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PubMed1985

Hypoprolactinemia induced by hypophysectomy and long-term bromocriptine treatment decreases tuberoinfundibular dopaminergic neuronal activity and the responsiveness of these neurons to prolactin.

The effect of long-term decreases in circulating concentrations of prolactin was determined on the responsiveness of tuberoinfundibular dopamine (DA) neurons to this hormone. The activity of these neurons in ovariectomized rats was estimated by measuring the rate of DA synthesis (DOPA accumulation after the administration of a decarboxylase inhibitor) in the median eminence at various times after serum concentrations of prolactin had been reduced by hypophysectomy or the chronic administration of a DA agonist (bromocriptine, 3 mg/kg/day). The concentration of DA in the median eminence, but not in striatum, declined progressively up to 12 days after hypophysectomy, but did not change at any time during bromocriptine treatment. On the other hand, norepinephrine concentrations in the median eminence were increased 12 days after both treatments. Within 24 h after hypophysectomy or the first injection of bromocriptine the rate of DA synthesis in the median eminence was decreased; this decrease was maintained for at least 12 days suggesting that tuberoinfundibular DA neuronal activity is normally maintained by endogenous prolactin. Intracerebroventricular (ICV) injections of prolactin (10 micrograms, 12 h prior to sacrifice) increased the rate of DA synthesis in the median eminence of control, 24-hour hypophysectomized and 24-hour bromocriptine-treated rats. After longer periods (6-12 days) of bromocriptine treatment or after hypophysectomy the responsiveness of tuberoinfundibular DA neurons to prolactin was reduced. Dose-response studies revealed that the sensitivity and magnitude of response to ICV prolactin was markedly reduced in 12-day hypophysectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas.

Bromocriptine or other dopamine agonists are usually effective for the treatment of prolactin-secreting adenomas. Five to 18% of prolactinomas, however, do not respond to such therapy. We have shown previously that such resistance to bromocriptine correlates with reduced binding to the D2 receptor subtype of dopamine, the major PRL inhibiting factor. In the present work, we demonstrated that reduced binding actually corresponds to decreased expression of the gene coding for the D2 receptor in the pituitary from bromocriptine-resistant patients, as shown by 4-fold lower levels of the corresponding mRNAs compared to those coding for actin. The existence of two D2 receptor isoforms, D2S and D2L generated by alternative splicing, has been described in several tissues, including the pituitary. Both are negatively coupled to adenylyl cyclase and inhibit prolactin secretion, but, in addition, the shortest one (D2S) is more efficiently coupled to phospholipase C. Consequently, we also investigated whether expression of a particular D2 receptor isoform was preferentially affected in resistant adenomas. The proportion of messengers corresponding to the short receptor isoform (D2S) was lower in resistant compared to responsive adenomas: D2S/D2L = 0.74 +/- 0.08 and 1.00 +/- 0.07, respectively. In parallel, much lower levels of D2 receptor mRNAs were found in growth hormone-secreting adenomas, with a D2S/D2L ratio comparable to those of both normal human pituitary and bromocriptine-sensitive prolactinomas (1.05 +/- 0.11). Thus, resistance to bromocriptine therapy seems to involve defects in D2 dopamine receptor expression and possibly in posttranscriptional splicing.

Adenoma↗
PubMed1987

Bromocriptine is unable to suppress TRH-stimulated beta-endorphin/beta-lipotropin and cortisol secretion in normal pregnant women after delivery.

The course of plasma beta-endorphin/beta-lipotropin, cortisol and prolactin (PRL) levels was followed from 0.5 till 5 h after normal delivery in 13 healthy women. Six subjects who did not want to breast-feed their child received 2.5 mg bromocriptine orally 1 h after delivery. After 3 h the effect of the intravenous administration of 200 micrograms thyrotropin-releasing hormone (TRH) was also measured. Elevated plasma beta-endorphin and cortisol levels decreased after delivery in a (log) linear fashion which was not influenced by bromocriptine. TRH elicited a significant short-lived identical increase in plasma beta-endorphin/beta-lipotropin concentrations in the control and the bromocriptine-treated subjects. TRH similarly delayed the rapid decline in plasma cortisol levels in both groups of women. Basal and TRH-induced PRL levels were rapidly suppressed by bromocriptine. These studies show the presence of a paradoxical increase of beta-endorphin/beta-lipotropin and cortisol levels in response to TRH occurring shortly after delivery in normal women. This response cannot be mediated by the placenta. The absence of an inhibiting effect of bromocriptine on basal and TRH-induced beta-endorphin and cortisol release does not lend support to the hypothesis of the presence of a functionally active intermediate pituitary lobe in man early in puerperium.

