing of puberty. scrotum and change in the texture and reddening of the scrotal skin) should take place between 9 and 14 years. Guidelines Recent data regarding earlier timing of puberty suggest that these traditional age cutoffs should be adjusted downward, but new age ranges have not yet been defined. To our knowledge, there are no recent guidelines regarding the evaluation and treatment of CDGP.

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40 Side Effects and Cautions cause premature epiphyseal closure; not for use in boys with boys in use for not closure; epiphyseal premature cause yr <10 of age bone a vertebral deformities vertebral hypertension arterial and thromboembolism of risk greater tially estrogens natural with than erythema, inflammatory reaction, and sterile abscess; priapism abscess; sterile and reaction, inflammatory erythema, of duration longer disease; cell sickle with patients in occur can propionate than enanthate testosterone for effect mal route may have advantages over oral administration oral over advantages have may route mal avoid close skin contact with others with contact skin close avoid levels testosterone circulating and secretion gonadotropin crease available in younger patients younger in available and because of reports of increased cardiovascular risks in post - in risks cardiovascular increased of reports of because and women menopausal apy (later if estrogen dose is increased slowly, sooner if break - if sooner slowly, increased is dose estrogen if (later apy occurs) bleeding through Erythrocytosis, weight gain, prostate hyperplasia; high doses can doses high hyperplasia; prostate gain, weight Erythrocytosis, Decreased level of high-density lipoprotein cholesterol, erythrocytosis, cholesterol, lipoprotein high-density of level Decreased letrozole than potent Less All administered by intramuscular injection; local side effects: pain, effects: side local injection; intramuscular by administered All Liver toxicity, increased levels of some plasma-binding proteins, poten proteins, plasma-binding some of levels increased toxicity, Liver transder - estrogens; synthetic to preferable be may estrogen, Natural Local irritation; applied topically at bedtime; after application, must application, after bedtime; at topically applied irritation; Local in may puberty, of onset after indication; this for approved yet Not No data on dose equivalent between estradiol patches and gel and patches estradiol between equivalent dose on data No Not estradiol precursors; use is questioned as not being physiological being not as questioned is use precursors; estradiol Not Added to induce endometrial cycling after 12–18 mo of estrogen ther - estrogen of mo 12–18 after cycling endometrial induce to Added

Table 3 in the Supplementary Appendix. In Children with CDGP 4 wk for 3 to 6 mo; repeated treatment with 25-to-50-mg incre - 25-to-50-mg with treatment repeated mo; 6 to 3 for wk 4 mg) 100 exceeding (not dose in ment per kilogram daily after 6–12 mo 6–12 after daily kilogram per dose pills available in Europe in available pills dose fourth of 25-μg 24-hr patch); increase by 3.1–6.2 μg per 24 hr every hr 24 per μg 3.1–6.2 by increase patch); 24-hr 25-μg of fourth mo 6 to 0.325 mg daily; dose depends on formulation on depends dose daily; mg 0.325 to 12 mo 12 2.5 mg daily mg 2.5 daily mg 1.0 Not recommended before 14 yr of age; initial dose, 50–100 mg every mg 50–100 dose, initial age; of yr 14 before recommended Not Initial dose, 5 μg per kilogram of body weight daily; increase to 10 μg 10 to increase daily; weight body of kilogram per μg 5 dose, Initial Initial dose, 2 μg daily; increase to 5 μg daily after 6–12 mo; lower- mo; 6–12 after daily μg 5 to increase daily; μg 2 dose, Initial No data available on intramuscular injection intramuscular on available data No available data No Overnight patch: initial dose, 3.1–6.2 μg per 24 hr (one-eighth to one- to (one-eighth hr 24 per μg 3.1–6.2 dose, initial patch: Overnight Initial dose, 0.1625 mg daily for 6–12 mo with subsequent adjustment subsequent with mo 6–12 for daily mg 0.1625 dose, Initial Usually necessary only if estrogen treatment continues longer than longer continues treatment estrogen if only necessary Usually

of contraceptive pills) contraceptive of Medications for the Treatment of Constitutional Delay of Growth and Puberty (CDGP).* Puberty and Growth of Delay Constitutional of Treatment the for Medications Oral Transdermal patch Transdermal Oral letrozole Oral anastozole Oral Enanthate, cypionate, and propionate and cypionate, Enanthate, 17β-Estradiol Ethinyl estradiol (component (component estradiol Ethinyl Undecanoate† preparations Transdermal Conjugated equine estrogens equine Conjugated Various options (usually oral) (usually options Various Table 3. Drug and Formulation Boys Testosterone Girls Estrogen Aromatase inhibitors Aromatase Progestin Testosterone undecanoate tablets or anabolic steroids are not recommended for the induction of secondary sexual characteristics. * For further discussion of these agents and of treatment of permanent hypogonadism, see †

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Conclusions and hypogonadotropic hypogonadism, should be re- Recommendations considered, and MRI of the brain is indicated. We believe that when CDGP is treated, therapy The patient in the vignette has delayed puberty. should be with testosterone alone, even if stature Given that he is male and has a family history of is a prominent concern. We do not use growth late pubertal development, CDGP is the most like- hormone or anabolic steroids for delayed pu- ly diagnosis. Before making this diagnosis, a care- berty, nor do we recommend aromatase inhibi- ful evaluation is required to rule out other causes; tors for this indication, pending more data from this is especially true among young women, in randomized trials. whom underlying disorders are more common. In CDGP, in which pubertal delay is transient, Dr. Palmert reports receiving funding as a member of the Hvidøre Study of Childhood Diabetes, which is supported by the decision regarding whether to treat should Novo Nordisk; payment for lectures at the 2011 Japanese Endo- be made by the patient; the goal of therapy, crine Society Meeting and the 2011 Asahikawa Winter Confer- when used, is to induce the acceleration of sec- ence on Molecular Medicine with support from Japan Chemical Research Pharmaceuticals; and payment for participating in a ondary sexual characteristics or growth and to symposium sponsored by Sandoz at the 2011 Annual Meeting of mitigate psychosocial difficulties. For boys who the European Society of Pediatric Endocrinology, as well as for a elect to be treated, we initiate monthly intramus- Grand Rounds lecture at McGill University sponsored by Eli Lilly. Dr. Dunkel reports receiving lecture fees from Pfizer and pay- cular injections of 50 mg of testosterone ester ment for participating in a symposium sponsored by Sandoz at for 3 to 6 months; this regimen can be repeated the 2011 Annual Meeting of the European Society of Pediatric for another 3 to 6 months with dose escalation Endocrinology. No other potential conflict of interest relevant to this article was reported. (Table 3). If spontaneous puberty has not occurred Disclosure forms provided by the authors are available with after 1 year, other diagnoses, such as permanent the full text of this article at NEJM.org.

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23. Wit JM, Rekers-Mombarg LT. Final hood. J Clin Endocrinol Metab 2010;95: 41. Wickman S, Dunkel L. Inhibition of height gain by GH therapy in children 2857-67. P450 aromatase enhances gonadotropin with idiopathic short stature is dose de- 31. Marshall WA, Tanner JM. Variations secretion in early and midpubertal boys: pendent. J Clin Endocrinol Metab 2002; in pattern of pubertal changes in girls. evidence for a pituitary site of action of 87:604-11. Arch Dis Child 1969;44:291-303. endogenous E. J Clin Endocrinol Metab 24. Resende EA, Lara BH, Reis JD, Fer- 32. Idem. Variations in the pattern of pu- 2001;86:4887-94. reira BP, Pereira GA, Borges MF. Assess- bertal changes in boys. Arch Dis Child 42. Pitteloud N, Hayes FJ, Boepple PA, ment of basal and gonadotropin-releasing 1970;45:13-23. et al. The role of prior pubertal develop- hormone-stimulated gonadotropins by 33. Counts DR, Pescovitz OH, Barnes ment, biochemical markers of testicular immunochemiluminometric and immuno- KM, et al. Dissociation of adrenarche and maturation, and genetics in elucidating fluorometric assays in normal children. gonadarche in precocious puberty and in the phenotypic heterogeneity of idiopath- J Clin Endocrinol Metab 2007;92:1424-9. isolated hypogonadotropic hypogonad- ic hypogonadotropic hypogonadism. J Clin 25. Grinspon RP, Ropelato MG, Gottlieb ism. J Clin Endocrinol Metab 1987;64: Endocrinol Metab 2002;87:152-60. S, et al. Basal follicle-stimulating hor- 1174-8. 43. Pitteloud N, Hayes FJ, Dwyer A, mone and peak gonadotropin levels after 34. Richman RA, Kirsch LR. Testosterone Boepple PA, Lee H, Crowley WF Jr. Predic- gonadotropin-releasing hormone infusion treatment in adolescent boys with consti- tors of outcome of long-term GnRH ther- show high diagnostic accuracy in boys tutional delay in growth and develop- apy in men with idiopathic hypogonado- with suspicion of hypogonadotropic hy- ment. N Engl J Med 1988;319:1563-7. tropic hypogonadism. J Clin Endocrinol pogonadism. J Clin Endocrinol Metab 35. Rosenfeld RG, Northcraft GB, Hintz Metab 2002;87:4128-36. 2010;95:2811-8. RL. A prospective, randomized study of 44. Warne DW, Decosterd G, Okada H, 26. Wu FC, Brown DC, Butler GE, Stirling testosterone treatment of constitutional Yano Y, Koide N, Howles CM. A combined HF, Kelnar CJ. Early morning plasma tes- delay of growth and development in male analysis of data to identify predictive fac- tosterone is an accurate predictor of im- adolescents. 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Bibliografia: Howard SR, Dunkel L. Management of hypogonadism from birth to adolescence. Best Pract Res Clin Endocrinol Metab. 2018 Aug;32(4):355-372. Dye AM, Nelson GB, Diaz-Thomas A. Delayed Puberty. Pediatr Ann. 2018 Jan 1;47(1):e16-e22

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Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372

Contents lists available at ScienceDirect Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem

2 Management of hypogonadism from birth to adolescence

Sasha R. Howard, MBBS, PhD, Dr *, 1, Leo Dunkel, MD, PhD, Professor 1

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, UK article info Management of patients with hypogonadism is dependent on the Article history: underlying cause. Whilst functional hypogonadism presenting as Available online 6 June 2018 delayed puberty in adolescence is relatively common, permanent hypogonadism presenting in infancy or adolescence is unusual. Keywords: The main differential diagnoses of delayed puberty include self- puberty limited delayed puberty (DP), idiopathic hypogonadotropic hypo- hypogonadism gonadism (IHH) and hypergonadotropic hypogonadism. Treatment gonadotropin therapy of self-limited DP involves expectant observation or short courses rFSH of low dose sex steroid supplementation. More complex and testosterone involved management is required in permanent hypogonadism to estradiol achieve both development of secondary sexual characteristics and to maximize the potential for fertility. This review will cover the options for management involving sex steroid or gonadotropin therapy, with discussion of benefits, limitations and specific con- siderations of the different treatment options. © 2018 Elsevier Ltd. All rights reserved.

Introduction

The hypothalamic-pituitary-gonadal (HPG) axis is measurably active in fetal life, and then un- dergoes a process of reactivation twice between birth and adulthood. The first is in early infant life,

* Corresponding author. E-mail addresses: [email protected] (S.R. Howard), [email protected] (L. Dunkel). 1 Full Address: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, 1st Floor North, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ. Fax: 2078826197. þ https://doi.org/10.1016/j.beem.2018.05.011 1521-690X/© 2018 Elsevier Ltd. All rights reserved.

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356 S.R. Howard, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372 during the so-called ‘mini-puberty’, and the second after a period of dormancy between the age of one and eight-to-nine years, during the onset of puberty [1]. While puberty is recognised as the matura- tional process of the reproductive endocrine system that results in achievement of adult height and body proportion, in addition to development of the genital organs and the capacity to reproduce, mini- puberty has also been increasingly recognised as vital for normal fertility development [2]. Development of the clinical features of puberty is initiated by the reactivation of the HPG axis after this relative quiescence, but the nature of the puberty ‘brake’ that acts on the axis after the mini- puberty, and how and when this brake is released, is not well understood. Whilst the timing of pu- bertal onset varies within and between different populations, it is a highly heritable trait with esti- mates of up to 80% of individual variation being under genetic regulation [3]. However despite strong heritability, the key genetic factors that determine human pubertal timing in the normal population and in cases of disturbed pubertal timing remain mostly unknown. In healthy boys the normal age limits for Tanner genital stage 2 (G2) development are between 9 and 14 years [4]. Similarly, the great majority of Caucasian girls have at least early signs of breast development (Tanner breast stage 2, B2) by 13 years of age (Fig. 1). Whilst a large variability in the timing of pubertal onset exists in both genders, clear age cut-offs for normal pubertal development have been drawn. However, for both genders the age limits for identifying children who need evalu- ation for delayed puberty (DP) may vary in different ethnic groups.

Diagnosis of hypogonadism, infants

Mini-puberty provides a window of opportunity for evaluation of the functionality of the HPG axis before puberty. However, even at birth a suspicion of hypogonadism may be raised by the assessment of genital appearance. In conditions of congenital gonadotropin-releasing hormone (GnRH) deficiency, such as in idiopathic hypogonadotropic hypogonadism (IHH), both fetal and postnatal pituitary gonadotropin secretion is low. In males during fetal life, placental human chorionic gonadotropin (hCG) stimulates the testis, resulting in masculinization of the external genitalia. However, later in fetal life, when hCG con- centration in fetal circulation falls, luteinizing hormone (LH) stimulates further penile growth and testicular descent. Consequently, boys with IHH often have micropenis and cryptorchidism at birth. It is important to consider the diagnosis of IHH in isolated congenital undescended testes [2]. Primary hypogonadism may also present at birth with under-developed genitalia in male infants if the condition is gonadotropin dependent, or alternatively as ambiguous or female genitalia if the defect is of early-fetal onset due a disorder of sex development (DSD) [5]. A full review of the diagnosis and management of DSD is beyond the scope of this review, and has been comprehensively addressed elsewhere [6]. If a suspicion of hypogonadism arises in the first 3e4 months of life it can be investigated on the basis of sex steroid and gonadotropin levels without the need for stimulation tests. Gonadotropin levels in healthy infants start to increase during the 1st week of life and then decrease towards the age of 6 months, except for FSH levels in girls that remain elevated until 3e4 years of age [7] (Fig. 2). Testosterone levels in boys increase in response to LH levels and peak at 1e3 months of age, but in girls estradiol levels fluctuate, probably reflecting ovarian follicular growth and atrophy. Estradiol levels in girls decline in the 2 nd year of life. Postnatal HPG axis activation during the mini-puberty has important roles in both sexes: in males, for penile and testicular growth [8] and in girls, for maturation of ovarian follicles and development of estrogen-sensitive target tissues (mammary gland and uterus) [9]. However, most studies on hormone levels during mini-puberty have had cross-sectional design, and hence the inter-individual differences in timing, duration, and magnitude of the mini-puberty have remained largely unexplored. Serial blood sampling from healthy infants is problematic because of its invasiveness and non-invasive urine or salivary sampling are a way around this problem; however, urine and saliva assays are not widely used in clinical routine. Recently, longitudinal data has provided new information about the hormonal patterns including the timing of the peak hormone levels and the decrease in hormonal activity according to develop- mental age [8e11]. Because of the large variability in reported estradiol levels during infancy, profiling of longitudinal hormone levels is particularly important to gain a better understanding of the nature of ovarian activity in infant girls. Consequently, these data may aid in defining aberrant HPG axis activity in infancy and facilitate early diagnosis of HPG axis disorders.

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Newer markers of gonadal function are useful, particularly in males, for diagnosis of hypogonadism, both soon after birth and after the mini-puberty is completed. In healthy newborn boys, inhibin A levels are undetectable [12], but rise from day 2 onwards to robust levels by the end of the first month [13], reflecting Sertoli cell activity. Inhibin B levels peak in boys at three months of age to levels higher than in adult men, but then decrease by 15 months of age [14], although remain detectable at the lower limit of the adult range through into mid-childhood [12]. In girls, inhibin B levels are low at birth but increase during the first months of life and then decrease again towards one year of age [14]. Thus,

Fig. 1. The distribution of pubertal timing in healthy boys and girls. These data have been incorporated into UK growth charts and are available at www.growthcharts.rcpch.ac.uk. Original data from [107].

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358 S.R. Howard, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372 inhibin B is a useful marker of Sertoli cell function from the neonatal period into early childhood and can be used to assess males infants with micropenis and/or cryptorchism, both due to central and primary hypogonadism [5]. Its use in female infants is less clear. Anti-mullerian hormone (AMH) is strongly expressed by Sertoli cells from the time of testicular differentiation to puberty and at much lower levels in females by the granulosa cells from birth until menopause. In boys, AMH levels increase after birth to peak levels around two months of age and then decrease by the age of one year [15]. Undetectable AMH and inhibin B are diagnostic of anorchia. In infant girls, a similar pattern in AMH levels during the first months of life has also been reported, but the levels in girls are significantly lower [16]. In primary hypogonadism with gonadal dysgenesis, anorchia or testicular regression, gonadotropin levels in the mini-puberty are generally raised, but may fall to normal levels in later childhood (Table 1). However, in Turner syndrome, infant girls with the 45, X0 karyotype have higher FSH levels than healthy girls, and the levels remain elevated for several years. In contrast, Turner girls with other karyotypes than 45, X0 often have close to normal FSH levels, suggesting some ovarian feedback effects on pituitary FSH secretion in these patients [17]. Often, infant boys with Klinefelter's syndrome (47, XXY karyotype) have normal levels of inhibin B, AMH, and INSL3, suggesting normal Sertoli and Leydig cell function in infancy, although they have elevated LH [18] and FSH levels [18,19]. Testosterone levels in these boys are either normal (or slightly elevated). Thus, low sex steroid and gonadotropin levels in an infant less than 3 months of age indicate central hypogonadism with an absence of the normal ‘mini-puberty’. In contrast, high gonadotropins asso- ciated with low/undetectable basal testosterone and INSL3 (in boys) are diagnostic of primary

Fig. 2. Patterns of postnatal gonadotropin and sex steroid secretion in boys (a) and girls (b). Gonadotropin levels start to increase during the 1st week of life, peak at 1e3 months, and then decline towards the age of 6 months. In boys, LH levels are higher than in girls, and in girls, FSH levels predominate and remain elevated until 3e4 years of age. Testosterone levels in boys increase following the LH levels and show a clear peak at 1e3 months of age, but in girls, estradiol levels fluctuate, probably reflecting ovarian follicular growth and atrophy. Estradiol levels in girls decline in the 2 nd year of life. From [7]; reproduced with author permission.

