Is the management of thyroid nodules and differentiated thyroid cancer in accordance with recent consensus guidelines? - Results of a national survey.

OBJECTIVE: To assess approaches to patients with a potentially malignant thyroid nodule and patients with differentiated thyroid carcinoma and compare them with the European Consensus and Guidelines by the American Thyroid Association. DESIGN: A survey of the 388 active members of the Belgian Thyroid Club. METHODS: A questionnaire addressing the management of an index case and four clinical variations (including variations in the size of the tumour and histological type). The index case was a 40-year-old euthyroid woman with a 3-cm solitary thyroid nodule. Fine-needle aspiration (FNA) cytology showed cellular aspirates with numerous follicular cells and no colloid. RESULTS: The overall response rate was 41%. For the index case, respondents favoured a right lobectomy. Variations in size and histopathology of the nodule altered the management. In the case of a papillary thyroid carcinoma (PTC) of 3 cm in diameter, a total thyroidectomy and prophylactic central lymph node dissection was preferred. After a lobectomy showing a 3.5-cm follicular thyroid carcinoma (FTC), completion surgery followed by radioiodine administration was the most frequent proposal. For the follow-up of the index case with a low-risk disease, determination of serum thyroglobulin (Tg) after recombinant human TSH (rhTSH) administration was considered by the majority of respondents. For the follow-up of a clinical variation with residual disease, immediate planning of a new treatment was (mistakenly) not considered by a majority of respondents. CONCLUSIONS: In most cases, respondents were in accordance with the guidelines, although there were some unexpected variations.

Is systematic screening for thyroid disorders indicated in subfertile men?

CONTEXT: Data on the prevalence of thyroid disorders in male subfertility remain scarce. OBJECTIVE: To investigate the prevalence of thyroid dysfunction and thyroid autoimmunity in men with normal and abnormal semen characteristics. SETTING: Tertiary referral center for reproductive medicine of the University Hospital AZ-VUB, Brussels, Belgium. PATIENTS AND DESIGN: Two hundred and ninety-two men were stratified according to the presence of normal (group 1; n = 39) or abnormal (group 2; n = 253) semen characteristics. Thyroid function was assessed by serum thyrotropin (TSH) and free thyroxine (FT4), and thyroid peroxidase antibodies (TPO-Ab) for thyroid autoimmunity (TAI or TPO-Ab > 34 kU/l); both were correlated with semen characteristics. MAIN OUTCOME MEASURES: Semen characteristics were determined by World Health Organisation criteria (rapid + slow motility > or = 50% and concentration > or = 20 x 10(6)) and Kruger criteria (morphology > or = 14% normal cells). RESULTS: In group 1, the mean (+/- s.d.) age was 33 +/- 4 years; serum TSH was 1.6 (0.3-29.6) mU/l (median (range)) and FT4 was 12.2 (8.8-15.6) ng/l. In group 2, the mean age was 33 +/- 5 years, serum TSH was 1.3 (0.3-5.2) mU/l and FT4 was 12.5 (8.4-17.5) ng/l; (compared with group 1 P = 0.008 for TSH and P = 0.037 for FT4). In both groups, one patient had increased TSH (2.6% and 0.4%; P = not significant (ns)). In group 1, one patient had TAI and in group 2 twelve patients had TAI (2.6% compared with 4.7%; P = ns). FT4 was an independent determinant for semen characteristics. CONCLUSIONS: The prevalence of thyroid dysfunction and autoimmunity is comparable between men with normal and abnormal semen characteristics. On the basis of these data, we do not advise systematic screening for thyroid disorders in subfertile men consulting a tertiary referral center for reproductive medicine.

Thyroid autoimmunity and female infertility.

In infertile women, the prevalence of thyroid autoimmunity (TAI) is significantly higher compared to that in parous age-matched women. This is especially the case in women with endometriosis and the polycystic ovarian syndrome. TAI does not interfere with normal fetal implantation and comparable pregnancy rates have been observed after assisted reproductive technology (ART) in women with and without TAI. During the first trimester however, pregnant women with TAI carry a significantly increased risk for a miscarriage compared to women without TAI, even when euthyroidism was present before pregnancy. It has further been demonstrated that controlled ovarian hyperstimulation (COH) in preparation for ART has a significant impact on thyroid function, particularly in women with TAI. It is therefore advised to measure thyroid function and detect TAI in infertile women, before ART, and to follow-up these parameters after COH and during pregnancy when TAI was initially present. Women with thyroid dysfunction before or at early gestation stages should be treated with 1-thyroxine to avoid assisted pregnancy or further pregnancy complications. Whether thyroid hormones should be given prior to or during pregnancy in euthyroid women with TAI remains controversial and needs further investigation.

