Anti-Müllerian Hormone (AMH) has emerged as one of the most significant biomarkers in reproductive medicine, offering valuable insights into ovarian reserve, fertility potential, and various reproductive disorders. This comprehensive article explores the biology of AMH, its clinical applications in fertility assessment, its role in both male and female reproductive health, and its emerging therapeutic potential.

Understanding AMH: Basic Biology and Physiology

Anti-Müllerian Hormone (AMH), also known as Müllerian-inhibiting substance (MIS), is a glycoprotein member of the transforming growth factor-β (TGF-β) superfamily. This dimeric molecule plays crucial roles in sexual differentiation and reproductive function across the lifespan 12.

Production and Secretion Patterns

In males, AMH is secreted by Sertoli cells of the testes beginning in fetal development. It serves the critical function of inducing regression of the Müllerian ducts during male sexual differentiation—a process typically completed within the first three months of fetal development. Remarkably, Sertoli cells continue to produce substantial amounts of AMH postnatally until puberty 2.

In females, AMH is produced primarily by the granulosa cells of small antral and preantral ovarian follicles. Ovarian AMH expression begins at approximately 36 weeks of gestation and continues throughout a woman’s reproductive life until menopause 2. The hormone plays a key regulatory role in follicular development by:

• Inhibiting primordial follicle recruitment
• Reducing follicle sensitivity to follicle-stimulating hormone (FSH)
• Modulating aromatase activity
• Participating in the selection of the dominant follicle 1

Lifecycle Variations in AMH Levels

AMH levels follow distinct patterns throughout life that differ significantly between sexes:

Male AMH trajectory:

• High at birth with a slight postnatal increase
• Begins declining around age 2
• Decreases rapidly during childhood and adolescence
• Maintains at relatively low levels in adulthood 2

Female AMH trajectory:

• Low at birth with gradual postnatal increase
• Peaks at age 9
• Declines until age 14
• Increases again to peak at approximately age 25
• Declines steadily with age as the antral follicle pool diminishes
• Drops precipitously at menopause to nearly undetectable levels 2

Unlike other reproductive hormones, AMH demonstrates relatively stable levels throughout the menstrual cycle, allowing for reliable testing at any point in the cycle 2.

AMH as a Biomarker of Ovarian Reserve

Assessing Ovarian Reserve

AMH has become the gold standard biomarker for evaluating ovarian reserve—the quantity of remaining oocytes in a woman’s ovaries. This assessment is crucial for:

• Predicting response to ovarian stimulation in fertility treatments
• Estimating reproductive lifespan
• Identifying diminished ovarian reserve
• Guiding fertility preservation decisions 18

Two primary methods exist for estimating ovarian reserve:

1. AMH blood test: Measures circulating levels of the hormone
2. Antral follicle count (AFC) ultrasound: Counts visible small antral follicles at the cycle’s beginning 8

These measures correlate strongly with the total remaining follicular pool. A typical AFC ranges from:

• 10-20 follicles for women in their 20s to early 30s
• 8-15 follicles for women in their late 30s
• Under 10 follicles for women in their 40s 8

Interpreting AMH Levels

Clinically, AMH levels are categorized as:

• Average: 1.0-3.0 ng/mL
• Low: <1.0 ng/mL
• Severely low: ≤0.4 ng/mL 8

However, these values must be interpreted in the context of age and clinical presentation. Importantly, while AMH reflects quantitative ovarian reserve, it does not directly measure oocyte quality—a critical factor in fertility potential 8.

Clinical Applications in Female Fertility

In Vitro Fertilization (IVF) and Assisted Reproduction

AMH plays a pivotal role in assisted reproductive technologies (ART), particularly IVF and intracytoplasmic sperm injection (ICSI):

1. Predicting ovarian response: AMH levels strongly correlate with the number of oocytes retrieved during stimulation cycles. Women with higher AMH tend to produce more eggs, while those with low AMH may require more aggressive stimulation protocols 18.
2. Individualizing stimulation protocols: AMH helps fertility specialists select appropriate medication types and doses, minimizing risks of poor response or ovarian hyperstimulation syndrome (OHSS) 1.
3. Predicting IVF outcomes: While AMH correlates with oocyte yield, its relationship with live birth rates is more complex. Studies show that AMH and AFC alone cannot reliably predict pregnancy success, as other factors like embryo quality and uterine receptivity play significant roles 15.

Research demonstrates that IVF patients with higher AMH levels typically require less gonadotropin (Gn), produce more mature (MII) oocytes, generate more high-quality embryos, and have more embryos available for transfer or cryopreservation 5. However, age remains a critical independent factor—younger women with low AMH often have better outcomes than older women with similar AMH levels 5.

