Endocrine, Paracrine and Cellular Regulation of Postnatal Anti-Müllerian Hormone Secretion by Sertoli Cells

doi:10.1016/S1043-2760(98)00069-1

Trends in Endocrinology & Metabolism

Volume 9, Issue 7, 1 September 1998, Pages 271-276

https://doi.org/10.1016/S1043-2760(98)00069-1 Get rights and content

Abstract

Anti-Müllerian hormone (AMH) is produced by Sertoli cells from early foetal life to puberty, when it is downregulated by the synergistic action of intratesticular testosterone and meiotic germ cells. During foetal and neonatal life, testosterone is incapable of inhibiting AMH, owing to the lack of androgen receptor expression in Sertoli cells. In the absence of an androgen inhibitory effect, follicle-stimulating hormone increases testicular AMH output.

Section snippets

Ontogeny of Testicular AMH Production After Birth

Production of AMH by the postnatal testis shows a similar ontogeny in all mammalian species studied to date, including humans (Baker et al., 1990, Hudson et al., 1990, Josso et al., 1990, Lee et al., 1996), monkeys (Lee et al., 1994), rats (Kuroda et al., 1990, Hirobe et al., 1992), mice (Münsterberg and Lovell-Badge, 1991, Al-Attar et al., 1997), cattle (Tran and Josso, 1982) and pigs (Tran et al., 1981). Prepubertal Sertoli cells secrete high amounts of AMH; during pubertal development, a

The AMH Gene

AMH is encoded by a 2.75-kb gene (Cate et al., 1986) located on chromosome 19 in humans (Cohen-Haguenauer et al., 1987). Sequences upstream to the coding region have been cloned in humans (Guerrier et al., 1990), mice (Dresser et al., 1995), rats (Haqq et al., 1992) and cattle (Cate et al., 1986). A housekeeping gene termed SAP62, encoding a spliceosome protein, has been localized to the 5′-flanking region of the AMH gene which, therefore, seems to have an open chromatin conformation in all

AMH Regulation by Androgens

During the onset of male puberty in humans, serum AMH and testosterone levels show a significant negative correlation: serum AMH decreases progressively as testosterone levels rise, irrespective of the levels of serum gonadotropins. In fact, serum AMH is low when testosterone levels are higher than 7 nmol l⁻¹ (∼2 ng ml⁻¹) in normal boys but also those suffering from either central precocious puberty, a disorder usually caused by tumours of the central nervous system that trigger the activation of

Regulation of Testicular AMH Secretion by Germ Cells

AMH expression is extinguished in Sertoli cells at the age that testicular spermatogenesis enters the meiotic phase (Münsterberg and Lovell-Badge, 1991, Hirobe et al., 1992). Furthermore, the decrease of AMH production shows a clear-cut topographical disposition in the pubertal testis: while tubules that have already entered meiosis no longer express AMH, neighbouring premeiotic tubules still synthesize the hormone (Fig. 5). Hence, during pubertal development, the progressive fall of serum AMH

Concluding Remarks

During postnatal life, androgens, FSH and meiotic entry are clearly implicated in the regulation of AMH expression. Intratesticular testosterone, acting as a paracrine factor via the androgen receptor present in Sertoli cells, is the most potent inhibitor of AMH during puberty, although a synergistic effect of meiotic germ cells is necessary to abolish AMH expression completely. In the foetus and neonate, high levels of intratesticular testosterone are not capable of downregulating AMH because

Acknowledgements

I would like to thank Dr N. Josso for constructive remarks on the manuscript, and for permanent encouragement and support, and L. Al-Attar and K. Noël who have been active participants in the research work carried out in our group. I am also indebted to Drs M.G. Forest and P. Burgoyne for their enriching collaboration.