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Table 1 Upper limits for creatinine-corrected urinary gonadotropin levels before term, at term, and at 2e6 months of corrected age. Values above the limits suggest primary gonadal failure.

Before term At term At 2e6 months corrected age

Girls FSH (IU/mmol Cr) 250 13 5 LH (IU/mmol Cr) 500 10 0.5 Boys FSH (IU/mmol Cr) 10 3 1.5 LH (IU/mmol Cr) 20 5 0.5

Values are based on original data published in Kuiri-Hanninen,€ T., Kallio, S., Seuri, R. et al., 2011a. Postnatal developmental changes in the pituitaryeovarian axis in preterm and term infant girls. J. Clin. Endocrinol. Metab. 96, 3432; Kuiri-Hanninen,€ T., Haanpa€a,€ M., Turpeinen, U. et al., 2013b. Postnatal ovarian activation has effects in estrogen target tissues in infant girls. J. Clin. Endocrinol. Metab. 98, 4709. hypogonadism. Outside of the mini-puberty period, useful tests for the investigation of hypogonadism include Inhibin B and AMH [5].

Diagnosis of hypogonadism, adolescence

Etiology

The pathogenesis of delayed puberty (DP) encompasses several conditions, but is most commonly due to self-limited DP. There are three main groups of differential diagnoses of self-limited DP (Table 2): functional hypogonadism, disorders causing primary hypogonadism and GnRH deficiency leading to hypogonadotropic hypogonadism (HH) [4,20], although up to 30 different aetiologies underlying DP have been identified [21]. Self-limited DP, also known as constitutional delay of growth and puberty (CDGP), represents the commonest cause of DP in both sexes. Up to 83% of boys, and 30e55% of girls, with pubertal delay have self-limited DP [20e23]. Individuals with self-limited DP lie at the extreme end of normal pubertal timing, with the absence of testicular enlargement in boys or breast development in girls at an age that is 2e2.5 standard deviations (SD) later than the population mean [4]. In addition, self-limited DP may also encompass older children with delayed pubertal progression, a diagnosis that is aided by the use of puberty normograms (Fig.1) [23]. Self-limited DP is associated with adverse health outcomes including short stature, reduced bone mineral density and compromised psychosocial health [24]. Self-limited DP segregates within families with complex patterns of inheritance including auto- somal dominant, autosomal recessive, bilineal and X-linked [25], although sporadic cases are also observed. The majority of families display an autosomal dominant pattern of inheritance (with or without complete penetrance) [25,26]. 50e75% of subjects with self-limited DP have a family history of delayed pubertal onset [25].

Table 2 Differential diagnoses of self-limited delayed puberty.

Hypergonadotropic Hypogonadotropic Functional Hypogonadism Hypogonadism Hypogonadotropic Hypogonadism

Common Causes: Male: Klinefelter's Syndrome Isolated Hypogonadotropic Inflammatory Bowel Congenital anorchia/testicular Hypogonadism Kallmann Disease Coeliac Disease regression syndrome Combined Pituitary Anorexia Nervosa Female: Turner Hormone Deficiency CNS Hypothyroidism Excessive Syndrome Premature ovarian Tumours/Infiltrative Exercise insufficiency Diseases Chemotherapy/ Both: Gonadal Radiation Therapy dysgenesis Chemotherapy/ Radiation Therapy

Table modified and reprinted with permission from Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012; 366:443e53 [4].

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The absence of pathological medical history, signs and symptoms, and a positive family history of pubertal delay in one or both of the parents suggests a diagnosis of self-limited DP; however, before making the diagnosis, significant pathological conditions must be excluded. These include the afore- mentioned differential diagnoses of DP (Table 2) [4,20]: functional hypogonadotropic hypogonadism, where late pubertal development is due to maturational delay in the HPG axis secondary to chronic disease (found in approximately 20%), malnourishment, excessive exercise, psychological or emotional stress; hypergonadotropic hypogonadism, with primary gonadal failure leading to elevated gonado- tropin levels due to lack of negative feedback (found in approximately 7% of male patients and 25% of female patients with DP); and permanent hypogonadotropic hypogonadism, characterized by low LH and FSH levels (9% of boys and up to 20% of girls). A thorough history should note evidence of chronic disease, anorexia, the intensity of athletic training, and the timing of puberty of both parents (Fig. 3). A history of chronic illnesses, such as coeliac disease and inflammatory bowel disease, will suggest a temporary or secondary delay of puberty. Permanent GnRH deficiency is due to congenital hypothalamic or pituitary disorders, or an acquired central dysfunction secondary to irradiation, tumour or vascular lesion. A picture of IHH with no associated anatomical or functional defect in the HPG axis occurs in 1e10 cases per 100,000 births. Because of different causes and incomplete penetrance, there is a wide spectrum of phenotypes, ranging from complete HH with lack of pubertal development to a partial hypogonadism with an arrest of pubertal development, and even reversible HH in some patients post treatment [27]. Despite recent advances, with over thirty genes linked to this disorder identified, the pathophysiological basis of HH in approximately 50% of individuals remains unclear. The condition may be due to failure of development of GnRH neurons, lack of activation of GnRH secretion or disrupted GnRH signaling. Kallmann Syndrome (KS, HH associated with anosmia) is the most common form of isolated HH, accounting for 60% of cases.

Assessment

It may be very difficult to distinguish clinically between the diagnosis of DP and congenital IHH in the teenage years. In the majority of subjects with constitutional delay there is delayed maturation during early childhood, and consequently they are shorter than their peers. It has been shown that those DP subjects who also have poor growth in childhood may not fully exploit their genetic height potential, resulting in an adult height below their mid-parental target height [28e31], with an average loss of 4.2 cm if untreated [31]. However, other studies showed only a negligible difference in final height, even in DP subjects who have received no intervention [32e38]. This may imply a patho- physiological mechanism additional to lack of sex steroids contributing to the growth phenotype in some patients with DP, but not in others [38]. By contrast, patients with congenital IHH usually have steady linear growth during childhood and only become short for their age with absence of the pubertal growth spurt. However, hypogonado- tropic states cannot be ruled out by short stature and slow growth rate. In DP adrenarche may also occur later than usual, in contrast to the normal age of adrenarche in patients with isolated HH [4]. Bone age in DP (X-ray film of left hand and wrist) is behind chronological age, but the developmental milestones are achieved at a normal bone age; that is, onset of signs of pubertal development by the bone age of 13 years in girls and 13.5 years in boys. However, whilst bone age delay provides useful information in the growth analysis, it contributes little to the differential diagnosis. Gonadotropin and testosterone concentrations increase in concert with the development of the bone age. Thus, all stages of pubertal development occur at an age later than usual. In congenital IHH the diagnosis is typically made during the second or third decade of life. Common presenting signs are delayed onset of puberty, poorly developed secondary sexual characteristics, eunuchoid body proportions, or infertility. In some cases the diagnosis can be suspected before the age of pubertal onset, as discussed above, during the mini-puberty. The presence or absence of “red flag” features remains the strongest discriminator between isolated DP and IHH. These red flags include microorchidism, cryptorchidism or micropenis, indicating a lack of prior ‘mini-puberty’, or the pres- ence of other features of GnRH deficiency which include anosmia or hyposmia due to hypoplasia of the olfactory bulbs (in Kallmann Syndrome) and occasionally cleft lip and palate, unilateral renal agenesis, short metacarpals, sensorineural hearing loss, synkinesia and color-blindness [39]. Evidence of other

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S.R. Howard, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372 361 syndromic diagnoses linked to central hypogonadism may also be present, particularly with neuro- logical phenotypes such as in the 4H syndrome (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) [40] or ataxia, as seen in GordoneHolmes syndrome [41,42]. Gonadotropin levels assessed by basal LH and FSH determination are often increased in adolescents with primary hypogonadism due to e.g. Klinefelter syndrome, but the basal gonadotropin values are not useful in the differential diagnosis of self-limited delay and HH [43]. Investigation of the differential diagnosis of these latter two conditions may involve a number of physiological and stimulation tests, including assessment of LH pulsatility by frequent sampling [44], prolactin response to provocation [45], gonadotropin response to GnRH [46,47], testosterone response to hCG [48e50] and first morning- voided urine FSH and LH [51]. Most recently, a single measurement of inhibin B < 35 pg/mL in pre- pubertal boys has been shown to discriminate IHH from self-limited DP with high sensitivity [52], but this has not been demonstrated in girls. The trio of testicular volume (cut-off 1.1 ml), GnRH-induced maximal LH (cut-off 4.3 IU/L) and basal inhibin B level have been proposed as the most effective discriminators of IHH from DP in a new study [21]. However, follow-up is often warranted before a definitive diagnosis can be made. An MRI pituitary with olfactory bulb views is warranted in cases of suspected hypogonadotropic hypogonadism. With the major advances in the discovery of genes causing IHH that have taken place in the last two decades, increasing genetic diagnosis is likely to inform future management [53]. However, variable penetrance and evidence for geneegene interactions in the inheritance of IHH can make prediction of phenotype from genetic testing difficult. Family history and certain clinical features, such as cleft palate in FGFR1/FGF8, obesity or sleep disorder in PROK2 or PROKR2, and anosmia in KAL1 can be used to guide genetic testing.

Fig. 3. Differential diagnosis of delayed puberty. Algorithm for the evaluation of a patient with delayed puberty. CDGP - constitu- tional delay of growth and puberty, GI - gastrointestinal, GH - growth hormone, GHD - GH deficiency, PRL - prolactin, IGF-1 - insulin- like growth factor 1. Reprinted with permission from Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012; 366:443e53 [4].

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In cases of primary hypogonadism a karyotype is important to confirm or exclude a diagnosis of Turner or Klinefelter's syndrome. Assessment of uterine development by ultrasound may aid diagnosis and response to treatment. Autoantibody screening may be informative in cases of female hyper- gonadotropic hypogonadism with premature ovarian insufficiency (POI). Measurement of AMH is valuable in POI to assess ovarian reserve.

Treatment of hypogonadism e males

Infancy

Postnatal HPG axis activation in boys, which results in testicular activation and proliferation of Sertoli cells during this period, has a role in the development of reproductive capacity. The association of testosterone levels at three months of age and early penile growth [54], and involution of the penis and scrotum in boys with IHH in infancy [55] suggests a role for postnatal testosterone in “stabilizing” male genitalia. Analogous to true puberty, androgens secreted early in life may also have effects on linear growth, skeletal development, body composition, and psychosexual development [56]. Hormone therapy has thus been advocated for penile growth and testicular descent in infant boys with IHH or Kallmann syndrome [57]. In boys with primary hypogonadism, slightly higher FSH and LH levels and lower inhibin B as well as INSL-3 levels are seen at three months of age compared to healthy controls [58]. Reported testosterone levels in cryptorchid boys are normal [59,60] or subnormal [61]. Decreased serum androgen bioactivity has also been reported in infant boys with at least one undescended testis [62]. Neonatal treatment with testosterone can be used to correct micropenis in both central and primary hypogonadism. Standard therapy is with either IM testosterone enanthate 25 mg every 3e4 weeks for 3 months, or topical therapy with either 5% testosterone cream or DHT [63]. Management of cryptor- chidism is with surgical correction, with the use of hCG or GnRH therapy adjuncts only likely to provide a small additional benefit [64]. However, these therapies will not address the microorchidism seen in a male infant with IHH. A small number of studies of infants with IHH have used recombinant LH and FSH treatment to increase both penile length and testicular volume [65,66]. Outcomes included improved testicular size and function (measured with inhibin B and AMH), but it is not known if such therapy will improve the response to pubertal treatments or fertility outcomes in men with IHH. Concerns remain about the possible deleterious effects of hCG on germ cells in cryptorchid testes in infants, as its use has been associated with smaller testis volumes and higher FSH levels in adulthood [67,68].

Adolescence

Induction or progression of puberty is commonly considered for adolescents who either have significantly delayed or arrested puberty, or have been diagnosed with hypogonadism. Appropriate treatment modalities are directed according to the underlying diagnosis. A management strategy of ‘watchful waiting’ may be appropriate in isolated DP, where pubertal onset is late but expected to occur spontaneously. However, this decision should be taken in conjunction with the patient, taking into consideration their concerns and expectations. One major concern often raised by patients and their families is the effect of pubertal delay on both current and adult height. Patients with DP are often short compared with their peers, and this is often compounded by the fact that many have pubertal delay combined with familial short stature. However, reassurance can be given to such patients as usually in DP an adult height only slightly below the genetic height potential (target height) is reached; although there may be large individual variation [30,69]. DP in adolescents can be associated with significant anxiety about body image in terms of physical size and pubertal immaturity, decreased self-esteem with social isolation, withdrawal from sporting activities and psychosocial and peer relationship difficulties. In these circumstances, there is evidence that hormonal therapy can be beneficial [70,71]. The link between DP and reduced academic perfor- mance, substance misuse and behavioral difficulties is less well established. In contrast, if “red flag” markers of hypogonadism are present or if endogenous gonadotropin- dependent puberty has not started after one year of treatment, then permanent HH and other di- agnoses should be reconsidered. In such instances treatment should be initiated promptly in order to

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Self-limited DP management The options for management of male patients with DP include monitoring with reassurance or therapy with low dose testosterone to augment growth rate and to induce secondary sexual charac- teristics (Table 3). There are a great number of published studies of treatment of DP in boys; these are mainly observational, with some small, randomized controlled trials [71e73]. Most report treatment with short courses of low dose androgens with outcomes of increased height velocity without advanced bone age, advanced sexual maturation and often improvement in psychosocial parameters. The most commonly used treatment regime with low dose testosterone for boys with DP is supplementation with intramuscular depot preparations of a testosterone ester [74], at a starting dose of 50 mg each month for 3e6 months; a further 3e6 months of treatment may be given, with dose escalation as required (Table 3). Monitoring via serum testosterone increase (to mid-reference range one-week post injection), height velocity and virilisation is appropriate. The length of the polymorphism Cytosine-Adenine-Guanine (CAG) trinucleotide repeats present in the androgen re- ceptor (AR) gene is associated with androgen receptor activity, which may in part modulate response to testosterone therapy [75]. A diagnosis of GH deficiency must be ruled out if height velocity does not increase on testosterone therapy. Testosterone esters are to be avoided in hepatic impairment and hypercalcaemia and used with caution in renal impairment. Preparations are generally well tolerated but side effects may include headaches, depression and androgenic effects such as acne. Oral testosterone undecanoate can be prone to wide variations in serum testosterone because of its short half-life and thus requires careful monitoring, although has been successfully used for pubertal induction at a dose of 40e160 mg daily [23]. Although anabolic steroids such as oxandralone have been used historically for short-term improvement in height velocity, they are less effective in stimulating pubertal virilisation and therefore they are not recommended for the management of DP. As discussed, DP is commonly seen in combination with idiopathic short stature (ISS) and such patients may present with concerns about short stature far out-weighing those about DP. After exclusion of those patients with GH deficiency, for example by the use of a primed GH-provocation test, the treatment of GH-replete DP patients with growth hormone remains controversial: it has been approved by the US FDA for the treatment of ISS and height SDS 2.25 for age, but leads to only a  modest increase in adult height and its use is not recommended [76,77]. A further potential pharmacological target in short boys with DP is inhibition of estrogen biosynthesis from androgens with aromatase inhibitors [78,79]. Epiphyseal closure is dependent on estrogens and thus aromatase inhibitors (AIs) can potentially act to extend the time period of long bone growth. Some published data supports this possible effect of AIs to delay bone maturation and to increase adult height in boys with short stature and/or DP [78,79]. However, despite recent data suggesting a good safety profile, there remains uncertainty about the efficacy and appropriateness of AI therapy in DP [80,81].

Permanent hypogonadism Although sex steroid replacement is used in nearly all conditions of hypogonadism for initiation of male puberty, more complex and involved management including gonadotropin treatment may be required in males with hypogonadism to achieve both the development of secondary sexual character- istics and to maximize the potential for fertility. Management of specific indications is discussed below.

Hypogonadotropic hypogonadism In young men with a diagnosis of IHH, induction of puberty with sex steroid therapy is similar to that in self-limited DP; however, treatment can be initiated at a younger age (12yrs) if the condition is confirmed. In some patients, it may not be initially possible to distinguish between a diagnosis of IHH and DP and, therefore, commencement of testosterone therapy may be delayed until 14yrs. The starting dose of testosterone ester for IHH patients is also commonly 50 mg, but doses are gradually increased to full adult replacement levels over approximately three years (Table 3). Monitoring of response to treatment and for possible side effects is required, and therapy is likely to be required life-long.

