THYROID FUNCTION IN EXPERIMENTAL AND CLINICAL UNDERNUTRITION Thyroidal activity is depressed in both clinical and experimental undernutrition probably due to hyposecretion of hypothalamic th yroid-releasinghormone. Key Words: thyroid function, thyroid-stimulating hormone, thyroxine, thyrotropin-releasing hormone, caloric deprivation, neonatal rat, infantile malnutrition
A recent review' commented that there was general agreement from measurement of plasma hormone levels and metabolic rates that thyroidal function i s depressed in malnutrition. A point of interest which remains unresolved is whether thyroidal hormone secretion i s depressed ab initio and so causes a low rate of oxygen consumption or whether there is depressed metabolism because of substrate lack which by a feedback mechanism causes inhibition of thyroidal function. The latter mechanism might act directly on the thyroid gland but could be manifest by the brain a t adenohypophyseal or hypothalamic levels. The development of assays for thyrotropin (TSH) and thyrotropin-releasing hormone (TRH)' have made it possible to investigate these hypotheses -directly. G. E. Shambaugh I11 and J. F. Wilber3 chose the neonatal rat as the model for their experiments. Newborn rats were made hypot h y r o i d b y t h e addition of propyl thiouracil (PTU) to their mothers' drinking water from day 19 of pregnancy onwards. Other animals were deprived of milk by being removed from the mother for 16 out of each 24 hours. Control animals were allowed t o feed continuously. The effects of these treatments were assessed by measurement of the total body weight of the pups, the weight of both kidneys, and the weight of the gastrocnemius-plantaris muscle group. Prenatal exposure to PTU for two days had no effect on these three weights. The pups made hypothyroid by suckling from PTU 00 NUTRITION R)NIEWS/VOL. 33,NO. MUARCH 1975
treated mothers also did not show a significant alteration in weight a t four or eight days but were approximately 25 percent lighter in all three measurements by 16 days. The nutritionally deprived animals were more severely affected, showing significant reductions in all three weights from the fourth day, and by the sixteenth postnatal day being between 25 to 33 percent the weight of the control animals. The authors did not attempt to document the growth retardation in cellular terms by either morphometric or chemical means. It would have been of interest to know i f the addition of an antithyroid drug to the maternal drinking water had the same type of action as caloric deprivation. Also unresolved are questions such as whether a PTU treated mother has as much milk as a control animal or if her offspring suckle as vigorously as normal pups. The effectiveness of the PTU treatment was estimated chemically by measurement of plasma TSH and thyroxine (T,) levels in the pups. On the fourth postnatal day the mean plasma TSH level in the experimental group was 31 mU per 100 ml compared to 4.7 mU per 100 ml in the control group. This indicated that a deficiency of peripheral thyroid hormone was causing a positive feedback a t the hypophyseal level. The mild nature of the hypothyroidism was evidenced by the fact that on the twelfth postnatal day the mean plasma T, level of PTU treated pups was 3.6 1.19 per 100 ml which was 70 percent of that of the controls (5.1 pg per 100 ml). The plasma T, level of the undernourished animals was very similar to that of the hypothyroid group being 3.4 p g per 100 ml on day 12 but interestingly their plasma TSH level
was also reduced being 4.9 mU per 100 ml compared with 10.1 mU per 100 ml in the control group. The plasma TSH levels of the hypothyroid animals on day 12 are not reported, but presumably they remained higher than those of the controls. The possibility that reduction in T, levels might result from lowered plasma concentrations of thyroid hormone binding capacity was considered and excluded by the demonstration that T, resin tests gave a lower result using pooled plasma from the underfed animals than from controls. The low plasma TSH levels of underfed pups was investigated by incubating the pituitaries of underfed and control pups in vitro under control conditions and in the presence of 25 or 50 pg TRH per milliliter. TSH i n t h e incubation medium was measured subsequently and TSH secretion was expressed as the difference between the release during a one hour incubation in the presence of TRH and that in the immediately preceding control hour. The weight of the pituitary from the underfed animals was approximately half that of the fed controls, being 0.37 k 0.04 mg compared with 0.68 f 0.08 mg. For this reason the in vitro incubations contained two experimental or one control gland. TRH a t 25 pg per milliliter concentration caused a modest stimulation of TSH release but a t 50 pg per milliliter the effect was much greater. The TSH response t o 50 pg TRH per milliliter was 2.8 U per milligram wet weight per hour from the control animals which was similar to that from the underfed, 2.6. It is impossible to calculate what increment above resting release rate this represented because of the method of presentation of results. The authors deduced from this finding that the pituitaries of the underfed pups had the same capacity to release TSH as those from the control group. This must be viewed with reserve, however, until the nature of the pituitary weight reduction of the experimental group is more clearly defined. The finding of a normal capacity for TSH secretion in vitro led the authors to study next the hypothalamic TRH content.
