BJOG: an International Journal of Obstetrics and Gynaecology June 2003, Vol. 110, pp. 633 – 634
Thyroid hormone resistance and pregnancy Simon Kane, Robert Fox*, Colin Close Case report A 31 year old nulliparous woman was seen in the antenatal booking clinic at eight weeks of gestation. She had developed a large goitre at age 7 and thyroid hormone resistance had been diagnosed at age 12. Her father was known to have thyroid hormone resistance. She had been clinically euthyroid and had required no treatment. The goitre had, however, gradually increased in size over time; her neck circumference was 39.5 cm in 1992 and 41.5 cm in September 1998. Genetic analysis had not yet been performed on the family. At eight weeks of gestation, she appeared clinically euthyroid with a normal pulse rate. Biochemical tests revealed an elevated concentration of free triiodothyronine (FT3) at 9.8 pmol/L (normal range 3.5 –6.5 pmol/L) and free thyroxine (FT4) at 44.2 pmol/L (normal range 10.1 – 20.9 pmol/L), with normal thyroid stimulating hormone (TSH) at 0.8 mU/L (normal range 0.5 –5.0 mU/L). These levels were similar to those measured one year earlier before her pregnancy. She remained well and asymptomatic during her pregnancy. Thyroid function tests were performed monthly. From 26 weeks of gestation, the serum concentrations of FT3 and FT4 both fell and at 34 weeks of gestation her triiodothyronine concentration was within the normal range. At term she had a normal labour and vaginal delivery of her baby son whose Apgar scores were 9 and 10 at 1 and 5 minutes, respectively, and who weighed 3.4 kg. The infant had no evidence of thyroid enlargement and his thyroid function tests were normal. A few weeks after delivery, the goitre enlarged and she experienced symptoms of obstruction to her airway. Her neck circumference (measured by the same observer since 1992) was now 44 cm. Pulmonary function analysis (flow volume loop) showed an inspiratory flow rate half that recorded two years earlier in October 1988. Her thyroid hormone concentration had returned to their pre-pregnancy values: FT3 8.4 pmol/L, FT4 42.0 pmol/L and TSH
1.1 mU/L (Fig. 1). In view of the rapid onset of respiratory symptoms, she underwent urgent total thyroidectomy. The gland weighed 328 g (normal 20– 25 g) and histological analysis revealed nodular hyperplasia.
Discussion Thyroid hormone resistance is a rare condition characterised biochemically by elevated levels of free thyroid hormones T3 and T4, together with an inappropriately normal TSH concentration. The condition is usually the result of a mutation in the T3 binding domain of the thyroid hormone receptor h (TRh). Most reported cases of thyroid hormone resistance with a TRh mutation have an autosomal dominant inheritance1, but familial cases without linkage to TRh have been described2, including one where both TRh alleles were deleted3. The TRh mutation leads to partial resistance of the receptor to T3; usually both the peripheral tissues and the pituitary thyrotrophs are resistant (generalised resistance), so the secretion of TSH is uninhibited and its production is inappropriate for the level of free thyroid hormones. The TSH is usually in the normal reference range. Although patients with thyroid hormone resistance have supraphysiological concentrations of FT3 and FT4, most are clinically euthyroid due to the peripheral tissue resistance. Typically, the only clinical manifestation of the condition is the presence of a large smooth goitre, which results from the
Departments of Obstetrics and Endocrinology/Diabetes, Taunton & Somerset Hospital, Taunton, UK * Correspondence: Dr R. Fox, Departments of Obstetrics and Endocrinology, Taunton & Somerset Hospital, Taunton TA1 5DA, UK. D RCOG 2003 BJOG: an International Journal of Obstetrics and Gynaecology doi:10.1016/S1470-0328(02)01692-0
Fig. 1. Serum FT4, FT3 and TSH concentrations. www.bjog-elsevier.com
need for increased thyroid hormone production in order to overcome the peripheral tissue resistance. However, a small number of patients exhibit manifestations of hyperthyroidism, particularly tachycardia; in these patients the resistance to T3 is largely confined to the thyrotrophs (pituitary resistance), with relatively normal peripheral tissue sensitivity. Asymptomatic patients require no treatment, but those with features of hyperthyroidism may require treatment with drugs that inhibit TSH secretion, such as dextrothyroxine (D-T4) or 3,5,3V-triiodothyroacetic acid (TRIAC). There have been two reports of the use of these drugs in pregnancy4,5. D-T4 was used to assist fertility in one woman with recurrent miscarriages and mild features of hyperthyroidism and the drug was stopped after conception4. Another woman with pituitary thyroid hormone resistance conceived while receiving TRIAC, discontinued the drug, only to restart treatment at 20 weeks of gestation due to a recurrence of hyperthyroidism5. Treatment with thyroxine is sometimes indicated in children with thyroid hormone resistance and growth retardation. Although the goitre is often large, surgery is usually avoided because thyroidectomy renders the patient hypothyroid and appropriate levels of thyroid hormone replacement can then be difficult to determine. There have been very few reports of the effect of thyroid hormone resistance in pregnancy4 – 6 and none in women with generalised resistance. This case demonstrates that normal pregnancy and delivery are possible, but we feel it is important to report the development of severe stridor after delivery. Although it is not certain that the two events were causally related, we recommend that women with thyroid hormone resistance should be monitored for airway obstruction by analysis of flow – volume curves before and following delivery. Serial measurement of thyroid hormone levels during pregnancy in untreated thyroid hormone resistance has not previously been reported. The woman in this case
report showed a remarkable reduction in circulating free thyroid hormone levels during pregnancy. Physiologically, serum concentrations of FT3 and FT4 rise in early pregnancy under the influence of hCG in women with normal thyroid function, but several studies have reported that levels of FT3 and TF4 are lower at delivery than in the non-pregnant state7,8. The profound decrease in FT3 and FT4 levels in this woman suggests that there may be some factor increasing T3 receptor sensitivity in pregnancy.
References 1. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14:348 – 399. 2. Weiss R, Hayashi Y, Nagaya T, et al. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective co-factor. J Clin Endocrinol Metab 1996;81:4196 – 4223. 3. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 1992;74:49 – 55. 4. Sarkissian G, Dace A, Mesmacque A, et al. A novel resistance to thyroid hormone associated with a new mutation (T329N) in the thyroid hormone receptor h gene. Thyroid 1999;9:165 – 171. 5. Asteria C, Rajanayagam O, Collingwood TN, et al. Prenatal diagnosis of thyroid hormone resistance. J Clin Endocrinol Metab 1999; 84:405 – 410. 6. Furlanetto TW, Kopp P, Peccin S, Gu W, Jameson JL. A novel mutation (M310L) in the thyroid hormone receptor h causing resistance to thyroid hormone in a Brazilian kindred and a neonate. Mol Gen Metab 2000;71:520 – 526. 7. Ball R, Freedman DB, Holmes JC, Midgley JEM, Sheehan CP. Low-normal concentrations of free thyroxine in serum in late pregnancy: physiological fact, not detected artifact. Clin Chem 1989; 35:1891 – 1896. 8. Glinoer D, DeNayer P, Bourdoux P, et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990;71:276 – 287. Accepted 21 August 2002
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 633 – 634