Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma

OBJECTIVE: This study was performed to evaluate the effect of prolonged treatment with the dopamine agonist quinagolide on serum gonadotropin and alpha-subunit concentrations and tumor volume in patients with clinically non-functioning pituitary adenomas (CNPA). DESIGN: Ten patients with CNPA were treated with quinagolide (0.3 mg daily). The median duration of treatment was 57 months (range 36-93 months). Blood samples for measurement of serum gonadotropin and alpha-subunit concentrations were drawn before treatment, after 5 days, and at each outpatient visit. Computerized tomography or magnetic resonance imaging of the pituitary region and Goldmann perimetry were done before and at regular intervals during treatment. RESULTS: A significant decrease of serum FSH, LH or alpha-subunit concentrations was found in nine patients. The levels remained low during the entire treatment period. In two out of three patients with pre-existing visual field defects a slight improvement was shown during the first months of treatment, but eventually deterioration occurred in all three patients. A fourth patient developed unilateral ophthalmoplegia during treatment. During the first year tumor volume decreased in three patients, but in two of them regrowth occurred after a few months. In six patients progressive tumor growth occurred despite sustained suppression of gonadotropin or alpha-subunit levels. CONCLUSIONS: Long-term treatment of patients with CNPA with high doses of the dopamine agonist quinagolide could not prevent progressive increase in tumor size in most patients. It remains unproven whether quinagolide retards CNPA growth. Additional studies are needed to investigate whether subgroups of patients, e.g. those with positive dopamine receptor scintigraphy or those with marked hypersecretion of intact gonadotropins or subunits, will respond more favorably to treatment with dopamine agonists.     

In vivo secretory potential and the effect of combination therapy with octreotide and cabergoline in patients with clinically non-functioning pituitary adenomas

The secretory capacity, in vivo, of clinically non-functioning pituitary adenomas may possibly predict tumour volume reduction during intensive medical therapy. Ten patients (mean (range) 53 years (26-73)) with clinically non-functioning macroadenomas, > or = 10 mm were studied. The secretory capacity of the adenomas was examined using basal, NaCl and TRH-stimulated LH, FSH and alpha-subunit levels. The effect on tumour volume of 6 months' therapy with the combination of a somatostatin analogue, octreotide 200 microg x 3/day and a dopamine-D2-agonist, cabergoline 0.5 mg x 1/day was studied. The basal LH, FSH and alpha-subunit levels were determined before and during 6 months' therapy with octreotide and cabergoline, and MR scans were used to evaluate tumour volume before and during this period of therapy. Octopus-perimetry was used to examine the visual fields. A reduction in tumour volume (mean +/- SEM (range); 30% +/- 4% (18-46%)) during 6 months of combination therapy with octreotide and cabergoline was recorded only in patients with in vivo secretory potential. Tumour volume was not reduced in four patients: in three of these patients it remained unchanged while in one patient it was observed to have increased (by 14%). Of the six patients with pretherapy secretory capacity, one displayed a very high basal level of alpha-subunit (74 microg/l) despite unmeasurable levels of LH and TSH, and an FSH-level of 1 IU/l. The other five patients presented paradoxical LH, FSH and/or alpha-subunit responses to TRH. A reduction in basal levels of LH, FSH and/or alpha-subunit was observed in all six patients, and the maximum reduction of at least one of the hormonal levels was 66% +/- 7% (50-98%). The basal levels of LH, FSH and alpha-subunit in the 10 patients were (mean +/- SEM (range)), 3.0 IU/l +/- 1.0 (0.0-7.4), 12.7 IU/l +/- 5.0 (0.0-39.0) and 9.0 IU/l +/- 7.0 (0.2-74.0). During six months of therapy with octreotide and cabergoline, the basal levels of LH, FSH and alpha-subunit were reduced by > or = 50% in seven patients - including the six patients with in vivo secretion prior to therapy. No new visual field defects were detected during therapy and no deterioration of existing visual field defects was recorded. The medical therapy was well tolerated. The in vivo basal and TRH-stimulated secretory capacity of LH, FSH and alpha-subunit predicted tumour reduction following intensive medical therapy in all of our patients with non-functioning pituitary adenomas.     

