AdultJia Zhu, MD, Yee-Ming Consequences Chan, MD, PhD of Self- Limited Delayed Pubertyabstract ≥ Delayed puberty is a common condition defined as the lack of sexual maturation by an age 2 SD above the population mean. In the absence of an identified underlying cause, the condition is usually self-limited. Although self-limited delayed puberty is largely believed to be a benign developmental variant with no long-term consequences, several studies have suggested that delayed puberty may in fact have both harmful and protective effects on various adult health outcomes. In particular, height and bone mineral density have been shown to be compromised in some studies of adults with a history of delayed puberty. Delayed puberty may also negatively affect adult psychosocial functioning and educational achievement, and individuals with a history of delayed puberty carry a higher risk for metabolic and cardiovascular disorders. In contrast, a history of delayed puberty appears to be protective for breast and endometrial Division of Endocrinology, Department of Medicine, Boston cancer in women and for testicular cancer in men. Most studies on adult Children’s Hospital, Boston, Massachusetts outcomes of self-limited delayed puberty have been in small series with Dr Zhu conducted the initial literature review, wrote significant variability in outcome measures and study criteria. In this the first draft, and revised the manuscript; Dr Chan article, we review potential medical and psychosocial issues for adults with conceptualized the review and reviewed and revised a history of self-limited delayed puberty, discuss potential mechanisms the manuscript; and both authors approved the final manuscript as submitted. underlying these issues, and identify gaps in knowledge and directions for future research. DOI: https://doi.org/10.1542/peds.2016-3177 Accepted for publication Jan 6, 2017 Address correspondence to Yee-Ming Chan, MD, Delayed puberty is commonly defined resolves by age 18 years, and in this PhD, Boston Children’s Hospital, 300 Longwood ≥ “ ” as the absence of physical signs of review, this condition is referred to as Avenue, Boston, MA 02115. E-mail: Yee-Ming.Chan@ childrens.harvard.edu puberty by an age 2 SD beyond the self-limited delayed puberty. This population mean for pubertal entry, condition is also called constitutional PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, “ ” 1098-4275). a statistical definition necessitated delay of puberty, development, or by our incomplete understanding maturation, with the word growth Copyright © 2017 by the American Academy of Pediatrics of how the timing1 of puberty is also frequently included (eg, determined. For girls, delayed constitutional delay of growth and FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships puberty [CDGP]). puberty is commonly defined as relevant to this article to disclose. the absence of breast development Self-limited delayed puberty is FUNDING: Dr Chan was supported by a Doris by age 13 years and for boys as the considered by many to be a benign Duke Clinical Scientist Development Award (grant absence of testicular enlargement by developmental variant with no 2013110). age 14 years. Of note, these clinical 14,15 long-term consequences. Thus, POTENTIAL CONFLICT OF INTEREST: The authors conventions do not reflect variation “ ” the mainstay of treatment is an have indicated they have no potential conflicts of in pubertal timing between racial interest to disclose. observational, watchful waiting and ethnic groups or a recent trend approach with reassurance for the toward earlier pubertal timing that – patient and family. However, some has been observed in the United States To cite: Zhu J and Chan YM. Adult Consequences 2 13 reports have suggested that the of Self-Limited Delayed Puberty. Pediatrics. and other developed countries. condition can have lasting physical 2017;139(6):e20163177 In the absence of any identifiable and psychological effects, which raises cause, delayed puberty usually the question whether sex-steroid Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 139, number 6, June 2017:e20163177 STATE-OF-THE-ART REVIEW ARTICLE 34 therapy should be initiated by a these individuals are typically shorter than the 90th percentile) or with certain age in all individuals with during the teenage years than peers a target height that is not short 17,18 – self-limited delayed puberty to with normal pubertal timing. (defined as37 target height less than prevent or temper any of these Further compounding the short 1.5 SDs) were found to reach or effects. These studies were conducted stature during early adolescence is exceed their target height (Tables 1 predominantly in Caucasian the fact that, in addition to having and 2). These studies suggest that populations and used traditional a delayed pubertal growth spurt, individuals with familial short stature cutoffs for delayed puberty and individuals with self-limited delayed in combination with self-limited may thus be limited in their puberty often have a slow19 growth delayed puberty are particularly generalizability; nonetheless, they velocity before puberty. When likely to fall short of their target provide insight into the potential these individuals do eventually Correlationsheight. With Prepubertal consequences of self-limited delayed undergo a pubertal growth spurt, Growth puberty. In this review, we examine the conventional teaching is that this “ ” consequences of self-limited pubertal growth spurt, albeit delayed, allows delay on height, bone mineral density them to catch up and attain20 their Another factor that has been (BMD), psychosocial functioning, Conflictingfull genetic height Observations potential. suggested to play a role in and educational