What is the primary treatment approach for a female of reproductive age with diminished ovarian reserve?

Treatment of Diminished Ovarian Reserve

Women with diminished ovarian reserve who desire future fertility should be immediately referred to a reproductive endocrinology specialist for oocyte cryopreservation, which is the primary treatment option, while simultaneously initiating sex steroid hormone replacement therapy to prevent serious long-term health consequences including osteoporosis, cardiovascular disease, and sexual dysfunction. 1, 2

Immediate Specialist Referral

• Urgent referral to reproductive endocrinology is mandatory as every month of delay significantly reduces treatment success in patients with diminished ovarian reserve 1, 2
• Timely referral is crucial because of the rapid loss of ovarian reserve in these women, and delays substantially reduce treatment outcomes 3, 1
• Women experiencing infertility for 6 months or more (or who have had more than one miscarriage) should be referred to a fertility specialist immediately 3

Primary Fertility Preservation Treatment

Oocyte Cryopreservation (First-Line)

• Oocyte cryopreservation via vitrification is the established first-line fertility preservation method for postpubertal women with diminished ovarian reserve 1, 2
• Cumulative live birth rates are 61.9% with 12 cryopreserved oocytes in women ≤35 years, and 43.4% with 10 oocytes in women >35 years 1
• Ovarian stimulation can be started at any time during the menstrual cycle using "random start stimulation" protocols, eliminating the need to wait for menses 1
• For women with low ovarian reserve who do not need urgent treatment initiation, double stimulation over 4 weeks can approximately double the number of oocytes retrieved 1

Ovarian Stimulation Protocols

• Initial starting dose of 150-200 International Units of follitropin (FSH) per day administered subcutaneously for at least the first 7 days 4, 5
• Subsequent dose adjustments based on ovarian response, with maximum individualized daily doses of 450-500 International Units 4, 5
• For hormone-sensitive cancers, letrozole or tamoxifen combined with gonadotropins reduces estradiol levels while maintaining adequate oocyte yield 1
• Clomiphene citrate throughout the entire stimulation cycle (rather than just 5 days) effectively prevents premature LH surge with non-inferior oocyte yield in diminished ovarian reserve patients 6

Alternative Fertility Preservation Options

• Embryo cryopreservation after IVF is an alternative for patients with partners or those willing to use donor sperm, with live birth rates of 45% reported in young women 3, 1, 2
• Ovarian tissue cryopreservation is the only viable option for prepubertal patients with diminished ovarian reserve 3, 1, 2

Mandatory Hormone Replacement Therapy

All patients diagnosed with diminished ovarian reserve or premature ovarian insufficiency require sex steroid replacement therapy immediately to prevent serious health consequences 3, 1, 2

• Estrogen may be replaced with oral, micronized, or transdermal preparations 3
• Progesterone therapy is also needed to avoid an unopposed estrogen effect and maintain endometrial health in women with a uterus 3
• Oral contraceptives and transdermal devices provide a variety of estrogen and progesterone forms and dosing options 3
• Bone mineral density testing should be considered for hypogonadal patients 3

Essential Diagnostic Evaluation

Laboratory Assessment

• FSH, LH, and estradiol levels should be screened in patients with irregular menses, amenorrhea, or clinical signs of estrogen deficiency 3
• Anti-Müllerian hormone (AMH) testing should be performed in women ≥25 years old to assess ovarian reserve, though interpretation requires caution in younger women due to normal fluctuations 2, 7
• Karyotype analysis is required to exclude Turner syndrome or chromosomal abnormalities, and fragile X premutation testing should be performed as a genetic cause 1

Imaging Assessment

• Transvaginal ultrasound can measure antral follicle count and ovarian volume; when ovarian volume is <3 cm³ and <5 antral follicles are present, this suggests diminished ovarian reserve 3
• Antral follicle count by transvaginal ultrasound remains the most established method for assessing ovarian reserve in adult women 3, 7

Critical Contraception Counseling

Contraception remains mandatory even with severely diminished ovarian reserve and amenorrhea, as spontaneous pregnancy can occur in 5-10% of cases 1, 2

• All patients must be counseled on the need for contraception because alkylator-associated gonadal toxicity is extremely variable 3
• Women should be counseled that menstruating women at risk of early menopause face increased risk when delaying childbearing 3

Alternative Family-Building Options

When fertility preservation is unsuccessful or not feasible, alternative options include 1:

• Gestational carriers
• Embryo donation
• Egg or sperm donation
• Adoption
• Psychosocial providers can assist patients in decision-making about these options 1

Common Pitfalls to Avoid

• Do not delay referral to reproductive endocrinology, as every month of delay reduces treatment success in diminished ovarian reserve patients 1, 2
• Do not rely on GnRH agonists as a fertility preservation strategy, as this is not evidence-based and does not protect ovarian reserve 3, 1
• Do not forget hormone replacement therapy, as failure to initiate HRT leads to serious long-term health consequences including bone loss, cardiovascular disease, and sexual dysfunction 3, 1, 2
• Do not assume contraception is unnecessary, as spontaneous pregnancy remains possible even with severely diminished reserve 1, 2
• Do not withhold hCG trigger if appropriate, as the trigger type (hCG) is the only significant factor linked to successful oocyte maturation rates in rescue in vitro maturation protocols 8

Special Populations

• BRCA mutation carriers, especially BRCA1, have diminished ovarian reserve and may be more prone to treatment-induced infertility 1
• Adolescents with mosaic Turner syndrome may be candidates for fertility preservation if diagnosed early, before complete follicle depletion 2
• Cancer survivors treated with alkylating agents and/or radiotherapy require AMH assessment as a marker of ovarian reserve 7