Syndrome of anosmia with hypogonadotropic hypogonadism (Kallmann syndrome): clinical and laboratory studies in 23 cases.
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Biomedical subjects
Publications and source records attributed to A D Rogol.
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The HL-60 cell is a human leukemic promyelocyte that can be grown in liquid suspension culture. This cell line binds radiolabeled insulin in a rapid, reversible specific manner indicating that it contains cells surface insulin-binding sites. these sites show a pH optimum of 7.8-8.0. Maximal binding was achieved in approx. 60 min at 22 degrees C and was linear with cell number between 5 X 10(6) and 10(8) cells per ml. Displacement of labeled insulin by unlabeled hormone was consistent with a 'two site' model with a high affinity site of 2.71 +/- 0.55 X 10(8) M-1 and 8700 sites per cell. Release of labeled insulin from its binding site was accelerated by unlabeled insulin at temperatures above 22 degrees C, but not at 4 or 15 degrees C. We conclude that the HL-60 cell contains cell surface binding sites for insulin with properties similar to other well-described insulin receptors of other tissues.
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A 21-yr-old woman with Turner's syndrome presented with signs and symptoms of acromegaly. The serum growth hormone (GH) (95+/-9.4 ng/ml; mean+/-SEM) and somatomedin C (11 U/ml) levels were elevated, and an increase in GH levels after glucose instead of normal suppression, increase after thyrotropin-releasing hormone (TRH) administration instead of no change, and decrease after dopamine administration instead of stimulation were observed. The pituitary fossa volume was greater than normal (1,440 mm(3)) and the presence of a pituitary tumor was assumed. After tissue removal at transsphenoidal surgery, histological study revealed somatotroph hyperplasia rather than a discrete adenoma. Postoperatively, she remained clinically acromegalic and continued to show increased GH and somatomedin levels. A search was made for ectopic source of a growth hormone-releasing factor (GRF). Computer tomographic scan revealed a 5-cm Diam tumor in the tail of the pancreas. Following removal of this tumor, serum GH fell from 70 to 3 ng/ml over 2 h, and remained low for the subsequent 5 mo. Serum somatomedin C levels fell from 7.2 to normal by 6 wk postoperatively. There were no longer paradoxical GH responses to glucose, TRH, and dopamine. Both the medium that held the tumor cells at surgery and extracts of the tumor contained a peptide with GRF activity. The GRF contained in the tumor extract coeluted on Sephadex G-50 chromatography with rat hypothalamic GH-releasing activity. Stimulation of GH from rat somatotrophs in vitro was achieved at the nanomolar range, using the tumor extract. The patient's course demonstrates the importance of careful interpretation of pituitary histology. Elevated serum GH and somatomedin C levels in a patient with an enlarged sella turcica and the characteristic responses seen in acromegaly to TRH, dopamine, and glucose do not occur exclusively in patients with discrete pituitary tumors and acromegaly. This condition can also occur with somatotroph hyperplasia and then revert to normal after removal of the GRF source. Thus, in patients with acromegaly a consideration of ectopic GRF secretion should be made, and therefore, careful pituitary histology is mandatory. Consideration for chest and abdominal computer tomographic scans before pituitary surgery, in spite of their low yield, may be justified.
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Reproductive system function in women cross-country runners. Med. Sci. Sports Exercise, Vol. 14, No. 4, pp. 263-269, 1982. The incidence and etiology of altered menstrual cycle function in women engaged in endurance athletic activities were investigated by studying endocrine, anthropometric, and training parameters in 41 cross-country runners. The prevalence of altered menstrual cycle patterns was significantly higher in the subjects than in college-aged; 49% reported normal cycles and 51% were either oligomenorrheic (46%) or amenorrheic (5%). No significant differences between those reporting normal menstrual cycling (N) and those reporting oligo/amenorrhea (O/A) were found in the following areas: number of miles run/week, number of years of training, age when training began, sum of skinfold thicknesses, somatotype, or post-exercise levels of growth hormone, prolactin, or hematocrit. However, a difference (P less than 0.05) was found in the mean age of menarche (N = 12.9 +/- 0.3 yr; O/A = 14.3 +/- 0.5 yr). In addition, more O/A (68%) than N (42%) began training in the year of or prior to menarche. Evaluation of seven runners from one school who qualified for the national meet (1 amenorrheic, 5 oligomenorrheic, and 1 normal) revealed that the basal estrogen, progesterone, prolactin, and thyroid hormone levels were normal and that there were normal luteinizing hormone and follicle-stimulating hormone responses to synthetic gonadotropin-releasing hormone (GnRH). These data are consistent with an alteration of hypothalamic-pituitary-ovarian function above the level of the pituitary.
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The effect of ammonium and acetate salts on glucose metabolism in isolated rat adipocytes was studied. Ammonia in low concentration (1-10 mM) was found to inhibit insulin-stimulated CO2 production. Acetate had no effect on this system except at high concentrations (100 mM), at which it stimulated CO2 production. Ammonium and acetate salts had an anti-lipolytic effect at high concentration (100 mM) but no effect on lipolysis at lower concentrations. The observation that trace amounts of salts can affect a biological assay system suggests that other biological assay system may also be altered by contaminating buffer salts from protein isolation steps.