achievement, as well determining adult height in as associations between delayed individuals with self-limited delayed puberty and the risks for adult puberty is the rate of growth during Consistent with this teaching, several cancers and cardiovascular disorders. the childhood years before puberty, observational studies report that with a slow rate of prepubertal Methods children with self-limited delayed growth associated with failure to puberty eventually achieve their attain target height in both boys and genetic height potential, with no girls with an otherwise unremarkable The PubMed database was searched significant difference between 36,39 medical evaluation. In boys, using the following medical subject measured adult height and predicted ∼ – such individuals had adult heights heading terms and keywords: adult height (ie, midparental target 21 25 0.63 SD ( 4 cm) less than predicted, delayed puberty, adult height, BMD, height) (Tables 1 and 2). whereas those with normal rates fracture, depression, substance use, However, other studies suggest that ∼ of prepubertal growth had no such self-esteem, educational achievement, these individuals fall short of their – height deficits (Fig 1). Height gain breast cancer, endometrial cancer, target height by 0.6 to 1.5 SD, 4 to 26 32 during the pubertal growth spurt testicular cancer, prostate cancer, 11 cm (Tables 1 and 2). These was comparable between the 2 cardiovascular disease, myocardial disparate findings may be due to groups, and thus the growth during infarction, peripheral arterial disease, variation in study populations due puberty did not compensate for stroke, hypertension, and metabolic to ascertainment criteria, inclusion the prepubertal growth deficit in syndrome. All relevant articles criteria (which sometimes include individuals with slow prepubertal published from 2006 to 2016 were growth delay), and/or use of sex- 36 growth (Table 1). In both boys and included in the review. Articles steroid treatment. Thus, these girls, individuals with slower growth published before 2006 were included findings have prompted attempts to rates in childhood also had shorter if they provided key background identify features that may predict parents, which support previous information, demonstrated a new or which individuals will fail to meet conclusions that familial short stature significant finding in the field, and/ their genetic height potential. Role of Familial Short Stature may limit individuals from reaching or summarized previous findings their target height and suggests a in a review and/or meta-analyses. possible genetic component to the References of selected articles were 34,37 One factor that appears to influence slowEffects growth of Sex-Steroid rate. Therapy reviewed for additional articles not whether target height is ultimately identified on the initial search. attained in self-limited delayed Height puberty is the target height itself. Sex-steroid therapy (eg, testosterone Delayed puberty is often (although in boys, estradiol in girls) can be
not always) seen in the context of offered to ameliorate psychosocial 1 Puberty is marked by a period of familial short stature, which can distress related to delayed puberty. rapid skeletal 16growth, the pubertal exacerbate1 concerns regarding short Several observational studies and growth spurt. Because this growth stature. Individuals with self-limited 2 randomized trials have examined acceleration is delayed in individuals delayed puberty with at least 1 tall the effects of sex-steroid therapy with self-limited delayed puberty, parent (defined as height greater on height in boys with self-limited Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 Zhu and Chan TABLE 1 Final Adult Height and Target Height in Boys with Self-Limited Delayed Puberty Study (Reference) Year Subgroup N FH (SD or cm) TH (SD or cm) Difference Bramswig et al26 1990 — 37 −0.7 — — Crowne et al27 1990 — 43 −1.6 −0.6 −1.0 SD LaFranchi et al29 1991 — 29 169.5 174.6 −5.1 cm von Kalckreuth et al22 1991 — 14 171.3 173.9 −2.6 cm Albanese and Stanhope30 1993 — 98 −1.9 −0.5 −1.4 SD Albanese and Stanhope31 1995 — 78 −2.0 −0.5 −1.5 SD Sperlich et al32 1995 — −1 −0.4 −0.6 SD Arrigo et al23 1996 Untreated 27 −0.9 −0.7 −0.2 SD Testosterone treated 22 −0.6 −0.8 0.2 SD Bertelloni et al24 1998 Untreated 7 −0.7 −0.4 −0.3 SD Testosterone treated 6 −0.6 −0.7 0.1 SD Oxandrolone treated 8 −0.7 −0.7 0 SD Rensonnet et al25 1999 Untreated 28 −0.76 −0.56 −0.2 SD Testosterone treated 11 −0.29 −0.35 0.06 SD Kelly et al33 2003 — 64 168.9 170.4 −1.5 cm — 168.2 171.1 −2.9 cm Butenandt et al34 2005 — 12 1.9 1.2 0.7 SD Poyrazoglu et al35 2005 — 105 −1.8 −0.9 −0.9 SD Wehkalampi et al36 2007 Early reduction in height 18 −0.65 −0.02 −0.63 SD No early reduction in 22 0.3 0.25 0.05 SD height Cools et al37 2008 — 33 −0.2 −0.3 0.1 SD Zucchini et al38 2008 Untreated 17 −1.02 −1.12 0.1 SD GH treated 25 −0.92 −1.26 0.34 SD Testosterone treated 12 −1.39 −1.45 0.06 SD FH, final height; GH, growth hormone; TH, target height;— , not available.
TABLE 2 Final Adult Height and Target Height in Girls With Self-Limited Delayed Puberty Study (Reference) Year Subgroup N FH (SDS or cm) TH (SDS or cm) Difference Bramswig et al26 1990 — 32 −0.7 — — von Kalckreuth et al22 1991 — 6 155.9 155.7 0.2 cm Crowne et al28 1991 — 15 −1.5 −0.8 −0.7 SD LaFranchi et al29 1991 — 13 156.4 161.7 −5.3 cm Albanese and Stanhope30 1993 — 34 −2.3 −0.8 −1.5 SD Butenandt et al34 2005 — 21 2.1 1.5 0.6 SD Poyrazoglu et al35 2005 — 46 −1.34 −1 −0.34 SD Zucchini et al38 2008 Untreated 16 −0.78 −0.88 0.1 SD GH treated 7 −0.92 −0.43 −0.49 SD Wehkalampi et al39 2011 Untreated 32 0.1 0.3 −0.2 SD Estrogen treated 7 −0.6 −0.1 −0.5 SD FH, final height; GH, growth hormone; TH, target height;— , not available.
