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Premature Ovarian Insufficiency or Failure

(Premature Menopause; Hypergonadotropic Hypogonadism; Primary Ovarian Insufficiency)

by JoAnn V. Pinkerton, MD

In premature ovarian insufficiency or failure, ovaries do not produce enough estrogen despite high levels of circulating gonadotropins (especially follicle-stimulating hormone [FSH]) in women < 40. Diagnosis is by measuring FSH and estradiol levels. Typically, treatment is with combined estrogen/progestin therapy.


Premature ovarian insufficiency and failure are characterized by one or more of the following:

  • The number of ovarian follicles present at birth is insufficient.

  • The rate of follicular atresia is accelerated.

  • The follicles are dysfunctional (as occurs in autoimmune ovarian dysfunction).

Premature ovarian insufficiency and premature ovarian failure are sometimes used synonymously, but failure more precisely refers to permanent infertility and complete depletion of primordial follicles.

Premature ovarian insufficiency or failure has various causes, including certain genetic disorders (see Common Causes of Premature Ovarian Insufficiency and Failure). Genetic disorders that confer a Y chromosome, which are usually evident by age 35, increase risk of ovarian germ cell cancer.

Common Causes of Premature Ovarian Insufficiency and Failure



Enzyme defects


17α-Hydroxylase deficiency

17,20-Lyase deficiency

Genetic defects

Accelerated ovarian follicular atresia (idiopathic)

Certain autosomal defects

FMR1 premutation (Fragile X syndrome)

Gonadal dysgenesis secondary to genetic defects (eg, Turner syndrome [45,X], pure [46,XX or 46,XY] or mixed gonadal dysgenesis)

Idiopathic hypogonadotropic hypogonadism

Kallmann syndrome

Myotonic dystrophy

Reduced germ cell number

Trisomy X with or without chromosomal mosaicism

Immune-mediated disturbances

Autoimmune disorders (most commonly, thyroiditis, Addison disease, hypoparathyroidism, diabetes mellitus, myasthenia gravis, vitiligo, pernicious anemia, and mucocutaneous candidiasis)

Congenital thymic aplasia

Isolated ovarian failure


Other causes

Addison's disease

Adrenal insufficiency

Chemotherapeutic (especially alkylating) drugs

Cigarette smoking


Irradiation of the gonads

Surgical extirpation of the gonads or adnexa

Viral infections (eg, mumps)

Symptoms and Signs

In women with occult or biochemical primary ovarian insufficiency (see Classification, below), the only sign may be unexplained infertility. Women with overt primary ovarian insufficiency or premature ovarian failure typically have amenorrhea or irregular bleeding and often symptoms or signs of estrogen deficiency (eg, osteoporosis, atrophic vaginitis, decreased libido).

The ovaries are usually small and barely palpable but occasionally are enlarged, usually when the cause is an immune disorder. Women may also have symptoms and signs of the causative disorder (eg, dysmorphic features due to Turner syndrome; intellectual disability, dysmorphic features, and autism due to Fragile X syndrome; rarely, orthostatic hypotension, hyperpigmentation, and decreased axillary and pubic hair due to adrenal insufficiency).

Unless women receive estrogen therapy, the risk of dementia, Parkinson's disease, and coronary artery disease is increased.


  • FSH and estradiol levels

  • Thyroid function tests, fasting glucose, electrolytes, and creatinine

  • Sometimes genetic testing

Premature ovarian insufficiency is suspected in women < 40 with unexplained infertility, menstrual abnormalities, or symptoms of estrogen deficiency.

A pregnancy test is done, and serum FSH and estradiol levels are measured weekly for 2 to 4 wk; if FSH levels are high (> 20 mIU/mL, but usually > 30 mIU/mL) and estradiol levels are low (usually < 20 pg/mL), ovarian insufficiency or failure is confirmed. Then, further tests are done based on which cause is suspected.

Genetic counseling and testing for the FMR1 premutation are indicated if women have a family history of premature ovarian insufficiency or failure or have intellectual disability, tremor, or ataxia. Karyotype is determined if women with confirmed ovarian insufficiency or failure are < 35. Bone density is measured if women have symptoms or signs of estrogen deficiency. Ovarian biopsy is not indicated.


Premature ovarian insufficiency and failure can be classified based on clinical findings and serum FSH levels:

  • Occult primary ovarian insufficiency: Unexplained infertility and a normal basal serum FSH level

  • Biochemical primary ovarian insufficiency: Unexplained infertility and an elevated basal serum FSH level

  • Overt primary ovarian insufficiency: Irregular menstrual cycles and an elevated basal serum FSH level

  • Premature ovarian failure: Amenorrhea, permanent infertility, complete depletion of primordial follicles, and an elevated basal serum FSH level


  • Estrogen/progestin therapy

Women who do not desire pregnancy are given cyclical estrogen/progestin therapy (combination hormone therapy—see Hormone therapy) until about age 51 unless these hormones are contraindicated; this therapy relieves symptoms of estrogen deficiency and helps maintain bone density.

For women who desire pregnancy, one option is in vitro fertilization of donated oocytes plus exogenous estrogen and a progestin, which enable the endometrium to support the transferred embryo (see In vitro fertilization (IVF)). The age of the oocyte donor is more important than the age of the recipient. This technique is fairly successful, but even without this technique, some women with diagnosed premature ovarian insufficiency become pregnant. No treatment has been proved to increase the ovulation rate or restore fertility in women with premature ovarian insufficiency.

Women with a Y chromosome require laparotomy or laparoscopy and bilateral oophorectomy because risk of ovarian germ cell cancer is increased.

Key Points

  • Suspect premature ovarian insufficiency or failure in women with unexplained menstrual abnormalities, infertility, or symptoms of estrogen deficiency.

  • Confirm the diagnosis by measuring FSH (which is high, usually > 30 mIU/mL) and estradiol (which is low, usually < 20 pg/mL).

  • Unless contraindicated, prescribe cyclic estrogen/progestin therapy to be taken until about age 51 to maintain bone density and relieve symptoms of estrogen deficiency.

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