THYROID Volume 2, Number 1, 1992 Mary Ann Liebert, Inc., Publishers
Goiter and
Pregnancy:
A New Insight into Old Problem: Comment
an
GEORG HENNEMANN
The is
study by a
serum T4 but no change in serum T3 and TSH, and thyroid weight and thyroid blood flow decreased. Apparently, modulation by iodine alone could change thyroid blood flow and weight independent of serum TSH. Similar conclusions were drawn from studies in humans (2). When 10 healthy volunteers were given diets containing low, normal and high amounts of iodine, it appeared that there was an inverse relationship be¬ tween intake and thyroid blood flow independent of serum TSH. In an additional study, the group reported that in rats treated with propylthiouracil or methimazole, the ratio úf vascular conductance/thyroid mass was elevated (3). There is no eleva¬ tion of this ratio when plasma TSH is elevated, e.g.. by TRH treatment, in the absence of thyrostatic drugs, and thyrostatic drugs in the presence of thyroid hormone treatment have no
Glinoer and Lemone is
prospective study
important because it large scale, using a sensitive thyroid volume (TV). The use of
increase in
on a
objective method to measure
the sensitive TSH assay and concomitant measurement of hCG render the results more interesting. In essence, the authors found that in an area of moderate iodine intake, normal pregnancy, especially in women with preexisting thyroid disorders, induces an increase in TV. They report that increase in TV is associated with biochemical features of thyroid stimulation, i.e., an in¬ creased serum T3/T4 ratio. This increased stimulation is affected by slightly elevated serum TSH levels at delivery or a high hCG concentration predominantly during the first trimester of preg¬ nancy. After delivery, regression of goiter is not complete. The authors find evidence in the literature and in their own results that a higher daily iodine intake, between 150 µg and 200 µg/day, could prevent most goiter formation. Studies are cited showing that with adequate iodine intake there is still a small increase in TV. A significant correlation is found between serum-free T4 and hCG, suggesting that hCG, besides TSH, plays a physiologic role in setting the free T4 serum concentration. This phenome¬ non may be of particular importance during the first trimester of pregnancy. Evidently, hCG stimulation sometimes leads to blunted serum TSH levels, again predominantly in the first trimester, and even sometimes leads to overt thyrotoxicosis. This phenomenon occurred in 1.4% of pregnancies, and this possibility should be kept in mind in evaluating thyroid function during gestation. The finding that women with underlying thyroid abnormalities are at particular risk of goiter and nodule formation is of clinical importance. The fact that volumetric changes in the gland are associated with biochemical features of thyroid stimulation suggests that the increase in TV represents true goitrogenesis rather than vascular swelling alone. Michalakiewicz et al. ( 1 ) reported that rats fed a low iodine diet, resulting in a slight decrease of plasma and TSH levels, exhibited an T4 but unaltered plasma increased thyroid weight and also an increased thyroid blood flow. In contrast, rats fed a high iodine diet showed a slight
effect on this ratio. The authors conclude that the effect of TSH elevation in combination with antithyroid drug treatment on relative (to thyroid mass) and absolute increase in thyroid blood flow is caused by the concomitant presence of TSH stimulation and iodine deficiency induced by thyrostatic drug treatment. The question, therefore, should be raised: Apart from possible increase in thyroid mass during pregnancy in areas of moderate iodine intake, is the increase in TV caused by increased blood flow of the thyroid? Maybe women with preexisting thyroid disorders, particularly autoimmune thyroid disorders known to induce iodine deficiency in the thyroid, are even more suscepti¬ ble to an increase in thyroid blood flow during pregnancy. The pathogenesis of goiter formation during pregnancy in the human may be even more complex. The presence of receptors binding epidermal growth factor (EGF) have been identified on human thyroid membrane preparations (4), and it has been suggested from in vitro studies that EGF stimulates the genera¬ tion of" new follicles (5). Serum EGF is increased in human pregnancy (6), and EGF is secreted in increased amounts during pregnancy (7). It is conceivable that EGF and maybe other growth factors play a role in goiter formation during gestation. It has been shown that catecholamincs stimulate the thyroid gland (8) and that vasointestinal peptide (VIP) stimulates thyroid blood flow but not thyroid hormone synthesis (9). However,
Academisch Ziekenhuis. Rotterdam, The Netherlands.