References (47)

RR Behringer et al.
Müllerian-inhibiting substance function during mammalian sexual development
Cell
(1994)
RL Cate et al.
Isolation of the bovine and human genes for müllerian inhibiting substance and expression of the human gene in animal cells
Cell
(1986)
M Dutertre et al.
A mouse Sertoli cell line expressing anti-Müllerian hormone and its type II receptor
Mol Cell Endocrinol
(1997)
MD Griswold et al.
Stimulation by FSH of DNA synthesis and of mitosis in cultured Sertoli cells prepared from testes of immature rats
Mol Cell Endocrinol
(1977)
C Haqq et al.
Isolation of the rat gene for Müllerian inhibiting substance
Genomics
(1992)
WH Shen et al.
Nuclear receptor steroidogenic factor 1 regulates the mullerian inhibiting substance gene: a link to the sex determination cascade
Cell
(1994)
L Al-Attar et al.
Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse
J Clin Invest
(1997)
WM Baarends et al.
A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the Müllerian duct
Development
(1994)
ML Baker et al.
Serum levels of Müllerian inhibiting substance in boys from birth to 18 years, as determined by enzyme immunoassay
J Clin Endocrinol Metab
(1990)
RR Behringer et al.
Abnormal sexual development in transgenic mice chronically expressing Müllerian inhibiting substance
Nature
(1990)

F Bidlingmaier et al.

Testosterone and androstenedione concentrations in human testis and epididymis during the first two years of life

J Clin Endocrinol Metab

(1983)

E Borrelli et al.

Signal transduction and gene control: the cAMP pathway

Crit Rev Oncogene

(1992)

BM Cattanach et al.

Male, female and intersex development in mice of identical chromosome constitution

Nature

(1982)

O Cohen-Haguenauer et al.

Mapping of the gene for anti-Müllerian hormone to the short arm of human chromosome 19

Cytogenet Cell Genet

(1987)

N di Clemente et al.

Cloning, expression and alternative splicing of the receptor for anti-Müllerian hormone

Mol Endocrinol

(1994)

DW Dresser et al.

The genes for a spliceosome protein (SAP62) and the anti-Mullerian hormone (AMH) are contiguous

Hum Mol Genet

(1995)

PN Goodfellow et al.

SRY and sex determination in mammals

Annu Rev Genet

(1993)

D Guerrier et al.

Expression of the gene for anti-Müllerian hormone

J Reprod Fertil

(1990)

CM Haqq et al.

Molecular basis of mammalian sexual determination: Activation of mullerian inhibiting substance gene expression by SRY

Science

(1994)

O Hatano et al.

Sex-dependent expression of a transcription factor, Ad4B. P, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development

Development

(1994)

S Hirobe et al.

Mullerian inhibiting substance messenger ribonucleic acid expression in granulosa and Sertoli cells coincides with their mitotic activities

Endocrinology

(1992)

PL Hudson et al.

An immunoassay to detect human Müllerian inhibiting substance in males and females during normal development

J Clin Endocrinol Metab

(1990)

S Imbeaud et al.

Insensitivity to anti-Müllerian hormone due to a spontaneous mutation in the human anti-Müllerian hormone receptor

Nat Genet

(1995)

Cited by (48)

