Long-lasting suppression of prolactin secretion and rapid shrinkage of prolactinomas after a long-acting, injectable form of bromocriptine

Since Corenblum reported in 1975 the first documented reduction of tumor size in two patients with macroprolactinoma, evidence has accumulated that bromocriptine causes shrinkage of PRL-secreting adenomas in most patients. Recently a long-acting form of bromocriptine (bromocriptine LA) was developed. A single dose of 50 mg i.m. decreases basal and sleep-related PRL secretion in normal subjects for 28 days. We treated 13 patients (8 women, 5 men) with PRL secreting tumors (5 macroadenomas and 8 microadenomas) with a single dose (50 mg) of bromocriptine LA. In the 5 patients with macroprolactinomas plasma PRL levels decreased markedly within 12 hours, reaching normal levels in only one patient. In all patients the suppression of PRL secretion lasted at least 28 days and the tumor size was reduced by 20% to 59% within 21 days after the injection. Visual fields improved in all 3 patients with abnormal vision prior to the injection. In one patient with bitemporal hemianopsia an almost normalization of the visual field was noted 24 hours after bromocriptine LA administration. In 7/8 patients with microprolactinomas plasma PRL levels decreased to within the normal range within 12 hours after the administration of bromocriptine LA. The normalization of PRL secretion lasted for at least 28 days. Menses resumed in all 6 women 7 to 41 days after the injection, galactorrhea disappeared in all 4 patients, and libido and potency become normal in both men with microprolactinomas. Patients treated with bromocriptine LA reported only short-lasting (1 hour - 2 days) mild or moderate adverse effects, consisting of dizziness (4 patients) and nausea (4 patients). Long-acting bromocriptine should be considered as the initial management for patients with PRL-secreting tumors. The use of bromocriptine LA could also overcome the compliance problems that occur in many patients soon after the initiation of oral bromocriptine therapy.     

LONG-LASTING LOWERING OF SERUM GROWTH HORMONE AND PROLACTIN LEVELS BY SINGLE AND REPETITIVE CABERGOLINE ADMINISTRATION IN DOPAMINE-RESPONSIVE ACROMEGALIC PATIENTS

Cabergoline, the new long-acting dopaminergic ergoline derivative, was given orally in single doses of 0.3 and 0.6 mg to eight dopamine-responsive acromegalic patients. Serum GH and PRL levels were determined before treatment, 3, 4, and 6 h and 1, 3, 5, 7 and 14 days after treatment. A control test with a single oral dose of 2.5 mg of bromocriptine was also performed. Cabergoline induced a marked fall in serum PRL level, starting within 3 h and continuing for 7 days after administering 0.3 mg, and for 14 days after 0.6 mg. The mean maximal decrease was 49% after 0.3 mg and 63% after 0.6 mg and occurred after 24 h in both cases. The latter was of similar magnitude to that induced by bromocriptine (67% at 4 h). Serum GH levels did not change after 0.3 mg of cabergoline, but decreased significantly from 3 h to 3 days after 0.6 mg of the compound with a mean maximal decrease of 42% after 24 h, and from 3 to 6 h after giving bromocriptine (mean maximal decrease 63% at 4 h). Once a week repeated administration of 0.3-0.6 mg of cabergoline was carried out in six patients, five of whom had completed the acute study; a normalization of serum GH and insulin-like growth factor I (IGF-I) levels occurred in three patients, one of whom had very high pretreatment values. In three poorly or nonresponsive patients, a better response, as assessed by both GH and IGF-I levels, was induced by increasing the dose up to 0.6 mg twice or 0.4 mg three times a week; in one case this was associated with marked tumour shrinkage. Sustained normalization of PRL levels was achieved in all cases. These data indicate that a single dose of 0.6 mg of cabergoline inhibits GH as well as PRL secretion in dopamine-responsive acromegalic patients and suggests that doses of 0.3-0.6 mg once to three times a week may prove suitable for treatment of this condition.     

Long-term treatment with bromocriptine of a plurihormonal pituitary adenoma secreting thyrotropin, growth hormone and prolactin.