[Status of iodine nutrition in France: prevention of iodine deficiency in pregnant and lactating women]. / Apport iodé en France: prévention de la carence iodée au cours de la grossesse et l'allaitement.

Iodine intake varies with age and physiological status: in pregnant and lactating women, recommended iodine intake ranges from 200 to 250 mg/day. Recent epidemiological studies in France demonstrate the presence of moderate iodine deficiency in the majority of pregnant and lactating women. This iodine deficiency induces maternal thyroid hyperplasia and then development of goiter in women, as well as impaired thyroid parameters. Maternal hypothyroxinemia during the first trimester of pregnancy can be associated with abnormal cognitive development and intellectual outcomes in the newborn and the children. According to the recent World Health Organization recommendations for the prevention and control of iodine deficiency in pregnant and lactating women, systematic iodine supplementation is indicated in France: 100 microg/day for women of reproductive age and 200 microg/day in pregnant and lactating women in order to eradicate iodine deficiency during pregnancy and lactation, and prevent the maternal and fetal consequences.

Comparison of human thyroxine-binding globulin purification by affinity chromatography procedures.

Three procedures for the isolation of thyroxine-binding globulin from human serum, using affinity chromatography on triiodothyronine (T3) linked to Sepharose (A), thyroxine (T4) linked to Sepharose (B) or T3 linked to epoxy-Sepharose (C) as the first purification step, were compared. With the use of additional purification steps, the three procedures yielded pure thyroxine-binding globulin without desialylation. With procedure A, the initial binding of T4-binding globulin to T3-Sepharose was very low, yielding a poor final recovery (17%). Procedure B gave the highest yield (35%) after a three-step purification, with a low T4 content (0.15-0.30 mol/mol). Procedure C also gave a high yield (28%) after only two purification steps, with a T4 content greater than 0.7 mol/mol. The microheterogeneity of T4-binding globulin obtained with these three procedures was demonstrated by isoelectric focusing: five major bands were observed between pH 4.1 and 4.6, and intermediate faint bands (often doublets) in the same pH range. However, with procedures A and C, the most acidic bands (pH 4.10-4.20) were always absent. Thyroxine-binding globulin was preincubated with radioactively labelled T3 or T4 and the hormone-protein complex was analyzed by isoelectric focusing. The binding of T3--compared to that of T4--was reduced in the most acidic protein subspecies. These results suggest differences in the thyroid hormone binding properties of the various subspecies of human T4-binding globulin.

Thyroxine-binding globulin biosynthesis in isolated monkey hepatocytes.

Thyroxine-binding globulin biosynthesis was demonstrated in hepatocytes isolated from normal adult Rhesus monkeys. Dispersed cells were obtained by in situ liver perfusion with collagenase, hyaluronidase and EDTA. Conditions for optimum cell survival and incorporation of radioactive leucine into newly synthesized proteins were defined. Protein synthesis, and specifically thyroxine-binding globulin synthesis, were shown to continue throughout the incubation period, while cell survival remained high (75% excluded trypan blue after 6h). Incubation medium, cytosol and a particulate fraction (extracted with digitonin) were analyzed for thyroxine-binding globulin. After extensive dialysis and purification by affinity chromatography, newly synthesized thyroxine-binding globulin was identified by specific double-antibody immunoprecipitation and by immunodiffusion and immunoelectrophoresis with autoradiography. Newly synthesized thyroxine-binding globulin was present after 4 h of incubation. After 6 h, the total synthesized had increased to 150% of the 4 h value, while the fraction present in the medium and increased to 300%, indicating probable thyroxine-binding globulin secretion

The systematic screening and management of hypothyroidism and hyperthyroidism during pregnancy.