Half-life of serum anti-Müllerian hormone and changes after gonadectomy in adult female and male dogs with normal and abnormal gonads
2024, Theriogenology
Anti-Müllerian hormone (AMH) is a biomarker for the presence of gonadal tissue. Changes in serum AMH after gonadectomy are not well established, and its serum half-life is unknown in dogs. We measured serum AMH with a validated electro-chemiluminescent immunoassay in adult female (n = 12) and male (n = 7) dogs with normal gonads, as well as in dogs with gonadal pathology (ovarian remnant syndrome, ORS n = 3, testicular tumor [Leydig cell, Sertoli cell, seminoma] n = 3, unilateral abdominal cryptorchid n = 4) on the day of gonadectomy (D0), and on D3, D7, D14 (females and males), and D21, D28 (males only). Males had higher AMH concentrations than females independent of gonadal status (P < 0.001). Dogs with ORS had lower initial AMH (0.45 ± 0.43 ng/ml) than bitches with normal gonads (1.16 ± 0.44 ng/ml; P = 0.027). Cryptorchid dogs had higher initial concentrations (80.57 ± 52.81 ng/ml) than males with normal gonads (7.92 ± 2.45 ng/ml; P = 0.004), and those with testicular tumors (18.63 ± 5.04 ng/ml) were intermediate (P ≥ 0.250). AMH decreased over time (P ≤ 0.012) and was 0.01–0.04 ng/ml by D14 in females and 0.02–0.12 ng/ml by D28 in males. Serum half-life in the whole study population was 2.85 ± 0.51 days and did not differ between groups. In conclusion, serum AMH can differentiate between intact and gonadectomized status of adult dogs by 14 days after ovario(hyster)ectomy in females and by 28 days after surgical castration in males.
Anti-Müllerian hormone, testosterone, and insulin-like peptide 3 as biomarkers of Sertoli and Leydig cell function during deslorelin-induced testicular downregulation in the dog
2021, Theriogenology
Citation Excerpt :
In fetal and early postnatal life, AMH expression is initially triggered independent of gonadotropins and then stimulated by FSH [24–26]. Following a gonadotropin-independent prepubertal period characterized by high AMH concentrations, AMH expression decreases during puberty as a result of increased androgen receptor (AR) expression of maturing Sertoli cells and inhibition by androgens, which override the FSH-dependent stimulation [26–30]. Furthermore, AMH expression is also modulated by the presence of maturing germ cells [24].
The role of anti-Müllerian hormone (AMH) and insulin-like peptide 3 (INSL3) in male infertility is not fully understood. We used the downregulated testis as a model of gonadotropin-dependent infertility. Serum testosterone and AMH concentrations were studied in five adult male Beagles implanted (day 0) with 4.7 mg deslorelin (Suprelorin®, Virbac) (DES group). Testicular expression of LH receptor (LHR) and androgen receptor (AR), AMH, type 2 AMH receptor (AMHR2), INSL3 and its receptor (RXFP2) was evaluated 112 days (16 weeks) after deslorelin treatment by qPCR and immunohistochemistry, and compared to untreated adult (CON, n = 6) and prepubertal (PRE, n = 8) dogs. Serum testosterone concentration decreased significantly by the onset of aspermia on study day 14 (four dogs) or day 21 (one dog), and was baseline on day 105 (week 15). In contrast, serum AMH started to increase only after the onset of aspermia and reached the maximum detectable concentration of the assay by day 49-105 in individual dogs. Testicular LHR gene expression in DES was lower than in CON and PRE (P < 0.0001), while AR gene expression in DES was similar to CON and significantly higher than PRE (P < 0.0001). Testicular AMH expression in DES was intermediate compared to the lowest mRNA levels found in CON and the highest in PRE (P ≤ 0.006). AMHR2 gene expression was similar between groups. AMH protein was detected in Sertoli cells only, while AMHR2 immunoreactivity was principally detected in Leydig cells which appeared to be increased in DES. INSL3 and RXFP2 gene expression was significantly downregulated in the DES testis along with noticeably weak Leydig cell immunosignals compared to CON. In conclusion, deslorelin treatment caused testicular LH insensitivity without affecting androgen sensitivity, and de-differentiation of Sertoli and Leydig cells. In DES, upregulation of the AMH-AMHR2 feed-back loop and downregulation of the INSL3-RXFP2 feed-forward loop are paracrine-autocrine mechanisms that may additionally regulate testosterone production independent of gonadotropins. Our results support AMH and INSL3 as unique biomarkers and paracrine-autocrine regulators of testis function involved in the intimate interplay between Sertoli and Leydig cells.
Efficient breathing at neonatal ages: A sex and Epo-dependent issue
2017, Respiratory Physiology and Neurobiology
Citation Excerpt :
In mice, the pattern of perinatal sexual steroids is similar, with testosterone surges occurring at gestational days 9 and between 14–18 days, with a peak at gestational day 17 (Barkley et al., 1979; Barkley and Goldman, 1977). At birth, there is a brisk increase in plasma testosterone that peaks one hour after birth (Corbier et al., 1992), and the last surge appears to be at approximately postnatal day 9, although this period has been less well documented (Rey, 1998). The increase in serum testosterone is clearly of testicular origin because it is not seen in females or males that are castrated at birth (Corbier et al., 1992).
During postnatal life, the respiratory control system undergoes intense development and is highly responsive to stimuli emerging from the environment. In fact, interruption of breathing prevents gas exchange and results in systemic hypoxia that, if prolonged, can lead to cardio-respiratory failure or sudden infant death. Moreover, in newborns and infants, respiratory disorders related to neural control dysfunction show significant sexual dimorphism with a higher prevalence in males. To this day, the therapeutic tools available to alleviate these respiratory disorders remain limited. Furthermore, the factors explaining the sexual dimorphism in newborns and during infancy remain unknown. Erythropoietin (Epo) was originally discovered as a cytokine able to increase the production of red blood cells upon conditions of reduced oxygen availability. We now know that Epo is a cytokine also secreted by neurons and astrocytes that protects the brain during trauma or hypoxic stress in a sex dependent manner. In this novel line of research, our previous studies demonstrated at adult ages that cerebral Epo acts as a respiratory stimulant in rodents and humans. These results provided a strong rationale for exploring the role of cerebral Epo in neuronal respiratory control during postnatal development. The objective of this review is to summarize our recent findings showing that cerebral Epo is a potent sex-specific respiratory stimulant at neonatal ages. Keeping in mind that Epo is routinely and safely administrated in newborn humans for anemia and neonatal asphyxia, we predict that our research provides the basis necessary to promote the clinical use of Epo against neonatal respiratory disorders related to neural control dysfunction.
