Cysteamine decreases prolactin responsiveness to thyrotropin-releasing hormone in normal men

Cysteamine depletes pituitary and plasma prolactin in rats. It acts through a nondopaminergic mechanism to alter both immunoactive and bioactive prolactin. The effect of cysteamine on prolactin secretion is reported in normal men. Six normal subjects received a control thyrotropin-releasing hormone (TRH) test at 0900 using 200 micrograms TRH intravenously; serum prolactin and TSH were measured at -10, 0, 10, 20, 30, 60, and 90 min after administration of TRH. Serum calcium and parathyroid hormones levels were measured at -10 min. Seven or more days later, they received cysteamine hydrochloride 15 mg/kg body weight orally every 6 hours for 5 doses. One hour after the last dose, the TRH test was repeated. Peak serum prolactin levels following TRH, prolactin levels at the 10-min time point, and total area from 0 to 30 min under the prolactin secretory curve were significantly decreased by cysteamine administration. TSH levels were unchanged. Serum calcium levels were significantly decreased by cysteamine administration, but parathyroid hormone levels were unchanged. It was concluded that cysteamine reduced TRH-stimulated prolactin secretion. Cysteamine also decreases serum calcium levels and suppresses the anticipated rise in serum parathyroid hormone levels. These effects on serum calcium and parathyroid hormone are similar to those previously shown for WR2721, another sulfhydryl compound. Cysteamine should be further considered as an alternative drug in the treatment of hyperprolactinemia and as a therapeutic agent for hypercalcemia.     

The relationship of changes in serum estradiol and progesterone during the menstrual cycle to the thyrotropin and prolactin responses to thyrotropin-releasing hormone.

The responses of serum TSH and PRL to TRH (500 microgram) were studied in normal young women in the early follicular, periovulatory, and midluteal phases of the menstrual cycle in order to examine the relationship of these responses to the levels of estradiol relationship of these responses to the levels of estradiol (E2) and progesterone. Each woman was studied twice in each phase in order to assess intraindividual variability. There was no significant difference in either the TSH or PRL responses among the phases of the menstrual cycle nor was either response affected by the periovulatory rise in E2 or by the luteal rise in both E2 and progesterone. Thus, the interpretation of the TSH and PRL responses to TRH in normal women is not affected by the menstrual cycle although both responses are greater in women that in men. Both the peak TSH and peak PRL after TRH were highly correlated with the basal levels of TSH (r = 0.85; P less than 0.01) and PRL (r = 0.67; P less than 0.01), respectively, indicating that the TSH and PRL responses to TRH in women are directly proportionate to the basal levels of the respective hormones, as previously shown for the TSH response in men. The mean intraindividual variability (coefficient of variation) of the TSH response to TRH was 18%, but ranged as high as 56%, while that of the PRL response was 16% and ranged up to 31%; variability was not affected by the phase of the menstrual cycle. The normal range of the peak TSH after TRH in women is 7-33 microU/ml (mean +/- 2 SD); however, because of the variability, a normal woman may sometimes have a peak TSH after TRH as low as 4 microU/ml. Repeating the test will result in a normal value if the woman is truly normal. Similarly, the normal peak PRL after TRH in women is 22-111 ng/ml (mean +/- 2 SD); usually, however, the lower limit is 30 ng/ml with lower values due to intraindividual variation. The data suggest that the higher average level of E2 in women compared to women, but that the cyclic changes in serum E2 or progesterone in women have little or no additional effect.     

Effects of disodium EDTA and calcium infusion on prolactin and thyrotropin responses to thyrotropin-releasing hormone in healthy man

