Hans H. Bode

Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature.

It has been suggested that complete catch-up growth is achieved with treatment in patients with juvenile acquired hypothyroidism. We tested this assumption by examining long-term growth in 18 girls (mean [+/- SD] age, 11.4 +/- 2.7 years; bone age, 6.2 +/- 3.1 years) and 6 boys (age, 10.6 +/- 4.7 years; bone age, 6.4 +/- 2.7 years) with severe primary hypothyroidism (serum thyroxine level 1.1 +/- 0.3 micrograms per deciliter [13 +/- 4 nmol per liter]). At diagnosis, heights were 4.04 +/- 0.5 and 3.15 +/- 0.4 SD below the mean heights for age of normal girls and boys, respectively. The patients were treated with levothyroxine (3.4 +/- 0.3 micrograms per kilogram of body weight per day) to maintain normal thyroid function. During the first 18 months of therapy, the childrens skeletal maturation exceeded the maturation expected for their statural growth, regardless of whether or not they were undergoing pubertal development. Predictions of decreased adult height were based on these observations. At maturity, girls and boys stood approximately 2 SD below normal adult stature, at 149 +/- 5.0 cm and 168 +/- 5.1 cm, respectively. Heights at maturity were also lower than midparental heights (P less than 0.01) and lower than pre-illness standard-deviation scores for height (P less than 0.01). The deficit in adult stature was significantly related to the duration of hypothyroidism before treatment (P less than 0.01). We conclude that despite treatment, prolonged juvenile acquired hypothyroidism results in a permanent height deficit related to the duration of thyroxine deficiency before treatment.

Long-term treatment of central precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. Effects on somatic growth and skeletal maturation

Abstract The gonadotropin-releasing hormone–like agonist d-Trp6-Pro9-NEt-LHRH (LHRHa) has been shown to induce a reversible short-term suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. Since accelerated statural growth and bone maturation are clinical features of precocity not well controlled by conventional therapies, we examined the effects of prolonged LHRHa therapy for 18 consecutive months on growth and skeletal maturation in nine girls with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin pulsations and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (±S.E.M.) of 9.35±0.64 cm per year during the 19 months before treatment to 4.58±0.60 cm per year during treatment (P<0.001). Bone age advanced a mean of 9.4 ±2.3 months during treatment. These changes resulted in a mean increase of 3.3 cm in predicted height (P<0.01). Complete suppression of the pituitary-gonadal axis can be maintained by LHRHa t...

Partial Target Organ Resistance to Thyroid Hormone

An 8-year old boy with a small goiter, normal basal metabolic rate (BMR), and elevated serum thyroid hormone levels (thyroxine [T(4)] 19.5 mug per 100 ml, free T(4) 4 ng per 100 ml, triiodothyronine [T(3)] 505 ng per 100 ml) was studied. He had measurable serum thyroid-stimulating hormone (TSH) levels (average 5.5 muU per ml), and the thyroxine-binding proteins, hearing, and epiphyseal structures were normal. There was no parental consanguinity nor were there thyroid abnormalities either in the parents or six siblings.Methimazole, 50 mg daily, depressed thyroxine synthesis (T(4) 10.5, free T(4) 2.5) and caused a rise in TSH to 11 muU per ml. After discontinuation of treatment, TSH declined to 4.2 muU per ml and chemical hyperthyroidism returned (T(4) 21.0 mug per 100 ml, free T(4) 4.2, and total T(3) 475 ng per 100 ml, radioactive iodine [RAI] uptake 68%), but studies of BMR and insensible water loss showed the patient to be clinically euthyroid. Thyrotropin-releasing hormone (TRH), 200 mug i.v., caused a brisk rise in TSH to 28 muU per ml, with T(4) rising to 28 mug per 100 ml, free T(4) to 5.6, and T(3) to 730 ng per 100 ml, thus indicating that the pituitary-thyroid system was intact and that the patients TSH was biologically active. The unusual sensitivity of the pituitary cells to TRH in spite of the markedly elevated serum thyroid hormone levels also suggested that the pituitary was insensitive to suppression by T(3) or T(4). Serum dilution studies gave immunochemical evidence that this patients TSH was normal. Neither propranolol, 60 mg, chlorpromazine, 30 mg, nor prednisone, 15 mg daily, influenced thyroid indices. Steroid treatment, however, suppressed the pituitary response to TRH, T(3) in doses increased over a period of 12 days to as much as 150 mug daily caused a rise in serum T(3) to above 800 ng per 100 ml, a decline of T(4) to euthyroid levels (T(4) 9.5 mug per 100 ml, free T(4) 1.6 ng per 100 ml), suppression of the RAI uptake from 68% to 35%, and marked blunting of the responses to TRH, but the BMR and insensible water loss remained normal. The data suggest that the patients disorder is due to partial resistance to thyroid hormone.

Puberty without gonadotropins: a unique mechanism of sexual development

Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

Nephrogenic Diabetes Insipidus in North America — The Hopewell Hypothesis

Abstract Nephrogenic diabetes insipidus is prevalent among the descendants of the so-called Ulster Scot who settled in Nova Scotia during the eighteenth century. The folklore description of its mod...

Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche.

