What is primary ovarian failure?

Primary Ovarian Insufficiency (POI)

Primary ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years, characterized by menstrual disturbance (amenorrhea or oligomenorrhea) with raised gonadotropins and low estradiol levels. 1

Definition and Diagnostic Criteria

• POI (previously called premature ovarian failure) is characterized by the triad of amenorrhea, hypergonadotropinism, and hypoestrogenism occurring before age 40 1
• The prevalence of POI is approximately 1% in the general population, with ethnicity potentially affecting prevalence rates 1
• Diagnosis requires:
  • Oligo/amenorrhea for at least 4 months
  • Two elevated serum FSH levels (>25 IU/L) obtained at least 4 weeks apart
  • Low estradiol levels 1

Etiology

POI can result from various causes:

• Genetic factors:

  • Fragile X premutation (most common single-gene mutation associated with POI) 1
  • X chromosome abnormalities (Turner syndrome, X chromosome deletions) 2
  • Autosomal genetic disorders (e.g., BPES syndrome) 1

• Autoimmune factors:

  • Associated with other autoimmune disorders (e.g., Addison's disease, thyroid disorders)
  • Screening for 21OH-Ab (adrenocortical antibodies) is recommended when immune disorders are suspected 1

• Iatrogenic causes:

  • Cancer treatments:
    • Alkylating agents (dose-dependent risk) 1
    • Radiation therapy to fields that include the ovaries 1
    • Effective sterilizing radiation doses vary by age: 20.3 Gy in infants, 18.4 Gy at age 10, and 16.5 Gy at age 20 1
  • Surgical (bilateral oophorectomy) 1

• Environmental factors:

  • Smoking 1
  • Toxins 3

• Idiopathic: No identifiable cause in many cases 3

Clinical Presentation

• Primary amenorrhea (never had menses)
• Secondary amenorrhea (cessation of previously regular menses)
• Oligomenorrhea (irregular menses)
• Vasomotor symptoms (hot flashes, night sweats)
• Vaginal dryness and dyspareunia
• Mood changes, sleep disturbances 4, 5

Evaluation

• Laboratory assessment:

  • FSH and estradiol levels (two measurements at least 4 weeks apart) 6
  • Karyotype analysis in women with primary amenorrhea or early-onset POI 1, 2
  • Fragile X premutation testing is indicated in women with POI of unknown cause 1
  • Screening for adrenocortical antibodies (21OH-Ab/ACA) should be considered when immune disorders are suspected 1
  • Thyroid function tests and prolactin levels to rule out other causes of amenorrhea 6

• Imaging:

  • Transvaginal ultrasound to assess ovarian reserve (antral follicle count) may be helpful but is not part of the diagnostic criteria 1

Health Consequences of POI

• Bone health: Increased risk of osteoporosis and fractures 4, 3
• Cardiovascular health: Increased risk of cardiovascular disease 4, 3
• Reproductive health: Infertility or reduced fertility 3
• Psychological health: Increased risk of depression, anxiety, and impaired quality of life 5, 3
• Neurological function: Potential cognitive effects 1, 3
• Urogenital health: Vaginal atrophy, urinary symptoms 4, 5
• Overall mortality: Increased all-cause mortality 4

Management

• Hormone replacement therapy (HRT):

  • First-line treatment for women with POI to reduce symptoms and prevent long-term health consequences 4
  • Should be continued until the average age of natural menopause (age 50-51 years) 4
  • Options include:
    • Estrogen replacement (oral or transdermal) with cyclic progestogen (for women with intact uterus) 4, 5
    • Combined hormonal contraceptives (may be preferred for women who need contraception) 4

• Fertility considerations:

  • Counseling regarding reduced fertility and options for family building 1
  • Oocyte or embryo donation may be options for women desiring pregnancy 3
  • Spontaneous pregnancies can occur in 5-10% of women with POI, so contraception may still be needed if pregnancy is not desired 4

• Monitoring and preventive care:

  • Bone density screening
  • Cardiovascular risk assessment
  • Regular follow-up to assess symptom control and medication adjustment 4, 3

Special Considerations

• Adolescents with POI:

  • Require specialized management for puberty induction if POI occurs before puberty 1, 6
  • Psychological support is particularly important 4

• Cancer survivors:

  • Require specialized follow-up and consideration of fertility preservation options before gonadotoxic treatments when possible 1
  • Risk of POI is highest in those treated with alkylating agents and/or radiation to fields that include the ovaries 1

POI is a condition with significant health implications that requires prompt diagnosis and comprehensive management to address both immediate symptoms and long-term health consequences.