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Biomedical subjects

M M Grumbach

Publications and source records attributed to M M Grumbach.

At least 91 records · Page 5Linked to original sources
PubMed1983

Gonadotropin-independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases.

Four boys with sexual precocity are described in whom pubertal concentrations of plasma testosterone were associated with premature Leydig and germinal cell maturation without activation of the hypothalamic-pituitary gonadotropin unit. Extensive laboratory evaluation localized the source of testosterone secretion to the testes, and testicular biopsy revealed maturation of Leydig cells and spermatogenic elements. These events appear to be nongonadotropin-dependent in view of the absence of a pubertal pattern of pulsatile LH secretion, persistence of a prepubertal LH response to LRF even after long standing sexual precocity, prepubertal basal levels of LH and undetectable hCG, and the absence of biologically active LH-hCG by bioassay. Indirect immunofluorescence studies failed to demonstrate an immunoglobulin in the patients' sera that bound to Leydig cells or seminiferous tubules of normal adult human testes. The potent LRF analog D-Trp6-Pro9-NEt-LRF did not result in suppression of plasma testosterone or Leydig cell function even after 3 months of daily treatment in two patients which provides additional support of pituitary gonadotropin independence and of the lack of a direct effect of the analog on Leydig cell function. Oral medroxyprogesterone acetate treatment in two patients was associated with a striking decrease in both plasma testosterone concentration and height velocity. In the only patient in whom a complete family history could be obtained (three of four patients were adopted), sexual precocity was noted in the maternal grandfather. As this familial syndrome is characterized by a prepubertal hypothalamic-pituitary gonadotropin unit and apparent gonadotropin-independent maturation of Leydig cells and germinal epithelium, possibly due to an intratesticular inborn error, we propose the term "familial testotoxicosis" to describe this group of sexually precocious boys.

Child, Preschool↗
PubMed1983

Synthetic human pancreas growth hormone-releasing factor (hpGRF1-44-NH2) stimulates growth hormone secretion in normal men.

A synthetic replicate of human pancreas growth hormone-releasing factor, hpGRF1-44-NH2, (hpGRF44), a 44-amino acid amidated peptide, was administered to seven normal men. In addition to placebo, 4 subjects received 3 doses of hpGRF44 (0.5 microgram/kg, 5 micrograms/kg, 10 micrograms/kg), while one subject received 2 doses (5 micrograms/kg, 10 micrograms/kg) and 2 subjects received one dose (0.5 microgram/kg or 5 micrograms/kg), each as a rapid intravenous injection. A significant increase in circulating growth hormone (GH) was observed at each dose (0.5 microgram/kg, p = 0.05; 5 micrograms/kg, p less than 0.005; 10 micrograms/kg, p = 0.01) when compared to placebo, with equivalent maximal responses. At all doses studied a rise in plasma GH occurred within 5 min, with a peak response in most patients at 30-45 min. There were no associated changes in any of the other anterior pituitary hormones or insulin. Other than transient flushing and minimal changes in vital signs, no side effects were noted. The results of these studies support the potential usefulness of hpGRF44 for the assessment of GH secretion and reserve, and of this peptide or an analog as a therapeutic agent to stimulate GH release.

Adult↗
PubMed1983

Endocrine, histological, and biochemical studies of adrenocorticotropin-producing islet cell carcinoma of the pancreas in childhood with characterization of proopiomelanocortin.

Two 8-yr-old children, a boy and girl, are described with Cushing's syndrome secondary to ectopic ACTH-secreting pancreatic islet cell carcinomas. The girl, seen 28 yr ago, had strong presumptive evidence of ectopic ACTH production and hypercalcemia. The boy, studied recently, had strikingly elevated concentrations of plasma ACTH (1,500 pg/ml) and beta-lipotropin (beta LPH; 2,500 pg/ml) and showed no suppression of urinary 17-hydroxycorticoids or cortisol with low and high dose dexamethasone. He had increased plasma calcitonin (257 pg/ml), glucagon (442 pg/ml), lactate dehydrogenase (497 IU/liter), and alpha-fetoprotein (5,144 pg/ml). He also had hypokalemic alkalosis with elevated plasma deoxycorticosterone (70 ng/ml) and PRA (6.9 ng/ml.h) but normal plasma aldosterone (8.2 ng/dl) and 18-hydroxycorticosterone (7.6 ng/dl). Preoperative localization of the tumor was accomplished by computed tomographic scan of the abdomen with concurrent barium enema. Cell-free translation of the tumor mRNA produced authentic proopiomelanocortin of 35,000 mol wt, indicating that the ACTH and beta LPH were produced by the tumor from a common precursor. After removal of a large amount of metastatic tissue from the boy, clinical progression of the remaining tumor was monitored by measuring plasma ACTH and beta LPH. Episodic secretion of ACTH and beta LPH was demonstrated by taking frequent plasma samples while suppressing pituitary ACTH with oral dexamethasone. Chemotherapy and radiation proved ineffective in controlling the growth of his tumor.

