Continued part 1, part 2 of ebook Clinical rounds in endocrinology (Volume II - Pediatric endocrinology) provide readers with content about: delayed puberty; turner syndrome; disorders of sex development; congenital adrenal hyperplasia; multiple endocrine neoplasia; diabetes in the young;... Please refer to the part 2 of ebook for details!
7 Delayed Puberty 7.1 Case Vignette A 19-year-old male presented with complaints of failure to develop secondary sexual characteristics He was born at term through normal vaginal delivery, and his developmental milestones were normal He was average in scholastic performance and studied up to tenth standard He had history of learning disabilities but no behavioral abnormalities He was tallest among his peers during late teenage He noticed appearance of pubic and axillary hair by 15 years of age, but failed to develop facial or body hair or increase in penile length or size of the testes There was no history of head trauma, surgery for midline defects, chronic systemic illness, testicular trauma, mumps, or drug abuse He had no history of abnormality in smell, visual deficits, headache, seizure disorder, or other neurological deficits There was no family history of delayed puberty, infertility, or gynecomastia He did not receive any medical treatment prior to visit to this hospital On examination, his height was 170 cm (height -1 SDS, height age 15 years, target height 173 cm), weight was 55 Kg (weight age 15 years), and blood pressure was 110/70 mmHg Anthropometry showed eunuchoidal proportions with upper segment/lower segment ratio (US: LS, 80:90 cm) 0.88 and arm span exceeding height by 10 cm There was no gynecomastia Tanner stage of pubertal development was A+, P2, and both testes were present within poorly developed scrotal sac and soft in consistency and measured 1 ml each The stretched penile length was 8 cm His sense of smell was normal He had genu valgum but no midline defects, synkinesia, nystagmus, ataxia, and visual deficits On investigations, complete blood count and liver and renal function tests were normal Hormonal profile revealed serum LH 0.29 mIU/ml (N 1.7–8.6), FSH 0.69 mIU/ml (N 1.5–12.4), testosterone 0.44 nmol/L (N 9.9–27.8), estradiol 12.3 pg/ml (N 7.6–42.6), prolactin 9.6 ng/ ml (N 4–15.2), T4 7.32 μg/dl (N 4.8–12.7), TSH 1.9 μIU/ml (N 0.27–4.2), and 0800h cortisol 447 nmol/L (N 171–536) His bone age was 15 years CEMRI sella and olfactory region did not display any abnormality LH response to triptorelin at 4h was 2.8 mIU/ml Serum testosterone at baseline was 0.45 nmol/L, and in response to hCG, it increased to 1.2 nmol/L (after 24h of last injection of hCG) Based on available © Springer India 2016 A Bhansali et al., Clinical Rounds in Endocrinology, DOI 10.1007/978-81-322-2815-8_7 211 212 7 Delayed Puberty clinical and biochemical profile, a diagnosis of congenital idiopathic hypogonadotropic hypogonadism (IHH) was considered, and he was initiated with testosterone enanthate 100 mg intramuscularly every fortnightly The doses of testosterone were increased gradually to 200 mg every fortnightly over a period of 2 years On testosterone therapy, he developed gynecomastia He is planned for gonadotropin therapy for induction of spermatogenesis after the attainment of virilization (Fig. 7.1) a b c Fig 7.1 (a) A 19-year-old male presented with delayed puberty (b) testicular volume of 1 ml with stretched penile length of 8 cm Patient is on testosterone therapy (c) T2W MR image shows normal olfactory bulb (white arrow) and sulci (red arrow) 7 Delayed Puberty 7.2 213 Stepwise Analysis The index case presented at the age of 19 years with delayed pubertal development Delayed puberty in boys is defined as lack of pubertal development by the age of 14 years which is in correspondence with 2.5 SD above the mean for the population The main differentials for the delayed pubertal development between the age of 14–18 years are constitutional delay in growth and puberty (CDGP) and hypogonadism However, the adolescents with CDGP enter into puberty by the age of 18 years; hence, the possibility of CDGP after this age is virtually excluded Our patient presented at the age of 19 years with poor development of secondary sexual characteristics; therefore, the diagnosis of hypogonadism as a cause of delayed puberty was considered Development of secondary sexual characteristics results from both adrenarche and gonadarche which may overlap or come in succession Though the first sign of puberty in boys is testicular enlargement (TV ≥ 4 ml), only in 1 % of boys’ pubarche precede the gonadarche On the contrary, in 20 % of girls, pubarche precedes the thelarche Patients with hypogonadism usually have normal onset of adrenarche, but pubarche is delayed as was seen in our patient who had appearance of pubic hair at the age of 15 years without evidence