Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood

Abstract

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 if their levels were also elevated in pregnant women with PCOS. Here, we measured AMH in a cohort of pregnant women with PCOS and control women and found that AMH is significantly more elevated in the former group versus the latter. To determine if the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modelled 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.

Rapid actions of anti‐Müllerian hormone in regulating synaptic transmission and long‐term synaptic plasticity in the hippocampus

“…Although null mutation of Amh or Amhr2 is very rare in humans, which limits detailed studies of the potential role of Amh in hippocampal function in patients, a population-based cohort study demonstrated a significant association between Amh single nucleotide polymorphisms and cognitive function parameters in man. 2,4 A recent study in mice demonstrated that Amh in the circulation did not cross the blood-brain barrier, 14 a highly selective barrier operating at birth. 13 However, the source of Amh ligand in the brain requires a thorough investigation.…”

A new evidence‐based guideline for assessment and management of polycystic ovary syndrome

“…Many women are not diagnosed or have long delays before the condition is recognised 2 . Key patient needs are not being met well, and knowledge gaps have been shown in both patients and health professionals alike 2 , 3 . This is of particular concern in a condition where the prevalence is generally considered to be between 9% and 18%, depending on the definition and the population studied 4 …”

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

“…Indeed, in addition to gonads, AMHR2 mRNA has recently been localized in rodent and human GnRH neurons, and intracerebroventricular or peripheral injections of AMH in mice were able to increase LH secretion [25, 26]. Furthermore, AMHR2 was identified in rodent pituitary as well as in gonadotrope cells, and AMH was shown to positively regulate FSH [16, 27, 65].…”

“…Furthermore, accumulating evidence shows that AMH contributes to the central control of gonadal functions. The AMH receptor was indeed identified in a significant subset of hypothalamic GnRH neurons in mice and humans, and AMH was found to potently activate the GnRH neuron firing [25, 26]. Amhr2 transcripts and proteins are also present in rat pituitary gland as well as in the gonadotrope cell line LβT2 [16, 27].…”