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Wilmar M Wiersinga

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T4) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T4/tri-iodothyronine (T3) combination therapy over T4 monotherapy. However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T4 (FT4) to free T3 (FT3) concentrations. Development of a sustained-release T3 preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT4–FT3 ratio's throughout 24 h. Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T4/T3 combination therapy than on T4 monotherapy.

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Wilmar M Wiersinga

About 5%–10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03–≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.

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Grigoris Effraimidis and Wilmar M Wiersinga

The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained – at least in part – by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD. As twin studies indicate that genes contribute for 70% of AITD, it follows that there must be many more loci, each of them contributing a little. While the genetic studies have clarified why various autoimmune diseases so often cluster in the same patient, the molecular mechanism of action of these genetic polymorphisms (frequently located in introns) has hardly been explained. Polymorphisms in AITD susceptibility genes may become helpful in clinical practice, e.g. in assessing risk of recurrent Graves' hyperthyroidism (GH) after a course of antithyroid drugs. Moderate alcohol intake decreases the risk on overt GH and overt Hashimoto's hypothyroidism. Current smokers – as well known – are at increased risk for Graves' disease, but – surprisingly – at diminished risk for Hashimoto's thyroiditis. Low selenium and low vitamin D levels might increase the risk of developing AITD, but data are still inconclusive. Current options for preventive interventions in subjects at risk to develop AITD are very limited.

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Ria Adriaanse, Johannes A Romijn, Erik Endert and Wilmar M Wiersinga

The nocturnal TSH surge was studied in controls, in 34 patients with hypothalamic/pituitary disease and in 21 patients with primary hypothyroidism. It was absent in 5/12 hypothyroid patients and in 5/22 euthyroid patients with hypothalamic/pituitary disease (42% vs 23%. NS). Central hypothyroidism relative to euthyroidism was associated with a lower absolute (0.3±0.4 vs 0.9±1.0 mU/l, p<0.05) and relative (24±31 vs 63±51%, p<0.05) nocturnal rise in TSH. In primary hypothyroidism, the nocturnal TSH surge was absent in eight often patients with overt, in one of five patients with mild and in none of six patients with subclinical hypothyroidism. The relative nocturnal rise in TSH was normal in mild (54±33%) and subclinical (92±69%), but decreased in overt hypothyroidism (2±10%). Plasma T4 was positively and 09.00 plasma TSH negatively related to the relative nocturnal TSH surge in primary hypothyroidism, but not in central lesions. In both conditions, however, a positive relationship was observed between the relative nocturnal TSH surge and the relative increase of TSH to TRH. In conclusion: (a) The nocturnal TSH surge is usually absent in overt hypothyroidism but present in mild primary hypothyroidism and equivocal in central hypothyroidism. This limits its usefulness as an adjunct in the diagnosis of central hypothyroidism. (b) The magnitude of the nocturnal TSH surge in patients with hypothalamic/pituitary disease or primary hypothyroidism is directly related to the TSH response to TRH, and thus appears to be determined by the directly releasable TSH pool of the pituitary.

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Maria F Wesche, Monique M Tiel-v-Buul, Nico J Smits and Wilmar M Wiersinga

Wesche MF, Tiel-v-Buul MM, Smits NJ, Wiersinga WM. Reduction in goiter size by 131I therapy in patients with non-toxic multinodular goiter. Eur J Endocrinol 1995;132:86–7. ISSN 0804–4643

A retrospective follow-up study of 131I treatment was performed in 10 females (median age 48 years, range 40–74 years) with non-toxic multinodular goiter. The median dose of 131I given was 20 mCi (range 14–65 mCi). Thyroid volume was measured by ultrasonography. The median follow-up period was 26 months (range 12–68 months). Nine patients had a reduction of goiter size: thyroid volume decreased from 88 ± 14.9 ml (mean±sem) to 49 ± 10.9 ml 1 year after 131I treatment. The relative decrease of goiter size was 48% after 1 year (N = 9) and 59% after 2 years (N = 5). One patient did not respond and was referred for operation. Side effects were mild spontaneously resolving radiation thyroiditis in one patient and subclinical hypothyroidism in four patients. In conclusion, 131I treatment of non-toxic goiter is an effective treatment at the expense of post-radiation (subclinical) hypothyroidism.

Maria F Wesche, Academic Medical Center, University of Amsterdam, Department of Internal Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

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Grigoris Effraimidis, Klaus Badenhoop, Jan G P Tijssen and Wilmar M Wiersinga


Vitamin D deficiency has been identified as a risk factor for a number of autoimmune diseases including type 1 diabetes and multiple sclerosis.