Bromocriptine↗
PubMed2000

Bromocriptine restores tolerance in estrogen-treated mice.

Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.

Animals↗
PubMed1979

Effects of metoclopramide and bromocriptine on the renin-angiotensin-aldosterone system in man. Dopaminergic control of aldosterone.

This study was designed to investigate the possible role of dopaminergic mechanisms in the control of the renin-angiotensin-aldosterone system in normal man. Six normal male subjects in metabolic balance at 150 meq sodium, 60 meq potassium constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. or placebo followed by angiotensin II infusion 1 h later on 2 consecutive days. Metoclopramide increased plasma aldosterone concentration from 8.2+/-2.2 to 21.0+/-3.3 ng/100 ml (P < 0.005) and plasma prolactin concentration from 18.0+/-4.0 to 91.7+/-4.0 ng/ml (P < 0.001) within 15 min of its administration. At 1 h, plasma aldosterone and prolactin concentrations remained elevated at 16.8+/-2.1 ng/100 ml (P < 0.01) and 86.8+/-15.9 ng/ml (P < 0.005), respectively. Angiotensin II at 2, 4, and 6 pmol/kg per min further increased plasma aldosterone concentration to 27.2+/-3.4, 31.9+/-5.7, and 36.0+/-6.7 ng/100 ml (P < 0.02), respectively. Placebo did not alter plasma aldosterone or prolactin concentrations, but angiotensin II increased plasma aldosterone concentration to 13.7+/-2.4, 19.0+/-1.9, and 23.3+/-3.2 ng/100 ml (P < 0.005). The increment of plasma aldosterone concentration in response to angiotensin II was similar after metoclopramide or placebo. The six subjects also received the dopamine agonist, bromocriptine, 2.5 mg or placebo at 6 p.m., midnight, and 6 a.m. followed by angiotensin II infusion on 2 consecutive d. Bromocriptine suppressed prolactin to <3 ng/ml. After placebo, plasma aldosterone concentration increased from 5.2+/-1.4 to 12.3+/-1.7, 17.2+/-2.2, and 21.8+/-3.5 ng/100 ml (P < 0.01) and after bromocriptine from 7.2+/-1.0 to 14.7+/-3.0, 19.8+/-3.2, and 23.4+/-1.6 ng/100 ml (P < 0.001) with each respective angiotensin II dose. No difference in the response to angiotensin II after bromocriptine or placebo was observed. Plasma renin activity, free 11-hydroxycorticoid concentration, and serum potassium concentration were unchanged by metoclopramide or bromocriptine. The results suggest that aldosterone production is under maximum tonic dopaminergic inhibition which can be overridden with stimulation by angiotensin II in normal man.

11-Hydroxycorticosteroids↗
PubMed1980

Dopaminergic inhibition of metoclopramide-induced aldosterone secretion in man. Dissociation of responses to dopamine and bromocriptine.

This study was designed to investigate the role of dopaminergic mechanisms in the control of aldosterone secretion in man. Five normal male subjects in metabolic balance at 150 meq sodium/d and 60 meq potassium/d constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. on 2 consecutive d. On the 1st d, the subjects received an infusion of 5% glucose solution (vehicle) from 60 min before to 60 min after metoclopramide administration; on the 2nd d, an infusion of dopamine 4 mug/kg per min was substituted for vehicle. Metoclopramide in the presence of vehicle increased plasma aldosterone concentrations from 2.4+/-1.1 to a maximum of 17.2+/-2.8 ng/100 ml (P < 0.01) and serum prolactin concentrations from 7.5+/-5.0 to a maximum of 82.2+/-8.7 ng/ml (P < 0.01). Dopamine 4 mug/kg per min did not alter basal plasma aldosterone concentrations, but blunted the aldosterone responses to metoclopramide significantly; in the presence of dopamine, plasma aldosterone concentrations increased from 3.1+/-0.5 to 6.2+/-1.4 ng/100 ml (P < 0.05) in response to metoclopramide. The incremental aldosterone responses to metoclopramide were significantly lower in the presence of dopamine than with vehicle. Dopamine 4 mug/kg per min suppressed basal prolactin to <3 ng/ml and inhibited the prolactin responses to metoclopramide; serum prolactin concentrations increased to a maximum of 8.5+/-2.3 ng/ml with metoclopramide in the presence of dopamine. The subjects were studied in the same manner except that dopamine 2 mug/kg per min was administered instead of the 4-mug/kg per min dose. Dopamine 2 mug/kg per min attenuated the aldosterone and prolactin responses to metoclopramide, but was less effective than the 4-mug/kg per min dose of dopamine. Metoclopramide 10 mg i.v. was administered to five additional subjects after pretreatment with the dopamine agonist, bromocriptine, 2.5 mg or placebo at 6 p.m., midnight, and 6 a.m. before study. Bromocriptine suppressed basal serum prolactin levels and completely inhibited the prolactin responses to metoclopramide. In contrast, bromocriptine did not alter basal plasma aldosterone concentrations or the aldosterone responses to metoclopramide. Plasma renin activity, plasma cortisol, and serum potassium concentrations were unchanged by metoclopramide, dopamine, or bromocriptine. The results of this study suggest that the aldosterone response to metoclopramide is mediated by metoclopramide's antagonist activity at the dopamine receptor level. The results further suggest dissociation of the responses to the dopamine agonists, dopamine and bromocriptine, and indicate that a new type of dopamine receptor may inhibit aldosterone secretion.

