What are the causes of elevated Anti-Mullerian Hormone (AMH) levels in a female patient with a normal Luteinizing Hormone (LH): Follicle-Stimulating Hormone (FSH) ratio?

Causes of Elevated AMH with Normal LH:FSH Ratio

The most common cause of elevated AMH in a female patient with a normal LH:FSH ratio is polycystic ovary syndrome (PCOS), particularly in phenotypes where polycystic ovarian morphology (PCOM) is present without the characteristic elevated LH:FSH ratio. 1

Primary Differential Diagnosis

Polycystic Ovary Syndrome (PCOS)

• PCOS is the leading cause of elevated AMH levels, with serum concentrations significantly higher in PCOS patients (median 7.6-9.3 µg/L) compared to normoovulatory women (median 2.1 µg/L). 2
• AMH levels correlate strongly with polycystic ovarian morphology, ovarian volume (r=0.521), and follicle number (r=0.461), making it a potent marker for ovarian dysfunction. 3
• While PCOS classically presents with elevated LH:FSH ratio, not all PCOS phenotypes demonstrate this hormonal pattern—the Rotterdam criteria require only 2 of 3 features (oligo/anovulation, hyperandrogenism, PCOM), meaning PCOS can exist with normal gonadotropin ratios. 1
• AMH levels are highest in PCOS phenotype A (12.67 ± 3.46 ng/ml) and lowest in phenotype B (7.28 ± 1.60 ng/ml) where PCOM is absent. 3

Functional Hypothalamic Amenorrhea (FHA) with Underlying PCOM

• FHA with PCOM represents a paradoxical but increasingly recognized entity where elevated AMH persists despite suppressed gonadotropins. 1
• Up to 48% of women with FHA demonstrate PCOM on ultrasound, which is overrepresented compared to the general population (14-33%). 1
• This may represent either: (1) incidental PCOM as a normal variant, (2) "hidden" or "masked" PCOS where hypothalamic suppression blunts typical PCOS features except PCOM, or (3) women with PCOS who subsequently developed FHA. 1
• The key distinguishing feature is that LH and FSH are both low (<2 IU/L) in FHA, whereas the LH:FSH ratio itself may appear mathematically normal or even elevated despite absolute low values. 1

Secondary Considerations

Age-Related Physiological Variation

• AMH naturally peaks around age 25 years in the general population, so elevated levels may represent normal physiological variation in younger women. 1
• AMH testing is more reliable for clinical interpretation in women ≥25 years where validated normative data exist. 1, 4

Increased Ovarian Reserve (Non-Pathological)

• Some women naturally have higher follicle counts without meeting PCOS criteria, representing the upper end of normal ovarian reserve distribution. 1
• This is particularly relevant if the patient has regular ovulatory cycles, no hyperandrogenism, and normal metabolic parameters.

Diagnostic Algorithm

To differentiate between these causes, evaluate the following systematically:

1. Menstrual pattern assessment:

   • Regular cycles with ovulation → Consider high normal ovarian reserve or mild PCOS
   • Oligomenorrhea/amenorrhea → Proceed to step 2 1

2. Absolute gonadotropin values (not just ratio):

   • Both LH and FSH <2 IU/L with estradiol <100 pmol/L → FHA with PCOM 1
   • Normal to elevated absolute LH with normal FSH → PCOS despite normal ratio 5, 2
   • Both in normal range → Proceed to step 3

3. Hyperandrogenism evaluation:

   • Clinical (hirsutism, acne) or biochemical (elevated testosterone, free androgen index) → PCOS 1, 2
   • Absent → Consider FHA triggers or physiological variant

4. FHA risk factors:

   • Low BMI (<20 kg/m²), eating disorders, excessive exercise (>6 hours/week), stress, weight preoccupation → FHA with PCOM 1
   • Endometrial thickness <4mm supports FHA diagnosis 1

5. Ultrasound confirmation:

   • PCOM (≥12 follicles per ovary measuring 2-9mm and/or ovarian volume >10mL) strengthens PCOS or FHA-PCOM diagnosis 1, 2

Critical Pitfalls to Avoid

• Do not assume normal LH:FSH ratio excludes PCOS—the ratio can be normal in certain PCOS phenotypes, and AMH elevation may be the primary marker. 1, 3
• Avoid using Rotterdam criteria without differential diagnosis, as this leads to false positives when FHA is present with PCOM. 1
• In women with low BMI and elevated AMH, specifically screen for FHA triggers before labeling as PCOS, as management differs fundamentally. 1
• Consider that oral contraceptives suppress but do not eliminate PCOM—follicle counts decrease by 30-40% but remain elevated, which could confound interpretation if recently discontinued. 1
• AMH assay variability exists—interpret values in context of specific laboratory reference ranges and consider repeat testing if clinically discordant. 1

Mechanistic Insights

• In PCOS, AMH is secreted by the increased number of small antral follicles and may be directly stimulated by LH in granulosa cells, explaining elevation even when LH:FSH ratio appears normal. 5, 2
• AMH itself inhibits primordial follicle recruitment and suppresses FSH action, contributing to ovulatory disturbances in PCOS. 1
• The correlation between AMH and LH (r=0.331) in PCOS suggests LH-mediated AMH production, though this relationship is complex and not always reflected in the LH:FSH ratio. 2, 3