After our observation of the failure of bromocriptine to inhibit LH secretion in hyperprolactinemic women, we have investigated the effects of bromocriptine and dopamine (DA) on LH secretion in normal ovulatory women within 5 days of the midcycle LH peak. Both bromocriptine (2.5 mg, orally) and DA (4 micrograms/kg . min, iv) for 4 h lowered serum PRL levels by more than 80%. Bromocriptine was ineffective in suppressing LH secretion and, in fact, resulted in a slight but significant stimulation, while, in contrast, DA was effective in lowering circulating LH levels by approximately 30% and reducing spontaneous LH fluctuations. The dissociation of the effects of these two dopaminergic agents on LH secretion may be explained by the existence of multiple DA receptors. The slight stimulatory effect of bromocriptine might be due to a preferential presynaptic action of bromocriptine inhibiting endogenous DA secretion in the hypothalamus and thus reducing this catecholamine's tonic inhibitory influence on LH secretion.
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Pergolide mesylate is a synthetic ergoline with dopamine agonist properties. The endocrine profile was studied in a double blind crossover design in six normal males. Circulating PRL, TSH, GH, LH, FSH, and cortisol were measured in the basal state and after TRH (500 micrograms iv) administration at 4.5, 11.5, and 23.5 h after placebo or pergolide (100 micrograms orally). Pergolide caused suppression of basal PRL from 2-8 ng/ml to less than 2 ng/ml commencing 60 min after administration and persisting throughout the 23.5-h study period. For the three TRH tests, a suppression of peak PRL (mean +/- SEM) response to TRH of 54.6 +/- 5.1 vs. 1.9 +/- 0.5, 45.2 +/- 4.1 vs. 4.5 +2- 0.6, and 34.4 +/- 2.9 vs. 6.9 +/- 1.4 ng/ml, respectively, for placebo and pergolide was noted. Basal TSH levels were unaffected by pergolide, but after pergolide the peak TSH response to the first two TRH challenges was blunted (placebo vs. pergolide: 12.3 +/- 1.2 vs. 6.8 +/- 1.0 and 14.8 +/- 2.0 vs. 9.6 +/- 1.0, respectively); however, the third TSH response (9.8 +/- 1.1 vs. 9.3 +/- 1.2) was not blunted after pergolide. GH secretion was stimulated by pergolide with a consistent pulse observed within 60 min of pergolide administration and an enhancement in the number and amplitude of subsequent GH pulses throughout the 24-h period. Cortisol levels rose after pergolide and returned to levels seen on the control day at 16.5 h. FSH levels were unaffected but LH levels were lowered pergolide. Side effects including nausea, vomiting, and hypotension were observed in all subjects. Pergolide is a potent dopamine agonist with the anticipated endocrine profile and clinical effects; its long duration of actions offers promise of single daily dose therapy for hyperprolactinemia.
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The concept that domapinergic mechanisms control LH secretion by modulation of gonadotropin-releasing hormone (GnRH) has been recently investigated in man. Since hyperprolactinemia is associated with increased hypothalamic dopamine turnover (which may reflect increased dopaminergic activity), inhibition of GnRH by dopamine in this situation would be maximal. Additional stimulation of dopamine receptors by a dopamine agonist would not be expected to result in further inhibition of LH release. Twelve hyperprolactinemic women were studied on 2 days during which measurements of serum PRL and LH were made over 11.5 h. Day 1 served as a control for day 2 when 2.5 mg of the dopamine agonist bromocriptine were administered orally at 0900 h. While serum PRL and LH levels on day 1 showed small fluctuations (+/- 10%), serum PRL on day 2 fell by 82%. Serum LH concentrations on day 2 remained unchanged. The demonstration or the efficacy of bromocriptine in lowering PRL levels documents the expected increase in dopaminergic tone; however, the lack of effect of bromocriptine in surpressing LH release suggests that either there is already maximal endogenous inhibition of GnRH in hyperprolactinemic women or, alternatively, that dopaminergic mechanisms are unimportant in the control of LH secretion.
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Two men are described who fulfill the criteria for both the Kallmann and the fertile eunuch syndrome, and we report the erythrocyte and HLA phenotypes of these men and their children. There were no paternal exclusions noted in red blood cell phenotypes encompassing seven separate red cell systems. The HLA phenotypes indicate that the probability that these men were the fathers of the children was greater than 99.99%.
Therapy for large prolactinomas remains controversial. Surgery is often unsuccessful in restoring endocrine function to normal. However, medical therapy with bromocriptine, a dopamine agonist, not only suppresses PRL levels, but may also lead to a reduction in tumor size. Previous reports have demonstrated radiographic evidence of tumor regression only after 3 or more months of bromocriptine therapy. We have now documented, for the first time, objective evidence of extremely rapid reduction in tumor size in two patients harboring large PRL-secreting pituitary tumors (mean pretreatment serum PRL levels, 2350 and 3900 ng/ml) who were prospectively treated with bromocriptine (7.5 mg/day) in preference to surgical intervention despite marked visual impairment in one of the patients. After 2 and 6 weeks of therapy, respectively, marked reduction in tumor size was demonstrated radiographically in both patients. Headache, visual acuity, and visual fields had improved after only 3 days. Although the mechanism of bromocriptine's antitumor activity is unclear, we believe that a large prospective trial to study the effects of bromocriptine therapy on the size of PRL-secreting macroadenomas is urgently needed to determine whether medical therapy should become the primary modality of treatment to reduce tumor size as well as restore endocrine function.
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