During puberty the effects of adrenal androgens upon skeletal maturation are obscured by the influence of gonadal steroids. Suppression of gonadarche with an analogue of luteinizing hormone releasing hormone (LHRHa) affords an opportunity to examine the onset and progression of adrenarche in the absence of pubertal levels of gonadal steroids in a controlled fashion and to explore the relationship between adrenal androgens and the rate of epiphyseal maturation. In 29 children with central precocious puberty, gonadarche was suppressed with LHRHa administration for 1-4 yr. During LHRHa exposure, dehydroepiandrosterone sulfate (DHAS) levels, as an index of adrenal maturation, were constant or increased in an age-expected manner. The change in bone age for change in chronologic age decreased from 1.7 +/- 0.1 to 0.49 +/- 0.05 (P = 0.00005), indicating that the LHRHa-induced return to a prepubertal gonadal steroid environment was associated with a slowing of skeletal maturation. DHAS levels were correlated with the rate of skeletal advancement before (r = 0.57, P = 0.001) and during 12 to 48 mo of exposure to LHRHa (r = 0.52, P = 0.003). A negative correlation of DHAS values with subsequent increases in predicted mature height was observed (r = -0.49, P = 0.007). Thus, in children with central precocious puberty, adrenarche progressed normally during LHRHa suppression of gonadarche. In children with the onset of progression of adrenarche during maintenance of a prepubertal gonadal steroid milieu, there was less evidence than in preadrenarchal children of a restraint upon skeletal maturation. These data suggest that adrenal androgens contribute importantly to epiphyseal advancement during childhood.

Home monitoring of 17 hydroxyprogesterone levels in congenital adrenal hyperplasia with filter paper blood samples

OBJECTIVE The purpose of this study was to evaluate the usefulness of 17 hydroxyprogesterone (17OHP) determination in dried filter paper blood samples from patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. It was hypothesized that these home samples would enhance patient treatment. STUDY DESIGN Results of 17OHP determination in simultaneously collected venous and dried filter paper blood samples were compared to establish assay reliability. Thereafter, parents mailed dried filter paper blood samples collected before each hydrocortisone dose. RESULTS The 17OHP levels in wet and dried blood samples correlated well (r = 0.98). Results did not change when stored for 2 weeks under various conditions. Blood sampling at different times of the day provided insights into the patterns of 17OHP secretion and identified times of inadequate adrenal suppression. Dose adjustments were then made considering the time of day when adrenal suppression was inadequate. CONCLUSION Home monitoring of 17OHP is a reliable and practical approach for assessing adrenal steroid activity in patients with congenital adrenal hyperplasia. Considering the time of day of 17OHP elevations also facilitates hydrocortisone dosing adjustment.

Restoration of normal drinking behavior by chlorpropamide in patients with hypodipsia and diabetes insipidus

Abstract The therapeutic efficiency of Chlorpropamide was evaluated in three patients with hypodipsia and diabetes insipidus. Hitherto extraordinarily difficult management problems, the patients responded with recovery of homeostatically appropriate thirst, improved renal concentrating ability and normalization of serum tonicity. Tests of their responses to fluid loading and water restriction indicated that normotonicity was protected during treatment through wide ranges of fluid intake varying from 2.2 to 5.0 L/twenty-four hours. Over a period of one year of treatment the patients have maintained normal fluid and electrolyte homeostasis despite abandonment of the strict fluid and diet regimens previously required to prevent wide swings in tonicity. Evidence is cited in support of the tenet that the beneficial effect of the sulfonylureas at the renal level depends upon amplification of the response of the adenyl cyclase system to residually low but facultatively controlled levels of vasopressin. The reappearance of appropriate drinking behavior during chlorpropamide treatment is probably similarly mediated, being attributable to a step-up of attenuated neural discharges by an effect of the drug on nucleotide system(s) in the brain.

X-linked Kallmann syndrome and renal agenesis occurring together and independently in a large Australian family.

Males with X-linked Kallmann syndrome (XLKS) may have renal agenesis. We studied a large kindred with a history of eight males affected by XLKS born in five generations. Their XLKS was shown to be due to an intragenic mutation of the KAL-1 gene. We also documented three male neonatal deaths due to bilateral renal agenesis (BRA), five males with unilateral renal agenesis (URA), and one female with a pelvic ectopic kidney in this kindred. Of four XLKS males who had renal imaging studies, two had URA. The kindreds KAL-1 mutation was not present in three of the males with URA, the female with the ectopic kidney, nor in preserved autopsy tissue from one infant with BRA. The high frequency of renal agenesis in this family, in the presence and absence of the KAL-1 mutation, suggests an autosomal dominant or X-linked gene which may independently or co-dependently contribute to renal agenesis.

In vivo total body electrical conductivity following perturbations of body fluid compartments in rats

Total body electrical conductivity (TOBEC) provides a rapid and safe noninvasive technique for the assessment of total body water in animals and man. An instrument employing this principle has been shown to measure body water in healthy Sprague-Dawley rats. With the exception of adult obesity in humans, alterations in body fluid compartments that could theoretically affect the utility of conductivity measurements have not been studied. We, therefore, applied the total body electrical conductivity measurement in rats following perturbations of body fluid/electrolyte spaces including obesity, furosemide diuresis, severe burn, and low protein diet. Our findings confirm that total body water can be accurately measured by TOBEC in conditions of abnormal body fluid distribution. However, when the ratio of intracellular to extracellular fluid is significantly reduced, such as the severe burn or low protein intake, TOBEC does not reflect the intracellular (potassium) space but does predict total water and extracellular (sodium) space.