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Anti-Müllerian hormone (AMH) is a member of the transforming growth factor β (TGFβ) superfamily, whose actions are restricted to the endocrine-reproductive system. Initially known for its role in male sex differentiation, AMH plays a role in the ovary, acting as a gatekeeper in folliculogenesis by regulating the rate of recruitment and growth of follicles. In the ovary, AMH is predominantly expressed by granulosa cells of preantral and antral follicles (i.e., post primordial follicle recruitment and prior to follicle-stimulating hormone (FSH) selection). AMH signals through a BMP-like signaling pathway in a manner distinct from other TGFβ family members. In this review, the latest insights in AMH processing, signaling, its regulation of spatial and temporal expression pattern, and functioning in folliculogenesis are summarized. In addition, effects of AMH variants on ovarian function are reviewed., Competing Interests: S.Y. and L.M.E.M. have no conflict of interest. J.A.V. has received royalties from AMH assays, paid to the institute/laboratory with no personal financial gain., (Thieme. All rights reserved.)

Little is known about the association of ambient ozone with ovarian reserve. Based on a retrospective cohort study of 6008 women who attended a fertility center in Hubei, China, during 2018-2021, we estimated ozone exposure levels by calculating averages during the development of follicles (2-month [W1], 4-month [W2], 6-month [W3]) and 1-year before measurement (W4) according to Tracking Air Pollution in China database. We used multivariate logistic regression and linear regression models to investigate association of ozone exposure with anti-müllerian hormone (AMH), the preferred indicator of ovarian reserve. Each 10 μg/m 3 increases in ozone were associated with 2.34% (0.68%, 3.97%), 2.08% (0.10%, 4.01%), 4.20% (1.67%, 6.67%), and 8.91% (5.79%, 11.93%) decreased AMH levels during W1-W4; AMH levels decreased by 15.85%, 11.90%, 16.92% in the fourth quartile during W1, W3, and W4 when comparing the extreme quartile, with significant exposure-response relationships during W4 (P < 0.05). Ozone exposure during W1 was positively associated with low AMH. Additionally, we detected significant effect modification by age, body mass index, and temperature in ozone-associated decreased AMH levels. Our findings highlight the potential adverse impact of ozone pollution on female ovarian reserve, especially during the secondary to small antral follicle stage and 1-year before measurement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Anti-Müllerian hormone (AMH) is a distinctive biomarker of the immature Sertoli cell. AMH expression, triggered by specific transcription factors upon fetal Sertoli cells differentiation independently of gonadotropins or sex steroids, drives Müllerian duct regression in the male, preventing the development of the uterus and Fallopian tubes. AMH continues to be highly expressed by Sertoli until the onset of puberty, when it is downregulated to low adult levels. FSH increases testicular AMH output by promoting immature Sertoli cell proliferation and individual cell expression. AMH secretion also showcases a differential regulation exerted by intratesticular levels of androgens and estrogens. In the fetus and the newborn, Sertoli cells do not express the androgen receptor, and the high androgen concentrations do not affect AMH expression. Conversely, estrogens can stimulate AMH production because estrogen receptors are present in Sertoli cells and aromatase is stimulated by FSH. During childhood, sex steroids levels are very low and do not play a physiological role on AMH production. However, hyperestrogenic states upregulate AMH expression. During puberty, testosterone inhibition of AMH expression overrides stimulation by estrogens and FSH. The direct effects of sex steroids on AMH transcription are mediated by androgen receptor and estrogen receptor α action on AMH promoter sequences. A modest estrogen action is also mediated by the membrane G-coupled estrogen receptor GPER. The understanding of these complex regulatory mechanisms helps in the interpretation of serum AMH levels found in physiological or pathological conditions, which underscores the importance of serum AMH as a biomarker of intratesticular steroid concentrations., Competing Interests: Until 2020, RR received royalties for the development of an AMH ELISA kit and honoraria for technology services using the AMH ELISA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Edelsztein, Valeri, Lovaisa, Schteingart and Rey.)

Anti-Müllerian Hormone (AMH) is produced by small antral follicles and has evolved over the past three decades as an assumed potential marker of the number of follicles in the human ovaries, also known as ovarian reserve. This quantitative measure, given the gradual decline over time and its non-replenishable feature, could be the dreamed marker for predicting the final exhaustion of ovarian storage: the post-menopause. This introductory chapter summarizes current knowledge with regard to the contribution of serum AMH measurements to predict age of normal menopause and critically discuss its potential in this regard. Furthermore, its predictive role in the context of menopause in association with several frequently occurring fertility disorders such as premature menopause, polycystic ovarian syndrome and endometriosis are discussed. Overall, while ovarian reserve markers including AMH are unmistakably related to age at menopause, they are insufficiently precise to inform on an individual's journey of ovarian aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Kat, Broekmans and Lambalk.)

Background: Whilst the ability of AMH to induce the regression of the Müllerian ducts in the male fetus is well appreciated, AMH has additional biological actions in relation to steroid biosynthesis and ovarian follicle dynamics. An understanding of the physiology of AMH illuminates the potential therapeutic utility of AMH to protect the ovarian reserve during chemotherapy and in the treatment of female malignancies. The translation of the biological actions of AMH into clinical applications is an emerging focus of research, with promising preliminary results., Objective and Rationale: Studies indicate AMH restrains primordial follicle development, thus administration of AMH during chemotherapy may protect the ovarian reserve by preventing the mass activation of primordial follicles. As AMH induces regression of tissues expressing the AMH receptor (AMHRII), administration of AMH may inhibit growth of malignancies expressing AMHR II. This review evaluates the biological actions of AMH in females and appraises human clinical applications., Search Methods: A comprehensive search of the Medline and EMBASE databases seeking articles related to the physiological functions and therapeutic applications of AMH was conducted in July 2021. The search was limited to studies published in English., Outcomes: AMH regulates primordial follicle recruitment and moderates sex steroid production through the inhibition of transcription of enzymes in the steroid biosynthetic pathway, primarily aromatase and 17α-hydroxylase/17,20-lyase. Preliminary data indicates that administration of AMH to mice during chemotherapy conveys a degree of protection to the ovarian reserve. Administration of AMH at the time of ovarian tissue grafting has the potential to restrain uncontrolled primordial follicle growth during revascularization. Numerous studies demonstrate AMH induced regression of AMHR II expressing malignancies. As this action occurs via a different mechanism to traditional chemotherapeutic agents, AMH has the capacity to inhibit proliferation of chemo-resistant ovarian cancer cells and cancer stem cells., Wider Implications: To date, AMH has not been administered to humans. Data identified in this review suggests administration of AMH would be safe and well tolerated. Administration of AMH during chemotherapy may provide a synchronistic benefit to women with an AMHR II expressing malignancy, protecting the ovarian reserve whilst the cancer is treated by dual mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rodgers, Abbott, Walters and Ledger.)

