Primary Ovarian Insufficiency

POI is caused by several types of exposures or medical issues (see table Etiologies of Primary Ovarian Insufficiency). The distribution of the prevalence of each type of etiology is approximately (1) as follows:

• Genetic (10 to 30%)

• Autoimmune (5 to 17%)

• Toxic, metabolic, or infectious (1%)

• Iatrogenic (6 to 47%)

• Idiopathic (39 to 67%)

Genetic disorders that can cause POI include (2):

• Turner syndrome (45,X or mosaic 45,X/46,XX or 45,X/47,XXX)

• Fragile X syndrome (caused by a premutation in the FMR1 gene)

Genetic disorders that confer a Y chromosome can also cause POI. These disorders, which are usually evident by age 35, increase risk of ovarian germ cell cancer.

Patients with POI often have other autoimmune disorders (eg, type 1 diabetes, thyroiditis).

Family history of early menopause, even without a genetic etiology, increases likelihood of premature menopause.

POI usually presents with primary or secondary amenorrhea, although some women may have irregular uterine bleeding due to intermittent ovulation or other causes of genital tract bleeding.

POI may include a spectrum of ovarian dysfunction, from subtle changes to complete cessation of ovarian function. Thus, symptoms or signs may include unexplained infertility, amenorrhea or irregular bleeding, and/or often symptoms or signs of estrogen deficiency (eg, osteoporosis, atrophic vaginitis, decreased libido). They may also have changes in mood, including depression.

On pelvic examination, there may be evidence of estrogen deficiency (ie, vulvovaginal atrophy). The ovaries are usually small and barely palpable, but may be enlarged if there is an immune-mediated oophoritis.

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).

• Follicle-stimulating hormone (FSH) and estradiol levels

• Tests to exclude other causes of amenorrhea or irregular menses (including pregnancy test)

• Tests to evaluate for associated autoimmune disorders (thyroid function tests, fasting glucose, electrolytes, and creatinine)

• Sometimes genetic testing

POI is diagnosed in women < 40 years who have amenorrhea lasting 4 to 6 months in combination with elevated FSH and decreased estradiol levels obtained one month apart (1).

The evaluation should exclude other causes of amenorrhea or irregular menses. Initial blood tests are a serum beta-human chorionic gonadotropin, FSH, estradiol, thyroid stimulating hormone, and prolactin.

Serum FSH and estradiol levels are measured weekly for 2 to 4 weeks; if FSH levels are high (> 20 mIU/mL, but usually > 30 mIU/mL) and estradiol levels are low (usually < 20 pg/mL), ovarian insufficiency is confirmed.

Antimüllerian hormone levels may also be measured. Some experts do not use this test routinely in the diagnosis of POI, but it is useful in assessing ovarian reserve in women desiring fertility (2). Because antimüllerian hormone is produced only in small ovarian follicles, blood levels of this hormone have been used to attempt to diagnose decreased ovarian reserve. Normal levels are between 1.5 and 4.0 ng/mL. A very low level suggests decreased ovarian reserve. Reproductive endocrinologists use antimüllerian hormone levels to help predict which women may respond poorly to fertility medications and generally which couples are less likely to be successful with fertility treatment. Antimüllerian hormone can be drawn at any time during the menstrual cycle. Newer, more sensitive antimüllerian hormone tests may help clinicians diagnose POI.

Further tests are done based on the suspected etiology.

Genetic counseling and testing for the FMR1 premutation are indicated if women have a family history of POI or have intellectual disability, tremor, or ataxia. Karyotype is determined if women with confirmed ovarian insufficiency or failure are < 35 or if the FMR1 premutation is suspected.

If karyotype is normal or if an autoimmune cause is suspected, tests for serum adrenal and anti-21 hydroxylase antibodies (adrenal autoantibodies) are done.

Anti-ovarian antibody tests are not recommended because precision in the testing is lacking (3). Ovarian biopsy is not indicated.