40,41 delayed puberty. These studies slower prepubertal growth, fail to at the end of skeletal growth in have reported no difference in attain their genetic target height. the mid-20s and is an important adult height between those treated Sex-steroid therapy after the age of predictor of the development42 with sex steroids and– those who 14 years in boys and 12 years in girls of osteoporosis later in life. In underwent observation23 25,33, 35, alone36, 38, 39 does not appear to enhance or reduce 2001, the National Institutes of (Tables 1 and 2). Thus, adult height. However, if started Health Consensus on Osteoporosis although there may be other beneficial too early (some suggest bone age Prevention, Diagnosis, and Therapy effects, treatment with sex steroids <10 years), such therapy may lead emphasized the need to better does not appear to enhance or reduce to premature closure of the growth understand how pubertal delay affects
Summaryadult height. plates and loss of adult height. bone mass and to develop strategies43 BMD and Fracture Risk toBMD maximize in Men peak bone mass.
Some individuals with self-limited delayed puberty, particularly those Most bone mass is acquired during In 1992, Finkelstein et al reported with familial short stature and puberty. Peak bone mass is attained that men with a history of self-limited Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 139, number 6, June 2017 3 women with risk factors for hypothalamic amenorrhea reported that subjects with menarche occurring later than the median age for the cohort (12.94 years) had lower BMD at the femoral neck and tibia compared with those with menarche occurring before the median age for the cohort (Table 4), with the negative correlation between menarchal timing and
BMD observed59, across60 all ages from 8 to 18 years. Extending to later adulthood, several observational studies have demonstrated that the age at menarche may influence the
risk of osteoporosis52, during54, 55, 61 both the premenopausal 53, 55, 56, and58, 61 postmenopausal years. FIGURE 1 Mean SD score for height and mean target height (arrows) of boys with delayed puberty who either The effect of pubertal timing on had (filled circles and solid line) or did not have (open circles and dashed line) an early reduction in BMD in women has been largely height. *P = .01 between final adult heights. (Reprinted with permission from page 102 of Wehkalampi K, Vangonen K, Laine T, Dunkel L. Progressive reduction of relative height in childhood predicts adult attributed to differences in estrogen stature below target height in boys with constitutional delay of growth and puberty. Horm Res. exposure. Specifically, both a later 2007;68(2):99–104.) age at menarche and earlier age at menopause have been associated with lower BMD, suggesting that a greater lifetime duration of estrogen delayed puberty had lower areal reported estimated volumetric exposure may 42have a protective BMD measured by dual x-ray BMD as calculated from DXA, and effect on BMD. However, in 1 absorptiometry (DXA) than men with44,45 concerns have been raised that such prospective study, differences in normal timing of puberty (Table 3). calculations may underestimate– BMD BMD were observed even before Two additional studies, Kindblom in smaller individuals even49 after51 the onset of puberty, with a lower et al and Kuh et al, have similarly corrections for body size. Future areal BMD observed as early as 9 reported that men with later puberty studies to resolve these questions years of age in subjects who went have lower volumetric BMD as may require direct measurements in on to have menarche later62 than directly measured by peripheral BMDlater inadulthood Women of volumetric BMD. the median age (Table 4). These quantitative46,47 computed tomography observations suggest that factors (Table 3). However, 2 other other than estrogen exposure may studies, by Bertelloni et al and Yap et influence BMD, possibly genetic and Many early studies have associated al, found no significant difference in – environmental factors that affect late menarche, a proxy of delayed volumetric BMD (derived from areal 52 58 both pubertal timing and bone puberty, with lower BMD. 62 DXA measurements) between men mass. However, most of these studies with a history of self-limited delayed24,48 puberty and controls (Table 3). did not explicitly exclude women Although these studies in women who had underlying causes of late suggest that menarche occurring One potential explanation for the menarche such as hypothalamic later but still within the normal age variability in findings is that the amenorrhea (a functional form of range may be associated with lower studies used different definitions gonadotropin-releasing hormone BMD during both young and later of pubertal delay with varying deficiency triggered by physical, adulthood, only 1 study specifically – cutoff ages (14 vs 15 years) and environmental, and/or psychosocial reported BMD in women with ages at follow-up (mean of 19 64 stressors), which is known to be frankly delayed puberty. In this years; Table 3). In addition, only associated42 with reduced bone study of postmenopausal women, 2 studies (Kindblom et al and Kuh density. One prospective, late menarche (>15 years) was et al) measured46,47 volumetric BMD longitudinal study of 124 healthy associated with reduced BMD at the directly ; the other studies women that specifically excluded lumbar spine and femoral neck when Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 Zhu and Chan " 95% CI 14% to Conclusion 4%; P = .001 < .009; no difference in vBMD, P = NS controls at both sites, all P s < .009 P = .016; LS aBMD lower in DP vs controls, P = .044, no difference in LS vBMD, P = NS; no difference in FN aBMD or vBMD P = .001; no versus average PHV, difference in LS or FN aBMD; radius aBMD and vBMD lower in late PHV P all <0.001; tibia versus average PHV, vBMD lower in DP versus controls, P all < 0.001 9% vs "fully mature, – Total body aBMD lower in DP vs controls, Total body aBMD lower in late PHV Trab vBMD lower in "preadolescent" by Trab 3 0.221 0.209 0.216 0.205 0.197 0.201 — — — — — — — — — — — — — — — — 0.5 aBMD and vBMD lower in DP vs normal 0.13 0.37 0.67 0.54 0.37 0.14 0.67 0.327 aBMD lower in DP vs normal controls, P 0.337 vBMD, g/cm Cort: 1.153; Trab: Cort: 1.153; Trab: Cort: 1.159; Trab: Cort: 1.159; Trab: Cort: 1.162; Trab: Cort: 1.162; Trab: Cort: 1.161; Trab: Cort: 4.36; Trab: 0.254 Cort: 4.36; Trab: Cort: 4.44; Trab: 0.267 Cort: 4.44; Trab: 2 — — — — — cm 1.24 1.18 0.58 Cort: 1.165; Trab: 1.101 1.14 0.56 Cort: 1.155; Trab: 0.73 1.03 1.2 1.21 1.02 1.08 1.00 1.04 0.99 1.05 0.97 1.01 1.222 1.1 0.8 1.28 1.13 1.16 Outcome Variable Location aBMD, g/ Tibia Total bodyLS FN Radius 1.25 Tibia LS Total body 1.184 FN Radius Radius LS LS Total bodyLS 1.23 Total hip LS Total hip Radius LS Total hip Radius LS Radius Total hip Radius LS LS FN Radius LS Total body 1.237 LS FN 60 – 64 60 – 64 60 – 64 60 – 64 26 ± 2 24 ± 3 18.9 ± 0.5 21.8 ± 1.7 24.7 ± 3.4 18.9 ± 0.5 19.3 ± 1.3 23.5 ± 2.9 Years ± SD 23 21 32 65 12 21 45 168 200 222 ty 14.5 y at 14.5 y 14.5 y 14.5 y Middle-tertile PHV 214 DP DP DP Fully mature at Advanced puberty Early puberty at Preadolescent at Controls Controls Controls defined by pubic hair stage and height achieved at ≥ 14 y achieved at ≥ 14 y development, voice breaking, and pubic hair growth 2016 Lack of or limited genital Year Delayed Puberty Criteria Subgroup N Age at Evaluation, 1992 Puberty onset >15 y as 1998 Testicular vol 4 mL 2004 Testicular vol 4 mL 2006 PHV in the latest tertile Late-tertile PHV 214 24 l 44 46 l l BMD in Men With a History of Self-Limited Delayed Puber
47 48 l l TABLE 3 Study (Ref) Finkelstein et a available. Trab, trabecular; vBMD, volumetric bone marrow density; — , not velocity; peak height delayed puberty; FN, femoral neck; LS, lumbar spine; NS, not significant; PHV, CI, confidence interval;density; marrow areal bone aBMD, Cort, cortical; DP, Kuh et a Yap et a Bertonelloni et a Kindbloom et a
Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 139, number 6, June 2017 5 Conclusion postmenopausal BMD decreased by 0.9% ( P = .02) timing group at all sites, P s <.02 vs earlier pubertal timing group in both young adult and premenopausal women, all P s <.004 early menarche group, all P s <.05 Each year increment in age at menarche, aBMD lower in later vs earlier pubertal FN and tibia aBMD vBMD lower in later LS and FN aBMD lower in late menarche vs 3 0.334 0.322 0.314 0.295 vBMD, g/cm 2 0.878 0.825 0.371 0.445 0.636 0.630 0.36 0.599 0.838 0.785 1.077 0.896 1.105 0.919 0.620 0.456 0.658 0.651 0.900 0.701 0.838 1.026 0.927 0.719 0.878 1.060 Outcome Variable Location aBMD, g/cm FN Tibia FN Tibia Radius Radius FN LS Tibia Radius Total body FN FN Tibia LS FN LS FN Total body Radius FN LS Total body Radius FN LS Total body Radius FN LS 71 ± 4.8 8.9 ± 0.5 9.0 ± 0.5 20.4 ± 0.6 45.6 ± 3.1 20.4 ± 0.6 46.0 ± 3.7 20.4 ± 0.6 53.4 ± 2.9 20.4 ± 0.6 Years ± SD Age at Evaluation, ty Subgroup (menarche <12.94 y) provided) provided) (menarche >12.94 y) (menarche >12.94 y) (menarche <12.94 y) Early menarche (no criteria Late menarche (no criteria 60 60 62 Earlier pubertal timing 62 Later pubertal timing 62 Later pubertal timing 62 Earlier pubertal timing N 223 Late menarche (>15 y) 1382 Early menarche (<15 y) 1993 2230 1995 2009 2009 55 l 62 60 l l BMD in Women With a History of Self-Limited Delayed Puber
53 l Fox et a delayed puberty; significant; vBMD, volumetric bone marrow density. FN, femoral neck; LS, lumbar spine; NS, not aBMD, areal bone marrow density; DP, Study (Reference) Year TABLE 4 Tuppurainen et a Chevalley et a Chevalley et a