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364 S.R. Howard, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372 10 yrs. < ammatory reaction fl nd have not previously received ammation locally in the testis, 53 (4). Requires extensive experience. Most physiological form of replacement. Erythrocytosis, weight gain, prostatic hyperplasia. High doses can cause premature epiphyseal closure. Not forin use boys with bone age and sterile abscess). Priapism canpatients occur with in sickle cell disease. dyspnoea post-injection, ascribed to lipid embolism from the vehicle; hencelicensed not in USA. Local irritation. After applying, avoidskin close contact with others, especially females Side Effects and Cautions hCG: In fl may induce apoptosis of germhypogonadotropic cells. hypogonadism In with prepubertal onset it is necessaryFSH to to add induce testicular growthspermatogenesis. and No data on effectsfuture on fertility. All IM preparations: local side(pain, effects erythema, in e . c 14 weeks. Very rarely, paroxysms of coughing and e 600 ng/kg/pulse 3 times weekly e e 225 IU 2 3000IU twice weekly, 80 mg daily. e e e 25 ng/kg/pulse every 90 12 months. After reaching e males. e e 150 mg monthly, decrease interval e 120 min; increase to 25 increased to every 2 days.based Dose on adjusted serum T levels. rhFSH: Dose 75 Can be started when approximatelyadult 50% dose with IM TAdult has dose been 50 achieved. hCG: Dose 500 Initial: 5 e Adult dose is 1000 mg every 10 Can initiate after age 12month. yrs Increase at with 50 50 mg/ mgevery increments 6 100 to every 2 weeks. Adult2 dose weeks. 200 mg every Hypogonadism Hypogonadism . [91] 50 mg increment in e 100 mg every 4 weeks for e cial in men with prepubertal testes 6 months. fi e Induction of Puberty in Boys No data available. Not recommended before 13.5 yrsInitial of dose age. 50 3 After review of response: repeated treatment with 25 Isolated DP Not recommended routinely No data available. dose (not exceeding 100 mg) Isolated DP b . Not recommended routinely or gonadotropins. 85] e [82 a s.c. pump ed and reprinted with permission from Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012; 366:443 fi topically at bedtime. enanthate has longer duration ofthan effect T propionate. IM injection. Testosterone undecanoate PO tablets orInduction anabolic of steroids fertility are may not be recommended less for successful the in induction menFSH of who pre-treatment secondary have for sexual lower 4 characteristics. months baseline may testicular be volumes, bene have received previously testosterone treatment, a c hCG (SC or IM) plus recombinant FSH (SC) T undecanoate IM injection T gel. Transdermal preparations, applied Treatment of Fertility in Boys and Men T enanthate, cypionate, and propionate. T Drug and Formulation Pulsatile GnRH Testosterone (T) a b treatment with GnRH Table 3 Medications used for the treatment of self-limited delay of puberty and permanent hypogonadism Table modi

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Maintenance therapy can be with IM testosterone, often as the longer acting testosterone undecanoate (Nebido), topical or oral therapy. Importantly, testosterone therapy does not induce testicular growth or spermatogenesis in men with HH, as this is dependent on high intra-testicular concentrations of testosterone produced by LH- stimulated Leydig cells, in conjunction with FSH acting on Sertoli cells. Therefore, induction of fertility requires treatment with either pulsatile GnRH [82e84] or exogenous gonadotropins [84]. Data from the last 5e10 years on a variety of regimens has been published, with treatments varying by indication, underlying diagnosis and severity of hypogonadism. Fertility outcomes also vary, with poorer re- sponses in patients with signs of absent mini-puberty (prepubertal testes, cryptorchidism, and/or low inhibin B) [83,85]. Genetic diagnoses may also guide therapy: treatment of patients with KAL-1 mu- tations can be more difficult as they may have defects at several levels of the HPG axis [86], and patients with IHH due to GnRHR mutations may be better treated with hCG and FSH than pulsatile GnRH [87]. A sub-set of adolescent patients with IHH will have had a spontaneous onset of pubertal develop- ment that has then arrested. In such patients, monotherapy with hCG can be trialled for both completion of pubertal development and induction of fertility [88]. FSH can then be added if there is persistent azoospermia after 6e12 months of treatment. In apubertal adolescent males, induction of puberty with either hCG monotherapy or with combinational therapy of hCG rFSH leads to better testicular growth þ and fertility outcomes than treatment with testosterone therapy [89]. Furthermore, a combined regime of hCG FSH has greater potential efficacy in the induction of spermatogenesis than monotherapy with þ hCG [89,90]. Additionally, timing of treatment is important, as FSH pre-treatment may theoretically optimise the Sertoli cell population prior to exposure to hCG or GnRH, and thus has the potential to improve fertility outcomes [91,92]. Although the optimal regimen in severe cases, i.e. those with testicular volume <4 mL, is unknown, FSH pre-treatment followed by GnRH or combination hCG and FSH treatment may maximize the potential for fertility [93]. Earlier age of treatment to induce sper- matogenesis may also be beneficial in increasing the capacity for and speed of sperm production once fertility is desired; however, assisted reproductive technologies may still be required [94]. At the other end of the spectrum, patients can exhibit reversal of their phenotype during treatment. This phenomenon is being increasingly recognized in up to 20% of IHH cases [27]. Awareness of this is important as a ‘trial off treatment’ can be utilized intermittently to assess requirements for mainte- nance therapy. However, these cases may also relapse off treatment and thus need ongoing monitoring. Patients with acquired HH, usually secondary to tumours or other structural lesions of the hypothalamicepituitary axis or haemochromatosis, require treatment of their underlying condition with sex steroid or gonadotropin therapy depending on their specific requirements [92,95].

Hypergonadotropic hypogonadism The commonest condition underlying hypergonadotropic hypogonadism in males is Klinefelter's syndrome (47, XXY), with a prevalence of 1 in 667 live births. The majority of those affected will enter puberty spontaneously at a normal age [96], although DP may be seen in those with a more complex karyotype (48, XXYY, 48, XXXY, 49, XXXXY). Sex steroid replacement is therefore not normally required for these patients at the start of puberty, but testosterone levels become increasingly deficient by Tanner stages 4e5, possibly as a result of secondary regression. However, only 10% of boys aged 10e14yrs with Klinefelter's syndrome have been diagnosed and many patients only come to the attention of an Endocrinologist in later adulthood [97]. These patients present potentially difficult management decisions in terms of optimizing fertility outcomes, mainly relating to timing of in- terventions [98,99]. For patients with Klinefelter's syndrome requiring treatment due to falling testosterone levels, haematocrit, bone density, patient well-being or sexual function, low dose sex steroid replacement is the most commonly used therapy (Table 3). However, testicular sperm extraction and cryopreservation can be considered, even in adolescence prior to testosterone treat- ment, before the progressive seminiferous tubule degeneration that occurs in Klinefelter's syndrome has had an irreversible impact on sperm production [47]. Unfortunately, the most invasive (& suc- cessful) sperm retrieval techniques have the potential to cause the most testicular damage, and so would ideally be reserved for those men actively desiring fertility. Balancing these opposing factors and giving clear information to young men who may not yet be concerned about their future fertility options, in order that they might make informed choices, is highly challenging.

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The treatment of anorchic young men, secondary to congenital absence, vanishing testis syndrome or failed orchidopexy, for induction and maintenance of puberty is similar to that in boys with IHH. Androgen replacement should be commenced at a low dose with incremental dose increases. IM testosterone esters administered monthly is the treatment of choice for pubertal induction, with testosterone gel via calibrated dispenser or 4-monthly intramuscular depot injections of Testosterone undecanoate 1 g used for long-term maintenance therapy (Table 3).

Management of hypogonadism - females

Infancy

There is currently no evidence for therapy in hypogonadic female infants. These girls are less commonly diagnosed at birth or in infancy due to the lack of physical abnormalities (as compared to males with cryptorchidism or micropenis). However, in future pre- or postnatal genetic diagnosis may led to increased awareness and research in this area.

Adolescence

Self-limited delayed puberty Similarly to male patients with self-limited DP, the options for management of female patients with DP include monitoring with reassurance or therapy using low dose sex steroids to initiate pubertal development. Initial short-term therapy should be regularly reassessed and discontinued once puberty is progressing (Table 4).

Permanent hypogonadism As in boys, in cases of permanent hypogonadism more intensive and long-lasting therapy is required. Goals of treatment are induction of secondary sexual characteristics, development of reproductive capacity and increasing adult height. Once puberty is complete, ovulation and pregnancy can be achieved by pulsatile GnRH administration or combination gonadotropin therapy. When estrogen therapy is required to induce pubertal development, the dosing and timing should be aimed at simulating the normal growth and development of secondary sex characteristics as closely as possible, taking account of the individual's desire to begin puberty and also of the family history of age at onset of puberty. Doses should be adjusted according to the needs and priorities of the indi- vidual. Response to therapy should be monitored in terms of the development of secondary sex characteristics, bone maturation, height velocity and uterine volume, with additional monitoring of blood pressure and bone density [100]. Both in young women with Turner syndrome and combined pituitary hormone deficiency, es- trogen therapy should be coordinated with the use of GH. Previous practice in Turner syndrome tended towards delaying estrogen therapy until the mid-teens in order to optimize growth pro- motion with GH. However, more recent studies point to potential benefits from treatment with combined very low-dose estrogen and GH from an early age, in terms of final height and potentially other areas including cognitive development and uterine maturation [101,102]. Whilst it remains unclear as to the best timing to initiate estrogen therapy in young women with Turner syndrome, the current consensus is that induction of puberty should not be delayed in order to promote linear growth [103]. Additionally, whilst ethinylestradiol has traditionally been the estrogen of choice for pediatric patients, 17b-estradiol in transdermal, gel or oral form displays a better risk profile in terms of growth restriction, liver toxicity and vascular side-effects. Data from women with combined pitui- tary hormone deficiencies receiving combined estrogen and GH treatment indicate a markedly greater impairment of GH-mediated IGF1 synthesis with ethinylestradiol than with 17b-estradiol. Uterine development may also be impaired with the use of ethinylestradiol as compared to 17b- estradiol ([104,105]). Conjugated equine estrogens have been used, but formulations vary in bio- logical potency and in view of reports of increased cardiovascular risks in postmenopausal women are best avoided.

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Table 4 Medications used for the treatment of self-limited delay of puberty and permanent hypogonadism e females.

Drug and Formulation Induction of Puberty in Girls Side Effects and Cautions

Isolated DP Hypogonadism

Estrogens Not recommended before 13 yrs of age. Transdermal Overnight patch: initial Starting dose as for DP, Patches may be difficult to use 17b-estradiol dose, 3.1e6.2 mg per 24 h increase by 3.1e6.2 mg per and fall off, especially if cutting e.g Evorel 25 (1/8-1/4 of 25-mg 24-hr patch); 24 h until 1 full Evorel 25 whole patches into smaller increase by 3.1e6.2 mg per patch continuouslyb fractions Reactions to adhesive 24 h after 6 monthsa Then maintenance with adult Inter-individual variation COCP or HRT in dose response Oral 17b-estradiol 0.5 mg (1/2 tablet) alternate Starting dose as for DP, Inter-individual variation in (estradiol valerate) days or 5 mg/kg of body increase by 5 mg/kg of body dose response weight daily; increase to 0.5 mg weight every 6e12 months (1/2 tablet) or 10 mg/kg daily until dose of 1 mg (1 tablet) after 6e12 months daily Then maintenance with adult COCP or HRT Oral Ethinylestradiol 2 mg daily, increase to 4 mg 2 mg daily, increase by 2 mg High cost Liver toxicity, (2 mg tablets) after 6 months if required every 6 months until 10 mg increased levels of some Then maintenance with adult plasma-binding proteins COCP or HRT Potential increased risk of hypertension and VTE Worse growth profile Progestins Not applicable Introduced once breakthrough bleeding or 2 yrs of þ continuous estrogen Norethisterone 5 mg More androgenic, increased risk of dysmenorrhoea Utrogestan 200 mg once daily Medroxyprogesterone 5 mg once daily acetate Combination e.g. Evorel sequi, Elleste-Duet preparations Treatment of Fertility in Women Pulsatile GnRH Not applicable Requires extensive experience, s.c. pump treatment only within specialist centres. Most physiological form of replacement. hCG (SC or IM) plus Not applicable Requires extensive experience, recombinant FSH (SC). treatment only within specialist fertility centres

a Adjustments for body weight may be required, published advice on cutting patches available [106]. b Once changed from overnight to all day use, patches to be changed twice weekly COCP e combined oral contraceptive pill, HRT, hormone replacement therapy, VTE e venous thromboembolism.

Estrogen therapy should be initiated at a low dose (one-eighth to one-quarter of the adult dose) and increased gradually (at intervals of 6e12 months) [100]. Doses can then be adjusted to the response (Tanner stage, bone age, and uterine growth), or if available, by ultrasensitive estradiol assay [106], with the aim of completing feminization gradually over a period of 2e3 years (Table 4). A progestin such as oral medroxyprogesterone acetate should be added either if more than one episode of significant breakthrough bleeding occurs or after 24e36 months of estrogen therapy to establish menstrual cycles, with a frequency of at least every 2e3 months to prevent endometrial hypertrophy. Individuals with Turner syndrome who have functioning ovaries and who progress through puberty spontaneously should receive contraceptive and genetic counseling. However, ovulatory function should be documented (FSH and LH measurements) because a peri-menopausal pattern of anovulation can lead to endometrial hyperplasia.

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Conclusion

There are multiple genetic and environmental influences on the timing of puberty in the general population, and appropriate age cutoffs for delayed puberty in different ethnic groups may vary. DP is a frequent problem, and the most common underlying condition is self-limited (or constitutional) DP. However, the differential diagnoses include hypogonadotropic hypogonadism and primary hypo- gonadism, and these conditions must be considered in young people with pubertal delay. Additionally, both of these forms of non-self-limiting hypogonadism may be diagnosed in infancy if the suspicion arises. Distinguishing between self-limited DP and permanent hypogonadotropic hypogonadism in adolescence remains difficult. Management of adolescents with DP is dependent on the underlying cause. Treatment of isolated DP involves expectant observation or short courses of sex steroids in low doses, whilst more complex and involved management is required in patients with permanent hypogonadism. Achievement of fertility in patients with central hypogonadism requires therapy with gonadotropins. The management of infants diagnosed with permanent central hypogonadism is an area of future research.

Practice points

The mini-puberty is an important window of opportunity for the evaluation of suspected  hypogonadism in an infant, and diagnosis during the mini-puberty may aid management and future outcomes. It is very important to diagnose the underlying cause of delayed puberty, especially to  distinguish between self-limited DP and IHH in adolescents, as treatment aims, options and duration are very different in these two patient groups. The consideration of fertility in hypogonadic males, even in adolescence, should be para-  mount for clinicians, as appropriate treatment may optimize future fertility potential in these patients in a time-sensitive manner that may not be possible later in life. We have highlighted the need for an awareness of the clinical spectrum in IHH, and the  differing requirements of patients with severe congenital HH versus partial or indeed reversible HH.

Research agenda

Because of the secular change in the timing of puberty, traditional limits which define  delayed puberty may need moderating in particular environments and ethnic groups. Because of the lack of controlled trials, it remains unclear what the optimal management of  males with severe hypogonadotropic hypogonadism (cryptorchidism, micropenis and lack of spontaneous increase in testicular size in puberty) should entail. Whether such patients would benefit from prepubertal (or even neonatal) FSH treatment to improve potential for future fertility is an unanswered question. The genetic and environmental basis for both DP and IHH is an area of research where there  is still much to be discovered, and one that may bring future benefits for informed man- agement of these patients. Our understanding of the key controllers of pubertal onset and its timing is advancing, but it is still a complex puzzle to be unlocked. In self-limited DP low dose sex steroid treatment is adequate for the majority of patients who  require intervention. However, a proportion of young men will remain adversely affected by their delayed pubertal development and/or short stature in adolescence, which may have long-term consequences. It is not known whether pubertal delay has a negative impact on adult bone mass and whether potentially compromised bone health is a reason to initiate sex-steroid replacement.

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Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. J Clin Invest 1997;100(9):2341e6. [68] Niedzielski JK, Oszukowska E, Slowikowska-Hilczer J. Undescended testis - current trends and guidelines: a review of the literature. Arch Med Sci 2016;12(3):667e77. [69] Poyrazoglu S, Gunoz H, Darendeliler F, et al. Constitutional delay of growth and puberty: from presentation to final height. J Pediatr Endocrinol Metabol 2005;18(2):171e9. [70] Rosenfeld RG, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and development in male adolescents. Pediatrics 1982;69(6):681e7. [71] Soliman AT, Khadir MM, Asfour M. Testosterone treatment in adolescent boys with constitutional delay of growth and development. Metab Clin Exp 1995;44(8):1013e5. [72] Kelly BP, Paterson WF, Donaldson MD. Final height outcome and value of height prediction in boys with constitutional delay in growth and adolescence treated with intramuscular testosterone 125 mg per month for 3 months. Clin Endocrinol 2003;58(3):267e72. [73] Wilson DM, Kei J, Hintz RL, et al. Effects of testosterone therapy for pubertal delay. Am J Dis Child 1988;142(1):96e9. [74] De Luca F, Argente J, Cavallo L, et al. Management of puberty in constitutional delay of growth and puberty. J Pediatr Endocrinol Metabol 2001;14(Suppl. 2):953e7. [75] Giagulli VA, Triggiani V, Carbone MD, et al. The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. J Sex Med 2011; 8(12):3471e8. [76] Jeong HR, Shim YS, Lee HS, et al. The effect of growth hormone treatment on height in children with idiopathic short stature. J Pediatr Endocrinol Metabol 2014 Jul;27(7-8):629e33. https://doi.org/10.1515/jpem-2013-0461. [77] Bryant J, Baxter L, Cave CB, et al. Recombinant growth hormone for idiopathic short stature in children and adoles- cents. Cochrane Database Syst Rev 2007;(3). PMID: 17636758. https://doi.org/10.1002/14651858.CD004440.pub2. [78] Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab 2005;90(12):6396e402. *[79] Wickman S, Sipila I, Ankarberg-Lindgren C, et al. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet 2001;357(9270):1743e8. [80] Hero M, Toiviainen-Salo S, Wickman S, et al. Vertebral morphology in aromatase inhibitor-treated males with idio- pathic short stature or constitutional delay of puberty. J Bone Miner Res 2010;25(7):1536e43. [81] Mauras N, Ross JL, Gagliardi P, et al. Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic, short stature. J Clin Endocrinol Metabol 2016;101(12):4984e93. [82] Pitteloud N, Hayes FJ, Boepple PA, et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002;87(1):152e60. [83] Pitteloud N, Hayes FJ, Dwyer A, et al. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002;87(9):4128e36. [84] Warne DW, Decosterd G, Okada H, et al. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril 2009;92(2):594e604. [85] Liu PY, Baker HW, Jayadev V, et al. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009;94(3): 801e8. [86] King TF, Hayes FJ. Long-term outcome of idiopathic hypogonadotropic hypogonadism. Curr Opin Endocrinol Diabetes Obes 2012;19(3):204e10. [87] Caron P, Chauvin S, Christin-Maitre S, et al. Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metabol 1999;84(3):990e6. [88] Pitteloud N, Boepple PA, DeCruz S, et al. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metabol 2001;86(6):2470e5. [89] Zacharin M, Sabin MA, Nair VV, et al. Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normal testicular growth and may promote early spermatogenesis. Fertil Steril 2012;98(4):836e42. [90] Barrio R, de Luis D, Alonso M, et al. Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism. Fertil Steril 1999;71(2):244e8. [91] Dwyer AA, Sykiotis GP, Hayes FJ, et al. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH- induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metabol 2013; 98(11):E1790e5. [92] Sato N, Hasegawa T, Hasegawa Y, et al. Treatment situation of male hypogonadotropic hypogonadism in pediatrics and proposal of testosterone and gonadotropins replacement therapy protocols. Clin Pediatr Endocrinol 2015;24(2):37e49.