A 48-year-old female presented with acromegaly, amenorrhea and hyperthyroidism associated with high serum free T4 levels and measurable TSH concentrations. The administration of GHRH induced significant increases in GH, PRL and TSH. Conversely, intravenous infusion of dopamine or oral administration of bromocriptine effectively inhibited GH, PRL and TSH secretion. Serum alpha-subunit levels were neither affected by GHRH, dopamine nor bromocriptine. Transsphenoidal surgery was performed and immunostaining of the tissue showed that the adenoma cells were positive for GH, PRL or TSH. The patient was treated with bromocriptine at a daily oral dose of 10 mg after surgery. Serum TSH were initially suppressed but returned within reference intervals with persistent normalized free T4 levels. Serum PRL became undetectable and GH levels were stable around 6 ng/ml except the periods of poor drug compliance, when serum TSH, GH and PRL levels rose considerably. The patient was followed-up for 10 years without any change in the residual adenoma tissues as detected by magnetic resonance imaging. These findings suggest that long-term bromocriptine therapy is effective in treating the hypersecretory state of a plurihormonal adenoma secreting TSH, GH and PRL.     

A double blind controlled study of the hormonal and clinical effects of bromocriptine in the polycystic ovary syndrome

Previous studies on the efficacy of bromocriptine for the treatment of patients with the polycystic ovary syndrome failed to include control groups. This study, therefore, was undertaken to determine the clinical and endocrine effects of bromocriptine and a placebo (given in a random double blind fashion) in 55 patients with PCOS. The plasma levels of estrone, estradiol, testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, and serum PRL and gonadotropins (LH and FSH) were measured before treatment. In addition the serum PRL response to TRH and the serum LH and FSH response to GnRH were determined. The effects of acute administration of bromocriptine (2 X 2.5 mg at 12-h intervals) on serum gonadotropins and their response to GnRH were studied to explore the possibility that this test might predict the response to chronic bromocriptine treatment. Bromocriptine then was given at an initial dose of 1.25 mg twice daily. If no clinical improvement occurred 2.5 mg were given twice daily for at least 6 months. Hormonal measurements and dynamic tests were repeated after 3 and 6 months of therapy. The endocrine profile of the two groups was not different before treatment. The clinical results were not better in the treatment group than in the placebo-treated patients: therapy was successful (restoration of ovulatory cycles of less than 35 days duration) in 12 of 28 patients taking bromocriptine vs. 8 of 27 taking placebo. Slight improvement (1 or 2 ovulations) occurred in 3 of 28 vs. 3 of 27, and failure (no clinical change) in 13 of 28 taking bromocriptine vs. 16 of 27 taking placebo, respectively. Serum PRL fell significantly in the bromocriptine group, and there was a significant fall in the serum LH response to GnRH in both groups. No hormonal measurement or response predicted the clinical response to treatment. The only significant effect of chronic bromocriptine therapy (5 mg/day) in patients with the polycystic ovary syndrome was to lower the serum PRL concentration.     

Prolactin (PRL) regulation of maternal behavior in rats: bromocriptine treatment delays and PRL promotes the rapid onset of behavior

Recent findings indicate that PRL helps stimulate the onset of maternal behavior in inexperienced hypophysectomized steroid-treated female rats. In a series of five experiments we have further examined the involvement of PRL in maternal behavior using nonhypophysectomized ovariectomized rats treated concurrently (type I) or sequentially (type II) with progesterone (P) and estradiol (E2) and administered either bromocriptine (to suppress endogenous PRL secretion) or bromocriptine plus ovine PRL. In Exp 1 plasma PRL concentrations were measured in ovariectomized rats treated for 2 weeks with a combination of E2 and P Silastic implants. Type I steroid-treated (2mm E2, days 1-24; three 30 mm P, days 3-13) rats exhibited elevated plasma PRL levels throughout the sampling period compared with nonsteroid-treated controls. In contrast, PRL concentrations in type II steroid-treated (P, days 3-13; E2, days 13-24) females were low (similar to controls) from days 3-13 when the type II steroid-treated females were exposed to P only. Like type I treated rats, PRL levels in type II steroid-treated rats were elevated from day 13 onward after E2 capsule insertion. In Exp 2, treatment of both type I and type II steroid-treated rats with bromocriptine (2 mg/kg, sc) twice daily beginning on treatment day 13 suppressed basal PRL concentrations and prevented the estrogen-induced diurnal PRL surge. Whereas PRL was effectively suppressed by bromocriptine in both steroid-treated groups, the absolute levels of PRL were lower in rats treated with the type II steroid regimen. Behavioral analyses in Exp 3, 4, and 5 revealed that bromocriptine administration, while failing to interfere with the onset of maternal behavior in rats treated with the type I concurrent steroid regimen, disrupted the onset of maternal care in rats treated with the type II sequential steroid regimen. When a separate set of type II steroid-treated rats was given both bromocriptine (2 mg/kg) plus ovine PRL (0.5 mg, sc) twice daily, maternal behavior rapidly appeared. Thus, suppression of endogenous PRL secretion delays the onset of maternal behavior in nonhypophysectomized steroid-primed rats, an effect prevented by concurrent administration of ovine PRL. In addition to providing further experimental support for PRL's role in maternal behavior, the development of this endocrine regimen provides researchers with a potentially fruitful model to examine neural sites and mechanisms of PRL regulation of maternal behavior in mammals.     