We hypothesized that low levels of vitamin D are related to the early stages of autoimmune thyroid disease (AITD).


Two case–control studies were performed. In the cross-sectional study A, euthyroid subjects with genetic susceptibility for AITD but without thyroid antibodies were compared with controls. Cases were subjects from the Amsterdam AITD cohort (euthyroid women who had first- or second-degree relatives with overt AITD) who at baseline had normal TSH and no thyroid antibodies; controls were healthy women examined at the same period. In the longitudinal study B, subjects who developed de novo thyroid peroxidase antibody (TPO-Ab) were compared with those who did not. Cases and controls were subjects from the Amsterdam AITD cohort who at baseline had normal TSH and no thyroid antibodies and during follow-up developed TPO-Ab (cases) or remained without thyroid antibodies (controls). Controls in both studies were matched for age, BMI, smoking status, estrogen use, month of blood sampling, and in study B for the duration of follow-up.


Serum 25(OH)D levels were as follows: study A: 21.0±7.9 vs 18.0±6.4 ng/ml (78 cases vs 78 controls, P=0.01); study B: baseline, 22.6±10.3 vs 23.4±9.1; follow-up 21.6±9.2 vs 21.2±9.3 ng/ml (67 cases vs 67 controls, NS).


Early stages of thyroid autoimmunity (in study A genetic susceptibility and in study B development of TPO-Ab) are not associated with low vitamin D levels.

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Peter H Bisschop, Arno W Toorians, Erik Endert, Wilmar M Wiersinga, Louis J Gooren and Eric Fliers

Objective: Estrogen and androgen administration modulate the pituitary–thyroid axis through alterations in thyroid hormone-binding globulin (TBG) metabolism, but the effects of sex steroids on extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in humans are unknown.

Design and methods: We studied 36 male-to-female and 14 female-to-male euthyroid transsexuals at baseline and after 4 months of hormonal treatment. Male-to-female transsexuals were treated with cyproterone acetate (CA) 100 mg/day alone (n=10) or in combination with either oral ethinyl estradiol (or-EE) 100 μg/day (n=14) or transdermal 17β-estradiol (td-E) 100 μg twice a week (n=12). Female-to-male transsexuals were treated with i.m. testosterone 250 mg twice a week. A t-test was used to test for differences within groups and ANOVAwith post hoc analysis to test for differences between the groups.

Results: Or-EE increased TBG (100 ± 12%, P<.001) and testosterone decreased TBG (−14 ± 4%, P =0.01), but free T4 did not change. Td-E and CA did not affect TBG concentrations. TSH was not different between groups at baseline or after treatment. CA decreased T3/T4 ratios (−9 ± 3%, P=0.04), suggesting that T4 to T3 conversion was lower. Testosterone increased T3/T4 ratios (30 ± 9%, P=0.02), which probably reflects higher T4 to T3 conversion.

Conclusion: Oral but not transdermal estradiol increases TBG, whereas testosterone lowers TBG. Testosterone increases T3/T4 ratios. Estradiol does not affect T3/T4 ratios, irrespective of the route of administration.

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Grigoris Effraimidis, Thea G A Strieder, Jan G P Tijssen and Wilmar M Wiersinga


To evaluate the progression in time from euthyroidism to overt autoimmune hypothyroidism or to overt autoimmune hyperthyroidism.

Subjects and methods

The design is that of a nested case–control study within the prospective Amsterdam autoimmune thyroid disease (AITD) cohort study in which 790 healthy euthyroid women with at least one first or second degree relative with documented AITD were followed for 5 years. Thyroid function tests were assessed annually. Contrast between cases (overt hypothyroidism – TSH>5.7 mU/l and free thyroxine (FT4)<9.3 pmol/l and overt hyperthyroidism – TSH<0.4 mU/l and FT4>20.1 pmol/l, also referred to as events) and controls (matched for age and duration of follow-up).


At baseline, the 38 hypothyroid cases had already higher TSH and lower FT4 concentrations than their 76 controls, and the difference between both the groups persisted 1 year before occurrence of the event. In contrast, neither TSH nor FT4 values differed between the 13 hyperthyroid cases and their 26 controls at baseline or 1 year before the event. The prevalence of thyroid peroxidase-Ab was higher in both hypothyroid and hyperthyroid cases than in controls. At the time of event, hypothyroid cases were less common among current smokers (P=0.083) and more common in the postpartum period (P=0.006) than their controls, whereas hyperthyroid cases were pregnant more frequently (P=0.063).


