History and exam

Key diagnostic factors

common

age <40 years

Beyond age 40, menopause is considered to be physiologically normal.

family history of primary ovarian failure

Women with a first-degree relative with POF are at significantly higher risk of POF. The patient should be asked whether there is a family history of early-onset menopause and mother's age at onset of menopause.[30][31]

menstrual irregularities

May present most commonly with amenorrhoea (primary or secondary), but can occur with abnormal uterine bleeding or irregular bleeding patterns.

uncommon

toxic exposures

Mumps, chemotherapy, radiation, tobacco, and other toxins.

Other diagnostic factors

common

hot flushes

Symptom of oestrogen deficiency, although patients may be asymptomatic.

sleep disturbance

Symptom of oestrogen deficiency, although patients may be asymptomatic.

irritability

Symptom of oestrogen deficiency, although patients may be asymptomatic.

vaginal dryness

Symptom of oestrogen deficiency, although patients may be asymptomatic.

infertility

Diminished ovarian function often results in infertility; however, intermittent ovarian function, ovulation, and pregnancy can occur.

vaginal atrophy

Common with long-standing oestrogen deficiency. May be noted on physical examination.

small uterus with non-palpable ovaries

Common with long-standing oestrogen deficiency. May be noted on physical examination.

uncommon

cognitive abnormalities

Carriers of fragile X premutation may show mild cognitive or behavioural impairment.

signs of thyroid dysfunction

The possibility of a goitre, exophthalmos, lid lag, abnormal heart rate, or skin changes should be sought.

signs of adrenal dysfunction

Evidence of adrenal insufficiency (Addison's disease) including orthostatic hypotension, pigment changes, and decreased axillary or pubic hair should be sought.

signs of hyperprolactinaemia

Signs may include lactation on expression and, if there is an expanding pituitary prolactinoma, bitemporal hemianopia.

signs of genetic syndromes

Include short stature, webbed neck, cubitus valgus (increased carrying angle of arms), and lack of sexual development at puberty (Turner syndrome).

Risk factors

strong

family history of POF

In patients with premature menopause, 37.5% reported a family history of early menopause.[8]

exposure to chemotherapy or radiation

Varies based on the agent used, the dose, the duration of exposure, and the age at time of exposure. Increased risk with advancing age: for example, <20% in women age <30 years versus the majority of women age >40 years.[11] Risk for chemotherapy is highest with alkylating agents, with the risk being 9 times higher with these therapies.[12][13]

autoimmune disease

Approximately 30% to 40% of women with POF and normal karyotypes will be found to have an autoimmune disease.[14][15]

The most commonly reported autoimmune disease associated with POF is thyroid disease, and 20% will demonstrate antithyroid antibodies.[15]

Non-endocrine autoimmune diseases that have been associated with POF include idiopathic thrombocytopenic purpura, vitiligo, alopecia, autoimmune haemolytic anaemia, pernicious anaemia, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and Sjogren syndrome.

family history of fragile X syndrome

Up to 28% of female fragile X permutation carriers develop POF.[16]

In patients diagnosed with POF, fragile X permutation has been documented in 15% of cases with a family history of POF and 3% of sporadic cases.[17]

galactosaemia

Patients with galactosaemia have an enzyme deficiency associated with mental retardation, cataracts, and hepatorenal damage. A galactose-restricted diet can help minimise these consequences, although most affected females develop POF.[18]

weak

hysterectomy

Women who have undergone hysterectomy without removal of the ovaries undergo menopause an average of 4 years earlier than women with spontaneous menopause.[19] The presumed mechanisms for this observation are decreased blood supply to the ovary or severe inflammation affecting the ovary.

uterine artery embolisation

Uterine artery embolisation has been associated with POF by decreasing blood flow to the ovary.[20]

smoking

Women who smoke have nearly twice the risk of developing POF.[21]

lower socioeconomic status, higher education level, nulliparity

One population-based study found weak associations with these characteristics, although no mechanisms have been determined.[22]

presence of specific genetic variants

Studies have begun to identify genetic variants that can be used to determine which women may be at risk of early menopause.[23] This may allow at-risk women to plan to conceive earlier, or to cryopreserve oocytes.

ovarian surgery

Women who have undergone ovarian surgery, for example for endometriosis or other ovarian cystic disorders, are at increased risk of POF due to follicle depletion following surgical damage.

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