Talk:Developmental Signals - Anti-Mullerian Hormone

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Cite this page: Hill, M.A. (2021, September 23) Embryology Developmental Signals - Anti-Mullerian Hormone. Retrieved from


AMH and AMHR2 mutations: A spectrum of reproductive phenotypes across vertebrate species

Dev Biol. 2019 Nov 1;455(1):1-9. doi: 10.1016/j.ydbio.2019.07.006. Epub 2019 Jul 10.

Mullen RD1, Ontiveros AE2, Moses MM3, Behringer RR4. Author information 1 Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. 2 Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, 77030, USA. 3 Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Program in Genetics and Epigenetics, MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. 4 Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, 77030, USA; Program in Genetics and Epigenetics, MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. Electronic address: Abstract Anti-Müllerian hormone (AMH) is a member of the Transforming Growth Factor-β family of secreted signaling proteins. AMH is expressed in Sertoli cells of the fetal and adult testes and granulosa cells of the postnatal ovary. AMH is required for the regression of the Müllerian ducts in mammalian fetuses during male differentiation. AMH signals through its Type II receptor, AMHR2. AMHR2 is expressed in mesenchyme adjacent to the Müllerian ducts, and in Sertoli, Leydig, and granulosa cells. Although AMH and AMHR2 genes have been identified in numerous vertebrate species, spontaneous or engineered mutations or variants have been found or created in only a few mammals and teleost fishes. AMH or AMHR2 mutations in mammals lead to the development of Persistent Müllerian Duct Syndrome (PMDS), a recessive condition in which affected males are fully virilized but retain Müllerian duct-derived tissues, including a uterus and oviducts, and in human and dog, undescended testes. Amh mutant female mice had accelerated ovarian primordial follicle recruitment, suggesting a role for AMH in regulating germ cells. amh and amhr2 mutations have also been experimentally generated in various teleost fishes. Depending on the fish species, loss of AMH signaling results in infertility, germ cell tumors, or male-to-female sex reversal. Here we compare the spectrum of phenotypes caused by AMH and AMHR2 mutations in a variety of vertebrate species. There are both common and unique phenotypes between species, highlighting the range of biological processes regulated by AMH signaling. Copyright © 2019 Elsevier Inc. All rights reserved. KEYWORDS: Fertility; Gametogenesis; Müllerian duct regression; Sex determination; Testicular descent PMID: 31301298 PMCID: PMC6754765 [Available on 2020-11-01] DOI: 10.1016/j.ydbio.2019.07.006

Anti-Müllerian hormone levels in recurrent embryonic miscarriage patients are frequently abnormal, and may affect pregnancy outcomes

J Obstet Gynaecol. 2019 Jul;39(5):623-627. doi: 10.1080/01443615.2018.1552669. Epub 2019 Mar 27.

McCormack CD1,2, Leemaqz SY1, Furness DL1, Dekker GA1, Roberts CT1.

This prospective cohort study measured anti-Müllerian hormone (AMH) levels in recurrent miscarriage (RM) patients, compared them to a normal population, and assessed the pregnancy outcomes. The RM patients demonstrated AMH levels that were significantly lower than the normal population, both in women aged ≤35 years, and those aged >35 years. AMH percentiles were found to be significantly lower in the study group of RM patients ≤35 years (p< .004) in the 5th and 50th percentiles, and in all percentiles in women >35 years (p< .03), were compared to women from a normal population. Serum AMH levels may reflect quality, and quantity of the remaining oocytes in these patients, and RM patients may have a low ovarian reserve, and a potentially poor oocyte quality, as shown by low circulating AMH. The evaluation of AMH levels in a RM work up may allow realistic counselling and possible ART referral in RM patients. Impact statement What is already known on this subject? There is some evidence to show that low AMH levels are associated with recurrent miscarriages and this is thought to be due to a decreased oocyte quality. The AMH levels are lower in the patients with endometriosis, and are often significantly higher in the patients with polycystic ovarian syndrome. Both conditions are independently associated with miscarriages. What the results of this study add? Anti-Müllerian hormone (AMH) levels were found to be significantly lower in recurrent miscarriage patients, compared to a normal population. This may be another factor contributing to miscarriages. The spontaneous pregnancy rates in the miscarriage group significantly improved with increasing AMH levels. This may confirm that patients with low AMH levels have poorer quality oocytes, and thus may be considered 'sub-fertile'. It was also found that the utilisation of assisted reproductive technologies (ART) to achieve a pregnancy was significantly reduced in the groups with a higher serum AMH. What the implications are of these findings for clinical practice and/or further research? Serum AMH levels should be offered to all patients as part of a recurrent miscarriage work up. Detecting the low AMH levels and counselling the patients on these findings may allow them the option of accessing ART. ART may have the ability to expedite conception rates, and with pre-implantation genetic analyses, could possibly select the embryos with the greatest chance of survival. Further research is needed to establish how the decreased AMH levels contribute to recurrent miscarriages. KEYWORDS: Anti-Müllerian hormone; embryonic losses; foetal losses; ovarian reserve; recurrent miscarriages; subfertility PMID: 30917731 DOI: 10.1080/01443615.2018.1552669