Altogether, thyroid function abnormalities during pregnancy can affect up to 10% of all women. The high prevalence of both hypo- and hyperthyroidism, the obstetrical repercussions associated with thyroid dysfunction in the mothers, as well as the potential role of maternal thyroid dysfunction as an influence on fetal development constitute solid arguments for a further increase of our knowledge of the pathophysiological processes underlying the alterations of thyroid function related to the pregnant state. In this review, the focus will be on the most clinically relevant aspects associated with hypothyroidism [autoimmune thyroid disorders (AITDs), subfertility, risk of miscarriage, risk of hypothyroidism in women with AITD and treatment of hypothyroid women] and with hyperthyroidism (clinical presentations during pregnancy, Graves' disease and its management, fetal hyperthyroidism in women with antithyroid-stimulating hormone receptor antibodies and gestational transient thyrotoxicosis associated with human chorionic gonadotropin stimulation of the maternal thyroid gland). I also propose a global strategy for the systematic screening of hypo- and hyperthyroidism in the pregnant state.

Stimulation of thyroxine-binding globulin synthesis by isolated rhesus monkey hepatocytes after in vivo beta-estradiol administration.

The rate of in vitro production of thyroxine-binding globulin (TBG) was studied in hepatocytes isolated from 6 control rhesus monkeys (serum TBG: 19.6 +/- 0.5 micrograms/ml; mean +/- SE) and 6 monkeys treated for 4-5 weeks with beta-estradiol (E2) (serum TBG: 45.1 +/- 1.8 micrograms/ml). Incorporation of [3H]leucine into intracellular soluble and particle-bound TBG, and into secreted TBG was determined for incubation periods up to 9 h. TBG was purified by affinity chromatography and measured by specific immunoprecipitation. The absolute amount of [3H]TBG and the ratio of [3H]TBG to total labeled protein in the same fraction were 3-fold higher in the particulate fraction and in the incubation medium of hepatocytes isolated from E2-treated monkeys. In separate experiments, TBG accumulation in the medium was measured for periods up to 19 h by radioimmunoassay. A 2.4-fold increase was observed with hepatocytes from E2-treated monkeys (3.48 ng TBG/h/10(7) cells, compared to 1.46 in controls). Correction of the production rates for the number of cells surviving during the incubation, and assuming 10.2 x 10(9) cells per liver, gave TBG production rates of 250 micrograms/liver/day in hepatocytes from E2-treated monkeys and 104 micrograms/day in hepatocytes from control monkeys. These experiments demonstrate that estrogen increases in vitro synthesis and secretion of TBG by isolated hepatocytes. The observed 2.4 to 3-fold increase was similar to the 2.9-fold increase in TBG production measured in vivo by kinetic analysis of TBG metabolism.

Effects of estrogen on thyroxine-binding globulin metabolism in rhesus monkeys.

To investigate the effects of estrogen on thyroxine-binding globulin (TBG) metabolism, 4 female Rhesus monkeys were studied before and 3-4 weeks after implantation of beta-estradiol (E2)-containing capsules. In addition, 2 of the animals were also studied for the first 7 days after the start of E2. Serum E2 increased 10-fold from 20 +/- 7 to 212 +/- 41 pg/ml. Serum TBG, initially 20.2 +/- 6 mug/ml, was elevated by 24 h after E2 implantation, and reached a steady level of 46.8 +/- 5.0 mug/ml by 7-10 days. For the turnover studies, highly purified [125I]iodo-TBG was injected iv and serum [125I]PBI and urinary 125I excretion were measured daily. TBG kinetics were evaluated by use of a compartmental model. Although a 2-compartment model was sufficient to fit the control and late E2 data, a 3-compartment model was developed in order to account for the modifications observed during the early E2 period. The final decay rate (k) of TBG was 0.26 +/- 0.01/day during the control period and was slightly lower after E2 (0.23 +/- 0.01/day). In the 2 monkeys studied during the early E2 period, the major effect of E2 was a stimulation of the TBG production rate. This was simulated in the model by a stepwise increase occurring in the last quarter of the first day after E2. There was also an abrupt redistribution of TBG in the compartments defined by the model. The total distribution or serum equivalent volume of TBG after 3-4 weeks of E2 increased 1.4-fold, from 338 +/- 37 ml to 458 +/- 22 ml, and the metabolic clearance rate increased 1.3-fold, from 90 +/- 10 ml/d to 113 +/- 12 ml/d. The increase in the final TBG production rate (2.9-fold) was only slightly greater than the rate calculated for the early E2 period, and was similar to the increase we have recently found in monkey hepatocytes studied in vitro after isolation from E2-treated animals. It appears that stimulation of hepatic synthesis of TBG accounts for the elevated serum levels of TBG observed after estrogen.