Downloaded from www.aappublications.org/news by guest on September 26, 2021 6 Zhu and Chan compared with BMD of women who 16 years or later) and found that found that androgen treatment of 6 underwent menarche before age these women had an 80% increased to 28 months did not significantly
15 years (Table 4). However, it is still risk of incident vertebral fracture in affect BMD in young adult men24, 48with unclear from the preceding studies later adulthood compared with 65those a history of delayed puberty. whether the finding of a lower BMD with menarche before 16 years. The influence of sex-steroid therapy in women with later menarche is Similarly, those with menarche at on BMD in women has not been due to a protective effect of earlier 15 years or later had a 50% increased reportedSummary. menarche or a detrimental effect risk of Colles fracture compared with of later menarche. Future studies those with66 menarche before 15 years on BMD specifically in women (Table 5). Another study showed Studies in men with a history of self- with frankly delayed puberty in a 45% increase in the risk of hip limited delayed puberty variably comparison with those with normal fracture in those with menarche at report low or normal BMD, and pubertal timing are needed to resolve age 15 years or later compared with previous androgen therapy does this question. those with menarche at 11 years 64 not appear to influence BMD in Fracture Risk or younger (Table 5). In contrast, these men. In women, later age at the other end of reproductive at menarche is associated with life, the age at menopause was not decreased BMD in early adulthood, In young adult men, Kindblom et significantly associated with Colles 65,66 late adulthood, and even before al found that each 1-year increase or vertebral fracture and had a pubertal onset. Later age at pubertal in age of puberty was associated smaller effect than age at menarche 64 initiation has also been associated with a 39% increase in odds of on the risk of hip fracture, suggesting with an increase in fracture risk upper extremity fractures46 during that lifetime duration of estrogen during adolescence for both boys adolescence (Table 5). A similar exposure is not the only factor that and girls and during adulthood for association was reported in a influences fracture risk. To date, women. longitudinal study of young women; associations between pubertal timing Psychosocial Outcomes individuals who experienced a and fracture risk in men have not fracture in childhood or adolescence been reported, possibly due to a had significantly later age of relatively lower fracture incidence in In addition to being a period of menarche and lower volumetric men and difficulty with65, 66 assessing age dramatic physical development, BMD at the distal radius than those at pubertal initiation. adolescence is also a time of marked who did not experience a fracture Sex-Steroid Therapy psychosocial changes. Studies have despite similar nutritional intake examined the effect of pubertal and physical activity63 level in the 2 timing on multiple psychosocial groups (Table 5). However, the One intervention that may temper aspects, including self-esteem, risk associated with frankly delayed any reduction in BMD in individuals psychopathology, and behavior, puberty was not reported. with self-limited delayed puberty with a predominant focus on the One study did identify women who is sex-steroid therapy. However, adolescent period and with limited TABLEhad frankly 5 Fracture delayed Risk in menarcheIndividuals With (at Delayed PuberYapty et al and Bertelloni et al both follow-up into adulthood. Study (Reference) Year Name N Age at Evaluation, Outcome Conclusion Years ± SD Variable Johnell et al64 1995 MEDOS 2086 women 78.1 ± 9.4 Hip fracture RR: 1.45, 95% CI: 1.12 to 1.87 for age at menarche ≥15 y vs ≤11 y Roy et al65 2003 EPOS 3173 men, 3402 63.1 ± 7.8 (men), 62.2 Vertebral RR: 1.8, 95% CI: 1.24 to 2.63 for age at women ± 7.6 (women) fracture menarche ≥16 y vs <16 y Silman et al66 2003 EPOS 3173 men, 3402 63.1 ± 7.8 (men), 62.2 Colles’ fracture RR: 1.5, 95% CI: 1.1 to 2.0 for age at women ± 7.6 (women) menarche >15 y vs ≤15 y Kindblom et al46 2006 GOOD 642 men 18.9 ± 0.6 Upper extremity OR: 1.39, 95% CI: 1.08 to 1.79, P = .01 for fracture each 1-y increment to PHV Chevalley et al63 2012 42 women 20.4 ± 0.6 Fracture OR: 2.09, 95% CI: ∼1.3 to 3.3, P = .002 for each 1.2-y delay in menarche; mean age at menarche greater for fracture group vs no fracture group (13.45 vs 12.78, P = .003) CI, confidence interval; EPOS, European Prospective Osteoporosis Study; GOOD, Gothenburg Osteoporosis and Obesity Determinants; MEDOS, Mediterranean Osteoporosis Study; OR, odds ratio; RR, relative risk; PHV, peak height velocity.
Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 139, number 6, June 2017 7 Self-Esteem Malignancy
Zealand and Finland studies, this79 Breast Cancer association was no longer seen. Two studies from the 1950s Further supporting the overall suggested that boys and girls who results of the meta-analysis, 2 recent The influence of pubertal timing mature later than their peers have ’ studies, the Growing Up Today Study, on the risk for breast cancer is well more negative beliefs and attitudes 67,68 a follow-up of the Nurses Health established, with studies in the toward self at age 17, although Study II, and the UK Biobank Study 1960s and 1970s demonstrating a subsequent study suggested found that later menarche (>14.3 and an association between early age that it is short stature rather than >15 years) was not associated with at menarche and increased risk of delayed puberty itself that affected 90 69 depressive symptoms in young and breast cancer ; subsequent studies self-image. However, 2 studies 80,81 later adulthood, respectively. further established an association in boys and girls with CDGP found between delayed age at menarche no significant difference in self- 91,92 and reduced breast cancer risk. esteem scores in early adulthood Although there is no clear ≥ One such study found that menarche between those with CDGP and those evidence for lasting psychosocial – 15 years was associated with a with normal development despite consequences of delayed puberty – twofold reduction in the risk of moderately shorter stature ( 1.6 in women, late pubertal timing has breast cancer among premenopausal and 1.5 SD, respectively). Race and been suggested to be associated women compared with normally ethnicity may modulate the effect with psychological issues in men. 91 timed menarche. Furthermore, a of pubertal timing, as 1 study of Perceived late pubertal timing in 2-year delay in menarche has been adolescents with self-perceived late boys has been associated with higher associated with a 10% decrease in puberty found a significant decrease levels of depression in settings82 with the risk of breast cancer in both pre- in body image with late development high levels of peer stress, disruptive 92 and postmenopausal women and in Hispanic and black boys, but not behavior disorder and83 substance use ≥ late initiation of breast development in white or Asian boys. For girls with in young adulthood, and depression ( 13 years) with a 20% decrease late development, lower body-image and anxiety81 in later adulthood in risk compared with breast scores were observed in Hispanic (Table 6). A review of psychological 70 development occurring at age 11 to girls only. outcomes associated with pubertal 93 Psychopathology and Behavior timing in boys supported these 12 years. findings and concluded that the The protective effect of delayed effects of late pubertal timing appear puberty on breast cancer risk Many studies have associated to be limited to higher rates of has been proposed to be due to a early pubertal timing with adverse internalizing symptoms (associated shorter lifetime duration of estrogen psychosocial outcomes including– with depression or anxiety) and exposure and, in turn, less breast depression, delinquency, and substance use in both adolescence 71 75 84 cell proliferation and a lower early sexual behavior. Fewer and young adulthood. chance of incurring carcinogenic studies have examined psychosocial 93 outcomes for men and women who mutations. Another factor that has Studies on educational achievement been suggested to independently experienced later pubertal timing in individuals with self-limited (summarized in Table 6). One study affect both pubertal timing and ≥ delayed puberty have– reported of a large UK birth cohort observed breast cancer risk is genetic worse academic performance85 87 variation. A recent study found that that girls with menarche 13.5 years during childhood and either no had up to a 52% reduction in odds of 88,89 2 single nucleotide polymorphisms difference or better performance83 associated with earlier age at experiencing depressive symptoms in during young adulthood. adolescence compared with girls with Summary menarche were also associated with an increased risk for breast cancer normal menarche, but this association76 disappeared by young adulthood. even after controlling for age at Similarly, a study in New Zealand Delayed puberty may be associated menarche, suggesting that these did not find any association between with increased internalizing genetic loci affect breast cancer risk independently of their94 effect on menarche at ages 14 to 15 and major77 symptoms and poorer academic depression during adolescence. In performance in adolescence, but it menarchalEndometrial timing. Cancer contrast, a study in Finland identified remains to be determined whether a 70% higher risk of depression in it has significant long-term effects ≥ women who had delayed78 puberty on psychological outcomes and Numerous case-control studies (menarche 16 years), but in a academic achievement in later have associated early menarche recent meta-analysis of both the New adulthood. with increased risk of endometrial Downloaded from www.aappublications.org/news by guest on September 26, 2021 8 Zhu and Chan TABLE 6 Psychopathology in Individuals With Delayed Puberty Study (Reference) Year Location/Name N Age at Evaluation, Outcome Variable Conclusion Years ± SD or Range Joinson et al76 2013 United Kingdom 3648 women 14–16.5 Depressive OR up to 1.52, 95% CI: 1.12 to 2.05 for symptoms age at menarche 11.5 to 13.5 y vs ≥13.5 y, P = .007 18–19 No difference in OR for age at menarche 11.5 to 13.5 y vs ≥13.5 (OR 1.07–1.18, all Ps >.05) Boden et al77 2011 New Zealand 497 women 15–18 Major depression No difference in % outcome for age at menarche 14–15 y vs 12–13 y (32.5% vs 30.9%, P > .50) Herva et al78 2004 Northern Finland 3952 women 31 Depression OR 1.7, 95% CI: 1.1 to 1.6 for age at menarche ≥16 y vs 12–15 y Galvao et al79 2014 Meta-analysis: New 4449 women 15–31 Major depression/ No significant risk of depression for Zealand and depression age at menarche ≥14 y vs <14 y (RR Northern Finland 1.28, 95% CI: 0.87 to 1.88) Opoliner et al80 2014 United States/ 9039 women 20–26 Depressive No difference in OR for age at Growing Up Today symptoms menarche >14.3 y vs 12–14.3 y (OR Study 0.91, 95% CI: 0.70 to 1.18) Day et al81 2015 United Kingdom/UK 250 037 40–69 Depression No difference in OR for age at Biobank Study women menarche 15–19 y vs 12–14 y (OR 1.07, 95% CI: 1.02 to 1.13, P > 7.48 × 10–5) Conley and Rudolph82 2009 United States 82 men 13.4 Depression Later perceived pubertal timing was associated higher levels of depression (β = −0.31, P < .05) Graber et al83 2004 United States 392 men 24.2 Disruptive behavior OR 2.1, 95% CI: 1.1 to 4.5 for perceived disorder late pubertal timing vs on time Substance use OR 2.5, 95% CI: 1.1 to 5.9 for perceived late pubertal timing vs on time Day et al81 2015 United Kingdom/UK 197 714 men 40–69 Anxiety/panic attacks OR 1.43, 95% CI: 1.22 to 1.67 for Biobank Study perceived late voice breaking vs on time, P < 7.48 × 10–5 Depression OR 1.36, 95% CI: 1.25 to 1.49 for perceived late voice breaking vs on time, P < 7.48 × 10–5 CI, confidence interval; OR, odds ratio; RR, relative risk.