Anti-Müllerian Hormone and Its Predictive Utility in Assisted Reproductive Technologies Outcomes

Clin Obstet Gynecol. 2019 Jun;62(2):238-256. doi: 10.1097/GRF.0000000000000436.

Granger E1, Tal R.

Anti-Müllerian hormone (AMH) has become one of the most informative biochemical markers of the ovary and is considered the earliest and most sensitive marker of reproductive aging. The accuracy of AMH in predicting ovarian response to controlled ovarian stimulation has led to AMH-based prognostication counseling and individualization of assisted reproductive technology (ART) stimulation protocols to optimize ovarian response and minimize hyperstimulation risks. Although AMH is considered a good predictor of quantitative ART outcomes, its correlation with qualitative ART outcomes is still controversial. The aim of this review is to provide an updated overview of the clinical utility of AMH in predicting ART outcomes. PMID: 30994481 DOI: 10.1097/GRF.0000000000000436


GnRH transactivates human AMH receptor gene via Egr1 and FOXO1 in gonadotrope cells

Neuroendocrinology. 2018 Oct 28. doi: 10.1159/000494890. [Epub ahead of print]

Garrel G, Denoyelle C, L'Hôte D, Picard JY, Teixeira J, Kaiser UB, Laverrière JN, Cohen-Tannoudji J.

Background/objectives: Anti-Müllerian hormone (AMH) signaling is critical for sexual differentiation and gonadal function. AMH receptor type 2 (AMHR2) is expressed in extragonadal sites such as brain and pituitary and emerging evidence indicates that AMH biological action is much broader than initially thought. We recently reported that AMH signaling enhances FSH synthesis in pituitary gonadotrope cells. However, mechanisms regulating AMHR2 expression in these extragonadal sites remain to be explored. Method/ Results: Here, we demonstrated in perifused murine LβT2 gonadotrope cells that Amhr2 expression is differentially regulated by GnRH pulse frequency with an induction under high GnRH pulsatility. Furthermore, we showed that GnRH transactivates the human AMHR2 promoter in LβT2 cells. Successive deletions of the promoter revealed the importance of a short proximal region (-53/-37 bp) containing an Egr1 binding site. Using site-directed mutagenesis of Egr1 motif and siRNA mediated-knock down of Egr1, we demonstrated that Egr1 mediates basal and GnRH-dependent activity of the promoter, identifying Egr1 as a new transcription factor controlling hAMHR2 expression. We also showed that SF1 and β-catenin are required for basal promoter activity and demonstrated that both factors contribute to the GnRH stimulatory effect, independently of their respective binding sites. Furthermore, using a constitutively active mutant of FOXO1, we identified FOXO1 as a negative regulator of basal and GnRH-dependent AMHR2 expression in gonadotrope cells. Conclusions: This study identifies GnRH as a regulator of human AMHR2 expression, further highlighting the importance of AMH signaling in the regulation of gonadotrope function.
. PMID: 30368511 DOI: 10.1159/000494890

Salivary and serum androgens with anti-Müllerian hormone measurement for the diagnosis of polycystic ovary syndrome

Sci Rep. 2018 Feb 28;8(1):3795. doi: 10.1038/s41598-018-22176-1.

