Severe thyroid dysfunction may lead to menstrual disorders and infertility via direct and indirect interactions with the hypothalamo–pituitary–ovarian axis and the reproductive organs. However, the exact prevalence of infertility in women with thyroid disorders remains unknown. Fertility problems may persist even after restoring normal thyroid function, and then surgery and/or an assisted reproductive technology (ART) may be necessary to obtain a pregnancy. The initial step in an ART treatment is the ovarian stimulation, putting strain on the thyroid gland, potentially leading to (permanent) hypothyroidism in women with thyroid autoimmunity (TAI) or when already treated with thyroid hormones (LT4). Moreover, women with ovarian and unexplained causes of infertility have a higher prevalence of TAI. In women treated with LT4, a serum TSH level <2.5 mIU/L should be targeted before ART. In women with TSH levels >4.0 mIU/L, fertilisation rates, embryo quality and live birth rates may be impaired but also improved with LT4 therapy. In euthyroid women with TAI, LT4 should not be given systematically, but on a case-by-case basis if serum TSH is >2.5 mIU/L. For all of the above reasons, women of infertile couples should be screened routinely for the presence of thyroid disorders. In this review, we will focus on the gaps in the current knowledge, the remaining questions on the associations between thyroid (disorders) and (assisted) reproduction and make proposals for future investigations that may lead to a better understanding and contribute to novel treatment options in the long term.
Patrick Haentjens, Alain Van Meerhaeghe, Kris Poppe, and Brigitte Velkeniers
To what extent persons with subclinical hyper- or hypothyroidism are more (or less) likely to die than euthyroid control subjects remains a matter of controversy.
We searched electronic reference databases up to July 31, 2007. Three reviewers independently assessed eligibility. Cohort studies published in full that reported data on the hazard ratio (HR) for mortality from all causes in persons with subclinical thyroid dysfunction versus euthyroid controls were included.
Based on seven cohorts including 290 participants with subclinical hyperthyroidism, random-effects models estimated that the pooled HR for all-cause mortality was 1.41 (95% confidence interval (CI), 1.12–1.79; P=0.004). Using the pooled HR and standard life-table methods applied to a US reference population, we estimated that a white US woman, when diagnosed with subclinical hyperthyroidism at age of 70, has an excess mortality of 1.5, 4.0, and 8.7% at 2, 5, and 10 years respectively after diagnosis. Likewise, a white US man has an excess mortality of 2.3, 5.7, and 10.7%. For the nine cohorts including 1580 participants with subclinical hypothyroidism, observed heterogeneity (Q test P=0.006; I 2=63%) disappeared after pooling cohorts in predefined subgroups according to the presence or absence of a comorbid condition. In doing so, the pooled HR for all-cause mortality was 1.03 (95% CI, 0.78–1.35; P=0.83) in cohorts from the community and 1.76 (95% CI, 1.36–2.30; P<0.001) in cohorts of participants with comorbidities (P=0.014 for heterogeneity among study groups).
Individuals with subclinical hyperthyroidism demonstrate a 41% increase in relative mortality from all causes versus euthyroid control subjects. Mathematical modeling suggests that absolute excess mortality after diagnosis might depend on age, with an increase beyond the age of 60, especially in aging men. For patients with subclinical hypothyroidism, the relative risk of all-cause mortality is increased only in patients with comorbid conditions.
Flora Veltri, Sarah Decaillet, Pierre Kleynen, Lidia Grabczan, Julie Belhomme, Serge Rozenberg, Thierry Pepersack, and Kris Poppe
Thyroid disorders and iron deficiency (ID) are associated with obstetrical and fetal complications. Iron is essential for the normal functioning of thyroid peroxidase (TPO-abs) and ID is frequent during pregnancy. The aim of this study was to compare the prevalence of thyroid autoimmunity (TAI) and dysfunction during the first trimester of pregnancy in women with and without ID.
Cross-sectional data analysis of 1900 pregnant women nested within an ongoing prospective collection of pregnant women’s data.
The study was performed in a single, tertiary referral center. During the first antenatal visit, ferritin, TPO-abs, thyroid-stimulating hormone (TSH) and free T4 (FT4) were measured and age and BMI were recorded. ID was defined as ferritin <15µg/L, TAI when TPO-abs was >60kIU/L, and subclinical hypothyroidism (SCH) when TSH was >2.5mIU/L.
ID was present in 35% of women. Age and BMI were comparable between both groups. In the ID group, the prevalence of TAI and SCH was significantly higher, compared with that in the non-ID group (10% vs 6% and 20% vs 16%; P=0.011 and 0.049 respectively). Ferritin was inversely correlated with serum TSH (ρ=−0.076; P=0.001) and positive with FT4 levels (ρ=0.112; P<0.001). In the logistic regression model, ID remained associated with TAI after correction for confounding factors (P=0.017). The association with SCH was absent after correction for the confounders in the logistic regression model (P=0.082), but remained present in the linear regression model (P=0.035).
ID was frequent during the first trimester of pregnancy and was associated with a higher prevalence of TAI, higher serum TSH, and lower FT4 levels.
Erik Debing, Els Peeters, William Duquet, Kris Poppe, Brigitte Velkeniers, and Pierre Van den Brande
Objective: To study the endogenous sex hormone levels in natural postmenopausal women and their association with the presence of internal carotid artery (ICA) atherosclerosis.