Osteocalcin levels in patients with microprolactinoma before and during medical treatment

Osteocalcin (OC) concentration, a specific index of bone formation, was measured in 29 female patients with microprolactinoma (serum prolactin, PRL: 105 +/- 10.9 ng/ml; mean +/- SE). Mean OC levels were significantly lower than in controls (1.7 +/- 0.2 vs 5.1 +/- 0.3 ng/ml; p less than 0.001), being below the normal range in 28 out of 29 patients. All patients were treated with dopaminergic agents (dihydroergocriptine, bromocriptine or cabergoline). After treatment mean serum PRL levels were significantly reduced (12 +/- 3.1 ng/ml; p less than 0.001), a full normalization being obtained in 26 patients. There were no significant differences in both basal and after treatment PRL levels among patients treated with different drugs, although a greater PRL decrease was induced by cabergoline. Serum OC levels significantly increased after 12 month therapy (4.7 +/- 0.6 ng/ml, p less than 0.001), a normal concentration being reached in 14 of 29 cases. During treatment there were no significant differences in serum estradiol and PRL concentrations between patients who normalized or not their OC levels, while the reduction in PRL levels with respect to baseline was more pronounced in the former group. The absolute increase in OC levels positively correlated with serum PRL decrements (p less than 0.01). It is noteworthy that serum OC normalized in 1/10 patients during dihydroergocriptine, 3/8 during bromocriptine and 10/11 during cabergoline. Four patients, previously treated with dihydroergocriptine and bromocriptine without normalizing OC and PRL levels, underwent a second course of therapy with cabergoline and then normalized OC concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of bromocriptine on endocrine environment in the polycystic ovary syndrome

In order to investigate the hormone feature and the effect of bromocriptine on endocrine profile in patients with polycystic ovary syndrome (PCO), twenty-four-hour secretion pattern of LH, FSH, PRL and testosterone were assessed in 8 PCO patients and 4 normal women as controls by obtaining serial blood samples, taken through a forearm cannula, at 30 minute intervals for 24 hours. Bromocriptine, 5 mg/day was given and 3 patients were reassessed in the follicular phase of the menstrual cycle after ovulatory periods were established during bromocriptine therapy. There was significant difference in pulse amplitude, but not in pulse frequency of LH and testosterone between PCO and normal women (23.1 +/- 9.49 vs 5.75 +/- 1.28 mIU/ml, p less than 0.01; 27.8 +/- 10.1 vs 10.2 +/- 2.63 ng/dl, p less than 0.01), and the 24 hour mean LH and testosterone levels were higher (p less than 0.01) in PCO (52.3 +/- 20.1 mIU/ml, 105.1 +/- 15.9 ng/dl) than in normal women (13.4 +/- 4.31 mIU/ml, 54.3 +/- 13.3 ng/dl). Though a pulsatility in FSH secretion was identified, no difference between normal women and PCO was observed. Mean PRL level was within the normal range in PCO but with a higher pulse frequency (p less than 0.01) and lower pulse amplitude (p less than 0.01) than those of the normal women. Furthermore, LH and testosterone secretions maintained the circadian changes in PCO patients against the normal women. During bromocriptine therapy, mean level and pulse amplitude of LH and testosterone were significantly suppressed, without changing in pulse frequency, whilst PRL secretory patterns were not reestablished. In conclusion we have found that PCO is associated with high level and pulse amplitude of LH and testosterone, with high frequency and low amplitude of PRL, and bromocriptine administration can blunt LH, PRL and testosterone secretion, suggesting a hypothalamic intervention in gonadotropic regulation in patient with PCO. In addition, the degree of bromocriptine to inhibit LH secretion might be related to the dose or duration of its administration, or to the sensitivity of the patients. The mechanism of bromocriptine for marked LH suppression in PCO patients remains to be elucidated.     