The data suggest that progression toward overt autoimmune hypothyroidism is a gradual process taking several years, but in contrast overt autoimmune hyperthyroidism develops faster in terms of months.

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Peter W Potgieser, Wilmar M Wiersinga, Noortje I Regensburg and Maarten P Mourits


To describe volumes of orbital fat (FV) and extraocular muscles (MV) in Graves' orbitopathy (GO) as a function of the duration of GO.


i) Cross-sectional survey among 95 consecutive patients with untreated GO who had been referred to the combined thyroid–eye clinics of our university hospital. ii) Longitudinal survey among 39 of the 95 patients who did not receive any therapeutic intervention and were followed for 1 year.


A computed tomography (CT)-based and well-validated method for calculating orbital soft tissues. In order to neutralize sex differences, results are expressed as ratios of FV:orbital volume (OV) and MV:OV.


i) Patients with GO duration of >1 year had greater FV:OV (0.65 vs 0.55, P=0.004), similar MV:OV (0.22 vs 0.21, not significant (NS)), and more proptosis (22 mm vs 21 mm, P=0.03) as compared to those with shorter duration. ii) As compared to baseline, after 1 year, FV:OV had increased (0.56 vs 0.63, P=0.000), MV:OV had not changed (0.19 vs 0.19, NS), proptosis was higher (20 mm vs 21 mm, P=0.003), and clinical activity scores had become lower (2 vs 1, P=0.02) (median values).


CT images show that a longer duration of GO is associated with a higher orbital FV. Extraocular MV, however, is not associated with GO duration; rather, it is related to the severity of GO.

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Ria Adriaanse, Georg Brabant, Erik Endert, Frederique J Bemelman and Wilmar M Wiersinga

Adriaanse R, Brabant G, Endert E, Bemelman FJ, Wiersinga WM. Pulsatile thyrotropin and prolactin secretion in a patient with mixed thyrotropin- and prolactin-secreting pituitary adenoma. Eur J Endocrinol 1994;130:113–20. ISSN 0804–4643

The circadian and pulsatile thyrotropin (TSH) and prolactin (PRL) release was investigated in a patient with slight hyperthyroidism due to a mixed TSH- and PRL-secreting pituitary adenoma. Blood was withdrawn every 10 min for 24 h (before and after medical treatment); pulse characteristics were analyzed by Desade and Cluster programs (values as mean±sd). The inappropriately high mean 24-h TSH concentration of 3.55 ±0.31 mU/l was associated with a higher mean 24-h TSH pulse amplitude but unaltered mean 24-h TSH pulse frequency relative to healthy controls. The nocturnal TSH surge (absolute surge 0.5 mU/l, relative surge 16%) was low, related to a loss of the usual nocturnal increase of TSH pulse amplitude and TSH pulse frequency. Chronic treatment with octreotide resulted in a modest clinical and biochemical improvement of the hyperthyroid state; addition of bromocriptine at a later stage had no further beneficial effect. At the end of the follow-up period the mean 24-h TSH paradoxically had increased to 5.33 ±0.81 mU/l. The nocturnal TSH surge also increased (absolute surge 1.9 mU/l, relative surge 42%), but circadian changes in TSH pulsatility remained absent. In the untreated period the increased mean 24-h PRL concentration of 234 ± 24 μg/l was associated with an increased mean 24-h PRL amplitude, whereas the 24-h PRL pulse frequency (N = 4) was lower relative to controls. No circadian PRL rhythm was present. After octreotide and bromocriptine treatment the mean 24-h PRL concentration and mean 24-h PRL pulse amplitude were unchanged, but a clear nocturnal increase of PRL now was observed. Analysis of the temporal coupling between TSH and PRL release by bivariate autoregressive modeling revealed significant cross-correlations in all three periods investigated (coefficients in the range 0.34–0.76, median 0.52; p<0.01) between TSH and PRL concentrations with a lag time of 10–20 min. We conclude that pulsatile TSH and PRL release in this mixed TSH- and PRL-secreting pituitary adenoma was autonomous in nature. The observed dampening of the nocturnal increase of TSH and PRL is putatively related to a lack of TRH receptors in these tumors. The observed co-secretion of TSH and PRL suggests synthesis of both hormones by the same cell.

R Adriaanse, Department of Endocrinology F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands