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Influence of female sex hormones on thyroid parameters determined in a thyroid screening
Abstract
This is a cross-sectional study with a non-randomly selected population to ascertain the influence of female sex hormones on thyroid function. TSH, TT4, FT4, TT3 and FT3 were determined in 251 women using either oral hormonal contraceptives or hormone replacement treatment, 255 women not taking either, and a control group of 900 men. Women with normal thyroid morphology using oral hormonal contraceptives in the pre-menopausal group had a significantly higher TT4 and TT3, and lower FT3, respectively, than both non-users and men. FT4 and TSH remained unchanged. In the peri-/post-menopausal group, thyroid function of women using hormone replacement treatment was not significantly different from non-users, but either women still had a significantly lower FT3 than men. We conclude that oral hormonal contraceptives and hormone replacement treatment increase TT4 and TT3 and do not influence FT4 and TSH. They decrease FT3 which is in contrast to what would be expected theoretically and what has been observed in earlier studies.
... Protein bound iodine was also increased in non-pregnant women by administration of pharmaceutical estrogens (Engstrom et al., 1952), while reduction of estrogens led to a marked increase in urinary excreted THs (Chan et al., 1972). Elevated serum total T 4 and T 3 (but not TSH or free T 4 ) were observed in women taking oral contraceptives compared to untreated women and men (Grüning et al., 2007) and in post-menopausal women receiving estrogen replacement therapy (Arafah, 2001). Changes in total T 4 and T 3 in response to estrogens is primarily due to an increase in circulating TBG. ...
... These observations may explain why estrogens can blunt the increase in TSH secretion in hypothyroid rats (Franklyn et al., 1987). In contrast, estrogens either have little impact (Grüning et al., 2007;Sawin et al., 1978;Tahboub and Arafah, 2009) or appear to increase TSH (Benvenga et al., 2017;Marqusee et al., 2000) in women. ...
Thyroid hormones (THs) are important regulators of growth, development, and homeostasis of all vertebrates. There are many environmental contaminants that are known to disrupt TH action, yet their mechanisms are only partially understood. While the effects of Endocrine Disrupting Chemicals (EDCs) are mostly studied as “hormone system silos”, the present critical review highlights the complexity of EDCs interfering with TH function through their interactions with other hormonal axes involved in reproduction, stress, and energy metabolism. The impact of EDCs on components that are shared between hormone signaling pathways or intersect between pathways can thus extend beyond the molecular ramifications to cellular, physiological, behavioral, and whole-body consequences for exposed organisms. The comparatively more extensive studies conducted in mammalian models provides encouraging support for expanded investigation and highlight the paucity of data generated in other non-mammalian vertebrate classes. As greater genomics-based resources become available across vertebrate classes, better identification and delineation of EDC effects, modes of action, and identification of effective biomarkers suitable for HPT disruption is possible. EDC-derived effects are likely to cascade into a plurality of physiological effects far more complex than the few variables tested within any research studies. The field should move towards understanding a system of hormonal systems’ interactions rather than maintaining hormone system silos.
... 51 Since estrogen increases levels of thyroxine binding globulin, total T4 levels will be elevated in patients taking hormonal replacement therapy. 52 This should therefore be taken into account when treatment of hypothyroidism is being considered. Further studies using age appropriate TSH cutoff values are needed to understand both the natural history of hypothyroidism in the elderly population and possible health impacts. ...
Hypothyroidism is a common disease that is more prevalent in female populations. The purpose of this paper is to discuss the evidence, risks, and benefits of screening asymptomatic women for hypothyroidism. There is lack of evidence to support clinical management of asymptomatic individuals with an elevated TSH and normal serum thyroxine levels. Patients with subclinical hypothyroidism, especially the elderly, are at risk of overtreatment. Given these considerations, the majority of US and UK professional organizations do not support universal screening. Many do offer caveats for special groups, including pregnant people, who may need screening if there are clinical symptoms or family history of autoimmune disease. In conclusion, targeted screening may be best recommended based on risk factors, symptoms, and clinical suspicion, rather than at a universal level.
... A possible influence of the use of contraceptives in women, however, should be taken into account [5]. This was also the conclusion of the study by Grüning et al. [21], who studied the influence of female sex hormones on thyroid parameters. ...
We conducted a study in a metropolitan area to establish regional reference intervals for thyreotropin (TSH) and the thyroid hormones free triiodthyronine (fT3) and free thyroxine (fT4). This was due to the different reference ranges, based on varying regional trials, presented for a widely used electrochemiluminescence immunoassay system.
We investigated 292 apparently healthy adult subjects and excluded those with known history of thyroid disease, abnormal findings in the ultrasonographic examination of the thyroid gland, or elevated thyroid autoantibodies in serum. Accordingly, 204 of 292 subjects were included as the reference collective. We measured serum concentrations of TSH, fT3, and fT4 using the Elecsys assays from Roche Diagnostics and calculated the 2.5th and 97.5th percentiles.