This was done by dissecting blocks of the brain which were bounded anteriorly by the optic chiasma, laterally by the hypothalamic sulci, posteriorly by the mamillary bodies, and which extended 4 mm dorsally from the ventral surface of the median eminence. TRH was extracted from the block with methanol and the hypothalamic protein content was also measured. The hypothalamic TRH content of the control pups increased five-fold by the sixteenth day of postnatal life when the mean value was 2.68 ng. In the underfed pups the level was significantly less from day eight onwards whether expressed per hypothalamus or per milligram of hypothalamic protein. This last observation demonstrated that the TRH concentration was not reduced because of less total hypothalamic mass or a nonspecific reduction of protein synthesis. The findings of Shambaugh and Wilber are noteworthy because they provide the first direct evidence for a cerebral origin of the hypothyroidism that accompanies undernutrition. The mechanism by which reduced TRH formation and presumably secretion occurs awaits further study. It i s interesting, however, t o observe that the modest hypothyroidism of the PTU treated pups which produced similar T, levels to that of the underfed animals resulted in a much smaller deficit in weight gain. Further work should also make it possible to state with confidence if this weight deficit is directly due to low circulating levels of T, or other experimental variab Ies. A recent detailed clinical study4 of thyroidal function in malnourished infants covers some of the same ground as the rat work and it is worthwhile to consider the two studies together. The children were of Mestizo origin from Peru. Six males with marasmus were studied within 24 hours of hospital admission a t the age of five to ten months; five were studied again following partial rehabilitation of 24 to 76 days with a balanced diet of 125 to 175 kcal per kilogram per day; the sixth dying from septicemia. All were examples of severe marasmus with normal serum protein NUTRlTlON RWIEWSIVOL. 33, NO. 3lMARCH 1975 09
levels. Blood was collected after an overnight fast the day after admission and just prior t o discharge. The serum concentrations of T, free T4 (FT,), thyroxine binding globulin (TBG), thyroxin binding pre-albumin (TBPA), and TSH concentrat i o n were measured on stored frozen samples. Control values were obtained from a group of 13 male siblings who were admitted to the hospital in good health before the age of three months and stayed up to two years, growing normally. Twentyseven blood samples taken from these children at the ages of three to 40 months were used to construct curves of normal serum thyroid hormone ranges. This was important as normal thyroid hormone concentrations change markedly as a function of age in the early months of lifeI5 T, in particular falling with increasing age. On admission the marasmic children had a mean serum T, level of 9.5 pg per 100 ml which was significantly less than that of controls of comparable age of height (12.3 p g per 100 ml). Serum TBG, TBPA, and FT, levels were not significantly different from those of controls and all but one of the TSH values were below the sensitivity of the assay. No remarkable differences were noted following recovery. Seven children with marasmic kwashiorkor were studied similarly. They were stunted and had the classical features of edema, hepatomegaly, skin and hair changes. On admission they were hypoproteinemic and anemic. Treatment included blood transfusion as well as nutritional rehabilitation. At the time of initial study they had low T, and TBG levelsand normal or high TBPA and FT, levels. In four, the FT, level was above the normal range. TSH levels were normal, being measurable in six. After 22 to 41 days treatment the TBG levels had returned t o normal and T, levels had risen but were still low. The TBPA values remained raised and the FT, fell to a significantly low mean. In five of the six in whom TSH had been detectable on admission there was a fall on recovery. 90 NUTRITION REVlEWS/VOL 33, NO. 3/MARCH 1975