Testicular Cancer cancer, but only 2 studies have findings. Although some studies have specifically evaluated the effect of reported up to a 25% –decrease in the In men, studies examining the late menarche. A retrospective case- odds of prostate cancer in individuals ≥ relationship between pubertal 109 111 control study in Italy found that with later puberty, others have timing and testicular cancer have 112,113 menarche 14 years was associated reported either no association produced inconsistent results. with a 32% decrease in the odds or up to a 6% increase in the odds Some studies have suggested that of endometrial cancer compared ∼ of prostate cancer for each year 95 later onset of puberty is associated 114 with menarche at age <12 years. – of pubertal delay. Difficulty in with an 40% to 65% decrease in A prospective study across Europe 97 101 assessment of pubertal timing in ≥ the odds of testicular cancer, reported similar findings in women – men may be a contributor to the but other studies have reported no with menarche 15 years compared 102 107 discrepant results; thus, 1 study used association. A recent meta- with women with menarche <12 a genetic risk score calculated from analysis of 8 studies found that later years, with a 7% to 8% reduction 13 single nucleotide polymorphisms age at reported onset of puberty was in risk per year that menarche as a proxy for pubertal development. 96 associated with a 19% reduced odds is delayed. Of note, neither 108 Although the researchers did not find of testicular cancer. study explicitly compared late Prostate Cancer a significant association between menarche with normal menarche, genetic risk score and the presence of so it is unclear if late menarche prostate cancer, they did identify an is protective against endometrial The role of pubertal timing on association between a higher genetic cancer, if early menarche is a risk prostate cancer risk is under active risk score (later onset of puberty) factor, or both. investigation with inconclusive and a 24% reduction in the odds of Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 139, number 6, June 2017 9 high-grade115 prostate cancer per score study of >1 million women in the with age at menarche at 13 years. Summarytertile. United Kingdom, both early and Whether this increased risk for late menarche were associated cardiovascular– disease extends to
with an increase in risk of coronary increased119 risk123 for mortality remains Late pubertal onset in girls is heart disease: compared with unclear. protective against breast cancer and women with an average age at Few studies have examined possibly against endometrial cancer. menarche (13 years), those with the effect of pubertal timing on Recent studies suggest that some menarche at 11 years had a 12% metabolic and cardiovascular genetic loci independently affect increase in risk and those with 116 disease in men. One study both breast cancer risk and age at menarche at 15 years had a 6% suggested that an earlier age at menarche. Late pubertal onset in increase in risk after adjustment for perceived age of voice breaking boys appears to be protective for covariates including BMI, smoking, was associated with up to a 39% testicular cancer, but the role of and socioeconomic status (Fig 2). ≤ increase in the odds of angina, heart pubertal timing in prostate cancer The highest risks were observed ≥ attack, hypertension, and type 2 remains unclear. for menarche at 10 years and at diabetes, with no observed effect 17 years, with >20% increase in Metabolic and Cardiovascular in men with later perceived age of Outcomes risk for each group. A similar but 81 voice breaking. less pronounced relationship was Potential Mechanisms Linking found between age at menarche and Pubertal Timing to Cardiovascular ≥ Risk Most studies of the effect of other conditions, with menarche at pubertal timing on metabolic and 17 years associated with a 13% cardiovascular disease have focused increase in risk for cerebrovascular on early pubertal maturation, which disease and a 7% increase in risk One proposed explanation for has been linked to increased risk for hypertensive disease compared the association between earlier for obesity, metabolic syndrome, and overall116 cardiovascular mortality. There is now evidence that delayed puberty has negative effects as well. Early studies suggested a protective effect of delayed puberty for cardiovascular disease. In a ≥ retrospective population-based study in Germany, menarche 15 years was associated with a 52% reduced odds of peripheral arterial disease compared with117 menarche at age 12 to 15 years. The same study also found an association between later age at menarche and lower BMI, waist circumference, fasting glucose, and 2-hour glucose, trends that extended into ≥ the late menarche118 group ( 15 years). More recent studies have suggested that later pubertal timing in fact has FIGURE 2 a negative effect. The association Relative risk and 95% confidence intervals (CI) of coronary heart disease by age at menarche. between coronary heart disease Reference category is menarche at 13 years of age. The area of the square is inversely proportional and menarchal timing exhibits a to the variance of the log risk. CHD, coronary heart disease; CI, confidence interval. (Reprinted with U-shaped curve, with an increased permission from page 240 of Canoy D, Beral V, Balkwill A, et al; Million Women Study Collaborators. Age at menarche and risks of coronary heart and other vascular diseases in a large UK cohort. risk of coronary heart disease Circulation. 