The nonparametrically calculated reference values for TSH and fT4 were 0.58–3.49 mIU/L and 11.58–20.46 pmol/L, respectively. Statistically remarkable is the finding of a normal Gaussian distribution of the fT3 serum concentration, leading to the parametric reference interval of 3.56–5.88 pmol/L.
The established reference values for this regional collective showed tighter intervals than the reference ranges provided by the manufacturer. A carefully selected study population, based on the correspondent National Academy of Clinical Biochemistry criteria, ensured a valid set of reference ranges for TSH, fT3, and fT4, providing a basis for accurate in vitro thyroid testing. The 2.5th percentile for the fT3 is now in better accordance with clinical findings.
... Treatment of prepubertal or adult female rats with estradiol significantly enhances thyroid weight (Lima et al., 2006). Serum T3 levels decrease in response to ovariectomy and are restored upon estradiol replacement (Lima et al., 2006), and women who use oral hormonal contraceptives have significantly higher serum thyroid hormone levels than nonusers (Gruning et al., 2007). Investigations into the cellular mechanisms whereby estradiol stimulates thyroid hormone secretion in mammals have revealed that the sex steroid stimulates the proliferation of thyrocytes in female rats and enhances thyrocyte sensitivity to the mitogenic effects of thyroid-stimulating hormone (TSH; Banu et al., 2002). ...
Although it is well established that estrogen regulates skeletal growth and ossification in mammals, the effects of estrogen on skeletal development in amphibians are relatively uncharacterized. This study was conducted to characterize the impact of 17β-estradiol exposure on skeletal development in Xenopus laevis tadpoles. On day 48 postfertilization, tadpoles were placed in tanks containing 50% Holtfreter's Solution ±17β-estradiol at one of four concentrations (10(-11), 10(-10), 10(-9), and 10(-8) M). At 7-11 day intervals until day 91, 7-10 tadpoles per group were killed, fixed, measured, and staged. Specimens were then cleared and double-stained for cartilage and bone, and 34 skeletal elements were analyzed for ossification. Results from the study indicate that both low (10(-11) M) and high (10(-8) M) concentrations of 17β-estradiol have a significant stimulatory effect on tadpole development. Both the larval stage and ossification index of tadpoles exposed to 10(-11) or 10(-8) M 17β-estradiol were significantly greater than those observed in control animals by day 91 postfertilization. These results are consistent with the hypothesis that endogenous and exogenous estrogen could play a role in the regulation of bone ossification in amphibians.
... It has also been shown that chronic estradiol treatment reduces total T4 levels in ovariectomized rats (36). Use of HRT and levothyroxine by women with hypothyroidism was shown to change the levels of thyroid-stimulating hormone and free T4 (37) and to require additional levothyroxine intervention (38). This change in thyroidstimulating hormone and free T4 levels is probably not mediated through changes in sex hormone-binding globulin protein levels (39) and is noted with oral but not with transdermal HRT (40). ...
Levothyroxine is a synthetic T(4) hormone commonly used to treat thyroid disease. Increased incidence of mostly autoimmune thyroid disease has been associated with breast and other malignancies, and thyroid hormone levels might also be associated with risk of colorectal cancer (CRC). In this population-based matched case-control study (2566 pairs) of CRC in northern Israel, use of levothyroxine for at least 5 years was assessed using structured interviews and validated by prescription records. The analysis included use of statins, aspirin, and hormone replacement therapy; CRC family history; physical activity; vegetable consumption; ethnicity; age; and sex. All statistical tests were two-sided. The use of levothyroxine was associated with a statistically significantly reduced relative risk of CRC (odds ratio = 0.59, 95% confidence interval = 0.43 to 0.82, P = .001). This association remained statistically significant after adjustment for age, sex, use of aspirin and statins, sports activity, family history of CRC, ethnic group, and level of vegetable consumption (odds ratio = 0.60, 95% confidence interval = 0.44 to 0.81, P = .001). No statistically significant interactions were seen between use of levothyroxine and aspirin, statins, or hormone replacement therapy.