of gonadarche This is because the weaker adrenal androgens require conversion to potent androgens in functional testes for induction of pubarche The presence of anosmia, midline defects, synkinesia, eunuchoidal proportions, small soft testes, skeletal anomalies, and neurological deficits (nystagmus and ataxia) usually suggests the diagnosis of IHH. Further, the manifestations of IHH vary according to the age of presentation; infants present with micropenis and cryptorchidism, adolescents with delayed or arrested puberty and gynecomastia, and adults with infertility Long- leggedness, gynecomastia, small firm testes, learning disabilities/behavioral abnormalities, and some degree of virilization favor the diagnosis of Klinefelter’s syndrome which is considered as prototype of hypergonadotropic hypogonadism Our patient had eunuchoidal proportions, skeletal deformities (genu valgum), and small soft testes which support the diagnosis of hypogonadotropic hypogonadism Low LH and low testosterone below the reference range confirm the diagnosis of hypogonadotropic hypogonadism LH response to short-acting GnRH agonist (triptorelin) and testosterone response to hCG were prepubertal in our patient, further substantiate the diagnosis of hypogonadotropic hypogonadism However, these dynamic tests help in differentiating between CDGP and IHH and are not required if the patient is above the age of 18 years High LH, FSH, and low testosterone indicate hypergonadotropic hypogonadism and require further evaluation by karyotyping to establish the diagnosis of Klinefelter’s syndrome Hypogonadotropic hypogonadism can be due to hypothalamic or pituitary lesion or due to familial or sporadic genetic mutations The index patient was diagnosed to have isolated hypogonadotropic hypogonadism, as other pituitary hormone profile was normal and MR brain imaging was unremarkable Patients of IHH with anosmia or hyposmia are termed as Kallmann syndrome Defective migration of olfactory neurons from olfactory placode to bulb results in impaired development of olfactory bulb and consequent anosmia This is evident in MRI as olfactory bulb aplasia/hypoplasia and absent olfactory sulci Since our patient did not have hyposmia/anosmia, he was considered to have normosmic variant of IHH. The aims of 214 7 Delayed Puberty treatment in a patient with IHH include induction and maintenance of secondary sexual characteristics and to improve the fertility prospects For induction of secondary sexual characteristics, testosterone therapy is initiated with a low dose of testosterone esters (testosterone enanthate 50–100 mg) intramuscularly every month which is gradually built up to 200–250 mg every fortnightly over a period of 2–3 years Improvement in libido, mood, and quality of life is observed over a period of 3–6 months, whereas increase in body hair, muscle mass and strength, and deepening of voice take longer time over a period of 1–2 years Serum testosterone should be measured midway between the two injections after 3 months of initiation of treatment to assess the adequacy of therapy; however, it may also be required to measure serum testosterone just prior to the next injection to decide about the dosing interval The adverse effects associated with testosterone therapy include gynecomastia, aggressive behaviour, priapism, mood swings, acne, and androgenic alopecia hCG has also been tried for the induction of puberty which is associated with stable level of serum testosterone, minimal fluctuation in hypogonadal symptoms, and initiation of spermatogenesis; however, frequent injections and cost preclude its routine use in clinical practice In addition, limited data is available regarding the use of gonadotropins as a primary therapy in induction of secondary sexual characteristics The index patient was initiated with 100 mg testosterone every monthly for 3 months, and later the dose frequency was increased to fortnightly At 6 months of follow-up, his serum testosterone was 5 nmol/L and he had improvement in generalized well-being The dose was further increased to 150 mg fortnightly Gonadotropin therapy is indicated when fertility is desired hCG is initiated at a dose of 1,000–2,000 IU twice or thrice a week with monthly monitoring of serum testosterone to achieve and sustain testosterone in eugonadal range If the target is not achieved the doses can be increased up to 5,000 IU thrice a week Once the serum testosterone level is maintained >9 nmol/L, semen analysis should be performed at monthly interval If spermatogenesis is not initiated despite continuation of hCG for 6–12 months after achieving the serum testosterone in normal range, hMG should be added at a dose of 75 IU thrice weekly If the sperm count is still 5 years between thelarche and menarche in girls or >5 years between onset of testicular enlargement and complete