The effects of bromocriptine on the pulsatile pattern and the circadian profile of gonadotropins and testosterone secretion in normal adult men

To investigate the effects of bromocriptine on the secretion mechanism of pituitary gonadotropins and testosterone, 5 mg of bromocriptine was administered to five young adult men who were normal in their endocrinological states. Blood samplings were taken from two hours before until six hours after the administration every 15 min., and after that, blood samplings were continued until 21 hours every one hour by an intravenous indwelling catheter. Serum FSH, LH, prolactin and testosterone levels were determined by RIA, and the changes of the pulsatile patterns of FSH and LH, and the circadian profile of these hormones by the administration of bromocriptine were analysed. Serum prolactin levels decreased significantly (p less than 0.005) from two hours after the administration of bromocriptine and remained in a very low range until the end of the experiment. The basal levels of FSH showed a significant decrease from two to six hours after the administration (p less than 0.005). Also the basal levels of LH showed a significant decrease from two to six hours after the administration (p less than 0.005). However, the basal levels of serum FSH and LH did not show significant decreases after that until the end of the experiment. No significant change was observed in the amplitude or the frequency of the pulsatile patterns of FSH and LH until six hours after the administration of bromocriptine. The serum levels of testosterone were also significantly decreased from two to six hours after the administration (p less than 0.005), but they did not show a significant decrease after that until the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effectiveness of a long-acting injectable form of bromocriptine in patients with prolactin and growth hormone secreting macroadenomas

OBJECTIVE With the development of new long-acting depot preparations of bromocriptine (bromocriptine LAR), we investigated the effectiveness of intramuscular injections of long-acting bromocriptine in patients with prolactin and GH secreting macroadenomas. STUDY DESIGN AND PATIENTS Fourteen patients with PRL secreting (8 patients) and GH secreting (6 patients) macroadenomas were treated with monthly intramuscular Injections of a long-acting and repeatable form of bromocriptine for 3–6 months. A 50-mg monthly dose was administered In the majority of patients with PRL secreting macroadenomas. A 100-mg monthly dose was administered In all patients with GH secreting macroadenomas. MEASUREMENTS Plasma PRL and/or GH levels were measured 6 and 12 hours after the first injection and then on days 1, 2,14 and 28 after each Injection, up to a maximum period of 6 months. Patients were hospitalized for 48 hours after each Injection and were specifically questioned with respect to side-effects. Pituitary imaging with MRI or CT scans was performed In all patients before commencing treatment and was subsequently repeated In 5/8 patients with macroprolactinomas and 5/6 patients with GH secreting macroadenomas after the completion of a 6-month course of treatment. RESULTS In ail patients with macroprolactinomas, serum PRL levels decreased significantly after their first 50-mg injection with nadir levels obtained by 24–48-hours post Injection (12815 ± 8704 vs 1480 ± 1859 mU/l; mean ± SD, P<0.01). At their latest follow-up, on a 50-mg monthly dose, 4 patients developed normoprolactinaemia (PRL levels <360mU/l) while two patients demonstrated a significant reduction In serum PRL levels (70 and 87% of pretreatment values). In two patients, although a substantial decrement of serum PRL levels was achieved 12-24 hours post injection, serum PRL levels Increased to pretreatment values by day 14 post injection. Both patients received a higher (100mg) monthly dose which was partially effective In one patient. In two patients with GH secreting macroadenomas, a sustained decrease of elevated GH levels was observed; in two patients, while a substantial reduction of the elevated serum GH levels was achieved 12–24 hours after the first and subsequent injections, serum GH levels increased to pretreatment values by day 14 post injection; in two patients there was no effect on the elevated serum GH levels. Significant tumour shrinkage (24–50%) was observed In 5/5 patients with PRL secreting macroadenomas assessed at completion of a 6-month course of treatment. Significant tumour shrinkage was also documented In 2/5 acromegalics tested (29 and 46% respectively). CONCLUSION It is concluded that bromocriptine LAR Is an effective treatment in the majority of patients with macroprolactinomas; it is also partially effective in some patients with GH secreting macroadenomas.     