Treatment of macroprolactinomas with a new non-ergot, long-acting dopaminergic drug, CV 205-502

Eleven patients with prolactin-producing pituitary adenomas were treated with the new non-ergot, long-acting dopamine agonist, CV 205-502, for a period of 2-18 months (mean 11 months). Tumour volumes ranged from 1.9 to 64 ml in seven patients who were newly diagnosed, and from 0.1 to 3.1 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3.5 to 360 U/l before institution of CV 205-502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once-daily doses of CV 205-502 between 0.075 and 0.300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205-502 treatment and/or during several days after a dose increase were observed in three patients. We conclude that CV 205-502 in a once daily dose is an effective and safe alternative in the long-term treatment of macroprolactinomas.     

CV205–502, A NEW NON-ERGOT DOPAMINE AGONIST, REDUCES PROLACTINOMA SIZE IN MAN

Seven patients with large prolactin-secreting pituitary adenomas were treated for 8 weeks with once-daily doses of the new, potent, non-ergot, long-acting dopamine agonist CV205-502. In five patients previous treatment with bromocriptine had failed to control their disease or been poorly tolerated and had therefore ceased. In all seven patients serum prolactin levels fell over the 8-week period of CV205-502 treatment with the decrease ranging from 33 to 99%. Associated with this decline in prolactin all patients showed symptomatic improvement with two of the five women beginning to menstruate and the two patients with visual field impairment showing marked improvement. Tolerance of the drug, with doses at 8 weeks ranging from 0.075 to 0.3 mg, was excellent with only minimal and transient side-effects being noted in three patients in none of whom was discontinuation of therapy necessary. In one patient noncompliance after 6 weeks of therapy was associated with a rapid return of her serum prolactin towards pretreatment levels. In all seven patients the clinical and biochemical improvement was accompanied by a marked reduction in tumour size.     

Comparison of hormonal secretory behavior of gonadotroph cell adenomas in vivo and in culture

To determine whether pituitary macroadenomas associated with supranormal serum FSH concentrations represent gonadotroph cell adenomas or nonsecreting adenomas that selectively impair LH secretion by normal gonadotroph cells, we studied the secretory behavior in dispersed cell culture of three pituitary adenomas from patients who had supranormal serum FSH concentrations. Similar comparisons were made for 11 other adenomas, which were associated with the in vivo hypersecretion of alpha-subunit (n = 4) or PRL/GH (n = 4) or with no obvious hypersecretion (n = 3). Adenomas associated with supranormal serum FSH in vivo released more FSH in culture (5.1-27.0 ng/well . 24 h) than they did other hormones (TSH, less than 0.33; GH, less than 0.10; PRL, less than 0.14 ng/well . 24 h) and more FSH than did PRL/GH-secreting (less than 0.1-0.9 ng/well . 24 h) and nonsecreting (less than or equal to 0.5 ng/well . 24 h) adenomas. Adenomas associated with supranormal serum alpha-subunit in vivo released not only more alpha-subunit in culture (7.2-22.0 ng/well . 24 h) than did other adenomas (0.1-2.4 ng/well . 24 h), but two of them also released as much FSH (12.7 and 17.0 ng/well . 24 h) as did adenomas associated with supranormal serum FSH. The close correlation between the hormonal secretory behavior in vivo and that in culture of the three pituitary macroadenomas associated with supranormal serum FSH concentrations suggests that these are indeed adenomas of gonadotroph cells that are hypersecreting FSH. The release of relatively large amounts of FSH by cultured cells of adenomas that appeared to be hypersecreting only alpha-subunit in vivo suggests that at least some alpha-subunit-secreting adenomas are also gonadotroph cell adenomas.     

