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Other Endocrine Disorders Causing Anovulation: Thyroid Disorders
Introduction
Thyroid dysfunction has profound effects on the chance of becoming and remaining pregnant (1). Hyperthyroidism as well as hypothyroidism is associated with irregular menstrual cycles. Similarly, thyroid dysfunction interferes with normal fertility, and hence, it is associated with subfertility. Moreover, relevant data point to an important role for thyroid hormone in the earliest phases of pregnancy with the well-described syndrome of cretinism on the one end of the spectrum and the less well-described syndrome of maternal hypothyroxinaemia on the other end of the spectrum (2). For the aim of the current chapter, it is important to point out that even small changes in thyroid hormone levels—such as can be induced by ovarian hyperstimulation (vide infra)—are already associated with impaired psychomotor development in the offspring.
During pregnancy, thyroid hormone metabolism changes in a well-characterized manner (2). There is quite a bit of literature on the physiological changes in thyroid hormone metabolism during normal pregnancy, and for an in-depth review on this topic, the reader is referred to the existing literature (2); however, in order to provide a better understanding, a short review of the normal response of the thyroid to pregnancy will be given first. Then, changes in thyroid function induced by ovulation induction will be discussed followed by an overview of how thyroid dysfunction will affect the results of ovulation induction. Finally, we will try to make some recommendations on what to advise women undergoing ovulation induction.
Thyroid Function and Becoming Pregnant
Menstrual disturbances are associated with thyrotoxicosis and hypothyroidism (1). The prevalence of menstrual disturbances in thyrotoxicosis varies between 22% and 65% and in hypothyroidism between 23% and 80%, with the lower prevalences reported in the more recent studies (1). Treatment of hypothyroidism reduces the prevalence of menstrual disturbances to the normal population level (1). The changes in menstrual cycle are due to changes in estrogens, androgens, gonadotrophins, and sex-hormone binding globulin (1).
Fertility—that is, the ability to conceive after 1 year of regular and unprotected intercourse—is generally thought to be negatively influenced by thyroid dysfunction. It should be noted, however, that the studies on fertility in women with thyroid dysfunction are mostly observational, uncontrolled, and retrospective.
Subclinical hypothyroidism is associated with subfertility: Women with higher TSHs have lower pregnancy rates and take longer to become pregnant (LOE 3). Moreover, thyroid hormone substitution improves the chances of becoming pregnant (1) (LOE 3). Considering overt hypothyroidism, there are only limited data; however, in analyzing menstrual disturbances or infertility, a TSH—and subsequent fT4 if it is outside the reference range—determination is indicated, and in case of overt hypothyroidism, treatment with thyroid hormone substitution is indicated (LOE 4) (1).
In a prospective study, thyrotoxicosis was not more prevalent in infertile women compared to controls (1). Data from older studies suggest that women with overt hyperthyroidism remain ovulatory, albeit with a higher prevalence of menstrual disturbances (1).
Thyroid autoimmunity—that is, the presence of thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies—is also associated with impaired fertility, suggesting a common immunological background for thyroid dysfunction and infertility (1). This notion is supported by the fact that the chances of a miscarriage are approximately doubled in euthyroid women with thyroid antibodies (1). This was investigated in 77 women with a normal thyroid function and without thyroid autoimmunity prior to their first assisted reproductive technology procedure; of these women, 32 suffered a miscarriage. In the women who suffered a miscarriage and in the ones with ongoing pregnancy, thyroid function changed significantly, but these changes were not different between those with ongoing pregnancies and those with a miscarriage (1) (LOE 2a).
Taken together, we can conclude that both hypo- and hyperthyroidism are associated with cycle disturbances. With respect to fertility, the data are less clear. Although not supported by high-quality intervention studies, treatment of subclinical hypothyroidism and overt hypothyroidism (i.e., a TSH level above the reference range) is advised as an attempt to restore fertility. Overt thyrotoxicosis should be treated, but clear data showing the extent of such an intervention on menstrual cycle and fertility are lacking.
Thyroid Function during Pregnancy
Several mechanisms are at play during pregnancy that lead to physiological changes in thyroid hormone metabolism (2).
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