Premature ovarian insufficiency (POI) refers to a decline in ovarian function occurring before the age of 40. Its primary manifestations include menstrual irregularities (amenorrhea, oligomenorrhea, or frequent menstruation), reduced fertility, elevated follicle-stimulating hormone (FSH) levels, and fluctuating decreases in estrogen levels. The prevalence of POI is approximately 3.5%, with an increasing trend, though reported prevalence may underestimate the actual incidence.
Ovarian function decline in women is a progressive process, with POI representing a state of disease at a certain stage of ovarian decline. Related conditions include diminished ovarian reserve (DOR) and premature ovarian failure (POF).
DOR refers to a reduction in the quantity and/or quality of oocytes in the ovaries, accompanied by decreased anti-Müllerian hormone levels, reduced antral follicle count, and elevated FSH levels. It presents as decreased fertility but does not emphasize age, etiology, or menstrual changes.
POF is characterized by the onset of amenorrhea before the age of 40, FSH >40 IU/L, and decreased estrogen levels, often accompanied by symptoms of low estrogen to varying degrees. POF represents the terminal stage of POI.
Etiology
POI is a highly heterogeneous clinical condition with a complex etiology. Any factor impairing oogenesis or follicle development that results in a reduced follicle pool, abnormal follicle activation and development, or accelerated follicle atresia and depletion may lead to diminished ovarian reserve, thereby triggering POI. Various factors are implicated in its pathogenesis, with the primary ones outlined below:
Genetic Factors
Genetic causes account for 30%–35% of POI cases, including chromosomal abnormalities and gene mutations. Chromosomal numerical and/or structural abnormalities are seen in 10%–15% of cases, with gene mutation rates of approximately 20%. The likelihood of genetic defects is higher in patients with primary amenorrhea compared to those with secondary amenorrhea.
X-Chromosome Abnormalities and Related Gene Variants
X-chromosome abnormalities comprise about 94% of abnormal chromosomal karyotypes, including karyotypes such as terminal deletions of the X chromosome, 45,XO and its mosaic forms, most commonly associated with Turner syndrome. Genes on the X chromosome implicated in POI include BMP15, DIAPH2, FMR1, and others.
Autosomal Abnormalities and Related Gene Variants
Autosomal abnormalities are observed in approximately 2% of patients, with reciprocal translocations between autosomes and X chromosomes being the primary karyotypic abnormality. Autosomal genes implicated in POI include those involved in meiosis, DNA damage repair, follicular development, and reproductive endocrine function. However, the mutation carriage rate for most pathogenic genes does not exceed 5%, limiting the clinical diagnostic value of individual genes. Aside from single-gene mutations, polygenic inheritance models are gaining increasing attention in the pathogenesis of POI.
Syndromic POI and Related Gene Mutations
Some hereditary syndromes include POI as one of their clinical manifestations, such as blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), Perrault syndrome, and leukodystrophy. Genes associated with syndromic POI include FOXL2, HARS2, EIF2B2, among others. Mutations exhibit high clinical heterogeneity, and associated mechanisms remain largely unclear.
A total of 23 genes have been designated as POF genes in the Online Mendelian Inheritance in Man (OMIM) database, including genes such as NOBOX (POF5), FIGLA (POF6), ERCC6 (POF11), MSH5 (POF13), BNC1 (POF16), XRCC2 (POF17), and C14orf39 (POF18).
Iatrogenic Factors
Approximately 10% of POI cases are attributed to medical interventions. With advances in medical treatments, survival and cure rates for malignancies and other severe diseases have improved significantly. However, this has also led to an increase in ovarian dysfunction caused by pelvic surgery, radiotherapy, and chemotherapy. Surgical procedures may result in ovarian tissue damage or localized inflammation, while radiotherapy and chemotherapy may induce oocyte apoptosis or impair granulosa cell function.
Immune Factors
Autoimmune dysregulation may lead to ovarian damage, accounting for about 15% of POI cases. Conditions such as autoimmune thyroid disease and Addison's disease are most closely associated with POI.