Shaw, Snigdha, Himashree Gidugu, Gopinath Bhaumik, Maramreddy Prasanna Kumar Reddy, Usha Panjwani, and Dishari Ghosh. Anti-Mullerian hormone and macrophage migration inhibitory factor determine the reproductive health of Ladakhi women residing at 3,500 m. High Alt Med Biol . 22:317-326, 2021. Background: Reproductive health of Ladakhi high-altitude (HA) native females was investigated for the first time in this study. Available literature suggest that, female reproductive cycle and hormonal profile varies in different HA populations due to heterogeneity. Although these studies illustrate some progress on the role of HA hypoxia, it still leaves scope for evaluation of the remaining mechanisms involved in the maintenance of reproductive health in this contemporary population. Materials and Methods: Menstrual details, phasic variations in circulatory steroid hormones, and gonadotropins along with oxytocin in sea level (SL) and HA (∼3,500 m) native females of India were assessed. Moreover, ovarian reserve marker anti-Mullerian hormone (AMH) and proinflammatory cytokine macrophage migration inhibitory factor (MIF) were measured. Results: A difference in Ladakhi women was registered compared to SL, regarding luteinizing hormone (LH) (2.6 mIU/ml vs. 4.4 mIU/ml, p  < 0.05) and progesterone (P) (4.1 ng/ml vs. 9.4 ng/ml, p  < 0.05) levels in their luteal phase. Reduced LH might contribute to poor development of the ovarian corpus luteum, subsequently diminish P level. Decreased AMH level in three age groups: 21-30 years (1.4 ng/ml vs. 3.2 ng/ml, p  < 0.01), 31-40 years (0.6 ng/ml vs. 2.1 ng/ml, p  < 0.01), and >40 years (0.4 ng/ml vs. 1.7 ng/ml, p  < 0.01) of Ladakhi women were recorded than their SL counterpart. Elevated oxytocin (83.5 ng/ml vs. 76.3 ng/ml, p  < 0.05) and MIF levels (70.2 ng/ml vs. 49.7 ng/ml, p  < 0.01) along with low P and AMH levels delineated the reason for recorded early menopause (43.9 years), shorter reproductive span (∼29 years), and history of miscarriage in HA dwellers compared to SL. Conclusion: Therefore, the findings insinuated that the response of the reproductive system to hypoxia in Ladakhi women differs from SL women, and the adaptive response in these women might be in favor of their reproductive health.

Insulin resistance (IR) is one of the most common features of polycystic ovary syndrome (PCOS), which is related to obesity. Whether increased anti-Müllerian hormone (AMH) levels in PCOS are involved in the pathogenesis of insulin resistance remains unclear. We investigated serum levels of leptin and AMH along with basic clinical and metabolic parameters in 114 PCOS patients and 181 non-PCOS women. PCOS patients presented higher fasting blood glucose, insulin concentrations and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in addition to body mass index (BMI), lipids profiles and hormone levels. HOMA-IR showed a positive correlation with BMI, AMH, leptin, and low-density lipoprotein-cholesterol (LDL-c) levels. Interestingly, AMH is strongly positively correlated with HOMA-IR and insulin concentrations for 1st and 2nd hours of glucose treatment after fasting. Among PCOS women with BMI≥25 kg/m 2 , high AMH level group showed an increased HOMA-IR when compared to normal AMH level. However, among PCOS women with normal BMI, women with high AMH presented an elevated fasting insulin levels but not HOMA-IR when compared to normal AMH group. In vitro treatment of isolated islet cells with high concentration of leptin (200 ng/ml) or high leptin plus high concentration of AMH (1 ng/ml) significantly enhanced insulin secretion. Importantly, co-treatment of AMH plus leptin upregulates the expression of pro-apoptotic proteins, such as Bax, caspase-3, and caspase-8 after incubating with a high level of glucose. These results suggest that AMH may involve in the pathological process of pancreatic β-cells in obese PCOS women., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Anti-Müllerian hormone (AMH/Amh) plays a role in gonadal differentiation and function across vertebrates. In zebrafish we demonstrated that Amh deficiency caused severe gonadal dysgenesis and dysfunction. The mutant gonads showed extreme hypertrophy with accumulation of early germ cells in both sexes, namely spermatogonia in the testis and primary growth oocytes in the ovary. In amh mutant females, the folliculogenesis was normal in young fish but receded progressively in adults, which was accompanied by progressive decrease in follicle-stimulating hormone (fshb) expression. Interestingly the expression of fshb increased in the pituitary of juvenile amh mutant males but decreased in adults. The upregulation of fshb in mutant male juveniles was likely one of the mechanisms for triggering gonadal hypergrowth, whereas the downregulation of fshb in adults might involve a negative feedback by gonadal inhibin. Further analysis using mutants of fshb and growth differentiation factor 9 (gdf9) provided evidence for a role of FSH in triggering ovarian hypertrophy in young female amh mutant as well. In summary, the present study provided comprehensive genetic evidence for dual roles of Amh in controlling zebrafish gonadal homeostasis and gametogenesis in both sexes. Amh suppresses proliferation or accumulation of early germ cells (spermatogonia in testis and primary growth oocytes in ovary) while promoting their exit to advanced stages, and its action may involve both endocrine and paracrine pathways., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: Controversy exists regarding if and how body mass index (BMI) impacts antimüllerian hormone (AMH) in women with and without polycystic ovary syndrome (PCOS). Understanding the BMI-AMH relationship has critical implications for clinical interpretation of laboratory values and could illuminate underlying ovarian physiology., Objective: To test the hypotheses that (1) BMI is associated with reduced AMH in PCOS and ovulatory controls (OVAs) and (2) the reduction in AMH is not accounted for by dilutional effects., Design/setting: Multicenter cohort., Participants: Women aged 25 to 40 years from 2 clinical populations: 640 with PCOS, 921 women as OVAs., Main Outcome Measures: Ovarian reserve indices: AMH, antral follicle count (AFC), and AMH to AFC ratio (AMH/AFC) as a marker of per-follicle AMH production., Results: In both cohorts, increasing BMI and waist circumference were associated with reductions in AMH and AMH/AFC, after adjusting for age, race, smoking, and site in multivariate regression models. Increasing BMI was associated with reduced AFC in PCOS but not OVAs. Body surface area (BSA), which unlike BMI is strongly proportional to plasma volume, was added to investigate a potential dilutive effect of body size on AMH concentrations. After controlling for BSA, BMI retained independent associations with AMH in both cohorts; BSA no longer associated with AMH., Conclusions: In an adjusted analysis, BMI, but not BSA, was associated with reduced AMH; these data do not support a role for hemodilution in mediating the relationship between increased body size and reduced AMH. Decreased AMH production by the follicle unit may be responsible for reduced AMH with increasing BMI., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: In this review, we will summarize research looking into anti-Müllerian hormone (AMH) as a measure of oocyte quality., Recent Findings: AMH is a key factor involved in embryogenesis but also in the development of early follicles. Owing to its relatively small inter and intracycle variability, it has become a widely used method of ovarian reserve testing. In the realm of assisted reproductive technology, it has demonstrated a reliable ability to gauge the number of oocytes obtained during an in-vitro fertilization cycle. For these purposes, AMH is a readily measured quantitative tool. However, its qualitative role is as yet undefined., Summary: Although levels of this hormone have been associated with fertilization, blastulation, implantation, and clinical pregnancy rates, there is no clear link with live-birth rates. Furthermore, AMH levels do not appear to correspond with risk of fetal trisomy. AMH does show significant predictive value for the risk of premature ovarian insufficiency and time to onset of menopause.

