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Biomedical subjects

A Klibanski

Publications and source records attributed to A Klibanski.

At least 145 records · Page 8Linked to original sources
PubMed1986

Divergent dopaminergic regulation of TSH, free alpha-subunit, and TSH-beta in pituitary cell culture.

TSH is a glycoprotein hormone composed of two nonidentical, noncovalently associated subunits, alpha and beta. We have previously shown in vivo that intrapituitary free alpha-subunit and intact TSH have divergent responses to hypothyroidism and thyroxine treatment, suggesting fundamental differences in their regulation. To explore this further, we exposed anterior pituitary cell cultures from rats previously rendered hypothyroid to thyrotropin releasing hormone (TRH), dopamine (DA), or TRH and DA and determined TSH, free alpha-subunit and TSH-beta responses. While positive or negative trends were noted at four hours, the most significant changes were observed at 24 and 48 hours. TRH increased media TSH at 24 hours to 180% of its basal value (P less than 0.01), with a comparable response at 48 hours. TRH also increased free alpha-subunit to 155% of the basal value (P less than 0.01) and TSH-beta to 145% of the basal value (P less than 0.01) at 24 hours. In contrast, DA produced concordant inhibition of TSH to 85% (P less than 0.05), free a-subunit to 42% (P less than 0.01), and TSH-beta to 53% (P less than 0.01) of the basal values at 24 hours. However, coincubation with both TRH and DA produced discordant responses: TSH was stimulated to 126% of the basal value at 24 hours (P less than 0.01), while both free alpha-subunit and TSH-beta fell significantly below the basal values (81% and 65% respectively, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Pulsatile secretion of thyrotropin in man.

To examine pulsatile TSH secretion, serum TSH was determined every 10 min for 24 h in 6 normal subjects and every 15 min in 10 euthyroid patients with underlying thyroid disease. Serum T4, T3, and PRL were simultaneously measured in the 10 patients. Pulsatile TSH secretion was identified in all individuals. There was a highly significant correlation between the mean 24-h TSH concentration and pulse amplitude (P less than 0.001). There was a highly significant inverse correlation between the mean 24-h TSH concentration and pulse frequency (P = 0.002) and between the pulse amplitude and frequency (P = 0.002). The mean serum TSH level at night (1800-0600 h) was significantly higher than that during the day (P less than 0.001) and was associated with increases in pulse amplitude (P = 0.008) and frequency (P = 0.007). TSH pulses did not correlate with serum T4 or T3, but did correlate with serum PRL (P = 0.03) in patients with thyroid disease. We conclude that TSH pulsations can be identified in normal subjects and patients with thyroid disease; elevations in serum TSH levels correlate with an increase in pulse amplitude and a decrease in pulse frequency; the nocturnal rise in serum TSH is associated with increases in both pulse amplitude and frequency; and peripheral serum T4 or T3 concentrations are not closely associated with pulsatile TSH secretion.

Adult↗
PubMed1986

Osteoporosis in men with hyperprolactinemic hypogonadism.

To ascertain the effects of chronic hyperprolactinemia and testosterone deficiency on skeletal integrity in men, we measured forearm bone density and hormone concentrations in 18 men aged 30 to 79 who had prolactin-secreting pituitary tumors. We also measured vertebral bone density in 12 of the men. Patients with hyperprolactinemia had significant decreases in both forearm (p less than 0.001) and vertebral bone density (p = 0.003) compared with age-matched controls. Cortical osteopenia was significantly related to the duration of hyperprolactinemia (p less than 0.01) but not to the absolute levels of prolactin or androgens. Seven patients had longitudinal follow-up measurements of forearm bone density. Normalization of serum levels of prolactin or testosterone was associated with an increase in forearm bone density (p less than 0.05). These data show that chronic hyperprolactinemia and testosterone deficiency in men have deleterious and previously unrecognized extragonadal effects that may be alleviated after normalization of hormone concentrations.

