Male hypogonadism: an extended classification based on a developmental, endocrine physiology‐based approach

Abstract

SUMMARYNormal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Mü llerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…72 In male individuals, INSL3 is secreted by Leydig cells during fetal and immediate postnatal life. 8,73 Testicular INSL3 secretion declines during childhood before increasing at the time of puberty and peaking during adulthood. 74 Early signs of puberty manifest around the age of 10 years in girls (breast development) and 11.5 years in boys (testicular enlargement and spermarche-appearance of spermatozoa in first morning void).…”

“…Furthermore, inhibin B, insulin-like 3 (INSL3), anti-Müllerian hormone (AMH) and kisspeptin have emerged as biomarkers for use in the diagnosis and treatment of CHH. 8,9 In addition, hormonal therapies are being personalized to maximize fertility outcomes. 10 Over the past few years, the traditional Mendelian view of CHH as a monogenic disorder has been revised following the identification of oligogenic forms of CHH, 11 which has altered the approach adopted for genetic testing and genetic counselling of patients with CHH.…”

Hormon anty-müllerowski i zespół policystycznych jajników

“…Poprzez aktywację receptora typu II (AMHR-II) powoduje regresję przewodów przyśródnerczowych. AMH odgrywa istotną rolę w procesie różnicowania jąder podczas życia płodowego i jego działanie utrzymuje się aż do okresu dojrzewania [6]. Sekrecja AMH u kobiet rozpoczyna się od 36. tygodnia ciąży i trwa aż do menopauzy.…”

“…Strong AMH expression is involved in testicular differentiation during foetal development up to puberty [6]. In the female foetus, the absence of AMH results in the development of the paramesonephric ducts into the oviduct, uterus, and the upper 2/3 of the vagina.…”

Obesity, a serious etiologic factor for male subfertility in modern society

“…In obese men, the hyperactivity of aromatase (cytochrome P450 enzyme) in redundant white adipose tissue causes excessive conversion of androgens into estrogens. Therefore, gonadotrophin secretion from the pituitary decreases through feedback inhibition on the hypothalamus and pituitary gland, and then further impacts on testosterone production through falls in gonadotrophin-releasing hormone (GnRH)-luteinizing hormone (LH)/FSH pulses (Mah & Wittert 2010, Michalakis et al 2013, Rey et al 2013. The disruption of the negative feedback loop of the hypothalamic pituitary gonadal (HPG) axis finally leads to the significant decline in testosterone production.…”