Management of Male Hypogonadotrophic Hypogonadism

Abstract

THE development of sexual maturity and reproductive function in the male is dependent upon appropriate secretion of hormones that orchestrate the sophisticated relationship between the hypothalamus, pituitary, and testes -the hypothalamic-pituitary-gonadal (HPG) axis. A state of hypogonadism, i.e. inadequate testicular function, is manifested by deficiencies in secretion of androgens, with a wide range of effects on a number of physiological processes, including gametogenesis. Any dysfunction in the HPG axis can result in hypogonadotrophic hypogonadism, where a decrease in endocrine and/or gametogenic function of the testes results in retardation of puberty and reproductive insufficiency [1].The hypothalamus is the centre of the reproductive axis. Messages received from the central nervous system and from the gonads are integrated by the hypothalamus to regulate the production and secretion of gonadotrophin releasing hormone (GnRH), which is released in a pulsatile manner that is essential for stimulating the production and release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. The anterior pituitary produces LH and FSH in response to pulses of GnRH stimulation, and in the male LH and FSH both bind to specific receptors on the Leydig and Sertoli cells within the testis. This stimulation regulates the release of androgens required for pubertal development, and subsequently for the initiation and maintenance of male reproductive function and spermatogenesis. Feedback mechanisms play an important role in maintaining the reproductive axis: testosterone inhibits LH secretion, and inhibin secreted by Sertoli cells regulates FSH secretion. A reduction in negative feedback results in an increased secretion of FSH, and, in a manner similar to that found in the female with diminished ovarian function, serum FSH levels in the male act as an indicator of germinal epithelial function in the testis [2,3].Episodic secretion of GnRH is an essential part of this process. The hypothalamic pituitary gonadal axis is first activated during the fetal/neonatal period, when an increase in testosterone stimulates completion of the inguinoscrotal phase of testicular descent and further growth of the penis. This is accompanied by a wave of Sertoli and germ cell proliferation in the testis. A second wave of increased HPG axis activity then occurs during the early stages of puberty, with a second wave of Sertoli cell proliferation. This wave of proliferation is followed by terminal differentiation, and Leydig cells begin to secrete testosterone, allowing the normal development of puberty [4].A disruption in any of these events, from fetal to adult life, can lead to hypogonadism, and this can be manifested in a wide variety of clinical symptoms, according to the time of onset and the severity of the resulting hormone deficiency. In many cases, the symptoms may not be recognised before puberty. Hypogonadism can be classified into three categories, which must be considered in establishing the diagnosis r...

Investigation of treatment for azoospermia due to male hypogonadotropic hypogonadism in Japan

“…Administration of rhFSH is essential for achieving spermatogenesis in the majority of men with MHH . Combination therapy with hCG and rhFSH is normally required to induce spermatogenesis in patients for whom the onset of MHH occurred before pubertal development, which is indicated by low initial testicular volume . In the present study, hCG + rhFSH combination therapy was the most effective treatment for all categories of MHH.…”

“…low initial testicular volume. 5 In the present study, hCG + rhFSH combination therapy was the most effective treatment for all categories of MHH. Furthermore, hCG + rhFSH was effective as a salvage therapy, inducing spermatogenesis in MHH patients who failed to respond to treatment with hCG alone or hCG + hMG.…”

Male Reproductive Endocrinology: When to Replace Gonadotropins

“…If the timing of HH onset is unclear, a testicular volume of less than 4 mL may help to identify that patient as most likely prepubertal. 41 As expected, an improved response to gonadotropin replacement using LH or hCG can be expected in men who develop hypogonadism postpubertal and who have greater testicular volume (>4 cm). Additional predictors for an adequate response include no history of cryptorchidism, no prior testosterone replacement, 42 prior gonadotropin or GnRH exposure, 43,44 larger baseline testicular volume (>4 mL) 42,[45][46][47] which may be a result of prior gonadotropin exposure, 48 a higher baseline LH/FSH levels, 49 advanced sexual maturity, and a lower BMI.…”

“…40 On the contrary, prepubertal HH will typically require both FSH and LH replacement. 41 After priming with both FSH and LH, ongoing spermatogenesis and testosterone production usually only requires LH replacement. If the timing of HH onset is unclear, a testicular volume of less than 4 mL may help to identify that patient as most likely prepubertal.…”

Approaches to testosterone supplementation in the young adult male

“…There is also a dose-dependent increase in hemoglobin levels. Testosterone therapy of healthy hypogonadal males is also known to increase bone mineral density [16].…”