Two independent Chinese cohorts were used to study the genetic association between the interleukin-23A (IL-23A) gene polymorphism (rs11171806) and susceptibility to Graves’ disease (GD). The initial Shanghai cohort consisted of 712 unrelated patients with GD and 705 healthy control subjects, and the replication cohort from Xiamen Island included 433 patients with GD and 410 healthy control subjects. The serum concentration of IL-23 in GD patients was measured significantly higher than in health controls. Moreover in the subgroup analysis, higher concentrations of IL-23 were identified in patients of older age (⩾40 years) and female gender. We also performed an association study with the IL-23 gene polymorphism rs11171806 in both cohorts, in Shanghai cohorts, the frequencies of rs11171806 alleles were strongly different between Graves’ disease patients (G 95.7% and A 4.3%) and healthy controls (G 97.7% and A 2.3%) (P = 2.6 × 10−3, OR = 1.93 (95% CI: 1.25–2.97)), and in Xiamen cohorts, the proportion of individuals carrying the A allele of rs11171806 was the same significantly higher in Graves’ disease patients than in controls [Graves’ disease vs. control, 4.8% vs. 4.3%, OR = 2.15 (95% CI: 1.23–3.79), Pallele = 6.3 × 10−3]. The distribution of rs11171806 genotype was also investigated in subgroups according to the age and gender. All of these findings suggested that IL-23 may play an important role in the development of GD, and the IL-23A gene is a genetic risk marker for GD in Han Chinese population.
Background
This study aimed to compare thyroid volume and Doppler sonographic evaluation of the inferior thyroid artery using ultrasound in current and previous users of oral contraceptives (OCs).Methods
We evaluated 119 women who either currently use (n = 66) or have previously used OCs (n = 53) using color Doppler ultrasound for thyroid volume and resistance index, peak-systolic, and end-diastolic velocities of the inferior thyroid artery. Previous OC users were divided into two groups: previous OC use for <1 year and previous OC use for ≥1 year.ResultsA comparison of the thyroid volume revealed an increased volume in women with previous OC use for ≥1 year and in current users compared with those with previous OC use for <1 year (previous OC use for ≥1 year: 7.49 mL versus previous OC use for <1 year: 6.13 mL; p < 0.01). The relationship between OC use and an enlarged thyroid remained after adjusting for thyroid-stimulating hormone levels (p = 0.03). There were no differences in the inferior thyroid artery blood flow measurements.Conclusions
In healthy women, current use and previous OC use for ≥1 year were associated with increased thyroid volume that was unrelated to increased blood flow in the gland. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound, 2014;
Thyroid function tests are commonly obtained by both primary care physicians and various specialists in ambulatory practice
for both the evaluation of symptomatic and screening assessment of asymptomatic thyroid disease. Abnormalities of thyroid
function testing, including those which may not be clinically apparent, are common in the general population. Epidemiological
studies have identified hypothyroidism (subclinical and overt) in 4.6–9.5% and hyperthyroidism (subclinical and overt) in
1.3–2.2% of individuals [1], while the incidence of mild/subclinical dysfunction in certain populations is much more common
[2–4].
To compare carbohydrate metabolism, adrenal and thyroid function during use of a combined contraceptive vaginal ring (NuvaRing, NV Organon, Oss, The Netherlands) with those of a combined oral contraceptive.
Healthy women aged 18-40 years used either the vaginal ring, delivering 15 microg ethinylestradiol and 120 microg of etonogestrel per day, or a combined oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel, for six cycles. Each cycle comprised 3 weeks of use of the ring or the pill followed by 1 ring- or pill-free week. The following parameters were measured at baseline and at the end of cycles 3 and 6: carbohydrate metabolism (glucose, insulin, glycosylated hemoglobin); adrenal function (total cortisol, cortisol binding globulin, dehydroepiandrosterone sulfate); thyroid function (thyroid stimulating hormone, free thyroxine).
Small and similar increases in insulin were seen in both groups. Concentrations of cortisol binding globulin and total cortisol rose significantly less during ring use than during combined oral contraceptive use (cycle 3, p= 0.0002; cycle 6, p < 0.0001). Levels of dehydroepiandrosterone sulfate did not change in either group. Thyroid stimulating hormone levels increased significantly more in the ring group at cycle 3 (p = 0.0016) but free thyroxine levels were unchanged in both groups.
Both the vaginal ring and the oral contraceptive have no clinically relevant effects on carbohydrate metabolism, adrenal or thyroid function.
Selection of appropriate laboratory determinations will enable the clinician to diagnose thyroid dysfunction readily in the majority of patients. At the present time, estimation of free thyroxine and a "sensitive" thyrotropin assay are recommended as the principal laboratory tests for thyroid disease. A decrease in serum free thyroxine estimate and a raised level of serum thyrotropin confirm the diagnosis of hypothyroidism caused by thyroid gland failure. An increase in free thyroxine estimate combined with a serum sensitive thyrotropin level suppressed to less than 0.1 mU/L establishes the diagnosis of thyrotoxicosis. In sick patients, a normal or raised serum free thyroxine estimate together with a normal level of serum thyrotropin suggests that the patient has neither hypothyroidism nor thyrotoxicosis. Patients with severe illnesses, generally in the intensive care unit, and those treated with certain drugs, as well as individuals with unusual thyroid disorders, may present with confusing laboratory findings. An understanding of the regulation of the thyroid hormone system and/or judicious consultation with an endocrinologist should enable the clinician to diagnose thyroid disease, if present, in such patients.(JAMA. 1990;263:1529-1532)
Hintergrund: Deutschland ist ein Strumaendemiegebiet. In den neuen Bundesländern, der früheren DDR, wurde die landesweite Jodierung von Paketspeisesalz 1985 eingeführt und bestand bis zur Wiedervereinigung 1990. Aufklärungskampagnen konzentrieren sich seitdem auf die Verwendung von jodiertem Speisesalz in den Produkten von Bäckern und Fleischern und in Fertignahrungsmitteln. In der Literatur werden Angaben zur Strumaprävalenz (zwischen 13 und 69%) gemacht, die in sich widersprüchlich sind und auch unserer klinischen Erfahrung (etwa 30%) nicht entsprechen.