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[93] Raivio T, Wikstrom AM, Dunkel L. Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome. Eur J Endocrinol Eur Fed Endocrine Soc 2007;156(1):105e11. [94] Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical E. American Association of Clinical Endocri- nologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patientse2002 update. Endocr Pract 2002;8(6):440e56. [95] Han TS, Bouloux PM. What is the optimal therapy for young males with hypogonadotropic hypogonadism? Clin Endocrinol 2010;72(6):731e7. [96] Juul A, Aksglaede L, Bay K, et al. Klinefelter syndrome: the forgotten syndrome: basic and clinical questions posed to an international group of scientists. Acta Paediatr 2011;100(6):791e2. [97] Blevins CH, Wilson ME. Klinefelter's syndrome. BMJ 2012;345. e7558. [98] Mehta A, Bolyakov A, Roosma J, et al. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril 2013;100(4):970e4. [99] Rives N, Milazzo JP, Perdrix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum Reprod 2013;28(6):1468e79. [100] Matthews D, Bath L, Hogler W, et al. Hormone supplementation for pubertal induction in girls. Arch Dis Child 2017; 102(10):975e80. [101] Saenger P, Wikland KA, Conway GS, et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metabol 2001;86(7):3061e9. [102] Ross JL, Quigley CA, Cao D, et al. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. N Engl J Med 2011;364(13):1230e42. [103] Bondy CA. Turner syndrome study G. Care of girls and women with turner syndrome: a guideline of the turner syndrome study group. J Clin Endocrinol Metabol 2007;92(1):10e25. [104] Bakalov VK, Shawker T, Ceniceros I, et al. Uterine development in Turner syndrome. J Pediatr 2007;151(5):528e31. 31 e1. [105] Doerr HG, Bettendorf M, Hauffa BP, et al. Uterine size in women with Turner syndrome after induction of puberty with estrogens and long-term growth hormone therapy: results of the German IGLU Follow-up Study 2001. Hum Reprod 2005;20(5):1418e21. [106] Ankarberg-Lindgren C, Kristrom B, Norjavaara E. Physiological estrogen replacement therapy for puberty induction in girls: a clinical observational study. Horm Res Paediatr 2014;81(4):239e44. [107] van Buuren S. Growth charts of human development. Stat Meth Med Res 2013;23(4):346e68.

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Delayed Puberty Alyssa M. Dye, MD; Grace B. Nelson, MD; and Alicia Diaz-Thomas, MD, MPH

Pubertal delay itself can present sig- ABSTRACT nificant stressors for both the patient Delayed puberty is defined as the absence of physical signs of puberty 2 to 2.5 standard and their parents. One study found that deviations above the mean age and affects approximately 2% of adolescents. Causes of de- in untreated CDGP, over one-half of layed puberty are broadly divided into two categories: hypergonadotropic hypogonadism the boys felt that their growth delay af- and hypogonadotropic hypogonadism. One exception to this classification system is con- fected their social and scholastic suc- stitutional delay of growth and puberty, the most common cause of delayed puberty. For cess.2-4 Girls were affected to a lesser the general pediatrician, knowledge of the different causes and initial steps to evaluation is extent, although still reported negative crucial when a patient with delayed puberty presents. [Pediatr Ann. 2018;47(1):e16-e22.] effects of growth delay on perceived success.5 Unwanted long-term physi- uberty is the universal process a certain age (2 to 2.5 standard devia- cal sequelae of delayed puberty can of maturation to reproductive tions above the mean age) in the popu- include impaired fertility and com- Pcapacity. The mechanisms that lation and affects approximately 2% of promised bone health. For the primary initiate puberty are an area of active adolescents.1 In girls, this is charac- care pediatrician, knowledge of steps research. Once the process initiates, terized as lack of breast development initial evaluation and when to refer for the hypothalamus begins to secrete go- by age 13 years, or more than 4 years further evaluation is crucial to timely nadotropin-releasing hormone (GnRH) between physical signs of thelarche and effective management of these in a pulsatile fashion with increas- (initiation of breast development) and adolescents. ing amplitude and frequency. GnRH menarche. In boys, lack of testicular stimulates pituitary gonadotropins, lu- enlargement by age 14 years or more DIFFERENTIAL DIAGNOSIS teinizing hormone (LH), and follicle- than 4 years between the onset of testic- Causes of delayed puberty are stimulating hormone (FSH). These ular development and the completion of broadly divided into two categories, gonadotropins in turn act at the level puberty defines delayed puberty.2,3 De- based on where the hypothalamic- of the gonad, causing release of estro- layed puberty most commonly presents pituitary-gonadal (HPG) axis failure gen and progesterone or testosterone. in boys and most cases are a variant of has occurred (Figure 1). Hypergo- These sex steroids are responsible for normal pubertal maturation called con- nadotropic hypogonadism is character- the development of secondary sexual stitutional delay of growth and puberty ized by an appropriate activation of the characteristics that we associate with (CDGP). However, for children lacking hypothalamic-pituitary component, but puberty. secondary sexual characteristics by the failure of gonadal sex steroid produc- Delayed puberty is defined as the aforementioned-time points, evaluation tion. Conversely, hypogonadotropic absence of physical signs of puberty by is necessary. hypogonadism (HH) is secondary to delay or failure of the hypothalamic/ Alyssa M. Dye, MD, is a Pediatric Resident. Grace B. Nelson, MD, is a Pediatric Endocrinology Fellow. pituitary portion of the HPG axis. Clas- Alicia Diaz-Thomas, MD, MPH, is an Associate Pediatric Endocrinology Fellowship Program Director. All sification of pubertal delay can proceed authors are affiliated with the University of Tennessee Health Science Center, Graduate Medical Educa- along these lines except for two etiolo- tion, Department of Pediatrics, Le Bonheur Children’s Hospital. gies: CDGP and complete androgen in- Address correspondence to Grace B. Nelson, MD, 51 N. Dunlap Street, Memphis, TN 38104; email: sensitivity syndrome (CAIS). [email protected]. The most common cause of puber- Disclosure: The authors have no relevant financial relationships to disclose. tal delay is CDGP, a delay of pubertal doi:10.3928/19382359-20171215-01 signs and symptoms but with eventual

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progression to normal puberty.1 This is difficult to distinguish from isolat- ed hypogonadotropic hypogonadism (IHH), a pathologic condition that re- quires treatment.2 Finally, AIS, a cause of delayed menarche after breast devel- opment, fits into neither classification, as both the hypothalamus and gonads function appropriately, but there is end-organ resistance to androgens. Un- derstanding the various causes and dif- ferential diagnosis of delayed puberty can assist the general pediatrician with initial evaluation.

HYPERGONADOTROPIC HYPOGONADISM Hypergonadotropic hypogonadism, Figure 1. Expected levels of gonadotropins and sex hormones in normal development, both types of also known as primary gonadal failure, hypogonadism and androgen insensitivity syndrome. is always a pathologic state. Levels of LH and FSH are elevated, indicating appropriate maturity of the HPG axis abnormalities including coarctation of somal anomalies such as Klinefelter’s but failure of gonadal sex steroid pro- the aorta.6,7 Females with Turner’s syn- syndrome (47,XXY) or multiple X duction to provide negative feedback. drome will develop pubic hair, and 15% syndrome (48,XXXY; 48,XXYY; One study showed that in boys, this is to 30% will have breast development. 49,XXXYY). Klinefelter’s syndrome uncommon (7%), but for girls, 26% of Some cases of Turner’s syndrome will has an incidence in males of 1 in 500 those presenting for delayed puberty not be noted until there is lack of de- to 1 in 1,000 and rarely presents as were found to have primary ovarian velopment of secondary sexual charac- pubertal delay, instead presenting as failure.6 Chromosomal abnormalities, teristics, lack of menarche, or less com- lack of completion of puberty. Males other congenital disorders, and ac- monly, abnormal menses and infertility. have small testes, tall stature, feminine quired injuries can all lead to gonadal A less common cause resulting in fat distribution (gynecomastia), and failure. ovarian failure is autoimmune ovarian behavioral problems noted most com- failure, which has been reported in both monly in school.3,7 Females type I and type II autoimmune poly- History of prenatal or acquired tes- Although there are many potential glandular syndromes. This should be ticular damage is another potential causes of primary ovarian failure, Turn- suspected in females with other auto- cause of testicular failure in males. er’s syndrome is the most common.6 immune conditions, such as Addison’s Testicular regression syndrome, or van- Turner’s syndrome occurs in 1 in 2,500 disease, type 1 diabetes mellitus, and ishing testes, is seen in less than 5% of females and can be diagnosed during in- hypoparathyroidism.3 One-half of fe- cryptorchidism cases. This is thought fancy and childhood. This is a primary males with galactosemia will develop to be the result of antenatal or perinatal chromosomal disorder caused by lack ovarian failure, thought to be secondary thrombosis or torsion.9 Bilateral testic- of sufficient X chromosome dosage, to the toxicity of galactose metabolites ular torsion at any age, damaged paren- ie, 45,X or 45,X/46,XX. Short stature and resulting in atresia of the primary chyma secondary to sickle cell disease is a characteristic finding, along with follicles.3,8 or trauma, or surgical attempt of cor- congenital lymphedema (webbed neck, rection of cryptorchidism can also be low posterior hairline), facial dysmor- Males causes of testicular failure. phism with high arched palate, skel- Testicular failure is rare, but is Of note, genetic associations with etal anomalies, and associated cardiac most commonly secondary to chromo- testicular failure include myotonic

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dystrophy, Noonan’s syndrome, and represents an exaggerated delay of (normosmic) or have variable degree changes in the LH receptor on the puberty. Patients present with short of impairment ranging from impaired testes (LH beta-receptor mutations). stature, delayed skeletal age (young- smell (hyposmic) to absent smell (an- These are associated with pubertal er than age 11 years in females and osmic) mechanism. People with IGD delay secondary to gonadal failure. younger than age 13 years in males) and either hyposmia or anosmia are and pubertal delay. In one-half of diagnosed with Kallmann’s syndrome Conditions Affecting Both Sexes the CDGP cases, a family history of (KS), whereas those with normal ol- History of irradiation and chemo- delayed puberty is present.11 Males factory function are diagnosed with therapy can result in gonadal failure present more frequently than females normosmic IGD (nIGD).13 KS is more in both sexes. One-half of females due to the negative psychosocial ef- frequently seen in males with an in- who receive pelvic irradiation devel- fects that arise with short stature and cidence of 1 in 8,000.11 Most cases op primary ovarian failure, the likeli- pubertal delay.12 Patients will begin are sporadic and result from a genetic hood dependent on the dose given and puberty spontaneously, and sexual defect in the KAL-1 gene, which en- age of the patient.3 A study performed maturity and growth potential are not codes the protein anosmin-1 that is in male childhood cancer survivors affected, as adult height is consistent involved in fetal GnRH neuronal mi- found that gonadal failure was present with genetic potential.3 gration.12 KS can also be associated in 25% of those patients.10 Cytotoxic Functional hypogonadotropic hy- with renal anomalies and midline fa- chemotherapy agents, like cyclophos- pogonadism or hypothalamic dys- cial defects. There are other genetic phamide, busulfan, procarbazine, and function can occur due to systemic defects that can cause KS, and skel- etoposide, have been shown to lead to illnesses. The HPG axis has normal etal anomalies can be associated with gonadal failure, but are particularly potential, but is disrupted second- these mutations. nIGD can be spo- devastating to the actively proliferat- ary to inflammation, poor nutrition, radic (66%) or familial (33%) and ing cells of the mature ovary.3 His- and chronic pain. Some patients may is caused by congenital dysfunction tory of infections, including mumps, present with stunted growth as well of the hypothalamic-pituitary struc- shigella, malaria, varicella, and cox- as delayed puberty. Hypothyroidism, ture.3,11 To date, there are more than sackie viruses, is also associated with diabetes mellitus, growth hormone 20 genetic defects leading to nIGD ovarian and testicular failure. deficiency, cystic fibrosis, inflam- that have been identified, although matory bowel disease, celiac disease, many more are expected.14 HYPOGONADOTROPIC juvenile rheumatoid arthritis, hemo- HH can also be seen as a feature HYPOGONADISM chromatosis, sickle cell disease, and of some genetic syndromes such as HH indicates either immaturity or systemic therapy for chronic condi- Prader-Willi syndrome, Noonan’s failure of gonadotropin production, tions (long-term glucocorticoids) syndrome, CHARGE syndrome, and or the failure of activation of the hy- have all been associated with puber- Laurence-Moon-Bardet-Biedel syn- pothalamic portion of the HPG axis. tal delay. Similarly, intense exercise drome. Additionally, leptin deficien- Low plasma gonadotropin levels and and undernutrition are known causes cy or resistance syndromes may have low testosterone levels (males) or lack of amenorrhea and HH. Although ge- HH as a feature. of pubertal signs (females and males) netic height potential might not be Central nervous system lesions indicate this as a diagnosis.11 Differ- achieved in all cases, aggressive man- and tumors are another potential entiating immaturity versus failure of agement of the underlying condition cause of HH. In patients of pubertal the HPG axis presents a challenge and is the first method of prevention and age, delayed puberty can be one of can be confirmed only by the onset of treatment for pubertal delay.3,12 the presenting symptoms of cranio- puberty. pharyngioma or other mass lesions in Pathologic Causes the hypothalamic-pituitary region.3,7 Self-Limited Causes Isolated gonadotropin-releasing Prolactinomas, resulting in pubertal CDGP is the most common cause hormone deficiency (IGD) repre- delay or secondary amenorrhea, pres- of HH in males (63%) and in females sents a heterogenous group of condi- ent with galactorrhea without gyneco- (30%).6 Constitutional delay of pu- tions. Males and females with IGD mastia.7 It is important for the general berty is a diagnosis of exclusion and can have an intact smell mechanism pediatrician to inquire about head-

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aches and visual disturbances to rule appropriately. Similarly, if a patient is there is uncertainty between IHH and out these conditions. Pituitary gland presenting due to malnutrition or an- CDGP.12,18 Referral to an endocrinolo- hypoplasia, associated with septo-op- orexia, nutritional management is the gist would also be appropriate for these tic dysplasia spectrum disorders, can most important first step in treatment. patients (Figure 3). also have pubertal delay from HH. Females MANAGEMENT EUGONADOTROPIC For the general pediatrician, evalua- Males EUGONADISM tion with karyotype to rule out Turner’s Replacement of sex steroids (tes- Physicians should consider ana- syndrome is the next appropriate step tosterone) can begin between ages tomical defects in females who present in management. If the karyotype sug- 12.5 and 13 years. For patients receiv- with normal levels of gonadotropins gests Turner’s syndrome, referral for ing growth hormone, delay of sex ste- and sex steroids based on age and Tan- endocrine evaluation and treatment is roid replacement may be considered ner stage, along with normal develop- necessary. Guidelines for management to allow for growth catch-up. Patients ment of secondary sexual characteris- of patients with Turner’s syndrome who have pubertal bone age do not tics. Imperforate hymen or incomplete have been developed and recommend need delay in hormonal treatment, or partial canalization of the vagina the following evaluations: renal ultra- as studies have shown that therapy in will result in amenorrhea with cyclical sound, cardiac, audiology, scoliosis/ boys age 14 years and older has no ef- abdominal pain.3 kyphosis, baseline laboratory, includ- fect on adult height.3,7 ing TSH and total or free T4. The fam- Differentiation between pubertal OTHER FORMS OF DELAYED ily and patient should be offered refer- delay and permanent gonadotropin PUBERTY ral to support groups.16 If karyotype is deficiency is often not made before Patients with CAIS do not fit into normal, referral to an endocrinologist sex steroid therapy is started. After the previously mentioned classifica- for further testing and possible in- treatment for 6 months, males with tions. People with CAIS typically pres- duction of puberty is the next step in CDGP should progress to subsequent ent with high levels of LH/FSH and management7 (Figure 2). pubertal testosterone levels and see testosterone, have female breast devel- an increase in size of the testes (a go- opment, and lack of pubic hair (signs Males nadotropin-dependent process). This of androgen activity).15 Evaluation of karyotype to look for confirms that the HPG axis is normal Klinefelter’s syndrome or multiple and puberty should progress without EVALUATION X syndrome should be the next step. intervention.3,7,18 Testosterone helps For patients who present with de- For males who have a 46,XXY karyo- to start the pubertal progress as sex layed puberty, a thorough history and type, referral for endocrine evaluation steroids have a direct permissive ef- physical examination is key to guide should be performed. Patients will also fect at the level of the hypothala- further evaluation and development of need evaluation by urology, psychol- mus.19 In males with IHH, testicular diagnostic possibilities. For females ogy, neuropsychology for possible enlargement will not be apparent and and males who meet criteria for de- speech delays and learning disabilities, testosterone levels will remain low; layed puberty, evaluation of body mass and referral for patients and families androgen replacement should con- index, history of intense exercise, and to support groups.17 For patients with tinue. Testosterone replacement, typi- laboratory assessment (complete blood a normal male karyotype, endocrine cally provided via injection, is slowly count, liver function test, erythrocyte evaluation of gonadotropin and go- increased over 3 to 4 years until adult sedimentation rate, thyroid-stimulating nadal status prior to possible trial of levels are reached. Once adult re- hormone (TSH), free T4, hemoglobin testosterone therapy is the next step. placement levels are reached, patients A1c) may be necessary to evaluate for For patients with CDGP, reassurance may opt for other methods of testos- secondary causes of delayed puberty. and waiting is appropriate, however, terone delivery such as gels or sprays. If delayed puberty is secondary to a many patients may wish to proceed Testosterone is continued until a male chronic disease, management focuses with short-term hormonal therapy to desires fertility, then FSH and LH an- on aggressive treatment of the chronic start puberty, especially when psycho- alogs may be administered to induce disease to allow the HPG axis to mature social dysfunction is present, or when adequate spermatogenesis.

