Brigitte Velkeniers

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.

Colles fracture, spine fracture, and subsequent risk of hip fracture in men and women: A meta-analysis

BACKGROUND In postmenopausal women, a history of any fracture is an important risk factor for a future hip fracture. Whether similar findings apply to aging men remains to be established. We conducted a systematic review and meta-analysis of the literature to compare men and women with respect to the relative risk of hip fracture after a wrist or spine fracture. METHODS Studies published in full from January 1982 through September 2002 in English, French, or German were identified from the PubMed database and from reference lists of retrieved articles. We included cohort studies that reported fractures associated with minimal trauma of the wrist or spine as a risk factor for a subsequent hip fracture among (white) women and men who were fifty years old or older. Data were extracted by two independent reviewers and were checked for accuracy in a second review. Differences in assessments were resolved by consensus of the two reviewers. RESULTS Nine cohort studies were included in this meta-analysis: five studies were conducted in the United States and four, in Europe. After homogeneity of association was demonstrated across all studies, a fixed-effects meta-analysis was used to calculate pooled relative risks with 95% confidence intervals. Among postmenopausal women, the relative risks for a future fracture of the hip after a fracture of the wrist or spine were 1.53 (95% confidence interval, 1.34 to 1.74; p < 0.001) and 2.20 (95% confidence interval, 1.92 to 2.51; p < 0.001), respectively. In older men, these relative risks were 3.26 (95% confidence interval, 2.08 to 5.11; p < 0.001) and 3.54 (95% confidence interval, 2.01 to 6.23; p < 0.001), respectively. Fractures of the distal part of the radius increased the relative risk of hip fracture significantly more in men than in women (p = 0.002). The impact of a spine fracture, conversely, did not differ between genders (p = 0.11). Sensitivity analyses with use of random-effects methodology confirmed these findings to be robust. CONCLUSIONS This meta-analysis suggests that a previous spine fracture has an equally important impact on the risk of a subsequent hip fracture in both genders. The prospective association between a Colles fracture and a subsequent hip fracture, however, is significantly stronger among men than among postmenopausal women. Men with a Colles fracture are at high risk for a future hip fracture and should be evaluated as candidates for preventive measures.

AcroBel – the Belgian registry on acromegaly: a survey of the ‘real-life’ outcome in 418 acromegalic subjects

OBJECTIVES To constitute a registry on acromegaly, AcroBel, to evaluate the epidemiology and quality of care of acromegaly in Belgium and Luxembourg. DESIGN A nationwide survey from June 2003 till September 2004 aiming to collect data from all patients with acromegaly who had visited the participating endocrine clinics after 1 January 2000. METHODS Retrospective data collection coupled to a visit within the survey period, allowing sampling of metabolic parameters and centralised determination of GH and IGF-I. RESULTS Four hundred and eighteen patients (51% men) were included, of which 96 were new cases, giving a mean incidence of 1.9 cases per million (c.p.m.) per year. The global prevalence was 41 c.p.m. but varied between 21 and 61 among different areas. Twenty-eight deaths were reported at a median age of 68 years in men and 74 years in women. The standardised mortality rate was significantly increased only in irradiated patients (2.70; confidence interval 1.60-4.55). Central measurements were available in 316 (75%) patients. Mean GH was < or = 2 microg/l in 65% and IGF-I was normal for age in 56%, while both criteria were fulfilled in 49%. Multimodal treatment was more effective than primary medical therapy, since 56.5% were controlled versus 24.3% (P < 0.0001). CONCLUSIONS AcroBel provides an excellent tool to analyse the prevalence, incidence, treatment modalities and outcome of acromegaly in Belgium. This real-life survey reveals that only half of acromegalic patients received an adequate therapy resulting in cure or disease control when stringent biochemical criteria are used.

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.

Two years of replacement therapy in adults with growth hormone deficiency

Although several studies have shown beneficial short‐term effects of recombinant human growth hormone (rhGH) therapy in adult GH deficient (GHD) patients, few data are available on large groups of patients treated for more than one year. In addition, the optimal dose of rhGH for each patient and the baseline parameters that predict which patients will benefit most from therapy or will have adverse events are not entirely elucidated.

Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in parathyroids, enteropancreatic endocrine tissues, anterior pituitary, and other tissues. The gene for MEN1 has recently been cloned and shown to code for a 610‐amino acid protein of enigmatic function which probably acts as a tumor suppressor. Several mutations causing the MEN1 phenotype have been recently identified. In order to determine the spectrum of MEN1 gene mutations in a sample of 25 Belgian patients, we have systematically screened the 10 exons and adjacent sequences of the MEN1 gene by means of an automatic sequencing protocol. Twelve different mutations were identified including nonsense, frameshift, splicing, and missense mutations. Two of these mutations (D172Y and 357del4) occurred more than once. A missense mutation was also found in a kindred with familial hyperparathyroidism. We observed no significant correlation between the nature or position of mutation and the clinical status. We have also detected 6 intragenic polymorphisms and DNA sequence variants and have analyzed their frequencies in our population. Hum Mutat 13:54–60, 1999.

Divergence between growth hormone and insulin-like growth factor-i concentrations in the follow-up of acromegaly.

CONTEXT Divergence between GH and IGF-I values is regularly observed in treated acromegalic patients, and its significance is unclear. OBJECTIVES The objective of the study was to explore the frequency and identify potential determinants of discordant serum GH and IGF-I concentrations in noncured acromegalic patients. PATIENTS Two hundred twenty-nine noncured acromegalic patients of the Belgian acromegaly registry (AcroBel) were grouped according to their mean GH level (< or = or > 2 microg/liter) and IGF-I z-score (< or = 2 or > 2). Clinical and metabolic parameters were compared between groups with active disease (high GH and IGF-I; n=81),high GH (with normal IGF-I; n=25), high IGF-I (with normal GH; n=55), and controlled disease (GH and IGF-I normal; n=68). RESULTS Compared with the high IGF-I group, the high GH group was characterized by younger age (52 vs. 58 yr, P < 0.05), female predominance (72 vs. 36%, P < 0.01), and lower body mass index (25 vs. 31 kg/m(2); P < 0.001), fasting glucose (91 vs. 99 mg/dl; P < 0.05), and glycated hemoglobin levels (5.7 vs. 6.1%; P < 0.01). There was no difference among the groups regarding baseline characteristics of pituitary adenoma, current medical treatment, or symptom score. CONCLUSIONS Thirty-five percent of noncured acromegalic patients exhibit a discordant GH and IGF-I pattern. The high GH phenotype was found predominantly in younger estrogen-sufficient females, implying a possible role for age, gender, and estrogens in this biochemical divergence. The high IGF-I phenotype was associated with a worse metabolic profile, suggesting that high IGF-I, rather than high GH, is indicative of persistently active disease.