Methode: Wir führten 1996 und 1997 jeweils eine prospektive Querschnittsstudie mit einer nicht randomisiert selektierten Studienpopulation (Beschäftigte von Handwerksbetrieben) durch, die das Gebiet des Freistaates Sachsen abdeckte. 1 129 bzw. 1 594 Erwachsene wurden durch Fragebogen, Sonographie und Bestimmung der Jodausscheidung im Urin (nur 1996) untersucht.
Ergebnisse: Unsere Ergebnisse bei Männern/Frauen waren 1996: Schilddrüsenvolumen 23,0±1,3/17,1±1,5 ml; Strumaprävalenz 32,1/31,3%; Prävalenz von Schilddrüsenknoten 21,1/23%; Jodausscheidung im Urin (bezogen auf Kreatinin) 86,4±1,3/104±24,1 nmol/mmol (97,1±1,4/117±27,1 μg/g). Im Jahre 1997 fanden wir: Volumen 20,9±1,2/15,7±2,1 ml; Struma 25,6/23,6%; Knoten 16,4/19,8%.
Schlussfolgerung: Obwohl Struma und Jodmangel in Sachen immer noch endemisch sind, ist es trotz der Abschaffung der generellen Speisesalzjodierung zu einer Verbesserung beider Parameter gekommen.
Factors influencing and interfering with free thyroxin (FT4) parameters and their measurement methods are presented. Mot serum thyroxin is bound to specific transport proteins by thyroxin-binding protein (TBG) thyroxin-binding prealbumin (TBPA) and albumin. The total serum thyroxin (TT4) depends not only on the amount of thyroid gland secretion but also on the concentration of these transport proteins. Measurement of direct and indirect parameters of a small amount of FT4 can indicate thyroid function when binding protein anomalies exist. Radioimmunoassay (RIA) is one FT4 determination method. Factors influencing FT4 parameters include age pregnancy disease medications (lower hormonal metabolism under phenytoin). Interfering factors are serum proteins (albumin deficiency) atypical serum components (abnormal T4 binding albumin T4 binding inhibitors) serum metabolites (free fatty acids in fasting) and medications (fatty acid liberation by heparin). Estrogen-induced TBG increase in pregnancy does not affect FT4 determination although it interferes with TT4 assessment. Nonthyroidal illness (NTI) and anorexia nervosa influence FT4 measurement as do drugs (salicylate). Indirect FT4 parameters are the FT4 Index (FT4-I) and the TT4/TBG Quotient used for the measurement of FT4 concentration by means of the T3 Uptake Test (3U). Dialysis procedure allows for direct measurement of FT4 serum concentration. T4 Analog Tracers resolve the methodical problems issuing from FT4-RIA. Various other FT4 assay methods include immune extraction 2 Step FT4-RIA GammaCoat FT4-RIA LisoPhasde and Liquisol Ft4-RIA. Finally highly sensitive immunoassays may make it possible in the near future to measure basal thyroid-stimulating hormone as a rational alternative to the determination of FT4 parameters.
The use of oral contraceptives results in an increase in thyroid-binding-capacity in conformity with a change of results by T3/T4-tests. Using Laurell-electrophoresis and an anti-serum produced by Behringwerke the determination of the thyroid-binding-globulin (TBG) in serum is easy to handle.
TBG was determined in serum from 137 women using oral contraceptives for more than 3 months. The apllication of oral contraceptives is followed by a statistically significant increase in the TBG level in serum. Thereby oral contraceptives change the TBG-level in a different degree. Preparations with a marked estrogen potency on the average effect a higher TBG-concentration than those with progesterone activity derived by menses-delay-test. The difference of TBG-level is statistically significant.
According by the increase of TBG-concentration in serum is caused by estrogen, the extent of the increase is modified by the progesterone component.
500 µg TRH (Thyrotropin-Releasing Hormone) were injected intravenously in 78 normal subjects aged between 20–85 years, TSH being estimated by radioimmunoassay from 0–120 min. The maximum increase of TSH (ΔTSHmax) was compared in age- and sex-specific groups.