Adult↗
PubMed1987

Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat.

The immunologic effects of bromocriptine and low dose cyclosporine on experimental autoimmune uveitis (EAU) induced in Lewis rats by S-antigen immunization were studied. Rats treated with a sub-optimal dose (low dose) of cyclosporine (2 mg/kg per d), bromocriptine (1.8 mg/kg per d), or both drugs were compared with untreated rats in regard to the development of EAU, lymphocyte proliferative responses, and anti-S-antigen serum antibodies. Bromocriptine alone decreased the incidence of EAU only in female rats (P less than 0.01), did not effect the lymphocyte proliferative response, but did significantly decrease antibody titers in both males (P less than 0.004) and females (P less than 0.0005). Low dose cyclosporine also partially decreased the incidence of EAU in female rats, but did not decrease antibody titers or lymphocyte proliferative responses. Bromocriptine plus low-dose cyclosporine led to more marked decreases in the incidence of EAU and anti-S-antigen antibody titers as well as in the lymphocyte proliferative assay (P less than 0.01 for males, P less than 0.0005 for females). This study suggests that bromocriptine can enhance the immunosuppression of low dose cyclosporine.

Animals↗
PubMed1997

Modulation of protein kinases and microtubule-associated proteins and changes in ultrastructure in female rat pituitary cells: effects of estrogen and bromocriptine.

This study focused on the intracellular signal transduction system and microtubule-associated proteins (MAPs), such as MAP-2 and Tau protein. The modulation of these proteins and their correlation with ultrastructural changes were investigated in rat pituitary prolactin (PRL) cells. Adult female Wistar rats were treated with estrogen and bromocriptine and their pituitary glands were removed for analysis of the expression of tubulin, MAP-2, Tau protein, protein kinase C (PKC), and calcium calmodulin (CaM) kinase. Western blot analysis showed that estrogen increased and bromocriptine decreased the expression of PKC alpha, beta 1, beta 2, CaM kinase alpha, beta, MAP-2, and Tau protein. MAP-2 and Tau protein, which are cytosolic proteins, being translated on free ribosomes, were associated with the membrane of whirling rough endoplasmic reticulum (RER) in estrogen-treated cells and dissociated with vesiculated RER induced by bromocriptine. These results suggested that the modulation of MAP-2 and Tau protein may reflect changes of PKC and CaM kinase, and that the quantitative changes and intracellular modulation of MAPs induced by estrogen and bromocriptine, i.e., estrogen-induced association and bromocriptine-induced dissociation of MAP-2 and Tau protein with membrane of RER, may reflect the dynamics of microtubules and are associated with structural changes in the RER and changes in the synthesis and intracellular transport of PRL.

Animals↗
PubMed1986

The safety of bromocriptine in hyperprolactinaemic female infertility: a literature review.