Control of prolactin-secreting macroadenomas with parenteral, long-acting bromocriptine in 30 patients treated for up to 3 years

OBJECTIVE We investigated the effect of intramuscular injections of long-acting bromocriptine in patients with macroadenomas. STUDY DESIGN AND PATIENTS Thirty patients with PRL-secreting pituitary macroadenomas were treated with repeated 4-weekly intramuscular injections of 50 or 100 mg of a long-acting, repeatable bromocriptine formulation for six to 37 injections, amounting to a total of 473 injections. Twenty patients received parenteral bromocriptine as primary therapy, ten had persisting hyperprolactinemia after previous therapies including pituitary surgery (n= 7), oral bromocriptine (7), and pituitary Irradiation (2). MEASUREMENTS A PRL day profile was obtained and the patients' clinical status and history were documented, at intervals. Detailed clinical, laboratory, and radiological (pituitary nuclear magnetic resonance or computed tomography scan) evaluations were performed at baseline, after 1 injection and every 6th injection therafter. RESULTS In all patients PRL was suppressed from a mean ± SEM pretreatment level of 32 620 ± 8680 to 4480 ± 1140 mU/l on the third day after the first injection. In 12 patients PRL levels normalized (< 400 mU/l) with the first to fourth injection, in three additional patients PRL levels normalized after 8–15 months. In 19 patients PRL was suppressed to less than 1000 mU/l. In three patients PRL did not decrease to less than 50% of pretreatment; in two of them on oral bromocriptine prior to this study there had been a comparable low efficacy. Of 28 patients with macroadenomas (median height 22 mm) tumour shrinkage was evident in 15 by nuclear magnetic resonance or computed tomography scan 28 days after the first injection, and in three additional patients after 6 months. There was further regression in seven cases after 12, 18 or 24 injections. Adenoma size (mean SEM) decreased to 66 ± 7% of the pretreatment value. The 40 adverse events noted in 20 of 30 patients during 24 hours after the first injection were similar to known side-effects of oral bromocriptine, nausea and postural hypotension being the most frequent. With repeated injections, on average 0 6 adverse events were noted per injection (mostly mild asthenia). There were no local adverse reactions at the injection site. CONCLUSION We conclude that long-acting repeatable bromocriptine in patients with macroprolactinomas offers a safe and efficacious primary treatment that ensures compliance and gives long-term control. Adverse reactions are comparable to oral bromocriptine but subside with repeated injections.     

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.     

Anterior pituitary function in patients with cerebrovascular disease: with special reference to growth hormone secretion in response to TRH administration (author's transl)]

HGH secretion in response to TRH was studied in patients with cerebrovascular disease in order to elucidate an influence of cerebrovascular lesions on the hypothalamus-anterior pituitary function. Blood specimens were obtained before and at the time of 10, 20, 30, 40, 60, 90 and 120 minutes after the intraveneous administration of 200 microgram of TRH in 17 patients with cerebral hemorrhage and in 8 patients with cerebral infarction. With regards to the natural fluctuations of serum HGH caused by cerebrovascular disease, the blood specimens were obrained at the time of 0, 30, 60, 90 and 120 minutes without the administration of TRH in 4 patients with cerebral hemorrhage and in 4 patients with cerebral infarction. Serum HGH was measured using the RIA method and the following results were obtained: 1) An increase in serum HGH was observed in 1 patient with cerebral hemorrhage out of 8 patients with cerebrovascular disease without TRH administration. 2) In 5 out of 17 patients with cerebral hemorrhage, an increase in serum HGH was observed following TRH administration. Three out of these 5 patients were included in the group of non-coma, and 4 out of the 5 patients were female. 3) In 2 out of 8 patients with cerebral infarction, an increase in serum HGH was observed following TRH administration.     

Prolactin enhancement of its own uptake at the choroid plexus.

