Spermatogenesis in fish.

Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole-exome analysis has proved to be a highly successful diagnostic tool in familial cases of male infertility. Despite such efforts, the aetiology of infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole-genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic male infertility.

Genetics of male infertility.

The serum level of anti-Mullerian hormone (AMH), a product from granulosa cells involved in follicle growth, has been shown to correlate tightly with the small antral follicle number (FN) at ultrasonography (U/S) in women who do not have polycystic ovary syndrome (PCOS). Because PCOS is associated with a 2- to 3-fold increase in growing FN, we investigated whether an increased AMH serum level correlates to other hormonal and/or U/S features of PCOS. Serum AMH has been assayed in 104 women (59 symptomatic PCOS, 45 controls) between d 2 and 7 after the last either spontaneous or progestin-induced (in PCOS) menstrual period. Mean serum AMH level was markedly increased in the PCOS group (47.1 ± 22.9 vs. 20.8 ± 11.6 pmol/liter in controls; P < 0.0001), an increase in the same order of magnitude as the one of the FN in the 2- to 5-mm range at U/S (12.8 ± 8.3 vs. 4.8 ± 1.9; P < 0.0001, respectively). The ratio AMH/FN was similar between the two groups (4.8 ± 3.4 vs. 4.8 ± 2.9; P = 0.55). By simple regression, bo...

/pdf/elevated-serum-level-of-anti-mullerian-hormone-in-patients-1pnk831gh4.pdf

Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest.

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

/pdf/androgen-excess-fetal-programming-of-female-reproduction-a-mqye2c2d9j.pdf

Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

Gonadal sex determination in vertebrates generally follows a sequence of genetically programmed events. In what is seemingly becoming a pattern, all confirmed or current candidate “master” sex-determining genes reported in this group, e.g., SRY in eutherian mammals, DMY/dmrt1bY in medaka, DM-W in the African clawed frog, and DMRT1 in chicken encode transcription factors. In contrast, here we show that a male-specific, duplicated copy of the anti-Mullerian hormone (amh) is implicated in testicular development of the teleost fish Patagonian pejerrey (Odontesthes hatcheri). The gene, termed amhy because it is found in a single metacentric/submetacentric chromosome of XY individuals, is expressed much earlier than the autosomal amh (6 d after fertilization vs. 12 wk after fertilization) and is localized to presumptive Sertoli cells of XY males during testicular differentiation. Moreover, amhy knockdown in XY embryos resulted in the up-regulation of foxl2 and cyp19a1a mRNAs and the development of ovaries. These results are evidence of a functional amh duplication in vertebrates and suggest that amhy may be the master sex-determining gene in this species. If confirmed, this would be a unique instance of a hormone-related gene, a member of the TGF-β superfamily, in such a role.

https://www.pnas.org/content/pnas/109/8/2955.full.pdf

A Y-linked anti-Müllerian hormone duplication takes over a critical role in sex determination

AMH/MIS: what we know already about the gene, the protein and its regulation

Anti-Mullerian hormone (AMH) production by testicular Sertoli cells is high before puberty and can be further induced by FSH. Our objective was to delineate the mechanisms by which FSH stimulates AMH production. Assay of serum AMH levels and histological morphometric analysis in prepubertal FSH-deficient transgenic mice showed that serum AMH and testicular mass were decreased owing to reduced Sertoli cell number. All parameters resumed normal values in mice treated with recombinant FSH. We also analyzed the ability of FSH and the factors involved in its signaling pathway to activate AMH transcription by transfecting AMH promoter-luc reporter constructs of different lengths in a prepubertal Sertoli cell line. Our results showed that FSH activates AMH transcription via adenylate cyclase, cAMP, and protein kinase A but involving a nonclassical cAMP-response pathway requiring nuclear factor-κB and activating protein 2 binding sites, which lie more than 1.9 kb upstream of the AMH transcription start site. This...

/pdf/follicle-stimulating-hormone-increases-testicular-anti-4fs1zgs7b8.pdf

Follicle-Stimulating Hormone Increases Testicular Anti-Müllerian Hormone (AMH) Production through Sertoli Cell Proliferation and a Nonclassical Cyclic Adenosine 5′-Monophosphate-Mediated Activation of the AMH Gene

Anti-Mullerian hormone (AMH) is best known for its role as an inhibitor of the development of female internal genitalia primordia during fetal life. In the testis, AMH is highly expressed by Sertoli cells of the testis from early fetal life to puberty, when it is downregulated by the action of testosterone, acting through the androgen receptor, and meiotic spermatocytes, probably acting through TNFalpha. Basal expression of AMH is induced by SOX9; GATA4, SF1, and WT1 enhance SOX9-activated expression. When the hypothalamic-pituitary axis is active and the negative effect of androgens and germ cells is absent, for example, in the fetal and neonatal periods or in disorders like androgen insensitivity, FSH upregulates AMH expression through a nonclassical cAMP-PKA pathway involving transcription factors AP2 and NFkappaB. The maintenance and hormonal regulation of AMH expression in late fetal and postnatal life requires distal AMH promoter sequences. In the ovary, granulosa cells express AMH from late fetal life at low levels; DAX1 and FOG2 seem to be responsible for negatively modulating AMH expression. Particular features are observed in AMH expression in nonmammalian species. In birds, AMH is expressed both in the male and female fetal gonads, and, like in reptiles, its expression is not preceded by that of SOX9.

Subcellular and molecular mechanisms regulating anti-Müllerian hormone gene expression in mammalian and nonmammalian species.

In Sertoli cells, anti-Mullerian hormone (AMH) expression is upregulated by FSH via cyclic AMP (cAMP), although no classical cAMP response elements exist in the AMH promoter. The response to cAMP i...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00187.2011

SOX9 and SF1 are involved in cyclic AMP-mediated upregulation of anti-Mullerian gene expression in the testicular prepubertal Sertoli cell line SMAT1

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AMH/MIS: what we know already about the gene, the protein and its regulation

Follicle-Stimulating Hormone Increases Testicular Anti-Müllerian Hormone (AMH) Production through Sertoli Cell Proliferation and a Nonclassical Cyclic Adenosine 5′-Monophosphate-Mediated Activation of the AMH Gene

Subcellular and molecular mechanisms regulating anti-Müllerian hormone gene expression in mammalian and nonmammalian species.

SOX9 and SF1 are involved in cyclic AMP-mediated upregulation of anti-Mullerian gene expression in the testicular prepubertal Sertoli cell line SMAT1