Environmental and Other Factors
Factors such as active or passive smoking, prolonged use of gonadotoxic drugs, and exposure to environmental toxins and endocrine-disrupting chemicals (e.g., organic solvents, pesticides, plasticizers, and industrial chemicals) may contribute to ovarian damage.
Idiopathic POI
Nearly half of POI cases have an unknown etiology and are classified as idiopathic POI.
Clinical Manifestations
Symptoms
Menstrual Changes
POI may present as primary amenorrhea or secondary amenorrhea, with the latter being more common clinically. During the transitional period from diminished ovarian reserve to ovarian failure, patients may experience frequent or infrequent menstruation, reduced menstrual volume, amenorrhea, sudden cessation of menses despite previously regular cycles, or the absence of menstruation after discontinuing contraceptive use or terminating pregnancy.
Low Estrogen Symptoms
Patients with primary amenorrhea may exhibit underdevelopment or poor development of female secondary sexual characteristics. Patients with secondary amenorrhea may experience varying degrees of symptoms such as hot flashes, night sweats, vaginal dryness or burning, reduced libido, osteoporosis, changes in mood and cognitive function, or cardiovascular symptoms. Perimenopausal symptoms are particularly prominent in POI caused by iatrogenic damage.
Reduced Fertility or Infertility
Fertility is significantly reduced. During the early stages of diminished ovarian reserve, spontaneous ovulation may still occur intermittently, allowing for a 5%–10% chance of natural conception, though the risks of spontaneous miscarriage and chromosomal abnormalities in the fetus are heightened.
Other Symptoms
Symptoms may vary based on the underlying etiology. For example, Turner syndrome may be associated with cardiovascular system developmental defects or intellectual disabilities. Certain syndromic forms of POI may present with features such as narrowed palpebral fissures or hearing loss.
Physical Signs
Patients with primary amenorrhea often present with underdeveloped sexual organs and secondary sexual characteristics, along with abnormalities in body development or height. Patients with secondary amenorrhea may exhibit signs such as breast atrophy, loss of pubic and/or axillary hair, and vulvovaginal atrophy.
Auxiliary Examinations
Baseline Endocrine Measurements
Baseline serum FSH levels exceeding 25 IU/L on at least two occasions, with an interval of 4 weeks, confirm a diagnosis. Testing is performed randomly during amenorrhea or on days 2–4 of the menstrual cycle. Estradiol levels may initially rise (>50 pg/mL) due to disordered follicular growth but subsequently decline (<5 pg/mL).
Ultrasound Imaging
Significant bilateral ovarian volume reduction and absence of visible antral follicles are common. The antral follicle count (AFC) on both sides is often less than five, with no evidence of dominant follicle development during serial monitoring. A small subset of patients may exhibit intermittent follicular development and ovulation.
Serum Anti-Müllerian Hormone (AMH) Levels
Serum AMH levels ≤1.1 ng/mL are indicative of diminished ovarian reserve.
Genetic and Immunological Testing
Karyotype analysis may reveal chromosomal abnormalities, with further genetic mutation testing performed as needed. Additional tests include thyroid function and adrenal antibody assessments to evaluate immune-related causes.
Diagnosis
Diagnosis is based on a combination of symptoms, physical signs, and findings from auxiliary testing.
Diagnostic Criteria
These include:
- Age <40 years
- Oligomenorrhea or amenorrhea persisting for at least 4 months
- Baseline serum FSH levels >25 IU/L on at least two occasions, measured 4 weeks apart
Subclinical POI is characterized by serum FSH levels between 15 and 25 IU/L and identifies high-risk individuals.
Etiological Diagnosis
Determining etiology involves evaluating the patient’s medical history, family history, past medical events, chromosomal studies, and other auxiliary test results to identify genetic, immunological, or iatrogenic causes.
Differential Diagnosis
Differential diagnosis includes ovarian resistance syndrome, reproductive tract development abnormalities, complete androgen insensitivity syndrome, Asherman syndrome, functional hypothalamic amenorrhea, and polycystic ovary syndrome (PCOS).