Current trends in the management of Graves' disease.

Members of the American Thyroid Association were invited to participate in a survey of the management of Graves' disease. One primary case and several variations were provided, which differed in respect to age, sex, goiter size, severity, etc. The questionnaire was based on the format used in a similar survey of members of the European Thyroid Association. The aim of the survey was to determine 1) how expert thyroidologist employ diagnostic procedures for this disorder, and 2) the choice of therapy of the three treatment options and its manner of implementation. Questionnaires were sent only to clinically active members. The overall response rate was 62%. Data analysis was possible on 52% of members surveyed and was performed using SPSS and a specific Fortran program. In the laboratory evaluation of the primary case a radioiodine uptake, scan, serum total T4, and basal TSH were requested by 92%, 47%, 83%, and 66%, respectively, with 84% of respondents using an ultrasensitive TSH assay. For management of the primary case, radioiodine treatment was the first choice of 69% of the respondents. Antithyroid drugs were used briefly (3-7 days) before 131I by 28%, whereas 41% said they would employ thioureas after 131I. Of those using 131I, 66% tailored the dose to achieve euthyroidism as the goal of therapy, while 34% aimed for hypothyroidism requiring T4 replacement. Only 30% of respondents chose thioureas as a first line of treatment (72% propylthiouracil; 28% tapazole). The duration of drug therapy was a predetermined fixed interval for 80% of the respondents, with 90% treating for 1-2 yr. Other specific trends in diagnostic approach and therapeutic preferences were identified for the eight variations on the primary case problem.

Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders.

A prospective study was undertaken in 87 healthy pregnant women with thyroid antibodies and normal thyroid function at initial presentation [asymptomatic autoimmune thyroid disorders (AITD)]. The aims of the study were to assess whether women with AITD constitute a group at risk of developing subclinical hypothyroidism during pregnancy, and whether a mild thyroid function impairment may be associated with obstetrical repercussions. The women investigated were selected among a cohort of 1660 consecutive pregnancies on the basis of 1) no previous history of thyroid disease, 2) euthyroidism at initial presentation, and 3) positive thyroglobulin antibodies and/or thyroid peroxidase antibodies (TPO-Ab). Women with AITD had a basal TSH value significantly higher, albeit still normal, in the first trimester (1.6 vs. 0.9 mU/L; P < 0.001) than that in women with healthy pregnancies used as controls. Despite a 60% average reduction in TPO-Ab titers during gestation, serum TSH remained higher in women with AITD than in controls throughout gestation: at delivery, 40% of the cases had serum TSH levels above 3 mU/L, and 16% had serum TSH levels above 4 mU/L. A TRH test carried out in the days after parturition showed an exaggerated response in 50% of the cases. Furthermore, free T4 concentrations were in the range of hypothyroid values in 42% of the women. Obstetrical repercussions were observed, namely increased rates of spontaneous miscarriage and premature deliveries. In conclusion, women with asymptomatic AITD who are euthyroid in early pregnancy carry a significant risk of developing hypothyroidism progressively during gestation, despite a marked reduction in antibody titers. Hypothyroidism results from the reduced ability of the gland to adjust to the changes in thyroidal economy associated with pregnancy. At the individual level, progression to subclinical hypothyroidism was broadly predictable on the basis of serum TSH levels and TPO-Ab titers in the first trimester. Hence, these parameters provide useful markers to identify women who carry a higher risk, allowing for a close monitoring of thyroid function during pregnancy and the administration of L-T4 in specific cases. Taken together with the known incidences of postpartum thyroiditis and hypothyroidism in women with AITD, the present observations in our opinion justify systematic screening of thyroid autoimmunity during pregnancy.

Partial reversibility during late postpartum of thyroid abnormalities associated with pregnancy.