Adenoma↗
PubMed1985

Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamic-pituitary disease.

The prolactin (PRL) response to thyrotropin-releasing hormone (TRH) was evaluated in 686 patients over a 4-year period. Of the 170 control subjects tested, none had a blunted PRL response to TRH. Eighty patients with prolactinomas documented by surgery were tested. Ninety-five percent (76 of 80) of these patients had an abnormally blunted PRL response to TRH. Of the 87 patients with a prolactinoma who did not undergo surgery, 98% (85 of 87) had a blunted PRL response to TRH. Many patients with other pituitary and hypothalamic diseases (pituitary tumors other than prolactinomas [Cushing's disease, acromegaly, chromophobe adenoma], craniopharyngioma) also had an abnormal PRL response to TRH (79 of 153, 52%). In the majority of patients with hyperprolactinemia due to dopamine antagonist medications, TRH stimulation did not produce a normal rise in PRL. The TRH test may be helpful in confirming the diagnosis of prolactinoma, but it is not a decisive factor in the diagnosis or management of this entity.

Adenoma↗
PubMed1985

Catecholestrogen regulation of prolactin synthesis in pituitary cell culture.

The 2-hydroxycatecholestrogens, 2-hydroxyestradiol [1,3,5-(10)estratriene-2,3,17 beta-triol] (2-OHE2) and 2-hydroxyestrone [2,3-dihydroxy-1,3,5-(10)-estratriene-17-one] (2-OHE1) were tested for their ability to alter PRL production and PRL messenger RNA (mRNA) levels in rat pituitary cell cultures. Treatment of cells with 10(-8) M 2-OHE1 or 2-OHE2 resulted in increased PRL secretion at 24 and 48 h (to 167% and 211% of control, respectively), but not at 4 h. Metabolism studies of radioactive 2-OHE1 and 2-OHE2 in parallel cultures demonstrated that the major metabolite at all times for either compound was the 2-methoxy derivative. After 24 h of treatment, nearly 40% of each compound was the original catecholestrogen, and at no time was there any detectable conversion to estradiol or estrone. Treatment of pituitary cells for 48 h with increasing concentrations of 2-OHE1 or 2-OHE2 resulted in a biphasic PRL dose response. PRL secretion was increased 3.6-fold for 2-OHE2 and 2.4-fold for 2-OHE1 between 10(-10) M and 10(-8) M. At concentrations above 5 X 10(-8) M, however, both compounds decreased PRL levels until, at 10(-6) M 2-OHE1 or 2-OHE2, PRL levels were 40-70% of control. Changes in PRL mRNA levels paralleled those of secretion. Treatment of pituitary cells with 10(-8) M of either 17 beta-estradiol (E2), 2-OHE1, or 2-OHE2 resulted in 2- to 5-fold increases in translatable and hybridizable PRL mRNA. The addition of 10(-7) M E2 plus 10(-8) M 2-OHE1 or 2-OHE2 resulted in PRL secretion and PRL mRNA levels equal to those resulting from E2 stimulation alone. The inhibition in PRL secretion and PRL mRNA levels caused by 10(-6) M 2-OHE1 or 2-OHE2 was partially overcome by coincubation of cultures with E2. Thus, 2-OHE1 and 2-OHE2 at low concentrations (less than 10(-8) M) can act on the pituitary as E2 agonists to increase PRL synthesis but at high concentrations may act as inhibitors of PRL production.

Animals↗
PubMed1985

Effect of carbohydrate supplementation on reproductive hormones during fasting in men.

