Daniel Glinoer

The role of thyroid autoimmunity in fertility and pregnancy

The thyroid gland and gonadal axes interact continuously before and during pregnancy. Hypothyroidism influences ovarian function by decreasing levels of sex-hormone-binding globulin and increasing the secretion of prolactin. In women of reproductive age, hypothyroidism can be reversed by thyroxine therapy to improve fertility and avoid the need for use of assisted reproduction technologies. For infertile women, preparation for medically assisted pregnancy comprises controlled ovarian hyperstimulation that substantially increase circulating estrogen concentrations, which in turn can severely impair thyroid function. In women without thyroid autoimmunity these changes are transient, but in those with thyroid autoimmunity estrogen stimulation might lead to abnormal thyroid function throughout the remaining pregnancy period. Prevalence of thyroid autoimmunity is significantly higher among infertile women than among fertile women, especially among those whose infertility is caused by endometriosis or ovarian dysfunction. Presence of thyroid autoimmunity does not interfere with normal embryo implantation, but the risk of early miscarriage is substantially raised. Subclinical and overt forms of hypothyroidism are associated with increased risk of pregnancy-related morbidity, for which thyroxine therapy can be beneficial. Systematic screening for thyroid disorders in pregnant women remains controversial but might be advantageous in women at high risk, particularly infertile women.

Pregnancy and iodine.

Hormonal changes and metabolic demands during pregnancy result in profound alterations in the biochemical parameters of thyroid function. For thyroid economy, the main events occurring during pregnancy are a marked increase in serum thyroxine-binding globulin levels; a marginal decrease in free hormone concentrations (in iodine-sufficient areas) that is significantly amplified when there is iodine restriction or overt iodine deficiency; a frequent trend toward a slight rise in basal thyrotropin (TSH) values between the first trimester and term; a transient stimulation of the maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG) resulting in a rise in free thyroid hormones and decrement in serum TSH concentrations during the first trimester; and finally, modifications of the peripheral metabolism of maternal thyroid hormones. Together, metabolic changes associated with the progression of gestation in its first half constitute a transient phase from preconception steady state to pregnancy steady state. In order to be met, these metabolic changes require an increased hormonal output by the maternal thyroid gland. Once the new equilibrium is reached, increased hormonal demands are maintained until term, probably through transplacental passage of maternal thyroid hormones and increased turnover of maternal thyroxine (T4), presumably under the influence of the placental (type 3) deiodinase. For healthy pregnant women with iodine sufficiency, the challenge of the maternal thyroid gland is to adjust the hormonal output in order to achieve the new equilibrium state, and thereafter maintain the equilibrium until term. In contrast, the metabolic adjustment cannot easily be reached during pregnancy when the functional capacity of the thyroid gland is impaired because of iodine deficiency. The ideal dietary allowance of iodine recommended by World Health Organization (WHO) is 200 microg of iodine per day for pregnant women. In conditions with iodine restriction, enhanced thyroidal stimulation is revealed by relative hypothyroxinernia and goitrogenesis. Goiters formed during gestation may only partially regress after parturition. Pregnancy, therefore, represents one of the environmental factors that may help explain the higher prevalence of goiter and thyroid disorders in women compared with men. An iodine-deficient status in the mother also leads to goiter formation in the progeny and neuropsycho-intellectual impairment in the offspring. When adequate iodine supplementation is given early during pregnancy, it allows for the correction and almost complete prevention of maternal and neonatal goitrogenesis. In summary, pregnancy is accompanied by profound alterations in the thyroid economy, resulting from a complex combination of factors specific to the pregnant state, which together concur to stimulate the maternal thyroid machinery. Increased thyroidal stimulation induces, in turn, a sequence of events leading from physiological adaptation of the thyroidal economy observed in healthy iodine-sufficient pregnant women to pathological alterations affecting both thyroid function and the anatomical integrity of the thyroid gland, when gestation takes place in conditions with iodine restriction or deficiency: the more severe the iodine deficiency, the more obvious, frequent, and profound the potential maternal and fetal repercussions.