The aim of the present work was to assess during late postpartum the reversibility of thyroidal alterations associated with pregnancy. Thyroid function was reinvestigated 6 months after delivery in 100 randomly selected healthy women and thyroid volume was reevaluated 12 months after delivery in 10 other selected women. The subjects had previously been carefully followed during gestation as they were included in a prospective cohort investigation of the regulation of the thyroid during pregnancy, in an area with a limited dietary iodine intake (less than 100 micrograms/day in 85% of the women). Six months after delivery, an overall normalization of thyroid function was observed. However, an increase in the T3/T4 ratio, which was present in half the cases at delivery, was still evident 6 months postpartum, suggesting the persistence of relative iodine deficiency, probably prolonged in some women through breast-feeding. Furthermore, serum thyroglobulin levels, which were increased in half the women at delivery, remained abnormally high in 40% of them 6 months later. Twelve months after delivery thyroid volume, which had increased in average by 54% during pregnancy, had not reverted to the values found during early gestation. Moreover a goiter was still evident in 2/4 cases in whom it had developed during pregnancy. In conclusion, the present study indicates that pregnancy may constitute a prolonged stimulus for the thyroid and shows for the first time that the alterations associated with gestation are not limited to the period of pregnancy, being only partially reversible during late postpartum. In conditions with a limited iodine intake, pregnancy constitutes a risk for the maternal thyroid: goitrogenesis does occur and may be maintained after delivery. The glandular stress of pregnancy may therefore provide a clue to understanding the high prevalence of thyroid disorders in women. The present study provides additional arguments to suggest that iodine supply be increased during pregnancy but also after parturition, in particular in breast-feeding mothers.

Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake.

Thyroid function was evaluated in cord serum of healthy full-term newborns and compared to that of mothers immediately after parturition. The study was carried out in an area without overt iodine deficiency, but with a marginal iodine supply (less than 100 micrograms/day in 80% of women). The aim of the study was to delineate the interrelationships between the thyroid statuses of mother and child at birth. Maternal thyroid function was characterized at delivery by relative hypothyroxinemia; increased T3/T4 ratios, indicating preferential T3 secretion; slightly increased TSH levels within the normal range in 97% of women; increased serum thyroglobulin (TG) values, which were above normal in 60% of women; and also goiter formation in almost 10% of women. The findings indicated glandular stimulation and confirmed our earlier reports that pregnancy constitutes a stress for the maternal thyroid economy, enhanced by the limited availability of iodine in the diet. By contrast, newborns showed a strikingly distinct pattern: there was no relative hypothyroxinemia and free T4 levels were significantly higher than in the respective mothers (19.4 vs. 14.7 pmol/L; P less than 0.001). In spite of these differences, however, mean neonatal TSH and TG levels were significantly higher than maternal values, respectively 6.0 vs. 1.9 mU/L for TSH (P less than 0.001) and 70 vs. 40 micrograms/L for TG (P less than 0.001). Furthermore, neonatal TG and TSH levels increased in parallel and were highly correlated with maternal data, suggesting a regulatory link between both thyroid economies. The results suggested that the common regulatory link is the limited availability of the iodine supply. In conclusion, the present study demonstrates that even in conditions with a marginally low iodine intake, pregnancy constitutes a stimulus for both the maternal and newborn thyroids. Changes in both groups are associated and the abnormalities in TSH and TG are amplified in the newborns. The TSH and TG alterations at birth in full-term healthy newborns, associated with similar alterations in maternal thyroid function, provide evidence for a common stimulatory factor, relative iodine deficiency. The data emphasize the hypersensitivity of neonatal thyroid function to marginal iodine deficiency and point to the need to increase the iodine supply in groups at risk, such as women during pregnancy, and also newborns in the perinatal period.

Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions.

