INTERACTIONS OF OESTRADIOL BENZOATE AND PROMEGESTONE UPON BASAL AND TRH-INDUCED PROLACTIN SECRETION IN POSTMENOPAUSAL WOMEN

The interactions of ovarian steroids with PRL secretion in women are still controversial. Ten healthy postmenopausal women, on no medication, received during the first period of 2 months later in a cross-over design study, i.m. injections of 0.625 mg of oestradiol benzoate (EB) alone for 10 d or in combination with 750 micrograms/d of a pure progestin promegestone for 10 d. A TRH (200 micrograms i.v.) stimulation test was performed before the start and at the completion of each treatment period. Basal plasma gonadotrophins, PRL and oestradiol were measured every day by radioimmunoassay. The EB-induced rise in oestradiol levels was similar during the two periods. In response to EB treatment serum PRL levels increased from 6.1 +/- 0.9 ng/ml to 22.9 +/- 3.4 ng/ml. With the addition of promegestone, the increase in PRL, from 6.7 +/- 1.3 ng/ml to 13.8 +/- 2.5 ng/ml, was significantly diminished (P less than 0.001). The PRL release induced by TRH was significantly greater with EB treatment than was the response with the combined treatment (P less than 0.05, Wilcoxon test to compare the areas under the curves). These data suggest that in postmenopausal women oestrogens act as stimulators of PRL release and promegestone is able to partially counteract the stimulatory effect of oestradiol benzoate upon basal and TRH-stimulated PRL secretion.     

Does bromocriptine block thyrotropin-releasing hormone-induced prolactin release during pregnancy?

PRL responses to 200 microgram of iv TRH were measured in 16 healthy women with normal early pregnancy before and at the endo of bromocriptine treatment of 5.0--7.5 mg daily for 1--2 weeks. Before the start of bromocriptine, TRH caused a PRL elevation from 19.1 +/- 2.2 to 95.2 +/- 12.6 ng/ml (mean +/- SE) after 20 min, with a mean maximal PRL increment of 71.7 +/- 11.6 ng/ml. Bromocriptine suppressed basal plasma PRL level to 3.6 +/- 0.8 ng/ml (P less than 0.001). TRH then caused a PRL rise to 18.8 +/- 1.8 ng/ml at 20 min, with a mean maximal PRL increment of 15.7 +/- 1.8 ng/ml. The absolute PRL response was significantly smaller (P less than 0.001) during bromocriptine intake than before, whereas the mean percent increments in PRL levels after TRH administration were similar in the presence and absence of bromocriptine. Fifteen of these women were restudied with TRH stimulation 4--6 weeks after legal abortion, and the PRL responses to TRH were normal. When 7 of these women were once again treated with bromocriptine and retested with TRH, no absolute or relative PRL response to TRH emerged. These results release differs between the pregnant and nonpregnant states.     

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.     

Prolactin secretion in acromegalic patients before and after selective adenomectomy

PRL secretion before and after transsphenoidal adenomectomy was studied in 13 patients with acromegaly. Six patient had elevated basal serum PRL levels before surgery, while 7 patients had normal levels. In every patient, the basal serum GH level decreased to less than 5.0 ng/ml after surgery. In the group (group A) with high basal serum PRL levels (mean +/- SD, 41.3 +/- 5.8 ng/ml) before surgery, the PRL levels decreased significantly (P less than 0.0002) to less than 10.0 ng/ml (4.8 +/- 3.6 ng/ml) after the operation. However, in the group (group B) with normal levels (10.8 +/- 4.4 ng/ml) before surgery, PRL levels changed little (7.8 +/- 3.1 ng/ml) after the operation. In group A, the increment of PRL after TRH injection decreased or disappeared (P less than 0.02; 4.1 +/- 2.4 ng/ml) after surgery compared with that before surgery (39.2 +/- 25.9 ng/ml). On the other hand, in group B, the increment of PRL after TRH injection was nearly unchanged (17.1 +/- 7.0 ng/ml) after surgery compared with that before surgery (19.3 +/- 8.0 ng/ml). The results indicate that PRL is secreted from the pituitary adenoma in acromegalic patients with hyperprolactinemia, while PRL secretion from the normal part of the pituitary gland is decreased.     