Results: 1) The rise of TSH is significantly lower in men than in women of 20–59 years. 2) In men, the TRH response is diminishing clearly but not significantly with increasing age, i.e. 9.73 µU/ml ± 4.49 SD for 20–39 years, 7.93 µU/ml ±4.94 SD for 40–59 years, 7.37 µU/ml ± 3.37 SD for 60–81 years (not significant). 3) In women, the two groups aged 20–39 and 40–59 years show both a high increase of TSH, ΔTSHmax 15.6 µU/ml±7.6 SD and 15.6 µU/ml±8.8 SD, whereas 60–85 year-old women have a significantly lower TSH elevation of 7.7 µU/ml±3.7 SD. 4) The TRH responses of women taking oral contraceptives and those of untreated women of the same age are similar. 5) In the women decreasing TSH responsiveness was observed after the onset of the menopause. 6) Basal TSH of 20–59 year-old women shows higher values than in males and older subjects. 7) There exists no correlation between serum thyroxine or triiodothyronine and the TRH response. 8) The increase of serum triiodothyronine 120 min after TRH injection is considerably inconstant and not significantly lower in subjects over 60 years.
Conclusions: The different age- and sex-specific ranges for the normal values of the TRH test have to be taken into account in clinical use. It is proposed that the ranges of the normal values should be fixed rather by the double standard deviation than by the 3-fold standard error (SEM). For quantitative evaluation of the maximum TSH release, values at 20, 30 and 40 min after injection are necessary in order to find the TSH peak.
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.
The mean maximal TSH response to 100 μ of TRH in 15 euthyroid women was 19 ± 2.5 μ per ml (mean ± sem) compared to a mean response of 30 ± 2.5 μU per ml in 14 euthyroid patients receiving oral contraceptive steroids (P < 0.02). The results indicate that women receiving oral contraceptives have an augmented TSH response to TRH.
Thyroid hormones and the thyroxine-binding globulin are increased during hormonal treatment with oral contraceptives without changes in the thyroidal economy. Now we report that even reverse triiodothyronine, the main peripheral catabolite of thyroxine, is significantly increased during therapy with oral contraceptives.
Factors influencing and interfering with free thyroxin (FT4) parameters and their measurement methods are presented. Mot serum thyroxin is bound to specific transport proteins by thyroxin-binding protein (TBG), thyroxin-binding prealbumin (TBPA) and albumin. The total serum thyroxin (TT4) depends not only on the amount of thyroid gland secretion, but also on the concentration of these transport proteins. Measurement of direct and indirect parameters of a small amount of FT4 can indicate thyroid function when binding protein anomalies exist. Radioimmunoassay (RIA) is one FT4 determination method. Factors influencing FT4 parameters include age, pregnancy, disease, medications (lower hormonal metabolism under phenytoin). Interfering factors are serum proteins (albumin deficiency), atypical serum components (abnormal T4 binding albumin, T4 binding inhibitors), serum metabolites (free fatty acids in fasting) and medications (fatty acid liberation by heparin). Estrogen-induced TBG increase in pregnancy does not affect FT4 determination, although it interferes with TT4 assessment. Nonthyroidal illness (NTI) and anorexia nervosa influence FT4 measurement, as do drugs (salicylate). Indirect FT4 parameters are the FT4 Index (FT4-I) and the TT4/TBG Quotient used for the measurement of FT4 concentration by means of the T3 Uptake Test (3U). Dialysis procedure allows for direct measurement of FT4 serum concentration. T4 Analog Tracers resolve the methodical problems issuing from FT4-RIA. Various other FT4 assay methods include immune extraction, 2 Step FT4-RIA GammaCoat, FT4-RIA LisoPhasde, and Liquisol Ft4-RIA. Finally, highly sensitive immunoassays may make it possible in the near future to measure basal thyroid-stimulating hormone as a rational alternative to the determination of FT4 parameters.
Total serum thyroxine levels are significantly increased throughout pregnancy, returning to normal by 6 weeks post partum. Conversely, percentage-free serum thyroxine is decreased throughout pregnancy (normal at 6 weeks post partum). Thus, the absolute concentration of free thyroxine, the most important component from the physiologic standpoint, remains normal during pregnancy. Thyroid-stimulating hormone (TSH) increases significantly during the first and second trimesters of pregnancy but returns to normal levels at term. In cord serum of neonates, absolute free thyroxine level is greater than that in pregnant women at term; TSH values are greater than those in women at term and in euthyroid nonpregnant women. The use of progestogens for four or more menstrual cycles results in total, percentage-free, and absolute free thyroxine levels comparable to those found in women during pregnancy. The serum levels of TSH are normal.
