[Thyroid hormone levels and thyroid dysfunction of French adults participating in the SU.VI.MAX study]. / Statut thyroïdien et fréquences des dysthyroïdies chez les adultes inclus dans l'étude SU.VI.MAX en 1994-1995.

Abnormal thyroid function has important public health consequences. However, the various degrees of thyroid dysfunction remain unsettled. The SU.VI.MAX cohort provided a unique opportunity to conduct a cross-sectional study of abnormal thyroid function in a large representative population of 11256 men and women representing the geographic distribution of the French continental adult population. Thyroid status was measured, in fasting blood samples, at baseline in 1994-1995. Serum thyrotropin (TSH) levels (abnormal < 0.4 mU/l or > or =4.0 mU/l) and free thyroxine (fT4) were both performed in duplicate on the same sample. Subjects with previous or present thyroid diseases or who were taking thyroid hormones or antithyroid drugs (n=920) were excluded (8.1%). Thus, the final study group consisted of 10346 subjects, 4121 men aged 45-60 years (mean +/-SD) (51.8+/-4.7 yrs), 2641 women aged 35-44 years (40.6+/-2.8 yrs), and 3584 women aged 45-60 years (51.4+/-4.4 yrs). Median (2.5th and 97.5th percentiles) for TSH (mU/l) were 1.52 (0.20-4.54) for men, 1.78 (0.22-5.54) for women aged 35-44 years, and 1.96 (0.22-6.80) for women aged 45-60 years. The TSH distribution of women was shifted to the right compared with men. Arithmetic mean fT4 (+/-SD) was 10.7+/-1.7 ng/l (13.8 +/-2.2 pmol/l) for men and 10.9+/-1.8 ng/l (14.0+/-2.3 pmol/l) for women. The prevalence of abnormal TSH values in men, and in women (35-44 yrs and 45-60 yrs) were TSH<0.4 mU/l 7.0%, 5.3% and 4.4%; TSH 4.0-9.9 mU/l 4.0%, 7.2% and 11.1% and TSH > or =10.0 mU/l 0.2%, 0.4% and 0.7%, respectively. Geometric mean serum TSH and arithmetic mean serum fT4 concentrations showed significant overall inter-regional differences for men and women (p<0.0001). There was also an inter-regional difference in the prevalence of thyroid dysfunction for men (p=0.003), and for the older group of women (i.e. > or =45 yrs) (p=0.04) exclusively. Over the age of 45 years, the women: men ratio for unrecognized elevated TSH levels (> or =4.0 mU/l) was 2.82, whereas it was 0.64 for low TSH levels (<0.4 mU/l). In summary, abnormal TSH values and thyroid dysfunction were more prevalent in women than men, increased with age and were significantly associated with environmental factors. A high prevalence of identified thyroid diseases in the French population was confirmed by the high number of subjects in this study with laboratory evidence of abnormal biochemical thyroid function. Further studies are needed to determine the geographical determinants of thyroid dysfunctions, especially regional differences in iodine intakes, and to assess the long-term adverse effects of biochemical thyroid dysfunction on all-cause morbidity.

[Ultrasonic assessment of thyroid nodules, and iodine status of French adults participating in the SU.VI.MAX study]. / Nodules thyroïdiens à l'échographie et statut en iode des adultes volontaires de l'étude SU.VI.MAX.