Adenoma, Islet Cell↗
PubMed1983

Serum luteinizing hormone and follicle-stimulating hormone and the response to luteinizing hormone-releasing factor in children and adolescents with isolated growth hormone deficiency.

Serum concentrations of LH and FSH were measured in 95 patients (62 males and 33 females) with presumed isolated GH deficiency [chronological age range, 5-17 yr; bone age (BA) range, 2-15.5 yr] before and after the iv administration of 100 micrograms LRF. The results were compared to those of patients of similar skeletal maturity, derived from a population of 136 children (79 males and 57 females) with constitutional short stature. Mean serum LH concentrations were similar in the GH-deficient and control patients of either sex within the age ranges studied. Mean basal FSH concentrations in males with GH deficiency were similar to the controls between BA 2 to less than 10 yr and more than 12 to 15.5 yr. The mean peak, peak minus basal, and integrated responses of LH concentrations after the iv administration of LRF were not significantly different in patients with GH deficiency from the responses in normal short children of similar ages. After LRF administration, GH-deficient males of BA between 2 and less than 10 yr had diminished FSH responses. The mean peak concentration was 1.9 +/- 0.2 ng/ml in GH-deficient males (n = 34) and 2.8 +/- 0.3 ng/ml (less than 0.05) in control males (n = 45). GH-deficient males of BA between 10-12 yr had slightly elevated mean peak and total integrated FSH concentrations; in GH-deficient patients (n = 15), these values were 2.7 +/- 0.2 ng/ml and 2.1 +/- 0.2 ng X min ml-1, respectively; and in controls (n = 18), they were 1.8 +/- 0.2 ng/ml (P less than 0.05) and 1.5 +/- 0.2 ng X min ml-1 (P less than 0.05). In the BA range from 4-8 yr, the mean peak response to LRF was diminished in GH-deficient females (n = 24; 4.0 +/- 0.4 ng/ml) compared to that in control females (n = 18; 6.0 +/- 0.9 ng/ml; P less than 0.05). In the BA range from more than 8 to 13 yr, the corresponding mean peak FSH concentration in GH-deficient females (n = 9) was 3.2 +/- 0.3 ng/ml; in control females (n = 39), it was 4.9 +/- 0.4 ng/ml (P less than 0.05). This study fails to confirm previous reports that LRF-evoked LH release is diminished in patients with isolated GH deficiency compared to that in normal short children of similar skeletal maturity. Small differences in group mean FSH concentrations were noted, but these findings are of limited clinical importance because an extensive degree of overlap of individual FSH concentrations was found in all comparisons between GH-deficient patients and normal children.

Adolescent↗
PubMed1982

Ontogeny and regulation of corticosteroid binding globulin capacity in plasma of fetal and newborn lambs.

The developmental pattern for plasma corticosteroid binding globulin (CBG) and unbound corticoids was studied in fetal and newborn sheep. CBG capacity in the fetus increased progressively from a value of 1.6 micrograms cortisol bound/dl plasma at 75 days gestation to 7.1 micrograms/dl at 141 days (n = 249), with a greater rate of increase after 120 days. By contrast total plasma proteins increased by about 50% during the third trimester. There was an accelerated increase in the concentration of both CBG and total proteins with labor, apparently reflecting hemoconcentration. The rate of increase in total plasma corticoids was similar to that for CBG capacity; however, corticoids began their major rise later in gestation (approximately 130 days). The concentration of unbound corticoids was 0.09 micrograms/dl at 115 days and did not increase until after 135 days, reaching a maximal level of 1.87 micrograms/dl on the day before spontaneous term delivery. After birth, CBG capacity decreased from a prepartum value of 11.4 micrograms/dl to 0.6 micrograms/dl at 14 days of age, whereas total plasma proteins were constant. Total and free corticoid levels also decreased postnatally, but at a slower rate than for CBG. The expected rise in fetal CBG capacity during the third trimester did not occur in hydranencephalic, stalk-sectioned, and hypophysectomized fetuses with loss of pituitary function. Under the conditions used, there was no precocious increase in CBG concentrations with infusion of hydrocortisone, PRL, or 17 beta-estradiol to intact fetuses, and infusion of ACTH to a hypophysectomized fetus did not affect the level of CBG. Thus, there is a marked increase in CBG capacity prenatally and a rapid decrease after birth. These changes in CBG may be responsible, at least in part, for the similar changes in total corticoid concentrations. We conclude that pituitary hormone(s) regulate CBG in the sheep fetus and speculate that this effect involves the placenta.

Adrenal Cortex Hormones↗
PubMed1981

Regulation of placental growth and chorionic somatomammotropin in the rhesus monkey: effects of protein deprivation, fetal anencephaly, and placental vessel ligation.