The dopamine agonist bromocriptine has been widely used to facilitate pregnancy in hyperprolactinaemic women, with a success rate of 80% in relevant cases. Neither the inappropriate hyperprolactinaemia consequent upon bromocriptine withdrawal after conception nor the relative hypoprolactinaemia caused by treatment throughout gestation appears to affect adversely the course and outcome of pregnancy or the endocrine status of the fetus. No teratogenic effect of bromocriptine has been evidenced in humans, and no disturbances in the physical, psychomotor, and intellectual development of the offspring have been observed. Pituitary-tumor enlargement during closely supervised pregnancies very rarely leads to severe and irreversible complications; both the re-institution of bromocriptine treatment in the event of tumor enlargement and its preventive use throughout pregnancy have been shown to be effective measures. It is interesting, moreover, that a reduction of hyperprolactinaemia, compared with pregestational levels, may be seen after bromocriptine-facilitated pregnancies.

Abnormalities, Drug-Induced↗
PubMed1986

The safety of bromocriptine in long-term use: a review of the literature.

This paper reviews the safety data on bromocriptine administration for 1 to 10 years at daily doses of 1.25 to 80 mg in over 1100 patients with pituitary hormone overproduction (mainly from prolactinomas and growth-hormone producing adenomas), at daily doses of 3.75 to 170 mg in over 700 patients with Parkinson's disease, and at daily doses of 2.5 to 20 mg in 28 patients with various other conditions. In addition, information is provided on the safety for mother and child of bromocriptine administered at daily doses of 2.5 to 35 mg throughout gestation (54 pregnancies) or during its later stages (39 pregnancies). The side-effects of long-term bromocriptine treatment are usually no different from those seen during short-term treatment; most of them are relatively benign, and they have been shown in virtually all patients to be reversible. Bromocriptine appears to have no harmful effect on hepatic, renal, haematologic, or cardiac functions. It is considered that a hitherto unknown, severe though rare side-effect of bromocriptine is unlikely to be reported after such long experience.

Acromegaly↗
PubMed1981

Effect of bromocriptine on thyroid hormone-induced growth hormone production in cultured GH1 cells.

L-triiodothyronine induces a three-fold increase in growth hormone production in cultured GH1 cells. The dopaminergic agonist, bromocriptine, inhibits the thyroid hormone-induced growth hormone production to the level of that produced by the control cells. This effect can be observed within eight hours of incubation and persists as long as forty-eight hours in culture and is not due to a change in cell population. In contrast, bromocriptine appears to have no effect on growth hormone production in the control cultures. The estimated concentration of bromocriptine which gives a half-maximal inhibitory effect is 0.3 nM, and concentrations above 5 nM give a complete inhibitory effect. The intracellular growth hormone concentration represents only a very small fraction of total hormone production and does not appear to be influenced by bromocriptine. Therefore, the inhibitory effect of bromocriptine on growth hormone production in thyroid hormone treated cultured GH1 cells may result from its action on the synthesis of growth hormone.

Animals↗
PubMed1980

Rapid regression of pituitary prolactinomas during bromocriptine treatment.

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.

Adenoma↗
PubMed1984

Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: responses to bromocriptine.

Pulsatile gonadotropin secretion was examined in seven women with hyperprolactinemia and amenorrhea by obtaining blood samples every 20 min for 24 h. When plasma PRL had returned to normal and menses had resumed during bromocriptine treatment, five women were restudied in an identical manner during the early to midfollicular stage of their cycles. Gonadotropin responses to a small dose of synthetic GnRH (25 ng/kg, iv) were measured after the initial 24-h study in each patient. In addition, low dose pulses of GnRH (25 ng/kg) were administered iv every 2 h for 88 h to three hyperprolactinemic women, and LH and FSH responses were determined. Before treatment with bromocriptine, mean +/- SE plasma gonadotropin concentrations (LH, 5.8 +/- 0.2 mIU/ml; FSH, 4.4 +/- 0.1 mIU/ml) were comparable to values during the follicular phase of normal menstrual cycles. LH pulse frequency during the pretreatment study in the hyperprolactinemic women (mean +/- SE, 7.6 +/- 1.2 pulses/24 h) was significantly less than that found during the early follicular stage of normal cycles (days 3-5; mean, 15.4 +/- 1.1 pulses/24 h). Mean +/- SE LH pulse amplitude before bromocriptine was 5.2 +/- 0.6 mIU/ml. The pattern of pulsatile LH secretion was highly variable before treatment and was characterized by prolonged periods (6-11 h) of low plasma LH concentrations. LH responses to GnRH were normal or increased (mean maximum increment in LH, 38.5 +/- 15.9; range, 4.3-125.2 mIU/ml), and no evidence of intermittent pituitary refractoriness was found during prolonged (88-h) administration of GnRH pulses. Treatment with bromocriptine was associated with the resumption of menses, and no significant change in mean gonadotropin concentrations. LH pulse frequency was increased (mean +/- SE = 10.2 +/- 1.0 pulses/24 h) and LH pulse amplitude was decreased (mean, 3.9 +/- 0.2 mIU/ml) in four of five patients receiving bromocriptine. Moreover, the pattern of pulsatile LH secretion was more uniform during treatment. We conclude that pituitary responsiveness to GnRH is not impaired in women with hyperprolactinemia and amenorrhea, and that periods of low LH secretion in these women are due to intermittent reductions in GnRH secretion. These observations suggest that the abnormal patterns of pulsatile gonadotropin secretion, and by inference GnRH secretion, are important factors in the etiology of amenorrhea associated with hyperprolactinemia.