To determine the impact of induced hypo- and hypercalcemia on TRH (400 micrograms)-stimulated TSH and PRL release, healthy subjects (n = 11) were infused with 5% glucose in water (n = 11), disodium EDTA (n = 11), or calcium gluconate (n = 7). TRH was given as an iv bolus 60 min (5% glucose and EDTA) and 120 min (calcium) after initiation of the respective infusion. Basal plasma concentrations of TSH remained unchanged during induced hypo- and hypercalcemia, whereas those of PRL fell during the latter (P less than 0.05). The mean sum of increments (0-90 min) in PRL and TSH was considerably greater during hypocalcemia than during hypercalcemia (PRL, P less than 0.002; TSH, P less than 0.005). The increments in the plasma hormone concentration above basal after iv TRH were increased compared to those in normocalcemia (PRL, 98.4 +/- 37.9 ng/ml; TSH, 38.9 +/- 11.8 microU/ml) during hypocalcemia [PRL, 128 +/- 47.8 ng/ml (P less than 0.002); TSH, 46.7 +/- 12.8 microU/ml; (P less than 0.005)], but were impaired during hypercalcemia [PRL, 70.1 +/- 27 ng/ml (P less than 0.002); TSH, 28.9 +/- 8.5 microU/ml (P less than 0.025)]. The mean sum of increments in PRL was related to concentrations of both serum calcium (r = -0.59; P less than 0.01) and PTH (r = 0.51; P less than 0.05). A relation was also seen between the incremental responses of TSH and serum calcium (r = -0.52; P less than 0.05), PTH (r = 0.55; P less than 0.01), and phosphorus (r = -0.55; P less than 0.01). We conclude that in healthy man, TRH-mediated release of both PRL and TSH are inversely related to serum calcium concentrations in such a manner that hormone secretion is enhanced by acute hypocalcemia, but blunted by hypercalcemia.     

Basal serum prolactin levels and prolactin responses to constant infusions of thyrotropin releasing hormone in healthy aging men

We measured serum prolactin (PRL) levels by RIA before and during a 240-min constant infusion of TRH (0.4 microgram/min iv) in three similarly sized groups of healthy aging men 30 to 49, 50 to 69, and 70 to 96 years. Basal data were evaluated by analysis of variance with Duncan's multiple range test and regression analysis. Mean basal serum PRL level was elevated (p less than .05) in the oldest group, attributable to PRL elevations (between 20 and 40 ng/ml) in 4 men over 75 years. Serum PRL levels decreased (p less than .001) from -30 min to 0 min before TRH infusion in all groups, but there was no age-dependent difference (p greater than .3) in the magnitude of the reduction. Repeated measures analysis of variance showed increased serum PRL levels (p less than .001) during TRH infusion in all age groups, and an age-dependent increase (p less than .05) in magnitude of peak PRL response. This significant difference was between the two oldest age groups early in the infusion. Chi-square analysis revealed an increased (p less than .05) frequency of early (less than 120 min) peak responses in the oldest age group. The present data suggest that basal and TRH-stimulated PRL secretion may be augmented in some healthy older men.     

Thyrotropin and prolactin responses to thyrotropin-releasing hormone in premenstrual syndrome

Recent reports of altered TSH responsiveness to its releasing hormone (TRH) in women with premenstrual syndrome (PMS) suggested that subclinical hypothyroidism may be responsible for the mood changes, such as depression, that occur in these women. In this study we measured basal and TRH-stimulated serum TSH and PRL levels in 15 women with PMS and in 19 age-matched normal women. The mean baseline serum TSH concentrations were similar in the 2 groups in both the follicular [normal, 1.3 +/- 0.2 (+/- SE); PMS, 0.9 +/- 0.2 mU/L] and luteal (normal, 1.1 +/- 0.2; PMS, 1.1 +/- 0.2 mU/L) phases of the cycle. The mean baseline serum PRL levels also were similar in the 2 groups in the follicular (normal, 16 +/- 2; PMS, 13 +/- 2 micrograms/L) and luteal (normal, 13 +/- 2; PMS, 14 +/- 2 micrograms/L) phases of the cycle. After TRH administration, peak serum PRL and TSH levels were reached at 15 and 30 min, respectively, and the response curves were virtually identical in the 2 groups in both phases of the cycle. One normal woman had elevated basal and TRH-stimulated TSH concentrations compatible with subclinical hypothyroidism, but had normal noncyclic scores on her prospective rating scales. Our findings suggest that PMS is not associated with thyroid dysfunction or abnormal PRL secretion and that thyroid hormone replacement therapy is not indicated in this condition.     

