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Inducing Puberty

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Inducing Puberty European Journal of Endocrinology (2008) 159 S9–S15 ISSN 0804-4643 Inducing puberty Eveline M Delemarre1, Bram Felius2 and Henriette A Delemarre-van de Waal2 1Medical School Leiden and 2Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands (Correspondence should be addressed to H A Delemarre-van de Waal; Email: [email protected]) Abstract Puberty is the result of increasing pulsatile secretion of the hypothalamic gonadotropin releasing hormone (GnRH), which stimulates the release of gonadotropins and in turn gonadal activity. In general in females, development of secondary sex characteristics due to the activity of the gonadal axis, i.e., the growth of breasts, is the result of exposure to estrogens, while in boys testicular growth is dependent on gonadotropins and virilization on androgens. Hypogonadotropic hypogonadism is a rare disease. More common is the clinical picture of delayed puberty, often associated with a delay of growth and more often familial occurring. Especially, boys are referred because of the delay of growth and puberty. A short course (3–6 months) of androgens may help these boys to overcome the psychosocial repercussions, and during this period an increase in the velocity of height growth and some virilization will occur. Hypogonadotropic hypogonadism may present in a congenital form caused by developmental disorders, some of which are related to a genetic disorder, or secondary to hypothalamic–pituitary dysfunction due to, among others, a cerebral tumor. In hypogonadotropic hypogonadism puberty can be initiated by the use of pulsatile GnRH, gonadotropins, and sex steroids. Sex steroids will induce development of the secondary sex characteristics alone, while combined administration of gonadotropins and GnRH may induce gonadal development including fertility. European Journal of Endocrinology 159 S9–S15 Introduction The GnRH test is often used as a diagnostic tool in the evaluation of delayed puberty. However, the response of Pubertal development is the result of increasing release gonadotropins to an acute challenge of GnRH can be of GnRH by the hypothalamus, which in turn increas- difficult to interpret, since in the pre-pubertal state the ingly stimulates the pituitary to release both gonado- pituitary, although intact, will not or hardly respond, tropins LH and FSH. The gonadotropins stimulate the similar to the situation in hypogonadotropic hypogo- gonads, ovary, and testis, to develop and produce the sex nadism (7). Repetitive administration of GnRH intrave- steroids estrogens and androgens respectively. At the nously does increase gonadotropin levels in patients in a onset of puberty, the first endocrine change is the pre-pubertal and hypogonadotropic state. Therefore, occurrence of an LH increase only during the night (1). this diagnostic test is not able to differentiate between With the progression of puberty, the LH pulse pattern the two conditions. In fact, the response to the GnRH shows an increase in frequency and amplitude with a test reflects the measure of previous stimulation by clear day/night rhythm (2). In adulthood, the day/night GnRH. rhythm has disappeared. The pulsatile pattern of LH The GnRH agonist test has been described to be an reflects the pulsatile release of GnRH. For FSH, a pulsatile alternative test in the diagnosis of hypogonadotropic secretion pattern in blood is hard to detect, presumably hypogonadism (8). However, for both the native GnRH due to the longer half-life of 4–6 h of FSH compared with and the GnRH agonist tests, the authors describe 20–30 min for LH (3, 4). In boys, the nocturnal LH significantly higher levels of LH and FSH levels in increase is associated with a concomitant increase in delayed puberty compared with hypogonadotropic testosterone, while in girls the highest estradiol increase patients. We therefore must conclude that there still is occurs during the day as a result of delayed response of no reliable test for differentiation in the pre-pubertal the ovaries (2, 5, 6). state between normal, but delayed puberty and hypogonadotropic hypogonadism. This paper was presented at the 5th Ferring International Paediatric However, clinical aspects such as the family history, Endocrinology Symposium, Baveno, Italy (2008). Ferring Pharma- height growth, and skeletal age can make a given ceuticals has supported the publication of these proceedings. diagnosis more probable. A patient with delayed puberty q 2008 European Society of Endocrinology DOI: 10.1530/EJE-08-0314 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 09/24/2021 07:40:28PM via free access S10 E M Delemarre and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159 mostly has a pre-pubertal dip, i.e., a