Background: Both follicle stimulating hormone (FSH) and anti-mullerian hormone (AMH) are widely used to assess the ovarian reserve in women for in vitro fertilization (IVF). However, studies also showed that both AMH and FSH are significantly associated with age: as age increases, AMH decreases and FSH increases. This study aims to investigate the mechanism of age effect on IVF live birth rate, particularly through mediation and interaction by AMH and FSH., Methods: We conducted a retrospective cohort study of 13970 IVF cycles collected by eIVF from 2010 to 2016. A series of logistic mixed models were used to estimate the association of live birth and AMH (or FSH). The mediation effects and proportion mediated, were quantified by our previously proposed mediation analyses. We further investigated the FSH-modified mediation effects on live birth rate through AMH, accounting for the nonlinear age effect., Results: Our analyses showed that age effect on live birth was mediated more by AMH than by FSH (18 vs. 6%). The mediation effect through AMH can be further modified by FSH level regardless of women's age., Conclusions: In summary, mediation model provides a new perspective elucidating the mechanism of IVF successful rate by age. The majority of the age effect on live birth rate remained unexplained by AMH and FSH, suggesting its importance and independent role in IVF.

Purpose: To determine the influence of endometriosis on the ovarian response during controlled ovarian hyperstimulation measured by number of oocytes retrieved and the follicular output rate (FORT)., Methods: A retrospective, single center study included 96 women, who underwent ICSI treatments for male factor infertility according to World Health Organisation between 2016 until 2018. A total of 96 patients were included in the study with 205 fresh ICSI cycles. The study group included 26 patients with endometriosis after surgical and medical treatment; the control group included 70 patients without endometriosis. The women with endometriosis underwent 47 and the control group 158 ICSI cycles. Women underwent fresh intracytoplasmatic sperm injection cycles after controlled ovarian hyperstimulation following a GnRH-antagonist protocol. The FORT was calculated as the ratio of pre-ovulatory follicle count × 100/small antral follicle count at baseline., Results: A lower number of retrieved oocytes (5.89 vs. 7.25, p = 0.045), lower FORT (75.67 vs. 94.63, p = 0.046), lower number of metaphase II oocytes (4.87 vs. 6.04, p = 0.046), and lower fertilization rate after intracytoplasmatic sperm injection (40.61 vs. 57.76, p = 0.003) were found in women with endometriosis compared to women without endometriosis. The number of oocyctes retrieved was 0.71 lower in the group with endometriosis than in the group without (p = 0.026). The FORT was 24.55% lower in the group with endometriosis (p = 0.025)., Conclusions: Endometriosis reduces the FORT and the number of metaphase-II oocytes after controlled ovarian hyperstimulation independly of women's age, antral follicle count and anti-Müllerian hormone.

Anogenital distance (AGD), which is an indicator of prenatal androgen exposure, has been reported to have high variability and negative association with fertility in dairy cows. Prenatal exposure to androgens could influence the development of primordial follicles and size of ovarian reserve, which is related to reproduction. However, the relationship between AGD and size of ovarian reserve has not been studied. Therefore, the present study was conducted to determine the association between AGD and circulating anti-Müllerian hormone (AMH), as an indirect marker of ovarian reserve, and to evaluate serum AMH concentration and reproductive performance in dairy cows with short and long AGD. Anogenital distance was measured 28 to 32 d postpartum, and based on the median of AGD, cows were divided into 2 subsets including short (n = 43) and long (n = 43) AGD groups. Afterward, serum AMH was evaluated on the day of estrus in cows that were estrus-synchronized. Furthermore, reproductive data of dairy cows during the previous lactation period were collected from the herd database. Concentrations of serum AMH tended to be positively associated with length of AGD, and there was a tendency for higher serum AMH concentrations in the long (634.89 ± 74.52 pg/mL) than short (451.39 ± 45.92 pg/mL) AGD group (0.05

0.05). Calving to conception interval was prolonged in long (194.30 ± 17.12 d) than short (147.14 ± 13.11 d) AGD cows (P ≤ 0.05). In conclusion, the present study revealed elevated serum AMH concentrations and poor reproductive performance in cows with longer AGD compared with cows with shorter AGD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

To investigate the relationship of birth weight (BW) of females born at full term with functional ovarian reserve (FOR) during menacme, based on serum level of anti-Müllerian hormone (AMH), among women who were 34-35 years old. This prospective birth cohort study assessed all women who were born in Ribeirão Preto City, State of São Paulo (Brazil) between June 1, 1978 and May 31, 1979. The primary endpoint was serum AMH, a marker of FOR, and its correlation with the BW of females classified as small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational (LGA). We included 274 women in this study, 19 were SGA, 238 were AGA, and 17 were LGA. The average of AMH concentration was not significantly different (p = 0.11) among women in the SGA group (2.14 ng/mL), AGA group (2.13 ng/mL), and LGA group (2.57 ng/mL). An analysis of variance indicated that the three groups also had no significant differences in the percentage of women who had adequate AMH levels (1 ng/mL; p = 0.11). There were no significant differences in the serum concentrations of AMH among 34 and 35 year-old women who were born at full term and classified as SGA, AGA, and LGA. Our sample size allowed detection of major differences between these groups (effect size of 0.8). Association of birth weight of females born at full term with functional ovarian reserve during menacme estimated by serum concentration of anti-Müllerian hormone.