genital development in boys) are also considered to have delayed puberty How were the age cutoffs for delayed puberty defined? The age of onset of puberty in a population is normally distributed (bell-shaped curve with a Gaussian distribution) In the studies by Tanner and Marshall, it was shown that the mean age of onset of puberty was 10.5 years in girls and 11.5 years in boys, with one standard deviation of approximately 1 year Considering the normal range of age of pubertal onset as mean ±2.5 SD, lack of any sign of pubertal development after the age of 13 years in girls or after 14 years in boys (+2.5 SD from the mean, i.e., 10.5 + 2.5 years in girls and 11.5 + 2.5 years in boys) suggests delayed puberty Why is pubarche not used to define the onset of normal puberty? Reactivation of hypothalamic–pituitary–gonadal (HPG) axis is manifested by thelarche in girls and testicular enlargement in boys, and these are considered as first signs of puberty Pubarche is a clinical manifestation of adrenarche and denotes the maturation of zona reticularis which is independent of reactivation of HPG-axis Therefore, pubarche is not used to define the onset of normal puberty What is kisspeptin? Kisspeptin is a neuropeptide secreted from the arcuate nucleus and anteroventral and periventricular (AVPV) nuclei of the hypothalamus The arcuate nucleus comprises of KNDy (pronounced as “candy”) neurons which co- secrete kisspeptin (K), neurokinin B (N), and dynorphin (Dy), whereas AVPV nuclei comprise of Kiss-1 neurons, which secretes only kisspeptin Both KNDy neurons and Kiss-1 neurons synapse with GnRH neurons Kisspeptin acts on its 216 7 Delayed Puberty receptor GPR-54, which is present on GnRH neurons in the hypothalamus Kisspeptin signaling is involved in initiation of puberty, regulation of gonadotropin secretion by sex steroids, and preovulatory LH surge (Fig. 7.2) AVPV ARC Kiss1 neuron KNDY neuron + Kiss 1R GnRH neuron + GnRH POA Kiss 1R Pituitary − AVPV - Anteroventral periventricular area DYN - Dynorphin KNDY - Kisspeptin Neurokinin B Dynorphin KOR - kopioid receptor NKB - Neurokinin B DYN KOR NK3R + GnRH neuron + KNDy neuron NKB Fig 7.2 “Kisspeptin-GnRH” axis How does kisspeptin regulate the onset of puberty? Kisspeptin is believed to be the “gateway to puberty.” Release of kisspeptin from KNDy neurons (arcuate nucleus) results in initiation of puberty The secretion of kisspeptin by KNDy neurons is modulated by neurokinin B and dynorphin, which has stimulatory and inhibitory effects on release of kisspeptin, respectively Further, the expression of kisspeptin is negatively regulated by MKRN3 gene product (makorin RING-finger protein 3) and polycomb group (a protein complex) Kisspeptin acts through its receptor GPR-54 present on GnRH neurons of the hypothalamus and results in activation of pulsatile GnRH secretion 7 Delayed Puberty 217 How does kisspeptin regulate the preovulatory LH surge? Kisspeptin is synthesized in both, arcuate nucleus (KNDy neurons) and AVPV nuclei (Kiss-1 neurons) However, kisspeptin from KNDy neurons is responsible for the initiation of puberty, whereas kisspeptin from Kiss-1 neurons is involved in preovulatory LH surge This effect is mediated by the stimulatory effect of estrogen at Kiss-1 neurons present in AVPV nuclei On the contrary, AVPV nuclei are devoid of Kiss-1 neurons in males What is the role of leptin in the initiation of puberty? It has been shown that a critical body weight/body fat is essential for the onset of puberty This is evidenced by the presence of delayed/absent puberty in girls with low body fat and early puberty in obese girls Adipose tissue s ignals to hypothalamus through the adipokine leptin, which stimulates KNDy neurons This results in the release of kisspeptin, which in turn activates HPGaxis The key role of leptin in the induction of puberty is evidenced by the occurrence of isolated hypogonadotropic hypogonadism in individuals with congenital leptin deficiency and initiation of puberty in these individuals with recombinant leptin therapy Despite these evidences, leptin is considered to have a permissive role, rather than a primary role as evidenced by timely onset of puberty in patients with congenital generalized lipodystrophy, who are deficient in leptin What is “mini-puberty”? Reactivation of Hypothalamic–pituitary–gonadal (HPG) axis during neonatal period occurs as a result of withdrawal of inhibitory effect of placental estrogen on HPG-axis and is termed as “mini-puberty.” It is characterized by postnatal surge of gonadotropins and sex steroids that initiate at approximately second week of life In boys, gonadotropins and testosterone peak at 3 months and decline by 6–9 months of age In girls, FSH and LH peak at 3 months; although LH levels decline by 6–9 months of age, FSH remains elevated for about 3–4 years of age Serum