Bromocriptine treatment of acromegaly

Bromocriptine at a dose of 7.5-30 mg/day was given to 12 acromegalics for 6 mo. Mean serum growth hormone (GH) levels during a glucose tolerance test (GTT) were significantly lowered by the drug. In four patients the serum GH response during a GTT was suppressed to normal (i.e. less than or equal to 5 mlU/liter). If bromocriptine had not brought the serum GH response to a GTT to normal at a dose of 20 mg/day, this effect was not achieved by raising the dose to 30 mg/day. Bromocriptine was effective for the duration of treatment. On discontinuing therapy there was an increase in serum GH levels. No obvious clinical changes in the acromegalic features were noted. One patient with impaired glucose tolerance and one with established diabetes had normal glucose tolerance while on bromocriptine and another two patients with impaired glucose tolerance showed no obvious changes while on the drug. Side effects were minor. X-rays of the pituitary fossa before starting and at the end of treatment showed no significant change. We conclude that although bromocriptine is the most promising form of medical treatment for acromegaly to date, it is fully effective only in a minority of patients.     

The effectiveness of external beam radiotherapy for acromegaly is not affected by previous pituitary ablative treatments

Thirty-three acromegalic patients were treated with radiotherapy and followed up for at least 3 years (mean 6 years, range 3 to 12). Seventeen had not had previous pituitary ablative therapy and 16 had. The mean GH level for these two groups before radiotherapy was comparable at 98 and 119 mIU/l. The observed frequency of reaching less than 10 mIU/l was 53% and 75% of patients in the two groups, respectively, the mean observed falls in growth hormone level were 81 and 85% of the initial level, and the calculated exponential decline rate of GH level was 72 and 52% per year. Considering all 35 patients, requirement for pituitary hormone replacement therapy increased from 15 patients before radiotherapy to 20 after radiotherapy, being mostly those who had had prior ablative therapies. There were no complications attributable to the radiotherapy treatment. It appears that radiotherapy is equally efficacious whether a prior unsuccessful ablative procedure had been used or not.     

Bromocriptine treatment over 12 years in acromegaly: effect on growth hormone and prolactin secretion.

It is not known whether bromocriptine treatment in acromegaly can be implemented for a life-long period. To elucidate this problem, the secretory GH and PRL states of 12 patients with acromegaly were determined, before bromocriptine treatment, under therapy (15.0 +/- 6.8 mg/day for 12 +/- 3 years; mean +/- SD) and during two-weeks long drug withdrawal after long-term treatment, respectively. Before therapy, all patients showed a non-sufficient GH suppression after oral glucose load (greater than 2 micrograms/l), whereas under dopaminergic treatment the post-glucose GH levels of three patients fell below 2 micrograms/l; normal IGF-I concentrations were found in five patients. However, under bromocriptine, only two patients showed GH suppressions below 2 micrograms/l following glucose, accompanied with normal IGF-I levels. During bromocriptine withdrawal, GH secretion at 60 min in the oral glucose tolerance test increased significantly (17.0 +/- 15.5 vs 5.7 +/- 5.2 micrograms/l; p less than 0.01); the mean IGF-I level rose from 2.1 +/- 0.8 to 4.9 +/- 2.2 kU/l (p less than 0.01). IGF-I was normal during bromocriptine cessation in only one patient; none of the 12 patients showed a GH suppression below 2 micrograms/l after oral glucose load. Under dopaminergic treatment hyperprolactinemia could not be detected. In conclusion, bromocriptine led to a stable suppression of both GH hypersecretion and--if present--concomitantly elevated PRL levels. Severe side effects or a further tumor growth could not be observed. Thus, the data of the longest follow-up investigation that has so far been published indicate that effective life-long bromocriptine therapy seems to be possible in selected patients with acromegaly.     