An isocaloric protein-deficient diet (0.5 gm/kg of body weight) was administered throughout pregnancy to 10 rhesus monkeys (Macaca mulatta). Ligation of the fetal interplacental bridging vessels (n = 6) and functional fetal hypophysectomy (experimental induction of anencephaly) (n = 10) were performed at midgestation. Monkey chorionic somatomammotropin (mCS) concentrations were measured serially in maternal plasma and in fetal plasma at birth. Fetal weight, trimmed placental weight, and placental DNA content were determined near term in the experimental groups and in controls matched for gestational age. Maternal mCS concentrations rose steadily until term and this rise paralleled the increase in placental weight (mCS at term = 16.5 +/- 0.90 microgram/ml in maternal plasma and 0.024 +/- 0.001 microgram/ml in fetal plasma). At term, maternal mCS correlated with placental DNA (r = 0.61, P less than 0.01) and placental weight (r = 0.49, P less than 0.01), but not fetal weight. Maternal mCS levels were not affected by protein deprivation, fetal anencephaly, or ligation of the interplacental bridging vessels. Maternal protein deprivation had a negative effect on fetal birth weight (409 +/- 22 versus 472 +/- 18 gm for controls, P less than 0.05) and maternal weight gain during pregnancy but had no effect on placental DNA or trimmed placental weight. Fetal anencephaly resulted in a 23% reduction in trimmed placental weight, no change in placental DNA, a 40% reduction in fetal body weight, and a reduced fetal/placental weight ratio. Ligation of interplacental bridging vessels resulted in atrophy of the secondary placental disc, an increase in weight and DNA content of the primary placenta, and normal fetal weight. We have concluded that the hemochorial placenta of the rhesus monkey responds to interruption of the fetal villous circulation in the first half of gestation by initiating compensatory hyperplasia. Placental cellular replication in the second half of rhesus pregnancy in minimally regulated by the fetal central nervous system or the pituitary gland. Secretion of mCS is primarily controlled by the mass of functioning trophoblast.

Anencephaly↗
PubMed1981

Hormonal and metabolic abnormalities associated with central nervous system germinoma in children and adolescents and the effect of therapy: report of 10 patients.

We describe the results of clinical and endocrinological investigations performed on 10 children and adolescents (5 males and 5 females) with a primary central nervous system germinoma. Eight of 10 patients were between 10-20 yr of age at the time of initial presentation. Polyuria (7 of 10) and a decrease in or cessation of linear growth (5 of 10) were the most common presenting symptoms, while only 2 of 10 patients complained of visual problems. Two patients presented with the syndrome of polyuria, adipsia, hypernatremia, profound muscle weakness, and hyperlipidemia. Initial physical exam revealed abnormal eye findings in 60%, short stature (greater than or equal to 2.5 SD) in 50%, and abnormal pubertal development in 30% of the patients. The neoplasm was located in the suprasellar-hypothalamic region in 8, caudate nucleus in 1, and pineal region in 1. Biopsy performed in 7 patients revealed the classic two-cell germinoma in all cases. Assessment of endocrine function before radiotherapy documented pituitary deficits in all patients studied. Antidiuretic hormone was deficient in 8 of 10 patients and was associated with hypoadipsia in 4. GH was deficient in al patients tested (7 of 7). TSH (5 of 8), ACTH (3 of 7), and gonadotropin (1 of 1) deficiencies were also common before treatment. Plasma PRL concentrations were elevated in 5 of 8 patients, all with suprasellar tumors. The hCG values were elevated only in the patient with sexual precocity (1 of 10). Endocrine evaluation during the postirradiation period revealed additional instances of GH (1), ACTH (1), and gonadotropin (5) deficiencies. All 10 patients are alive without evidence of active disease 6 months to 10 yr after radiation therapy (4500-5100 R). Evidence of hypothalamic-pituitary dysfunction is an early and almost universal feature of central nervous system germ cell tumors. The importance of careful evaluation and follow-up of children with acquired anterior or combined anterior and posterior pituitary dysfunction for a suprasellar tumor is stressed.

Adolescent↗
PubMed1980

Fetal sex and prenatal betamethasone therapy.

We examined the influence of fetal sex on the occurrence of respiratory distress syndrome in premature infants after maternal treatment with betamethasone. Among treated infants of 1,251 to 1,750 gm birth weight, the incidence of RDS was 40.9% in 22 males and 7.1% (P = 0.03) in 14 females. Cord serum levels of betamethasone were similar for infants of both sexes, and there was no sex difference in suppression of serum cortisol, dehydroepiandrosterone sulfate, and growth hormone after treatment. These findings suggest that prenatal corticosteroid therapy is less effective in male infants than in female infants. This effect is not due to a difference in transfer or metabolism of betamethasone, nor is it reflected in the responsiveness of the fetal hypothalamic-pituitary-adrenal axis to synthetic glucocorticoid.

Betamethasone↗