In primary ovarian insufficiency, ovaries do not regularly release eggs and do not produce enough sex hormones despite high levels of circulating gonadotropins (especially follicle-stimulating hormone [FSH]) in women
In primary ovarian insufficiency, the ovaries stop functioning normally in women who are < 40. This disorder used to be called premature ovarian failure or premature menopause; however, these terms are misleading because women with primary ovarian insufficiency do not always stop menstruating and their ovaries do not always completely stop functioning. Thus, a diagnosis of primary ovarian insufficiency does not always mean that pregnancy is impossible. Also, this disorder does not imply that a woman is aging prematurely; it means only that her ovaries are no longer functioning normally.
In primary ovarian insufficiency, the ovaries
Stop releasing eggs or release them only intermittently
Stop producing the hormones estrogen, progesterone, and testosterone or produce them only intermittently
Etiology of Primary Ovarian Insufficiency
Primary ovarian insufficiency has various causes (see table Common Causes of Primary Ovarian Insufficiency), including the following:
The number of ovarian follicles present at birth is insufficient.
The rate of follicular atresia is accelerated, as occurs when the ovaries are damaged during surgery, chemotherapy, or radiation therapy.
The follicles are dysfunctional (as occurs in autoimmune ovarian dysfunction).
Certain genetic disorders are present.
Genetic disorders that can cause premature ovarian insufficiency include
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 primary ovarian insufficiency. These disorders, which are usually evident by age 35, increase risk of ovarian germ cell cancer.
Symptoms and Signs of Primary Ovarian Insufficiency
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). They may also have changes in mood, including depression.
The ovaries are usually small and barely palpable but occasionally are enlarged, usually when the cause is an immune-mediated 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 with primary ovarian insufficiency 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.
If primary ovarian insufficiency is caused by an autoimmune disorder, women are at risk of potentially life-threatening primary adrenal insufficiency (Addison disease).
Diagnosis of Primary Ovarian Insufficiency
Follicle-stimulating hormone (FSH) and estradiol levels
Thyroid function tests, fasting glucose, electrolytes, and creatinine
Sometimes genetic testing
Primary ovarian insufficiency is suspected in women < 40 with unexplained infertility, menstrual abnormalities, or symptoms of estrogen deficiency (1).
A pregnancy test is done, and 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. Then, further tests are done based on which cause is suspected.
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 early menopause.
Genetic counseling and testing for the FMR1 premutation are indicated if women have a family history of primary ovarian insufficiency 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 (2).
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; they include a complete blood count with differential, erythrocyte sedimentation rate, and measurement of antinuclear antibody and rheumatoid factor.
Bone density is measured if women have symptoms or signs of estrogen deficiency.
Ovarian biopsy is not indicated.
Classification
Primary ovarian insufficiency can be classified based on clinical findings and serum FSH levels:
Occult primary ovarian insufficiency (diminished ovarian reserve): 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: Irregular or occasional periods for years, the possibility of pregnancy, and an elevated basal serum FSH level
Premature menopause: Amenorrhea, permanent infertility, and complete depletion of primordial follicles
Diagnostic references
1. Stuenkel CA, Gompel A, Davis SR, et al: Approach to the patient with new-onset secondary amenorrhea: Is this primary ovarian insufficiency? J Clin Endocrinol Metab 107 (3):825–835, 2022. doi: 10.1210/clinem/dgab766
2. Novosad JA, Kalantaridou SN, Tong ZB, Nelson LM: Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: A controlled evaluation. BMC Womens Health 3 (1):2, 2003. doi: 10.1186/1472-6874-3-2 PMID: 12694633; PMCID: PMC153539.
Treatment of Primary Ovarian Insufficiency
Estrogen/progestogen contraceptives or hormone therapy (combination hormone therapy or hormone replacement therapy)
In vitro fertilization if pregnancy is desired
Women who have primary ovarian insufficiency 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).
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 primary ovarian insufficiency become pregnant. No treatment has been proved to increase the ovulation rate or restore fertility in women with primary ovarian insufficiency. 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 (2).
About 5 to 10% of women with primary ovarian insufficiency eventually become pregnant on their own, without fertility treatments.
Unless contraindicated, hormonal therapy or estrogen/progestin contraceptives are recommended rather than other bone-specific treatments (eg, bisphosphonates) to prevent bone loss in women with premature ovarian insufficiency; 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 a Y chromosome require bilateral oophorectomy via laparotomy or laparoscopy because risk of ovarian germ cell cancer is increased.
Treatment references
1. Committee on Gynecologic Practice: Committee Opinion No. 698: Hormone therapy in primary ovarian insufficiency. Obstet Gynecol 129 (5):e134–e141, 2017. doi: 10.1097/AOG.0000000000002044
2. Sheshpari, S., Shahnazi, M., Mobarak, H. et al: Ovarian function and reproductive outcome after ovarian tissue transplantation: A systematic review. J Transl Med 17:396, 2019.
Key Points
Suspect primary ovarian insufficiency in women with unexplained menstrual abnormalities, infertility, or symptoms of estrogen deficiency.
Measure the antimüllerian hormone level to help predict which women may respond poorly to infertility treatments.
If an autoimmune cause is identified, test for other autoimmune disorders.
Unless contraindicated, prescribe cyclic estrogen/progestogen therapy (combination hormone therapy) to be taken until about age 51 (the average age for menopause) to maintain bone density and relieve symptoms and complications of estrogen deficiency.