decrease in height development. With respect to pubertal arrest, mutations growth velocity preceding the pubertal growth spurt, and polymorphisms in gonadotropin genes and their while hypogonadotropic patients tend to continue their receptors can be responsible for this phenotype or for growth with pre-pubertal height growth velocity. In complete hypogonadotropic hypogonadism. addition, in delayed puberty,skeletal age will be retarded, The congenital form of hypogonadism may be but conforms to the biological physical status, while in suspectedinthenewbornwithmultiplepituitary hypogonadotropic hypogonadism, skeletal age will start deficiencies. Cryptorchidism and a micropenis may be to delay from the age of onset of puberty and this delay presenting symptoms in boys. The first months can be increases, but finally remains not in conformity with the used to diagnose a GnRH deficiency, since there is a biological, pre-pubertal status of the patient. spontaneous GnRH-related gonadotropin increase. Absence of this gonadotropin peak confirms hypogona- dotropic hypogonadism (10). Kallmann syndrome, hypogonadotropic hypogonad- Pathophysiology of hypogonadotropic ism in combination with anosmia, is the result of a hypogonadism genetic disorder. An X-linked form, an autosomal dominant and an autosomal recessive form are identi- Timing of puberty is the result of both genetic fied. A mutation of the KAL1 gene located on the Xp22.3 constitution and environmental influences. Well region encoding for the protein anosmin has been known is the familial nature of delayed puberty, detected. Anosmin is involved in the neuronal migration whereby mothers exhibit a late menarche and/or and axonal path finding. In the absence of anosmin, fathers always belong to the shortest adolescents during migration of the GnRH releasing, as well as of the their first years in high school, but reach a final height olfactory neurons, cannot be completed, resulting in within the normal range. Chronic systemic diseases hypogonadotropic hypogonadism and anosmia (11). such as Crohn’s disease and asthma are often associated The autosomal form of Kallmann syndrome is the result with delayed puberty. It appears that under these of a mutation of a gene encoding the fibroblastic growth circumstances the body does not expend energy on factor receptor 1 located on the short arm of chromo- growth, puberty, and fertility. Cure will result in the some 8 (12). For the autosomal recessive form, no catchup of growth and progression of the develop- genetic mutation has been identified yet. mental process. Downstream to the GnRH neurons, receptor abnorm- Delayed puberty is defined as the start of puberty at a alities may be responsible for partial to complete forms chronological age older than C2 S.D.ofaverage of hypogonadotropic hypogonadism. Inactivating maturers: from the Dutch data, for boys, when testicular mutations of the GnRH receptors result in the absent growth (testes volume 4 ml or more) has not started at to low pulsatile levels of gonadotropins in combination the age of 14 years, and for girls, when breast with low sex steroid levels. These patients show an development is not present at the age of 13 years or inadequate response to exogenous pulsatile GnRH. menarche did not occur at the age of 15 years. Throughout Europe, there are only slight differences (9). The NR0B1 gene is involved in the development and Hypogonadotropic hypogonadism can develop first due function of the adrenal gland, as well as the hypo- to a developmental abnormality or secondly due to an thalamic–pituitary axis related to gonadotropin underlying disease interfering with the function of the secretion. Mutations of the NR0B1 gene may present hypothalamic–pituitary axis such as a cerebral tumor with an X-linked congenital adrenal hypoplasia and (Table 1). Also, a pubertal arrest may result in lack of pubertal development in boys. With NR0B1 hypogonadotropic hypogonadism after some spontaneous gene mutation, heterozygous girls may have delayed puberty (13). GPR54 is described as a novel regulator of the central Table 1 Causes of hypogonadotropic hypogonadism. control of puberty. The GPR54 gene encodes for a Primary/congenital: G-protein-coupled receptor. Patients with mutations of Idiopathic the GPR54 gene have hypogonadotropic hypogonad- Mutations of LH b and FSH b-subunits ism, while they do respond to exogenous pulsatile GnRH Kallmann syndrome GnRH receptor gene mutations stimulation. In affected mice, GnRH levels at the NR0B1 gene mutation hypothalamic level are normal. Therefore, it appears GPR54 gene mutation that GPR54 is not involved in the production, but in the Transcription factor genes mutation: PROP1, LHX3, and HESX1, release of GnRH (14). in combination with other pituitary hormone deficiencies
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