Lack of dissociation of prolactin responses to thyrotropin releasing hormone and metoclopramide in chronic alcoholic men

Prolactin, growth hormone and thyroid stimulating hormone responses to thyrotropin releasing hormone (TRH) and metoclopramide were determined in 12 alcoholic men with biopsy proven liver disease and were compared to those of 8 age matched normal controls. All subjects were challenged with TRH (400 micrograms) and metoclopramide (10 mg) given as an intravenous bolus each on a separate day. Alcoholics had increased basal prolactin and growth hormone levels compared to controls. Alcoholics had a brisk and statistically significant (p less than 0.01) response for each of the 3 hormones studied in response to TRH. In contrast to the alcoholics, the controls did not demonstrate a growth hormone response to TRH. Moreover, the TSH response to TRH of the alcoholics was exaggerated (p less than 0.05) compared to that of the controls. In response to metoclopramide, alcoholics had a brisk prolactin response, failed to demonstrate a TSH response, and had a decline in growth hormone when compared to controls. These results for alcoholics with liver disease differ from those reported for individuals with renal failure while those for the controls are similar to previously reported normal responses. These data suggest that liver disease and renal disease must differ in terms of their patterns of hypothalamic-pituitary neuroregulation as documented by their differing pituitary hormone responses to TRH and metoclopramide.     

Suppression of prolactin and thyrotropin secretion in the rat by antiserum to thyrotropin-releasing hormone.

Administration of antiserum to synthetic thyrotropin-releasing hormone (TRH) to male and female rats cause a 50% and a 70% suppression in serum levels of prolactin and thyrotropin, respectively, as compared with controls injected with normal rabbit serum. The degree of suppression was similar in diestrous and proestrous female rats and in male rats. These findings support the view that, in addition to its original designation, TRH also has a physiological role in regulating release of pituitary prolactin.     

Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short term triiodothyronine suppression

Serum TSH and PRL levels and their response to TRH were measured in 11 patients with generalized resistance to thyroid hormone (GRTH), 6 euthyroid subjects, and 6 patients with primary hypothyroidism. TSH and PRL levels and their response to TRH were also measured after the consecutive administration of 50, 100, and 200 micrograms T3 daily, each for a period of 3 days. Using a sensitive TSH assay, all GRTH patients had TSH values that were elevated or within the normal range. On the basis of a normal or elevated TSH level, GRTH patients were classified as GRTH-N1 TSH (5 patients) or GRTH-Hi TSH (6 patients), respectively. Only GRTH patients with previous thyroid ablative therapy had basal TSH values greater than 20 mU/L. TSH responses, in terms of percent increment above baseline, were appropriate for the basal TSH level in all subjects. No GRTH patient had an elevated basal PRL level. PRL responses to TRH were significantly increased only in the hypothyroid controls compared to values in all other groups. On 50 micrograms T3, 7 of 12 (58%) nonresistant (euthyroid and hypothyroid) and 1 of 11 (9%) resistant subjects had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, 2 of 12 (17%) nonresistant and 4 of 11 (36%) resistant subjects had a greater than 50% suppression of the PRL response to TRH. On 200 micrograms T3, all subjects, except for 1 with GRTH, had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, while 11 of 12 (92%) nonresistant subjects had a greater than 50% reduction of the PRL response to TRH, only 3 of 10 (30%) resistant patients showed this degree of suppression (P less than 0.005). Without previous ablative therapy, serum TSH in patients with GRTH is usually normal or mildly elevated. The TSH response to TRH is proportional to the basal TSH level and is suppressed by exogenous T3. However, on 200 micrograms T3 basal TSH was not detectable (less than 0.1 mU/L) in all euthyroid subjects, but it was measurable in three of four GRTH patients with normal TSH levels before T3 treatment. PRL levels in GRTH are normal even when TSH is elevated. The PRL response to TRH is not increased in GRTH. In all subjects, exogenous T3 suppresses the PRL response to TRH to a lesser degree than the TSH response, but this difference is much greater in patients with GRTH.     