We previously demonstrated that during a 10-day fast in mildly obese men, urinary gonadotropin excretion significantly increased, and serum testosterone concentrations significantly decreased. The mechanisms by which these changes occur are unknown. We postulated that the mechanism of the gonadotropinuria might involve decreased proximal renal tubular reabsorption of gonadotropins during fasting and might be related to renal tubular reabsorption of ketones during fasting, a process that is enhanced by carbohydrate (CHO) administration. We studied the effects of CHO supplementation on ketosis, ketonuria, and reproductive hormone secretion and excretion in 14 mildly obese men, 24-54 yr old, who were 14-69% above ideal body weight. Group I (n = 6) received no CHO supplementation, group II (n = 4) received 15 g CHO, and group III (n = 4) received 45 g CHO daily during the 10-day fast (F). During the control (C) and refeeding (R) periods, all subjects received a 1500-cal diet. Daily 24-h urine collections were made for the measurement of total ketones (millimolar concentrations) and LH and FSH (expressed as international units of the Second International Reference Preparation of human menopausal gonadotropin). Values (mean +/- SE) for 3 representative days (control day 3, fasting day 8, and refeeding day 3) for all subjects are shown below: (table; see text) We also studied the effects of CHO supplementation on serum levels of pituitary gonadotropins, LH and FSH responses to exogenous LHRH stimulation, biological activity of LH, and circulating total and free testosterone levels. Neither dose of CHO prevented the decline in total and free testosterone levels. Serum LH concentrations, as measured by both the RIA and in vitro bioassay did not change significantly with fasting. Serum FSH concentrations in daily samples did not change significantly. The previously reported decline in the FSH response to LHRH stimulation with fasting was not prevented by CHO. We conclude that CHO supplementation prevents the gonadotropinuria of fasting in men. The effect appears to occur in the kidney. The mechanisms may be related to that by which CHO promotes the renal tubular reabsorption of ketones. The reduced serum testosterone level cannot be explained by a lack of biologically active LH. It appears that fasting has a direct effect on the testis, possibly by reducing its responsiveness to gonadotropic stimulation or by inhibiting steroidogenesis.

Adult↗
PubMed1985

Hormonal responses to short term fasting in postmenopausal women.

Urinary excretion of gonadotropins increases during fasting. We investigated whether this increase results from increased pituitary secretion of LH and FSH or from altered renal excretion of protein molecules. To this end, we studied urinary gonadotropin excretion, serum gonadotropin levels, and pituitary responsiveness of LHRH during control, 10-day fasting, and refeeding periods in 10 mildly obese postmenopausal women. Additionally, we measured urinary cortisol and estriol excretion and circulating levels of dehydroepiandrosterone sulfate, estradiol, estrone, melatonin, norepinephrine, epinephrine, and dopamine during the control, fasting, and refeeding periods. While urinary excretion of gonadotropins increased markedly during fasting, there were no significant changes in serum gonadotropin levels or in the pituitary sensitivity to LHRH. Plasma norepinephrine and serum melatonin increased significantly during fasting, but serum and urinary estrogens, indices of adrenal activity, and plasma levels of epinephrine and dopamine did not change. These results show that the stress of short term fasting selectively activates only certain components of the neuroendocrine system without any appreciable changes in the function of the gonadotropin-secreting system. Fasting-induced gonadotropinuria is probably explained by altered renal handling of gonadotropin molecules.

Adult↗
PubMed1984

Gonadotropin and prolactin pulsations in hyperprolactinemic women before and during bromocriptine therapy.