A prospective study was undertaken during pregnancy in 120 euthyroid women presenting with mild thyroid abnormalities (TA): 11 with a past history of thyroid disorder, 44 with goiter, 20 with nodules, and 45 with thyroid autoantibodies. The aims of the study were to assess whether the pattern of thyroid alterations during gestation was different in women with TA compared to that in healthy control pregnant subjects and to evaluate possible obstetrical and neonatal repercussions. The overall prevalence of underlying subtle thyroid abnormalities in the cohort was 17%, probably as the result of the environmental moderately low iodine intake. Despite the intrinsic heterogeneity of the four groups of women with TA, the adaptation of the thyroid to the stress of pregnancy was different from that of the control subjects. Noteworthy were 1) the marked elevation of serum thyroglobulin in women with past history of thyroid disorder, goiter and thyroid nodules; 2) the increase in goiter size in a third of the goitrous women, associated with biochemical evidence of functional stimulation of the gland; 3) the indirect evidence of partial thyroidal autonomy in goitrous patients; and 4) the increase in the number and size of thyroid nodules during gestation. Taken together, the data indicated that pregnancy was associated with a greater thyroidal risk in patients with TA compared to healthy subjects. In relation to thyroid autoimmunity, most patients remained euthyroid during gestation, but in a few cases, TSH was elevated at delivery, suggesting diminished thyroidal reserve. Also, 40% of newborns from mothers with thyroid autoimmunity had elevated thyroid peroxidase antibody titers at birth, and there was a highly significant correlation between maternal and neonatal thyroid peroxidase antibody titers. Finally, thyroid autoimmunity was clearly associated with an increased risk of spontaneous abortion (13.3 vs. 3.3%; P less than 0.001). Thyroid function in newborns from mothers with TA was normal and not different from that in controls; similarly, obstetrical features were similar in patients with TA and control subjects. In conclusion, pregnancy is associated with a greater thyroidal risk in women with TA, thereby emphasizing a potential link between pregnancy and thyroid disorders. It is recommended that patients with known, even subtle, thyroid abnormalities be closely monitored during pregnancy, in particular those with a goiter, nodules, or thyroid autoimmunity, especially in areas with a moderately low iodine intake, where the prevalence of mild thyroid disturbances is high.

A randomized trial for the treatment of mild iodine deficiency during pregnancy: maternal and neonatal effects.

One hundred and eighty euthyroid pregnant women were selected at the end of the first trimester of gestation on the basis of biochemical criteria of excessive thyroid stimulation, defined as supranormal serum thyroglobulin (TG > 20 micrograms/L) associated with a low normal free T4 index (< 1.23) and/or an increased T3/T4 ratio (> 25 x 10(-3)). Women were randomized in a double blind protocol into three groups and treated until term with a placebo, 100 micrograms potassium iodide (KI)/day, or 100 micrograms iodide plus 100 micrograms L-T4/day. Parameters of thyroid function, urinary iodine excretion, and thyroid volume were monitored sequentially. Neonatal thyroid parameters, including thyroid volume by echography, were also assessed in the newborns from mothers of the three groups. In women receiving a placebo, the indices of excessive thyroid stimulation worsened as gestation progressed, with low free T4 levels, markedly increased serum TG and T3/T4 ratio. Serum TSH doubled, on the average, and was supranormal in 20% of the cases at term. Urinary iodine excretion levels were low, around 30 micrograms/L at term. The thyroid volume increased, on the average, by 30%, and 16% of the women developed a goiter, confirming the goitrogenic stimulus associated with pregnancy. Moreover, the newborns of these mothers had significantly larger thyroid volumes at birth as well as elevated serum TG levels. In both groups of women receiving an active treatment, the alterations in thyroid function associated with pregnancy were markedly improved. The increase in serum TSH was almost suppressed, serum TG decreased significantly, and changes in thyroid volume were minimized (group receiving KI) or almost suppressed (group receiving KI combined with L-T4). Moreover, in the newborns of the mothers in the two groups receiving an active treatment, serum TG was significantly lower, and thyroid volume at birth was normal. The effects of therapy were clearly more rapid and more marked in the group receiving a combination of T4 and KI than in the women receiving KI alone. The differences could be partly attributed to the slightly higher amount of iodine received by women in the combined treatment. However, the main benefits of the combined treatment were almost certainly attributable to the hormonal effects of the addition of L-T4. Furthermore, the study demonstrated that the administration of T4 did not hamper the beneficial effect of iodine supplementation. In conclusion, the present work emphasizes the potential risk of goitrogenic stimulation in both mother and newborn in the presence of mild iodine deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Parity as a thyroid size-determining factor in areas with moderate iodine deficiency.