Thyroid disease and female reproduction

The menstrual pattern is influenced by thyroid hormones directly through impact on the ovaries and indirectly through impact on SHBG, PRL and GnRH secretion and coagulation factors. Treating thyroid dysfunction can reverse menstrual abnormalities and thus improve fertility. In infertile women, the prevalence of autoimmune thyroid disease (AITD) is significantly higher compared to parous age‐matched women. This is especially the case in women with endometriosis and polycystic ovarian syndrome (PCOS). AITD does not interfere with normal foetal implantation and comparable pregnancy rates have been observed after assisted reproductive technology (ART) in women with and without AITD. During the first trimester, however, pregnant women with AITD carry a significantly increased risk for miscarriage compared to women without AITD, even when euthyroidism was present before pregnancy. It has also been demonstrated that controlled ovarian hyperstimulation (COH) in preparation for ART has a significant impact on thyroid function, particularly in women with AITD. It is therefore advisable to measure thyroid function and detect AITD in infertile women before ART, and to follow‐up these parameters after COH and during pregnancy when AITD was initially present. Women with thyroid dysfunction at early gestation stages should be treated with l‐thyroxine to avoid pregnancy complications. Whether thyroid hormones should be given prior to or during pregnancy in euthyroid women with AITD remains controversial. To date, there is a lack of well‐designed randomized clinical trials to elucidate this controversy.

Thyroid dysfunction and autoimmunity in infertile women

A prospective study was undertaken in 438 women (ages, 32 +/- 5 years) with various causes of infertility, and in 100 age-matched (33 +/- 5 years) healthy parous controls with the aim of assessing the prevalence of autoimmune thyroid disease (AITD) and hitherto undisclosed alterations of thyroid function. Female origin of the infertility was diagnosed in 45% of the couples, with specific causes including endometriosis (11%), tubal disease (30%), and ovarian dysfunction (59%). Male infertility represented 38% and idiopathic infertility 17% of the couples. Overall, median thyrotropin (TSH) was significantly higher in patients with infertility compared to controls: 1.3 (0.9) versus 1.1 (0.8) mIU/L. Serum TSH above normal (>4.2 mIU/L) or suppressed TSH (<0.27 mIU/L) levels were not more prevalent in the infertile women than in controls. The prevalence of positive thyroid peroxidase antibody (TPO-Ab) was higher in all investigated women of infertile couples, compared to controls (14% vs. 8%), but the difference was not significant. However, in infertility of female origin, a significant higher prevalence of positive TPO-Ab was present, compared to controls: 18% versus 8%. Furthermore, among the female causes, the highest prevalence of positive antibodies was observed in women with endometriosis (29%). When thyroid antibodies were positive, both hypothyroidism and hyperthyroidism were more frequent in all women of infertile couples and in the women with a female infertility cause, compared to women in the same groups but without positive TPO-Ab. The present study shows that in infertile women, thyroid autoimmunity features are significantly more frequent than in healthy fertile controls and this was especially the case for the endometriosis subgroup.

THE IMPORTANCE OF IODINE NUTRITION DURING PREGNANCY

OBJECTIVE To examine the importance of iodine nutrition during pregnancy. DESIGN Review of existing literature of iodine in pregnancy. SETTING Population surveys and metabolic studies. SUBJECTS Pregnant women. RESULTS The main changes in thyroid function associated with pregnancy are due to an increase in hormone requirements that begin in the first trimester of gestation. This increase can only be met by a proportional increase in hormone production, something that depends directly upon the availability of iodine. When dietary iodine is lacking, an adequate physiological adaptation is difficult to achieve and is progressively replaced by pathological alterations that occur in parallel with the degree and duration of iodine deprivation. CONCLUSIONS Iodine prophylaxis should be given systematically to women during pregnancy. In most public health programmes dealing with the correction of iodine deficiency disorders, iodised salt has been used as the preferred means to deliver iodine to households. Iodised salt, however, is not the ideal means of delivering iodine in the specific instances of pregnancy, breast-feeding and complementary feeding because of the need to limit salt intake during these periods. In European countries, presently it is proposed that iodine is given to pregnant women and breast-feeding mothers by systematically administering multivitamin tablets containing iodine in order to reach the recommended dietary allowance of 250 microg iodine day-1.