Puberty arises with testicular alterations and defective AMH expression in rams prenatally exposed to testosterone
2017, Domestic Animal Endocrinology
Citation Excerpt :
AMH is a cytokine produced by the Sertoli cells that reflects the degree of maturity and functioning of the testis during prepubertal stages. Elevated levels of AMH predicts a still immature testis or a delay in growth and puberty [7], reflecting specifically Sertoli cell dysfunction [8,9]. The follicle-stimulating hormone (FSH) and testosterone play key roles in regulating AMH levels and hence, in the differentiation and function of Sertoli and germ cells.
The male gonadal tissue can be a sensitive target to the reprogramming effects of testosterone (T) during prenatal development. We have demonstrated that male lambs born to dams receiving T during pregnancy—a model system to the polycystic ovary syndrome (PCOS)—show a decreased number of germ cells early in life, and when adult, a reduced amount of sperm and ejaculate volume. These findings are a key to put attention to the male offspring of women bearing PCOS, as they are exposed to increased levels of androgen during pregnancy which can reprogram their reproductive outcome. A possible origin of these defects can be a disruption in the expression of the anti-Müllerian hormone (AMH), due to its critical role in gonadal function at many postnatal stages. Therefore, we addressed the impact of prenatal T excess on the expression of AMH and factors related to its expression like AP2, SOX9, FSHR, and AR in the testicular tissue through real-time PCR during the peripubertal age. We also analyzed the testicular morphology and quantified the number of Sertoli cells and germ cells to evaluate any further defect in the testicle. Experiments were performed in rams at 24 wk of age, hence, prior puberty. The experimental animals (T-males) consisted of rams born to mothers receiving 30 mg testosterone twice a wk from Day 30 to 90 of pregnancy and then increased to 40 mg until Day 120 of pregnancy. The control males (C-males) were born to mothers receiving the vehicle of the hormone. We found a significant increase in the expression of the mRNA of AMH and SOX9, but not of the AP2, FHSR nor AR, in the T-males. Moreover, T-males showed a dramatic decrease in the number of germ cells, together with a decrease in the weight of their testicles. The findings of the present study show that before puberty, T-males are manifesting clear signs of disruption in the gonadal functions probably due to an alteration in the expression pattern of the AMH gene. The precise way by which T reprograms the expression of AMH gene remains to be established.
Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: A randomized, controlled trial
2013, Fertility and Sterility
Citation Excerpt :
The lack of INHB suppression in our study is likely related to the brief duration of gonadotropin suppression and less suppression of FSH (89%) as compared with LH (95%) (3). In contrast to INHB, AMH is primarily produced by prepubertal Sertoli cells in response to FSH stimulation (38). Antimüllerian hormone subsequently declines with rising LH stimulation and seems to be suppressed by high intratesticular androgen concentrations (39).
To study the potential role for using serum biomarkers, including insulin-like factor 3 (INSL3), 17α-hydroxyprogesterone, antimüllerian hormone, and inhibin B, as correlates of intratesticular T (IT-T) concentrations in men.
Prospective, randomized, controlled trial.
University-based medical center.
Thirty-seven healthy men aged 18–50 years.
All men received the GnRH antagonist acyline, plus very low doses of hCG (0 IU, 15 IU, 60 IU, or 125 IU) SC every other day or 7.5 g T gel daily (75 mg delivered). The IT-T concentrations obtained by percutaneous testicular aspiration with simultaneous serum protein and steroid concentrations were measured at baseline and after 10 days of treatment.
Intratesticular and serum hormone and gonadotropin concentrations.
After 10 days of gonadotropin suppression, serum INSL3 decreased by more than 90% and correlated highly with IT-T concentrations. In contrast, serum inhibin B, antimüllerian hormone, and 17α-hydroxyprogesterone did not correlate with IT-T. Serum INSL3 increased with the dose of hCG administered and returned to baseline after treatment.
Serum INSL3 correlates highly with IT-T and serum T concentrations during acute gonadotropin suppression in men. Human chorionic gonadotropin stimulates dose-dependent increases in INSL3 and IT-T in healthy men and might be a useful biomarker of IT-T concentration in some clinical settings.
NCT# 00839319.
Immunohistochemical Evaluation of the Expression of Anti-Müllerian Hormone in Mature, Immature and Neoplastic Canine Sertoli Cells
2012, Journal of Comparative Pathology
In mammals, the earliest specific protein expressed by Sertoli cells (SCs) is the anti-Müllerian hormone (AMH), which induces the regression of Müllerian ducts and is produced by SCs until the functional maturation of the testes. The aim of this study was to evaluate the expression of AMH by canine SCs during testicular maturation and neoplastic transformation. Testes from two fetuses, 18 newborn puppies, five puppies aged 43–180 days and six adult dogs, and 24 canine Sertoli cell tumours (SCTs) were studied immunohistochemically for expression of AMH. Fifteen of the 24 SCTs were classified as typical, eight as lipid-rich and one was considered malignant based on evidence of lymph node metastasis. SCs from fetuses and neonatal puppies and puppies up to 45 days old expressed AMH, while SCs from older puppies and adults were negative. All SCTs expressed AMH, suggesting that AMH expression is a useful marker of immature and neoplastic canine SCs.

