Thyroid Autoimmunity, Infertility and Miscarriage

Gerasimos E. Krassas; Petros Perros; Athina Kaprara

Disclosures

Expert Rev Endocrinol Metab. 2008;3(2):127-136. 

In This Article

Abstract and Introduction

Abstract

Thyroid autoimmunity (TAI), infertility and miscarriage are currently issues of extreme interest that have attracted the attention of many investigators. Several papers have been published, focusing on women of childbearing age that include healthy women, women with recurrent miscarriage and those undergoing assisted conception. Most of these studies show a significant association between the presence of thyroid autoantibodies, infertility and a higher miscarriage rate. The underlying pathogenetic mechanisms, which might explain the association between TAI and infertility, remain speculative given the scarce information from animal models and from in vitro data addressing the potential effects of TAI on fertility. Adequate levels of circulating thyroid hormones are of primary importance for normal reproductive function and inadequate delivery of triiodothyronine to granulosa and stromal cells may disrupt normal female reproductive function. With regards to the association between TAI and miscarriage, a close relationship has been largely confirmed in recent studies. The aim of this review is to present the relevant information published so far in the literature regarding TAI and miscarriage in euthyroid female individuals.

Introduction

Autoimmune thyroid disorders are characterized by the presence of thyroid auto-antibodies (Abs), particularly thyroid peroxidase (TPO) autoAbs and anti-thyroglobulin (Tg) autoAbs. TPO is an enzyme responsible for iodination of tyrosine residues and coupling of iodinated residues to form thyroid hormones.[1] Tg is a molecule produced by thyroid cells that is stored in the thyroid colloid. The primary function of Tg is the storage and synthesis of thyroid hormones. Thyroid autoAbs may be present in apparently healthy populations and are more frequently observed in women during their reproductive years.[2]

Female causes account for 35% of infertility among couples. Assisted-reproduction technology encompasses in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). These techniques are often the ultimate options available to childless couples when all other treatments have proved unsuccessful. The live birth rate after one cycle of assisted-reproduction technology in women aged between 30 and 35 years is between 25 and 30%.[3]

Thyroid autoimmunity (TAI) is the most common autoimmune disorder in women of reproductive age, with a prevalence varying between 5 and 15%. It is five- to ten-times more common in women than in men and can be present without thyroid dysfunction, thus remaining undiagnosed.[3] The effects of estrogens in promoting autoimmunity, genetic factors and perhaps maternal microchimerism and chromosome X abnormalities, may potentially explain the high prevalence of TAI in women.

The relationship between autoimmune abnormalities and reproductive failure has been investigated extensively. Numerous studies have focused on TAI in infertile women. Interpretation of the available data is difficult for a variety of reasons, most notably because of the heterogeneity of the samples of women studied and the largely retrospective uncontrolled experimental design of the studies. Some variability among studies can be further explained by differences in sample size (generally small series), by differences in assays used to detect TAI and different geographical locations of the studies.[3] Overall, however, the studies indicate an increased prevalence of TAI among women attending infertility clinics ( Table 1 ).

Pregnancy is associated with profound changes in thyroid function. The requirements for thyroid hormone increase, a process mediated by the direct thyrotropic effects of human chorionic gonadotropin (hCG), a rise in the binding capacity of serum (thyroxine binding globulin) and possibly alterations in the peripheral metabolism of thyroid hormones.[4] Iodine excretion in the urine rises during pregnancy, accounting for the increase of thyroid volume in iodine-deficient areas.[5] In early pregnancy, women with thyroid Abs have higher serum thyrotropin-stimulating hormone (TSH) levels compared with thyroid Ab-negative women, although the mean TSH levels may still fall within the normal range. These Ab-positive women are prone to develop subclinical or overt hypothyroidism during pregnancy[6] owing to the reduced functional reserve of their thyroid, which is unable to compensate for the increased hormone requirement of pregnancy.[7] As pregnancy progresses, a striking decrease in thyroid auto-Ab levels occurs, both in women with initially extremely elevated, and those with only modest elevations of, TPO Ab titers. At parturition, on average, TPO Ab titers are 60% lower than at the beginning of pregnancy.[6]

Some diseases of the thyroid gland, such as hypothyroidism and hyperthyroidism, are associated with fetal loss.[8,9] More recent studies have confirmed this association[10,11] and linked TAI with recurrent abortions.[12,13,14] The mechanism involved in the association between TAI and pregnancy loss is not clear. It is postulated that the presence of thyroid Abs reflects a generalized activation of the immune system and a heightened autoimmune state against the fetal–placental unit.[14] It is known that immunological factors play an important role in the reproductive processes of fertilization, implantation and placental development.[15] Women with thyroid Abs have abnormal T-cell function.[16] Thyroid Abs may serve as peripheral markers for abnormal T-cell function, which may be responsible for pregnancy loss.[17]

Overall, the association between the presence of thyroid Abs and recurrent pregnancy loss has been confirmed in several studies.

The aim of this review is to present all relevant information published to date in the literature regarding TAI, infertility and miscarriage. It concentrates only on women with positive thyroid Abs and normal thyroid hormones. However, it must be noted that few patients in some of the studies have slightly elevated TSH levels. Currently, there is little doubt that women with even mild abnormalities in thyroid function, for example, subclinical hypothyroidism, should be treated with thyroxine.

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