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Figure 2. Algorithm for delayed puberty evaluation in females. CAIS, complete androgen insensitivity syndrome; BMI, body mass index; BP, blood pressure; CDGP, constitutional delay of growth and puberty; EKG, electrocardiogram; FSH, follicle-stimulating hormone; LH, luteinizing hormone.

In males who have primary gonad- usually ineffective, and when therapy years. Once the patient reports vaginal al failure, hormone replacement will is started, it is usually continued un- spotting, cyclical estrogen-progester- only achieve pubertal maturation and til completion of puberty.18 Induction one therapy to begin regular menses change in physical appearance. Sper- of puberty with low-dose estrogen is added.3,18 matic production and fertility will still therapy starting at age 10 to 12 years In females with gonadotropin de- be absent, and counseling for families can begin the process of thelarche. Es- ficiency that is permanent, pulsatile and patients is indicated. For males trogen can be administered via daily GnRH can help achieve fertility. In without testes, prosthetic testes can be pill or transdermal preparations twice females with primary ovarian failure, placed for physical appearance.3 weekly. Transdermal patches may be fertility is compromised. Referral to more metabolically favorable.20 Dos- a fertility specialist to advise patients Females age is increased slowly to allow for about their options including in vitro Unlike males, treatment to dif- appropriate breast development, with fertilization is indicated for these ferentiate between CDGP and HH is a goal of reaching full dosage in 3 to 4 patients.

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Figure 3. Algorithm for delayed puberty evaluation in males. BMI, body mass index; CDGP, constitutional delay of growth and puberty; FSH, follicle- stimulating hormone; LH, luteinizing hormone.

Evaluation of delayed puberty: what di- NEW HORIZONS and dioxin-like compounds, lead, and agnostic tests should be performed in the Current research has focused on polybrominated biphenyls have been seemingly otherwise well adolescent? Arch Dis Child. 2016;101(8):767-771. understanding the mechanisms behind identified as possible causative agents of doi:10.1136/archdischild-2015-310375. pubertal initiation and identifying the delayed puberty in girls.23 Research also 2. Harrington J, Palmert MR. Distinguishing con- different signaling pathways that are continues in understanding best prac- stitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: involved in the control of puberty. tices in pharmacological pubertal ini- critical appraisal of available diagnostic tests. Kisspeptin, a puberty-regulating neu- tiation and management with emphasis J Clin Endocrinol Metab. 2012;97(9):3056- ropeptide, has emerged as a central on fertility preservation and discussion 3067. doi:10.1210/jc.2012-1598. 3. Lee PA, Houk CP. Puberty and its disorders. factor in control of GnRH release; of reproductive options for children and In: Lifshitz F, ed. Pediatric Endocrinology. research is underway to understand if families. Finally, understanding whether 5th ed. London, United Kingdom: Informa kisspeptin replacement may hold val- there are long-term health or psychoso- Healthcare USA, Inc; 2009:273-303. ue in the treatment of HH.21,22 Other cial risks associated with delayed puber- 4. Crowne EC, Shalet SM, Wallace WH, Emin- son DM, Price DA. Final height in boys with researchers are investigating whether tal development will also be important. untreated constitutional delay in growth and exposure to environmental endocrine puberty. Arch Dis Child. 1990;65(10):1109- disruptors may interfere with puber- REFERENCES 1112. 1. Abitbol L, Zborovski S, Palmert MR. 5. Crowne EC, Shalet SM, Wallace WH, Emin- tal timing. Substances such as dioxin son DM, Price DA. Final height in girls with

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untreated constitutional delay in growth and atr Rev. 2001;22(9):309-315. doi:10.1542/ understanding and management of delayed puberty. Eur J Pediatr. 1991;150(10):708- pir.22-9-309. puberty. Arch Dis Child. 2016;101(5):481- 712. 13. Lewkowitz-Shpuntoff HM, Hughes VA, Plum- 488. doi:10.1136/archdischild-2014-307963. 6. Sedlmeyer IL, Palmert MR. Delayed pu- mer L, et al. Olfactory phenotypic spectrum in 19. Dungan HM, Clifton DK, Steiner RA. berty: analysis of a large case series from idiopathic hypogonadotropic hypogonadism: Minireview: kisspeptin neurons as central an academic center. J Clin Endocrinol pathophysiological and genetic implications. processors in the regulation of gonadotro- Metab. 2002;87(4):1613-1620. doi:10.1210/ J Clin Endocrinol Metab. 2012;97(1):E136- pin-releasing hormone secretion. Endocrinol- jcem.87.4.8395. 144. doi:10.1210/jc.2011-2041. ogy. 2006;147(3):1154-1158. doi:10.1210/ 7. Kaplowitz PB. Delayed puberty. Pediatr Rev. 14. Choi J-H, Balasubramanian R, Lee PH, et al. en.2005-1282. 2010;31(5):189-195. doi:10.1542/pir.31-5- Expanding the spectrum of founder mutations 20. Jospe N, Orlowski CC, Furlanetto RW. Com- 189. causing isolated gonadotropin-releasing hor- parison of transdermal and oral estrogen ther- 8. Flint AC, Hopwood NJ, Kasa-Vubu JZ. Di- mone deficiency. J Clin Endocrinol Metab. apy in girls with Turner’s syndrome. J Pedi- agnostic quandary: premature ovarian failure 2015;100(10):E1378-1385. doi:10.1210/ atr Endocrinol Metab. 1995;8(2):111-116. and galactosemia variants in adolescent girls jc.2015-2262. 21. Francou B, Paul C, Amazit L, et al. Preva- with delayed puberty. J Pediatr Adolesc Gy- 15. Mongan NP, Tadokoro-Cuccaro R, Bunch lence of KISS1 Receptor mutations in a se- necol. 2009;22(5):330-335. doi:10.1016/j. T, Hughes IA. Androgen insensitivity syn- ries of 603 patients with normosmic congeni- jpag.2008.07.020. drome. Best Pract Res Clin Endocrinol tal hypogonadotrophic hypogonadism and 9. Pirgon Ö, Dündar BN. Vanishing testes: a Metab. 2015;29(4):569-580. doi:10.1016/j. characterization of novel mutations: a single- literature review. J Clin Res Pediatr Endo- beem.2015.04.005. centre study. Hum Reprod. 2016;31(6):1363- crinol. 2012;4(3):116-120. doi:10.4274/ 16. Bondy CA; Turner Syndrome Study Group. 1374. doi:10.1093/humrep/dew073. Jcrpe.728. Care of girls and women with Turner syn- 22. Manfredi-Lozano M, Roa J, Ruiz-Pino F, et 10 Giwercman A, Lundberg Giwercman Y. Hy- drome: a guideline of the Turner Syndrome al. Defining a novel leptin-melanocortin-kiss- pogonadism in young men treated for cancer. Study Group. J Clin Endocrinol Metab. peptin pathway involved in the metabolic con- Hormones (Athens). 2015;14(4):590-597. 2007;92(1):10-25. doi:10.1210/jc.2006-1374. trol of puberty. Mol Metab. 2016;5(10):844- doi:10.14310/horm.2002.1650. 17. Groth KA, Skakkebæk A, Høst C, Gravholt 857. doi:10.1016/j.molmet.2016.08.003. 11. Villanueva C, Argente J. Pathology or normal CH, Bojesen A. Clinical review: Klinefelter 23. Lee Y, Styne D. Influences on the onset and variant: what constitutes a delay in puberty? syndrome--a clinical update. J Clin Endocri- tempo of puberty in human beings and impli- Horm Res Paediatr. 2014;82(4):213-221. nol Metab. 2013;98(1):20-30. doi:10.1210/ cations for adolescent psychological devel- doi:10.1159/000362600. jc.2012-2382. opment. Horm Behav. 2013;64(2):250-261. 12. Rosen DS, Foster C. Delayed puberty. Pedi- 18. Wei C, Crowne EC. Recent advances in the doi:10.1016/j.yhbeh.2013.03.014.

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Implicações na fertilidade no feminino e no masculino Maria Miguel Gomes

Bibliografia: Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, et al. European Consensus Statement on congenital hypogonadotropic hypogonadism - pathogenesis, diagnosis and treatment. Nature Reviews – Endocrinology (2015). 11:547-564.

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CONSENSUS STATEMENTS

EXPERT CONSENSUS DOCUMENT European Consensus Statement on congenital hypogonadotropic hypogonadism —pathogenesis, diagnosis and treatment Ulrich Boehm, Pierre-Marc Bouloux, Mehul T. Dattani, Nicolas de Roux, Catherine Dodé, Leo Dunkel, Andrew A. Dwyer, Paolo Giacobini, Jean-Pierre Hardelin, Anders Juul, Mohamad Maghnie, Nelly Pitteloud, Vincent Prevot, Taneli Raivio, Manuel Tena-Sempere, Richard Quinton and Jacques Young

Abstract | Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH- synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10–20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

Boehm, U. et al. Nat. Rev. Endocrinol. 11, 547–564 (2015); published online 21 July 2015; doi:10.1038/nrendo.2015.112

University of Saarland Introduction School of Medicine, Congenital hypogonadotropic hypogonadism (CHH) (virilization and/or estrogenization) and induction Germany (U.B.). University College is caused by deficient production, secretion or action of fertility. London, UK (P.‑M.B., of gonadotropin-releasing hormone (GnRH), a key A number of important developments in the field have M.T.D.). Université Paris Diderot, France neuro peptide that orchestrates mammalian reproduc- emerged over the past decade. Reversal of CHH occurs in 1 6,7 (N.d.R.). Université tion. CHH is characterized by incomplete or absent ~10–20% of patients, which challenges the dogma that Paris Descartes, France puberty and infertility in the setting of isolated hypo- the condition is lifelong. These data have implications (C.D.). William Harvey Research Institute, UK gonadotropic hypogonadism (that is, otherwise normal for the management of CHH and suggest a plasticity of (L.D.). Endocrinology, anterior pitui tary function). CHH can present solely as the GnRH neuronal system. Furthermore, inhibin B, Diabetes and Metabolism Sevice of congenital GnRH deficiency or be associated with other insulin-like 3 (INSL3), anti-Müllerian hormone (AMH) the Centre Hospitalier develop mental anomalies such as cleft lip or palate, and kisspeptin have emerged as biomarkers for use in Universitaire Vaudois dental agenesis, ear anomalies, congenital hearing the diagnosis and treatment of CHH.8,9 In addition, hor- (CHUV), du Bugnon 46, Lausanne 1011, impairment, renal agenesis, bimanual synkinesis or skel- monal therapies are being personalized to maximize fer- Switzerland (A.A.D., etal anomalies. When associated with anosmia or hyp- tility outcomes.10 Over the past few years, the traditional N.P.). University of Lille, France (P.G., V.P.). o s mia, CHH is termed Kallmann syndrome, which Mendelian view of CHH as a monogenic disorder has Institut Pasteur, France results from abnormal embryonic migration of GnRH been revised following the identification of oligogenic (J.‑P.H.). University of neurons from their origin in the olfactory placode to forms of CHH,11 which has altered the approach adopted Copenhagen, Denmark 2,3 (A.J.). University of the forebrain. CHH has a male predominance of 3–5 for genetic testing and genetic counselling of patients Genova, Italy (M.M.). to 1.4,5 Most patients with CHH are diagnosed late in with CHH. Finally, the availability of next-generation University of Helsinki, Finland (T.R.). adolescence or early in adulthood as CHH is challen ging sequencing has started to unravel the complex molecular University of Cordoba, to differentiate from other causes of delayed puberty. basis of CHH. This Consensus Statement focuses on the Spain (M.T.‑S.). Newcastle University, Effective therapies in both men and women are available pathogenesis, diagnosis and treatment of CHH in light of UK (R.Q.). Bicêtre for the development of secondary sexual characteristics recent discoveries and differs from existing guidelines for Hospital, France (J.Y.). the treatment of hypogonadism12–14 as it focuses exclu-

Correspondence to: N.P. Competing interests sively on CHH. Definitions of several key terms used in [email protected] The authors declare no competing interests. this article are presented in the glossary (Box 1).

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Box 1 | Glossary suggest that GnRH neurons originate from both the Anosmia neural crest and ectodermal progenitors, and migrate Complete lack of sense of smell in close association with growing axons of olfactory 15,16 Cryptorchidism and/or terminal nerves. Once in the hypothalamus, Maldescended testes that are not in the scrotum (that is, GnRH neurons detach from their axonal guides, disperse in the inguinal canal or abdomen); can occur in unilateral further into the brain parenchyma and stop migrating. At or bilateral forms birth, GnRH neurons have reached their final destination GnRH in the brain and many of them project into the median GnRH is produced by specialized hypothalamic neurons eminence, where they release the GnRH decapeptide in a pulsatile manner that stimulates the release from their axon terminals into the hypophyseal portal of gonadotropins (luteinizing hormone and follicle- vasculature.1 GnRH acts via the GnRH receptor, which is stimulating hormone) from the pituitary, which activate expressed on gonadotropic cells in the anterior pituitary gonadal maturation and fertility gland. This action regulates both synthesis and release Oligogenicity of gonadotropins such as luteinizing hormone (LH) Mutations in two (or more) CHH genes in one patient and follicle-stimulating hormone (FSH), which control Reversal gonadal maturation and adult reproductive physiology Recovery of the hypothalamic–pituitary–gonadal axis (normal circulating levels of sex steroids and/or fertility) via the hypothalamic–pituitary–gonadal (HPG) axis. after treatment discontinuation Several genes mutated in Kallmann syndrome affect Secondary sexual characteristics the fate and migration of GnRH neurons. Genes encoding Physical characteristics that result from increased sex fibroblast growth factor 8 (FGF8) signalling pathway pro- hormone production during puberty teins,17–22 chromodomain helicase DNA-binding protein 7 23–27 Virilization (male) (CHD7) and sex determining region Y-Box 10 Change in external genitalia with phallic development, (SOX10)28,29 affect the neurogenic niche in the nasal area appearance of pubic and/or axillary and/or facial hair, and craniofacial development. Conversely, Kallmann syn- enlarged larynx and/or deepening of voice and increased drome protein, which is now officially known as anosmin 1 lean body mass (encoded by KAL1; following nomenclature change, the Estrogenization (female) gene is now denoted as ANOS1),2 prokineticin- 2 and pro- Breast development with prominence of nipples, kineticin receptor 2 (encoded by PROK2 and PROKR2, development of pubic and axillary hair, widening of hips respectively),30–33 WD repeat domain 11 (encoded by and development of labia minora WDR11),34,35 semaphorin 3A (encoded by SEMA3A)36–38 Abbreviations: CHH, congenital hypogonadotropic hypogonadism; 39 GnRH, gonadotropin-releasing hormone. and FEZ family zinc finger 1 (encoded by FEZF1) influence migration of GnRH neurons. Postmigratory GnRH neurons are embedded in a com- Methods plex neuronal network of afferents that send information This Consensus Statement is the work of the European about permissive reproductive cues such as steroid and consortium studying GnRH biology (COST Action metabolic hormones to these cells. Individual components BM1105, http://www.gnrhnetwork.eu/). The COST of the underlying neural circuits are beginning to emerge. network includes clinician investigators, geneticists, bio- Some key molecules have been discovered through the informaticians, basic scientists and patient advocates from study of the genetics of CHH.1 Inactivating mutations 28 countries. Our recommendations are based on a review in genes encoding kisspeptin-1 (KISS1)40 and its recep- of the literature published in the English language between tor (KISS1R)41,42 halt pubertal development in humans. 1990 and 2015 using the following search terms: “congeni- Extensive experimental studies in various species have tal hypogonadotropic hypogonadism”, “idiopathic GnRH demonstrated that kisspeptin-producing neurons are deficiency”, “central hypogonadism” and “Kallmann major afferents to GnRH neurons and are essential for dif- syndrome”. The reference lists of identified papers were ferent aspects of GnRH function, ranging from the tonic searched for additional relevant articles. A series of meet- feedback control of GnRH and/or gonadotropin secre- ings and focused discussions with expert clinicians (spe- tion to generation of the pre-ovulatory surge responsible cialized in paediatric and adult CHH) were conducted, for ovulation.43 Interestingly, although kisspeptins do not with a final vetting process involving experts partici- seem to be mandatory for proper GnRH neuron migration, pating in the network from the fields of endo crinology, compelling experimental work has documented that pop- andrology, genetics and reproductive medicine. ulations of kisspeptin neurons undergo a dynamic process of prenatal and postnatal maturation that enables them to Biology of the GnRH neuronal system establish connections with GnRH neurons early in devel- GnRH neurons are unusual neuroendocrine cells as opment44 (under the control of steroid hormones45–47). they originate outside the central nervous system in Similarly, identification of mutations in TAC3 (encoding the olfactory placode and then migrate into the brain tachykinin-3, which is cleaved to form neurokinin- B) and during embryonic development.2,3 This route provides a TACR3 (encoding tachykinin receptor 3; also known as developmental link between the central control of repro- neuromedin-K receptor [NKR])48–50 in patients with CHH duction and the sense of smell, which are both affected highlights the important role of members of the tachyki- in Kallmann syndrome. Data from the past few years nin family in the control of GnRH neurons. Furthermore,