PERIFUSION STUDIES OF BROMOCRIPTINE-TREATED AND UNTREATED MACROPROLACTINOMAS: EFFECTS OF DOPAMINE, BROMOCRIPTINE AND TRH

There have been no detailed in-vitro studies of PRL secretion by human macroprolactinoma cells exposed to bromocriptine (BC) to within a few days of surgical removal. We have studied cells from four such tumours (serum PRL 7.05-247 U/l) and six untreated tumours (serum PRL 4-80.35 U/l) using a perifusion technique. The BC-treated tumours had shown tumour shrinkage and were treated until 40-96 h before surgery, but in one patient serum PRL had not suppressed below 15 U/l despite chronic treatment. Pretreatment serum PRL responses to TRH were blunted in all 10 patients. During perifusion with dopamine (DA, 5 mumol/l) untreated prolactinomas had a higher PRL secretion rate (19.3 +/- 2.7 microU/mg tissue/min, mean +/- SEM) than BC-treated (3.9 +/- 0.7, P = 0.005). When DA was removed, PRL secretion from untreated tumours increased to 129.7 +/- 18.7 microU/mg/min, but in three of the BC-treated, little increase occurred. In the fourth (from the patient whose serum PRL had not fully suppressed) PRL secretion increased from 4.4 to 25.6 microU/mg/min after DA withdrawal, and DA and BC dose-related inhibition of PRL was similar to that observed in untreated tumours. TRH (10 ng/ml), without DA, provoked increased PRL release from both untreated (266% basal secretion, n = 3) and BC-treated (298%, n = 3) tumours; this effect was completely inhibited by DA (5 mumol/l). The absence of hormones other than PRL following potassium (55 mmol/l) excluded contaminating normal pituitary. We conclude: (1) The effects of BC on prolactinoma PRL secretion may persist for at least 4 days; (2) partial in-vivo BC resistance can be due to factors other than DA receptor malfunction; (3) the apparent discrepancy between in-vivo and in-vitro TRH responses was consistent with the presence of increased hypothalamic DA tone in vivo; and (4) BC may have differential effects on TRH and DA-controlled PRL pools in the tumourous lactotroph.     

Decreased growth hormone (GH) response to oral clonidine in endemic cretinism: effect of L-T3 therapy

As GH secretion is dependent upon thyroid hormone availability, the GH responses to clonidine (150 micrograms/m2) and the TSH and PRL response to TRH were studied in eight endemic (EC) cretins (3 hypothyroid, 5 with a low thyroid reserve) before and after 4 days of 100 micrograms of L-T3. Five normal controls (N) were also treated in similar conditions. Both groups presented a marked increase in serum T3 after therapy (N = 515 +/- 89 ng/dl; EC = 647 +/- 149 ng/dl) followed by a decrease in basal and peak TSH response to TRH. However, in the EC patients an increase in serum T4 levels and in basal PRL and peak PRL response to TRH after L-T3 therapy was observed. One hypothyroid EC had a markedly elevated PRL peak response to TRH (330 ng/dl). There were no significant changes in basal or peak GH values to treatment with L-T3 in normal subjects. In the EC group the mean basal plasma GH (2.3 +/- 1.9 ng/ml) significantly rose to 8.8 +/- 3.2 ng/ml and the mean peak response to clonidine (12.7 +/- 7.7 ng/ml) increased to 36.9 +/- 3.1 ng/ml after L-T3. Plasma SM-C levels significantly increased in N from 1.79 +/- 0.50 U/ml to 2.42 +/- 0.40 U/ml after L-T3 (p less than 0.01) and this latter value was significantly higher (p less than 0.05) than mean Sm-C levels attained after L-T3 in the EC group (respectively: 1.14 +/- 0.59 and 1.78 +/- 0.68 U/ml). These data indicate that in EC the impaired GH response to a central nervous system mediated stimulus, the relatively low plasma Sm-C concentrations, and the presence of clinical or subclinical hypothyroidism may contribute to the severity of growth retardation present in this syndrome.     