Histamine-induced paradoxical growth hormone response to thyrotropin-releasing hormone in normal men

GH responses to TRH occur in patients with certain diseases, such as acromegaly, severe liver disease, uremia, and mental disorders, and presumably reflect disruption of normal hypothalamic control of GH secretion. Since histamine (HA) inhibits hypothalamic stimulation of GH secretion, we investigated the combined effect of HA receptor activation and TRH administration on GH secretion in normal men. Eight men were given 4-h infusions of the following: saline, HA, HA plus mepyramine (Me; and H1-antagonist), HA plus cimetidine (C; an H2-antagonist), and C alone. TRH (200 micrograms) was injected iv 2 h after the start of each infusion. HA alone or in combination with either antagonist had no effect on basal or TRH-stimulated TSH secretion and no effect on basal GH secretion. However, when TRH was injected during H1 stimulation by HA plus C, GH secretion increased significantly [from 0.7 +/- 0.1 to 7.1 +/- 1.8 (+/- SEM) ng/ml; P less than 0.01] in seven of eight subjects. This GH response was reproducible and did not occur when saline was administered instead of TRH. A smaller and delayed GH response to TRH occurred during infusions of HA alone (from 0.8 +/- 0.1 to 4.9 +/- 1.0 ng/ml; P less than 0.05). No effect of TRH on GH secretion occurred during the infusion of saline (1.2 +/- 0.3 ng/ml), HA plus Me (0.9 +/- 0.1 ng/ml), or C (2.2 +/- 1.0 ng/ml). There was a significant increase in GH secretion after cessation of the infusions of HA (from 3.4 +/- 1.1 to 7.5 +/- 2.2 ng/ml) and HA plus Me (from 0.8 +/- 0.1 to 5.1 +/- 1.8 ng/ml). This rebound in GH secretion might indicate an inhibitory effect of TRH during H2-receptor stimulation. This concept is supported by the significantly smaller GH response to TRH during HA infusion than during HA plus C infusion (P less than 0.01). The study indicates that H1-receptor stimulation induces a stimulatory effect of TRH on GH secretion in normal men and that H2-receptor stimulation possibly induces an inhibitory effect of TRH on GH secretion.     

Unchanged thyrotropin and prolactin responses to thyrotropin releasing hormone after indomethacin treatment.

Experimental effects of prostaglandin synthetase inhibitors have been considered in the literature as a clue to the possible interactions of prostaglandins with the hypothalamic releasing hormones at the pituitary level. Some results of the administration to man of these drugs are apparently in contrast with the in vivo and in vitro animal data. The present investigation deals with the comparison between the thyrotropin releasing hormone (TRH) effect on prolactin and thyrotropin when the hormone was administered intravenously at doses of 50, 100 and 200 microgram respectively to three groups of six men (aged 22 to 30 years), before and on the sixth day of indomethacin administration (50 mg orally at 6-hour intervals). No significant change in the releasing hormone effect was observed either in the case of prolactin, where TRH caused a consistently similar release of the hormone at every dose employed, or in the case of thyrotropin, where a dose-dependent releasing effect was obtained before and after indomethacin treatment.     

The dissociation of the exaggerated prolactin and thyrotropin responses in seminiferous tubule failure following the administration of a double-pulse of thyrotropin-releasing hormone

PRL and TSH secretion has been evaluated in 11 patients with seminiferous tubule failure and 9 controls. When compared to the controls, the patients had increased basal FSH, TSH and PRL levels. However, LH, E2, T and thyroid hormone levels were similar to the controls. Both groups were given two pulses of TRH (200 micrograms) at 30 min intervals. Following the initial pulse of TRH, the patients demonstrated exaggerated TSH and PRL responses. The administration of a second pulse of TRH led to a further increment of TSH secretion in the patients. There was, however, no PRL response to the second TRH pulse in either patients or controls although mean PRL levels remained significantly greater in the patients.     