Long-term effect of 90Y pituitary implantation in acromegaly

This report examines the long-term trends in GH levels and pituitary function in a group of 38 acromegalic patients who were selected insofar as we were able to follow them up for more than 10 years after a single dose of 90Y interstitial pituitary irradiation as the sole treatment. Mean serum GH had fallen from 106 to 24 mIU/l within 3-6 months and then slowly declined to 4 mIU/l after 10 years. GH levels of less than or equal to 5 mIU/l during a 50 g oral glucose tolerance test were obtained in 8% of patients at 3-6 months and in 18% at 1 year, the cumulative percentage increasing to 53% at 10, and 76% at 14 years. The percentage of patients requiring hormone replacement therapy rose from nil pre-implant to 16% by 3-6 months, and then slowly increased to 39% by 14 years. Serial coned radiographs of the pituitary fossa were available for 32 patients. By 10 years, 16 showed thickening of the dorsum sellae and/or reduction of at least one diameter by 3 mm. Concerning symptoms, all 29 patients whose GH level fell to less than or equal to 5 mIU/l showed improvements, 22 becoming asymptomatic. Seven patients with lesser falls in GH levels (from a mean of 193 to a mean of 15 mIU/l) all improved, one becoming asymptomatic. Two showed no variation. These results show that 90Y pituitary implants have a cumulative effect over the years in inducing remission and hypopituitarism in acromegalic patients, the early decline in GH levels being swifter than from other forms of irradiation.     

Bromocriptine reduces growth hormone in acromegaly

We assessed serum growth hormone (GH) levels in ten patients with acromegaly during a 24-hour profile and a 75-g oral glucose tolerance test (GTT). Serum GH levels were measured after five weeks of bromocriptine mesylate therapy, 20 mg daily (P1), after five weeks without bromocriptine mesylate therapy (P2), and again five weeks following restarting treatment with bromocriptine, 20 mg daily (P3). During the 24-hour profile, the following occurred: (1) mean serum GH level of the group was lower during P1 (20.5 mU/L) and P3 (20.8 mU/L) than P2 (49.6 mU/L); (2) in six individual patients during P1 and P3, there was a significant reduction in the mean serum GH value; and (3) a marked circadian variation in the serum GH value was present both with and without the drug therapy in five patients. During the GTT, the mean serum GH value was lower during P1 (18.4 mU/L) and P3 (16.7 mU/L) than P2 (43.3 mU/L), and in seven individual patients during P1 and P3, there was a significant reduction in the mean serum GH value. Overall, a clear reduction in serum GH values due to bromocriptine was demonstrated. In individual patients, serum GH values during a 24-hour profile and GTT gave similar indications of response.     

EFFECTIVE LONG-TERM TREATMENT OF ACROMEGALY WITH A LONG-ACTING SOMATOSTATIN ANALOGUE (SMS 201–995)

Nine acromegalic patients, six previously untreated, were studied before and after 3-15 months of treatment with a long-acting somatostatin analogue (SMS 201-995; 100 micrograms injected s.c. three times daily). During treatment, the mean (+/- SEM) 24-h GH concentration fell from 82 +/- 22 mIU/l to 33 +/- 7 mIU/l (P less than 0.001), and eight of the 9 patients showed a reduction of at least 50% in GH levels in the fasting state and/or during a glucose tolerance test. There was a significant 30% fall in serum concentrations of insulin-like growth factor (IGF-1) with SMS. All patients showed rapid clinical improvement, with diminished sweating and headaches, and reduction in skinfold thickness, hand volumes and finger size. Computer tomographic scanning of the pituitary in eight patients showed no change in the size of the pituitary tumour during treatment. The only side-effects of SMS noted were transient abdominal discomfort and loose stools in two patients on initiating therapy. Although fasting plasma glucose concentration did not change during treatment (5.4 +/- 0.3 vs 5.5 +/- 0.3 mmol/l), mean 24-h plasma glucose concentration was higher with SMS (6.6 +/- 0.5 mmol/l vs 6.0 +/- 0.4 mmol/l; P less than 0.02). Mean 24-h plasma insulin concentration fell from 87 +/- 11 mIU/l before treatment to 39 +/- 6 mIU/l during treatment (P less than 0.005). No change in other anterior pituitary hormones was observed. SMS appears to be a safe, rapidly effective, long-term treatment for certain patients with acromegaly.     