71
HENNEMANN
72 these mechanisms probably do not play a role in goiter formation pregnancy, since neither catacholamines nor VIP levels are increased in pregnancy (10,11). The possible detrimental effect of iodine deficiency on intel¬ lectual and somatic development of the fetus in areas of moder¬ ate iodine intake bears consideration. In the 1990 study by Glinoer et al. (their ret". 18), they discuss the finding, confirmed by others, that free T4 and T3 levels decrease by about 30% in late pregnancy as compared to early pregnancy and to nonpreg¬ nant controls. It is now established that T4 (and maybe also T3) is transferred to the fetus (12). It also has been shown that during fetal development of rats, T4 is the main source of T3 in the brain of the fetus (13). Although an adaptive mechanism exists in the brain to counteract the decreased supply of T4, it is not known if this mechanism is fully compensatory. In areas of iodine deficiency and cretinism (but also where cretinism is absent), apparently euthyroid normal children show subtle abnormalities in neuromotor, cognitive, and hearing abilities (14-16). There¬ fore, one should consider the possibility that children born in areas of higher, but still subnormal, iodine intake are at risk of similar abnormalities when their mother's intake is near the lower range for that region. For instance, the developmental abnormalities cited by Boyages et al. (15) were found to be present in an area with iodine intake up to 70 µg per day (mean intake 31.3 ± 18.7 µg iodine/day). Some overlap in iodine intake may be present between this area and that studied by Glinoer et al., since they reported (their ref. 18) an intake between 50 µg and 100 µg per day in more than 90% of the cohort. Their suggestion to supply iodine to pregnant women in these areas is, therefore, important not only to prevent goiter formation but also to prevent possible permanent damaging effects to the offspring.
during
REFERENCES 1. Michalakiewicz M, Huffman LJ, Connors JM, Hedge GA 1989 Alterations in thyroid blood flow induced by varying levels of
iodine intake in the rat. Endocrinology 125:54-60. 2. Arntzenius AB, Smit LJ, Schipper I, van der Heide D. Meinders AE 1991 Inverse relation between iodine intake and thyroid blood flow: Color Doppler How imaging in euthyroid humans. J Clin Endocrinol Metab 73:1051 -1055. 3. Connors JM, Huffman LJ. Michalakiewicz M. Chang BSH. Dey RD, Hedge GA 1991 Thyroid vascular conductance: Differential effects of elevated plasma thyrotropin (TSH) induced by treatment with thioamides or TSH-releasing hormone. Endocrinology 129:117-125. 4. Kamamuri A. Abey Y. Yajima Y, Manabe Y. Ito 1989 Epider¬ mal growth factor receptors in plasma membranes of normal and diseased human thyroid glands. J Clin Endocrinol Metab 68:899.