Thyroid nodules were assessed by ultrasound in 3 621 presumably healthy free-living French subjects participating in the SU.VI.MAX cohort (2 160 females aged 35-60 years and 1 461 males aged 45-60 years). Urinary iodine was measured in all participants in random morning urine samples. Nodular thyroid structures ranging from 3 mm to 57 mm in diameter were found in 14.5% of the population, without significant differences between regions in the different age and sex groups. Single nodules and multiple lesions were found in, respectively, 9.7% and 3.1% of the subjects. In females, nodules increased from 12.9% to 19.2% between 35-45 years and 45-60 years, respectively (p<0.001). Thyroid nodularity was more frequent among women aged 45-60 years than among men of those ages (19.2% vs. 11.0%, p=0.001). Descriptive data provided by ultrasound differentiated the nodules into solid (43.4%), cystic (38.4%), and mixed solid-cystic (18.2%). Most solid thyroid nodules, 76.1%, were hypoechoic, while 16.6% were iso-, and 7.3% were hyperechoic. The median of iodine concentrations (n=3 276) was 8.0 microgram/100 ml, with 19.4% of the samples being<5 microgram/100 ml. Median iodine concentrations displayed wide regional variations, with values significantly higher in residents of western regions than among those living in the eastern areas (p<0.001), independently of age and sex. No relationship was found between prevalence of nodular thyroid structure and the state of borderline iodine status observed in France.

[Suppressive hormone therapy for thyroid nodules. Prospective evaluation. Preliminary results]. / Hormonothérapie freinatrice pour nodule thyroïdien. Evaluation prospective. Résultats préliminaires.

The benefit of thyroid hormone for patients with thyroid nodule is still controversial. Suppressive therapy is not useful to distinguish benign or malignant tumors, since some malignant nodules become smaller and most benign nodules do not shrink with thyroid hormone therapy. A prospective evaluation was conducted by the french Groupe de Recherche sur la Thyroïde on 123 patients with solitary nodules : ultrasonographic volume of the nodules regressed from 2.76 to 2.39 ml with suppressive doses of levothyroxine for 18 months, while a progression from 3.6 to 4.1 ml was seen for patients with placebo. The benefit of the suppressive therapy was also obvious on the micronodular dystrophy detected by ultrasonography. No side effects were seen in treated patients. These preliminary results argue for the benefit of suppressive therapy, as suggested by meta-analysis of the published randomized trials.

Pharmacokinetics and metabolism of moxestrol in animals--rat, dog and monkey.

The pharmacokinetics and metabolism of moxestrol have been compared in the rat, dog and monkey (rhesus and baboon) and, in some instances, confronted with data simultaneously obtained for ethynl estradiol and previously obtained in humans. The apparent initial volume of distribution (AIVD) of total radioactivity after i.v. administration was of the order of body volume in all species under study; the AIVD of intact moxestrol was even higher. This is in agreement with moxestrol's low binding to specific and non-specific plasma proteins. The half-life of total radioactivity elimination was 14-18 h in the rat and rhesus monkey, but longer (43 and 78 h, i.v. and oral respectively) in the baboon. In the dog, the elimination phase could not be distinguished from the distribution phase and had a half-life of 2 h. The half-life of unchanged moxestrol elimination was shorter and very similar in the rhesus, baboon and human (6.6, 7.5 and 8.2 h respectively) and only 1.4 h in the dog. Regardless of the route of administration or the species under study, the clearance and elimination rate of unchanged moxestrol were higher than of total radioactivity implying that metabolites and/or conjugation products were eliminated more slowly than intact product from plasma. Orally administered moxestrol was rapidly absorbed in all species. Since clearance of total radioactivity and of moxestrol was faster after i.v. than oral administration, but the radioactivity levels excreted in the urine were identical for the two routes, a significant first-pass-effect probably occurred in the liver. Radioactivity distribution in tissues was examined in the rat. Total radioactivity was higher 24 h after administration of labelled moxestrol than of labelled ethynyl estradiol in endocrine tissues; it was equivalent or less in the other tissues. For all tissues, the elimination rate of moxestrol was greater than, or equal to, that of ethynyl estradiol. In dog urine, the only product identified was moxestrol; in rhesus or baboon monkey urine, the principal metabolites were catechol estrogens, which were also present in appreciable amount in rat bile (as methyl ethers) but were minor metabolites in human urine. Hydroxylation in position 16 occurred in rats and humans only, in position 15 alpha in humans and, to a much lesser extent, in rats and monkeys. Thus, the metabolic profile of moxestrol in rats most closely resembles that in humans.

Pharmacokinetics and metabolism of moxestrol in humans.