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Serum anti-Müllerian hormone (AMH) level is considered to be a reliable marker of ovarian reserve. However, there are conflicting reports on the role of AMH level in predicting pregnancy after intrauterine insemination (IUI) cycles. The aim of this study is to investigate the clinical value of AMH in predicting pregnancy in younger and older women with unexplained infertility undergoing gonadotropin stimulation and IUI., Methods: The medical records of 84 women who underwent first gonadotropin-stimulated IUI cycle owing to unexplained infertility were retrospectively evaluated. The relation of AMH levels with clinical pregnancy rate was analyzed., Results: The overall clinical pregnancy rate was 19%. There was no significant difference in AMH levels between the pregnant and nonpregnant women (2.0 ± 1.0 vs 2.8 ± 2.0 ng/mL, respectively, p = 0.250). A further analysis according to age also failed to reveal significant differences in AMH levels between pregnant and nonpregnant women for both the younger (<35 years, n = 61) and the older (≥35 years, n = 23) subgroups (p = 0.714 and 0.532, respectively). Post-hoc power analysis showed a power of 0.80 with a 5% level of significance and a 0.8 effect size., Conclusion: These findings indicate that AMH levels cannot predict pregnancy in women with unexplained infertility undergoing gonadotropin-stimulated IUI cycle. In addition, AMH is not a strong predictive factor for pregnancy either in younger or older women.

The objectives of this study were to evaluate; 1) the stability of measured serum anti-Müllerian hormone (AMH) concentrations in samples after multiple freeze-thaw cycles, 2) the repeatability of AMH concentrations within mares during the same breeding season as well as across breeding seasons, and 3) the relationship between serum AMH concentrations and fertility (measured as first cycle pregnancy rates) in thoroughbred mares. For the first aim, AMH concentrations (n = 9) were examined across four freeze-thaw cycles with no significant change in measured AMH concentrations. For the second aim, serum AMH concentrations (n = 12) were examined over three successive estrous cycles and over two successive breeding seasons and AMH levels were significantly correlated for individual animals within (r; 0.71-82) or across breeding seasons (r = 0.81). For the third aim, Thoroughbred mares (n = 419) on farms in central Kentucky had blood samples taken during estrus. Pregnancy was determined with transrectal ultrasonography at Days 13-18 after mating and ovulation, and pregnancy outcome was recorded as open, pregnant or twins. The relationships between mare age, serum AMH concentrations and the interaction of age and AMH with pregnancy outcome was examined by nominal logistic regression, and the relationship between serum AMH concentrations and mare age, pregnancy outcome and the interaction of age and pregnancy outcome was examined by ANOVA. Data in this study were then stratified according to quartiles into lower (25%), mid-50% (second and third quartiles combined - 50%) and upper (25%) quartiles for age and serum AMH concentration for further analysis by logistic regression. There were significant effects of mare age and pregnancy outcome, but not their interaction on serum AMH concentrations which were higher (P = 0.04) in pregnant than in open mares (0.65 ± 0.03 vs 0.55 ± 0.04 ng/mL, respectively). Likewise, logistic regression revealed significant effect of mare age and AMH but not their interaction on pregnancy outcome on the first mated cycle. Mares in the lower AMH quartile were more likely to be open at Day 13-18 than mares in the middle (odds ratio (OR) = 1.87)=13 or upper quartile (OR = 2.62) for AMH concentrations. Mares in the mid-50% (OR = 3.91) or upper (OR = 4.97) age quartile were more likely to be open at Day 13-18 compared to mares in the young age quartile. Based upon a Chi-squared analysis, the proportion of pregnant mares differed across age quartiles (P < 0.0001) and was greater (P < 0.05) in the young mare quartile. The proportion of pregnant mares tended to differ across AMH quartile (P = 0.1), and when adjusted for age quartile using the Cochran-Mantel-Haenszel Test, the proportion of pregnant mares differed (P < 0.05) across AMH quartile. In conclusion, mares with peripheral AMH concentrations in the lowest quartile had lower fertility compared to mares in the mid-50% or upper quartile., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This chapter describes ovarian anatomy and embryology in humans. The formation of the ovarian reserve is discussed, and events of folliculogenesis are described, including description of developmental events in primordial, primary, secondary, antral and periovulatory follicles. Paracrine and autocrine factors play critical roles in oocyte maturation and follicular development, and research related to the hypothesised roles of individual factors is discussed. Gonadotrophin-dependent events relating to dominant follicle selection are discussed. The two-cell, two-gonadotrophin hypothesis of ovarian steroidogenesis is explained. The clinical role of AMH is outlined. Premature ovarian failure and known associated aetiological factors are described. In the conclusion, with an understanding of the principle events of ovarian folliculogenesis, the follicular wave theory is described, and it is explained how adaptation of ovarian stimulation regimens may achieve time-efficient fertility preservation treatment options for patients with cancer., (Copyright © 2018. Published by Elsevier Ltd.)

The follicular ovarian reserve, constituted by primordial follicles (PMFs), is established early in life, then keeps declining regularly along reproductive life. The maintenance of a normal female reproductive function implies the presence of a vast amount of dormant PMFs. This process involves a continuous repression of PMF activation into early growing follicle through the balance between factors activating the initiation of follicular growth, mainly actors of the PI3K signaling pathway, and inhibiting factors such as anti-Müllerian hormone (AMH). Any disruption of this balance may induce follicle depletion and subsequent infertility. It has been recently proposed that cyclophosphamide (Cy), an alkylating agent commonly used for treating breast cancer, triggers PMF activation, further leading to premature ovarian insufficiency. Preventing chemotherapy-induced ovarian dysfunction might represent an interesting option for preserving optimal chances of natural or medically assisted conceptions after healing. The aim of the present study was to evaluate, in a model of Cy-treated pubertal mice, whether AMH administration might restrain PMF depletion. The counting of the total PMF number within mouse ovaries showed that recombinant AMH prevented Cy-induced PMF loss. Western blot analysis revealed activation of PI3K signaling pathway after Cy administration. After AMH injection, FOXO3A phosphorylation, a main actor of PMF activation, was significantly decreased. Taken together, these results support a protective role of AMH against Cy-induced follicular loss. We also provide evidence for a possible role of autophagy in the preservation of follicular pool reserve. Therefore, concomitant recombinant AMH administration during chemotherapy might offer a new option for preserving young patients' fertility.-Sonigo, C., Beau, I., Grynberg, M., Binart, N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice.