Subnormal prolactin responsiveness to thyrotropin-releasing hormone (TRH) in women with primary empty sella syndrome

Basal prolactin (PRL) levels and PRL responsiveness to thyrotropin-releasing hormone (TRH) were studied in 10 women with primary empty sella (PES) syndrome (mean age 38.2 yr). Hyperprolactinemia (34 to 72 ng/ml) was found in 5 patients (hyperprolactinemic PES, H-PES), whereas 5 patients showed normal (9.5 to 19 ng/ml) PRL levels (normoprolactinemic PES, N-PES). The results were compared with those obtained in 10 healthy women (mean age 32.8 yr, PRL = 7 to 15 ng/ml) and in 8 women with a PRL-secreting pituitary microadenoma (MA) (mean age 37.5 yr, PRL = 39 to 85 ng/ml). The mean basal levels of PRL were significantly higher in patients with H-PES (50.8 +/- 13.2 ng/ml) or MA (64.0 +/- 18.3 ng/ml) than in the control group (10.9 +/- 2.6 ng/ml, p less than 0.02) and in the patients with N-PES (13.9 +/- 3.7 ng/ml, p less than 0.02). In contrast, the relative maximum response (RMR) of PRL to TRH (peak PRL/basal PRL) was significantly lower in the patients with PES (both H-PES and N-PES) or MA (1.4 +/- 0.4, 2.3 +/- 0.7 and 1.2 +/- 0.2, respectively) than in the control subjects (3.6 +/- 1.1; p less than 0.02, less than 0.05 and less than 0.02, respectively). Our results show that the pituitary responsiveness to the acute stimulation with TRH is significantly decreased both in patients with a PRL-secreting pituitary MA and in those with PES. Therefore, the clinical value of the TRH test in distinguishing the PES syndromes from prolactinomas seems to be questionable.     

Neuroendocrine regulation of anterior pituitary function in patients during and after molar pregnancy

Only partial studies evaluating the endocrine profile in molar pregnancy have been performed. In order to characterize the neuro-endocrine pattern during and after molar pregnancy, we studied the basal hormonal levels of hCG, human placental lactogen (hPL), FSH, GH, TSH, free thyroxine index (FTI), oestradiol-17 beta (E2), and progesterone (PG), as well as the anterior pituitary response to TRH, GnRH, and hypoglycaemia induced by insulin in 7 patients during molar pregnancy and one week after molar abortion. hCG showed significantly higher serum levels during rather than after molar pregnancy and hPL was detectable in only 4 patients during, but in none after molar pregnancy. FSH values were in the follicular phase range before and after molar abortion (12.7 +/- 0.8 and 12.7 +/- 3.5 IU/l). PRL had elevated basal levels before and after molar abortion; 103.0 +/- 16.5 and 43 +/- 10.6 micrograms/l, respectively (P less than 0.05). GH levels were distinctly elevated in 3 patients during molar pregnancy; after molar abortion, the basal GH values were normal in all patients less than 10 micrograms/l. Basal cortisol and TSH levels were in the normal range before and after molar abortion. The FTI was above the normal range in 3 patients during molar pregnancy, whereas after molar abortion the values were normalized. E2 levels were elevated before and after molar abortion, 1881 +/- 477 and 96.5 +/- 39.2 ng/l, respectively (P less than 0.01). PG levels before and after molar abortion were 30.9 +/- 5.4 and 10 +/- 6.7 micrograms/l, respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

INTERACTION OF THYROTROPHIN RELEASING HORMONE AND THE ENKEPHALIN ANALOGUE DAMME ON PITUITARY HORMONE SECRETION

Because TRH counteracts the inhibitory effect of opiate peptides on LH secretion in cultured cells from normal pituitaries, six normal postmenopausal women were studied to determine whether TRH interacts in vivo with opioid peptides in the regulation of pituitary hormone secretion. At two different times a constant 3 h infusion of either saline or TRH (5 micrograms/min) was initiated. At 60 min a 250 micrograms bolus of the opiate agonist peptide D-Ala2-MePhe4-met-enkephalin-0-ol (DAMME) was injected in one of the two saline and TRH infusion tests. The four treatments, i.e. saline infusion alone, saline infusion with a DAMME bolus, TRH infusion alone; and TRH infusion with DAMME bolus were given at random with an interval of at least 7 d. Blood samples were taken every 15 min during the 3 h study. DAMME induced a significant fall (P less than 0.05) in serum LH (from 35 +/- 8.5 to 18.3 +/- 5.1 mIU/ml) (mean +/- SEM) without significantly affecting FSH levels (from 29 +/- 11.2 to 26.9 +/- 12.4 mIU/ml). These changes were not antagonized by the continuous infusion of TRH. PRL had a monophasic response pattern to continuous isolated TRH infusion; the basal levels increased from 4.2 +/- 1.2 to 24.5 +/- 6.8 ng/ml at 30 min and then slowly decreased with a plateau from 90 min until the end of the study. DAMME administration at 60 min induced a significant second peak of PRL secretion (44 +/- 6.5 ng/ml) 30 min later (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of bromocriptine on anovulatory patients with high LH and euprolactinemia