2015;131(3):237–244.) associated with both earlier and later pubertal timing. In a recent Downloaded from www.aappublications.org/news by guest on September 26, 2021 10 Zhu and Chan Conclusions and Future Directions puberty and cardiovascular risk to alter this approach, but we is the association between early recommend that reassurance be puberty and childhood obesity. provided with appropriate caveats. The findings that delayed pubertal A review of studies on childhood Tempered expectations should timing may have lasting negative BMI showed that in 5 of 8 studies, be set regarding adult height, and •consequences• raise several questions. adjusting for childhood obesity clinicians must be careful to not attenuated the association between Does delayed puberty truly have be dismissive or overly optimistic early menarche and higher adult lasting negative consequences? when counseling these patients. BMI, but only partially, suggesting There are discrepancies in the Treatment with sex steroids is the presence of additional,116 yet-to- existing literature on nearly all an option for individuals with be-identified factors. Similarly, outcomes of delayed puberty delayed puberty, but its effects on later exposure to sex steroids in that have been examined, adult outcomes remain unclear. individuals with delayed puberty and publication bias may be a Because it would be difficult to may have effects on metabolic contributing factor. Nevertheless, perform a definitive clinical trial function and cardiovascular health the studies reviewed in this to determine whether treatment either directly or by affecting article raise the possibility can avert potential negative other factors such as BMI and lipid that delayed puberty may not outcomes of delayed puberty, an metabolism. be a completely benign entity, alternative approach to addressing particularly with regard to height, this question may come from large Notably, recent genome-wide BMD, psychological outcomes, and electronic health record databases. association studies have identified •• cardiovascular disease. Such data may be limited by clinical overlap between genetic loci that Are there subsets of individuals confounders, but they can shed light influence timing of menarche with self-limited delayed puberty on whether sex-steroid treatment and those associated with adult 124,125 who are at greatest risk for of delayed puberty can modify bone BMI. In one meta-analysis, negative outcomes? The studies density, cardiovascular disease risk, the influence of these loci on age cited in this review suggest that and other adult outcomes and, if so, at menarche was not attenuated 126 familial short stature and slow the age at which such127, treatment128 is by adjustment for BMI. These growth rates before puberty maximally effective. findings suggest that these genetic are associated with lower adult Contrary to what is commonly factors affect pubertal timing and height, and race and ethnicity may taught, self-limited delayed puberty BMI independently and serve influence psychosocial outcomes may not be an entirely benign as a common genetic link that (eg, self-esteem). Most reports entity and may be associated with may account, at least in part, for have studied primarily Caucasian shorter stature, lower BMD, negative the association between timing populations, and the implications psychological outcomes, and of menarche and the risk for for other racial and ethnic increased risk for cardiovascular cardiovascular disease. Data from groups remain unclear. Further disease. Further investigations large electronic health record 127,128 identification of subgroups, incorporating pubertal timing into databases, phenotyping 129 which could be achieved through both genotype- and phenotype- studies, and genetic studies “ ” large-scale phenotyping studies association studies can further may reveal how pubertal timing or big data approaches to inform our understanding of the influences cardiovascular disease 129 analyze medical records, may links between pubertal timing risk and in turn how this risk is reconcile discrepancies between and these outcomes and, more determined more generally. Summary existing studies. Genetic analyses broadly, the physiology underlying may identify specific genetic loci growth, bone health, psychosocial associated with these phenotypes development, and cardiovascular and allow for improved prediction Emerging evidence shows a health. •• of adverse outcomes. U-shaped association curve, with Abbreviations both earlier and later onset of Does current clinical practice pubertal timing associated with an need to change? Reassurance increased risk of cardiovascular and observation remain the BMD: bone mineral density disease in women. Factors that foundations for management of CDGP: constitutional delay of may contribute to this association individuals with delayed puberty. growth and puberty include common genetic links and We do not feel the existing DXA: dual x-ray absorptiometry obesity. evidence is sufficiently definitive Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 139, number 6, June 2017 11 References Pubertal development timing in urban 22. von Kalckreuth G, Haverkamp F, Kessler Chinese boys. Int J Androl. 2011;34(5 Pt M, Rosskamp RH. Constitutional delay 1. Palmer t MR, Dunkel L. Clinical practice. 2):e435 e445 of growth and puberty: do they really Delayed puberty. 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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/139/6/e20163177 References This article cites 127 articles, 12 of which you can access for free at: http://pediatrics.aappublications.org/content/139/6/e20163177#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Endocrinology http://www.aappublications.org/cgi/collection/endocrinology_sub Puberty http://www.aappublications.org/cgi/collection/puberty_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml
Downloaded from www.aappublications.org/news by guest on September 26, 2021 Adult Consequences of Self-Limited Delayed Puberty Jia Zhu and Yee-Ming Chan Pediatrics 2017;139; DOI: 10.1542/peds.2016-3177 originally published online May 18, 2017;
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