Anti-Müllerian hormone (AMH), known for its role during sexual differentiation, is a dimeric glycoprotein that belongs to the transforming growth factor-β (TGF-β) family. AMH has recently been identified as a reliable marker of ovarian reserve that can help predict early ovarian follicle loss and menopause onset. AMH levels also reflect the effects of damaging gynecologic surgeries or gonadotoxic treatments such as chemotherapy on ovarian reserve. Furthermore, AMH participates in the diagnosis of certain diseases such as granulosa cell tumors or Polycystic Ovary Syndrome (PCOS). Currently used to establish patient profiles and predict ovarian response to stimulation, its role in ART techniques is crucial. Nevertheless, AMH appears to be a weak independent predictor of qualitative outcomes such as implantation, pregnancy, and live birth. As the reliability and reproducibility of AMH dosage have raised many doubts due to different existing standards and thresholds, an international consensus is still expected to improve AMH measurement and interpretation., (Copyright © 2018. Published by Elsevier Masson SAS.)

Purpose of Review: The nascent field of oncofertility is quickly gaining traction as novel experimental treatments are being developed, driving a renewed interest in Müllerian inhibiting substance (MIS) as an ovarian fertoprotectant., Recent Findings: MIS is unique in its mechanisms of ovarian protection by virtue of acting directly on granulosa cells of primordial follicles and for being a benign reproductive hormone, with few side effects. We will explore in this review how it may be utilized to protect the ovary from chemotherapy, or to enhance ovarian tissue cryopreservation therapy. We will also examine potential mechanisms of action of MIS across multiple cell types, as well as current limitations in our understanding of the pharmacology of recombinant MIS., Summary: The usefulness of MIS as a fertoprotectant may be dependent on the mechanisms of gonadotoxicity of each chemotherapeutic. Further investigation is needed to determine how to best deliver and combine MIS treatment to existing fertility management strategies.

Purpose of Review: Iatrogenic ovarian damage can occur after chemotherapy, radiotherapy and surgery for cancer as well as for non-malignant conditions. This review describes the effects of such treatment on antimullerian hormone (AMH) and the implications of the fall in AMH in relation to ovarian function and fertility, especially in the era of improved fertility preservation strategies., Recent Findings: The risk of gonadotoxicity differs between chemotherapy regimens. There is growing evidence that pretreatment AMH has prognostic significance for the degree of fall in AMH after treatment, the reversibility of ovarian damage and risk of premature ovarian insufficiency. The accuracy of prediction increases when age is coupled with AMH. The adverse effect of removal of endometriomas is increasingly clear, and AMH pre and post surgery useful is assessing the degree of damage to the ovary. The implications of low AMH after such treatment on natural fertility and reproductive lifespan are less clear. Apart from treatment effects, there are other coexisting conditions that can affect AMH which needs to be taken into consideration during interpretation of AMH before and after treatment., Summary: A fall in AMH in women after gonadotoxic treatment has been consistently described, with variable recovery, the accurate interpretation and clinical application of post-treatment AMH level on reproductive lifespan and fertility prediction needs to be studied in future larger prospective studies with longer follow-up.

Purpose of Review: Determine if literature supports the use of anti-Müllerian hormone (AMH) as a useful biomarker of reproductive potential when cumulative live birth rates (CLBRs) per retrieval are used as the outcome variable., Recent Findings: Advances in technology used in in-vitro fertilization (IVF) permit the use of single embryo transfer to achieve expected pregnancy success rates. Many IVF cycles result in the creation of more than a single embryo suitable for transfer per oocyte retrieval. Cryopreservation permits subsequent use of other embryos with no loss in total reproductive potential from single retrievals. Therefore, an emerging concept in IVF is the CLBR per retrieval as an indicator of the patient's reproductive potential. Using the total reproductive potential from a single retrieval may help patients decide on IVF. As such, any predictor of success that relies upon the live birth rate for a single transfer, as opposed to CLBR per retrieval, is inadequate to estimate the true reproductive potential for patient. AMH has been proposed as a biomarker for reproductive potential, but most studies have correlated an AMH value to a single embryo transfer., Summary: A more appropriate way to use AMH levels may be to correlate the AMH with CLBR per retrieval. AMH may thus prove to be a useful biomarker when counseling patients about what to expect from their treatment.

Purpose of Review: Polycystic ovarian syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women and represents a true public health concern and an economic burden., Recent Findings: The pathophysiology of PCOS is still not fully understood, but progresses have been made and the relationships between anti mullerian hormone (AMH), follicle stimulating hormone, luteinizing hormone, E2 and androgens have been explored. The follicle excess plays a central role in the syndrome and AMH is definitively a major component of this phenomena., Summary: The aim of this chapter is to present the recent work studying the role of AMH in the pathophysiology of PCOS and to discuss the improvement that serum AMH assay brings in the diagnosis of PCOS.

Purpose of Review: Anti-Müllerian hormone (AMH), a marker of ovarian reserve, declines over a woman's reproductive lifespan. AMH is highly correlated with a woman's age and number of primordial ovarian follicles, and has been shown to predict time to menopause in women in their 40s. For these reasons, it was assumed that AMH levels could predict a woman's reproductive potential or serve as a 'fertility test'. Recently, studies have sought to determine the association between AMH and fertility., Recent Findings: Although a small, prospective, time-to-pregnancy study of 98 women suggested that an AMH level less than 0.7 ng/ml was associated with lower day-specific probabilities of conception, the follow-up, larger cohort did not identify an association with AMH and fecundability. Women with AMH values less than 0.7 ng/ml had similar pregnancy rates after 12 cycles of attempting to conceive as women with normal AMH values after adjusting for age. Four additional studies, including a secondary analysis of the NICHD EAGER trial including over 1200 women confirmed these findings., Summary: Although AMH is a marker of ovarian reserve, existing literature does not support the use of AMH as a marker of reproductive potential in the general population.

In mammals, the developing reproductive tract primordium of male and female fetuses consists of the Wolffian duct and the Müllerian duct (MD), two epithelial tube pairs surrounded by mesenchyme. During male development, mesenchyme-epithelia interactions mediate MD regression to prevent its development into a uterus, oviduct, and upper vagina. It is well established that transforming growth factor-β family member anti-Müllerian hormone (AMH) secreted from the fetal testis and its type 1 and 2 receptors expressed in MD mesenchyme regulate MD regression. However, little is known about the molecular network regulating downstream actions of AMH signaling. To identify potential AMH-induced genes and regulatory networks controlling MD regression in a global nonbiased manner, we examined transcriptome differences in MD mesenchyme between males (AMH signaling on) and females (AMH signaling off) by RNA-seq analysis of purified fetal MD mesenchymal cells. This analysis found 82 genes up-regulated in males during MD regression and identified Osterix ( Osx )/ Sp7 , a key transcriptional regulator of osteoblast differentiation and bone formation, as a downstream effector of AMH signaling during MD regression. Osx /OSX was expressed in a male-specific pattern in MD mesenchyme during MD regression. OSX expression was lost in mutant males without AMH signaling. In addition, transgenic mice ectopically expressing human AMH in females induced a male pattern of Osx expression. Together, these results indicate that AMH signaling is necessary and sufficient for Osx expression in the MD mesenchyme. In addition, MD regression was delayed in Osx -null males, identifying Osx as a factor that regulates MD regression., Competing Interests: The authors declare no conflict of interest.