Effects of thyrotropin-releasing hormone in vitro on thyrotropin and prolactin release from the turtle pituitary

Effects of synthetic thyrotropin-releasing hormone (TRH) on thyrotropin (TSH) and prolactin (PRL) release by hemipituitaries of adult turtles, Chrysemys picta, were studied in an in vitro superfusion system. Significant increases in the rates of secretion of both immuno-reactive TSH and PRL occurred at doses between 0.01 and 10 ng/ml TRH. TSH secretion increased acutely by two-, to sixfold over nonstimulated secretion levels; responses tended to decline after many hours of continual stimulation, but output remained elevated above baseline in most cases. PRL secretion increased, parallel to TSH secretion during TRH stimulation. No significant difference was found in secretion rates between males and females, and no clear relationship between TRH responsiveness and reproductive stage was evident. These data provide the first direct evidence for the stimulation of TSH secretion by TRH in a reptile and confirm earlier reports that TRH stimulates the release of PRL in the turtle. Although previous in vivo studies indicated that TSH secretion was not affected by TRH in turtles, the present data indicate that the dose sensitivity of the chelonian gland is comparable with that of mammalian and avian pituitaries. Evidence for the role of TRH in endogenous TSH regulation is still lacking in reptiles but the present data provide evidence for functional TRH receptors on the chelonian thyrotrope and, hence, argue against the hypothesis that TSH stimulating activity of TRH evolved relatively recently in association with endothermy.     

Growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with severe liver disease.

Thyrotropin-releasing hormone (TRH) was administered iv to 10 patients with severe liver disease and 10 control subjects. Injection of 400 microgram TRH as a bolus induced in 7 out of 10 patients a clear-cut GH rise (larger than or equal 10 ng/ml) occurring 15-120 min after the injection, and no effect on GH levels in controls. Mean baseline GH levels wre higher in patients than in controls. An exaggerated and sustained PRL rise was present after TRH in the subjects with liver disease, whose mean baseline plasma PRL levels were within normal range.     

Molecular heterogeneity of serum follicle-stimulating hormone in hypogonadal patients before and during androgen replacement therapy and in normal men

OBJECTIVE The present study was performed to characterize the molecular heterogeneity of serum FSH in normal males and to investigate the possible influence of testosterone on serum FSH in androgen-deficient men before and during testosterone administration. DESIGN AND PATIENTS Serum samples were taken at 10-minute intervals between 0730 and 0830 h from nine healthy, eugonadal men and from eight men with primary hypogonadism (Klinefelter's syndrome). In the hypogonadal patients, sampling was performed before treatment (n= 8), 4-5 days after the first and the third injection of 250 mg testosterone enanthate given intramuscularly at three-weekly intervals (n= 6), as well as 3 months after the onset of therapy (n= 3). Sampling was repeated 7 days apart in two of the nine healthy volunteers. MEASUREMENTS Aliquots from the individual serum samples were pooled and fractionated by chromatofocusing in the pH range 6-3. Immunoreactive FSH was measured by immunofluorimetric assay (IFMA) in each fraction and the individual serum samples. In each serum pool, bioactive FSH was determined by in-vitro bioassay (rat Sertoli cell aromatase bioassay), testosterone by RIA and LH by IFMA. RESULTS After grouping the percentage of immunoreactive FSH recovered in the individual fractions into intervals of 0 5 pH units, significant differences between controls and patients were observed in the pH regions 4-4.5, 5.5-6 and 6-6.5. No statistically significant changes in the isoform distribution of FSH were detected during therapy in the Klinefelter patients. A high degree of variability, which did not follow a common pattern, was observed in the isoform distribution of FSH within the same individuals, both in the hypogonadal patients during treatment and in the two normal men whose blood samples were taken on two different occasions. CONCLUSIONS Serum FSH is highly heterogeneous in normal and hypogonadal men. There is a spontaneous intra-individual variability in the relative abundance of the different FSH isoforms in serum that may most probably be related to metabolic deglycosylation of FSH. Minor but significant differences in the molecular heterogeneity of serum FSH could be demonstrated in Klinefelter patients compared to normal men. These differences are not modified by administration of testosterone enanthate at doses achieving normal androgenization, suggesting that factors different from testosterone may modulate FSH pleomorphism.