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these findings led to the identification of a subpopula- Leydig cells to produce testosterone. The concerted stimu- tion of afferent neurons in the arcuate and/or infundibu- lation of Sertoli cells by FSH and intragonadal testos terone lar hypothalamic region, which co-express kiss peptins levels 50–100-fold higher than in the systemic circulation and NKB.51 Interestingly, data from the past few years leads to the initiation of spermatogenesis. In girls, the suggest that the actual number of kisspeptin and/or NKB early stages of follicular growth are primarily driven by neurons might change during development.52,53 Mutations intra-ovarian factors. FSH and LH are needed for follicular in proteins that regulate ubiquitination such as OTU maturation, which leads to ovulation. More specifically, domain-containing protein 4 (encoded by OTUD4) and LH stimulates theca cells to produce androgens and FSH E3 ubiquitin-protein ligase RNF216 (also known as ring stimulates recruitment of secondary ovarian follicles and finger protein 216; encoded by RNF216),54 as well as in the secretion of estradiol from granulosa cells. Inhibin B proteins involved in lipid metabolism such as neuropathy and AMH are produced by prepubertal Sertoli cells and target esterase (also known as patatin-like phospholipase granulosa cells.68 Circulating levels of inhibin B increase domain-containing protein 6; encoded by PNPLA6)55,56 during puberty in girls and boys.69,70 AMH concentrations have been identified in patients with Gordon Holmes syn- show only minor fluctuations during female puberty.71 In drome (with associated CHH and ataxia). Thus, mutations boys, AMH concentrations fall as Sertoli cells differenti- in these three genes give rise to a broad and progressive ate and testos terone production increases.72 In male indi- neurodegenerative syndrome that includes CHH. In 2014, viduals, INSL3 is secreted by Leydig cells during fetal and haploinsufficiency of DMXL2, which encodes synaptic immediate postnatal life.8,73 Testicular INSL3 secretion protein DmX-like protein 2, was shown to cause a complex declines during childhood before increasing at the time new syndrome associating CHH with polyendocrine of puberty and peaking during adulthood.74 deficiencies and polyneuropathies.57 Early signs of puberty manifest around the age of Peripheral signals that convey information about meta- 10 years in girls (breast development) and 11.5 years in bolic status indirectly modulate GnRH neuro secretion. boys (testicular enlargement and spermarche—appearance This modulation is well illustrated by the reproductive of spermatozoa in first morning void).75–77 Considerable phenotype of absent pubertal development and hypo- interindividual variation in the timing of pubertal onset gonadotropic hypogonadism in patients with inacti- exists, ranging from 8 years to 13 years in girls and 9 years vating mutations in the genes encoding leptin (LEP) or to 14 years in boys.78,79 Subsequent hallmarks of puberty in its receptor (LEPR).58 Exactly how the effects of leptin boys include deepening of the voice and a growth spurt. In are transmitted to GnRH neurons is unknown, as this girls, menarche occurs at ~12.5 years of age.78 neuro nal population does not express the leptin recep- tor.59 Experimental data suggest that kisspeptin neurons Clinical presentation of CHH are sensitive to changes in leptin concentrations and Neonatal and childhood metabolic conditions,43 yet they apparently do not express Lack of neonatal activation of the HPG axis can provide functional leptin receptor, which indicates the mode of early diagnostic cues for identifying CHH at birth or action is indirect.60 Primary leptin targets for conduction during mini-puberty.80–83 In male infants, crypt orchidism of its reproductive effects probably include nitric oxide- (that is, maldescended testes) and micropenis can be producing neurons in the pre-optic hypothalamus61 and signs of GnRH deficiency (Figure 1), yet these fea- neuronal circuits in the ventral premammillary nucleus,60 tures are by no means invariable.84–86 As penile growth which might transmit metabolic information to GnRH occurs during infancy and childhood, micropenis can neurons through kiss peptin dependent and/or indepen- be assessed using available cross-sectional normative dent pathways. Taken together, the identification of genes data.87,88 These two clinical clues warrant hormonal mutated in the different forms of CHH has facilitated an monitoring during mini-puberty. However, more severe improved understanding of the neuroendocrine control genital anomalies, such as hypospadias, point away from of reproduction. a diagnosis of CHH and, instead, indicate a defect of human chorionic gonadotropin (hCG)-driven androgen Puberty and reproduction secretion and/or action in early fetal life, before the initi- Puberty represents a period of transition from child- ation of endogenous GnRH activity. No specific clinical hood into adulthood during which complete reproduc- signs of CHH present in female neonates. Regardless tive capacity is attained. Puberty is regulated by the HPG of sex, when infants are born to parents with CHH, axis. The axis is active in utero and shortly after birth62,63 we recommend monitoring reproductive hormones (a phenomenon referred to as mini-puberty), is subse- during mini-puberty and performing genetic testing if quently silenced and remains quiescent for years until mutations have been identified in the parents. reawakening at the onset of puberty. Multiple central and peripheral inputs are integrated into pubertal Adolescent reacti vation of the GnRH pulse generator.64 At the onset The timing and onset of puberty varies widely in the of puberty, GnRH-induced pulses of LH are initially general population.89 Delayed puberty is classically nocturnal and, gradually, the pulsatility extends to the defined as absence of testicular enlargement (volume daytime as puberty progresses.65–67 <4 ml) in boys by the age of 14 years and absent breast In boys, FSH stimulates proliferation of immature development in girls by the age of 13 years.90 In addition, Sertoli cells and spermatogonia, whereas LH stimulates use of the stage-line diagram enables the identification of

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Fetal Neonatal Childhood Puberty Adulthood congenital hearing impairment with or without pigmen- tation defects, bimanual synkinesia (mirror movements), GnRH/LH dental agenesis, cleft lip and/or palate and crypt orchid- ism with or without micropenis.17,28,104–108 Family history indicative of autosomal inheritance cannot be used as a diagnostic tool, as this feature can be observed in both

HPG-axis activity CHH and CDGP.109 CHH

■ Cryptorchidism (M) ■ Prepubertal testes ■ Infertility (M and F) Adulthood ■ Micropenis (M) (M) ■ Undervirilization (M) CHH might be diagnosed after adolescence, when ■ Absent breast patients present for evaluation of infertility or even development (F) ■ Primary for osteo poro tic fractures. This delay in diagnosis amenorrhoea (F) might be related to missed opportunities to diagnose Figure 1 | Activity of the HPG axis across the lifespan. Normal GnRH and LH CHH in adolescence or a reluctance of patients to seek secretion from fetal life to adulthood (blue line) comparedNature with Reviews non-reversible | Endocrinology medical evaluation. CHH (red line). Reproductive phenotypes observed in CHH are listed under the respective stage of development. Abbreviations: CHH, congenital hypogonadotropic Genetics of CHH hypogonadism; F, female; GnRH, gonadotropin-releasing hormone; HPG, CHH is genetically heterogeneous, with both sporadic hypothalamic–pituitary–gonadal; LH, luteinizing hormone; M, male. and familial cases. Several modes of inheritance have been identified, including X chromosome-linked reces- patients with delayed puberty, which is based not only on sive, autosomal recessive and dominant.1 By examining pubertal onset but also on the tempo of pubertal devel- milder phenotypes (such as delayed puberty or isolated opment.91 In most of these individuals, puberty is initi- anosmia), the frequency of familial cases increases.110,111 ated and eventually completed (that is, constitutional Understanding of the molecular genetics of CHH and delay of growth and puberty [CDGP]). By contrast, Kallmann syndrome has advanced tremendously in adolescents with CHH lack pubertal activation of the the past 20 years, since the first gene associated with HPG axis, which leads to absent puberty and infertil- Kallmann syndrome (KAL1 [ANOS1]) was identified by ity (Figure 1). In the majority of patients, puberty never a positional cloning strategy in 1991 (Table 1).112–115 KAL1 occurs (absent puberty); less commonly, puberty is initi- (ANOS1) encodes anosmin-1, a transiently expressed, ated then arrested (partial puberty).92–94 Adolescents locally restricted glycoprotein of embryonic extracellu- with CHH exhibit steady linear growth and thus lack the lar matrices116 that is involved in fibroblast growth factor so-called growth spurt.91,95,96 Given the delayed epiphy- (FGF) signalling.117,118 To date, >25 different genes have seal closure, these individuals often have eunuchoidal been implicated in Kallmann syndrome and/or CHH, proportions. The most common complaints in male which accounts for ~50% of cases.21 Causative genes adolescents with CHH include absent and/or minimal for Kallmann syndrome include: KAL1 (ANOS1) in viriliza tion, low libido and lack of sexual function. the X-linked form; FGFR1 (encoding fibroblast growth Among female adolescents, lack of breast develop ment factor receptor 1),17,18 FGF8,19,119 CHD7,23–27 HS6ST1 and/or primary amenor rhoea by the age of 15 years (encoding heparan-sulphate 6-O-sulphotransferase 1),20 are frequent complaints. In addition, patients with SOX10,28,29 SEMA3A (encoding semaphorin-3A),36–38 CHH often have low self-esteem, distorted body image, WDR11 (encoding WD repeat-containing protein 11)34,35 impaired psychosexual development and, in some and IL17RD (encoding interleukin-17 receptor D)21 cases, problems with sexual identity.97,98 Furthermore, in the autosomal dominant form; and PROKR2 and/or small studies have shown increased anxiety and depres- PROK2,30–33 and FEZF139 in the autosomal recessive form, sion among adolescents with CHH and, as such, these even though it should be noted that most patients carry- symptoms merit attention.99,100 ing mutations in PROKR2 or PROK2 carry these muta- The clinical heterogeneity of CHH makes differen- tions in the heterozygous state.120,121 Genes involved tiation from CDGP, which is usually associated with in CHH that are associated with a normal sense of short stature, poor growth velocity and delayed skeletal smell include GNRHR (encoding gonadotropin- maturation, difficult.90,95 The presence of micropenis releasing hormone receptor),122,123 GNRH1 (encoding and/or cryptorchidism argues firmly in favour of CHH, gonadotropin-releasing hormone 1),124,125 KISS1R,41,42 as these features are rarely seen in CDPG. Associated KISS1,40,126 TACR3 and TAC3.48–50 Other genes such as congenital phenotypes are also very useful as they indi- FGFR1 or PROKR2 can be mutated in patients with either cate a syndromic form of CHH. The classic, and by far Kallmann syndrome or CHH (Table 1). Remarkably, most frequent, form being Kallmann syndrome, which mutations in each Kallmann syndrome or CHH gene includes anosmia. Other phenotypes like cleft palate or identified so far account for <10% of cases.11,21,127 sensorineural deafness also suggest a syndromic form of CHH has classically been categorized as a monogenic CHH,94 most often associated with Kallmann syndrome, disorder, which means that one defective gene is suffi- but not exclusively so.18 The clinical sign that points cient to account for the disease phenotype. As such, CHH away from CDGP is a poor sense of smell, which sug- and Kallmann syndrome caused by mutations in GNRHR gests Kallmann syndrome.101–103 Other ‘red flags’ include (a recessive gene) and KAL1 (ANOS1; an X-linked gene),

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Table 1 | Genes implicated in CHH Gene OMIM CTO CHH phenotypes Overlapping syndromes KS CHH CHH CPHD CPHD WS CHARGE HS SHFM D‑WS MGS PEPNS GHS reversal + SOD KAL1 300836 × × × × × × × × × × × (ANOS1) SEMA3A 614897 × × × × × × × × × × × × SOX10 602229 × × × × × × × × × × × × OL14RD 606807 × × × × × × × × × × × × HESX1 182230 × × × × × × × × × × × FEZF1 613301 × × × × × × × × × × × × × FGFR1 147950 × × × × × × FGF8 612702 × × × × × × × × × × CHD7 612370 × × × × × × × × × × FGF17 603725 × × × × × × × × × × HS6ST1 614880 × × × × × × × × × × PROK2 610628 × × × × × × × × × × × PROKR2 147950 × × × × × × × × SEMA7A 607961 × × × × × × × × × × × WDR11 614858 × × × × × × × × × × NSMF 614838 × × × × × × × × × × AXL 109135 × × × × × × × × × × × × GNRH1 614841 × × × × × × × × × × × × × GNRHR 146110 × × × × × × × × × × × KISS1 614842 × × × × × × × × × × × × × KISS1R 614837 × × × × × × × × × × × × TAC3 614839 × × × × × × × × × × × TACR3 614840 × × × × × × × × × × × LEP 614962 × × × × × × × × × × × × × LEPR 614963 × × × × × × × × × × × × × PCSK1 162150 × × × × × × × × × × × × × DMXL2 616113 × × × × × × × × × × × × RNF216 609948 × × × × × × × × × × × × OTUD4 611744 × × × × × × × × × × × × PNPLA6 603197 × × × × × × × × × × × × NR0B1 300200 × × × × × × × × × × × × ×

Abbreviations: CHH, congenital hypogonadotropic hypogonadism; CHARGE, coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, ear anomalies or deafness; CPHD, combined pituitary hormone deficiency; CTO, contributes to oligogenicity; D-WS, Dandy-Walker syndrome; GHS, Gordon Holmes syndrome; HS, Hartsfield syndrome; KS, Kallmann syndrome; MGS, Morning Glory syndrome; OMIN, online Mendelian inheritance in man; PEPNS, polyendocrine deficiencies and polyneuropathies; SHFM, split-hand/foot malformation; SOD, septo-optic dysplasia; WS, Waardenburg syndrome.

respectively, are highly penetrant,127 yet such a pattern This genetic model might be useful to predict genotype– is not observed for all genes involved in CHH and/or phenotype correlations.5 Interestingly, genome-wide Kallmann syndrome. For instance, the p.Arg622X FGFR1 associ ation studies have identified >100 loci affecting mutation has been reported in unrelated Kallmann syn- the age of menarche,129 which confirms a genetic con- drome and CHH probands (Figure 2). Examination of tribution to pubertal timing. Surprisingly, little overlap pedigrees reveals low penetrance for most CHH genes exists between the genes implicated in age at menarche and variable expressivity among affected individuals and CHH.129 carry ing the same gene defect. Such an observation led to the hypothesis that multiple gene defects could syner- Diagnosis of CHH gize to produce a more severe CHH phenotype (that is, Central to the evaluation process for diagnosing CHH is oligogenicity). 30,128 Studies in large CHH cohorts indi- the exclusion of differential diagnoses such as pituitary cate that at least 20% of cases are oligogenic11,21 (Table 1). tumour or functional causes (Box 2).

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Family 1 Family 2 Family 3 Family 4 1 2 1 2 1 2 1 2 I +/+ Arg622X/+ Arg622X/+ Arg622X/+ 1 2 1 2 3 1 2 3 1 2

II Arg622X/+ Arg622X/+ Arg622X/+ Arg622X/+ Arg622X/+ Arg622X/+

1 2 3 1 2 1 1 2 III

Arg622X/+ Arg622X/+ Arg622X/+ Arg622X/+ Arg622X/+ Arg622X/+

CHH Anosmia Delayed puberty Cleft palate Carrier Proband

Figure 2 | FGFR1 mutation p.Arg622X in an autosomal dominant form of CHH with incomplete penetrance and variable Nature Reviews | Endocrinology expressivity. In family 1, the CHH phenotype is fully penetrant.147 In the three other pedigrees, family members carrying the same FGFR1 mutation have variable reproductive and olfactory phenotypes and family 2 includes an asymptomatic carrier.17,148 + denotes wild-type allele. Abbreviation: CHH, congenital hypogonadotropic hypogonadism.