The choroid plexus contains PRL receptors that function in part to transport PRL from the blood into the cerebrospinal fluid (CSF). The blood PRL concentration of female rats was altered by 1) three daily injections of haloperidol (chronic hyperprolactinemia) with or without bromocriptine administration 4 h before death, 2) bromocriptine alone for 4 h (acute hypoprolactinemia), and 3) a single vascular injection of ovine PRL (acute hyperprolactinemia). Changes in the uptake of PRL by the choroid plexus was assessed by quantitative in vivo autoradiography after the injection of radiolabeled PRL. Correlation of changes in PRL uptake at the choroid plexus with changes in PRL transport from blood to CSF was evaluated by subjecting CSF samples to sodium dodecyl sulfate-polyacrylamide gel electrophoresis after vascular injection of radiolabeled PRL. Autoradiography revealed that both chronic and acute hyperprolactinemia resulted in a significant increase in the uptake of radiolabeled PRL by the choroid plexus compared to that in untreated control animals. In contrast, bromocriptine had no effect on PRL uptake at the choroid plexus relative to that in control (untreated) animals. Chronic hyperprolactinemia, but not acute hyperprolactinemia, resulted in a significant increase in the transport of radiolabeled PRL from the blood to the CSF compared to that in untreated controls. The results are consistent with the up-regulation of PRL receptors in the choroid plexus by circulating PRL and the consequent augmentation of transport of PRL from blood to CSF.     

Hyperprolactinemia inhibits gonadotropin-releasing hormone (GnRH) stimulation of the number of pituitary GnRH receptors

Gonadotropin secretion is diminished in the presence of hyperprolactinemia, and previous studies have shown that PRL can reduce GnRH secretion and impair LH responses to GnRH. To investigate the mechanisms of the inhibitory effects of PRL on the pituitary, we administered intraarterial pulse injections of GnRH (25 ng/pulse every 30 min) to castrate testosterone-implanted male rats placed in restraint cages. Serum PRL, GnRH receptor (GnRH-R), and LH responses to GnRH were measured at intervals over 72 h. In control animals which received saline pulses, serum PRL was transiently elevated to the range of 100-150 ng/ml during the first 24 h, GnRH-R remained stable (approximately 300 fmol/mg protein) and serum LH was low (less than 10 ng/ml) throughout the 72 h. GnRH pulses in castrate testosterone-implanted animals increased GnRH-R to values (approximately 600 fmol/mg) similar to those in castrate controls (no testosterone implant, saline pulses) through 48 h, but GnRH-R declined to baseline values by 72 h in both groups. Serum LH responses to GnRH pulses were only present at 24 h. Administration of bromocriptine throughout the 72 h to immobilized castrate rats or to castrate testosterone-replaced animals treated with GnRH pulses suppressed serum PRL, and GnRH-R concentrations remained elevated through 72 h. Serum LH responses to GnRH pulses were 5- to 20-fold higher in bromocriptine-treated rats, and responses were present throughout the 72 h of the experiment. Delaying the start of bromocriptine treatment until 36 h (after the spontaneous PRL peak) resulted in reduced GnRH-R and LH responses at 72 h. Similarly, administration of ovine PRL (during the first 48 h) to bromocriptine-treated rats produced low GnRH-R concentrations at 72 h. Thus, the transient elevation of PRL seen in immobilized rats can inhibit the GnRH-stimulated increase in GnRH-R and is associated with reduced LH responses to GnRH. These results indicate that PRL has a direct inhibitory effect on the gonadotrope and suggest that impaired GnRH-R responses to GnRH are one of the mechanisms involved in the diminished gonadotropin secretion seen in hyperprolactinemia.     

Serum lactogens possessed normal bioactivity in patients with lactation insufficiency

OBJECTIVE A new long-acting injectable form of bromocriptine has become available for long-term treatment of hyperprolactinaemic patients. The objective of this study was to compare efficacy and tolerability of injectable and oral forms of bromocriptine. DESIGN A double-blind randomized study. All patients received either one injection of bromocriptine 50 mg intramuscularly and placebo tablets for 28 days (Group A) or one placebo injection and oral bromocriptine 7 5 mg daily for 28 days (Group B). PATIENTS Twenty-three (12 patients for Group A and 11 patients for Group B) hyperprolactinaemia patients with (19 patients) or without (4 patients) CT/MRI evidence of tumour were studied. MEASUREMENTS Plasma PRL levels and serum bromocriptine levels were assessed during a follow-up of 42 days. MRI and/or CT were evaluated before and 28 days after the beginning of the study. RESULTS All patients had significant reductions of PRL levels from 1000 h and 1100 h of day 1 to 2000 h of day 35. Normoprolactinaemia was shown in eight patients of Group A and six of Group B on days 1-28. Normal PRL levels were still present in five patients of Group A and in one patient of Group B on day 35; only three patients of Group A had normoprolactinaemia on day 42. A significantly greater decrease in Group A in comparison with Group B was shown at 1200 h on day 1 and at all times as a percentage decrease from basal levels. Significantly higher levels of bromocriptine were shown in Group A at all timepoints studied. No difference was shown in tolerability and incidence of side-effects. CONCLUSION Our data show that injectable bromocriptine more frequently induced a prolonged normoprolactinaemia than did the oral drug. Moreover, bromocriptine levels released during injectable bromocriptine were significantly higher than during oral bromocriptine. On the other hand no difference was shown in the tolerability of bromocriptine according to the route of administration.     