Among the factors that may influence thyroid size, pregnancy and its goitrogenic effect have been widely investigated, but thyroid volume and pregnancy have never been compared retrospectively, and there are no data on the possible relationship between thyroid size and parity. The purpose of this work was to evaluate the effects of pregnancy on thyroid volume in a moderate iodine deficiency area, to assess the possibility of a relationship between thyroid size and parity status in healthy females. A group of 208 nongoitrous healthy women underwent thyroid volume estimation by ultrasound examination. All subjects were euthyroid and negative for thyroid autoantibodies. They were assigned to different groups, according to the number of completed pregnancies. Five groups were formed (0, 1, 2, 3, 4 or more term pregnancies). Mean thyroid volume increased progressively among the groups: group 0 (14.8 +/- 0.7 mL); group I (16.0 +/- 0.9 mL); group II (17.1 +/- 0.6 mL); group III (18.2 +/- 0.6 mL); group IV (20.3 +/- 0.9 mL). The increment in thyroid volume was statistically significant between group 0 and groups III (P: < 0.01) and IV (P: < 0.001), and also between group I and group IV (P: < 0. 05). No independent effect of body weight and age on thyroid volume was seen. Our results indicate that, in an area with moderate iodine deficiency, the goitrogenic effect of pregnancy is not fully reversible. Moreover, the statistically significant increase in thyroid volume, observed in relation to parity, is the first clinical demonstration of a cumulative goitrogenic effect of successive pregnancies, providing a strong argument to increase the iodine supply during pregnancy, even in conditions with moderate iodine deficiency.

Regulation of maternal thyroid during pregnancy.

A prospective study was undertaken in 606 healthy women during pregnancy to evaluate the changes occurring in maternal thyroid economy as a result of 1) the increased thyroid hormone-binding capacity of serum, 2) the effects of increased levels of hCG on TSH and on the thyroid, and 3) a marginally low iodine intake in the population (50-75 micrograms/day). Four main features were observed. First, thyroidal activity adjusted to the marked increase in serum T4-binding globulin: pregnancy was accompanied by an overall reduction in the T4/T4-binding globulin ratio, with lower free T4 and T3 levels, although in most cases free hormone levels remained within the normal range. The adjustment of thyroidal output of T4 and T3 did not occur similarly in all subjects. In approximately one third of the women, there was relative hypothyroxinemia, higher T3/T4 ratios (presumably indicating preferential T3 secretion), and higher, although normal, serum TSH concentrations. Second, high hCG levels were associated with thyroid stimulation, both functionally (lower serum TSH) and anatomically (increased thyroid size). The data are consistent with a TSH-like effect of hCG on the thyroid. Hence, regulation of the maternal thyroid is complex, resulting from both elevated hCG (mainly in the first half of gestation) and increasing TSH (mainly in the second half of gestation). Third, a significant increase in serum thyroglobulin levels was observed throughout gestation, especially during the last trimester. Fourth, increased thyroid volume was common, and goiter formation not uncommon (goiter was found in 9% of women at delivery). In conclusion, the alterations in maternal thyroid function during gestation are intricate and far from fully understood. In areas of marginally low iodine intake, gestation is associated in a significant number of women with relative hypothyroxinemia, increased thyroglobulin, and enlarged thyroid.

Total amounts of circulating human chorionic gonadotrophin alpha and beta subunits can be assessed throughout human pregnancy using immunoradiometric assays calibrated with the unaltered and thermally dissociated heterodimer.

The aim of the present study was to determine the variations in the balance between total (free plus combined) circulating alpha and beta subunits of human chorionic gonadotrophin (hCG) throughout human pregnancy. The equivalence between the International Units (IU) of hCG (IRP 75/537) and those assigned to the alpha (IRP 75/569) and beta (IRP 75/551) free subunits was experimentally determined by using intact and thermally dissociated hCG. Heat exposure (2 min at 100 degrees C) of hCG preparations resulted in a complete dissociation of hCG into free, soluble and intact alpha and beta subunits. The hCG and alpha and beta subunit contents of unaltered and heated hCG preparations were assessed by specific immunoradiometric assays. The amount of immunoreactive subunits dissociated by heat from hCG could then be evaluated on a molar basis. Circulating hCG and its free alpha and beta subunits were immunoassayed in 836 blood samples collected from healthy pregnant women at different gestational ages. After conversion of hCG and its subunits into a common IU system, the gestational profiles of the total amounts (free plus combined) of alpha- and beta hCG subunits increased together and peaked at 9-10 weeks of gestation. Thereafter, total alpha and beta subunits decreased and subsequently remained stable until term. The decline in total alpha hCG subunit was less marked than that of total beta hCG subunit. The alpha- to beta hCG ratio was equimolar until 10 weeks of gestation when it increased almost fourfold until term (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study.