Clinical, biochemical & imaging investigations In such cases, hormone profiling at 4–8 weeks of life can The mini-puberty provides a brief opportunity to iden- be used to make a diagnosis83,85 based on comparisons tify CHH. For male infants, cryptorchidism with or with established reference ranges for gonadotropins, sex without micropenis can be suggestive of CHH (Figure 1). steroids and inhibin B levels.62,63,70,130 Female neonates born to parents with CHH should undergo biochemical Box 2 | Forms of CHH and differential diagnosis evaluation; serum levels of FSH during the mini-puberty seem to be the most sensitive indicator of CHH in this Forms of CHH 131 GnRH deficiency and defective sense of smell setting. During childhood, diagnosis of CHH is very ■ Kallmann syndrome challenging as this interval is a physiologically hypo- Isolated GnRH deficiency (normal sense of smell) gonadal period of development. Undetectable levels of ■ Normosmic CHH FSH (but not of LH) or absence of response to a GnRH Complex syndromes including CHH or KS test in childhood might indicate CHH. ■ Combined pituitary hormone deficiency CHH diagnosis is typically made during adolescence ■ Septo-optic dysplasia or early adulthood (Table 2). Approximately half of CHARGE syndrome ■ patients with CHH have Kallmann syndrome.101 Self- ■ Adrenal hypoplasia congenita with HH report of anosmia is reliable, yet claims of having a ■ Waardenburg syndrome ■ Bardet–Biedl syndrome ‘good’ sense of smell do not always align with formal ■ Gordon Holmes syndrome smell testing. Most patients with Kallmann syndrome ■ Others display olfactory bulb hypoplasia and/or aplasia on Differential diagnosis brain MRI; however, this finding is not fully concordant Functional causes with sense of smell.102 An assessment of family history is ■ Malnutrition and/or malabsorption important to identify familial cases. A family history of ■ Any chronic disease (for example, IBS or asthma) CDGP does not exclude CHH as pedigrees of patients ■ Coeliac disease with CHH seem to be enriched in delayed puberty, Eating disorders ■ subfertility and anosmia or hyposmia.132 A detailed ■ Excessive exercise Systemic causes physical examination is needed, with particular atten- ■ Haemochromatosis tion paid to genitalia (that is, measurement of testicular ■ Sarcoidis volume using a Prader orchidometer) and virilization ■ Histiocytosis and/or estrogenization (that is, Tanner staging for ■ Thalassaemia breast development and pubic hair133,134). Eunuchoidal Acquired causes proportions are often present.135 A stage-line diagram ■ Pituitary adenomas and/or brain tumours is useful for providing developmental stages ±SD or as ■ Rathke’s cleft cyst Pituitary apoplexy percentiles, as well as the tempo of pubertal develop- ■ 91 ■ Radiation (brain or pituitary) ment ±SD per year. Additionally, signs of associated ■ Medication induced (such as, by steroids, opiates developmental anomalies such as cryptorchidism with or chemotherapy) or without micropenis, midline defects or signs sugges- Abbreviations: CHARGE, coloboma, heart defects, atresia of tive of combined pituitary hormone deficiency should choanae, retardation of growth and/or development, genital be evaluated (Box 2). and/or urinary defects, ear anomalies or deafness; CHH, congenital hypogonadotropic hypogonadism; GnRH, gonadotropin- Biochemical evaluation includes a variety of tests to releasing hormone; HH, hypogonadotropic hypogonadism; IBS, exclude other causes of CHH such as pituitary tumour or irritable bowel syndrome; KS, Kallmann syndrome. functional causes (Table 3). Isolated hypogonadotropic

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Table 2 | Clinical evaluation of CHH Inhibin B is a marker of Sertoli cell number and cor- 92 Assessment Signs Focus relates with testicular volume. In men with CHH and severe GnRH deficiency, serum levels of inhibin B are Growth Evaluation of growth (growth chart) Linear growth, acceleration and/or deceleration in growth typically very low (<30 pg/ml; Figure 3). However, for partial forms of CHH, inhibin B levels overlap with those Eunuchoidal proportions Closure of epiphysis in patients with CDGP and in healthy controls.138,139 Sexual Cryptorchidism and micropenis Severe CHH in male individuals INSL3 is a good marker of Leydig cell function144 and, as Sexual development (Tanner staging Puberty (Tanner stage 2 such, levels of INSL3 are typically low in male individuals of pubic hair, penis and gonads genitalia in male individuals with CHH (at diagnosis or on testosterone therapy) and in male individuals and breasts in indicates the onset of puberty) 74 female individuals) increase with LH and/or hCG stimulation. However, further studies are needed to identify the potential clini- Male individuals: testicular Male individuals: at age volume (Prader orchidometer) 14 years, testicular volume cal utility of INSL3 measurements, such as differentiating and penile length <4 ml indicates absent puberty CHH from CDGP or as a predictor of reversible CHH. Assess micropenis (versus Kisspeptin is a potent stimulator of GnRH-induced LH cross-sectional normative data) secretion.9 Exogenous kisspeptin administration failed Female individuals: breast Female individuals: at age to induce a response in patients with CHH regardless development and age at menarche 13 years, Tanner stage 1 of genotype. However, a male individual with revers- breasts indicate absent puberty Primary amenorrhoea by age ible CHH exhibited a robust response to exogenous 15 years kisspeptin145 and continuous kisspeptin infusion was Other Olfaction (using odorant panel Hyposmia and/or anosmia demonstrated to overcome genetic defects in the kiss- and/or olfactometry) peptin signalling pathway.146 In terms of clinical applica- Snellen eye chart, ocular fundoscopy Optic nerve hypoplasia tion, kiss peptin has been used with therapeutic effect in 147 External ear shape and audition Hearing impairment women with hypothalamic amenorrhoea, as well as for egg maturation during assisted fertility.148 Thus, although Number of teeth Cleft lip and/or palate, missing tooth or teeth still investigational, kisspeptin seems to be emerging as useful in several therapeutic areas. Pigmentation of skin and hair Achromic patches CHH work-up also includes cranial MRI to assess Rapid sequential finger–thumb Bimanual synkinesis for tumours and/or space occupying lesions and to opposition Neurodevelopmental delay visualize inner ear and olfactory structures, bone age Abbreviation: CHH, congenital hypogonadotropic hypogonadism. in adolescents to compare with chronological age and to assess epiphyseal closure, abdominal and/or pelvic hypogonadism is characterized by low serum levels of ultra sonography to assess unilateral renal agenesis and testosterone in male individuals (usually <2 nmol/l) in to visualize the ovaries and/or uterus or testis, and bone the setting of low or normal serum levels of gonado- densitometry (dual-energy X-ray absorptiometry) to tropins (LH and FSH) with otherwise normal pituitary assess bone density. function (Figure 3). In female individuals, serum levels of estradiol are often low, sometimes undetectable in the Genetic testing setting of low-normal gonadotropin levels. Serum levels Genetic testing is useful for diagnosis, prognosis149 and of estradiol seem to correlate with breast development, as genetic counselling in CHH.127 The first step in priori- most women with absent breast development have very tizing genes for genetic testing is to establish the inheri- low or undetectable levels, whereas women with breast tance pattern. Briefly, X-linked inheritance is observed in development exceeding Tanner stage B2 usually have pedigrees when male-to-male transmission of the disease measurable serum levels of estradiol. phenotype does not occur but the disease is observed in In early adolescence (13–16 years), a diagnosis of CHH male members of the maternal line. This feature is typical is challenging to make as isolated hypogonadotropic for KAL1 (ANOS1) mutations underlying Kallmann syn- hypogonadism is common to both CHH and CDGP. In drome.150 Autosomal dominant inheritance is observed in CHH, the GnRH stimulation test has a poor diagnostic a family with vertical transmission of the disease pheno- value. In the absence of a gonadotropin response, this test type across one or more generations. In this setting, male can help to confirm severe GnRH deficiency, yet clini- and female individuals are equally affected and male-to- cal signs are often already evident (that is, prepubertal male transmission can be observed. Importantly, incom- testes or absence of breast development). By contrast, the plete penetrance and variable expressivity of the disease GnRH stimulation test rarely enables differentiation of among people with identical mutations can be observed CDGP from partial forms of CHH—the most challen- for most CHH genes (Figure 2).17,151,152 In autosomal ging differential diagnosis. A number of other tests have recessive inheritance, vertical transmission of the disease been proposed to differentiate between these two enti- phenotype does not occur and ~25% of offspring are ties, including a combination of GnRH and hCG stimu- affected. Examples of autosomal recessive forms include lation tests, as well as measurement of serum levels of those involving mutations in GNRHR, KISS1R, TACR3, inhibin B, AMH or INSL3.74,136–142 However to date, no PROKR2 or FEZF1 (Table 1). gold-standard diagnostic test exists to fully differentiate Genetic testing can also be guided by the presence of CHH from CDGP.143 additional phenotypic features. Cleft lip and/or palate

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Table 3 | Biochemical, radiological and genetic evaluation of CHH Genetic counselling Assessment Marker Focus A legitimate question often raised by patients with CHH relates to the risk of passing on the disease to their off- Biochemical 0800–1000 h hormonal Assess for combined pituitary hormone 26,127,162 measurements (LH, FSH, deficiency spring. When autosomal dominant transmission testosterone or estradiol, Demonstrate isolated hypogonadtropic is suspected, the patient and partner should receive

prolactin, free T4, TSH, cortisol, hypogonadism genetic counselling before fertility-inducing treatment. IGF-1 and IGFBP3) This counselling should include clear explanation of the Specialized endocrine tests Evaluate the degree of GnRH deficiency 50% theoretical risk of transmitting the disease. In such (serum inhibin B, AMH, and function of the gonads cases, hormonal profiling during mini-puberty should INSL3, GnRH and/or hCG stimulation test) be conducted. In proven autosomal recessive forms, which affect both male and female individuals, the risk Spermiogram Assess fertility of disease transmission to offspring is very low in the Liver and/or renal function and Assess systemic and/or inflammatory absence of consanguinity (that is, inter-related parents). inflammatory markers (LFTs, disease BUN, lytes, CBC, Ca, CRP, ESR This reduced risk is due to the very low frequency of and faecal calprotectin) heterozygous healthy carriers in the general population, Screen for coeliac disease Assess malabsorption which should be reassuring for intended parents. Male individuals with X-linked Kallmann syndrome should Iron overload screen (ferritin, Assess juvenile haemochromatosis TIBC% saturation) be informed of the automatic transmission of the muta- tion to their unborn daughters (obligate carriers) and the Radiologic Wrist radiography (bone age) Delayed bone age (chronological age greater than bone age) necessity for genetic counselling of these girls after the age of puberty. When patients carry several mutations Brain MRI Exclude hypothalamo–pituitary lesion Assess olfactory bulbs and sulci in different CHH or Kallmann syndrome genes (that Visualize optic nerve is, oligogenicity), genetic counselling is difficult and Assess inner ear (semicircular canals) the transmission risk is variable.127 Finally, the advent Renal ultrasonography Rule out unilateral renal agenesis of next-generation sequencing will probably improve 163 Bone density (DXA) Assess osteopenia and/or the molecular genetic diagnosis of CHH. More spe- osteoporosis cifically, this technology will help identify cases of oligo- Genetic Comparative genomic Large, rare deletions and/or insertions genicity and might promote personalized approaches to hybridization array or karyotype to identify contiguous gene syndromes genetic counselling. Gene screening (Sanger or Mutations in CHH and/or KS genes next-generation sequencing) Treatment of CHH

Abbreviations: AMH, anti-Müllerian hormone; BUN, blood urea nitrogen; CBC, complete blood count; CHH, No treatments exist for many of the CHH-associated congenital hypogonadotropic hypogonadism; CRP, C-reactive protein; DXA, dual-energy X-ray absorptiometry; phenotypes such as anosmia, bimanual synkinesia ESR, erythrocyte sedimentation rate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IGF-1, insulin growth factor 1; IGFBP3, insulin-like growth or renal agenesis. Others phenotypes such as cleft lip factor-binding protein 3; INSL3, insulin-like 3; KS, Kallmann syndrome; LFTs, liver function tests; LH, luteinizing hormone; TIBC, total iron-binding capacity. and/or palate, hearing loss or various skeletal defects require surgical and/or specialist intervention early in life. The approach to CHH treatment is largely deter- and skeletal anomalies indicate mutations in genes mined by goals such as developing only virilization or encoding components of the FGF8 signalling pathway estrogenization, or inducing fertility as well. (for example, FGFR1, FGF8 and HS60ST1).17,20,21,104,153 Signs associated with CHARGE syndrome (CHARGE: During infancy and childhood coloboma, heart defects, atresia of choanae, retardation In affected boys, the focus of most treatment is on of growth and/or development, genital and/or urinary appropriate testicular descent and penile growth. defects, and ear anomalies and/or deafness) favour Cryptorchidism (particularly bilateral) can have far screening for mutations in CHD7.24–26,104 Likewise, the reaching negative effects on future fertility potential.164,165 association of CHH with congenital hearing impairment As such, current recommendations advocate surgical should direct screening towards CHD7, SOX10 and/or correction at 6–12 months.166–168 Micropenis should be IL17RD.21,28,104 Bimanual synkinesia or renal agenesis treated early using short-term, low-dose testos terone are important clinical cues suggestive of KAL1 (ANOS1) (dihydrotestosterone or testosterone esters) to induce mutations.101,104,114,154,155 Early onset of morbid obesity penile growth (Table 4).86,169 Importantly, as the duration associated with CHH suggests mutations in LEP, LEPR of treatment is brief, no major concerns regarding viril- or PCSK1.58,156 Indeed, combining CHH with specific ization or the development of secondary sexual charac- associated phenotypes can increase the probability of teristics exist; however, erections might be observed. finding causal mutations by targeted gene sequencing Gonadotropins (LH and FSH) have been used to treat (Figure 4).21,28,104,157 CHH accompanied by other syn- patients with micropenis and evidence of absent mini- dromic features such as congenital ichthyosis158 or sphero- puberty.170,171 Such an approach might be beneficial for cytosis159 is suggestive of a contiguous gene syndrome for the additional stimulatory effect on gonadal develop- which a karyotype or comparative genomic hybridization ment. Indeed, treatment with FSH stimulates prolifera- array analysis might be useful for identifying underlying tion of immature Sertoli cells and spermatogonia in men chromosomal abnormalities.159–161 with CHH before pubertal induction.10 Furthermore,

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a b P < 0.0001 estradiol + progesterone in female individuals) induces P < 0.0001 10 10 P < 0.0001 the characteristic changes of puberty, which includes FSH LH psychosocial development (Table 4). 8 8 Induction of male sexual characteristics 6 6 Virilization is typically the primary objective of treat- ing CHH174 in order to diminish the psychological suf- 97,98,176 4 4 fering caused by sexual infantilism. Accordingly, prompt initiation of therapy after diagnosis is important Gonadotropins (IU/l) 2 2 and usually involves an injectable testosterone ester Total testosterone (ng/ml) Total (aromatizable androgen such as enanthate, cypionate or 0 0 undecanoate) or transdermal testosterone application with the precise protocol depending on the age at diag- 94,177,178 78 103 60 86 60 87 Controls = CHH/KS Controls = CHH/KS = Controls = = nosis and local practice. Paediatric endocrinolo- n = n n n CHH/KSn n gists treating young patients (that is, from 12 years of c d age) usually begin treatment with low-dose testos- 400 P < 0.0001 2,000 terone (for example, 50 mg of testosterone enanthate monthly, 10 mg transdermal testosterone every second 1,750 P < 0.0001 day, or 40 mg oral testosterone undecanoate daily) and 300 1,500 gradually increase to full adult dosing over the course 1,250 of 18–24 months, depending on age at the start of treat-

200 1,000 ment. Such regimens help mimic natural puberty and maximize statural growth while affording time for 750

INSL3 (pg/ml) psycho sexual development and minimizing the risk of Inhibin B (pg/ml) 100 500 precocious sexual activity.95,174 250 Adult endocrinologists often see patients with CHH

0 0 in late adolescence or early adulthood when the main complaint is the lack of pubertal development.94 In such

48 80 82 91 cases, the therapeutic approach is often more incisive Controls = CHH/KS = Controls = CHH/KS = n n n n than for younger patients, involving higher initial tes- Figure 3 | Hormonal profile of patients with CHH and/orNature KS Reviewscompared | Endocrinology with healthy tosterone doses (200 mg testosterone enanthate monthly, controls. a | Serum testosterone levels. b | Serum gonadotropin (LH and FSH) then every 2–3 weeks) than those used by paediat- levels. c | Serum inhibin B levels. d | Serum INSL3 levels. Healthy male individuals ric endocrinologists to induce more rapid virilization (controls; aged 17—27 years) versus untreated patients with CHH and/or KS (Box 4). The frequency of injections should be guided (aged 17–29 years). Abbreviations: CHH, congenital hypogonadotropic by trough serum testosterone measurement targeting hypogonadism; FSH, follicle-stimulating hormone; INSL3, insulin-like 3; LH, luteinizing hormone; KS, Kallmann syndrome. Adapted with permission from The the lower end of the normal range to avoid periods of Endocrine Society © Trabado, S. et al. J. Clin. Endocrinol. Metab. 99, E268–E275 hypogonadism between injections. Of note, testoster- (2014) and Young, J. J. Clin. Endocrinol. Metab. 97, 707–718 (2012). one treatment will not induce gonadal maturation or fertility in these patients.94,177 Importantly, increased testicular volume following testosterone treatment is an neonatal gonadotropin therapy can increase intra- indicator of reversal6,7,179–185 and requires re-assessment testicular testosterone concentrations without fear of of the HPG axis in the absence of testosterone replace- inducing spermatogenesis or negatively affecting the ment therapy. An estimated 10–20% of patients with ultimate number of Sertoli cells (an important deter- CHH undergo spontaneous recovery of reproductive minant of fertility), as Sertoli cells do not express the function,6,7 and this includes patients with mutations in androgen receptor during the first 5 years of life.172,173 known CHH genes (Table 1). Moreover, reversal is not Although initial studies involving neonatal administra- always lasting7,184 and, as yet, no predictors to identify tion of gonadotropin have been promising, these studies those who will reverse or relapse exist (Box 3). Ongoing are limited, both in number of studies and number of monitoring is thus justified. participants, and further investigations are needed to Virilization in adolescents or young adults can also examine the effectiveness of gonadotropin and its effect be achieved with pulsatile GnRH186–188 or gonadotropin on long-term outcomes such as fertility (Box 3). therapy (hCG alone or combined with FSH).189,190 These fertility-inducing treatments stimulate endogenous During adolescence and adulthood testosterone (and estradiol) production by testicular The aim of treatment is to induce virilization or estro- Leydig cells and are associated with good physical and genization and normal sexual function, to stimulate psychological outcomes.191 In clinical practice, testos- statural growth, to promote bone health and to address terone enanthate is the most frequently used treatment concerns about future fertility as well as psychological for young adults, yet clinicians should avoid adher- and emotional wellbeing.174,175 Sex steroid therapy (that ence to an overly dogmatic approach. Few published is, testosterone in male individuals and estradiol before studies have examined the effects of treatment to induce