The sensitivity of growth hormone secretion to medical treatment in acromegalic patients: influence of age and sex

OBJECTIVE: We investigated the relationship between age, sex, pituitary tumour volume, serum GH, PRL and IGF-I levels with the responsiveness of GH to TRH, bromocriptine and octreotide in patients with acromegaly. DESIGN: We performed a retrospective study. Correlations were determined between all variables using univariate regression analysis. PATIENTS: One hundred previously untreated acromegalic patients were studied (60 males (age 23-76; mean 49 years) and 40 females (age 25-83; mean 51 years)). MEASUREMENTS: We studied tumour volume, fasting morning circulating levels of GH, PRL and IGF-I, mean 24-hour circulating GH levels and the acute GH responses to TRH, bromocriptine and octreotide. RESULTS: Tumour size was related to serum and mean 24-hour GH levels, but not to IGF-I. Circulating IGF-I and GH levels were related only for the group of patients whose fasting and unsuppressed GH level was 80 mU/l (40 micrograms/l) or less. Older patients tended to have lower circulating GH and IGF-I levels. There was a close similarity in the responsiveness of tumorous GH secretion to TRH, bromocriptine and octreotide. An elevated serum PRL level predicted a stronger inhibitory response of bromocriptine on GH. The sensitivity of GH release to octreotide was highest in elderly (especially male) acromegalics, as well as in patients with lower IGF-I levels. CONCLUSIONS: Hormone secretion by GH secreting pituitary tumours, as well as circulating IGF-I levels, tend to be lower in elderly patients. These tumours are more sensitive to octreotide, especially in elderly male patients. This suggests that octreotide might be used especially successfully as a primary medical therapy in elderly, male acromegalics.     

Dynamics of the acute effects of octreotide, bromocriptine and both drugs in combination on growth hormone secretion in acromegaly.

The separate and combined GH-lowering effects of single doses of octreotide and bromocriptine were assessed in 51 acromegalic patients on 4 occasions each 2 days apart. Patients received sequentially: placebo sc (N = 51), 50 micrograms octreotide sc (N = 51), 2.5 mg bromocriptine po (N = 40) or a combination of both drugs (N = 25). With octreotide, in 28 patients (55%) GH levels were suppressed to less than 5 micrograms/l and 39 of them (76.5%) had a 50% or greater decrease of their basal GH level from 2 to 6 h. During bromocriptine, GH values were suppressed to below 5 micrograms/l in 11 patients (27.5%) and reduced by 50% or more in 21 (52.5%). The combination of both drugs acutely suppressed GH levels to less than 2 micrograms/l in 32%, to less than 5 micrograms/l in 56%, and by more than 50% in 84% of patients. Octreotide produced a stronger and faster suppression of GH levels than bromocriptine in most patients. The combination of both drugs had an additive effect on the lowering of GH levels, especially between 7 and 10 h after drug administration. These results suggest that chronic therapy with a combination of both drugs may be as effective as therapy with higher doses of either compound alone. Albeit transient, octreotide caused a rapid near total suppression of insulin release in the morning, 15 to 45 min after administration. Postprandial glucose rise, between 2 and 3.5 h after breakfast was significantly higher during octreotide than on the control day.     

