madman
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Congenital hypogonadotropic hypogonadism (CHH) is characterized by the complete or partial failure of pubertal development because of inadequate secretion of gonadotropic hormones. CHH consists of hypogonadotropic hypogonadism with anosmia or hyposmia, Kallmann syndrome, and the normosmic variation normosmic idiopathic hypogonadotropic hypogonadism. CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction have irreversibly diminished spermatogenic capacity. The approach to CHH treatment is determined by goals such as developing virilization or inducing fertility. This review focuses on the current knowledge of therapeutic modalities for inducing puberty and fertility in men with CHH.
Introduction
Puberty is one of the most significant changes in human development and is accompanied by the expression of secondary sexual characteristics, such as breast engorgement and testicular enlargement, achievement of adult height, and completion of fertilization ability.1) These pubertal changes can be attributed to the activation of the hypothalamic-pituitary-gonadal (HPG) axis. In the hypothalamus, gonadotropin-releasing hormone (GnRH) stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), eventually triggering testicular development in males as well as testosterone production and reproductive functions such as spermatogenesis.2)
Congenital hypogonadotropic hypogonadism (CHH) is characterized by the complete or partial failure of pubertal development due to inadequate secretion of LH and FSH. Hypogonadotropic hypogonadism includes (1) hypogonadal hypogonadism associated with abnormal olfactory neuronal migration (anosmia/hyposmia), called Kallmann syndrome (KS); (2) hypogonadotropic hypogonadism with normal olfactory function (normosmic isolated hypogonadotropic hypogonadism, nIHH); and (3) acquired hypogonadism.3)
CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction show irreversibly diminished spermatogenic capacity.4-6) The approach to CHH treatment is determined by goals such as developing only virilization or inducing fertility. In this review, we describe therapeutic options from different perspectives. To this end, we also reviewed the normal physiology of the reproductive axis.
Normal physiology of the reproductive axis
GnRH is a peptide consisting of 10 amino acids and is encoded by a gene located on chromosome 8.7) In the fetus, at 14 weeks of gestation, neurons containing GnRH exist in the hypothalamus, As the hypothalamus-pituitary portal system develops, GnRH in the hypothalamus reaches the gonadotroph in the pituitary gland. At 20 weeks of pregnancy, LH and FSH are secreted by the pituitary gland. Thereafter, secretion of gonadotropin increases by GnRH stimulation until the middle of pregnancy and then decreases until birth when LH and FSH are inhibited in the upper central nervous system. During labor, the concentration of gonadotropins is lower than that in the second trimester but is still relatively high.8) Even after birth, gonadotropins are secreted intermittently in large amounts, and the HPG axis remains active during the first 6 months of life, with increased secretion of gonadotropin approaching pubertal level. This so-called "mini-puberty" is a significant clue to the diagnosis of CHH among males exhibiting cryptorchidism with or without micropenis, as low serum testosterone, and LH levels can be used to identify congenital GnRH deficiency.9)
The HPG axis is reactivated at pubertal onset, with the reappearance of pulsatile GnRH release. In men, just before entering puberty, intermittent LH secretion occurs mainly during sleep; as puberty progresses, the frequency and amplitude of GnRH secretion increase, as does daytime secretion. This is due to the activation of kisspeptin signals, which direct GnRH neurons to control pulsatile GnRH release. This occurs via the elevation of LH and FSH levels through the pituitary, with downstream activation of sex steroids, including estrogen and testosterone.10) LH stimulates the maturation of interstitial Leydig cells, which secrete testosterone and insulin-like factor 3. When LH binds to the cell membrane receptor of Leydig cells, the level of cAMP increases through adenylate cyclase, which stimulates protein kinases to convert cholesterol to pregnenolone by P450scc, the first step in testosterone production.11) In addition to direct secretion from the testes, testosterone is produced in small amounts by the conversion of androstenedione secreted by the testes and adrenal glands. Secretion of testosterone induces and maintains spermatogenesis in Sertoli cells. In addition, FSH stimulates the proliferation of immature Sertoli cells, which are indispensable for the development of the seminiferous tubule, where spermatogenesis occurs. Seminiferous tubules account for approximately 90% of the testicular volume.12) Testicular volume is an important predictor of fertility in males with CHH.13) FSH-induced proliferation of immature Sertoli cells determines the final seminiferous tubule length. Therefore, both FSH and testosterone levels are essential for normal spermatogenesis.14)