Anti-Müllerian hormone (AMH) is an ovarian regulator that affects folliculogenesis. AMH inhibits the developmental activation of the dormant primordial follicles and the oocyte within. In more mature follicles, AMH reduces granulosa cell sensitivity to follicle-stimulating hormone (FSH). We examined the effects of AMH overexpression on the stages of ovarian folliculogenesis, and the development of embryos, with a transgenic mouse that overexpresses human AMH in central nervous system neurons under the control of the mouse Thy1.2 promoter ( Thy1.2-AMH Tg mice). These mice are severely sub-fertile, despite relatively normal ovulation rates. The embryos of Thy1.2-AMH Tg females exhibited delayed preimplantation development and extensive mid-gestation fetal resorption. Young Thy1.2-AMH Tg mouse ovaries exhibited only a slight reduction in the rate of primordial follicle activation but large declines in the number of developing follicles surviving past the primary stage. It was expected that Thy1.2-AMH Tg mice would retain more primordial follicles as they aged, but at 5 months, their number was significantly reduced relative to wild-type females. These data indicate that moderate elevations in AMH levels can severely restrict reproductive output and the number of developing follicles in the ovary. This evidence suggests that early antral follicles are a target for AMH signaling, which may regulate early follicle survival., (© 2018 Society for Endocrinology.)

Purpose: High levels of circulating anti-Müllerian hormone are unique to developing males, but the function of anti-Müllerian hormone in boys is unknown. In mice, anti-Müllerian hormone contributes to the male biases in the brain, but its receptors are present throughout non-sexually dimorphic portions of the brain. In humans, the speed of maturation is the most overt difference between girls and boys. We postulate that this is because anti-Müllerian hormone slows the maturation of the male human brain., Methods: One hundred and fourty three 5-year or 6-year-old boys and 38 age-matched girls drew a person and donated a blood sample. The children's drawings were blind-scored to generate a maturity index. The level of anti-Müllerian hormone and the other Sertoli cell hormone, inhibin B, were measured by ELISA. The relationship between the children's age, hormones and maturity index were examined by linear regression analysis., Results: The girls drew more complex and realistic person than the boys (32%, p = 0.001), with their drawings also being larger (39%, p = 0.037) and more coloured-in (235%, p = 0.0005). The maturity index in boys correlated with age (+r = 0.43, p < 0.0005) and anti-Müllerian hormone level (-r = -0.29, p < 0.0005). The association between maturity index and anti-Müllerian hormone level persisted when corrected for age and for inhibin B (r = -0.24, p = 0.0005). The calculated effect of the median level of anti-Müllerian hormone (1 nM) was equal to 0.81 months of development. The size and colouring of the drawings did not correlate with the boys' age, anti-Müllerian hormone or inhibin B., Conclusions: This exploratory study provides the first indicative evidence that circulating anti-Müllerian hormone may influence the development of the human brain.

Background: Ovarian reserve (OR) testing with serum anti-Müllerian hormone (AMH) can provide information about a woman's fertility potential. The aim of this study was to assess interest and knowledge about OR testing and investigate the utility of measuring AMH in women of reproductive age deferring pregnancy., Methods: Women ages 27-37 years currently delaying childbearing were invited to take a survey regarding attitudes and knowledge about OR testing before and after an AMH measurement with explanation of their results., Results: Of 121 women who took the pre-test survey, 96% believed OR testing was beneficial. The median AMH of the 97 women who underwent testing was 3.3 ng/mL (IQR 1.9-5.4 ng/mL). Nineteen percent of women had AMH <10th percentile for age and 3% had an undetectable AMH. Although 83% of these women were using hormonal contraception, none had known risk factors for diminished ovarian reserve. Seventy-eight percent of women with low AMH levels for age planned to seek fertility preservation or pregnancy, while those with AMH levels within established age normograms were reassured. On the post-test survey, 100% reported benefit in knowing their AMH level. Follow-up testing, 6-8 months after the initial measurement, showed stable AMH levels for most participants., Conclusions: Women are interested in OR testing. Most women will be reassured by knowing their AMH level, whereas those with a lower AMH can be counseled on fertility preservation options or may attempt pregnancy earlier.

Purpose of Review: Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder that appears to have its origins during the peripubertal years. The diagnostic conundrum is that the typical clinical features, irregular menses and acne, occur during normal female puberty. Understanding the physiologic origins and molecular basis of the dysregulated hypothalamic-pituitary-gonadal axis in PCOS is fundamental to interrupting the distinctive vicious cycle of hyperandrogenism and chronic anovulation., Recent Findings: Newer ultrasound technology with better spatial resolution has generated controversy regarding the optimal imaging criteria to define polycystic ovary morphology. Using such equipment, the Androgen Excess PCOS Society Task Force Report recommends a threshold of at least 25 follicles per ovary as the definition of polycystic ovary morphology. The implementation and results of genome-wide association studies has opened a new window into the pathogenesis of PCOS. Recent genome-wide association studies have identified several loci near genes involved in gonadotropin secretion, ovarian function, and metabolism. Despite the impediments posed by phenotypic and genetic heterogeneity among women with PCOS, investigation into one locus, the DENND1A gene, is providing insight into the ovarian steroidogenesis. Anti-Mullerian hormone (AMH) has long been recognized to play a major role in the ovarian dysfunction. Recent animal data implicate AMH in the neuroendocrine dysregulation by demonstrating AMH-stimulated increased gonadotropin releasing hormone and luteinizing hormone secretion., Summary: PCOS is a common complex multifaceted disorder associated with genetic and environmental influences affecting steroidogenesis, steroid metabolism, neuroendocrine function, insulin sensitivity, pancreatic β cell function, and alternative adaptations to energy excess. Current research into the genetics and pathophysiology is reviewed. The difficulties inherent in diagnosing PCOS in adolescent girls are discussed.

