What are the treatment options for a patient with low Antimullerian Hormone (AMH) levels?

Treatment Options for Low Anti-Müllerian Hormone (AMH) Levels

The primary treatment approach for low AMH depends on the underlying cause and clinical context: hormone replacement therapy for hypogonadism/premature ovarian insufficiency, fertility preservation counseling with prompt referral to reproductive endocrinology, and assisted reproductive technology when pregnancy is desired. 1

Initial Assessment and Specialist Referral

Patients with low AMH require immediate referral to endocrinology, gynecology, or reproductive endocrinology for comprehensive evaluation and management. 1

• Endocrinology/gynecology referral is indicated for: delayed puberty, persistently abnormal hormone levels (elevated FSH/LH, low estradiol), or confirmed hypogonadism 1
• Reproductive endocrinology referral is warranted for: infertility evaluation, consultation on assisted reproduction, gestational surrogacy options, and fertility preservation strategies 1
• For postpubertal females with regular menstrual cycles but gonadotoxic treatment history: referral is recommended even without symptoms of premature ovarian insufficiency (POI), as they remain at risk for decreased ovarian reserve and reduced fertility 1

Hormone Replacement Therapy (HRT)

For patients with hypogonadism or premature ovarian failure, hormone replacement therapy is the cornerstone of treatment to normalize ovarian hormone levels and prevent long-term complications. 1

Estrogen Replacement Options:

• Oral, micronized, or transdermal estrogen preparations 1
• Oral contraceptives and transdermal devices provide various estrogen and progesterone formulations 1

Critical Considerations:

• Progesterone therapy is mandatory in women with a uterus to avoid unopposed estrogen effects and maintain endometrial health 1
• HRT regimens differ significantly between survivors who were prepubertal before gonadotoxic therapy versus those who experience gonadal failure after menarche 1
• In pubertal patients, timing and tempo of estrogen HRT are crucial to ensure acceptable final height and should be managed by providers with expertise in pediatric development (pediatric endocrinologist, adolescent gynecologist) 1
• Postmenarchal women with amenorrhea can be monitored for resumption of menses for 1 year; those remaining amenorrheic, symptomatic, or with elevated gonadotropins should receive HRT in consultation with a specialist 1

Benefits of HRT:

• Promotes pubertal progression 1
• Maintains bone health (bone mineral density should be evaluated in hypogonadal patients) 1
• Supports cardiovascular health 1

Fertility Preservation and Reproductive Options

Women with low AMH who desire future pregnancy should receive urgent fertility counseling, as low AMH indicates diminished ovarian reserve with reduced fertility potential. 2

Immediate Actions:

• Oocyte cryopreservation should be considered for patients wishing to preserve fertility options 1
• Prompt fertility evaluation and attempts are recommended per American Society for Reproductive Medicine guidelines for women with diminished ovarian reserve 2
• Closer monitoring and earlier referral to reproductive specialists is warranted for women with AMH <0.7 ng/ml 2

Assisted Reproductive Technology (ART):

• Consultation on in vitro fertilization (IVF) with own eggs or donor eggs 1
• Gestational surrogacy options 1
• Important caveat: Women with severely low AMH may have higher rates of aneuploid embryos and increased miscarriage risk 2

Ovulation Induction:

• Clomiphene citrate may be considered for anovulatory patients with low AMH, starting at 50 mg daily for 5 days, with dose escalation to 100 mg daily if ovulation does not occur 3
• Treatment should not exceed 6 cycles total 3

Contraception Counseling

Contraception is mandatory even in patients with low AMH and amenorrhea, as spontaneous pregnancy can occur despite low ovarian reserve. 1

• All patients need contraception counseling because alkylator-associated gonadal toxicity is extremely variable 1
• Spontaneous resumption of menses may not accurately reflect fertility, as natural conception has been reported despite post-treatment amenorrhea and low AMH levels 1
• Menstruating women at risk of early menopause should be counseled about risks of delaying childbearing 1

Monitoring and Follow-up

Laboratory Evaluation:

• FSH, LH, and estradiol levels for patients with suspected diminished ovarian reserve 2
• Reproductive specialists should include: FSH, LH, estradiol, AMH (in women), and testosterone (in men) in endocrine work-up 1
• For women with irregular menstrual cycles and low AMH: monitor for symptoms of premature ovarian insufficiency 2

Imaging:

• Bone mineral density testing for hypogonadal patients 1
• High-level ultrasound evaluation of genitourinary tract after pubertal development in patients contemplating pregnancy 1

Important Caveats and Pitfalls

AMH interpretation has critical limitations that must be understood:

• Age-dependent interpretation: AMH of <0.7 ng/ml is more reliable as an indicator of diminished ovarian reserve in women ≥25 years; interpretation should be cautious in women <25 years due to potential fluctuations 2, 4
• AMH does not predict spontaneous pregnancy: Case reports document ongoing pregnancies despite undetectable AMH levels 5
• AMH reflects growing follicular pool only: It may not solely reflect the underlying primordial pool, as demonstrated in cases where AMH increased with gonadotropin stimulation 6
• Different assays yield varying results: Values should be interpreted in context of specific laboratory reference ranges 2
• AMH is not a marker of fertility in prepubertal girls: 12% of healthy prepubertal girls have AMH <8 pmol/l, so low AMH does not indicate approaching menopause in this population 7

Special Considerations for Cancer Survivors

For patients with low AMH following gonadotoxic therapy (chemotherapy/radiation):

• AMH levels may recover after low doses of alkylating chemotherapy 1
• AMH shows promise as a predictor of ovarian reserve and timing of menopause onset in pediatric cancer patients 1
• Gonadotropin-releasing hormone agonist treatment before gonadotoxic therapy should be considered to attenuate risk of premature menopause, though evidence for fertility preservation remains insufficient 1