Moxestrol, the 11 beta-methoxy derivative of ethynyl estradiol and a highly potent estrogen, is rapidly distributed in the body (AIVD = 148.6 +/- 19.71, MCR = 79.9 +/- 10.5 1/h) after i.v. administration because it is not bound by SBP and has low affinity for albumin. Its oral bioavailability is about 33% after administration of 30 or 100 micrograms to healthy volunteers and slightly lower than that of ethynyl estradiol (50%) due to a "first-pass effect". Moxestrol is rapidly metabolized by the liver as shown by the much increased bioavailability (60.5%) in patients with impaired liver function. The radioimmunoassay for moxestrol measures plasma moxestrol levels ranging from 100 pg/ml (maximum) to 10 pg/ml (24 h value) after treatment with a 100 micrograms commercial formulation (Surestryl). Moxestrol metabolism was studied on urine which contained 28% of administered radioactivity after i.v. or oral administration. Hydroxylation was the main transformation pathway as for ethynyl estradiol. Moxestrol yielded metabolites hydroxylated (or methoxylated) at C-2, C-15 and C-16, but not at C-6, and also gave rise to D-homo derivatives. The main difference between moxestrol and ethynyl estradiol lies in the relative importance of these pathways. The presence of the ethynyl group of ethynyl estradiol impedes attack at C-16 and hydroxylation at C-2 to form catechol estrogens becomes a major pathway, whereas the 11 beta-methoxy group of moxestrol impedes hydroxylation at C-2 and ring D hydroxylated products of moxestrol are formed. The low amount of catechol estrogens obtained with moxestrol compared to ethynyl estradiol could have important physiological implications in the human.

Differences in the biotransformation of a 17 beta-hydroxylated steroid, trenbolone acetate, in rat and cow.

1. The metabolism of trenbolone acetate, 17 beta-acetoxyestra-4,9,11-trien-3-one (TBA), an anabolic compound used as a growth promoter, was compared in rat and cow. 2. [6,7-3H] TBA was injected i.v. into rats and a heifer, and bile was collected for 24 h. In both species, the bile was the major route of excretion. TBA undergoes an extensive hydrolysis to 17 beta-hydroxyestra-4,9,11-trien-3-one and the unchanged compound was not detected, but subsequent major metabolic pathways are different in the two species. 3. In the rat, oxidation of the 17 beta-hydroxyl to the 17-oxo group and hydroxylation in the 16 alpha-position are the major routes. The three major metabolites are 17 beta-hydroxyestra-4,9,11-trien-3-one, 16 alpha, 17 beta-dihydroxyestra-4,9,11-trien-3-one and 16 alpha-hydroxyestra-4,9,11-trien-3, 17-dione. 4. In the heifer, 17 alpha-epimerization is the major pathway and the main metabolite is the 17 alpha-hydroxyestra-4,9,11-trien-3-one. 5. In both species, estra-4,9,11-trien-3,17-dione and the other metabolites, resulting either from hydroxylation in 1, 2, 6 beta, 16 alpha or 16 beta positions, or from aromatization of the A ring, were minor products. 6. Overall, 60% of the 3-oxotriene structures identified in the rat bile were 17 beta-hydroxylated and the remainder were 17-keto metabolites, whereas in the heifer bile 90% were 17 alpha-hydroxylated compounds. 7. Thus, in bovine species, the major pathway is similar to those of testosterone or 17 beta-estradiol which are mainly excreted as their 17 alpha-epimers. The epimerization strongly decreases the biological potency, as with the natural 17 beta-hormones, and leads to detoxication of tissue residues.

Reference compounds for the study of moxestrol metabolism.

Reference compounds for the subsequent identification of the metabolites of the potent estrogen, moxestrol (R 2858) , in various species were isolated from the bile of phenobarbital pretreated rats or obtained via enzymatic hydroxylation by microorganisms. A few of them were prepared by chemical synthesis. The structures of all these compounds were determined by physical and chemical methods.