What are the treatment options for diminished ovarian reserve in adolescents?

Treatment Options for Diminished Ovarian Reserve in Adolescents

Adolescents with diminished ovarian reserve should be immediately referred to reproductive endocrinology for fertility preservation, with oocyte cryopreservation as the primary option for postpubertal patients and ovarian tissue cryopreservation for prepubertal patients, while simultaneously initiating sex steroid replacement therapy to prevent long-term health consequences of estrogen deprivation. 1

Immediate Specialist Referral

All adolescents with confirmed or suspected diminished ovarian reserve require urgent referral to gynecology, endocrinology, and/or reproductive endocrinology consultation. 1 This applies to:

• Prepubertal females with no signs of puberty by age 13 years with elevated FSH levels, primary amenorrhea by age 16 years despite other pubertal signs, or failure to initiate/progress through puberty 1
• Postpubertal females with menstrual cycle dysfunction suggestive of premature ovarian insufficiency (POI), even if they have regular cycles but were exposed to gonadotoxic treatments 1

The critical pitfall here is assuming regular menstrual cycles indicate adequate ovarian reserve—survivors with regular cycles who received gonadotoxic therapy remain at high risk for decreased ovarian reserve and reduced fertility. 1

Fertility Preservation Options

For Postpubertal Adolescents

Oocyte cryopreservation (vitrification) is the first-line fertility preservation method for postpubertal adolescents with diminished ovarian reserve. 1 This approach:

• Is no longer considered investigational by the American Society of Reproductive Medicine 1
• Overcomes ethical and practical issues related to embryo storage, making it ideal for adolescents without partners 1
• Yields fertilization and pregnancy rates similar to fresh oocytes 1
• Can be attempted even with diminished ovarian reserve, though success rates vary 2, 3

Controlled ovarian stimulation protocols can be modified for adolescents with diminished ovarian reserve. 2, 3 Recent data shows that even with mean anti-Müllerian hormone (AMH) levels of 0.653 ng/mL, an average of 3.8 mature oocytes can be retrieved. 2 While this is lower than optimal, it represents a meaningful opportunity for future fertility. 2, 3

Embryo cryopreservation after IVF is an alternative for adolescents with partners or willing to use donor sperm. 1 This established method has shown live birth rates of 45% in young women, comparable to infertile couples without cancer history. 1

For Prepubertal Adolescents

Ovarian tissue cryopreservation is the only viable option for prepubertal patients with diminished ovarian reserve. 1, 4 This technique:

• Does not require hormonal stimulation, avoiding treatment delays 1
• Is endorsed by the American Society for Reproductive Medicine for prepubertal patients 4
• Remains investigational at some institutions but should be discussed when available 1
• Is contraindicated when there is risk of reintroducing malignant cells (e.g., leukemia, ovarian involvement) 1

Immature oocyte harvesting with in vitro maturation (IVM) represents an emerging option for prepubertal girls or those unable to undergo controlled ovarian stimulation. 1 This avoids hormonal stimulation requirements but has less established success rates. 1

Sex Steroid Replacement Therapy

All adolescents diagnosed with diminished ovarian reserve or POI require sex steroid replacement therapy to prevent serious health consequences. 1 The benefits include:

• Bone health preservation - preventing osteoporosis from estrogen deprivation 1
• Cardiovascular health protection - reducing long-term cardiovascular risks 1
• Sexual function maintenance - supporting normal sexual development and function 1
• Pubertal induction and progression - for prepubertal patients 1

A critical caveat: while POI reduces radiation-associated breast cancer risk, the effects of sex steroid replacement therapy on breast cancer risk and other secondary malignancies in cancer survivors remain unknown. 1 This uncertainty must be discussed but should not prevent therapy given the established harms of estrogen deprivation. 1

Ovarian Reserve Assessment

AMH testing should be performed in adolescents ≥25 years old to assess ovarian reserve and guide fertility counseling. 1, 5 However, AMH interpretation requires caution in adolescents under 25 years due to normal fluctuations throughout the menstrual cycle. 5

For surveillance in at-risk adolescents:

• Annual monitoring with Tanner staging and menstrual history at minimum 1
• Laboratory evaluation with FSH and estradiol when menstrual dysfunction occurs 1
• AMH and antral follicle count (AFC) may provide additional information but are not part of POI diagnostic criteria 1

Treatment Timing and Urgency

Fertility preservation should ideally be initiated before any gonadotoxic treatment begins. 1 However, when impractical or impossible before treatment, it should be readdressed later in the treatment course. 1

For adolescents already diagnosed with diminished ovarian reserve post-treatment:

• Immediate consultation is warranted regardless of menstrual status 1
• Oocyte cryopreservation should be attempted even with low ovarian reserve markers, as 69% of eligible patients in one series successfully completed the procedure 3
• Do not delay - ovarian reserve continues declining over time 6, 7

Special Populations

Adolescents with mosaic Turner syndrome may be candidates for fertility preservation if diagnosed early, before complete follicle depletion. 1, 2 However, most Turner syndrome patients reach puberty with already depleted reserves, limiting options. 1

Adolescents with endometriosis requiring bilateral surgery or recurrent procedures should be counseled about fertility preservation before additional ovarian damage occurs. 1

What NOT to Do

• Do not use GnRH agonists as a primary fertility preservation strategy—evidence remains insufficient and inconsistent regarding ovarian function protection 1
• Do not assume regular menses indicate adequate fertility potential in adolescents exposed to gonadotoxic treatments 1
• Do not delay referral waiting for complete pubertal development or specific age thresholds 1
• Do not withhold sex steroid replacement due to theoretical cancer concerns when POI is diagnosed 1