Pulsatile gonadotropin secretion and its relationship to PRL and estradiol (E2) secretion were investigated in 20 hyperprolactinemic amenorrheic women by obtaining serial blood samples for 6- to 24-h periods. Thirteen patients were restudied in the early follicular phase of the menstrual cycle (days 3-5) after ovulatory periods were established during bromocriptine therapy. In the hyperprolactinemic women, the number of LH peaks ranged from 0-12/24 h, and LH peak amplitude ranged from 0-1.7 mIU/ml. Serum E2 correlated with mean LH concentrations (P less than 0.001) and LH pulse frequency (P less than 0.05), but not with LH pulse amplitude. FSH pulsations were identified in 3 of the 20 women. There was no correlation between mean FSH concentrations and either serum E2 or PRL. There was a significant correlation between LH and FSH concentrations (P less than 0.001). During bromocriptine therapy, with comparable E2 concentrations, 5 of the 6 patients studied with blood sampling every 20 min for 24 h had a significant decrease (P less than 0.01) in the number of LH peaks per 24 h, with no change in LH peak amplitude. Mean FSH concentrations were unchanged in bromocriptine-treated patients; however, there was a significant (P less than 0.02) decrease in FSH levels during sleep. Serum PRL was normal in all bromocriptine-treated patients, but normal PRL secretory patterns were not reestablished, and there was no correlation between LH pulsations and serum PRL concentrations. We conclude that 1) hyperprolactinemic women have a heterogeneous pattern of pulsatile gonadotropin secretion; 2) serum E2 correlates with LH pulse frequency but not pulse amplitude; 3) LH pulsations and PRL pulsations are asynchronous in hyperprolactinemic women before and during bromocriptine therapy; and 4) normal PRL secretory patterns are not required for ovulatory function in hyperprolactinemic women treated with bromocriptine.

Adenoma↗
PubMed1983

Dopaminergic modulation of TSH and its subunits: in vivo and in vitro studies.

We have studied the effects of dopamine on the secretion of TSH and its subunits in vivo and in vitro. Four normal controls, seven patients with primary hypothyroidism, two patients with peripheral resistance to thyroid hormone (PRTH), and two patients with alpha-secreting pituitary tumours underwent a 3-h dopamine infusion (4 micrograms/kg/min). Serial blood samples were drawn for TSH, PRL, alpha, and TSH-beta subunit. In normal subjects, TSH fell from 2.1 +/- 0.9 (+/- SE) to 0.7 +/- 0.1 microU/ml (P less than 0.05), and alpha declined from 1.5 +/- 0.4 to 1.0 +/- 0.1 ng/ml (P less than 0.01). TSH-beta was at or slightly above the detection limits of the assay before and after dopamine. In hypothyroidism, basal serum TSH was 81 +/- 14 microU/ml. With dopamine, TSH fell to 35 +/- 8 microU/ml (P less than 0.001), while alpha decreased from 3.2 +/- 0.4 to 2.0 +/- 0.3 ng/ml (P less than 0.01). Serum TSH-beta also declined from 0.97 +/- 0.06 to 0.57 +/- 0.05 ng/ml (P less than 0.001). A similar fall in TSH and alpha was seen in the two patients with PRTH. In normals and hypothyroid patients, the percentage change in alpha concentration was significantly less than that observed for intact TSH. This is due presumably to the contribution of the gonadotrophs to the circulating alpha pool. TSH and TSH-beta were undetectable in the two pituitary tumour patients, and alpha declined only slightly in each patient after dopamine. The in vitro effects of dopamine were studied using cultured bovine anterior pituitary cells. Dopamine (10(-4)-10(-8) mol/l) did not change basal TSH, alpha, or TSH-beta release. However, dopamine at all doses significantly blunted TRH (10(-7) mol/l)-stimulated TSH and TSH-beta release, and blunted TRH-mediated alpha release at the two highest dopamine doses. These data suggest that dopamine modulates both TSH and TSH subunit secretion. These effects may be exerted directly at the level of the thyrotroph.

Adult↗
PubMed1983

The effect of somatostatin on the release of thyrotropin and its subunits from bovine anterior pituitary cells in vitro.