OBJECTIVE: In Graves' hyperthyroidism treated with antithyroid drugs (ATD), the overall relapse rate reaches 30-50% following ATD discontinuation. Conflicting results have previously been reported with regard to the usefulness of combining ATD with thyroxine (l-T4), and thereafter maintaining l-T4 treatment after ATD withdrawal. Also, clinicians are in search of useful parameters to predict the risk of a recurrence of hyperthyroidism after ATD treatment. DESIGN: Eighty-two consecutive patients (70 women and 12 men; mean age 36 years) with a first episode of Graves' hyperthyroidism were investigated prospectively; they were treated with ATD for a total of 15 months, combined with l-T4 (for at least 12 months) after they had reached euthyroidism, with the aim of maintaining serum TSH below 2.5 mU/l during the combined therapy. Following ATD discontinuation, the patients were randomly assigned (double-blind placebo-controlled trial) to taking 100 microg/day l-T4 (vs placebo) for an additional year. METHODS: The following determinations were carried out at initial diagnosis: serum total T4 and tri-iodothyronine (T3), free T4 and T3, TSH, TSH-receptor antibodies (TSHR-Ab), thyroid scintigraphy and echography. During ATD treatment, serum free T4 and T3 and TSH concentrations were recorded after 1 (optional), 2, 4, 6, 9, 12 and 15 months, and echography at the end of ATD treatment. During the randomized trial, serum free T4 and T3 and TSH concentrations were checked every 3 months (or until a recurrence). TSHR-Ab titers were measured at initial diagnosis, after 6 months with ATD, and at the end of ATD treatment. RESULTS: l-T4 administration, both during and after ATD treatment, did not improve the final outcome and recurrence rates were similar in placebo and l-T4-treated patients (30%). Two parameters were identified that might be useful to help predict recurrence risks after ATD: (i) positive TSHR-Ab (at the end of ATD treatment) was significantly associated with a greatly increased recurrence risk; and (ii) despite the relatively small number of patients who were smokers, regular cigarette smoking was shown, for the first time, to be significantly associated with an increased recurrence risk. Also, the deleterious effect of smoking was shown to manifest its impact independently of TSHR-Ab titers at the end of ATD treatment. Thus, compared with the overall 30% recurrence risk, non-smoking patients with a negative TSHR-Ab (at the end of ATD) had a lower (18%) recurrence risk; smoking patients with negative TSHR-Ab (at the end of ATD) had a 57% recurrence risk; non-smoking patients with positive TSHR-Ab (at the end of ATD) had a high (86%) recurrence risk; the recurrence risk was 100% in those few patients who both smoked and maintained a positive TSHR-Ab at the end of ATD treatment. CONCLUSIONS: The present study confirmed that l-T4 administration during and after ATD withdrawal did not improve remission rate. Two factors, namely positive TSHR-Ab at the end of ATD treatment and regular smoking habits may represent clinically useful (albeit not absolute) predictors of the risk of recurrence in patients with Graves' hyperthyroidism treated with ATD. However, due to the relatively small number of smoking patients in the present cohort, this conclusion needs to be confirmed by a larger study.

What happens to the normal thyroid during pregnancy?

Hormonal changes and metabolic demands during pregnancy result in profound alterations in the biochemical parameters of thyroid function. For the thyroidal 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 conditions) that is significantly amplified when there is iodine restriction or overt iodine deficiency; a frequent trend toward a slight increase in basal thyrotropin (TSH) values between the first trimester and term; a direct stimulation of the maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG), which occurs mainly near the end of the first trimester and can be associated with a transient lowering in serum TSH; 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 a preconception steady-state to the 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 thyroid hormones and increased turnover of maternal thyroxine (T4), presumably under the influence of the placental (type III) 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 when the functional capacity of the thyroid gland is impaired (such as in autoimmune thyroid disease and hypothyroidism) or when pregnancy takes place in healthy women residing in areas with a deficient iodine intake. The ideal dietary allowance of iodine recommended by the World Health Organization (WHO) is 200 microg iodine per day for pregnant women. In conditions with iodine restriction, enhanced thyroidal stimulation is revealed by relative hypothyroxinemia and goitrogenesis. Goiters formed during gestation may only partially regress after parturition. Pregnancy, therefore, represents one of the environmental factors that may explain the higher prevalence of goiter and thyroid disorders in the female population. An iodine-deficient status in the mother also leads to goiter formation in the progeny. 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 thyroidal 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.