Conditioning regimens that include cyclophosphamide (CY) and total body irradiation (TBI) induce severe gonadal toxicity and permanent infertility in approximately 90 % of female patients who undergo hematopoietic stem cell transplantation (HSCT). However, the use of ovarian shielding or non-myeloablative regimens may preserve ovarian function. To evaluate the ovarian reserve, serum anti-Müllerian hormone (AMH) levels were retrospectively measured in 11 female HSCT recipients aged less than 40 years, including seven with acute leukemia (AL) and four with aplastic anemia (AA), who received a myeloablative conditioning regimen with ovarian shielding or a reduced-intensity conditioning regimen. In most patients, menstruation had stopped and AMH level had decreased to an undetectable level (<0.1 ng/ml) after HSCT. Most patients showed a recovery of regular menstruation, but AMH levels did not increase immediately after the resumption of menstruation. However, in three AL patients and two AA patients who were evaluable for long-term recovery, AMH level increased gradually beyond 1 year after HSCT. In conclusion, recovery of the serum AMH level may be delayed after HSCT, and the AMH level early after HSCT may not accurately reflect ovarian reserve. A prospective study is required to address the usefulness of measuring the AMH level in HSCT recipients.

The factors which govern the subtle links between follicle loss and mammalian female reproductive ageing remain unclear despite extensive studies undertaken to understand the critical physiological and biochemical mechanisms that underly the accelerated decline in follicle numbers in women older than 37 years. It is not certain whether there is a sole control by the ovary or whether other factors which affect ageing also intersect with the ovarian effect. There is convincing experimental evidence for an interplay of several processes that seem to influence the follicle loss-female reproductive ageing links, with specific hormones (follicle-stimulating hormone, anti-Müllerian hormone, dehydroepiandrosterone) noted to play important roles in follicular dynamics and ovarian ageing. In this work, we examine the subtle links between the rate of follicular decline with ageing and the role of hormones via a series of non-autonomous equations. Simulation results based on the time evolution of the number of ovarian follicles and biochemical changes in the ovarian environment influenced by hormone levels is compared with empirical data based on follicle loss-reproductive ageing correlation studies., (© Crown copyright 2015.)

Anti-Müllerian hormone (AMH) is a glycoprotein produced by the granulosa cells of preantral and small antral follicles. AMH concentrations reflect ovarian physiology with high precision, thus serving as a more sensitive marker of the ovarian re-serve than chronological age. This hormone plays a role in the pathogenesis of menstrual disorders and fertility in both obesity and polycystic ovary syndrome. The evaluation of AMH may also be useful in diagnosing or monitoring therapy of granulosa cell ovarian tumors.

Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women. Excessive ovarian production of Anti-Müllerian Hormone, secreted by growing follicles in excess, is now considered as an important feature of PCOS. The aim of this review is first to update the current knowledge about the role of AMH in the pathophysiology of PCOS. Then, this review will discuss the improvement that serum AMH assay brings in the diagnosis of PCOS. Last, this review will explain the utility of serum AMH assay in the management of infertility in women with PCOS and its utility as a marker of treatment efficiency on PCOS symptoms. It must be emphasized however that the lack of an international standard for the serum AMH assay, mainly because of technical issues, makes it difficult to define consensual thresholds, and thus impairs the widespread use of this new ovarian marker. Hopefully, this should soon improve.

One of the biggest mysteries of ovarian physiology is what controls the emergence of adult primordial follicles from the resting stage, and their steady depletion over the woman's lifetime. A related mystery is why do early oogonia begin meiosis in the fetus and then suddenly arrest for most of fetal and adult life. If fetal oocyte arrest did not occur after meiotic activation, there would be no oocytes left in the female baby by the time she is born. Similarly, without a steady controlled release in the adult ovary of resting follicles, the adult woman would run out of her eggs prematurely and have an early menopause. Could there be a similarity between what causes fetal oocyte arrest and what causes adult oocyte recruitment? The answer begins with the observation of a sudden massive recruitment of primordial follicles after human ovarian transplantation, and the embryologic discoveries about oocyte activation and the time of differentiation of cortex and medulla. The unifying theory is that ovarian cortical tissue pressure controls both fetal oocyte arrest and adult oocyte recruitment., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: This review summarizes recent technological developments in the measurement of anti-Müllerian hormone (AMH) and presents an update of the relative performance characteristics of both AMH and antral follicle count (AFC) in predicting the ovarian response to controlled stimulation., Recent Findings: The introduction of two automated AMH immunoassays appears to have resolved the majority of preanalytical and analytical limitations of the manual assays thereby facilitating the delivery of consistent and accurate results. However, as they exhibit different calibration from preexisting assays, derivation of new reference ranges and clinical thresholds for prediction of ovarian response categories will be required. Randomized controlled trials have highlighted the superiority of AMH to AFC in ovarian response prediction and provide a sound basis for its ongoing assessment for stratification and personalization of treatment., Summary: Trial evidence combined with full automation of AMH assay measurement suggests that the future for ovarian response prediction will be AMH focused. Sonography will continue to be invaluable for the identification of tubal, ovarian and endometrial pathologies, but the days of counting follicles are numbered.

Anti-Müllerian hormone (AMH) is produced by the growing follicles in the ovaries. The number of follicles in this pool is proportional to the number of primordial follicles in the resting pool (the "ovarian reserve"), thus AMH is believed to be a surrogate marker of the ovarian reserve. AMH is a useful adjunct in the evaluation of a woman's "reproductive age", being an important parameter in counselling for reproduction. AMH is also used in pretreatment evaluation of infertile patients guiding proper hormone stimulation. Furthermore, AMH can be used as a tumour marker for granulose cell tumours.

Objective: To determine whether there is a correlation between antimüllerian hormone (AMH) and stem cell factor (SCF) in serum, follicular fluid (FF), and granulosa cells (GCs), and to investigate a possible regulatory mechanism of AMH on SCF in human granulosa cells., Design: Prospective clinical and experimental study., Setting: Academic center., Patient(s): 163 women undergoing IVF., Intervention(s): Serum, FF, and GCs obtained in all women, primary cultures of human GCs., Main Outcome Measure(s): AMH and SCF were analyzed in serum, FF, and GCs, using enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction, and immunoblotting., Result(s): There was a significant negative correlation between AMH and SCF protein level in FF, and in the mRNA expression of AMH and SCF in GCs. Conversely, there was no correlation between AMH and SCF levels in serum. In primary cultures of human GCs, SCF was down-regulated by treatment with recombinant human AMH and was increased by cyclic adenosine 3':5' monophosphate (cAMP) in a dose-dependent manner. A protein kinase A (PKA) inhibitor (H89) significantly reversed the effects of recombinant human AMH and cAMP on SCF mRNA and protein expression., Conclusion(s): This is the first report on a modulatory role for AMH as an ovarian/follicular autocrine/paracrine factor controlling SCF expression via the cAMP/PKA pathway., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Anti-mullerian hormone (AMH) is expressed in women in the granulosa cells, in growing follicles. There is a high correlation between antral follicle count and AMH assay, which therefore makes it a good marker of ovarian reserve. Its indications are the fertility work-up, and the menstrual cycle disorders, to detect polycystic ovarian syndrome (PCOS) or premature ovarian failure on the opposite. During assisted reproductive techniques, AMH assay is very useful choosing the ovarian stimulation protocol and the dose of gonadotropins to begin with, in order to limit the risks of ovarian hyperstimulation syndrome or on the other hand, cancellation of cycles due to poor ovarian response. Finally, with the development of fertility preservation in the context of cancer, AMH assay is useful in evaluating the ovarian reserve after treatments that can be toxic for the ovaries, and the impact of the treatments on ovarian function, as well as organizing fertility preservation. AMH assays techniques are evolving, leading to a better homogeneisation of the results, and allowing the determination of thresholds used by everyone. Furthermore, we have to know that the AMH assay doesn't belong to the official definition of PCOS or premature ovarian failure for the moment, although it is useful in daily practice.