The natural history of idiopathic hyperprolactinemia

Idiopathic hyperprolactinemia (IH) can be defined as the presence of elevated serum PRL levels in a patient in the absence of demonstrable pituitary or central nervous system disease and of any other recognized cause of increased PRL secretion. This study examined the long term clinical outcome of 41 patients (mean age, 26 yr) with IH followed for up to 11 yr (mean, 5.5 yr). Initial and final PRL levels were determined by RIA in the same laboratory. A correction factor was used to obviate periodic changes in the potency of the NIH standards used in the PRL assay, so that all results are expressed in terms of the original VLS no. 1 standard. The initial serum PRL levels ranged from 27.2-243 ng/ml, with a mean of 57 ng/ml. Only three patients had initial serum PRL levels greater than 100 ng/ml. All had a normal skull x-ray and/or brain computed tomographic scan during their initial visit. All 41 patients had galactorrhea and/or amenorrhea. Serum PRL levels remained the same, decreased, or returned to normal in 34 of 41 patients. The mean PRL level at the time of reevaluation was 35 ng/ml. Thirty-four percent of the patients had a normal serum PRL level. Only 17% of the patients had serum PRL levels that were significantly higher (greater than 50% of their original value). Six of 9 patients with an initial serum PRL level less than 40 ng/ml had normal levels. One patient developed a pituitary tumor (initial PRL, 150 ng/ml). All patients reevaluated with brain computed tomographic scans had normal pituitary size. No patient reported a worsening of signs or symptoms, and in many, improvement (n = 16) or complete resolution (n = 8) of the amenorrhea and/or galactorrhea occurred. Twenty-seven spontaneous or bromocriptine-induced normal pregnancies and deliveries occurred without development of a pituitary tumor. Therefore, our data clearly challenge the use of ablative pituitary therapy for IH and raises questions of the benefit of chronic medical therapy for this condition.     

NORMAL GROWTH AND PUBERTAL DEVELOPMENT DURING BROMOCRIPTINE TREATMENT FOR A PROLACTIN-SECRETING PITUITARY MACROADENOMA

An 11-year-old male presented with a 2-year history of headache and lethargy. Serum PRL was elevated at 14,000 mU/l and computerized tomography showed a pituitary macroadenoma. Visual fields and fundi were normal and the testes showed early pubertal changes. There was normal responsiveness of serum cortisol but absence of GH response to hypoglycaemia. After bromocriptine therapy for 4 months serum PRL had fallen to 90 mU/l and the tumour was not visible on repeat computerized tomography. After 7 months treatment, repeat pituitary function testing showed restoration of GH response to hypoglycaemia. Treatment with bromocriptine was continued and there was spontaneous progression of normal puberty; the serum testosterone continued to rise, and height maintained the 50th centile. Bromocriptine therapy should be considered as initial therapy in the management of prolactinomas in prepubertal patients.     

Effectiveness of adding dopamine agonist therapy to long-acting somatostatin analogues in the management of acromegaly

BACKGROUND: The excess mortality and morbidity associated with acromegaly are secondary to prolonged elevation of GH and IGF-I. Vigorous control of these biochemical parameters results in improved morbidity and mortality. Somatostatin analogues (SAs) allow adequate control of GH and IGF-I in approximately 65% of subjects, leaving a significant cohort uncontrolled. Dopamine agonists (DAs), a cheap alternative to SAs, allow control of GH and IGF-I in less than 20% of patients with acromegaly. AIMS: To assess the effectiveness of adding DA therapy to SA in the biochemical control of acromegaly. SUBJECTS: One hundred and twenty cases from the Sheffield Acromegaly Register were reviewed; 24 (20%) did not require medical treatment following pituitary surgery alone; 16 (13%) had safe GH levels following surgery and radiotherapy; and 58 (48%) required medical treatment despite having had surgery, radiotherapy or both. The remaining 22 (18%) received only medical treatment. METHODS: In nine subjects a DA (three bromocriptine, six cabergoline) was added to an SA to control active disease. GH day curves and IGF-I levels were compared before and after the addition of a DA to existing SA treatment. All were on stable maximum-dose treatment with an SA, with inadequate biochemical control prior to addition of DA therapy. Mean duration of treatment on a DA before biochemical assessments were made was 10.3 months. Six subjects had previously been treated with either transsphenoidal surgery, radiotherapy or both. In three subjects SA was the primary therapy. RESULTS: All subjects exhibited a fall in median GH and IGF-I levels. Introduction of a DA resulted in a 36.1% reduction in median GH levels (8.3 vs 5.3 mIU/l; P = 0.008) on a GH day curve and a 35.2% reduction in IGF-I levels (387.2 vs 251.0 microg/l; P = 0.018). Only four subjects had elevated prolactin levels prior to the addition of a DA (>368 mIU/l). CONCLUSION: Addition of DAs to SAs is of benefit in the biochemical control of acromegaly and should be considered in those inadequately controlled. Furthermore, the beneficial effects of DAs occur even when pre-treatment prolactin levels are within the normal range.     

Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly

In acromegaly, pituitary irradiation is a slow, but effective, intervention in decreasing GH concentration. Few studies addressing the outcome of radiotherapy have used the currently accepted strict criteria for remission in the analysis of data. These studies report a low percentage of remission after radiotherapy. Doubt has especially been raised as to whether radiotherapy is effective in normalizing serum insulin-like growth factor (IGF)-I concentration. We analyzed the long-term follow-up data of postoperatively administered radiotherapy in 36 patients with postoperative persistent acromegaly, using both the normalization of GH suppression during oral glucose loading (GTT) and the normalization of IGF-I concentration as criteria for remission. Before radiotherapy, mean suppressed GH was 9.8 +/- 1.9 mU/L (n = 31), and mean IGF-I concentration was 44.3 +/- 3.9 nmol/L, equivalent to + 4.76 +/- 0.78 age-related IGF-I SD score (n = 13). The median radiation dose was 40 Gray (range, 25-50 Gray). At 5, 10, and 15 yr follow-up, 18 out of 30 patients (60%), 23 out of 31 patients (74%), and 16 out of 19 patients (84%), respectively, achieved normal serum IGF-I concentration. At the last assessment of all patients, after a mean follow-up period of 139 +/- 12 months, 27 out of 36 (75%) patients had a normal IGF-I concentration without additional medication, whereas 5 patients still required treatment with octreotide. Remission, as judged by normalization of GH suppression during GTT, was documented in 65% of patients from 2-5 yr after radiotherapy (n = 34); in 69% of patients, up to 10 yr after radiotherapy (n = 29); and in 71% of patients, up to 15 yr post irradiation (n = 17). At the latest assessment, a mean of 125 +/- 11 months after radiotherapy, 71% of patients (n = 35) were in remission, as defined by normal suppression of serum GH during GTT. Remission, as judged by normalization of both GTT and IGF-I, was found in 40% of patients 3-5 yr after radiotherapy (n = 30); in 61% of patients, 6-10 yr after radiotherapy (n = 28); in 65%, after 11-15 yr after radiotherapy (n = 17); and in 63% of patients, at the end of the follow-up period (n = 35). Substitution of one or more pituitary hormone deficiencies was required in 11% of patients postoperatively; in 29%, 5 yr after radiotherapy; in 54%, 10 yr after radiotherapy; and in 58%, more than 15 yr after radiotherapy. Our findings support the use of radiotherapy as an effective intervention in the treatment of residual clinical activity of disease after surgery for acromegaly.     

The role of prolactin in the inhibitory action of bromocriptine on growth hormone secretion in acromegaly