PROTEIN-BOUND iodine and the uptake of 131I-triiodothyronine by resin have been measured in a group of pregnant women, in women taking 'Ovulen' and in a control group of healthy volunteers. From these data a free-thyroxine factor, which is proportional to the concentration of free thyroxine in the serum, has been calculated. Values for the free-thyroxine factor in pregnancy and in women taking ovulen were within the range for euthyroid individuals. These results suggest that thyroid status is normal in women taking œstrogen/ progestogen compounds. The free-thyroxine factor may be used to assess thyroid status in pregnancy and in women taking oral contraceptives.
Ethinyl estradiol was administered orally in a daily dose of 0.18-0.3mg for seven days to subjects with normal and abnormal thyroid function, and the changes of several parameters of the thyroid function during estrogen administration were investigated. The concentration and maximum T4 binding capacity of thyroxine-binding prealbumin (TBPA) were estimated by polyacrylamide gel electrophoresis. Estrogen increased the serum PBI value and the binding capacity of thyroxinebinding globulin (TBG), while it lowered Triosorb test value, elutable fraction and the concentration and binding capacity of TBPA. However, free T4 value, BMR, thyroidal 24-hour uptake of 131I and thyroidal effective half-life of 131I did not change. T4 half-life in serum was prolonged. These results show that ethinyl estradiol may have an effect at first on the metabolism of thyroxine-binding proteins. The concentration and binding capacity of thyroxine-binding proteins may increase as a whole. The fact that T4 half-life is prolonged and free T4 level stays as before in spite of the rise of PBI in estrogen administration might be due to suppressed decomposition of free T4. These results are observed equally in subjects with intact and abnormal thyroid functions, and it is concluded that these phenomena have no relation to the pituitary-thyroid system.
The effects of various doses of conjugated estrogens on modern thyroid function tests were studied in 14 euthyroid menopausal women before and after 6 wk of therapy with each of these daily doses: 0.625 mg, 1.25 mg, 2.5 mg, and, again, 0.625 mg. Serum thyroxine, triiodothyronine, thyroxine binding globulin, and thyrotrophin were measured by radioimmunoassay, free thyroxine by dialysis, and triiodothyronine binding index by a conventional method. Increasing doses of conjugated estrogens led to stepwise elevations of thyroxine, triiodothyronine, thyroxine binding globulin, and the binding index, with a threshold dose below 0.625 mg/day. The peak effect seemed to be between 1.25 and 2.5 mg/day. Free thyroxine and thyrotrophin concentrations did not change at any dose. (23 references.)
The influence of estrogen on the pituitary-thyroid system of the adult rat was determined after sc administration of small daily doses of estradiol benzoate (EB: .004, .016, .064 and .246 μg; 9–11 days) to 26–28 day ovariectomized animals and after pituitary implantation of 17β-estradiol in rats bearing median eminence lesions (18–39 days). It was demonstrated that estradiol has a biphasic action on TSH secretion and thyroid gland activity. Chronic administration of the .064 μg dose of EB produced thyroid hyperplasia. Lower doses of the steroid had no significant effect on thyroid histology, whereas a 4-fold increase in dose (.256 μg) induced histological regression in the gland (accumulation of colloid with reduction in acinar cell height). TSH blood titers and thyroid activity were markedly diminished in spayed ratswith hypothalamic lesions. Intrahypophysial estradiol implants in such animals stimulated thyroid function and significantly elevated TSH levels. Cholesterol implants were ineffective. The implantation of relatively large amounts of estradiol inhibited pituitary-thyroid function. The results clearly indicate that the ovarian hormone has both stimulatory and inhibitory actions TSH secretion by the adenohypophysis. Physiological levels of estradiol promote TSH secretion; it is suppressed in estrogen deficiency excess. The fact that this biphasic effect on TSH can be elicited in rats with lesions in the median eminence supports the view that estrogen acts at the pituitary rather than at the hypothalamic level to influence thyroid function. (Endocrinology 84: 117, 1969)
The influence of estrogen on the pituitary-thyroid system of the adult rat was determined after sc administration of small daily doses of estradiol benzoate (EB: .004, .016, .064 and .246 μg; 9–11 days) to 26–28 day ovariectomized animals and after pituitary implantation of 17β-estradiol in rats bearing median eminence lesions (18–39 days). It was demonstrated that estradiol has a biphasic action on TSH secretion and thyroid gland activity. Chronic administration of the .064 μg dose of EB produced thyroid hyperplasia. Lower doses of the steroid had no significant effect on thyroid histology, whereas a 4-fold increase in dose (.256 μg) induced histological regression in the gland (accumulation of colloid with reduction in acinar cell height). TSH blood titers and thyroid activity were markedly diminished in spayed ratswith hypothalamic lesions. Intrahypophysial estradiol implants in such animals stimulated thyroid function and significantly elevated TSH levels. Cholesterol implants were ineffective. The implantation of relatively large amounts of estradiol inhibited pituitary-thyroid function. The results clearly indicate that the ovarian hormone has both stimulatory and inhibitory actions TSH secretion by the adenohypophysis. Physiological levels of estradiol promote TSH secretion; it is suppressed in estrogen deficiency excess. The fact that this biphasic effect on TSH can be elicited in rats with lesions in the median eminence supports the view that estrogen acts at the pituitary rather than at the hypothalamic level to influence thyroid function. (Endocrinology 84: 117, 1969)
Recent evidence indicates that thyroid function in man may be regulated by stimuli other than circulating levels of thyroid hormone. For example, glucocorticoids, in both physiological and pharmacological doses, appear to play a significant role in acutely altering the release of thyrotropin. This present study was designed to evaluate the possible regulatory effects of other biologically active steroids on thyroid glandular function. Doses of 0.1–0.5 mg ethinyl estradiol (EE) acutely suppressed circulating levels of immunoassayable TSH, while higher doses (3.0 mg) directly inhibited thyroid release. None of these actions of EE appeared to be mediated by alterations in serum cortisol, thyroxine-binding globulin, total thyroxine or free thyroxine. Other biologically active steroids, such as testosterone, progesterone and desoxycorticosterone acetate, in doses ranging from 10 to 20 mg, were ineffective in changing thyroidal iodine release. From this study it would appear that circulating estrogens,...