Management
Psychological and Lifestyle Interventions
Psychological stress may be alleviated, and a healthy diet, regular physical activity, smoking cessation, and avoidance of exposure to reproductive toxicants may be beneficial. Calcium and vitamin D supplementation may be appropriate, especially in individuals with reduced bone mineral density.
Fertility Counseling
Women with a family history of POI or early menopause, or who carry genetic variants associated with POI, may benefit from early childbearing or timely fertility preservation. Research into the genetic mechanisms of POI provides a foundation for early identification and intervention in high-risk individuals.
Treatment
The pathogenesis of POI remains unclear in most patients, and no effective therapy currently exists to restore ovarian function.
Hormone Replacement Therapy (HRT)
HRT can alleviate hypoestrogenic symptoms and serve as primary prevention for cardiovascular disease and osteoporosis. In the absence of contraindications, HRT is generally recommended for women with POI. Since spontaneous pregnancy may still occur after POI diagnosis, contraception may be needed. HRT can be combined with other contraceptive methods, or combined oral contraceptives may be used. For women desiring fertility, supplementation with natural estrogens and progestogens may be considered.
Primary POI
Continuous treatment may be necessary from puberty through adulthood. High doses of estrogen may accelerate bone maturation and affect final height. Estrogen supplementation may begin at age 11–12 in low doses (1/8 to 1/4 of the adult dose), possibly combined with growth hormone to support height development. Based on changes in bone age and height, estrogen dosage may be gradually increased every six months over 2–4 years until adult levels are reached. Once the uterus develops, progestogen should be added regularly based on endometrial proliferation or the occurrence of vaginal bleeding, or a sequential regimen of estrogen and progestogen may be used to protect the endometrium.
Secondary POI
Long-term treatment is required. Management principles include:
- Timing: Initiate HRT as early as possible in the absence of contraindications or with careful assessment of precautions.
- Duration: Continue treatment until the average age of natural menopause; treatment beyond that may follow postmenopausal HRT guidelines.
- Dosage: Standard doses are recommended, rather than low-dose regimens, with adjustments based on individual needs.
- Regimen: Estrogen therapy in women with an intact uterus should include progestogen; estrogen monotherapy may be used if the uterus is absent or has been removed.
- Medications: Long-term HRT should use natural or bioidentical estrogens and progestogens to minimize potential impacts on breast tissue, metabolism, and cardiovascular health.
- Follow-up: Annual follow-up is necessary to monitor medication adherence, satisfaction, side effects, and to adjust the treatment plan, dosage, medication, or formulation as needed.
Long-term Health and Complication Management
Women with POI are at increased risk for osteoporosis, cardiovascular disease, and cognitive impairment. A healthy lifestyle may mitigate these risks, including weight-bearing exercise, smoking avoidance, and maintaining a healthy weight. For urogenital symptoms such as vaginal dryness or dyspareunia, local estrogen therapy or vaginal lubricants may provide relief. POI patients carrying mutations in DNA damage-related genes should be followed long-term for potential malignancies.
Fertility-related Management
Assisted Reproductive Technology (ART)
Donor oocyte IVF-ET (in vitro fertilization and embryo transfer) may be an effective fertility solution for POI patients, with pregnancy rates exceeding 50%. Subclinical patients may attempt IVF-ET using their own oocytes, though success rates are low and no optimal treatment protocol has been established. POI patients with Turner syndrome should undergo thorough cardiovascular evaluation to rule out contraindications to pregnancy.
Fertility Preservation
This is mainly indicated for women at high risk for POI or those undergoing treatments that impair ovarian function. Depending on personal preferences, age, and marital status, various fertility preservation methods may be considered, including embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, and use of GnRH agonists. Embryo cryopreservation is the preferred method for adult married women. There have been reports of live births following oocyte and ovarian tissue cryopreservation in women at high risk for POI. However, challenges remain, including limited awareness of fertility preservation and uncertainty regarding the developmental potential of thawed oocytes.