5. Westmark . Nilsson M. Ebendal , Westmark 1991 Thyrocyte migration and hystiotypic follicle regeneration are promoted by epidermal growth factor in primary culture of thyroid follicles in collagen gel. Endocrinology 129:2180-2186. 6. Anees IG 1973 Serum concentrations of epidermal growth factor in human pregnancy. Am J Obstet Gynecol 115:257-262. 7. Hofmann GE. Verao Ch. Braun MJ. Murray LF. Schultz GF. Siddiqi TA 1988 Epidermal growth factor in urine of nonpregnant women and pregnant women throughout pregnancy and at delivery. J Clin Endocrinol Metab 66:119-123. 8. Melander A 1986 Autonomie nervous control: Adrenergic. cholinergic. and peptidergic regulation. In: Ingbar SH. Braverman LE (eds) Werner's The Thyroid. JB Lippincott Co, Philadelphia, pp 331-338. 9. Huffman L, Hedge G A 1986 Effects of vasoactive intestinal peptide on thyroid blood How and circulating thyroid hormone levels in the rat. Endocrinology 118:550-557. 10. Pedersen EB. Rasmussen AB. Christensen NH. Johannesen P. Lauritsen JG, Kristensen S. Wohlert M 1982 Plasma noradrenaline and adrenaline in pre-eclampsia essential hypertension in preg¬ nancy and normotensive pregnant control subjects. Acta Endocrinol (Copenh) 99:594-600. 11. Jenssen TG. Haukland HH. Vonen B. Forholmen J. Burhol PG, Maltau JM 1988 Changes in postprandial release patterns of gastrointestinal hormones in late pregnancy and in the early post¬ partum period. Br J Obstet Gynaecol 95:565-570. 12. VulsmaT, Gons MH. de VijlderJJM 1989 Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. Engl J Med 321:13—15. 13. Silva JE, Larsen PR 1982 Comparison of iodothyronine 5'-deiodinase and other thyroid-hormone-dependent enzyme activities in the cerebral cortex of hypothyroid neonatal rat: Evidence for adaptation lo hypothyroidism. J Clin Invest 70:1110-1123. 14. Yan-Yoe W, Shu-Hua Y 1985 Improvement in hearing among otherwise normal schoolchildren in iodine-deficient areas of Guizhou China, following use of iodized salt. Lancet 2:518-519. 15. Boyages SC, Collins JK, Maberly GF. Jupp JJ. Morris J, Eastman CJ 1989 Iodine deficiency impairs intellectual and neuromotor development in apparently normal persons. Med J Austr 150:676-682. 16. Vermiglio F. Sidoti M. Defino Cchiaro M, BattiatoS, LoPresti VP. BenvengaS. Trimarchi F 1990 Defective neuromotor and cognitive ability in iodine-deficient schoolchildren of an endemic goiter region in Sicily. J Clin Endocrinol Metab 70:379-384.
Address reprint requests to: Dr. Georg Hennemann Academish Ziekenhuis Rotterdam dr. Molewaterplein 40 3015 GD Rotterdam The Netherlands
Goiter and
Pregnancy:
A New Insight into Old Problem: Comment
an
GEORG HENNEMANN
The is
study by a
serum T4 but no change in serum T3 and TSH, and thyroid weight and thyroid blood flow decreased. Apparently, modulation by iodine alone could change thyroid blood flow and weight independent of serum TSH. Similar conclusions were drawn from studies in humans (2). When 10 healthy volunteers were given diets containing low, normal and high amounts of iodine, it appeared that there was an inverse relationship be¬ tween intake and thyroid blood flow independent of serum TSH. In an additional study, the group reported that in rats treated with propylthiouracil or methimazole, the ratio úf vascular conductance/thyroid mass was elevated (3). There is no eleva¬ tion of this ratio when plasma TSH is elevated, e.g.. by TRH treatment, in the absence of thyrostatic drugs, and thyrostatic drugs in the presence of thyroid hormone treatment have no
Glinoer and Lemone is
prospective study
important because it large scale, using a sensitive thyroid volume (TV). The use of
increase in
on a
objective method to measure
the sensitive TSH assay and concomitant measurement of hCG render the results more interesting. In essence, the authors found that in an area of moderate iodine intake, normal pregnancy, especially in women with preexisting thyroid disorders, induces an increase in TV. They report that increase in TV is associated with biochemical features of thyroid stimulation, i.e., an in¬ creased serum T3/T4 ratio. This increased stimulation is affected by slightly elevated serum TSH levels at delivery or a high hCG concentration predominantly during the first trimester of preg¬ nancy. After delivery, regression of goiter is not complete. The authors find evidence in the literature and in their own results that a higher daily iodine intake, between 150 µg and 200 µg/day, could prevent most goiter formation. Studies are cited showing that with adequate iodine intake there is still a small increase in TV. A significant correlation is found between