AMH and INSL3 in testicular and extragonadal pathophysiology: what do we know?

Abstract

Background: It is commonly accepted that testicular function is prevalently regulated by the hypothalamic-pituitary-gonadal axis: The pulsatile secretion of GnRH by the hypothalamus induces pituitary expression of the two gonadotropins FSH and LH, which then stimulate Sertoli and Leydig cells, respectively, therefore regulating steroidogenesis and spermatogenesis. However, a growing body of evidence has recently suggested that other hormones act on the reproductive tract since the early phases of fetal development. Anti-M€ ullerian hormone and INSL3 are still largely used only for research purposes despite being increasingly recognized as markers of Sertoli and Leydig cells function, respectively. Objectives: Provide an up-to-date review of the role of anti-M€ ullerian hormone and INSL3 in human pathophysiology according to current evidence. Materials and Methods: A thorough literature review was performed on PubMed, OVID MEDLINE/EMBASE and Google Scholar for papers concerning anti-M€ ullerian hormone and INSL3 in human males. Results: INSL3 is not acutely regulated by the hypothalamic-pituitary axis but is constitutively secreted by Leydig cells, therefore representing a valid marker for their number and status. Anti-M€ ullerian hormone expression, on the other hand, is downregulated by androgens, therefore occurring mostly at the early stages of testicular differentiation and before the onset of puberty. Several conditions affecting testicular development, such as male hypogonadotropic hypogonadism, and their treatment have been associated to specific pattern of INSL3 and anti-M€ ullerian hormone expression, proving a role for both hormones in the diagnostic and therapeutic management. Recent reports suggest a role for both anti-M€ ullerian hormone and INSL3 in extra gonadal physiology, such as cardiovascular and bone health. Conclusion: Anti-M€ ullerian hormone and INSL3 are markers of Sertoli and Leydig cells maturation, respectively, usually involved in the pathogenesis of disorders of sexual differentiation. However, their role in testicular pathology has only been hinted at in the last decades. Recent evidence supports an involvement of both anti-M€ ullerian hormone and INSL3 in extragonadal pathophysiology as well.

Immunohistochemical characterization of the anti-Müllerian hormone receptor type 2 (AMHR-2) in human testes

“…Despite almost nonmeasurable serum levels, intratubular concentrations of AMH are far greater [7,24]. Several studies have reported a progressive decrease of AMH levels during aging [25][26][27], suggesting a progressive decline in Sertoli cell function, which is also fitting with current hypothesis on the negative effects of aging on the male reproductive system [28,29]. As previously mentioned, several authors have investigated the possibility of AMH measurement as a prognostic tool for successful sperm retrieval with testicular sperm extraction techniques (TESE or microTESE): a meta-analysis study conducted by Toulis et al [10] concluded that while the diagnostic value of AMH is not supported, the evidence in these regards is extremely limited.…”

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

“…During the course of treatment, serum AMH level decreased in both groups, suggesting that both exogenous low-dose T and an increase in endogenous T levels are sufficient to down-regulate AMH secretion in early puberty. As AMH expression is considered to reflect maturation status of Sertoli cells (Sansone et al, 2019), our finding argues against unduly rapid maturation of Sertoli cell population in Lz-treated boys exposed to elevated gonadotrophin levels. Considering that Sertoli cell maturation is intimately related to their replicative capacity, our finding indirectly argues against untoward effect of Lz on future sperm producing capacity.…”

Serum concentrations of dihydrotestosterone are associated with symptoms of hypogonadism in biochemically eugonadal men

“…These symptoms can also be associated with other endocrine parameters: erectile disorders might actually be the clinical manifestations of several conditions affecting other glands or be the result of cardiovascular impairment or damage of nerves as seen in, e.g., type 2 diabetes mellitus [47]. Also muscle weakness has been associated with an impairment in another byproduct of Leydig cells, INSL3 [48,49], as well as with thyroid [50] and adrenal [51] disorders. Several endocrine pathways have been explored in these regards in the EMAS Study, suggesting a complex interplay between the psychological aspects of male sexual behavior, mostly regulated by E2, and the sexual functioning under more direct control from T [52].…”