Design: Case-control study
Methods: We compared 56 patients with severe ICA atherosclerosis referred for carotid artery endarterectomy (CEA) with 56 age-matched control subjects free of severe atherosclerotic disease. The presence of atherosclerosis was determined by high-resolution B-mode ultrasound. Metabolic parameters and sex hormones were measured or calculated: total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin, quantitative insulin sensitivity check index, insulin resistance index, IGF-I, DHEA, DHEA sulfate (DHEA-S), free testosterone, total testosterone, estrone, estradiol, androstenedione, and sex hormone-binding globulin.
Results: The cases had statistically significant lower levels of both total testosterone (0.23 ± 0.12 vs 0.31 ± 0.20 μg/l, P = 0.043) and free testosterone (3.42 ± 1.94 vs 4.59 ± 2.97 ng/l, P = 0.009) and significantly lower levels of androstenedione (625.3 ± 168.7 vs 697.0 ± 211.9 ng/l, P = 0.017) when compared with controls. Multivariate linear regression analysis, adjusted for traditional cardiovascular risk factors, baseline and physiologic characteristics, showed a significant inverse relationship between both serum free testosterone (β = −0.234, P = 0.028) and androstenedione (β = −0.241, P = 0.028) levels with the presence of severe atherosclerosis of ICA.
Conclusions: The study provides evidence of a positive association between low serum androgen levels and severe ICA atherosclerosis in postmenopausal women. It suggests that higher, but physiological, levels of androgens in postmenopausal women have a protective role in the development of atherosclerosis of ICA.
Bijay Vaidya, Alicja Hubalewska-Dydejczyk, Peter Laurberg, Roberto Negro, Francesco Vermiglio, and Kris Poppe
Maternal hypothyroidism in pregnancy is associated with several adverse outcomes. The Endocrine Society Guidelines for the management of thyroid diseases in pregnancy were published in 2007; however, impact of the guidelines in routine clinical practice is unknown. Therefore, we have carried out a survey of members of the European Thyroid Association (ETA) to study current practices relating to the management of hypothyroidism in pregnancy.
Subjects and methods
In December 2010, we emailed an electronic questionnaire survey based on clinical case scenarios to 605 members of the ETA. Responses from 190 clinician members (from 28 European countries) were analyzed.
For a pregnant woman with newly diagnosed overt hypothyroidism, most responders initiated a full dose of l-thyroxine (l-T4). For a woman with hypothyroidism planning pregnancy, 50% recommended increasing the dose of l-T4 as soon as pregnancy is confirmed, whilst 43% favored testing thyroid function before adjusting the dose. Responders used diverse combinations of tests to monitor the dose of l-T4. The target of thyroid function tests that responders aimed to achieve with l-T4 was also inconsistent. Forty-two percent responders or their institutions screened all pregnant women for thyroid dysfunction, 43% performed targeted screening of only the high-risk group, whilst 17% did not carry out systemic screening. Timing of the screening, tests used, and criteria for starting treatment and monitoring were variable.
There is wide variation in the clinical practice relating to the treatment and screening of hypothyroidism during pregnancy in Europe.
Flora Veltri, Pierre Kleynen, Lidia Grabczan, Alexandra Salajan, Serge Rozenberg, Thierry Pepersack, and Kris Poppe
In the recently revised guidelines on the management of thyroid dysfunction during pregnancy, treatment with thyroid hormone (LT4) is not recommended in women without thyroid autoimmunity (TAI) and TSH levels in the range 2.5–4.0 mIU/L, and in a recent study in that particular group of pregnant women, more complications were observed when a treatment with LT4 was given. The objective of the study was therefore to investigate whether variation in thyroid function within the normal (non-pregnant) range in women free of thyroid disease was associated with altered pregnancy outcomes?
Cross-sectional data analysis of 1321 pregnant women nested within an ongoing prospective collection of pregnant women’s data in a single centre in Brussels, Belgium.
Thyroid peroxidase antibodies (TPO-abs), thyroid-stimulating hormone (TSH), free T4 (FT4) and ferritin levels were measured and baseline characteristics were recorded. Women taking LT4, with TAI and thyroid function outside the normal non-pregnant range were excluded. Pregnancy outcomes and baseline characteristics were correlated with all TSH and FT4 levels within the normal range and compared between two groups (TSH cut-off < and ≥2.5 mIU/L).
Tobacco use was associated with higher serum TSH levels (OR: 1.38; CI 95%: 1.08–1.74); P = 0.009. FT4 levels were inversely correlated with age and BMI (rho = −0.096 and −0.089; P < 0.001 and 0.001 respectively) and positively correlated with ferritin levels (rho = 0.097; P < 0.001). Postpartum haemorrhage (>500 mL) was inversely associated with serum FT4 levels (OR: 0.35; CI 95%: 0.13–0.96); P = 0.040. Also 10% of women free of thyroid disease had serum TSH levels ≥2.5 mIU/L.
Variation in thyroid function during the first trimester within the normal (non-pregnant) range in women free of thyroid disease was not associated with altered pregnancy outcomes. These results add evidence to the recommendation against LT4 treatment in pregnant women with high normal TSH levels and without TPO antibodies.