Interestingly, Sertoli cells do not express androgen receptors during mini-puberty.9) Thus, despite the LH-induced high intratesticular testosterone level, Sertoli cells remain immature. As puberty progresses, testosterone production by Leydig cells increases and leads to the maturation of Sertoli cells and the onset of spermatogenesis.15) In particular, the level of testosterone secreted by Sertoli cells is much higher than that in the peripheral circulation, which is required for spermatogenesis. This has been demonstrated in studies of men with CHH, where FSH was shown to bind to LH-induced testosterone and stimulate spermatogenesis, but not FSH or exogenous testosterone.16)
Congenital hypogonadotropic hypogonadism
CHH is characterized by absent or incomplete sexual development and/or infertility due to GnRH deficiency. Unlike acquired diseases caused by damage to the pituitary gland and hypothalamus, which are characterized by deficiencies in multiple pituitary/hypothalamic hormones, CHH is characterized by isolated GnRH deficiency. GnRH deficiency is more common in boys than in girls and occurs in 1 in 4,000– 10,000 men.17)
Patients with CHH typically present with absent puberty in adolescence or early adulthood. Adolescent boys tend to have prepubertal testicular volumes less than 4 mL with undervirilization. The biochemical profile of CHH consists of low testosterone levels and inappropriately low or normal serum gonadotropin levels. In addition, CHH shows a spectrum of severities along with a number of associated phenotypes that appear at variable rates, including cleft palate, labia majora, renal malformation, nystagmus, and bimanual synkinesia (mirror movements).18)
Causes of congenital hypogonadotropic hypogonadism
Treatment of CHH
1. Infants
The focus of most treatments in affected boys with micropenis or cryptorchidism is appropriate testicular descent and penile growth. Cryptorchidism has a negative effect on future fertility potential.
2. Adolescence and adulthood
Delayed puberty is associated with significant psychosocial impairments, including low self-esteem, social withdrawal, low academic achievement, and higher rates of substance abuse disorders. Therefore, the treatment goals are to achieve virilization, normal sexual function, fertility, optimal adult height, and normal psychosocial development.
1) Induction of male secondary sexual characteristics
2) Induction of male fertility
3) Pulsatile GnRH treatment
4) hCG monotherapy
5) Combined gonadotrophin treatment
6) Sequential gonadotrophin treatment: FSH pretreatment followed by combined FSH and hCG therapy
Conclusion
CHH is a rare and treatable form of male infertility. Men with CHH usually have a poor prognosis because of severely early impaired fetal testicular development. Thus, treatment strategies throughout life are very important, and proper approaches can significantly improve the long-term quality of life. To date, no clear protocol has been established for the treatment of men with CHH. Further studies, including randomized controlled trials with large patients, are needed to establish treatment guidelines for males with CHH
Introduction
Puberty is one of the most significant changes in human development and is accompanied by the expression of secondary sexual characteristics, such as breast engorgement and testicular enlargement, achievement of adult height, and completion of fertilization ability.1) These pubertal changes can be attributed to the activation of the hypothalamic-pituitary-gonadal (HPG) axis. In the hypothalamus, gonadotropin-releasing hormone (GnRH) stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), eventually triggering testicular development in males as well as testosterone production and reproductive functions such as spermatogenesis.2)
Congenital hypogonadotropic hypogonadism (CHH) is characterized by the complete or partial failure of pubertal development due to inadequate secretion of LH and FSH. Hypogonadotropic hypogonadism includes (1) hypogonadal hypogonadism associated with abnormal olfactory neuronal migration (anosmia/hyposmia), called Kallmann syndrome (KS); (2) hypogonadotropic hypogonadism with normal olfactory function (normosmic isolated hypogonadotropic hypogonadism, nIHH); and (3) acquired hypogonadism.3)
CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction show irreversibly diminished spermatogenic capacity.4-6) The approach to CHH treatment is determined by goals such as developing only virilization or inducing fertility. In this review, we describe therapeutic options from different perspectives. To this end, we also reviewed the normal physiology of the reproductive axis.