This study has confirmed the earlier report of F. Varga and 6. Mess6 who, using a bioassay, had found low plasma and pituitary TSH concentrations in marasmus and kwashiorkor. These findings fit well w i t h those from the rat experiments especially when it is recollected that marasmic infants have a normal thyroid hormone response to an injection of exogenous TSM7 It seems reasonable to propose that the malnourished infant, with marasmus or kwashiorkor, like the underfed rat, has depression of hypothalamohypophyseal-thyroid axis of central origin. Differences between marasmus and marasmic-kwashiorkor seem to be largely explicable by changes in plasma thyroidbinding protein concentration in the latter condition. In neither study was plasma t r i iod o t h y r o n ine concentration (T3) measured; it would, however, be surprising i f such measurements were discordant with a series of animal and human studies which are noteworthy for their consistency. Finally there remains the question of what effect early malnutrition may have on thyroid function in later life following recovery. D. Blackmore' studied this with a rat model. Male pups were overfed or underfed from the second to eighth day of life by adjustment of litter size and restriction of access by the underfed 'pups to the mother to seven hours each day. From the ninth day to the time of weaning a t 21 days both groups were allowed unlimited access to suckle. Between 30 to 35 days and 50 to 55 days of age some of the aniI and sacrificed mals were injected with 24 hours later. The underfed animals still had a weight deficit a t 30 to 35 days and a t 50 to 55 days which was paralleled by that of the thyroid gland. When thyroid weight was expressed as a fraction of body weight (milligram per 100 g), the fraction was significantly lower in the overfed animals a t both ages. It must be remembered, however, that the overfed animals might have been fatter a t the time of sacrificing so that body weight was not as appropriate a
denominator of thyroidal weight as lean body mass. The fraction of the injected radioactive iodide remaining in t h e thyroid after 24 hours was similar in the over- and underfed animals but slightly and significantly more in those overfed. Also, the serum protein iodine a t 50 to 55 days was slightly but significantly greater in the overfed animals. The author concluded that a short period of undernutrition in the neonatal period can have prolonged effects on thyroidal function in the rat, although, as he points out, the biological as opposed to the statistical significance of these findings remains open to speculation. Even more conjectural i s the relevance of these findings to human infantile malnutrition. Several questions raised by this research are of great interest. How does the brain perceive the undernourished state so that thyroidal function is dampened, and is there a teleological interpretation to the depression of thyroidal activity i n order to conserve fuel in short supply? 1. R. D. G. Milner: Endocrine Adaptation to Malnutrition. Nutrition Reviews 30: 103-106, 1972
2. R. M. Bassiri and R. 0.Utiger: The Preparation and Specificity of Antibody to Thyrotropin Releasing Hormone. Endocrinology 90:
722-727,1972 3. G. E. Shambaugh 111 and J. F. Wilber: The Effect of Caloric Deprivation upon Thyroid Function in the Neonatal Rat. Endocrinology
94: 1145-1149,1974 4. G. G. Graham, J. M. Baertl, G. Claeyssen, R. Suskind, A. H. Greenberg, R. G. Thompson, and R. M. Blizzard: Thyroid Hormonal Studies in Normal and Severely Malnourished Infants and Small Children. J. Pediat. 83:
321 -331, 1 973 5. M. T. O'Halloran and H. L. Webster: Thyroid Function Assays in Infants. J. Pediar. 81:
916-919,1972 6. F. Varga and 6. Mess: Serum Thyrotrophin in Semistarvation. Acta Paediat. Acad. Sci. (Hung.) 9: 197-203,1968
7. F. Beas, F. Monckeberg and I . Horwitz: The Response of the Thyroid Gland to Thyroid Stimulating Hormone (TSH) in Infants with Malnutrition. Pediatrics 38: 1003-1008,1966.