It is well known that an acute administration of Bromocriptine (dopamine agonist) suppresses the serum LH level either in normal women or in women with polycystic ovary syndrome, in whom the serum LH level is elevated. The present study was carried out to examine the effectiveness of Bromocriptine on anovulatory women with a high LH level (serum LH greater than 30 mIU/ml). Bromocriptine was administered for 3 months, 5 mg daily, to 9 anovulatory women with euprolactinemia (serum PRL less than 25 ng/ml). Ovulation was observed by their BBT charts. Before and after the treatment of Bromocriptine, FSH, LH and PRL secreting capacities were tested by LHRH and TRH injection. Also, estrone, estradiol and testosterone levels were measured before and after the Bromocriptine administration. Resting levels of LH, FSH and PRL were 45.4 +/- 11.0 mIU/ml, 11.4 +/- 3.0 mIU/ml, and 14.3 +/- 4.7 ng/ml (M +/- SD), respectively, before the treatment. As a result of the treatment, the LH level was markedly decreased to 27.3 +/- 14.5 (M +/- SD, P less than 0.05), and PRL decreased to 3.76 +/- 4.2 ng/ml (M +/- SD, P less than 0.005). On the other hand, FSH did not show a marked change. The responsiveness of LH to LHRH before the treatment showed a marked increase, which was suppressed by Bromocriptine. However, FSH showed no change. The responsiveness of PRL to TRH was suppressed by Bromocriptine. Serum estrone, estradiol and testosterone levels before the treatment were 115.5 +/- 76.7 pg/ml, 93.7 +/- 61.0 pg/ml and 0.809 +/- 0.209 ng/ml (M +/- SD), respectively, which showed no significant change after the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE INTERRELATIONSHIPS BETWEEN PROLACTIN AND THYROTROPHIN SECRETION FOLLOWING DOPAMINERGIC BLOCKAGE IN PATIENTS WITH MILD HYPERPROLACTINAEMIA WITHOUT ANY DEMONSTRABLE PITUITARY TUMOUR

PRL, TSH and gonadotrophin responses to the dopaminergic antagonist, metoclopramide, were studied in mildly hyperprolactinaemic patients with normal sella radiology and CT scan. Eleven female patients with basal PRL levels ranging from 23 to 124 ng/ml were challenged with intravenous metoclopramide (10 mg) and on subsequent occasions with TRH (200 micrograms) and LHRH (100 micrograms). On the basis of the PRL secretory pattern following metoclopramide and TRH stimulation, the patients were divided into two groups. Group I comprised six subjects who were PRL non-responsive to TRH and metoclopramide. Group II (five subjects) demonstrated PRL responses to TRH and metoclopramide indistinguishable from female controls. Mean +/- SD basal PRL levels were 68.5 +/- 29.9 ng/ml in Group I and not different in Group II (40.6 +/- 12.0 ng/ml). Basal LH levels were increased in Group II, whereas FSH was increased in Group I. Basal TSH levels were lower in Group I than the controls. Following metoclopramide, Group I patients had an increase in TSH from a basal of 2.4 +/- 0.7 microU/ml to a peak of 5.9 +/- 2.7 microU/ml (P less than 0.005) which occurred at 30 min. TSH values were increased above basal at all time intervals following metoclopramide. In contrast, TSH levels did not change in Group II patients or the controls after metoclopramide administration. Both patient groups had TSH responses to TRH similar to the controls. Following LHRH, the LH increase was greater in Group II and the FSH in Group I. In neither group nor the controls did gonadotrophin levels change after metoclopramide. In Group II females, PRL responsiveness to metoclopramide was associated with TSH non-responsiveness. In Group I females, PRL levels failed to rise, whereas TSH increased. The PRL and TSH profile in Group I females is typical of a prolactinoma. It is concluded that PRL as well as TSH determinations following metoclopramide are useful indices in the assessment of hyperprolactinaemia and may be of value in differentiating the functional state from that of a pituitary tumour.     

