What is the recommended evaluation and treatment approach for a female patient of reproductive age with concerns about fertility and abnormal Anti-Mullerian Hormone (AMH) levels?

Evaluation and Management of Abnormal AMH Levels in Reproductive-Age Women

For reproductive-age women with abnormal AMH levels, the evaluation and management strategy depends critically on whether AMH is low (suggesting diminished ovarian reserve) or elevated (suggesting PCOS), with immediate specialist referral required for low AMH and fertility counseling being paramount in both scenarios. 1

Initial Clinical Assessment Based on AMH Level

Low AMH Levels

Women with low AMH require immediate referral to reproductive endocrinology, gynecology, or endocrinology for comprehensive evaluation and management. 1 The urgency stems from the fact that low AMH indicates diminished ovarian reserve with reduced fertility potential, though it is important to understand that AMH primarily reflects the quantity of growing follicles responsive to gonadotropins rather than the entire primordial pool. 2

Key diagnostic workup for low AMH includes:

• FSH, LH, and estradiol levels to assess for premature ovarian insufficiency (POI), with markedly elevated FSH and LH providing stronger discrimination for POI diagnosis 3, 1
• Repeat testing if POI is suspected, as undetectable AMH (<0.01) combined with severely low estradiol (<5) is diagnostic of POI 3
• Karyotype analysis to exclude Turner syndrome or chromosomal abnormalities 3
• Fragile X premutation testing as a genetic cause of POI 3
• Thyroid function tests to evaluate for autoimmune oophoritis 3
• Bone mineral density (DEXA scan) to assess for osteoporosis from chronic estrogen deficiency 3, 1

Elevated AMH Levels

Elevated AMH suggests polycystic ovary syndrome (PCOS), which is the most common endocrine disorder affecting 8-13% of reproductive-aged women and the leading cause of anovulatory infertility. 4 AMH levels are significantly higher in women with PCOS compared to normal ovulatory women, and AMH has been proposed as a valuable surrogate marker for detecting polycystic ovarian morphology (PCOM). 4

For suspected PCOS, transvaginal ultrasound (TVUS) remains the primary imaging modality to confirm PCOM, defined as >25 small follicles in at least one ovary or a single ovarian volume >10 mL. 4 However, PCOS diagnosis requires fulfilling two of three Rotterdam criteria: oligo- or anovulation, clinical/biochemical hyperandrogenism, and/or polycystic ovaries on ultrasound. 4

Critical Fertility Counseling Points

Regardless of AMH level, contraception remains mandatory even in patients with low AMH and amenorrhea, as spontaneous pregnancy can occur in 5-10% of POI cases and alkylator-associated gonadal toxicity is extremely variable. 3, 1 This is a common pitfall—assuming that low AMH or amenorrhea equals infertility.

For women desiring future pregnancy with low AMH:

• Urgent fertility counseling is required as low AMH indicates diminished ovarian reserve 1
• Oocyte cryopreservation should be considered for fertility preservation 1
• Prompt fertility evaluation and attempts are recommended per American Society for Reproductive Medicine guidelines for women with diminished ovarian reserve 1
• Alternative options include oocyte donation, gestational surrogacy, or adoption if natural conception fails 3

Hormone Replacement Therapy for Low AMH/POI

Hormone replacement therapy is the cornerstone of treatment for confirmed POI or hypogonadism to prevent long-term complications including osteoporosis, cardiovascular disease, and sexual dysfunction. 3, 1 This should be initiated immediately upon diagnosis. 3

Progesterone therapy is mandatory in women with a uterus to avoid unopposed estrogen effects and maintain endometrial health. 1 The timing and tempo of estrogen HRT are crucial in pubertal patients to ensure acceptable final height and should be managed by providers with expertise in pediatric development. 1

Imaging Considerations

Transvaginal ultrasound is the primary imaging modality for evaluating ovarian reserve through antral follicle count (AFC), which shows strong positive correlation with AMH levels. 4, 5 When ovarian volume is <3 cm³ and <5 antral follicles are present, this suggests diminished ovarian reserve. 4

Transabdominal ultrasound should only be relied upon if the ovaries are not adequately evaluated via transvaginal approach. 4 MRI without IV contrast might be useful in the few patients for whom ovaries are not adequately visualized with ultrasound, though there is no literature supporting contrast-enhanced MRI for assessing antral follicle counts. 4

Important Caveats and Limitations

AMH has significant limitations as a fertility predictor in the general population. Multiple large studies, including a cohort of over 1,200 women, found that women with AMH values <0.7 ng/ml had similar pregnancy rates after 12 cycles of attempting to conceive as women with normal AMH values after adjusting for age. 6 AMH reflects ovarian reserve quantity but does not assess oocyte or embryo quality. 7

AMH interpretation is most reliable in women ≥25 years where validated normative data exist, as AMH can fluctuate throughout the menstrual cycle particularly in young women under 25 years. 5, 2 The lack of an international standard for AMH limits comparison between different AMH assays, and direct comparison of results remains problematic. 5

Recent international PCOS guidelines recommend against using ultrasound in PCOS diagnosis within 8 years of menarche due to overlap between multi-follicular appearance and PCOM diagnostic cut-offs in adolescents. 4

Age-Specific Considerations

AMH is inversely correlated with increasing age in women ≥25 years, making it a clinically useful marker of ovarian reserve in this population and providing information about remaining reproductive lifespan. 5, 8 The fertility peak occurs in the early 20s and starts to decline in the third and fourth decades of life, falling sharply after age 35. 8

For at-risk postpubertal females without signs of POI who desire assessment of future fertility, referral for specialist consultation is recommended rather than relying on a single AMH test. 5

Special Populations

In cancer survivors treated with alkylating agents and/or radiotherapy, AMH is frequently used as a marker of ovarian reserve, though AMH levels may recover after low doses of alkylating chemotherapy. 1, 5 Gonadotropin-releasing hormone agonist treatment before gonadotoxic therapy should be considered to attenuate risk of premature menopause. 1