Laboratory Studies
Three groups of tests should be performed when ovarian failure is suspected or has been diagnosed. They include tests that establish the diagnosis of POI/POF, tests that help clarify the etiology, and screening tests for other diseases known to have higher prevalence among women with POI/POF.
A pregnancy test (urine or beta human chorionic gonadotropin [bhCG] in the blood) should be the first study performed in every woman of reproductive age who presents with amenorrhea.
Studies to establish the diagnosis of POI/POF are as follows:
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Measuring serum FSH level is the core study to establish the diagnosis of POI/POF after pregnancy has been ruled out. By convention, 2 FSH levels in the menopausal range for the specific assay (>40 µIU/mL by radioimmunoassay), measured at least 1 month apart, are diagnostic of POI/POF.
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Measurement of serum LH is also important. In most cases of spontaneous POI/POF, FSH is higher than LH. If autoimmune oophoritis is present, FSH may be only mildly elevated, sometimes below the cutoff of 40 µIU/mL, while LH is markedly elevated.
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A parallel test of serum estradiol is necessary. As a rule, serum estradiol is low in women with POI/POF and is similar to or less than the early follicular phase estradiol of women who cycle normally. The combination of low estradiol and high gonadotropins defines POI/POF.
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Occasionally, women with POI/POF may have spontaneous follicular activity, and, if hormonal tests are performed during such episodes, levels of FSH, LH, and estradiol could be in the normal range or FSH and LH could be elevated only minimally (below the menopausal range). This may lead to an erroneous rejection of the diagnosis of POI/POF. In these cases, persistent amenorrhea or oligomenorrhea accompanied by menopausal symptoms necessitates a repeat of the above tests in 1-2 months.
Studies to clarify the etiology of ovarian failure are as follows:
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Karyotype: A karyotype should be performed as a part of the routine evaluation after the diagnosis of POI/POF is established. A history of previous pregnancies or age older than 35 years should not discourage the test. X chromosome abnormalities have been described in women who have had normal puberty, have delivered children without abnormalities, and subsequently have developed POI/POF. In addition, unexpected karyotype findings may have important implications for relatives and for future pregnancies. A normal karyotype may be reassuring to the patient, while an abnormal one could provide an explanation of the patient's problem.
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Refer for genetic counseling and testing for the FMR1 premutation if a family history of POI, mental retardation, or a tremor/ataxia syndrome is present.
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Ovarian antibodies: Currently, no reliable ovary-specific tests exist for the diagnosis of autoimmune ovarian failure. The different ovarian antibody assays that are available commercially are of little diagnostic value because of problems with specificity and sensitivity. Adrenal antibodies are predictive of autoimmune oophoritis based on the presence of steroid cell autoantibodies.
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The presence of a second autoimmune endocrine or nonendocrine disease is traditionally used as an argument that the ovarian failure of a particular patient is of autoimmune etiology. In most cases, this is not true, the only exception being the combination of Addison disease and POI/POF.
Imaging Studies
Primary ovarian insufficiency: Ovarian ultrasonography can be useful in the workup of patients with POI/POF as it will identify those women with multifollicular ovaries and suggest the diagnosis of either autoimmune oophoritis or 17-20 desmolase deficiency.
Secondary ovarian insufficiency: An MRI of the pituitary and hypothalamus is indicated in the evaluation of secondary ovarian insufficiency in the following circumstances:
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Hyperprolactinemia
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Associated headache or visual-field cuts
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Profound estrogen deficiency with otherwise unexplained amenorrhea
Other Tests
Overt primary ovarian insufficiency
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Obtain serum free T4 and thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies, and fasting blood sugar measurements.
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Measure adrenal antibodies.
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Perform bone density scan (DEXA) to evaluate bone mineral density.
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Perform an adrenocorticotropic hormone (ACTH) stimulation test if the adrenal antibody test is positive.
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Perform other antibody tests such as antinuclear antigens (ANA) and rheumatoid factor tests only as clinically indicated.
Secondary ovarian insufficiency
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Consider the need for an ACTH stimulation test to evaluate secondary adrenal insufficiency as an additional finding.
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Consider the need for diurnal TSH measurements to evaluate for the presence of central hypothyroidism as an additional finding.
Procedures
Primary ovarian insufficiency: Clinically, ovarian biopsy is not indicated. The procedure should be performed only as part of an investigation that is approved by an institutional review board.
Secondary ovarian insufficiency: Surgical procedures should be performed as indicated when hypothalamic or pituitary lesions are identified.
Tables
Ovarian Clinical Situation |
Menses |
Gonadotropins |
Fertility |
Occult insufficiency |
Normal |
Normal |
Reduced |
Biochemical insufficiency |
Abnormal |
Elevated |
Reduced |
Overt insufficiency |
Abnormal |
Elevated |
Reduced |
Premature ovarian failure |
Absent |
Elevated |
Zero |