PITUITARY MICROADENOMA: DIAGNOSTIC STUDIES

Forty-one women with oligo-menorrhoea and/or galactorrhoea were subjected to hypothalamic pituitary-thyroid testing in an attempt to establish the presence or absence of an underlying pituitary microadenoma. They were divided into two groups in accordance with the serum level of prolactin (PRL): Group I (N = 25, mean +/- SE 17.6 +/- 1.5 ng/ml) and Group II (N = 16, 102.8 +/- 29.7 ng/ml). The dynamic tests performed were a TRH test, a stimulation test with metoclopramide (MCP) and a suppression test with bromocriptine. The results of these tests were compared with those obtained in nine normal women and eleven patients with surgically proved pituitary microadenoma. Radiologically abnormal pituitary fossas were found in ten subjects from Group I and in fourteen from Group II. All patients were euthyroid. A persistently elevated serum TSH in response to TRH was observed in patients of Group II suggesting an hypothalamic abnormality and a progressive decrease in the 120-min use of serum T3 was noted with increasing evidence of the existence of a pituitary tumour. A negative correlation was found between the basal serum PRL and the rise of serum PRL with TRH. Patients from Group II showed a lower PRL response to MCP when compared to Group I and again a negative correlation between basal level of serum PRL and the change after MCP was observed. No clear difference in the 4-h response to bromocriptine was found between the different groups of subjects. In conclusion, none of the three tests analysed permitted us to establish which of the patients had an underlying pituitary microadenoma.     

THE INFLUENCE OF OESTROGENS ON THE SENSITIVITY OF PRL, TSH AND LH TO THE INHIBITORY ACTIONS OF DOPAMINE IN HYPERPROLACTINAEMIC PATIENTS

The effects of oestrogen priming on the response of serum PRL, LH and TSH to dopamine (DA) infusion have been studied in hyperprolactinaemia. Seven hyperprolactinaemic females (aged 22-57 years; basal PRL 911-5130 mU/l, normal less than 420 mU/l), had submaximal DA infusions (0.06 micrograms/kg/min) over 3 h. The DA was repeated at the same dose after pretreatment with ethinyl oestradiol (E2) 100 micrograms daily by mouth for 3 d, and after a further 2 week interval, following pretreatment with tamoxifen (TAM) 20 mg twice a day by mouth for 3 d. Ethinyl oestradiol pretreatment stimulated a rise in basal PRL levels in all subjects (mean +/- SE, mU/l; 2903 +/- 761 vs 2293 +/- 684, P less than 0.05) while TAM produced a higher but more variable increase in basal PRL levels (mean +/- SE, mU/l; 3402 +/- 757, P = n.s.). The individual increments in basal PRL levels after both E2 and TAM pretreatment showed a significant positive correlation with the greater decrement in PRL levels during E2 and TAM primed DA infusions (E2, r = 0.93, P less than 0.01, TAM, r = 0.83, P less than 0.05). E2 pretreatment produced a rise in basal LH levels in 5/7 patients, and there was a significant positive correlation between the rise in basal LH levels after E2 and the decremental change in LH levels in E2 primed DA infusions (r = 0.94, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of calcium channel blockade with verapamil on the prolactin responses to TRH, L-dopa, and bromocriptine.