Polycystic Ovary Syndrome (PCOS)

PCOS patients characteristically exhibit elevated AMH levels (typically 2-3 times higher than normal) due to increased numbers of small antral follicles. AMH has emerged as both a diagnostic marker and potential therapeutic target in PCOS 37.

Diagnostic utility:

• Chinese studies established age-specific AMH cutoffs for PCOS diagnosis:
  • 8.16 ng/mL for women aged 20-29
  • 5.89 ng/mL for women aged 30-39 2

Pathophysiological role:
Emerging evidence suggests AMH may actively contribute to PCOS pathology rather than simply reflecting follicle count. Recent preclinical studies indicate that elevated AMH may:

• Cause premature follicular maturation
• Disrupt synchronization between follicular and oocyte development
• Contribute to anovulation 7

This new understanding opens potential avenues for AMH-targeted therapies in PCOS management.

Diminished Ovarian Reserve and Reproductive Aging

Low AMH levels indicate diminished ovarian reserve (DOR), but this diagnosis requires careful interpretation:

• DOR does not equate to infertility: Many women with low AMH conceive naturally
• DOR doesn’t imply poor egg quality: Quality is primarily age-dependent
• DOR doesn’t mandate fertility treatment: Natural conception remains possible 8

However, low AMH, particularly in older women, may signal a shortened reproductive window, warranting more proactive family planning or fertility preservation 28.

AMH in Male Reproductive Health

While less prominent than in female reproduction, AMH plays several important roles in male fertility:

Sexual Differentiation and Development

During male fetal development, AMH induces regression of Müllerian ducts, preventing formation of female reproductive structures. Absent or extremely low AMH in genetic males can result in persistent Müllerian duct syndrome (PMDS), characterized by the presence of both male and female reproductive structures 210.

Assessing Testicular Function

In males, AMH serves as a sensitive marker of Sertoli cell function:

• Childhood: High AMH levels reflect active Sertoli cell function
• Puberty: AMH declines as testosterone increases
• Adulthood: Maintains at low but detectable levels 210

Male Infertility Applications

AMH measurement aids in:

1. Differentiating obstructive vs. non-obstructive azoospermia: Men with non-obstructive azoospermia (NOA) typically show significantly lower AMH than those with obstructive causes 2.
2. Evaluating Klinefelter syndrome: These patients demonstrate:
   • Normal AMH during childhood
   • Delayed AMH decline at puberty onset
   • Very low levels in adulthood reflecting testicular failure 2
3. Assessing sperm production: Some evidence suggests AMH may enhance sperm motility, though research remains limited 2.

Factors Influencing AMH Levels

Several endogenous and exogenous factors can affect AMH measurements:

Endogenous Factors

• Age: The primary determinant in both sexes
• Body composition: Obesity correlates with lower AMH 2
• Vitamin D status: May influence serum AMH levels 2
• Hypogonadotropic hypogonadism: Can falsely suppress AMH 2

Exogenous Factors

• Hormonal contraceptives: May reduce AMH by up to 50% within 9 weeks, though this effect is reversible after discontinuation 2
• Acupuncture: Some studies suggest follicular phase acupuncture may improve reproductive outcomes in PCOS patients undergoing IVF, though without altering AMH levels 4

Limitations and Controversies

While AMH has revolutionized reproductive medicine, several limitations merit consideration:

1. Not a fertility test: AMH doesn’t predict natural conception ability in normally cycling women without known infertility 68.
2. Quality vs. quantity: AMH reflects follicle number but not oocyte competence 28.
3. Predictive limitations: In long-term studies, low AMH (<0.7 ng/mL) didn’t predict reduced future live birth rates in women aged 30-44 2.
4. Overuse concerns: Routine AMH testing in women without fertility concerns remains controversial due to potential for unnecessary anxiety 6.

Emerging Research and Therapeutic Potential

Recent investigations explore novel applications of AMH:

1. PCOS treatment: AMH may represent a new therapeutic target for restoring ovulation 7.
2. Fertility preservation: AMH helps identify candidates for oocyte or embryo cryopreservation.
3. Male contraception: Potential role in regulating spermatogenesis.
4. Oncofertility: Predicting chemotherapy-induced ovarian damage.

Conclusion

Anti-Müllerian Hormone has transformed our understanding and management of reproductive health across genders and life stages. As a robust marker of ovarian reserve, it plays an indispensable role in assisted reproduction, fertility assessment, and reproductive aging. However, clinicians must interpret AMH values judiciously, recognizing that they represent just one piece of the complex fertility puzzle. Ongoing research continues to uncover new biological roles and clinical applications for this remarkable hormone, promising to further enhance reproductive care in the years ahead.