Sathyapalan T1, Al-Qaissi A1, Kilpatrick ES2, Dargham SR3, Keevil B4, Atkin SL5.


To determine the predictive value of a raised androgen level with an elevated anti-Müllerian hormone (AMH) for the diagnosis or exclusion of polycystic ovary syndrome (PCOS), a prospective cross-sectional study of 170 women (105 with PCOS type A and 65 normal) was undertaken. AMH was combined with one of, total serum testosterone (T); calculated free androgen index; salivary testosterone (salT); serum androstenedione (A); salivary androstenedione (salA). The diagnostic sensitivity and specificity of AMH (>35 pmol/l) alone for PCOS were 55% and 79% respectively. The diagnostic sensitivity and specificity of AMH (>35 pmol/l) with either an elevated T or raised FAI level for PCOS showed 100% specificity and a 100% positive predictive value. Conversely, diagnostic exclusion of PCOS was shown by an AMH <35 pmol/l with a normal T or FAI salivary testosterone giving 100% specificity and 100% positive predictive value. AMH with an elevated A or elevated salA level gave specificities of 87% and 94%, and positive predictive values 80% and 94%, respectively. Therefore, the combination of an AMH with a cut off of 35 pmol/l combined with a raised T and/or a FAI will confirm PCOS whilst a normal AMH with a normal T and/or FAI will exclude PCOS, thus addressing diagnostic uncertainty.

PMID: 29491484 DOI: 10.1038/s41598-018-22176-1

In-vitro regulation of primordial follicle activation: challenges for fertility preservation strategies

Reprod Biomed Online. 2018 Feb 13. pii: S1472-6483(18)30051-8. doi: 10.1016/j.rbmo.2018.01.014. [Epub ahead of print]

Bertoldo MJ1, Walters KA2, Ledger WL2, Gilchrist RB2, Mermillod P3, Locatelli Y4.


Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. While the only available option to restore fertility is autologous transplantation, this treatment is not appropriate for all patients due to the risk of reintroducing cancer cells and causing disease recurrence. Harnessing the full reproductive potential of this tissue to restore fertility requires the development of culture systems that support oocyte development from the primordial follicle stage. While this has been achieved in the mouse, the goal of obtaining oocytes of sufficient quality to support embryo development has not been reached in higher mammals despite decades of effort. In vivo, primordial follicles gradually exit the resting pool, whereas when primordial follicles are placed into culture, global activation of these follicles occurs. Therefore, the addition of a factor(s) that can regulate primordial follicle activation in vitro may be beneficial to the development of culture systems for ovarian tissue from cancer patients. Several factors have been observed to inhibit follicle activation, including anti-Müllerian hormone, stromal-derived factor 1 and members of the c-Jun-N-terminal kinase pathway. This review summarizes the findings from studies of these factors and discusses their potential integration into ovarian tissue culture strategies for fertility preservation. KEYWORDS: AMH; Anti-Müllerian hormone; Fertility preservation; In-vitro culture; Primordial follicle activation; c-Jun PMID: 29503209


Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women

Hum Reprod. 2014 Aug;29(8):1764-72. doi: 10.1093/humrep/deu142. Epub 2014 Jun 12.

Kissell KA1, Danaher MR2, Schisterman EF3, Wactawski-Wende J4, Ahrens KA3, Schliep K3, Perkins NJ3, Sjaarda L3, Weck J3, Mumford SL5. Author information Abstract STUDY QUESTION: Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women? SUMMARY ANSWER: Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women. WHAT IS KNOWN ALREADY: Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration ≤5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle. MAIN RESULTS AND THE ROLE OF CHANCE: Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03). LIMITATIONS, REASONS FOR CAUTION: Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US. KEYWORDS: anovulation; anti-Müllerian hormone; menstrual cycle PMID: 24925522 PMCID: PMC4093994 DOI: 10.1093/humrep/deu142