The effects of somatostatin (SRIF) on the production and release of TSH and its subunits have been investigated in bovine anterior pituitary monolayer cultures. SRIF caused a dose-dependent inhibition of TSH and subunit release by TRH, with a half-maximal effective dose of 3 X 10(-8) M. This effect was time dependent and was greater for TSH than for its subunits. However, the basal release and total production of TSH and its subunits over a 24-h period were not affected by SRIF. The effect of SRIF was additive to that of thyroid hormones in suppressing the release of TSH and its subunits by TRH. A combination of SRIF and thyroid hormone completely suppressed the release of TSH and its subunits by TRH. In contrast, thyroid hormones caused a dose-dependent inhibition of the total production, as well as the release, of TSH and its subunits induced by TRH. Furthermore, thyroid hormones produced a dose-dependent increase (r = 0.81; P less than 0.001) in the effectiveness of a single dose of SRIF in suppressing TSH release by TRH. Analysis of these data revealed that thyroid hormones interacted synergistically with the SRIF effect to suppress TRH-mediated TSH and subunit release.

Animals↗
PubMed1983

Direct adrenergic stimulation of the release of thyrotropin and its subunits from the thyrotrope in vitro.

Adrenergic effects on TSH and subunit secretion were investigated in bovine anterior pituitary monolayer cultures. Epinephrine (E) (10(-6) M) caused a significant increase in TSH, alpha-subunit, and TSH beta release into the medium (P less than 0.001, P less than 0.001, and P less than 0.01, respectively). E, norepinephrine, and phenylephrine, all alpha-adrenergic agonists, caused significant increases in TSH release, with half-maximal effects at 4.3 X 10(-7), 6.8 X 10(-7), and 8.2 X 10(-7) M, respectively. However, isoproterenol, a beta-adrenergic agonist (10(-7)-10(-4) M), did not alter TSH or subunit release. Clonidine, an alpha 2-adrenergic agonist (10(-7)-10(-4) M), had no effect on TSH or subunit secretion; however, coincubation of clonidine (5 X 10(-7) M) with a submaximal concentration of phenylephrine (5 X 10(-7) M) caused a rise in TSH release greater (P less than 0.02) than that seen with P alone. The alpha-adrenergic antagonists phentolamine and fluphenazine completely inhibited (P less than 0.001) the E-induced rise in TSH and subunits. In contrast, the beta-adrenergic antagonists propranolol and metoprolol did not significantly inhibit the stimulation of TSH by E. TSH and subunit secretion is stimulated by adrenergic agonists acting directly on the pituitary, and this is probably mediated via an alpha-adrenergic receptor.

Adrenergic alpha-Agonists↗
PubMed1983

alpha-Subunit and gonadotropin responses to luteinizing hormone-releasing hormone in hyperprolactinemic women before and after bromocriptine.

alpha-Subunit and gonadotropin responses to a LHRH infusion (0.2 micrograms/min) for 4 h were studied in eight hyperprolactinemic amenorrheic women, ages 23-40, and in five normal women in the early follicular phase of the menstrual cycle. Basal alpha-subunit and LH concentrations were comparable to normal women; however, basal FSH concentrations were significantly (P less than 0.05) lower. Peak serum alpha, LH, and FSH concentrations during the LHRH infusion were significantly higher than controls (P less than 0.01, P less than 0.05, and P less than 0.01, respectively). Gel chromatography of serum confirmed the presence of both free alpha-subunit and intact LH which had normal biological activity. Six of the women were restudied in the early follicular phase of the cycle after return of normal ovulatory function and normalization of serum PRL concentrations. During bromocriptine therapy, peak serum alpha, LH, and FSH concentrations decreased significantly (P less than 0.02, P less than 0.05, and P less than 0.001, respectively) and were comparable to control subjects. The changes in serum alpha and gonadotropin responses to the LHRH infusion during bromocriptine therapy occurred independently of the serum estradiol concentrations. Abnormalities in the regulation of alpha-subunit and gonadotropin secretion are present in hyperprolactinemia. These abnormalities reverse with bromocriptine therapy and may occur independently of changes in gonadal steroids.

Adult↗
PubMed1983

Pure alpha subunit-secreting pituitary tumors.