estradiol levels widely fluctuate during mini-puberty in girls, whereas serum testosterone is stable in boys The wide fluctuation in serum estradiol during mini-puberty is possibly due to cyclical maturation of ovarian follicles (Fig. 7.3) 218 7 Delayed Puberty LH a FSH Testosterone Birth Age (months) LH b FSH Estradiol Birth Age (months) Fig 7.3 (a) Gonadotropins and serum testosterone during mini-puberty in boys, (b) gonadotropins and serum estradiol during mini-puberty in girls What is the importance of mini-puberty? The physiological importance of mini-puberty is better described in boys The postnatal surge of gonadotropins and testosterone leads to growth and proliferation of Leydig cells, Sertoli cells, and germ cells, thereby resulting in increase in testicular volume (by approximately 1 ml) and penile size and also contributing to postnatal testicular descent Further, mini-puberty also helps in priming of pilosebaceous units and development of male psyche The role of minipuberty in girls remains elusive 7 Delayed Puberty 219 10 What are the disorders associated with absence of mini-puberty? Mini-puberty is absent in children with congenital hypogonadotropic hypogonadism and complete androgen insensitivity syndrome; however, it is present in children with partial androgen insensitivity syndrome This underscores the importance of androgens in priming of GnRH-gonadotropin axis for the onset of mini-puberty In addition, infants with CAH and androgen excess of any etiology (e.g., congenital adrenocortical carcinoma) may not experience mini- puberty because of suppression of gonadotropins by excess androgen 11 What are the gender dimorphisms acquired during peripubertal period? Negative feedback between most of the target glands and hypothalamic–pituitary axis is usually established by 2–3 years of age However, estrogen-mediated positive feedback for LH in girls is acquired only during peripubertal period and is responsible for initiation of ovulatory cycles Further, the gender difference in serum prolactin level, i.e., higher levels in women as compared to men, is also acquired during peripubertal period consequent to estrogen production 12 How to define hypogonadism? Hypogonadism refers to a clinical syndrome characterized by impaired gonadal function resulting in decreased gonadal steroidogenesis and/or gametogenesis However, in clinical practice, those with isolated germ cell dysfunction but with normal gonadal steroidogenesis are not considered as having hypogonadism Similarly, a well-feminized female with normal circulating levels of estradiol, but with chronic anovulation (e.g., polycystic ovarian disease), is not considered to have hypogonadism 13 How to classify hypogonadism? Hypogonadism is classified based on the site of primary defect in the hypothalamic–pituitary–gonadal (HPG) axis Disorders caused by abnormalities of hypothalamus and pituitary gland are termed as hypogonadotropic hypogonadism, whereas those with a primary defect at the level of gonads are termed as hypergonadotropic hypogonadism (primary gonadal failure) 14 What are the causes of delayed puberty? The most common cause of delayed puberty is CDGP, followed by hypogonadotropic hypogonadism and hypergonadotropic hypogonadism The prevalence of various causes of delayed puberty is summarized in the table given below Disorders CDGP Hypogonadotropic hypogonadism Functional Permanent Hypergonadotropic hypogonadism Boys 65 % Girls 30 % 20 % 10 % 5–10 % 20 % 20 % 25–30 % 220 7 Delayed Puberty The causes of functional hypogonadotropic hypogonadism include anorexia nervosa and chronic systemic illness like celiac disease, Crohn’s disease, nephrotic syndrome, and rheumatoid arthritis The causes of permanent hypogonadotropic hypogonadism include congenital isolated hypogonadotropic hypogonadism, congenital multiple pituitary hormone deficiency, and tumors/ cysts in sellar–suprasellar region Turner syndrome, Klinefelter syndrome, and post-chemotherapy/gonadal irradiation are the common causes of hypergonadotropic hypogonadism (Fig. 7.4) a b Fig 7.4 (a) An 18-year-old girl with poor development of secondary sexual characteristics due to hypogonadotropic hypogonadism, (b) Tanner breast stage B1 in the same patient ... DYN - Dynorphin KNDY - Kisspeptin Neurokinin B Dynorphin KOR - kopioid receptor NKB - Neurokinin B DYN KOR NK3R + GnRH neuron + KNDy neuron NKB Fig 7 .2? ?? “Kisspeptin-GnRH” axis How does kisspeptin... present in children with partial androgen insensitivity syndrome This underscores the importance of androgens in priming of GnRH-gonadotropin axis for the onset of mini-puberty In addition, infants... PCSK1 Therefore, inactivating mutations of these genes results in congenital isolated hypogonadotropic hypogonadism (normosmic) 22 What is anosmin? Anosmin is a 680-amino-acid protein which is coded