POI occurs in about 1% of women under the age of 40, while the probability that a woman under this age with absent menstruation has POI is 5–10%.
The ovaries normally have two main functions: to produce hormones (estrogens, progesterone, androgens) and to produce follicles for ovulation. The number of follicles at 20 weeks of fetal life is about 6–7 million, and by the time a woman reaches reproductive age, this number decreases to 300–400, which are used until approximately age 51, when menopause occurs. When this process happens before the age of 40, it is called POI..
Causes
The causes are numerous (genetic, autoimmune, inflammatory, environmental, and iatrogenic). However, 70–90% of cases are idiopathic (this percentage is decreasing to 39–67% due to improved genetic testing).
In 30% of cases with a family history, a genetic cause (Turner syndrome, trisomy X, fragile X premutation, single-gene defects) is likely and should be investigated.
Autoimmune mechanisms account for 4–30% of cases, most commonly:
- Hashimoto thyroiditis
- Addison’s disease
- Sjögren syndrome
- Type 1 diabetes mellitus
- Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
POI may be an early symptom of adrenal insufficiency, as antibodies against 21-hydroxylase can destroy ovarian follicles and cause oophoritis.
Environmental factors include:
- Smoking
- Bisphenol A (found in canned foods and plastics, mimics estrogen)
- Phthalates (used to make plastics flexible, toxic to ovaries)
- Heavy metals (arsenic, cadmium, mercury) from contaminated water or food
- Polychlorinated biphenyls (PCBs), still present despite being banned since the 1970s
Iatrogenic causes include:
- Chemotherapy (especially alkylating agents)
- Radiation
- Bilateral oophorectomy
Notably, 10.9–18.6% of children treated with chemotherapy develop POI, with effects depending on dosage.
Inflammatory causes (1–5%) include:
- Mumps (most common; 5% of post-pubertal girls develop oophoritis)
- Tuberculosis, HIV, varicella, malaria, cytomegalovirus (less common)
Clinical Presentation, Differential Diagnosis, and Evaluation
POI differs from menopause in that it does not necessarily mean permanent cessation of menstruation, but rather irregular or intermittent cycles.
In adolescence, it may present as:
- Delayed puberty (absence of breast development)
- Primary amenorrhea (no menstruation by age 15)
- Secondary amenorrhea or oligomenorrhea (<4 cycles/year)
At all ages, symptoms may include:
- Hot flashes, night sweats
- Vaginal dryness, dyspareunia
- Mood changes (irritability, anxiety, depression)
- Sleep disturbances, fatigue
- Reduced libido
- Difficulty concentrating
Long-term risks include osteoporosis and cardiovascular disease.
Diagnosis is made by:
- Elevated gonadotropins (FSH, LH >25 IU/L on two tests 4 weeks apart)
- Low estradiol (<50 pg/mL)
Differential diagnosis includes:
- Hypothalamic amenorrhea
- Polycystic ovary syndrome (PCOS)
- Thyroid dysfunction
- Pregnancy
- Hyperprolactinemia
- Adrenal hyperplasia
Evaluation includes:
- Detailed history and physical examination
- Karyotype analysis
- Fragile X testing (FMR1 premutation)
- Autoimmune antibody testing
- Thyroid antibodies
- Celiac disease screening
- HbA1c
- Pelvic ultrasound
- Bone density measurement
Management
Management addresses the two ovarian functions: hormone production and ovulation.
Hormone production:
Hormone replacement therapy (HRT) with estrogen and progesterone (if the uterus is present) reduces symptoms and long-term complications.
Fertility:
Options include:
- Egg donation
- Embryo donation
- Cryopreservation of oocytes or ovarian tissue
Hormone Replacement Therapy (HRT)
- If diagnosed before age 12 without puberty onset, estrogen starts at age 11
- If puberty has started, treatment begins immediately
Goals:
- Breast development
- Bone mineralization
- Restoration of menstrual cycles
- Maintenance of estrogen levels
Estrogen is given gradually (every 6 months increase) to allow normal growth and avoid premature closure of growth plates. It can be administered:
- Transdermally (preferred, lower thromboembolic risk)
- Or orally
Progesterone is added:
- After menstruation begins
- Or after 2 years of estrogen therapy in adolescents
Forms include:
- Medroxyprogesterone acetate (MPA)
- Natural progesterone (fewer side effects)
- Intrauterine device (IUD)
Regimens:
- Cyclic (10–12 days/month) for withdrawal bleeding
- Continuous for no menstruation
Treatment continues until about age 51 (natural menopause).
HRT does not provide contraception. Pregnancy can still occur (5–10%). Safe contraception includes hormonal or copper IUDs.
Fertility Considerations
- Spontaneous ovulation may occur in 20–25% of adolescents
- Early stages: consider oocyte or ovarian tissue cryopreservation
- Ovarian tissue can later be transplanted
Success rates:
- Egg donation: ~40% pregnancy per cycle
- 70–80% after 4 cycles