Kris Poppe

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.

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.

Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies

OBJECTIVES 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Fully endoscopic transsphenoidal surgery for functioning pituitary adenomas: A retrospective comparison with traditional transsphenoidal microsurgery in the same institution

BACKGROUND The efficacy and the minimally invasive nature of the fully transnasal endoscopic procedure in the treatment of pituitary adenomas and other lesions of the sellar area have been widely reported in the literature. Many authors observed similar results in terms of the correction of hormonal hypersecretion in functioning pituitary adenomas using endoscopic endonasal surgery or the traditional microscopic technique. We report the endocrinologic outcome in 2 series of patients operated on at the same institution for functioning pituitary adenomas using these 2 different techniques. METHODS This study includes 2 successive series of 60 consecutive patients presenting with a hormonally active pituitary adenoma operated on by the same surgeon. The surgical results obtained in the most recently operated group using a fully endoscopic endonasal technique were compared with those obtained previously using the traditional microsurgical transsphenoidal procedure. The classification of tumors into 4 grades according to Hardy was based on modern MRI and intraoperative findings. RESULTS The overall remission rate of hypersecretion was 63% in the endoscopic group compared with 50% in the microsurgical group. The most obvious difference between the 2 groups was observed in noninvasive macroadenomas. In this specific grade of tumors, the remission rate of hypersecretion obtained using endoscopy was 78% compared with 43% using microsurgery. The endocrinologic results achieved for microadenomas were similar in the 2 groups. Postoperative CSF leaks occurred more frequently (6 cases) in the endoscopic group. CONCLUSIONS In our experience, fully endoscopic transsphenoidal surgery for functioning pituitary adenomas leads to a better endocrinologic outcome for noninvasive macroadenomas compared to the traditional microsurgical technique. However, morbidity with the endoscopic technique was higher in terms of the rate of postoperative CSF leaks.

Endocrine disorders & female infertility

Female infertility occurs in about 37% of all infertile couples and ovulatory disorders account for more than half of these. The ovaries are in continuous interaction with the other endocrine organs. The interplay may account for infertility occurring at different levels and may render the diagnosis of infertility a difficult exercise for the involved physician. A hypothalamic cause of female infertility should be considered in an appropriate clinical context, with tests pointing to a hypogonadotropic hypogonadism. It can be functional, physiological or related to organic causes. Hyperprolactinemia has well characterized effects on the normal gonadal function and treatment is well established. Acromegaly and Cushings disease may impair fertility at different levels, mechanisms involved however remain ill defined. Thyroid disorders, both hyperthyroidism and hypothyroidism, can interact with the ovaries, through a direct effect on ovarian function, but autoimmunity may be involved, as well as alterations of the sex hormone binding protein levels. Primary ovarian disorders, such as the polycystic ovary syndrome and primary ovarian insufficiency are frequent diseases, for which novel treatments are currently being developed and discussed. We will propose an algorithm for the diagnosis and approach of the female patient presenting with infertility on the basis of the available evidence in literature.

FT4 immunoassays may display a pattern during pregnancy similar to the equilibrium dialysis ID–LC/tandem MS candidate reference measurement procedure in spite of susceptibility towards binding protein alterations

BACKGROUND Serum free thyroxine (FT4) testing in pregnancy is known to be challenging for immunoassays (IAs). We verified the reliability of FT4 results by 3 commercial IAs throughout pregnancy, by comparison of the pattern to that obtained with an equilibrium dialysis isotope dilution-mass spectrometry (ED ID-MS) candidate reference measurement procedure. METHODS Pregnant females (107) and age-matched non-pregnant controls (26) were enrolled. The IAs tested were those performed on the Cobas 6000 (Roche Diagnostics), ARCHITECT i2000SR (Abbott Diagnostics) and Immulite 2000 (Siemens Healthcare) platforms. RESULTS Compared to the controls (mean FT4: 18.2pmol/L), ED ID-MS gave in the late first trimester pregnancy an 8.8% lower (p<0.05) mean; in the second trimester it was 29.1% lower (p<0.001), to stabilize in the third trimester (p=0.99). Similar observations were made for the Cobas and Immulite IAs. The ARCHITECT IA showed no significant decrease in the late first trimester (mean 13.5pmol/L versus 13.6pmol/L in controls), but a significant, less pronounced, decrease in the second and third trimesters (15% and 14.4%, respectively). All IAs were susceptible towards alterations in T4 binding proteins during pregnancy. CONCLUSION We proved that IAs may give a FT4 pattern during pregnancy similar to that obtained by ED ID-MS.