To determine the mechanisms by which calcium channel blockade with verapamil causes hyperprolactinemia, the authors investigated the effects of this blockade on the prolactin (PRL) responses to stimulation by thyrotropin releasing hormone (TRH) and inhibition by dopamine, using L-dopa and bromocriptine. Verapamil, given for 1 week at a dosage of 240 mg orally to eight healthy volunteers, induced a significant elevation of basal PRL levels (17.3 +/- 1.8 ng/ml to 30.9 +/- 4.3 ng/ml, p < 0.005). Verapamil also caused an increase in the PRL response to a TRH (100 micrograms). However, when the increased basal level was considered by calculating the area under the THR response curve and subtracting the basal values, this increase (1763.4 +/- 202.6 ng/ml.min to 2260.6 +/- 223.9 ng/ml.min) was not found to be statistically significant (p > 0.05). Verapamil had no effect on the basal or TRH-stimulated thyroid stimulating hormone levels. In these same volunteers, PRL levels decreased from 13.2 +/- 2.5 ng/ml to a nadir of 5.5 +/- 1.6 ng/ml in response to L-dopa. After 1 week of verapamil 240 mg, basal PRL levels were elevated to 21.5 +/- 3.1 ng/ml, then decreased to 8.2 +/- 1.8 ng/ml with L-dopa. The percentage decreased in PRL in response to L-dopa (60 +/- 5% versus 62 +/- 3%) were not significantly different (p > 0.05). Verapamil had no effect on the basal or L-dopa-stimulated growth hormone levels. Bromocriptine 2.5 mg given to five volunteers twice daily caused PRL levels to fall from 13.3 +/- 1.6 ng/ml to 5.0 +/- 0.9 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of long-term low dose thyrotropin-releasing hormone infusions on serum thyrotropin and prolactin concentrations in man

The purpose of the present study was to evaluate in man the relative thyrotroph and lactotroph response to a 48-h low dose constant TRH infusion. Before, during, and after the 75 ng/min TRH constant infusion, serum samples were obtained every 4 h in six euthyroid ambulating male subjects for measurements of TSH, PRL, T4, and T3. The TSH response, employing a specific and sensitive human TSH RIA, demonstrated a significant rise from the mean basal pre-TRH value of 2.35 +/- 0.64 microU/ml (+/- SEM) to 3.68 +/- 0.80 (P < 0.005) during the TRH infusion; this value fell below the basal level to 1.79 +/- 0.47 (P < 0.05) post infusion. Serum T4 values were increased above basal both during (P < 0.025) and after (P < 0.025) TRH infusion, whereas serum T3 values were not significantly changed throughout the entire study period. The daily TSH nocturnal surge was augmented in both absolute and relative terms during the first 24 h or the TRH infusion, unchanged during the second 24 h of infusion, and inhibited during the first postinfusion day. Other than a minimal increase in serum PRL during the first few hours of the infusion, no significant alteration in the mean basal concentration or circadian pattern of PRL secretion was evident during or after the low dose TRH infusion. These findings would indicate that 1) near-physiological stimulation of the pituitary with TRH produces a greater stimulation of TSH release than of PRL release and 2) the factor or factors producing the circadian TSH surge may not be mediated through fluctuations in endogenous TRH.     

THE HIGHER THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE THE LOWER THE RESPONSE TO BROMOCRIPTINE AND THYROTROPHIN RELEASING HORMONE IN ACROMEGALY

In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty-one acromegalic patients, 18 women and 13 men (age 46.2 +/- (SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1-44, Bachem 100 micrograms i.v. bolus), TRH (Thyroliberin, Hoechst 200 micrograms i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (delta GH 1-995 ng/ml), which correlated significantly with the basal GH levels (r = +0.85, P less than 0.0001, n = 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r = -0.49, P less than 0.01, n = 30). This decrease correlated with the basal PRL level (r = +0.45, P less than 0.02, n = 29) and also the GH response to TRH (r = +0.66, P less than 0.0001, n = 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r = -0.43, P less than 0.02, n = 29). The data are consistent with the existence of GH-secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph-like adenomas) responsive to TRH and Br but less responsive to GHRH.     

Does 1,25-dihydroxyvitamin D participate in the regulation of hormone release from endocrine glands?

