Anti-Müllerian Hormone’s Role in PCOS: A New Target for Treatment

Understanding PCOS: A Complex Hormonal Disorder

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects millions of women of reproductive age. Characterized by hyperandrogenism, irregular ovulation, and polycystic ovarian morphology (PCOM), PCOS has multifactorial roots. Genetics, neuroendocrine imbalances, ovarian dysfunction, and metabolic factors all contribute to its development.

One of the central mechanisms driving PCOS is gonadotropin dysregulation. An increased pulse frequency of gonadotropin-releasing hormone (GnRH) leads to a disproportionately high secretion of luteinizing hormone (LH) over follicle-stimulating hormone (FSH). This hormonal imbalance stimulates theca cells to produce androgens excessively, worsening hyperandrogenism.

Insulin resistance (IR) is another key contributor. Elevated insulin levels act synergistically with LH to promote androgen synthesis and reduce sex hormone-binding globulin (SHBG) levels, increasing circulating androgens. IR is also linked to obesity, dyslipidemia, and impaired glucose tolerance, compounding the reproductive and metabolic dysfunctions in PCOS.

AMH in Focus: More Than a Marker

Among the hormonal disruptions in PCOS, anti-Müllerian hormone (AMH) stands out as a potential linchpin. A glycoprotein from the transforming growth factor-beta (TGF-β) family, AMH is secreted by granulosa cells in pre-antral and small antral follicles.

In individuals with PCOS, AMH levels are two to three times higher than in healthy controls. Elevated AMH reduces ovarian follicles’ sensitivity to FSH, contributing to follicular arrest and anovulation. It also enhances GnRH neuron activity, which increases LH secretion, further entrenching hormonal imbalance. High AMH also inhibits aromatase activity, leading to androgen accumulation.

Though primarily studied in the ovarian context, emerging evidence suggests AMH may also impact metabolic processes, including insulin sensitivity and lipid metabolism. However, this review focuses specifically on AMH’s regulatory mechanisms and therapeutic potential in PCOS.

What Drives AMH Overexpression in PCOS?

The study breaks down the regulation of AMH expression into three main levels: transcriptional, post-transcriptional, and post-translational. The complexity of this control suggests multiple potential targets for therapy.

Transcriptional Regulation

Several transcription factors interact at the AMH gene promoter:

• GATA4, which plays a pivotal role in gonadal development, especially during male embryogenesis.

• Steroidogenic factor 1 (SF1) and FOXL2, which cooperatively activate AMH expression in granulosa cells.

• Wilms tumor 1 (WT1), which also modulates AMH and its receptor (AMHR2).

Notably, the human AMH promoter contains CpG islands, which are targets for DNA methylation. The review cites studies linking altered methylation of AMH in PCOS patients to disrupted gene expression, underlining a potential epigenetic layer to the condition.

Post-Transcriptional Regulation: The Role of Non-Coding RNAs

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) fine-tune AMH levels after transcription:

• miR-200 family, miR-140-3p, and miR-155 have been shown to target AMH mRNA, reducing its translation or promoting degradation.

• The lncRNA H19 regulates AMH by sequestering Let-7 miRNA, which otherwise suppresses AMH expression. Reduced H19 levels, seen in women with diminished ovarian reserve, correlate with lower AMH.

These findings point to a layered network of regulation, where non-coding RNAs contribute to the pathogenesis of PCOS by maintaining or suppressing AMH.

Post-Translational Modifications: Activating the AMH Protein

For AMH to become biologically active, it must undergo specific modifications:

• Proteolytic cleavage by enzymes like furin.

• Glycosylation, ensuring protein stability and secretion.

• Dimerization, necessary for receptor binding.

• Interaction with the prodomain, which regulates AMH’s activity timing.

Disruptions at this level can render AMH inactive despite normal gene expression—highlighting additional checkpoints in its biological role.

AMH Signaling: The SMAD Pathway and Beyond

Once activated, AMH binds to its receptor, AMHR2, and initiates a SMAD1/5/8 signaling cascade. These SMAD proteins enter the nucleus and influence genes involved in follicle development and granulosa cell differentiation.

In PCOS, excessive AMH leads to overactivation of SMAD signaling, further inhibiting follicular recruitment and FSH sensitivity. This causes the accumulation of small antral follicles—a hallmark of PCOS.

Hormonal Interplay: AMH, FSH, and Androgens

The balance between AMH and FSH governs healthy folliculogenesis. AMH reduces granulosa cells’ sensitivity to FSH, controlling how many follicles mature each cycle. In PCOS, elevated AMH tips this balance, stalling follicle development.

Androgens also feed into this loop. Granulosa cells have androgen receptors, and exposure to dihydrotestosterone (DHT) increases AMH expression. In PCOS, hyperandrogenism thus intensifies AMH overproduction and worsens ovulatory dysfunction.

Therapeutic Potential: Targeting the AMH Pathway

Several therapeutic avenues are under exploration:

• AMHR2 antagonists, including monoclonal antibodies like murlentamab and GM102, aim to block AMH signaling at the receptor level.

• GnRH antagonists, such as cetrorelix and ganirelix, reduce LH and androgen production, indirectly lowering AMH levels.

• Aromatase inhibitors (e.g., letrozole) increase FSH levels by decreasing estrogen feedback, helping counteract AMH’s effects.

• Anti-androgens (e.g., spironolactone, flutamide) reduce AMH stimulation by lowering androgen levels.

These approaches show promise in restoring normal folliculogenesis and improving fertility in PCOS patients.

Toward Personalized Therapies

PCOS is a heterogeneous disorder, with different phenotypes showing variable AMH levels. Targeted therapies may be most effective in patients with elevated AMH and severe anovulation. The authors advocate for a personalized medicine approach, where hormonal profiles guide treatment selection.

Final Thoughts

This review underscores AMH’s central role in PCOS—not only as a diagnostic biomarker but also as a functional driver of disease. By unraveling the regulatory mechanisms behind AMH expression and signaling, researchers are identifying novel therapeutic targets that may one day lead to more effective, individualized treatment options for women with PCOS.

The translation of the preceding English text in Chinese:

了解多囊卵巢综合征（PCOS）：一种复杂的激素紊乱疾病