Endogenous sex hormone levels in postmenopausal women undergoing carotid artery endarterectomy

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 microg/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 (beta = -0.234, P = 0.028) and androstenedione (beta = -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.

Thyroglobulin autoantibodies: is there any added value in the detection of thyroid autoimmunity in women consulting for fertility treatment?

BACKGROUND Thyroid autoimmunity (TAI) is frequent in infertile women, but to what extent thyroglobulin autoantibodies (Tg-Abs) contribute to TAI is unclear in the literature. The aims of the present study were to determine the prevalence of TAI in women consulting for fertility problems and to investigate the impact of isolated Tg-Abs, isolated thyroid peroxidase autoantibodies (TPO-Abs), and the presence of both autoantibody types on thyroid function. Furthermore, thyroid function was compared between women with and without TAI and between infertile and fertile women. METHODS A cross-sectional data analysis nested within an ongoing prospective cohort study was performed in order to determine the prevalence of TAI in unselected women consulting our tertiary referral center for reproductive medicine (CRM). The women underwent a determination of serum thyrotropin (TSH), free thyroxine (FT4), TPO-Abs, and Tg-Abs. The cause of infertility, age, body-mass index (BMI), and smoking habits were recorded. RESULTS The prevalence of TAI was 16% (163/992). In 8% of cases, both types of autoantibodies were present, in 5% isolated positive Tg-Abs were found, and 4% had isolated positive TPO-Abs (p=0.025 and p=0.003 respectively). The prevalence of TAI was significantly higher in infertile women as compared to that in fertile controls (19% vs. 13%; p=0.047). The median serum TSH level was significantly higher in the women with TAI and with isolated positive Tg-Abs compared to that in women without TAI (1.83 [1.44] and 1.90 [0.85] vs. 1.47 [0.94] mIU/L; p<0.001 respectively). The median FT4, age, BMI, and smoking habits were comparable between the study groups. CONCLUSIONS The prevalence of TAI was higher in infertile women as compared to fertile women consulting our CRM. Five percent of the women had isolated positive Tg-Abs and a significantly higher serum TSH compared to that in women without TAI.

IDENTIFYING NON-ALCOHOLIC FATTY LIVER DISEASE AMONG ASYMPTOMATIC OVERWEIGHT AND OBESE INDIVIDUALS BY CLINICAL AND BIOCHEMICAL CHARACTERISTICS

Abstract Objective: To determine the prevalence of liver steatosis among asymptomatic individuals attending an out-patient clinic for a problem of overweight, and to define the discriminatory value of several characteristics for predicting liver steatosis among them. Design and participants: Consecutive patients with a body mass index (BMI) of ≥ 25 kg/m2 who consented to undergo liver ultrasound and blood tests were recruited for inclusion. Receiver operating characteristic (ROC) curves were generated and statistical indices of diagnostic performance and their corresponding 95% confidence intervals (95% CI) were computed. Logistic regression analyses were performed to determine whether a combination of characteristics could improve diagnostic accuracy. Results: We enrolled sixty-eight subjects (mean BMI, 37.5 kg/m2), of whom 39 (57.4%) had liver steatosis on ultrasound. Logistic regression analyses indicated that only 3 variables were significantly and independently correlated with liver steatosis: female gender, low adiponectin levels, and high insulin resistance index. A composite index for predicting liver steatosis was calculated by summing the risk factors of female gender, low adiponectin, and insulin resistance index (FAIR score). The accuracy of this score was determined by ROC analysis to be 0.85 (95% CI, 0.74-0.96; P < 0.001). The presence of two or more risk factors (FAIR score > 2) had a sensitivity, specificity, positive predictive value, and negative predictive value of 77%, 91%, 92%, and 74%, respectively. The likelihood ratio for a positive result was 8.43. Conclusions: Among asymptomatic overweight individuals attending an out-patient clinic, the prevalence of liver steatosis on ultrasound is 57%. Female gender, the insulin resistance index, and low adiponectin are significant and independent predictors of liver steatosis. A combination of these three factors allows sensitivity and specificity for non alcoholic fatty liver of 77 % and 91 %, respectively.