Normal physiology of the reproductive axis
GnRH is a peptide consisting of 10 amino acids and is encoded by a gene located on chromosome 8.7) In the fetus, at 14 weeks of gestation, neurons containing GnRH exist in the hypothalamus, As the hypothalamus-pituitary portal system develops, GnRH in the hypothalamus reaches the gonadotroph in the pituitary gland. At 20 weeks of pregnancy, LH and FSH are secreted by the pituitary gland. Thereafter, secretion of gonadotropin increases by GnRH stimulation until the middle of pregnancy and then decreases until birth when LH and FSH are inhibited in the upper central nervous system. During labor, the concentration of gonadotropins is lower than that in the second trimester but is still relatively high.8) Even after birth, gonadotropins are secreted intermittently in large amounts, and the HPG axis remains active during the first 6 months of life, with increased secretion of gonadotropin approaching pubertal level. This so-called "mini-puberty" is a significant clue to the diagnosis of CHH among males exhibiting cryptorchidism with or without micropenis, as low serum testosterone, and LH levels can be used to identify congenital GnRH deficiency.9)
The HPG axis is reactivated at pubertal onset, with the reappearance of pulsatile GnRH release. In men, just before entering puberty, intermittent LH secretion occurs mainly during sleep; as puberty progresses, the frequency and amplitude of GnRH secretion increase, as does daytime secretion. This is due to the activation of kisspeptin signals, which direct GnRH neurons to control pulsatile GnRH release. This occurs via the elevation of LH and FSH levels through the pituitary, with downstream activation of sex steroids, including estrogen and testosterone.10) LH stimulates the maturation of interstitial Leydig cells, which secrete testosterone and insulin-like factor 3. When LH binds to the cell membrane receptor of Leydig cells, the level of cAMP increases through adenylate cyclase, which stimulates protein kinases to convert cholesterol to pregnenolone by P450scc, the first step in testosterone production.11) In addition to direct secretion from the testes, testosterone is produced in small amounts by the conversion of androstenedione secreted by the testes and adrenal glands. Secretion of testosterone induces and maintains spermatogenesis in Sertoli cells. In addition, FSH stimulates the proliferation of immature Sertoli cells, which are indispensable for the development of the seminiferous tubule, where spermatogenesis occurs. Seminiferous tubules account for approximately 90% of the testicular volume.12) Testicular volume is an important predictor of fertility in males with CHH.13) FSH-induced proliferation of immature Sertoli cells determines the final seminiferous tubule length. Therefore, both FSH and testosterone levels are essential for normal spermatogenesis.14)
Interestingly, Sertoli cells do not express androgen receptors during mini-puberty.9) Thus, despite the LH-induced high intratesticular testosterone level, Sertoli cells remain immature. As puberty progresses, testosterone production by Leydig cells increases and leads to the maturation of Sertoli cells and the onset of spermatogenesis.15) In particular, the level of testosterone secreted by Sertoli cells is much higher than that in the peripheral circulation, which is required for spermatogenesis. This has been demonstrated in studies of men with CHH, where FSH was shown to bind to LH-induced testosterone and stimulate spermatogenesis, but not FSH or exogenous testosterone.16)
Congenital hypogonadotropic hypogonadism
CHH is characterized by absent or incomplete sexual development and/or infertility due to GnRH deficiency. Unlike acquired diseases caused by damage to the pituitary gland and hypothalamus, which are characterized by deficiencies in multiple pituitary/hypothalamic hormones, CHH is characterized by isolated GnRH deficiency. GnRH deficiency is more common in boys than in girls and occurs in 1 in 4,000– 10,000 men.17)
Patients with CHH typically present with absent puberty in adolescence or early adulthood. Adolescent boys tend to have prepubertal testicular volumes less than 4 mL with undervirilization. The biochemical profile of CHH consists of low testosterone levels and inappropriately low or normal serum gonadotropin levels. In addition, CHH shows a spectrum of severities along with a number of associated phenotypes that appear at variable rates, including cleft palate, labia majora, renal malformation, nystagmus, and bimanual synkinesia (mirror movements).18)
Causes of congenital hypogonadotropic hypogonadism
Treatment of CHH
1. Infants
The focus of most treatments in affected boys with micropenis or cryptorchidism is appropriate testicular descent and penile growth. Cryptorchidism has a negative effect on future fertility potential.
2. Adolescence and adulthood
Delayed puberty is associated with significant psychosocial impairments, including low self-esteem, social withdrawal, low academic achievement, and higher rates of substance abuse disorders. Therefore, the treatment goals are to achieve virilization, normal sexual function, fertility, optimal adult height, and normal psychosocial development.
1) Induction of male secondary sexual characteristics
2) Induction of male fertility
3) Pulsatile GnRH treatment
4) hCG monotherapy
5) Combined gonadotrophin treatment
6) Sequential gonadotrophin treatment: FSH pretreatment followed by combined FSH and hCG therapy
Conclusion
CHH is a rare and treatable form of male infertility. Men with CHH usually have a poor prognosis because of severely early impaired fetal testicular development. Thus, treatment strategies throughout life are very important, and proper approaches can significantly improve the long-term quality of life. To date, no clear protocol has been established for the treatment of men with CHH. Further studies, including randomized controlled trials with large patients, are needed to establish treatment guidelines for males with CHH