Bromocriptine treatment results in clinical improvement and inhibition of plasma GH levels in only part of the acromegalic patients. The possible role of the simultaneous presence of Prl and GH in GH-secreting pituitary adenomas was investigated with regard to the inhibitory action of bromocriptine on GH secretion and the paradoxical increase of GH release in reaction to TRH. Surgically obtained pituitary tumour tissue from 35 consecutive acromegalic patients was studied immunohistochemically. In 21 patients no Prl was present in the tumour tissue. These patients had normal plasma Prl levels. In the other 14 patients Prl was present in the tumour tissue. Hyperprolactinaemia was found in 10 of these 14 patient. Plasma GH levels from 2 till 10 h after the administration of 2.5 mg bromocriptine measured before operation were significantly more suppressed in the patients with mixed GH/Prl-containing than in those with pure GH-containing pituitary adenomas, being 38 +/- 4% and 65 +/- 4% of basal values, respectively (P less than 0.01). The response of GH to TRH, however, did not differ significantly between the two groups. Conclusions: 1. In about 70% of patients with 'mixed' GH/Prl containing adenomas, hyperprolactinaemia is present. 2. The simultaneous presence of Prl and GH in a GH-secreting pituitary tumour increases the sensitivity of GH secretion to bromocriptine. 3. The plasma Prl level is of value to predict which patients with acromegaly are likely to respond to bromocriptine with an inhibition of GH secretion.     

Treatment with octreotide and bromocriptine in patients with acromegaly: an open pharmacodynamic interaction study

OBJECTIVE Several studies suggest that the combination of octreotide and bromocriptine is more effective than octreotide alone in reducing GH levels in patients with acromegaly. However, these studies have evaluated either the acute effects of single doses of octreotide and bromocriptine, or the effects of long-term combination therapy, in which octreotide was given only twice a day. The aim of the study was to evaluate the effects of the combination of octreotide and bromocriptine compared to octreotide alone, using a treatment scheme of three daily injections of octreotide during a period long enough to ensure a pharmacokinetic and pharmacodynamic steady state. PATIENTS Eleven patients with acromegaly. DESIGN AND MEASUREMENTS Different treatment regimes were performed during three periods. During the first period there was no administration of octreotide or bromocriptine, during the second period 100 μg octreotide was given subcutaneously three times a day, and during the third period 100 /ig octreotide was given subcutaneously three times a day in combination with bromocriptine, given orally 5 mg twice daily. When the patients were without any treatment a single oral dose of 5 mg bromocriptine was given at 0730 h. Individual GH levels were assessed as the mean value of 11 observations during the day, at hourly Intervals from 0730 to 1530 h, and at 1730 and 1930 h, and the GH levels for the whole group were calculated as the mean of the individual mean values. Serum IGF-I and PRL were measured in fasting samples at 0730 h on the same days as GH. GH, IGF-I, and PRL were evaluated at the end of each treatment regime. RESULTS Basal mean GH value for all 11 patients was 54.2 ± 17.4 mU/l. During octreotide therapy mean GH value was significantly reduced compared to basal mean GH level; 19.86±6.82 mU/l (P<0 05). The reduction of mean GH during combination therapy was also significant compared to basal, 18.70 ±6.72 mU/l (P<0.05). Basal mean IGF-I value for all 11 patients was 716 ±96 μg/l. During octreotide therapy mean IGF-I value was significantly reduced compared to basal mean IGF-I level; 458 ±100 μg/l (P<0.05). The reduction of mean IGF-I during combination therapy was also significant compared to basal, 456 ±93 μg/l (P<0.05). There was no difference between the levels of mean IGF-I during the two treatment periods. One patient, the only patient with hyperprolactinaemia, showed an additional reduction of GH levels of >50% during combination therapy. This was also the patient showing the most pronounced reduction of GH levels after the administration of a single dose of bromocriptine. CONCLUSION When octreotide is administered three times a day, the additive effect of bromocriptine on GH and IGF-I suppression seems to be negligible in most patients with acromegaly.     

