Approach
When women present with infertility, amenorrhoea, or symptoms of hypo-oestrogenism, the diagnosis of POF is made by documenting persistently elevated serum follicle-stimulating hormone (FSH) levels in the presence of low or low-normal serum oestrogen levels. If elevated FSH is confirmed, a cause for the early cessation of ovarian function should be sought, keeping in mind that the majority of cases are idiopathic. Associated medical conditions should be screened for and treated if present. Finally, the goal of further testing should be to monitor and minimise the complications of premature menopause.
History
The most common presenting symptom is amenorrhoea (primary or secondary). Some women present with amenorrhoea before 40 years of age as the only symptom of premature menopause. Early POF can also present with abnormal uterine bleeding or irregular bleeding patterns. Patients should be asked about their menstrual cycle, including last spontaneous menstrual period. The patient may describe symptoms of hypo-oestrogenism (hot flushes, sleep disturbance, irritability, and vaginal dryness), although many women do not report these symptoms.
Another common presenting symptom is infertility, although it should be noted that intermittent ovarian function, ovulation, and pregnancy can occur. A history of pelvic surgery, uterine artery embolisation, radiation or chemotherapy, viral infections, or unusual exposure to environmental toxins in the workplace should be established. It is also important to ask about a family history of POF, autoimmune diseases, or cognitive abnormalities (suggestive of fragile X syndrome).
Finally, the patient should be asked whether she is experiencing any symptoms of adrenal insufficiency (e.g., abdominal pain, anorexia) or hypothyroidism (e.g., fatigue, constipation, or intolerance of cold), whether there is a family history of early-onset menopause, and mother's age at onset of menopause.[30][31]
Physical examination
A pelvic examination may show vaginal atrophy, which is common with long-standing oestrogen deficiency. The ovaries are usually non-palpable, but may occasionally be enlarged in cases of autoimmune oophoritis.
The presence of physical stigmata of genetic syndromes such as Turner syndrome should be noted. These include short stature, webbed neck, cubitus valgus (increased carrying angle of arms), and lack of sexual development at puberty.
Signs of adrenal insufficiency such as orthostatic hypotension, pigment changes on the skin, and decreased axillary or pubic hair should be sought. Exophthalmos, goitre, lid lag, and coarse dry skin are examples of physical signs in thyroid dysfunction.
Signs of hyperprolactinaemia may include lactation on expression and, if there is an expanding pituitary prolactinoma, bitemporal hemianopia. Occasionally, POF may be a presenting symptom of panhypopituitarism.
Initial tests
A pregnancy test should always be performed in amenorrhoeic women of reproductive age. When POF is suspected clinically, the diagnosis is made by obtaining FSH levels persistently in the menopausal range (>40 IU/L). FSH is measured on two separate occasions (at least 4-6 weeks apart) because ovarian function can fluctuate in the early stages of POF, and the diagnosis can be a devastating blow to a young patient. An elevated serum luteinising hormone (LH) level supports the diagnosis, but is not used as a primary indicator of POF because mid-cycle LH is routinely elevated ('LH surge') in normally cycling women. Serum estradiol levels are usually undetectable (<50 picomol/L), but can be in the low-normal range in some women as a result of lingering ovarian production or peripheral aromatisation of androgens from the adrenal gland. Transvaginal ultrasound is frequently performed, and may show abnormally low ovarian volumes and a low to non-existent antral follicle count. Laparoscopic ovarian biopsy is occasionally performed, but is not currently recommended.
Other laboratory tests that should be considered include serum thyroid-stimulating hormone and prolactin to exclude other common causes of secondary amenorrhoea in women of reproductive age, such as hypothyroidism and hyperprolactinaemia.
Increasingly, reproductive endocrinologists are also measuring serum concentrations of anti-Müllerian hormone (AMH), which is released from the developing cohort of small antral follicles within the ovaries. A fall in AMH can give an early warning of incipient ovarian failure and may have a role when diagnosis is inconclusive.[32][33]
Further tests
Women with POF before 35 years of age should have their karyotype evaluated to exclude Turner syndrome or mosaicism, or X chromosome abnormalities such as X chromosome trisomies, deletions, or translocations. Patients with a family history of POF should be screened for fragile X syndrome by evaluating for FMR1 gene mutations.
While there is no direct test for autoimmune oophoritis, it can be suspected based on the presence of other autoimmune disorders, as evidenced by positive thyroid or adrenal antibodies, or the appearance of enlarged ovaries on ultrasound.[34] Thyroid dysfunction has been associated with up to 30% of cases of POF.[34] Women found to have anti-adrenal antibodies should be tested for adrenal insufficiency with an adrenocorticotropic hormone stimulation test; as many as 3% will be found to have adrenal insufficiency.[35]
Blood glucose, renal profile, and electrolytes should be requested as women with POF should be screened for underlying endocrinological disorders such as type 1 diabetes (raised fasting glucose) and Addison's disease (hyponatraemia). Calcium and phosphorus will help detect hypoparathyroidism (low calcium, raised phosphorus).
Decreases in bone density parallel decreases in ovarian function; by the time cessation of ovarian function is confirmed, bone density may already be significantly affected. Within 18 months of diagnosis, 50% of women show significant decreases in their bone mineral density, and two-thirds of these women will have reductions so significant that they are at high risk of fractures.[18] A dual-energy x-ray absorptiometry bone scan can be performed to determine if there is a decrease in bone density as this has therapeutic implications..
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