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KAL1 SOX10 IL17RD CHD7 FGFR1 In clinical practice, when testicular volume is <4 ml, the classic treatment is either pulsatile GnRH (25 ng/kg every 5% 2% 3% 6% 10% 2 h, titrated for trough serum testosterone level) or com- bined gonadotropin therapy (hCG: 1,000–1,500 IU + FSH: 75–150 IU 2–3 times weekly, based on available formu- KS KS KS or CHH CHH lations). In patients with some gonadal development + synkinesia + hearing loss + hearing loss + SHFM (testicular volume >4 ml) and no history of cryptorchi- dism, induction of spermatogenesis can be achieved KAL1 SOX10 IL17RD CHD7 FGFR1 with hCG mono therapy.194,206–208 If no sperm is present in the ejaculate after 3–6 months of treatment, FSH can 43% 35% 33% 40% 88% be used to stimulate the seminiferous tubules.198 In the most severely affected men with CHH (testicular volume <4 ml), a sequential treatment has emerged in an attempt Figure 4 | Combined phenotypes can facilitate identificationNature Reviews of the causal | Endocrinology gene to maximize fertility potential.10,209,210 The unopposed FSH 104 28 21 104 in CHH. Examples shown for KAL1 (ANOS1), SOX10, IL17RD, CHD7 and treatment before maturation by hCG (or alternatively, 157 FGFR1. Abbreviations: CHH, congenital hypogonadotropic hypogonadism; GnRH-induced LH) stimulates proliferation of imma- KS, Kallmann syndrome; SHFM, split-hand/foot malformation. ture Sertoli and germ cells. Outcomes of patients treated with this regimen demonstrate successful induction of tes- virilization, as well as fertility treatment, on quality of ticular development and fertility in men with CHH who life and sexuality in men with CHH,97,98,192 particularly have prepubertal testes.10,210 To definitively determine the in those with severe CHH (micropenis and cryptorchid- optimal approach to fertility treatment in men with CHH ism). Regardless of the therapy considered, patients and severe GnRH deficiency (with or without cryptorchi- and their entourage (that is, spouse, partner or family) dism), an international, multicentre randomized trial is should be clearly informed that treatment is likely needed (Box 3). to be lifelong and to require regular monitoring for Assessment of the fertility status of the female optimal benefit. partner is crucial before induction of spermatogen- esis and includes a detailed reproductive and/or men- Induction of male fertility strual history and evaluation of the integrity of the CHH manifests as a lack of gonadal development and uterine cavity and tubal permeability (by use of sono- infertility. Importantly, CHH is one of the rare treat- hysterosalpingography or hysterosalpingography). able causes of male infertility. Spermatogenesis can be Anovulation and ovarian reserve can be assessed via a induced either by long-term pulsatile GnRH admin- combination of history of menstrual cycle abnormali- istration (pump)193 or more commonly by subcutan- ties, laboratory examination and pelvic ultrasonography. eous gonadotropin injections (2–3 times weekly).194–198 Couples should be counselled appropriately on the basis These therapies induce both testicular testosterone of the identified predictors of CHH fertility-inducing production by Leydig cells and spermatogenesis in the treatment,193–198,200 as well as the partner’s reproductive seminiferous tubules.199–202 The majority of patients status and age in order to develop realistic expectations with CHH develop sperm in their ejaculate with long- regarding treatment outcome. term therapy.149,193,196,197 Although these treatments For men with CHH who have severely impaired seem to have similar fertility outcomes,199–202 compar- sperm counts (or quality), assisted reproductive technol- ing their efficacy is difficult owing to the small numbers ogy (ART) treatments such as in vitro fertilization can of patients studied, heterogeneity in terms of degrees of be used to improve fertility. More invasive procedures GnRH deficiency (testicular volume before treatment), than ART include surgical testicular sperm extraction prior treatment and a lack of randomized studies followed by in vitro intracytoplasmic sperm injection performed to date. (ICSI). ICSI was initially used in men with CHH as a A number of predictors of fertility outcome have means to shorten the duration of treatment;211 however, emerged in CHH. First, cryptorchidism indicates a outcomes are improved after maximal testicular volume poor fertility prognosis.193,195 Men with CHH who have is attained. Overall, fertilization is achieved in 50–60% cryptor chidism often require extended courses of treat- of cases of ICSI, with pregnancy occurring in about a ment (18–24 months).203,204 Prepubertal testicular volume third of cycles.212–215 Although a study of sperm quality (<4 ml) and/or low serum levels of inhibin B are also neg- in men with CHH who received fertility-inducing treat- ative determinants of fertility outcome.193–197 Clinicians ment revealed neither altered DNA integrity nor an should be aware that although ~75% of men will develop increased risk of chromosomal abnormalities,216 the sperm, counts rarely reach the normal range with long- possibility of an increased risk of birth defects with ART term therapy. A 2014 meta-analysis identified a mean remains controversial. Once pregnancy is achieved, men sperm count of 5.9 × 106/ml (range: 4.7–7.1 × 106/ml) with CHH can be transitioned to testosterone replace- for gonadotropin therapy and 4.3 × 106/ml (range: ment therapy (injectable or transdermal preparations) 1.8–6.7 × 106/ml) for GnRH therapy.200 However, an for long-term treatment. Our consensus is that treat- important feature of patients with CHH is that low sperm ment be continued through the first trimester of preg- concentrations do not preclude fertility.205 nancy, in order to maintain male fertility capability in

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Table 4 | Approach to treatment of CHH Target Goals Treatment Clinical monitoring Laboratory Comments population monitoring Neonatal and childhood Male Testicular Cryptorchidism: orchidopexy Testicular volume Testosterone, LH, Baseline levels of individuals with descent (patients aged <1 year) FSH, inhibin B and testosterone, LH and FSH cryptorchidism AMH levels between days 14–90; for Penis growth Micropenis: testosterone, DHT Penile growth with or without later timepoints, measure or gonadotropin therapy micropenis after GnRH agonist (patients aged 1–6 months) stimulation No current indication for female individuals Adolescent Patients aged Virilization or Male patients: testosterone Genital development Morning serum Testosterone treatment will 14–15 years estrogenization (oral, injectable or Growth and epiphyseal closure testosterone levels not induce testicular growth (earlier in the Sexual function transdermal) Virilization (trough levels for or fertility presence of Growth and bone Gonadotropins? Sexual function injections), LH, specific signs health Wellbeing FSH and inhibin B such as Gonadal Adherence levels, haemocrit anosmia) maturation and Reversibility future fertility Female patients: Breast development No specific Estradiol must be increased Psychological estradiol (oral or transdermal) Growth and epiphyseal closure slowly before the combination wellbeing followed by estradiol + Estrogenization of estradiol + progesterone or progesterone or progestin Feminized body progestin to maximize breast Menses development and avoid Sexual function areolar protrusion Bone health Wellbeing Adherence Reversibility Adulthood All patients Sexual function Male patients: Pubertal development Tough serum Sex steroid replacement Fertility Testosterone (injectable Sexual function and libido testosterone levels, will not induce fertility Limiting or transdermal) Bone health LH, FSH and comorbidities hCG ± FSH Wellbeing inhibin B levels, Psychological FSH, FSH + hCG Adherence haematocrit, wellbeing GnRH pump Fertility PSA levels Puberty Reversibility induction Female patients: Pubertal development Serum levels of Sex steroid replacement Estradiol (oral or transdermal) Sexual function and libido estradiol, LH, FSH, will not induce fertility Progesterone or progestin Bone health inhibin B and AMH FSH + hCG or GnRH pump Wellbeing Adherence Fertility Reversibility

Abbreviations: AMH, anti-Müllerian hormone; CHH, congenital hypogonadotropic hypogonadism; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; PSA, prostate-specific antigen.

the event of miscarriage. Furthermore, although previous over 12–24 months, after which time cyclic gestagen is gonadotropin cycles seem to shorten the time to fertility added (or after the first menstrual bleed) in order to max- in subsequent treatments,196 fertility in the future is not imize breast development. In adulthood, estradiol is typi- guaranteed. We, thus, recommend cryopreserving sperm cally given orally (at a dose of 1–2 mg) or transdermally once fertility has been attained. (50 μg daily by patch or 1–2 pumps of 0.06% gel daily) as a maintenance dose with a cyclic progestin regimen Induction of female sexual characteristics (progesterone 200 mg for 14 days of the cycle, depending Puberty can be induced by oral or preferably transder- on formulation) to avoid endometrial hyperplasia. In the mal estradiol administration in girls. The use of specific majority of women with CHH, estroprogestin therapy low-dose estradiol formulations (for example, 0.1 mg is effective in inducing harmonious development of the daily) are important.174 Transdermal estradiol adminis- breasts and genitals, as well as an increased sense of femi- tration is started (from age 10 years at the earliest) at low ninity that contributes to a satisfactory emotional and doses (typically 0.05–0.07 μg/kg nocturnally), with the sexual life. Estrogen treatment increases uterine size goal of mimicking estradiol levels during gonadarche. and combined estrogen and progestin therapy induces In older girls, when breast development is a high pri- monthly withdrawal bleeding, but does not induce ovu- ority, the starting dose of transdermal estradiol can be lation. For fertility, gonadotropins or GnRH therapy are 0.08–0.12 μg/kg.217 The estradiol dose is slowly increased necessary and effective.

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Box 3 | Challenges for management of CHH and goals and fallopian tubes. One must also ensure regular sexual intercourse takes place and rule-out an associated male Detection and diagnosis of CHH 220 ■ Discover novel biomarkers for CHH diagnosis and factor in infertility by semen analysis. Couples should assess the utility of refining the phenotype to enhance be advised on the optimal timing of sexual intercourse genetic testing during the ovulation induction as this first-line therapy 221 Best treatment and timing of initiating treatment does not require in vitro fertilization. The goal of ovu- ■ Long-term studies evaluating: neonatal gonadotropin lation induction therapy in female patients with CHH is treatment to optimize fertility; gonadotropin treatment to obtain a single ovulation and to avoid multiple preg- during adolescence versus adulthood for fertility nancies. Ovulation can be achieved either with pulsatile optimization; and role of prior androgen treatments GnRH therapy222–224 or, alternatively, with FSH treatment on fertility outcomes followed by hCG or LH to trigger ovulation.225 One caveat Adherence to treatment and transition to adult services is that most women with CHH do not secrete endogenous Interventions to promote adherence and structured ■ LH and, thus, require a complement of LH to stimulate transitional care from paediatric to adult services local production of androgen substrates by theca cells, Psychological distress and psychosexual effect which facilitates sufficient secretion of estradiol by the ■ Targeted psychosocial interventions and enhanced 226–228 peer-to-peer support dominant follicle. Physiologic estradiol secretion promotes optimal endometrial development and the Specialized care for fertility induction ■ International, multicentre trials to identify optimal cervical mucus production needed for sperm transit and 229 approach to treatment embryo implantation. Typically, subcutaneous FSH 223–225,229 Genetic counselling (monogenic versus oligogenic forms doses of 75–150 IU per day are sufficient. The of CHH) usual time required to obtain a dominant mature follicle 223–225,229 ■ Personalized counselling of patients using results (>18 mm) is ~12 days. The starting dose of FSH obtained by next-generation sequencing technologies is often increased or decreased depending on the ovarian Abbreviation: CHH, congenital hypogonadotropic hypogonadism. response, as assessed by repeated serum estradiol meas- urements or by counting maturing follicles (using ultra- sonography) performed approximately every 3–4 days. Box 4 | Goals for testosterone replacement therapy* This regimen helps to minimize multiple pregnancies and 230 Promote the risk of ovarian hyperstimulation syndrome. After ■ Virilization (for example, axillary, body and facial hair) ovulation, progesterone production can be stimulated by ■ Development of muscle mass and strength repeated hCG injections or direct administration of pro- ■ Pubertal growth spurt gesterone during the postovulatory phase, until embryonic ■ Skeletal maturation and bone mass endogenous hCG secretion takes over. ■ Deepening of voice Ovulation induction with a pulsatile GnRH pump can ■ Growth of penis be effective even in the presence of GnRH resistance, ■ Libido and sexual function such as in women with CHH who have mutations in ■ Self-confidence and wellbeing GNRHR.231 GnRH can be administered at different pulse Monitor and minimize Acne frequencies across the cycle, mimicking physiological ■ 232 ■ Gynaecomastia ovarian stimulation. Alternatively, pulsatile GnRH at a ■ Aggressiveness constant frequency also induces maturation of ovarian fol- ■ Polycythaemia licles and triggers an LH peak. The usual doses comprise *In male patients with congenital hypogonadotropic hypogonadism. 3–10 μg per pulse, injected subcutaneously every 90 min. Monitoring ovulation induction with GnRH is useful, as the risk of multiple pregnancy and ovarian hyperstimula- Induction of female fertility tion syndrome is much lower than that with gonadotropin Infertility in women with CHH is related to insufficient therapy.233 Once ovulation is obtained, the corpus luteum follicular maturation, which leads to chronic anovula- is stimulated to produce progesterone, which is neces- tion.218 GnRH-induced pituitary gonadotropins induce sary for embryo implantation. Short-term GnRH treat- absent or decreased physiological ovarian stimulation; ment is necessary to induce progesterone release until the however, no evidence of a decreased follicular reserve endogenous secretion of hCG from the embryo begins. exists. This point must be emphasized as decreased circu- lating AMH concentrations observed in female patients Reducing long-term health effects of CHH with CHH and severe GnRH deficiency could wrongly With appropriate and long-term treatment, many of the suggest an alteration in ovarian reserve and therefore long-term effects of hypogonadism can be minimized. a poor fertility prognosis.219 By contrast, women with Adherence to treatment is key to supporting pubertal CHH should be informed that their infertility is treat- development, sexual function and psychological health.234 able and that their reproductive prognosis is quite good Patients with psychosexual problems, low self-esteem and in the absence of a male factor of infertility. distorted body image might require psychological coun- Before considering ovulation induction, sono- selling and often benefit from peer–peer support.98,192 hysterosalpingography or hysterosalpingography should Bone-health concerns in patients with CHH are well- be performed to evaluate the integrity of the uterine cavity recognized.235 Lack of sex steroids is the presumed cause

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of osteoporosis in patients with CHH236–238 and although follow-up to ensure that the initial consultation has been sex steroid treatment typically improves bone density, it completed. The timing of transition not only depends on does not fully reverse the pheno type. Notably, mutations structural aspects of a given health-care system but also in FGF8, FGFR1 or SEMA3A might not only cause GnRH on the individual patient’s psychological and emotional deficiency but also directly affect bone.153,239 We recom- development and capacity for autonomy and self-care. mend a baseline bone density measurement in all patients with CHH at final height and after 2 years of treatment. To Conclusions date, insufficient evidence exists to use the WHO–FRAX CHH is a condition that is clinically and genetically risk calculator240 in this population of patients. Long-term hetero geneous. It is often challenging to diagnose, par- effects of hypogonadism also include an increased risk of ticularly during adolescence. In male individuals, crypt- developing metabolic problems. Several meta-analyses orchidism with or without micropenis might suggest have demonstrated an association between low testos- neonatal CHH; however, similarly useful signs are lacking terone levels and the metabolic syndrome.241–244 In male for female individuals. During adolescence, the diagnosis individuals, low testosterone levels are also strongly associ- of CHH is difficult to discern from constitutional delay of ated with an increased risk of developing type 2 diabetes growth and puberty. The presence of anosmia and/or mellitus.245 However, few studies have examined metabolic olfactory bulb hypoplasia and/or aplasia (visualized by risk specifically in patients with CHH. Interestingly, even MRI) points to Kallmann syndrome, yet measurement short-term hypogonadism (such as that resulting from dis- of levels of serum gonadotropins, sex steroids, AMH and continuation of sex steroids for 2 weeks) induces increased inhibin B are not always fully informative in confirming fasting insulin concentrations in young men with CHH,246 the diagnosis. At this stage, pubertal induction is com- which suggests that adherence to treatment is also impor- menced and a clinical and/or biochemical reassessment tant for promoting metabolic health. Accordingly, thera- is conducted following therapeutic pause at final height, peutic education is important for promoting adherence in thus enabling a definitive diagnosis of CHH. Effective the ongoing management of CHH. treatment is available not only for inducing virilization or estrogenization, but also for successful development of Transitional care for CHH fertility. Advances in our understanding of the molecular Transition of young adults from paediatric care to adult basis of CHH have helped explain the genetic cause in care is a well-recognized challenge for patients with 50% of cases and uncovered a complex model of gen etics chronic endocrine conditions247,248 including CHH.175 (oligogenicity) that might apply to a large proportion of For patients with CHH, discontinuation of care and patients. Furthermore, cases of reversal in adulthood resulting gaps in treatment can have considerable health point to gene–environment interactions.6,7 To advance consequences. Several types of model for transition the field, identification of novel biomarkers to aid early exist from a simple transfer of care to more structured diagnosis of CHH, assembly of a large CHH population programmes.249 Consensus among paediatric and adult to study the complex molecular basis of the disease, and endocrinologists in the European consortium study- development of targeted treatments to optimize fertility ing GnRH biology (COST Action BM1105, http:// outcomes are important. The COST network was created www.gnrhnetwork.eu/) is that a structured transition is to address these issues as well as to promote translational preferable and the process should include an evaluation of research into human reproduction and improve the patient readiness, communication between providers and manage ment of CHH.

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CONSENSUS STATEMENTS

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