EFFECTS OF THYROID HORMONES (T4, T3), BROMOCRIPTINE AND TRIAC ON INAPPROPRIATE TSH HYPERSECRETION

Inappropriate TSH hypersecretion was diagnosed in a 38-year-old woman (case 1) and in a 38-year-old man (case 2). Both of them had earlier been treated by ablative therapy for hyperthyroidism. The present diagnosis was based on elevated basal serum TSH levels despite elevated serum free thyroid hormone levels. Both of them had exaggerated TSH responses to TRH (peak value 240 mU/l in case 1 and 408 mU/l in case 2). Their albumin and prealbumin levels were normal. The serum TBG level was normal in case 1 but was elevated in case 2. Serum levels of alpha-subunits of TSH, and pituitary CT scans were normal. Despite mild clinical hyperthyroidism, peripheral indices of thyroid hormone action were normal. They had also relatives with apparent resistance to thyroid hormones. In view of the possibility that prolonged pituitary thyrotrophic stimulation is detrimental, various therapeutic approaches to suppress TSH levels were tried. Both T3 and T4 treatments lowered serum TSH levels, but were poorly tolerated. Acute administration of L-dopa or bromocriptine reduced serum TSH levels, but this was not seen during long-term therapy. TRIAC treatment lowered serum TSH levels, and the drug was well tolerated. Serum TSH responses to TRH were not blunted during T3, T4 or TRIAC treatments. Somatostatin also reduced serum TSH levels, but did not potentiate the effect of low dose T3 therapy. Our results suggest that the patients had unbalanced pituitary and peripheral thyroid hormone resistance, predominantly at the pituitary level. Of the drugs studied, TRIAC seemed to be the most suitable therapy.     

THE INFLUENCE OF BROMOCRIPTINE ON SERUM LEVELS OF GROWTH HORMONE AND OTHER PITUITARY HORMONES AND ITS METABOLIC EFFECTS IN ACTIVE ACROMEGALY

The effect of treatment with bromocriptine for 12--18 months on serum GH and metabolic responses was studied in sixteen patients with active acromegaly. Of this group ten patients showing a sustained GH reduction of more than 50% during an 8 h bromocriptine test, proved to be responsive to long-term therapy. In the responding patients GH levels decreased to 38% of the pretreatment level after 12 months of therapy. A dose higher than 10 mg did not produce a significantly greater effect. Prolactin and LH levels decreased in all patients, FSH levels showed a significant rise. Testosterone levels in the male patients increased significantly, indicating that the state of hypogonadism can at least be partially reversed. The GH levels became normal in only one patient. We conclude that the role of bromocriptine in acromagaly is limited and selective pituitary operation and/or irradiation is preferred as definitive treatment in most patients.     

EFFECT OF BROMOCRIPTINE ON LH PULSATILITY IN THE POLYCYSTIC OVARY SYNDROME

The effects were studied of bromocriptine, 10 mg daily for 1 year, on luteinizing hormone (LH) pulse characteristics in patients with classical polycystic ovarian syndrome (PCOS). All patients were hirsute, had been oligomenorrhoeic since menarche, had LH: FSH ratios of greater than 3:1, and either elevated serum testosterone (T) or dehydroepiandrosterone sulphate (DHAS) concentrations. In 10 subjects who completed the study menstrual frequency increased from an average of 3.6 to 8 per year but few of the cycles were ovulatory. Mean (SE) serum testosterone fell from 4.4 (0.5) nmol/l pretreatment to 2.8 (0.3) nmol/l (P less than 0.01) and DHAS from 7.9 (1.1) mumol/l to 5.4 (1.1) mumol/l (P less than 0.05). Serum delta 4 androstenedione and oestradiol did not change with bromocriptine treatment. Mean serum LH fell from 17.4 (2.4) IU/l to 11.2 (1.8) IU/l (P less than 0.03) after 12 months of bromocriptine. No pattern of LH pulsatility specific to PCOS was detected during 10 min sampling for an 8 h period prior to dopamine agonist treatment. LH interpeak interval (58 (5.2) min) and peak amplitude (156 (7.2%) of mean nadir) in untreated PCOS were similar to that of the mid-follicular stage of ovulatory cycles, and bromocriptine for 1 year did not alter these variables. We conclude that while bromocriptine reduces serum androgen levels and increases menstrual frequency it has no effect centrally to modify hypothalamic GnRH secretion. The reduction in LH levels by bromocriptine may be the result of diminished gonadotroph sensitivity to GnRH or reduced pituitary stores of LH available for release. Despite the return towards normal of various hormonal characteristics of PCOS, bromocriptine has little place in the management of this condition.     