Adult↗
PubMed1985

Different responses of growth hormone secretion to guanfacine, bromocriptine, and thyrotropin-releasing hormone in acromegalic patients with pure growth hormone (GH)-containing and mixed GH/prolactin-containing pituitary adenomas.

There is great variability in the GH secretory responses to different stimuli in patients with acromegaly. In the present study, we compared the effects on GH secretion of two compounds (bromocriptine and TRH), which presumably act directly at the pituitary level, with the effect of the centrally acting alpha-adrenergic agonist guanfacine in 14 untreated acromegalic patients. These in vivo responses of GH release were correlated with the results of immunocytochemical studies of the pituitary adenomas. In nine patients with pure GH-containing adenomas, GH secretion was suppressed by bromocriptine by more than 50% in one patient, while TRH stimulated GH release by more than 100% in another patient. Guanfacine (2 mg, orally) did not elicit a change in circulating GH levels in any of these nine patients. In the group of five patients with mixed GH/PRL-containing adenomas, however, bromocriptine suppressed GH levels by more than 50% in all patients, and TRH stimulated GH release by more than 100% in four of them. Guanfacine stimulated GH secretion significantly in four of these five patients. Guanfacine inhibited GH secretion significantly in five other acromegalic patients who had been treated 5-10 yr previously by external pituitary irradiation. We conclude that in acromegaly, the presence of PRL within the GH-secreting pituitary adenoma makes GH secretion more sensitive to bromocriptine and TRH, while normal sensitivity to hypothalamus-mediated stimulation (alpha-adrenergic agonist) is retained to some extent. In contrast, pure GH-secreting tumors responded little or not at all to bromocriptine, TRH, or guanfacine.

Acromegaly↗
PubMed1985

Effect of bromocriptine treatment on the aldosterone response to angiotensin II and adrenocorticotropin in idiopathic hyperaldosteronism.

Bromocriptine can prevent an increase in plasma aldosterone during the infusion of angiotensin II in normal subjects and during upright posture in some patients with idiopathic hyperaldosteronism. To determine if bromocriptine prevents the increase in plasma aldosterone concentration during angiotensin II infusion in idiopathic hyperaldosteronism, we infused angiotensin II in five patients with idiopathic hyperaldosteronism, before and after treatment with bromocriptine (2.5 mg, three times daily for 5 days), and measured the resulting plasma aldosterone and angiotensin II concentrations. We also determined the adrenal response to ACTH infusion before and after bromocriptine treatment in four of these patients. Bromocriptine treatment did not significantly change the plasma concentrations of aldosterone before or during the infusions of angiotensin II and ACTH. It did significantly decrease mean blood pressure and increase the plasma corticosteroid concentrations in the preinfusion periods, but it did not alter the response of blood pressure to angiotensin II or of plasma corticosteroid concentrations to the ACTH infusions.

Adrenal Cortex Hormones↗
PubMed1986

The effect of bromocriptine on gonadotropin and steroid secretion in polycystic ovarian disease.

Use of bromocriptine in some women with polycystic ovarian disease (PCO) has resulted in ovulation induction, although a mechanism has not been established. The purpose of this study was to determine the effect of bromocriptine on gonadotropin and steroid secretion in this disorder. Two groups of seven patients were given bromocriptine at a dose of either 5 mg/day for 2 months or 10 mg/day for 1 month. Ten normal ovulatory women served as controls. In PCO patients, mean serum levels of LH, bioactive LH, androstenedione, testosterone, unbound testosterone, dehydroepiandrosterone sulfate (DHEA-S), and estrone were significantly greater (P less than 0.05) than those of normal women, whereas FSH, PRL, dihydrotestosterone, 3 alpha-androstanediol, and estradiol were not different. Assessment of gonadotropin secretion before and during treatment revealed that basal levels, episodic secretion, and responses to GnRH (25 micrograms, iv) were unaltered by either dose of bromocriptine. Of the remaining hormones, PRL and DHEA-S significantly decreased in response to both doses. There were no changes in the clinical status of patients during treatment. These findings indicate that in PCO patients with normal PRL levels, gonadotropin secretion is unaltered by bromocriptine therapy. The concomitant declines of PRL and DHEA-S confirm previous data reported for this syndrome and suggest a role for PRL in the production of adrenal androgens.