serum-free T4 and hCG, suggesting that hCG, besides TSH, plays a physiologic role in setting the free T4 serum concentration. This phenome¬ non may be of particular importance during the first trimester of pregnancy. Evidently, hCG stimulation sometimes leads to blunted serum TSH levels, again predominantly in the first trimester, and even sometimes leads to overt thyrotoxicosis. This phenomenon occurred in 1.4% of pregnancies, and this possibility should be kept in mind in evaluating thyroid function during gestation. The finding that women with underlying thyroid abnormalities are at particular risk of goiter and nodule formation is of clinical importance. The fact that volumetric changes in the gland are associated with biochemical features of thyroid stimulation suggests that the increase in TV represents true goitrogenesis rather than vascular swelling alone. Michalakiewicz et al. ( 1 ) reported that rats fed a low iodine diet, resulting in a slight decrease of plasma and TSH levels, exhibited an T4 but unaltered plasma increased thyroid weight and also an increased thyroid blood flow. In contrast, rats fed a high iodine diet showed a slight
effect on this ratio. The authors conclude that the effect of TSH elevation in combination with antithyroid drug treatment on relative (to thyroid mass) and absolute increase in thyroid blood flow is caused by the concomitant presence of TSH stimulation and iodine deficiency induced by thyrostatic drug treatment. The question, therefore, should be raised: Apart from possible increase in thyroid mass during pregnancy in areas of moderate iodine intake, is the increase in TV caused by increased blood flow of the thyroid? Maybe women with preexisting thyroid disorders, particularly autoimmune thyroid disorders known to induce iodine deficiency in the thyroid, are even more suscepti¬ ble to an increase in thyroid blood flow during pregnancy. The pathogenesis of goiter formation during pregnancy in the human may be even more complex. The presence of receptors binding epidermal growth factor (EGF) have been identified on human thyroid membrane preparations (4), and it has been suggested from in vitro studies that EGF stimulates the genera¬ tion of" new follicles (5). Serum EGF is increased in human pregnancy (6), and EGF is secreted in increased amounts during pregnancy (7). It is conceivable that EGF and maybe other growth factors play a role in goiter formation during gestation. It has been shown that catecholamincs stimulate the thyroid gland (8) and that vasointestinal peptide (VIP) stimulates thyroid blood flow but not thyroid hormone synthesis (9). However,
Academisch Ziekenhuis. Rotterdam, The Netherlands.
71
HENNEMANN
72 these mechanisms probably do not play a role in goiter formation pregnancy, since neither catacholamines nor VIP levels are increased in pregnancy (10,11). The possible detrimental effect of iodine deficiency on intel¬ lectual and somatic development of the fetus in areas of moder¬ ate iodine intake bears consideration. In the 1990 study by Glinoer et al. (their ret". 18), they discuss the finding, confirmed by others, that free T4 and T3 levels decrease by about 30% in late pregnancy as compared to early pregnancy and to nonpreg¬ nant controls. It is now established that T4 (and maybe also T3) is transferred to the fetus (12). It also has been shown that during fetal development of rats, T4 is the main source of T3 in the brain of the fetus (13). Although an adaptive mechanism exists in the brain to counteract the decreased supply of T4, it is not known if this mechanism is fully compensatory. In areas of iodine deficiency and cretinism (but also where cretinism is absent), apparently euthyroid normal children show subtle abnormalities in neuromotor, cognitive, and hearing abilities (14-16). There¬ fore, one should consider the possibility that children born in areas of higher, but still subnormal, iodine intake are at risk of similar abnormalities when their mother's intake is near the lower range for that region. For instance, the developmental abnormalities cited by Boyages et al. (15) were found to be present in an area with iodine intake up to 70 µg per day (mean intake 31.3 ± 18.7 µg iodine/day). Some overlap in iodine intake may be present between this area and that studied by Glinoer et al., since they reported (their ref. 18) an intake between 50 µg and 100 µg per day in more than 90% of the cohort. Their suggestion to supply iodine to pregnant women in these areas is, therefore, important not only to prevent goiter formation but also to prevent possible permanent damaging effects to the offspring.