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)     

Impotence associated with low biological to immunological ratio of luteinizing hormone in a man with a pituitary stone

Quantitative reduction in LH secretion resulting from hypothalamic-pituitary dysfunction is a known cause of impotence. Qualitative abnormalities of secreted LH, however, have not been described under these circumstances. During evaluation of a 39-yr-old man with impotence and a calcified pituitary mass (pituitary stone), we detected a qualitative abnormality of LH characterized by a low ratio of bio- to immunoactivity (B:I). Initial work-up revealed basal morning serum testosterone levels of 2.14, 3.18, 3.97, and 3.11 ng/ml on 4 separate days, low to low normal urinary LH (300, 200, and 478 mIU/h), and normal GH, TSH, PRL, and ACTH secretion after provocative testing. The response of impotence to testosterone but not placebo in a double blind trial confirmed the clinical significance of the borderline low androgen levels. These findings prompted a systematic analysis of 24-h LH pulses as well as clomiphene and GnRH responsiveness. By RIA, mean serum LH levels [9.1 +/- 0.3 (+/- SE) mIU/ml] and all other response parameters were normal. In striking contrast, mean serum LH by bioassay was low (9.9 +/- 0.4 mIU/ml vs. 41.4 +/- 5.7 in normal subjects), as were B:I ratios (1.0 +/- 0.03 vs. control values of 3.1 +/- 0.5 to 5.3 +/- 0.3). Only during maneuvers designed to increase GnRH were B:I ratios increased to 3.3 +/- 0.22 (exogenous GnRH) and 1.8 +/- 0.12 (clomiphene). Mean testosterone levels before and after exogenous GnRH treatment were 3.28 +/- 0.24 and 4.76 +/- 0.16, respectively (P less than 0.001). The results suggest an association between the low LH B:I ratio and the anatomical disruption of the hypothalamic-pituitary portal system by the pituitary stone. The increased B:I ratio during GnRH or clomiphene administration indicates a functional link between pituitary GnRH exposure and the greater potency of the LH secreted.     

DEPOT-BROMOCRIPTINE TREATMENT FOR PROLACTINOMAS AND ACROMEGALY

Fifteen patients with hyperprolactinaemia and pituitary macroadenomas (5 patients), microadenomas (6 patients), or acromegaly (4 patients) were given a single intramuscular injection of 50 mg bromocriptine bound to polylactic acid microspheres, depot-bromocriptine. None of the patients had any short-term or long-term discomfort from the injection. In the 11 patients with prolactinomas, serum prolactin fell to minimum levels 12-72 h post-injection; nine patients were highly responsive to depot-bromocriptine, with a mean serum prolactin of 12.9% of basal levels 24 h post-injection, rising to 19% at 28 days. Two patients with prolactinomas were resistant to both depot-bromocriptine, and large doses of oral dopamine agonists. Initiating side-effects (nausea, vomiting, symptomatic postural hypotension) were seen in five patients in the first 24 h post-injection, but were minimal or absent thereafter. Five of six patients previously intolerant of oral dopamine agonists were able to be transferred successfully to bromocriptine 5 mg daily at 4 weeks. Of the four patients with acromegaly, raised prolactin levels were successfully lowered to normal for 4 weeks after injection; serum GH was also partially lowered, but returned to baseline levels at 2-4 weeks. In one patient serum GH was resistant to suppression by both depot bromocriptine and high doses of oral bromocriptine. One patient with a large tumour and visual field defects showed a rapid and maintained improvement in visual fields and acuity after depot-bromocriptine, and was successfully transferred to high-dose oral bromocriptine at 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)