8. D. Blackmore: Effect of Early Postnatal Starvation on Subsequent Thyroid Function. Bioi. Neonat. 23:359-365,1973
CELLULAR DEVELOPMENT AFTER FETAL THYROIDECTOMY Thyroidectomy of the sheep fetus causes complex disturbances in the patterns of cellular development of various organs and particularly in the brain. Key Words: fetal thyroidectomy, cellular growth, placental permeability, thyroxine, triiodothyronine
The growth of the ovine fetus after thyroidectomy in utero has been reviewed recently in this journal.' Thyroidectomy impairs fetal growth in the sheep as it does in man but the stunting is not severe and questions unresolved a t the time of the last review related to the possible role of maternal thyroid hormones in fetal development and the nature of the growth deficit in cellular terms. Some of these points have since been clarified. A. Erenberg and his colleagues studied the
effects of fetal thyroidectomy on both materno-fetal thyroid interrelationships2 and the cellular growth of the fetus3 In the first report2 the changes in fetal and maternal iodothyronine kinetics were studied after fetal thyroidectomy of seven lambs a t 90 to 125 days gestation which is early in the third trimester. In four of the animals, indwelling catheters in the fetal carotid artery and maternal jugular vein were inserted a t the time of operation. In the other three animals, the catheters were placed a t a second operation three to four weeks later. After thyroidectomy the maternal plasma thyroxine (T,) level reNtJ7RITfOff RNIEWS/VOL 33, NO. 3lMARC.H 1975 91
A recent review' commented that there was general agreement from measurement of plasma hormone levels and metabolic rates that thyroidal function i s depressed in malnutrition. A point of interest which remains unresolved is whether thyroidal hormone secretion i s depressed ab initio and so causes a low rate of oxygen consumption or whether there is depressed metabolism because of substrate lack which by a feedback mechanism causes inhibition of thyroidal function. The latter mechanism might act directly on the thyroid gland but could be manifest by the brain a t adenohypophyseal or hypothalamic levels. The development of assays for thyrotropin (TSH) and thyrotropin-releasing hormone (TRH)' have made it possible to investigate these hypotheses -directly. G. E. Shambaugh I11 and J. F. Wilber3 chose the neonatal rat as the model for their experiments. Newborn rats were made hypot h y r o i d b y t h e addition of propyl thiouracil (PTU) to their mothers' drinking water from day 19 of pregnancy onwards. Other animals were deprived of milk by being removed from the mother for 16 out of each 24 hours. Control animals were allowed t o feed continuously. The effects of these treatments were assessed by measurement of the total body weight of the pups, the weight of both kidneys, and the weight of the gastrocnemius-plantaris muscle group. Prenatal exposure to PTU for two days had no effect on these three weights. The pups made hypothyroid by suckling from PTU 00 NUTRITION R)NIEWS/VOL. 33,NO. MUARCH 1975
treated mothers also did not show a significant alteration in weight a t four or eight days but were approximately 25 percent lighter in all three measurements by 16 days. The nutritionally deprived animals were more severely affected, showing significant reductions in all three weights from the fourth day, and by the sixteenth postnatal day being between 25 to 33 percent the weight of the control animals. The authors did not attempt to document the growth retardation in cellular terms by either morphometric or chemical means. It would have been of interest to know i f the addition of an antithyroid drug to the maternal drinking water had the same type of action as caloric deprivation. Also unresolved are questions such as whether a PTU treated mother has as much milk as a control animal or if her offspring suckle as vigorously as normal pups. The effectiveness of the PTU treatment was estimated chemically by measurement of plasma TSH and thyroxine (T,) levels in the pups. On the fourth postnatal day the mean plasma TSH level in the experimental group was 31 mU per 100 ml compared to 4.7 mU per 100 ml in the control group. This indicated that a deficiency of peripheral thyroid hormone was causing a positive feedback a t the hypophyseal level. The mild nature of the hypothyroidism was evidenced by the fact that on the twelfth postnatal day the mean plasma T, level of PTU treated pups was 3.6 1.19 per 100 ml which was 70 percent of that of the controls (5.1 pg per 100 ml). The plasma T, level of the undernourished animals was very similar to that of the hypothyroid group being 3.4 p g per 100 ml on day 12 but interestingly their plasma TSH level
was also reduced being 4.9 mU per 100 ml compared with 10.1 mU per 100 ml in the control group. The plasma TSH levels of the hypothyroid animals on day 12 are not reported, but presumably they remained higher than those of the controls. The possibility that reduction in T, levels might result from lowered plasma concentrations of thyroid hormone binding capacity was considered and excluded by the demonstration that T, resin tests gave a lower result using pooled plasma from the underfed animals than from controls. The low plasma TSH levels of underfed pups was investigated by incubating the pituitaries of underfed and control pups in vitro under control conditions and in the presence of 25 or 50 pg TRH per milliliter. TSH i n t h e incubation medium was measured subsequently and TSH secretion was expressed as the difference between the release during a one hour incubation in the presence of TRH and that in the immediately preceding control hour. The weight of the pituitary from the underfed animals was approximately half that of the fed controls, being 0.37 k 0.04 mg compared with 0.68 f 0.08 mg. For this reason the in vitro incubations contained two experimental or one control gland. TRH a t 25 pg per milliliter concentration caused a modest stimulation of TSH release but a t 50 pg per milliliter the effect was much greater. The TSH response t o 50 pg TRH per milliliter was 2.8 U per milligram wet weight per hour from the control animals which was similar to that from the underfed, 2.6. It is impossible to calculate what increment above resting release rate this represented because of the method of presentation of results. The authors deduced from this finding that the pituitaries of the underfed pups had the same capacity to release TSH as those from the control group. This must be viewed with reserve, however, until the nature of the pituitary weight reduction of the experimental group is more clearly defined. The finding of a normal capacity for TSH secretion in vitro led the authors to study next the hypothalamic TRH content.