If an autoimmune cause is suspected, tests to check for autoimmune hypothyroidism are also done; they include measuring thyroid-stimulating hormone (TSH), thyroxine (T4), and antithyroid–peroxidase and antithyroglobulin antibodies.

If adrenal insufficiency is suspected, measurement of a morning cortisol level or an adrenocorticotropic hormone (ACTH) stimulation test can confirm the diagnosis.

Other tests for an autoimmune dysfunction should be done if history, symptoms, and signs suggest a particular disorder.

At time of diagnosis of POI, a baseline bone density may be measured and then routine screening should begin several years after diagnosis.

Lower levels of estrogen increase the risk of atherosclerosis possibly related to endothelial dysfunction possibly related to endothelial dysfunction. Women with POI should be evaluated for cardiac risk factors.

Patients should be asked about vaginal dryness and dyspareunia or other symptoms of genitourinary syndrome of menopause and evaluated periodically for vulvovaginal atrophy with pelvic examination.

• Estrogen/progestogen contraceptives or hormone therapy (combination hormone therapy or hormone replacement therapy)

• In vitro fertilization if pregnancy is desired

Women who have POI and do not desire pregnancy may be treated with estrogen/progestin contraceptives (cyclical or extended cycle) or estrogen/progestin therapy (cyclical or continuous).

Cyclical combination hormone therapy is given until about age 51 (the average age for menopause) unless these hormones are contraindicated (1); this therapy relieves symptoms of estrogen deficiency, helps maintain bone density, and may help prevent coronary artery disease, Parkinson disease, mood changes (including depression), atrophic vaginitis, and dementia. Once women reach the average age of menopause, whether to continue hormone therapy depends on the woman's individual circumstances (eg, severity of symptoms, risk of fractures).

Unless women with POI receive estrogen therapy until about age 51 (the average age for menopause), the risk of osteoporosis, dementia, Parkinson disease, depression, and coronary artery disease is increased.

For women who desire pregnancy, one option is in vitro fertilization of donated oocytes plus exogenous estrogen and a progestogen, which enable the endometrium to support the transferred embryo. 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 POI become pregnant. No treatment has been proved to increase the ovulation rate or restore fertility in women with POI (2). However, fertility restoration is being studied.

Other options for women who desire pregnancy include cryopreservation of ovarian tissue, oocytes, or embryos and embryo donation. These techniques may be used before or during ovarian failure, especially in cancer patients. Neonatal and adult ovaries possess a small number of oogonial stem cells that can stably proliferate for months and produce mature oocytes in vitro; these cells may be used to develop infertility treatments in the future. Ovarian tissue transplantation has been successful and, in the future, may become an option for women who are no longer fertile (3). Activation of dormant follicles with phosphatase and TENsin homolog (PTEN) inhibitor followed by re-implantation of treated ovarian samples is being explored (4).

About 5 to 10% of women with POI eventually become pregnant on their own, without fertility treatments.

Unless contraindicated, menopausal hormone therapy or estrogen/progestin contraceptives are recommended rather than other bone-specific treatments (eg, bisphosphonates) to prevent bone loss in women with POI; these treatments are given until women reach the average age for menopause (about age 51), when treatment may be reassessed.

To help prevent osteoporosis, women with POI should consume an adequate amount of calcium and vitamin D (in the diet and/or as supplements)., women with POI should consume an adequate amount of calcium and vitamin D (in the diet and/or as supplements).

Women with genitourinary syndrome of menopause should be treated with nonhormonal lubricants and moisturisers, vaginal hormone therapy, or other measures, as needed to control symptoms.

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

The following is a list of professional medical society or government clinical practice guidelines regarding this medical issue (this is not a comprehensive list):

• American College of Obstetricians and Gynecologists (ACOG) Committee Opinion. Primary Ovarian Insufficiency in Adolescents and Young Women. 2014 (reaffirmed 2021).

• ACOG Committee Opinion. Hormone Therapy in Primary Ovarian Insufficiency. 2017 (reaffirmed 2021).