The authors describe six patients with pituitary macroadenomas hypersecreting only the alpha subunit of the glycoprotein hormones. These patients had been previously diagnosed as having "non-functioning chromophobe adenomas." All of the patients had visual field abnormalities and partial hypopituitarism. The elevated serum alpha concentrations showed a variable response to stimulation by thyrotropin-releasing hormone, and could not be suppressed by thyroid hormone administration. Immunological, gel chromatographic, and immunocytochemical studies documented that only the alpha subunit was present. Following pituitary surgery and radiotherapy, serum alpha levels decreased. These patients represent a new subset of functioning pituitary tumors. Determination of alpha subunit concentration is useful in managing some patients with pituitary tumors previously thought to have non-functioning chromophobe adenomas.

Adenoma↗
PubMed1981

Pure alpha-secreting pituitary adenomas.

Isolated hypersecretion of the alpha subunit of the glycoprotein hormones occurred in two men with previously diagnosed "nonfunctioning chromophobe adenomas." The alpha hypersecretion was unresponsive to hypothalamic releasing hormone, thyroid hormone, and sex-steroid hormones. After trans-sphenoidal surgery and conventional pituitary irradiation, alpha secretion was decreased. Increased quantities of immunologically active and biologically inactive luteinizing hormone (LH) material were detected in serum and in tumor homogenate. Immunologic and gel-chromatographic studies determined that only the alpha subunit was present and that it was cross-reacting in the LH immunoassay. These studies suggest that the alpha subunit may be a useful marker of pituitary tumors, particularly in patients without clinical evidence of hormonal hypersecretion.

Adenoma, Chromophobe↗
PubMed1981

Reproductive function during fasting in men.

To investigate reproductive function during fasting, six men 20-74% over ideal body weight completed an 18-day study consisting of a 3-day control period, a 10-day total fast, and a 5-day refeeding period. All men lost at least 4.1% of total weight and demonstrated ketonemia and ketonuria. The FSH response to LRH (0.2 microgram/min for 4 h) stimulation was significantly lower (P less than 0.05) during fasting and remained so during refeeding. Serum FSH concentrations were significantly lower (P less than 0.05) during the fast in five of six patients compared to those during the control period, whereas serum LH concentrations were unchanged. The effects of fasting on endogenous LH and FSH pulsations were studied by obtaining serum at 20-min intervals for 6 h on days 2, 11, and 16. Neither the amplitude nor the frequency of LH and FSH pulsations changed significantly during fasting or refeeding. Serum testosterone concentrations were significantly lower (P less than 0.025) by fasting day 9 compared to control values. The 24-h urinary excretion of both LH and FSH increased significantly (P less than 0.05) by fasting day 6 and reached a maximum by fasting day 8. Urinary LH excretion did not return to normal after 3 days of refeeding, whereas urinary FSH excretion returned to baseline by the first day of refeeding. We conclude that during short term fasting in obese men: 1) serum FSH concentrations decrease, 2) the pituitary responsiveness of FSH and LRH is blunted, 3) serum testosterone decreases, and 4) the urinary excretion of both LH and FSH increase.

Adult↗
PubMed1981

Reduction of plasma immunoreactive somatomedin C during fasting in humans.

We have assessed the effect of fasting for 10 days on plasma concentrations of immunoreactive somatomedin C and urinary urea excretion in seven obese male volunteers. From a mean prefast value of 0.83 U/ml, plasma somatomedin C fell to 0.21 U/ml after 10 days of fasting. A prompt increase was observed with refeeding. The change in somatomedin C during fasting showed a highly significant correlation with the change in urinary urea nitrogen excretion (r = 0.74; P less than 0.001). It also was shown that inhibitors which interfere with quantitation in somatomedin bioassays are not observed in the RIA for somatomedin C. The results of this study suggest that measurement of plasma somatomedin C provides a sensitive indicator of nitrogen loss and may be useful in monitoring the changes in protein metabolism that occur during alterations in nutritional status.

Adult↗