Androstenedione↗
PubMed1987

Phorbol ester and phospholipase C-induced growth hormone secretion from pituitary somatotroph adenoma cells in culture: effects of somatostatin, bromocriptine, and pertussis toxin.

To clarify the role of the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) in GH secretion in human somatotrophs and the effects of inhibitors of GH secretion on this mechanism, we studied the effects of 12-tetradecanoylphorbol-13-acetate (TPA) and phospholipase C (Plase C) on GH secretion and the interactions of somatostatin (SRIH), bromocriptine, and pertussis toxin (IAP) with TPA or Plase C, using human GH-secreting pituitary adenoma cells in culture. SRIH (10(-9)-10(-7) M) inhibited and TPA (10(-10)-10(-8) M) and Plase C (0.125-1.0 U/mL) stimulated GH secretion. SRIH (10(-9)-10(-7) M) inhibited GH release induced by TPA (10(-8) M) or Plase C (1.0 U/mL). Bromocriptine (10(-8) M) also inhibited 10(-8) M TPA-induced GH secretion. When adenoma cells were treated with 100 ng/mL IAP for 24 h, basal and TPA-induced GH secretion rates did not change. However, the inhibitory effects of SRIH (10(-8) M) or bromocriptine (10(-8) M) on basal and 10(-8) M TPA-stimulated GH secretion were attenuated. In addition, IAP reduced GH secretion induced by 0.5 U/mL Plase C, while SRIH inhibition of Plase C-evoked GH release was diminished by IAP. We conclude that the hydrolysis of PIP2 by Plase C, which causes activation of protein kinase C by 1,2-diacylglycerol and Ca2+ mobilization by inositol 1,4,5-triphosphate, is a physiological intracellular mechanism leading to GH secretion in human somatotrophs; SRIH inhibits GH secretion mediated by this mechanism, and bromocriptine blocks at least protein kinase C-mediated GH release; the inhibitory guanine nucleotide-binding protein (Ni) is involved in these inhibitory effects of SRIH and bromocriptine; and Ni modulates the breakdown of PIP2 by Plase C.

Adenoma↗
PubMed1989

Bromocriptine-responsive Cushing's disease associated with anterior pituitary corticotroph hyperplasia or normal pituitary gland.

Cushing's disease may originate from either the anterior pituitary lobe or the neurointermediate lobe, a major characteristic of the latter group being bromocriptine responsiveness. This study of two patients with Cushing's disease demonstrates that bromocriptine responsiveness also may be associated with anterior pituitary corticotroph hyperplasia or a normal pituitary gland. The two patients were a 14-yr-old boy (patient 1) and a 29-yr-old woman (patient 2); their cortisol production rates were 121 and 234 mumol/24 h (normal values, less than 80 mumol/24 h), respectively. A single oral dose of 2.5 mg bromocriptine resulted in a gradual decrease in plasma cortisol from 680 to 130 nmol/L after 6 h in patient 1 and from 640 to 170 nmol/L after 4 h in patient 2. Both patients then received medical treatment for a period of 2 yr. Whereas sodium valproate was ineffective, bromocriptine (5 mg/day) abruptly decreased the cortisol production rate to 60 mumol/24 h in patient 1 and to 138 mumol/24 h in patient 2, and both patients had a partial clinical remission. Despite an increase in bromocriptine dosage to 30 mg daily and 24 mg/day cyproheptadine, the clinical and biochemical remission was not sustained in patient 1, and no further improvement occurred in patient 2. Total hypophysectomy then was performed in both patients. Sections of the pituitary from patient 1 showed diffuse anterior pituitary corticotroph hyperplasia, with early nodule formation in some areas. The sections from patient 2 showed normal numbers and distribution of corticotrophs. We conclude that the heterogeneous nature of Cushing's disease cannot be explained on the basis simply of anterior vs. intermediate lobe origin of the disease.

Adolescent↗