The effects of dopamine agonist (bromocriptine) on the secretion of pituitary gonadotropins and ovarian sex steroids in normally cycling women

To investigate the effects of bromocriptine on the secretion mechanism of pituitary gonadotropins and ovarian sex steroids, 5 mg of bromocriptine was administered to four normally cycling women in the follicular, pre-ovulatory, mid-luteal or menstrual phase, respectively. Blood samplings were taken from two hours before until six hours after the administration every 15 min. by an intravenous indwelling catheter. Serum FSH, LH, prolactin, estradiol and progesterone were determined by RIA, and the changes of basal levels and the pulsatile patterns of these hormones were analysed in each of the four phases. Serum prolactin levels decreased significantly (p less than 0.005) from two hours after the administration of bromocriptine and remained in a very low range in all phases of the cycles until the end of the experiments. The basal levels of FSH showed a significant decrease in the pre-ovulatory and mid-luteal phases two to six hours after the administration (p less than 0.025 approximately p less than 0.005). Also the basal levels of LH showed a significant decrease in the follicular, pre-ovulatory and mid-luteal phases two to six hours after the administration (p less than 0.05 approximately p less than 0.005). However, no significant change was observed in the amplitude or the frequency of the pulsatile patterns of FSH and LH in all phases of the menstrual cycles. The serum levels of estradiol did not show marked changes by the administration of bromocriptine, but the serum levels of progesterone were significantly decreased in the mid-luteal phase two to six hours after the administration (p less than 0.005). These facts suggest that bromocriptine acts mainly on the pituitary rather than the hypothalamus to decrease the serum levels of gonadotropins, and also may have some role in the steroidogenesis of the ovary.     

Transsphenoidal surgery in hypersecreting pituitary tumors: endocrine follow-up (author's transl)

Among 18 patients suffering prolactin adenoma and 16 acromegalic patients, plasma levels of PRL and HGH respectively returned to normal vlues (PRL = 9 +/- 2 ng/ml HGH = 4.2 +/- 0.8 ng/ml) immediately after selective removal of the pituitary adenoma by transspheno?dal route. In all cases tumoral symptoms were reduced. Menses were recovered 36 +/- 5 days after surgery in all patients with prolactin adenoma. Pregnancy succeeded in nine of these women. Per-operative studies of HGH and PRL plasma variations proved to be of good prognostic value. The evaluation of the pituitary functions was performed before and after surgery. In no case pituitary deficiency occured after treatment. Furthermore the regulation of somatotropic and prolactin functions have been documented by the use of different provocative tests before and after treatment. They allow discussion of the pathogenecity of these hypersecreting tumors.     

Long-lasting prolactin-lowering effect of cabergoline, a new dopamine agonist, in hyperprolactinemic patients

The new long-acting ergoline derivative cabergoline was given orally in a single dose of 300 micrograms to 15 hyperprolactinemic patients (including 4 acromegalic patients, 2 of whom were dopamine responsive). Serum PRL and GH levels were determined before and 3, 4, and 6 h and 1, 2, 3, 4, 5, 6, and 7 days after treatment. A control test with a single oral dose of 2.5 mg bromocriptine was also performed; serum PRL and GH levels were measured at the same time intervals for 2 days. Cabergoline induced a marked fall in serum PRL which began within 3 h and continued for 7 days. The maximal decrease ranged between -49.2% and -55.2% and occurred after 2-5 days. This maximal effect was only slightly less than that 6 h after bromocriptine treatment (-63.8%). After cabergoline treatment, serum GH levels did not change significantly in either nonacromegalic or acromegalic patients, whereas the two dopamine-responsive acromegalic patients had a marked GH fall after bromocriptine. A moderate blood pressure decrease, more evident in the standing position, occurred after both cabergoline and bromocriptine treatments. The only symptomatic side-effect was orthostatic hypotension after cabergoline in an elderly woman. These data indicate that cabergoline has potent and prolonged dopaminergic activity and may prove suitable for once weekly treatment of hyperprolactinemic patients.     

