Iatrogenic Causes of Primary Ovarian Insufficiency Radiation, chemotherapy (especially alkylating agents such as cyclophosphamide) (98), surgical interference with ovarian blood supply, and infections can cause ovarian failure from early loss of follicles. A radiation dose of 800 cGy causes sterility in most individuals. Ovarian failure can be caused by as little as 150 cGy in some patients, especially if they are older than 40 years of age with limited ovarian reserve. In an evaluation of ovarian function in 100 childhood cancer survivors, 17 had premature ovarian failure. Those with spontaneous menses had smaller ovarian volume, fewer antral follicles, and lower inhibin B levels when compared with controls (99). Ovarian suppression with GnRH agonists and oral contraceptives to reduce the risk of ovarian failure was attempted with limited success (100,101). Cigarette smoking decreases the age at which menopause will occur. But smoking would not be expected to be the primary cause of amenorrhea occurring before the age of 40.
Infections In rare cases, mumps was associated with premature ovarian failure (102). Women with human immunodeficiency virus (HIV) infection may prematurely lose ovarian function compared to women without HIV infection (103). Cytomegalovirus was shown postmortem to cause oophoritis, but premature ovarian failure had not yet developed clinically in the patient, so the relationship of cytomegalovirus to ovarian failure remains unclear (104).
Autoimmune Disorders In one series, 4% of women with POI were noted to have steroidogenic cell immunity with lymphocytic oophoritis as the mechanism for follicle dysfunction (105). Autoimmune lymphocytic oophoritis is associated with a theca cell infiltrate that spares granulosa cells (106). Ultrasound examination reveals the presence of numerous ovarian follicles, despite elevated serum FSH levels and hypoestrogenism (82). Ovarian antibody testing is not clinically reliable for diagnosing the disorder, as women with biopsy-proven autoimmune oophoritis may have a negative test for ovarian antibody. However, women with autoimmune lymphocytic oophoritis appear to reliably test positive for adrenal antibodies. The most readily available antibody is the 21-hydroxylase antibody (by immunoprecipitation). Ideally, antibody to the adrenal gland itself, as assessed by indirect immunoﬂuorescence, is reasonable to test if available. Testing for 21-hydroxylase antibody is strongly recommended for women who are determined to have POI because women who test positive for this antibody are at risk for potentially fatal hypoadrenalism. Signs that suggest a risk for potentially fatal adrenal insufficiency include hyperpigmentation, weakness, nausea, vomiting, diarrhea, and weight loss.
POI may be part of a polyglandular autoimmune syndrome. Antibodies are present in a variable number of patients with POI, depending on the autoimmune studies performed. One study showed that 92% of patients with premature ovarian failure had autoantibodies (107). Only 20% of these patients exhibited signs of immunologic dysfunction, most frequently in the form of a thyroid disorder that is common in the general population of women who do not have POI. Presence of antithyroid antibodies does not confirm that there is an autoimmune cause for POI. Rarely, POI is associated with myasthenia gravis, idiopathic thrombocytopenia purpura, rheumatoid arthritis, vitiligo, autoimmune hemolytic anemia, diabetes mellitus, and other autoimmune disorders (108–110).