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Summary
Primary ovarian insufficiency (POI) is impaired ovarian function before the age of 40 years due to a defect in the ovaries that decreases follicle numbers or results in an insufficient follicular response to gonadotropin stimulation (i.e., hypergonadotropic hypogonadism). The underlying etiology is unknown in 70% of cases; known etiologies include genetic disorders, autoimmune diseases, and iatrogenic causes (e.g., chemotherapy or pelvic surgery). Because ovarian insufficiency affects ovulation and estrogen production, symptoms include amenorrhea or abnormal uterine bleeding, and climacteric symptoms. Unlike premature menopause, ovarian function in POI may not have permanently ceased; function is intermittent, and individuals may become pregnant, although infertility is common. POI is often discovered during diagnostics for amenorrhea; a low estradiol level with elevated FSH suggests POI. If FSH is normal or low, secondary ovarian insufficiency (inadequate gonadotropic stimulation of the ovaries by the hypothalamus and/or pituitary glands, i.e., hypogonadotropic hypogonadism) should be considered. POI is confirmed if values remain abnormal when repeated at least a month later. Assessment for the underlying cause involves genetic studies and, potentially, autoantibodies. Management of POI includes long-term hormone replacement therapy (HRT), management of infertility, and ongoing monitoring for the development of complications of POI (e.g., cardiovascular disease and osteoporosis).
Etiology
- Idiopathic (up to 70% of cases) [4]
-
Genetic disorders
- Disorders associated with gonadal dysgenesis; (e.g., Turner syndrome, Swyer syndrome)
- Fragile X syndrome
- Autoimmune diseases, e.g.:
- Toxins
- Tobacco smoke [6]
- Environmental chemicals (e.g., phthalates, bisphenols)
-
Iatrogenic
- Radiation and/or chemotherapy
- Pelvic surgery (e.g., cyst excision)
- Infectious diseases (e.g., mumps, HIV)
Pathophysiology
Clinical features
- Amenorrhea or abnormal uterine bleeding
- Climacteric symptoms such as vaginal dryness, vasomotor symptoms, dyspareunia, and irritability
- Infertility
- May be accompanied by features of the underlying etiology (e.g., symptoms of hypothyroidism)
Diagnosis
POI is often detected on diagnostic studies for amenorrhea.
Approach [2][3][4]
- Initial diagnostic studies, including FSH and estradiol
- Repeat in one month if results are abnormal. POI is likely if: [2][6]
- Age is < 40 years
- There has been irregular menstruation for ≥ 3 consecutive months [2]
- Two sets of laboratory studies recorded > 1 month apart, in patients not using hormonal contraception, show: [2]
- Evaluate for underlying causes.
- Refer patients who want to preserve fertility to a reproductive endocrinologist for additional evaluation, including ovarian reserve testing. [2][4]
If estradiol is low but FSH is normal or low, assess for secondary ovarian insufficiency. [3]
Hormonal contraception can affect gonadotropin and estradiol values; stop any exogenous hormones before obtaining diagnostic studies. [2]
Initial diagnostic studies [2][3][4]
See also “Diagnostics for amenorrhea.”
Evaluation of underlying causes [2][6]
- May not be required for patients with a clear cause of iatrogenic POI [6]
- For all other patients:
-
Assess for genetic anomalies.
- Karyotyping
- FMR1 gene premutation for fragile X syndrome
- Family history of POI or early menopause: Refer for additional genetic testing. [4]
- If genetic studies are normal, evaluate for autoimmune disease with:
- 21-hydroxylase adrenal antibodies [7]
- Anti-TPO antibodies [2][6]
- Pelvic ultrasound [5]
- Additional studies for other autoimmune disorders (e.g., diabetes, rheumatoid arthritis, SLE) depending on underlying symptoms
-
Assess for genetic anomalies.
Differential diagnoses
- Secondary ovarian insufficiency: symptoms of POI with a normal or low FSH
- Other potential differential diagnoses of POI depend on symptoms.
- Climacteric symptoms: premature menopause
- Absent menstrual bleeding: See “Causes of amenorrhea.”
- Irregular bleeding: See “Causes of abnormal uterine bleeding.”
- Infertility: See “Causes of infertility.”
Secondary ovarian insufficiency
Secondary ovarian insufficiency is impaired ovarian function due to inadequate gonadotropic stimulation of the ovaries by the hypothalamus and/or pituitary glands (i.e., hypogonadotropic hypogonadism). [8]
Etiology
See “Ovulatory dysfunction” for hypogonadotropic causes of hypogonadism.
Diagnosis [3][8]
- Usually detected during diagnostics for amenorrhea
- As in POI, estradiol is low, but FSH is low (or normal) rather than elevated.
- Further studies depend on the suspected underlying etiology (e.g., MRI brain for CNS lesions).
Management
- Treat the underlying cause. [3]
- Genetic disorders: Consider long-term HRT. [9][10]
- Infertility: Consider ovulation induction. [11]
The differential diagnoses listed here are not exhaustive.
Management
The following outlines management of postpubertal individuals with POI; refer patients who have not completed puberty to a specialist for management.
Approach [2][4][6]
- Treat any underlying causes (e.g., autoimmune disease).
-
Discuss reproductive goals.
- Not planning pregnancy: Initiate HRT.
- Planning pregnancy: Refer to a fertility specialist; assisted reproductive technology is usually required.
- Offer a referral for psychological counseling.
- Screen for and initiate measures to prevent complications of POI. [6]
- Osteoporosis screening (including a vitamin D level) and osteoporosis prevention [12]
- Check BP, BMI, HbA1c, and a lipid panel, and initiate ASCVD prevention.
- Inquire about sexual dysfunction.
- Treat urogenital atrophy. [6]
- Refer for counseling as needed.
- Advise patients with noniatrogenic POI that female relatives are at increased risk and should seek testing. [6]
HRT [12]
- Screen for contraindications to HRT; refer to a specialist as needed.
- Educate patients on the importance of HRT for reducing the risks of POI complications.
- Determine if contraception is required (HRT alone is not effective contraception). [3][12]
- Individuals not requiring contraception
- Combined HRT
- OR estrogen-only HRT plus cyclical progestin for endometrial protection [3][4]
- Individuals requiring contraception
- Estrogen-only HRT plus levonorgestrel IUD [2][12]
- Continuous combined estrogen-progestin hormonal contraception (CHCs) [12]
- Nonhormonal contraceptive methods can also be added to HRT regimens that do not provide contraception.
- Individuals not requiring contraception
- For dosages, see:
- “Options for HRT”; doses at the higher end of the range are usually required. [12]
- “Hormonal contraception”
- Continue until 50–51 years of age (the average age of menopause); can be continued longer to manage symptoms (see “Treatment of menopause”). [12]
Individuals who do not wish to become pregnant require contraception, since spontaneous pregnancy occurs in up to 10% of individuals with POI, and HRT does not provide adequate contraception. [3][12]
Reassure patients that HRT has not been associated with breast cancer when used before the age of menopause. [6]
Ongoing management [2]
- Follow up with patients annually.
- Assess for changes in their reproductive life plan; refer to a fertility specialist as needed.
- Check blood pressure.
- In patients with low bone density or osteoporosis, repeat bone density scanning. [6][12]
- Monitor periodically for development of thyroid disease. [2][6]
- Assess lipid levels every 5 years. [2]
Complications
- Similar to complications of menopause, e.g.: [6][12]
- Elevated risk of cardiovascular disease
- Osteoporosis
- Urogenital atrophy
- Additional risks in POI include:
- Cognitive impairment and dementia
- Increased mortality
We list the most important complications. The selection is not exhaustive.
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