The presence of receptors for 1,25-dihydroxyvitamin D3 in the pituitary, pancreas, testis, and ovary has raised the question of a possible direct role for 1,25-dihydroxyvitamin D (1,25(OH)2D) in the regulation of hormone synthesis and secretion. To evaluate this problem, six children with the syndrome of resistance to 1,25(OH)2D with rickets and alopecia underwent dynamic tests of insulin, TSH, PRL, GH, and testosterone secretion. Oral glucose loading resulted in normal glucose curves, subnormal peak insulin responses of 12-20 microU/ml in three hypocalcemic patients, and normal peak serum insulin values of 30-40 microU/ml in two normocalcemic patients. Basal serum, TSH, PRL, T4, and T3 concentrations were normal in all patients. Peak serum TSH values after TRH were 11-17 and 16-32 microU/ml in the hypo- and normocalcemic patients, respectively. The PRL response to TRH stimulation in either hypocalcemic or normocalcemic patients was normal [mean 26.2 +/- 5.1 (SD) ng/ml]. Peak serum GH levels were greater than 8 ng/ml in all five patients studied after one or more of the various stimuli. Serum testosterone concentrations after hCG stimulation were normal in the three patients studied (4.1-8.0 ng/ml). Thus, in children with resistance to 1,25(OH)2D, we could find no significant abnormalities in hormone secretion from the pituitary, pancreas, and testis apart from those presumably due to the hypocalcemia itself.     

Pituitary-thyroid function in spironolactone treated hypertensive women.

Four weeks high dose spironolactone treatment (Aldactone Searle, 100 mg q. i. d.) significantly enhanced the TSH (delta max. 8.5 +/- 4.1 vs. 4.6 +/- 3.1 microunits/ml, P less than 0.05) and T3 (delta max. 32 +/- 27 vs. 11 +/- 16 ng/100 ml, P less than 0.05) responses to an intravenous TRH/LH-RH bolus injection in 6 eumenorrhoeic euthyroid hypertensive women, without affecting basal serum TSH, T3 or T4 levels or the basal and stimulated LH, FSH and prolactin values (P greater than 0.10). The mean serum testosterone, 17-hydroxyprogesterone and oestradiol levels were also similar before and during therapy. Spironolactone, possibly by virtue of its antiandrogenic action, may exert its enhancing effect on pituitary-thyroid function by modulating the levels of receptors for TRH in the thyrotrophs or by altering the T3 receptor in the pituitary permitting a greater response to TRH.     

Effect of TRH on beta-gonadotropin subunits in patients with pituitary microincidentalomas.

OBJECTIVE: To explore the hypothesis that most of the pituitary abnormalities compatible with the diagnosis of microadenoma, and detected in about 10% of the normal adult population, represent asymptomatic gonadotropinomas. DESIGN: Patients diagnosed with pituitary microincidentalomas at the Institute of Endocrinology of the Tel Aviv Medical Center were evaluated. Circulating beta-subunits of gonadotropin hormones were measured before and 30, 45, 60 and 90 min after the intravenous injection of 400 microgram TRH. PATIENTS: Twenty-two patients with pituitary incidentaloma and 16 normal volunteers were tested. RESULTS: In 16 of the 22 patients, an abnormal beta-subunit response was detected after the TRH challenge. Three patients had an abnormal increase in both beta-FSH and beta-LH after TRH administration. Isolated pathological beta-FSH or beta-LH responses were demonstrated in five and eight patients respectively. Six patients had normal basal and stimulated gonadotropin subunit values, raising the possibility that their lesions were not pituitary microadenomas. There was a significant overall difference between the response to TRH of the patient and control groups. In the gonadotropin positive group, comprising 16 patients, serum beta-FSH increased from 6.4+/-1.6 ng/ml to 9.2+/-1.3 ng/ml (P=0.042) 1 h after TRH stimulation, whereas no changes were detected in the control group after TRH injection (basal: 4.1+/-0.8 ng/ml, peak: 5.1+/-0.8 ng/ml; P=0.15). Serum beta-LH increased from 10.5+/-3.2 ng/ml to 23.4+/-4.9 ng/ml (P=0.0037) at this time, in contrast to a lack of response in controls (basal: 6.4+/-1.5 ng/ml, peak: 8.2+/-2.3 ng/ml; P=0.24). CONCLUSION: In about 73% of patients with pituitary incidentalomas smaller than 10 mm, TRH elicits an increase in gonadotropin beta-subunits. This observation raises the possibility that non-functioning pituitary micro- and macroadenomas, which share a similar response to TRH, originate in a common ancestor cell type, probably a pituitary gonadotrope.