This was done by dissecting blocks of the brain which were bounded anteriorly by the optic chiasma, laterally by the hypothalamic sulci, posteriorly by the mamillary bodies, and which extended 4 mm dorsally from the ventral surface of the median eminence. TRH was extracted from the block with methanol and the hypothalamic protein content was also measured. The hypothalamic TRH content of the control pups increased five-fold by the sixteenth day of postnatal life when the mean value was 2.68 ng. In the underfed pups the level was significantly less from day eight onwards whether expressed per hypothalamus or per milligram of hypothalamic protein. This last observation demonstrated that the TRH concentration was not reduced because of less total hypothalamic mass or a nonspecific reduction of protein synthesis. The findings of Shambaugh and Wilber are noteworthy because they provide the first direct evidence for a cerebral origin of the hypothyroidism that accompanies undernutrition. The mechanism by which reduced TRH formation and presumably secretion occurs awaits further study. It i s interesting, however, t o observe that the modest hypothyroidism of the PTU treated pups which produced similar T, levels to that of the underfed animals resulted in a much smaller deficit in weight gain. Further work should also make it possible to state with confidence if this weight deficit is directly due to low circulating levels of T, or other experimental variab Ies. A recent detailed clinical study4 of thyroidal function in malnourished infants covers some of the same ground as the rat work and it is worthwhile to consider the two studies together. The children were of Mestizo origin from Peru. Six males with marasmus were studied within 24 hours of hospital admission a t the age of five to ten months; five were studied again following partial rehabilitation of 24 to 76 days with a balanced diet of 125 to 175 kcal per kilogram per day; the sixth dying from septicemia. All were examples of severe marasmus with normal serum protein NUTRlTlON RWIEWSIVOL. 33, NO. 3lMARCH 1975 09
levels. Blood was collected after an overnight fast the day after admission and just prior t o discharge. The serum concentrations of T, free T4 (FT,), thyroxine binding globulin (TBG), thyroxin binding pre-albumin (TBPA), and TSH concentrat i o n were measured on stored frozen samples. Control values were obtained from a group of 13 male siblings who were admitted to the hospital in good health before the age of three months and stayed up to two years, growing normally. Twentyseven blood samples taken from these children at the ages of three to 40 months were used to construct curves of normal serum thyroid hormone ranges. This was important as normal thyroid hormone concentrations change markedly as a function of age in the early months of lifeI5 T, in particular falling with increasing age. On admission the marasmic children had a mean serum T, level of 9.5 pg per 100 ml which was significantly less than that of controls of comparable age of height (12.3 p g per 100 ml). Serum TBG, TBPA, and FT, levels were not significantly different from those of controls and all but one of the TSH values were below the sensitivity of the assay. No remarkable differences were noted following recovery. Seven children with marasmic kwashiorkor were studied similarly. They were stunted and had the classical features of edema, hepatomegaly, skin and hair changes. On admission they were hypoproteinemic and anemic. Treatment included blood transfusion as well as nutritional rehabilitation. At the time of initial study they had low T, and TBG levelsand normal or high TBPA and FT, levels. In four, the FT, level was above the normal range. TSH levels were normal, being measurable in six. After 22 to 41 days treatment the TBG levels had returned t o normal and T, levels had risen but were still low. The TBPA values remained raised and the FT, fell to a significantly low mean. In five of the six in whom TSH had been detectable on admission there was a fall on recovery. 90 NUTRITION REVlEWS/VOL 33, NO. 3/MARCH 1975
This study has confirmed the earlier report of F. Varga and 6. Mess6 who, using a bioassay, had found low plasma and pituitary TSH concentrations in marasmus and kwashiorkor. These findings fit well w i t h those from the rat experiments especially when it is recollected that marasmic infants have a normal thyroid hormone response to an injection of exogenous TSM7 It seems reasonable to propose that the malnourished infant, with marasmus or kwashiorkor, like the underfed rat, has depression of hypothalamohypophyseal-thyroid axis of central origin. Differences between marasmus and marasmic-kwashiorkor seem to be largely explicable by changes in plasma thyroidbinding protein concentration in the latter condition. In neither