An immunoadsorption technique employing a rabbit antiserum specific for human serum prealbumin has been devised to remove thyroxine (T(4))-binding prealbumin (TBPA) from serum completely without affecting the T(4)-binding activity of thyroxine-binding globulin (TBG) or the concentration of the other major proteins in serum. As judged from the proportion of T(4) associated with the antigen-antibody precipitate, only about 15% of the endogenous T(4) is bound by TBPA, a value considerably less than that indicated by electrophoretic methods. As judged from the increase in the proportion of free T(4) that followed immunoadsorption of TBPA, TBPA does act as one determinant of the proportion of free T(4) but is far less important than TBG in this respect. A decrease in the T(4)-binding capacity of TBPA cannot solely account for the increase in the proportion of free T(4) in the sera of ill patients, since a comparable increase does not occur in normal sera after complete removal of TBPA. From data obtained in normal and abnormal sera before and after immunoadsorption of TBPA, estimates of the equilibrium constants for the interactions between T(4) and its binding proteins, as they exist in serum, have been derived. The values obtained were: K(ALB), 6.2 x 10(5); K(TBPA), 2.3 x 10(8); and K(TBG), 1.7 x 10(10).
Circulating concentrations of triiodothyronine (T3) were measured in human serum by the method of Sterling et al. (1). Values in control nonpregnant subjects were compared with women in all three trimesters and at term. Concentrations of T3 in blood increased from a mean of 196 ng/100 ml during the first trimester to 299 ng/100 ml in the third trimester. Values during labor averaged 421 ng/100 ml as compared with 193 ng/100 ml in corresponding cord blood. These studies indicated a progressive rise in total T3 concentration during pregnancy that paralleled the increase in circulating thyroxine (T4) and thyroxine binding globulin (TBG) normally observed. They provide further information on the binding of T3 to TBG in vivo and on the interrelationships of T3, T4, and TBG in serum.
The double antibody radioimmunoassay of serum thyroid-stimulating hormone (TSH) allows measurement of circulating levels of the hormone in most normal subjects. The serum TSH level in normal subjects is 1.6 +/- 0.8muU/ml. Patients with non-toxic goitre and acromegaly have normal TSH levels. Values are always raised in hypothyroid patients (with primary thyroid disease) and are significantly lowered in those with hyperthyroidism. Of the many stimuli used in an attempt to raise TSH levels in normal adult subjects only three-synthetic thyrotrophin-releasing hormone, ethinyloestradiol, and carbimazole plus iodides-have been effective. The major clinical application of the TSH immunoassay lies in the diagnosis of minor degrees of hypothyroidism. An impaired response of serum TSH to synthetic thyrotrophin-releasing hormone should also help in the diagnosis of hypopituitarism affecting TSH production.
This research shows that the adenohypophysis of the adolescent differs from that of the adult by sensibility variations vis-a-vis of LHRH and TRF in relation to the growing rates of the ovarian steroids and their actions on the steroid and peptide receptors of the hypophyseal cells. During the first few years after the menarche, the increasing secretion of estradiol provokes a greater secretion of the four adenohypophyseal hormones both before and after LHRH and TRF. As the adolescent grows older, the increasing amounts of progesterone in relation to the increasing amounts of estradiol reduce the sensibility of the hypophysis to the releasing hormones; the release of its trophic hormones and prolactin is diminished. This would indicate that the hypothalamic-pituitary-ovarian system undergoes progressive maturation for a number of years after the menarche. The sensibility of the adolescent pituitary, ovary, and thyroid during the luteal phase of the first menstrual cycle after oral contraceptives have been discontinued is the same in girls who have taken oral contraceptives for 24 months or longer as it is in girls who are five to six years after the menarche and have not taken oral contraceptives.
