A novel resistance to thyroid hormone associated with a new mutation (T329N) in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor-beta (TRbeta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. Dextrothyroxine (D-T4) therapy was instituted. At 8 mg per day 2 pregnancies followed with the delivery of a healthy boy and an RTH-affected girl another miscarriage occurred on D-T4 treatment at 6 mg per day. The T329N mutation, which was also identified in the daughter, markedly reduces the affinity of TRbeta for triiodothyronine (T3). Formation of T329N mutant TR homodimers and heterodimers with RXRalpha on thyroid hormone response element F2 (TRE F2) was not affected, but the ability of T3 to interrupt T329N mutant TRbeta homodimerization was markedly reduced. The T329N mutant TRbeta was transcriptionally inactive in transient expression assays. In cotransfection assays with wild-type TRbeta1, the mutant TRbeta1 functioned in a dominant negative manner. The results suggest that the T329N mutation in the T3-binding domain of TRbeta is responsible for RTH in the proposita's family.

Myxoedema coma: response of thyroid hormones with oral and intravenous high-dose L-thyroxine treatment.

Myxoedema coma is a medical emergency with high mortality. In this study, clinical response and plasma variations of thyroid hormones were analysed in 7 patients, 6 presenting with myxoedema coma and one with myxoedema ileus. These patients were treated with intravenous or oral l-thyroxine (l-T4). 1000 mu l-T4 iv were administered in two patients. Within 3 h, plasma T4 and triiodothyronine (T3) reached a peak upper normal range, then diminished slowly during 5-9 days. The 5 remaining patients were treated with 500 micrograms l-T4 po on the first day, then 100 micrograms l-T4 daily by mouth. Plasma T4 and T3 increased slowly, remaining in hypothyroid range but clinical response (assessed on mental status, pulse rate and body temperature) occurred within 24-72 h. Cortisone therapy was used in 3 patients. Two patients died of myocardial infarction, or septicemia, one while receiving cortisone therapy and i.v. l-T4, another one treated only by oral l-T4. This study suggests: 1) oral absorption of l-T4 is variable, but clinical response occurs quickly even in myxoedema ileus; 2) the intravenous route involves high peaks of plasma T4 and T3; 3) peripheral conversion of T4 to T3 allows gradually T3 delivery to organ systems, even if only l-T4 is used and 4) initial and daily dosage determinations need further studies.

A case of pseudo-Nelson's syndrome: cure of ACTH hypersecretion by removal of a bronchial carcinoid tumor responsible for Cushing's syndrome.

It may sometimes be difficult to distinguish Cushing's disease from ectopic ACTH syndrome. A case is described here of a patient with a Cushing's syndrome and diagnostic difficulties. Initial features were consistent with a Cushing's disease (in particular metopirone test was positive). Because of relapse of hypercortisolism after mitotane therapy, total adrenalectomy was performed. Thereafter features occurred that evoked Nelson's syndrome, including high plasma ACTH levels and a pituitary mass syndrome. Pituitary reserve testings by vasopressin or corticotropin-releasing factor were positive, although inconstantly, in that plasma ACTH increased. A lung tumor was discovered about 20 yr after the first clinical signs of hypercortisolism. Its removal led to the discovery of a bronchial carcinoid tumor and was followed by normalization of plasma ACTH levels. An analysis of proopiomelanocortin-related peptides was performed postoperatively on the blood drawn before and after the tumor resection and on the tumor; the results of this study would have been contributive to the diagnosis of occult ectopic ACTH tumor. In conclusion this case demonstrates the limitations of the conventional procedures in the diagnosis of the ectopic ACTH syndrome. At contrast the newer biochemical procedures may be very useful in determining the type of hypercortisolism.

[Contraception for the diabetic woman]. / Contraception chez la femme diabetique.

PIP: Because of their vascular and metabolic risks for diabetic women, pregnancies must be carefully programmed to occur before the onset of degenerative diabetic manifestations. Diabetic women need an effective contraceptive method without undesirable side effects. The numerous side effects of combined oral contraceptives (OCs) are due to both the estrogens and progestins. Combined OCs have a diabetogenic effect whose mechanism is not clearly understood. Blood sugar levels are elevated under OCs and the insulin response is retarded and exaggerated. The number and affinity of insulin receptors are reduced. Norsteroid- derived progestins increase the state of insulin resistance. Combined OCs usually increase triglyceride levels. Changes in the level of high- density lipoprotein cholesterol under combined OCs vary with the estrogen and progestin content. Synthetic estrogens increase platelet aggregability, and blood pressure increases during OC use. Use of combined OCs represents increased vascular risk for diabetic women, with the risk of thrombosis multiplied by 4. Low dose progestin pills permit continued secretion of a small amount of luteinizing hormone and follicle stimulating hormone which may cause a relative hyperestrogenism and undesirable side effects. The secondary effects are often poorly tolerated. Use of this type of pill is limited except among diabetic women, 25% of whom are users. The failure rate is estimated at .2-2%. Standard-dosed norsteroids are unsuitable for diabetic women because of their metabolic and vascular side effects. 2nd and 3rd generation progestins have yielded more promising results. IUDs are used by about 12% of the overall female population but 32% of diabetic women, mostly multiparas, despite the increased risk of infection. Local methods have a higher failure rate and their success depends on patient compliance with instructions. 14% of diabetic women in a recent survey reported having undergone tubal ligation, which is not strictly speaking a contraceptive method. Combined OCs should be avoided in insulin- dependent diabetics because of their metabolic and vascular effects. Diabetic retinopathy should be added to the list of absolute contraindications to these methods. Low-dose progestins can be used in insulin-dependent diabetics or if they are poorly tolerated a standard dose pill can be substituted. IUD is the method of choice for older, multiparous insulin-dependent diabetics. Sterilization may be considered, especially if pregnancy is absolutely contraindicated. Combined OCs are formally contraindicated for noninsulin-dependent diabetics. Low-dose progestins could be tried. IUDs are suitable for multiparas.^ieng