study was plasma t r i iod o t h y r o n ine concentration (T3) measured; it would, however, be surprising i f such measurements were discordant with a series of animal and human studies which are noteworthy for their consistency. Finally there remains the question of what effect early malnutrition may have on thyroid function in later life following recovery. D. Blackmore' studied this with a rat model. Male pups were overfed or underfed from the second to eighth day of life by adjustment of litter size and restriction of access by the underfed 'pups to the mother to seven hours each day. From the ninth day to the time of weaning a t 21 days both groups were allowed unlimited access to suckle. Between 30 to 35 days and 50 to 55 days of age some of the aniI and sacrificed mals were injected with 24 hours later. The underfed animals still had a weight deficit a t 30 to 35 days and a t 50 to 55 days which was paralleled by that of the thyroid gland. When thyroid weight was expressed as a fraction of body weight (milligram per 100 g), the fraction was significantly lower in the overfed animals a t both ages. It must be remembered, however, that the overfed animals might have been fatter a t the time of sacrificing so that body weight was not as appropriate a
denominator of thyroidal weight as lean body mass. The fraction of the injected radioactive iodide remaining in t h e thyroid after 24 hours was similar in the over- and underfed animals but slightly and significantly more in those overfed. Also, the serum protein iodine a t 50 to 55 days was slightly but significantly greater in the overfed animals. The author concluded that a short period of undernutrition in the neonatal period can have prolonged effects on thyroidal function in the rat, although, as he points out, the biological as opposed to the statistical significance of these findings remains open to speculation. Even more conjectural i s the relevance of these findings to human infantile malnutrition. Several questions raised by this research are of great interest. How does the brain perceive the undernourished state so that thyroidal function is dampened, and is there a teleological interpretation to the depression of thyroidal activity i n order to conserve fuel in short supply? 1. R. D. G. Milner: Endocrine Adaptation to Malnutrition. Nutrition Reviews 30: 103-106, 1972
2. R. M. Bassiri and R. 0.Utiger: The Preparation and Specificity of Antibody to Thyrotropin Releasing Hormone. Endocrinology 90:
722-727,1972 3. G. E. Shambaugh 111 and J. F. Wilber: The Effect of Caloric Deprivation upon Thyroid Function in the Neonatal Rat. Endocrinology
94: 1145-1149,1974 4. G. G. Graham, J. M. Baertl, G. Claeyssen, R. Suskind, A. H. Greenberg, R. G. Thompson, and R. M. Blizzard: Thyroid Hormonal Studies in Normal and Severely Malnourished Infants and Small Children. J. Pediat. 83:
321 -331, 1 973 5. M. T. O'Halloran and H. L. Webster: Thyroid Function Assays in Infants. J. Pediar. 81:
916-919,1972 6. F. Varga and 6. Mess: Serum Thyrotrophin in Semistarvation. Acta Paediat. Acad. Sci. (Hung.) 9: 197-203,1968
7. F. Beas, F. Monckeberg and I . Horwitz: The Response of the Thyroid Gland to Thyroid Stimulating Hormone (TSH) in Infants with Malnutrition. Pediatrics 38: 1003-1008,1966.
8. D. Blackmore: Effect of Early Postnatal Starvation on Subsequent Thyroid Function. Bioi. Neonat. 23:359-365,1973
CELLULAR DEVELOPMENT AFTER FETAL THYROIDECTOMY Thyroidectomy of the sheep fetus causes complex disturbances in the patterns of cellular development of various organs and particularly in the brain. Key Words: fetal thyroidectomy, cellular growth, placental permeability, thyroxine, triiodothyronine
The growth of the ovine fetus after thyroidectomy in utero has been reviewed recently in this journal.' Thyroidectomy impairs fetal growth in the sheep as it does in man but the stunting is not severe and questions unresolved a t the time of the last review related to the possible role of maternal thyroid hormones in fetal development and the nature of the growth deficit in cellular terms. Some of these points have since been clarified. A. Erenberg and his colleagues studied the
effects of fetal thyroidectomy on both materno-fetal thyroid interrelationships2 and the cellular growth of the fetus3 In the first report2 the changes in fetal and maternal iodothyronine kinetics were studied after fetal thyroidectomy of seven lambs a t 90 to 125 days gestation which is early in the third trimester. In four of the animals, indwelling catheters in the fetal carotid artery and maternal jugular vein were inserted a t the time of operation. In the other three animals, the catheters were placed a t a second operation three to four weeks later. After thyroidectomy the maternal plasma thyroxine (T,) level reNtJ7RITfOff RNIEWS/VOL 33, NO. 3lMARC.H 1975 91