Goitre occurs primarily in women. As oestrogens may be an aetiologic factor, the use of oral contraceptives (OC) could be associated with an increased risk of goitre. This is supported by experimental data, but a recent population study suggested decreased thyroid volumes among users of OC.
Cross-sectional, observational study.
A random population sample of 3712 women from two Danish cities.
Ultrasound and clinical examination of the thyroid, measurement of serum TSH, T3, T4 and thyroglobulin, and personal interviews with registration of use of OC or post-menopausal oestrogen therapy. Data were analysed in linear models and logistic regression adjusting for age and iodine status.
Thyroid volume was lower among users than non-users of OC, 11.1 ml vs. 12.1 ml (P < 0.001). Use of OC was correspondingly associated with a reduced prevalence of thyroid enlargement on ultrasound (odds ratio 0.53, 95% confidence interval 0.37-0.74) and of palpable and visible goitre (OR 0.24, 95% CI 0.07-0.81). Serum TSH was 1.24 mU/l in non-users of OC and 1.35 mU/l in users (P = 0.002). The percentage of goitre cases prevented by OC compared to a hypothetical population without use of OC was 29%. Post-menopausal oestrogen therapy showed similar, but statistically non-significant, associations.
Use of oral contraceptives was associated with a lower thyroid volume and reduced risk of goitre, and clinically evident goitre was four times more frequent among non-users than among users of oral contraceptives.
An apparent paradox in thyroidal economy is presented by the normally pregnant woman. Thus, there occurs during pregnancy thyroidal hyperplasia, augmentation of the thyroidal accumulation of radioiodine, and an increase in the concentration of circulating thyroid hormone (1–5). These changes, ordinarily associated with the thyrotoxic state, are not accompanied during pregancy by symptomatic stigmata of thyrotoxicity nor by increases in basal oxygen consumption beyond those which have been attributed to fetal needs (6).
Increase of serum thyroxine binding globulin (TBG) resulting from estrogen action may lead to problems in thyroid diagnostics. The aim of the present study was to define the most diagnostically reliable thyroid parameters in women exposed to differentially elevated estrogens. Sera of three groups of healthy women were analyzed: women taking no medicine (controls), those taking oral contraceptives and pregnant women (in weeks 16 or 32 of gestation). All women involved in the study lived in a moderately iodine-deficient geographical area. Thyroid stimulating hormone (TSH), TBG, total thyroxine (T4), total tri-iodothyronine (T3) and free T3 were determined and free T4 indices (total T4 x T3 uptake; total T4/thyroxine binding capacity (TBC); total T4/TBG) were calculated. Free T4 was measured simultaneously with a one-step T4-analog enzyme-linked immunosorbent assay (ELISA), a labeled T4 antibody radioimmunoassay (RIA), and a two-step microparticle enzyme immunoassay (MEIA). Estrogen-dependent differences were found in all investigated parameters; however, they remained in the reference interval for TSH, total T4 x T3 uptake, total T4/TBC,free T3 and free T4 MEIA. It was concluded that simultaneous estimations of free T4 and free T3 should follow a primary TSH measurement. The necessity of a distinct reference range has emerged for free thyroid hormones in midterm and late pregnancy as well as in the use of oral contraceptives, especially in iodine-deficient areas.
There are few studies in the literature investigating pituitary size at an age consistent with the menopause and the influence of estrogen replacement therapy on pituitary height. We therefore evaluated the effect of estrogen on pituitary size, prolactin and thyroid-stimulating hormone (TSH) levels in menopausal women. Sixty-nine women were evaluated, 47 using estrogen and 22 controls. The measure of pituitary height was obtained from magnetic resonance imaging. Hormone evaluation did not show a statistically significant difference in mean (+/-standard deviation) prolactin level between the group using estrogen (7.6 +/- 6.4 ng/ml) and controls (5.1 +/- 3.4 ng/ml; p = 0.15), yet mean TSH level was significantly higher in the treated group (1.9 +/- 1.5 vs. 1.2 +/- 0.9 microU/ml; p = 0.03). Mean pituitary height in the estrogen-treated group (5.2 +/- 1.4 mm) was greater than in the controls (4.4 +/- 1.4 mm; p = 0.04). However, when such potential confounders as age, prolactin and TSH levels, treatment and duration of estrogen exposure were considered, the magnitude of difference did not attain significance. In conclusion, estrogen may play a role in pituitary size, since a mean difference in pituitary height, estimated as 0.78 mm, was detected between the groups in favor of the estrogen-treated group. This suggestion can be investigated in further studies.