The prevalence of hyperprolactinemia in patients with primary Sj?gren's syndrome.

OBJECTIVE: To assess the prevalence of hyperprolactinemia in 55 patients with primary Sj?gren's syndrome (SS), and its clinical significance. METHODS: Concentrations of serum prolactin (PRL) were determined in 55 consecutive patients with primary SS and 110 controls by a fluoroimmunometric assay in a prospective case-control design. RESULTS: The 55 patients with primary SS had higher serum PRL than 110 matching controls (271.5 vs 205.9 mIU/l; p < 0.02), and this difference was most evident in patients diagnosed before the age of 45 years (374.8 vs 245.5 mIU/l; p < 0.05), a patient population characterized by active immunological disease. Serum PRL did not correlate to disease duration, serum immunoglobulin, autoantibodies, or focus score in biopsies from minor salivary glands, but did correlate to score for internal organ disease (r = 0.33, p < 0.05). Two patients were diagnosed as having primary SS 12 years after hyperprolactinemia was first detected, and both patients had aggressive primary SS as indicated by extraglandular manifestations. One of the patients developed primary SS after being treated with bromocriptine, an inhibitor of PRL synthesis, for 12 years. CONCLUSION: Patients with primary SS have moderately increased levels of serum PRL, especially evident in patients diagnosed at a young age with active immunological disease. Serum PRL is correlated to index for internal organ disease, and primary SS may be preceded by hyperprolactinemia for many years.     

Regulation of testicular prolactin and luteinizing hormone receptors in golden hamsters

Iodinated ovine PRL (oPRL) was used to detect the presence of PRL receptors in hamster testes. Binding to these receptors was specific for PRL and was saturable and incompletely reversible. Testicular PRL receptors possessed a single class of independent, high affinity binding sites (Ka = 2.4 X 10(10) M-1). The ability of PRL to regulate testicular PRL and LH receptors was measured in experiments wherein mature hamsters were injected daily for 10 days with 600 micrograms bromocriptine, 600 micrograms bromocriptine plus 250 micrograms oPRL, or injection vehicles. Bromocriptine injections, which caused significant reductions in serum PRL, produced commensurate decreases in concentrations (femtomoles per mg protein) of testicular LH and PRL receptors, without affecting binding of PRL to adrenal or liver tissue preparations. Decreases in testicular PRL binding were not always statistically significant, but were consistently measured. The administration of oPRL with bromocriptine significantly increased both concentration and total content (femtomoles per paired testes) of testicular LH receptors and PRL-binding sites above those measured in bromocriptine-injected and control hamsters. Liver PRL-binding sites were, likewise, increased above values measured in controls and bromocriptine-injected hamsters by this latter treatment, which had no significant effect on adrenal PRL-binding sites. Neither bromocriptine nor bromocriptine plus oPRL had any effect on the affinity (Ka) of testicular PRL receptors for labeled oPRL. Serum testosterone and FSH concentrations were unaltered by treatment, thereby suggesting that effects on receptors did not occur secondary to changes in these hormones, but, rather, represent direct effects of PRL. An additional experiment in prepubertal male hamsters (aged 14-30 days) demonstrated that bromocriptine injections for 17 days significantly reduced the total content of testicular PRL receptors. In vitro experiments eliminated the possibility of direct effects of bromocriptine on testicular receptors. The data demonstrate the possibility that PRL is required for maintenance of normal concentrations of testicular LH/hCG and PRL receptors in adult and immature golden hamsters. An increase in putative serum anti-oPRL antibodies was measured in oPRL-injected hamsters. Since such antibodies could contribute, to an unknown degree, to PRL binding measured in tissue preparations, the present data indicate only that increased testicular binding occurs subsequent to injection of heterologous PRL, without demonstrating that this binding is indeed due to increased PRL receptors.