Serum levels of intact human chorionic gonadotropin (HCG) and its free a and β subunits, in relation to maternal thyroid stimulation during normal pregnancy

The main objective of the present study was to present additional evidence of the potentially important thyrotropic role of hCG to regulate the maternal thyroid gland during normal pregnancy. Sequential determinations (first and last trimesters) of intact hCG, free α and β-hCG subunits concentrations (using monoclonal IRMAs), and assessment of parameters of thyroid function and thyroid volume were carried out in 62 pregnant women who exhibited during the first trimester of gestation low TSH levels (≤0.20 mU/L), and compared to 276 pregnant women with normal TSH levels. The prevalence of having low serum TSH represented 18% of all pregnancies, with almost one half of cases who transiently had undetectable TSH levels. Lowering of TSH was associated with high hCG levels, and occurred primarily during the first trimester. About 10% of women with low TSH presented transient gestational thyrotoxicosis, frequently associated with vomiting. In comparison to control subjects, women with a suppressed serum TSH had significantly and markedly higher intact hCG and free β-hCG subunit concentrations. The results suggest that TSH reduction may result from a relative oversecretion of both intact hCG and free β-hCG subunits, compatible with three hypotheses: a) transient overexpression of the β-hCG gene, leading to enhanced production of hCG heterodimer; b) increased glycosylation of circulating hCG, with in turn a prolonged half life; c) larger syncytiotrophoblast mass with increased hCG production. Increased hCG in women with low TSH was clearly associated with thyroidal stimulation: comparing women with or without low TSH, it was shown that high hCG production was accompanied during the first trimester by a 20% mean increase in free T4 levels and a parallel increase in the TBG saturation levels by T4. Furthermore, thyroidal stimulation during the first trimester was associated with a larger median thyroid volume. During the last trimester and at term, most parameters of thyroid function were similar in both groups. In conclusion, a partial or total serum TSH suppression is a frequent finding during normal pregnancy, usually occurring as a transient feature near the end of the first trimester, in association with high serum hCG levels. The present data indicate for the first time that in these women, circulating hCG is characterized by elevated free β-hCG subunit and intact hCG levels, perhaps resulting from an imbalanced production of hCG. In approximately one percent of pregnancies, excessive thyroidal stimulation may lead to gestational transient thyrotoxicosis during the first trimester. The present studies confirm the role of hCG as an important thyroidal regulator during normal pregnancy.

Increased risk of primary hypothyroidism in preterm infants.

Serum levels of thyroid stimulating hormone, thyroxine, triiodothyronine, free T4, thyroxine-binding globulin, reverse T3, and the TSH secretory areas and peak T3 after intravenous injection of 40 micrograms thyrotropin-releasing hormone were determined weekly from day 5 to 6 to 11 weeks of age in 42 unselected full-term and 61 preterm Belgian infants. The results on day 5 indicated a progressive deficit of thyroid function related to the degree of prematurity. In 92 infants this deficit progressively decreased with age and disappeared at 5 to 7 weeks. However, 11 infants developed biochemical evidence of overt but transient hypothyroidism. Belgian neonates are relatively iodine deficient, and this factor affects the constitution of iodine stores within the thyroid gland: (1) the urinary concentrations of iodine in the 103 infants studied in Belgium were markedly lower than in 30 infants from California; and (2) The iodine concentration of the thyroid gland in preterm infants who died during the 10 first days of life was almost three times lower in Brussels than in Toronto. The results indicate that, in Belgium, the effects of relative iodine deficiency on thyroid function are superimposed on and mask the physiologic state of tertiary hypothyroidism in prematurity.

The thyrotrophic role of human chorionic gonadotrophin (hCG) in the early stages of twin (versus single) pregnancies.

Human chorionic gonadotrophin (hCG) is known to possess thyroid‐stimulating activity. The aim of the present study was to assess the role of hCG in stimulating the maternal thyroid gland in the early stages of normal gestation.

Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension

Objective To assess whether asymptomatic abnormalities, including thyroid auto‐antibodies, were associated with an abnormal miscarriage rate or a poor obstetric outcome.

Serum TSH determinations in pregnancy: how, when and why?

Improvements in the sensitivity of the serum TSH assay have revolutionized our strategies for investigating thyroid function and firmly established TSH as the first-line thyroid function test for most clinical situations, including pregnancy. As a single hormone determination, serum TSH provides the most sensitive index to reliably detect thyroid function abnormalities. Normal thyroid function is important to ensure the best possible pregnancy outcome; in addition, disorders of the thyroid gland are relatively frequent in women of childbearing age. The aim of this article is, therefore, to present relevant information on analytical, as well as clinical, aspects regarding serum TSH determination and its usefulness to detect subtle thyroid function abnormalities associated with the pregnant state, namely overt and subclinical hypothyroidism and hyperthyroidism. As these disorders are associated with poor pregnancy outcome, the authors of the present article are in favor of serum TSH measurement for all pregnant women.