We discuss the hypothesis that AMH is an intraovarian regulator that inhibits follicular atresia within the human ovary. Several indirect lines of evidence derived from clinical and basic science studies in a variety of different patient populations and model systems collectively support this hypothesis. Evidence presented herein include 1) timing of onset of menopause in women with polycystic ovary syndrome, 2) site of cellular origin and timing of AMH production, 3) AMH's influence on other critical growth factors and enzymes involved in folliculogenesis, and 4) AMH's inhibition of granulosa apoptosis. If this hypothesis is true, it may provide insight for treatment strategies for prevention and treatment of premature ovarian insufficiency, slowing natural ovarian aging, and/or delaying eventual ovarian failure. Such findings may lead to the development of 1) AMH agonists for retarding the onset of menopause and/or as a chemoprotectant prior to cancer therapy and 2) AMH antagonists for the treatment of PCOS.

The existence of the anti-Müllerian hormone (AMH) has been postulated by Professor Alfred Jost to explain the regression of the Müllerian ducts during male sexual differentiation. Since then, AMH has been purified, its gene and specific receptor, AMHR-II have been cloned. Further, the signaling pathways were identified and it has been observed that AMH was produced by the granulosa cells of growing follicles. From the 2000s, unexpected roles of AMH have been highlighted, reactivating international research on this hormone. It is now well established that AMH plays a key role in the follicular recruitment and development. Over the past years, serum AMH measurements have been proposed as a marker of the follicular ovarian status, and a predictor of assisted reproductive cycles. AMH is also useful to assess the effectiveness of treatment of some gynecological tumors. This article is a review of the past five years advances on the regulation of the expression of AMH and its specific receptor AMHR-II in female., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objective: To demonstrate interregulation between FOXL2 and antimüllerian hormone (AMH) in ovarian folliculogenesis., Design: Cell culture and animal study., Setting: University research laboratory., Animal(s): Five-week-old B6C3F1 mice., Interventions(s): Molecular analysis and in vivo mouse experiment were performed to demonstrate that AMH is a target gene of FOXL2 in the ovary., Main Outcome Measure(s): To determine whether FOXL2 transactivates AMH, luciferase reporter assay, electrophoretic mobility shift assay, and chromatin immuniprecipitation were conducted. Using an in vivo nucleic acid delivery system, the expression of AMH and/or FOXL2 was modulated in the mouse, and the ovaries were histologically analyzed., Result(s): AMH is an endogenous target gene of FOXL2. In contrast, mutated FOXL2s found in premature ovarian failure patients were defective in their ability to activate AMH transcription in human granulosa cells. In vivo mouse gene delivery experiments revealed that Amh-knockdown accelerated follicle growth; however, the acceleration was prevented by ectopic expression of FOXL2., Conclusion(s): AMH and FOXL2 collaboratively work to reserve ovarian follicles., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The anti-mullerian hormone (AMH) is a member of the transforming growth factor β (TGF-β) superfamily, which is responsible of the regression of the mullerian duct. AMH is expressed in the normal endometrium, where, acting in a paracrine fashion, negatively regulates cellular viability. Our objective was to evaluate the in vitro effects of the treatment with AMH of endometriosic cells., Methods: AMH expression in human endometriosis glands was evaluated by immunohistochemistry. RT-PCR has been used to quantify the expression levels of AMH and AMH RII isoforms, as well as of cytochrome P450 in both endometriosis epithelial and stromal cells Effects of AMH and AMH-cleaved treatment in endometriosis cells were evaluated by flow-cytometry analysis. Finally, it has been evaluated the effect of plasmin-digested AMH on cytochrome P450 activity., Results: AMH and AMH RII isoforms, as well as cytochrome P450, were expressed in both endometriosis epithelial and stromal cells. Treatment of endometriosis stromal and epithelial cell growth with AMH was able to induce a decrease in the percentage of cells in S phase and increase percentage of cells in G1 and G2 phase; coherently, decreased cell viability and increased percentage of cells death fraction was observed. The plasmin-digested AMH was able to suppress most of the cytochrome P450 activity, causing an increase of pre-G1 phase and of apoptosis induction treating with plasmin-digested AMH in both cell lines, most marked in the epithelial cells., Conclusions: The data produced suggest a possible use of AMH as therapeutic agents in endometriosis.

BACKGROUND The measurement of circulating anti-Müllerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood.

The growing follicles develop from a reserve of primordial follicles constituted early in life. From this pre-established reserve, a second ovarian reserve is formed, which consists of gonadotropin-responsive small antral growing follicles and is a dynamic reserve for ovulation. Its size, evaluated by direct antral follicular count or endocrine markers, determines the success of assisted reproductive technologies in humans and embryo production biotechnologies in animals. Strong evidence indicates that these two reserves are functionally related. The size of both reserves appears to be highly variable between individuals of similar age, but the equilibrium size of the dynamic reserve in adults seems to be specific to each individual. The dynamics of both follicular reserves appears to result from the fine tuning of regulations involving two main pathways, the phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDPK1)/v-akt murine thymoma viral oncogene homolog 1 (AKT1) and the bone morphogenetic protein (BMP)/anti-Müllerian hormone (AMH)/SMAD signaling pathways. Mutations in genes encoding the ligands, receptors, or signaling effectors of these pathways can accelerate or modulate the exhaustion rate of the ovarian reserves, causing premature ovarian insufficiency (POI) or increase in reproductive longevity, respectively. With female aging, the decline in primordial follicle numbers parallels the decrease in the size of the dynamic reserve of small antral follicles and the deterioration of oocyte quality. Recent progress in our knowledge of signaling pathways and their environmental and hormonal control during adult and fetal life opens new perspectives to improve the management of the ovarian reserves.