during
REFERENCES 1. Michalakiewicz M, Huffman LJ, Connors JM, Hedge GA 1989 Alterations in thyroid blood flow induced by varying levels of
iodine intake in the rat. Endocrinology 125:54-60. 2. Arntzenius AB, Smit LJ, Schipper I, van der Heide D. Meinders AE 1991 Inverse relation between iodine intake and thyroid blood flow: Color Doppler How imaging in euthyroid humans. J Clin Endocrinol Metab 73:1051 -1055. 3. Connors JM, Huffman LJ. Michalakiewicz M. Chang BSH. Dey RD, Hedge GA 1991 Thyroid vascular conductance: Differential effects of elevated plasma thyrotropin (TSH) induced by treatment with thioamides or TSH-releasing hormone. Endocrinology 129:117-125. 4. Kamamuri A. Abey Y. Yajima Y, Manabe Y. Ito 1989 Epider¬ mal growth factor receptors in plasma membranes of normal and diseased human thyroid glands. J Clin Endocrinol Metab 68:899.
5. Westmark . Nilsson M. Ebendal , Westmark 1991 Thyrocyte migration and hystiotypic follicle regeneration are promoted by epidermal growth factor in primary culture of thyroid follicles in collagen gel. Endocrinology 129:2180-2186. 6. Anees IG 1973 Serum concentrations of epidermal growth factor in human pregnancy. Am J Obstet Gynecol 115:257-262. 7. Hofmann GE. Verao Ch. Braun MJ. Murray LF. Schultz GF. Siddiqi TA 1988 Epidermal growth factor in urine of nonpregnant women and pregnant women throughout pregnancy and at delivery. J Clin Endocrinol Metab 66:119-123. 8. Melander A 1986 Autonomie nervous control: Adrenergic. cholinergic. and peptidergic regulation. In: Ingbar SH. Braverman LE (eds) Werner's The Thyroid. JB Lippincott Co, Philadelphia, pp 331-338. 9. Huffman L, Hedge G A 1986 Effects of vasoactive intestinal peptide on thyroid blood How and circulating thyroid hormone levels in the rat. Endocrinology 118:550-557. 10. Pedersen EB. Rasmussen AB. Christensen NH. Johannesen P. Lauritsen JG, Kristensen S. Wohlert M 1982 Plasma noradrenaline and adrenaline in pre-eclampsia essential hypertension in preg¬ nancy and normotensive pregnant control subjects. Acta Endocrinol (Copenh) 99:594-600. 11. Jenssen TG. Haukland HH. Vonen B. Forholmen J. Burhol PG, Maltau JM 1988 Changes in postprandial release patterns of gastrointestinal hormones in late pregnancy and in the early post¬ partum period. Br J Obstet Gynaecol 95:565-570. 12. VulsmaT, Gons MH. de VijlderJJM 1989 Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. Engl J Med 321:13—15. 13. Silva JE, Larsen PR 1982 Comparison of iodothyronine 5'-deiodinase and other thyroid-hormone-dependent enzyme activities in the cerebral cortex of hypothyroid neonatal rat: Evidence for adaptation lo hypothyroidism. J Clin Invest 70:1110-1123. 14. Yan-Yoe W, Shu-Hua Y 1985 Improvement in hearing among otherwise normal schoolchildren in iodine-deficient areas of Guizhou China, following use of iodized salt. Lancet 2:518-519. 15. Boyages SC, Collins JK, Maberly GF. Jupp JJ. Morris J, Eastman CJ 1989 Iodine deficiency impairs intellectual and neuromotor development in apparently normal persons. Med J Austr 150:676-682. 16. Vermiglio F. Sidoti M. Defino Cchiaro M, BattiatoS, LoPresti VP. BenvengaS. Trimarchi F 1990 Defective neuromotor and cognitive ability in iodine-deficient schoolchildren of an endemic goiter region in Sicily. J Clin Endocrinol Metab 70:379-384.
Address reprint requests to: Dr. Georg Hennemann Academish Ziekenhuis Rotterdam dr. Molewaterplein 40 3015 GD Rotterdam The Netherlands
