Androgens, FSH, anti-Müllerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood.
The ...purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS).
A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980-2015 and the databases interrogated were PubMed and Web of Science.
During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS.
Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS.
Objective To determine whether the different antimüllerian hormone (AMH) immunoassays on the market offer the same performance for the diagnosis of polycystic ovary syndrome (PCOS). Design A total of ...95 serum AMH samples were retrospectively evaluated for a period of 3 months in the same laboratory. Setting Academic center laboratory. Patient(s) Forty-eight control women with regular menses and no hyperandrogenism and 47 patients with classic PCOS (i.e., hyperandrogenism plus oligoanovulation) attending our department for infertility. Intervention(s) None. Main Outcome Measure(s) AMH measurement using five commercial assays. Method comparison and evaluation of the diagnostic performance by receiver operating characteristic analysis. Result(s) Values obtained with Gen II and AL-105i ELISAs were similar to those provided by EAI AMH/MIS, whereas automatic assays generated lower values. A significant mean difference was observed between Access Dxi (1.35 ng/mL) or Cobas (1.73 ng/mL) and EIA AMH/MIS ELISA. By ROC analysis each assay displayed similar efficiency for PCOS diagnosis. Sensitivities varied from 49% to 74% when setting the specificity at 92%. Cluster analysis run in the control group identified a subgroup of asymptomatic women with polycystic ovary morphology (PCOM). After exclusion of PCOM, the 95th percentile of controls was 4.2 ng/mL (30 pmol/L) with the automatic assays and 5.6 ng/mL (40 pmol/L) with the manual assays. Conclusion(s) Performance of the different AMH assays for PCOS diagnosis is comparable, providing that different threshold values are used for manual and automatic assays. Measurement of serum AMH level appears as a robust tool for the definition of PCOM.
Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation ...to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.
Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain ...unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS.
Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. ...Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, the current knowledge related to the role of RNA-binding proteins in the whole mRNA life-cycle is summarized. This field opens up a new angle for understanding the importance of the post-transcriptional control of gene expression in cancer cells. The emerging role of non-classic RNA-binding proteins is highlighted. The goal of this review is to encourage readers to view, through the mRNA life-cycle, novel aspects of the molecular basis of cancer and the potential to develop RNA-based therapies.
Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with ...anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (
) and its receptor,
, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of
-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.
The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and ...hypoglycemia unawareness and/or a functioning kidney graft.
We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median interquartile range) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function.
The primary outcome was met by (Kaplan-Meier estimates 95% CI) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence.
Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.
Abstract Susceptibility of the ovarian reserve to chemotherapy is highly variable from one patient to another and poorly documented. To better characterize the evolution of follicular depletion in ...patients treated for lymphoma, serum anti-Müllerian hormone (AMH) assay was used. A total of 30 young women (mean age 24 years) were prospectively recruited before initiation of chemotherapy for lymphoma. They were assigned either to an adriamycin, bleomycin, vinblastine and dacarbazine protocol (ABVD group) or to a protocol that included cyclophosphamide (non-ABVD group). AMH assays were performed before and during chemotherapy, and then every 3 months after the end of treatment for a period of 1 year. In all patients, AMH concentrations fell drastically just after the start of chemotherapy and were close to the detection limit at the end of the treatment. In the ABVD group, AMH concentrations increased from the third month after the end of chemotherapy and returned to pretreatment values 12 months after the end of chemotherapy. Conversely, no significant change was observed in the non-ABVD group throughout the follow-up period. In conclusion, longitudinal analysis of AMH during chemotherapy highlights differences between protocols that could contribute to an understanding of ovarian toxicity and, ultimately, be useful in fertility preservation counselling.
PDF
