What are the treatment options for a diminished ovarian reserve?

Treatment Options for Diminished Ovarian Reserve

For women with diminished ovarian reserve who desire future fertility, immediate referral to a reproductive endocrinology specialist is mandatory, with oocyte cryopreservation as the primary treatment option for postpubertal patients and ovarian tissue cryopreservation for prepubertal patients. 1

Immediate Specialist Referral

• All patients with confirmed or suspected diminished ovarian reserve require urgent referral to reproductive endocrinology and infertility specialists as soon as possible 2, 1
• Timely referral is crucial because of the rapid loss of ovarian reserve in these women, and delays significantly reduce treatment success 2
• The referral should occur immediately upon diagnosis, not after 6 months of attempting conception, given the accelerated follicular depletion 1

Primary Fertility Preservation Options

Oocyte Cryopreservation (First-Line)

• Oocyte cryopreservation via vitrification is the established first-line fertility preservation method for postpubertal women with diminished ovarian reserve 2, 1
• This is considered standard practice and widely available 2
• Ovarian stimulation can be started at any time during the menstrual cycle using "random start stimulation" protocols 2
• 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 2
• Success rates depend heavily on the number of oocytes retrieved: cumulative live birth rate of 61.9% with 12 cryopreserved oocytes in women ≤35 years, and 43.4% with 10 oocytes in women >35 years 2

Embryo Cryopreservation (Alternative)

• Embryo cryopreservation after IVF is an alternative for patients with partners or those willing to use donor sperm 1
• Live birth rates of 45% have been reported in young women, comparable to infertile couples without cancer history 1
• This is also considered standard practice alongside oocyte cryopreservation 2

Ovarian Tissue Cryopreservation

• Ovarian tissue cryopreservation is the only viable option for prepubertal patients with diminished ovarian reserve 1
• This technique is rapidly advancing and may evolve to become standard therapy in the future 2
• The procedure involves laparoscopic biopsy of ovarian cortex or unilateral ovariectomy under general anesthesia 2
• No pretreatment is required, allowing chemotherapy to start the following day if needed 2
• At least 19 live births have been reported using cryopreserved ovarian tissue or oocytes in cancer survivors 2
• For postpubertal patients, ovarian stimulation can be combined with ovarian tissue cryopreservation to increase success rates in women receiving highly gonadotoxic treatments 2

Ovarian Stimulation Protocols for Diminished Ovarian Reserve

Standard Approaches

• High-dose gonadotropins are typically used in patients with diminished ovarian reserve 3
• For hormone-sensitive cancers (e.g., breast cancer), letrozole or tamoxifen combined with gonadotropins reduces estradiol levels while maintaining adequate oocyte yield 2
• Letrozole does not reduce the number of mature oocytes obtained or their fertilization capacity, and no effect on congenital abnormality rates has been observed 2

Alternative Protocol: Long Clomiphene Citrate

• A "long CC" protocol, where clomiphene citrate is continued throughout the entire stimulation cycle instead of GnRH antagonist, shows non-inferior oocyte yield in DOR patients 3
• This approach is associated with lower rates of premature ovulation (0.3% vs. 3.0% with standard 5-day CC + GnRH antagonist) 3
• This protocol reduces costs, decreases injection burden, and effectively prevents premature ovulation 3

What NOT to Use: GnRH Agonists for Ovarian Suppression

• GnRH agonists (GnRHa) are NOT an effective method of fertility preservation and should not be used in place of proven fertility preservation methods 2
• There is conflicting evidence and insufficient data showing that GnRHa preserves fertility 2
• Complete ovarian suppression is not achieved for several weeks after administration 2
• Multiple studies and meta-analyses have failed to demonstrate beneficial effects on either maintenance of menstruation or fertility 2
• GnRHa has adverse effects including hot flashes and bone loss 2
• In emergency or extreme circumstances where proven options are not available, GnRHa may be considered only as an unproven option, preferably as part of a clinical trial 2

Essential Concurrent Management

Hormone Replacement Therapy

• All patients diagnosed with diminished ovarian reserve or premature ovarian insufficiency require sex steroid replacement therapy immediately 1, 4
• This prevents serious health consequences including osteoporosis, cardiovascular disease, and sexual dysfunction 1, 4
• Hormone replacement should be initiated by a provider with expertise in pubertal hormone replacement therapy 4
• Treatment is essential for bone health preservation, cardiovascular health protection, and sexual function maintenance 1

Contraception Counseling

• Contraception remains mandatory even with severely diminished ovarian reserve and amenorrhea, as spontaneous pregnancy can occur in 5-10% of cases 4

Special Considerations

Genetic and Autoimmune Evaluation

• BRCA mutation carriers, especially BRCA1, have diminished ovarian reserve and may be more prone to treatment-induced infertility 2
• Karyotype analysis is required to exclude Turner syndrome or chromosomal abnormalities 4
• Fragile X premutation testing should be performed as a genetic cause 4
• Thyroid function tests are necessary to evaluate for autoimmune oophoritis 4

FSHR Polymorphisms

• FSHR gene polymorphisms (rs6165 and rs6166) are associated with ovarian response to stimulation in DOR patients 5
• Presence of G alleles in both rs6165 and rs6166 correlates with reduced oocyte retrieval, independent of baseline ovarian reserve markers 5

Timing Considerations

• Fertility preservation should ideally be initiated before any gonadotoxic treatment begins 1
• When impractical before treatment, it should be readdressed later in the treatment course 1
• For breast cancer patients on tamoxifen, interruption after 2-3 years could be considered to allow pregnancy, though this carries potential detrimental effects on breast cancer outcome 2

Alternative Family-Building Options

• When fertility preservation is unsuccessful or not feasible, alternative options include gestational carriers, embryo donation, egg or sperm donation, and adoption 2
• Psychosocial providers such as social workers and psychologists can assist patients in decision-making about these options 2

Common Pitfalls to Avoid

• Do not delay referral to reproductive endocrinology - every month of delay reduces treatment success in DOR patients 2, 1
• Do not rely on GnRH agonists as a fertility preservation strategy - this is not evidence-based 2
• Do not forget hormone replacement therapy - failure to initiate HRT leads to serious long-term health consequences 1, 4
• Do not assume contraception is unnecessary - spontaneous pregnancy remains possible even with severely diminished reserve 4