View all citing articles on Scopus

¹: Currently at the Unité de Recherches sur l'Endocrinologie du Dévelopment (INSERM), Ecole Normale Supérieure, Montrouge, France.

View full text

Trends in Endocrinology & Metabolism

Endocrine, Paracrine and Cellular Regulation of Postnatal Anti-Müllerian Hormone Secretion by Sertoli Cells

Abstract

Section snippets

Ontogeny of Testicular AMH Production After Birth

The AMH Gene

AMH Regulation by Androgens

Regulation of Testicular AMH Secretion by Germ Cells

Concluding Remarks

Acknowledgements

Cell

Cell

Mol Cell Endocrinol

Mol Cell Endocrinol

Genomics

Cell

Hormonal and cellular regulation of Sertoli cell anti-Müllerian hormone production in the postnatal mouse

J Clin Invest

A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the Müllerian duct

Development

Serum levels of Müllerian inhibiting substance in boys from birth to 18 years, as determined by enzyme immunoassay

J Clin Endocrinol Metab

Abnormal sexual development in transgenic mice chronically expressing Müllerian inhibiting substance

Nature

Testosterone and androstenedione concentrations in human testis and epididymis during the first two years of life

J Clin Endocrinol Metab

Signal transduction and gene control: the cAMP pathway

Crit Rev Oncogene

Male, female and intersex development in mice of identical chromosome constitution

Nature

Mapping of the gene for anti-Müllerian hormone to the short arm of human chromosome 19

Cytogenet Cell Genet

Cloning, expression and alternative splicing of the receptor for anti-Müllerian hormone

Mol Endocrinol

The genes for a spliceosome protein (SAP62) and the anti-Mullerian hormone (AMH) are contiguous

Hum Mol Genet

SRY and sex determination in mammals

Annu Rev Genet

Expression of the gene for anti-Müllerian hormone

J Reprod Fertil

Molecular basis of mammalian sexual determination: Activation of mullerian inhibiting substance gene expression by SRY

Science

Sex-dependent expression of a transcription factor, Ad4B. P, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development

Development

Mullerian inhibiting substance messenger ribonucleic acid expression in granulosa and Sertoli cells coincides with their mitotic activities

Endocrinology

An immunoassay to detect human Müllerian inhibiting substance in males and females during normal development

J Clin Endocrinol Metab

Insensitivity to anti-Müllerian hormone due to a spontaneous mutation in the human anti-Müllerian hormone receptor

Nat Genet