Gonadotroph cell adenomas of the pituitary

Although the frequency of gonadotroph cell adenomas among all unselected pituitary adenomas is not yet known, it is probably much higher than previously suspected. The true incidence is probably somewhere between the 3-4% found in surgical and autopsy series, which is probably an underestimate because of its reliance on tissue content, and the 17% (24% when alpha-secreting adenomas are included) of 139 patients from this institution, which may be an overestimate of the incidence among all adenomas, because it is heavily weighted to very large adenomas in men only. Most patients who have been reported to have gonadotroph cell adenomas have similar clinical characteristics. Most are middle-aged men who have a history of normal pubertal development and a normal fertility history, and by examination are normally virilized and have testes of normal size. They are brought to medical attention because of visual impairment, which is the result of the enormous size of the adenoma. The most common hormonal characteristic of gonadotroph cell adenomas in vivo is hypersecretion of FSH, which is often accompanied by hypersecretion of FSH beta and alpha-subunit and less often by hypersecretion of LH beta or intact LH. Another common characteristic is secretion of FSH and/or LH in response to TRH. A few patients with gonadotroph cell adenomas hypersecrete intact LH and, therefore, have supranormal serum testosterone concentrations. A larger number have secondary hypogonadism because the adenomas are not secreting intact LH, but are compressing the normal gonadotroph cells and impairing LH secretion. These patients have concentrations of intact LH that are not elevated in spite of subnormal testosterone concentrations. Testosterone levels increase markedly in response to hCG. The hormonal characteristics of gonadotroph adenomas in dispersed cell culture are similar to their characteristics in vivo, including hypersecretion of FSH and LH subunits and responsiveness to TRH. Both the clinical and hormonal characteristics of gonadotroph cell adenomas usually make them readily distinguishable from pituitary enlargement due to long-standing primary hypogonadism. Pituitary adenomas that hypersecrete only alpha-subunit in vivo may also be adenomas of gonadotroph cells, because some of them secrete large amounts of FSH as well as alpha-subunit in culture. Most gonadotroph cell adenomas are now treated first by transsphenoidal surgery, to attempt to restore vision as quickly as possible, and then by supervoltage radiation to prevent regrowth of the remaining adenomatous tissue.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gonadotropin release by clinically nonfunctioning and gonadotroph pituitary adenomas in vivo and in vitro: relation to sex and effects of thyrotropin-releasing hormone, gonadotropin-releasing hormone, and bromocriptine

We studied in vivo hormone levels and in vitro hormone and subunit release in a group of 22 patients who were operated upon because of a clinically nonfunctioning or gonadotroph pituitary adenoma. In vivo, 5 of the 22 patients, all men, had hypersecretion of FSH, LH beta, or alpha-subunit. An elevated ratio of serum alpha-subunit to LH and FSH was found in 6 of 8 women in vivo, although in all 6 women serum LH, FSH, and alpha-subunit levels were low. LH, FSH, alpha-subunit, LH beta, or a combination of these glycoprotein hormones could be demonstrated in 19 of 22 cultured adenomas. We conclude that 1) virtually all clinically nonfunctioning adenomas contain or release gonadotropins or their subunits in vitro; 2) in vivo hypersecretion of these hormones and subunits occurs infrequently, and in this series only in men; 3) an elevated ratio of alpha-subunit to LH and FSH is frequently found in women and may prove to be a useful diagnostic tool; 4) responses to TRH and bromocriptine do not depend on baseline gonadotropin levels, either in vitro or in vivo, implying that the distinction between gonadotroph adenomas and adenomas without hypersecretion of gonadotropins in vivo is absent where hormone dynamics are concerned.     

Effect of the new dopaminergic agonist CV 205–502 on plasma prolactin levels and tumour size in bromocriptine-resistant prolactinomas

Bromocriptine is currently and successfully used for the treatment of pituitary prolactinomas. However, bromocriptine appears unable to normalize plasma prolactin levels in about 10% and to reduce tumour size in one-third of cases. The lack of normalization of plasma prolactin levels in spite of a daily dose of bromocriptine equal to or higher than 15 mg suggests a bromocriptine resistance. We compared the long-term effects of bromocriptine and CV 205-502 (a non-ergot derivative D2 dopamine agonist) on plasma prolactin levels and tumour size in seven bromocriptine-resistant prolactinomas. Bromocriptine reduced significantly (P less than 0.001) plasma prolactin levels (from 2307 +/- 518 to 568 +/- 279 micrograms/l) (conversion to Sl units: 1 microgram/l = 20 mU/l). Visual field defects observed in five patients improved in four. However, CT scan analysis showed a decrease in tumour size in only three patients. Except for transient and minor side-effects at the beginning of the treatment, CV 205-502 was well tolerated in five of seven patients. In the remaining two patients nausea and vertigo occurred with high dosages of CV 205-502 and it was necessary to reduce the daily dose. CV 205-502 lowered plasma prolactin to levels similar to those obtained after bromocriptine therapy in four cases. In the three remaining patients, CV 205-502 was more potent than bromocriptine as demonstrated by the further 90% reduction in plasma levels obtained in one case and by the normalization of plasma prolactin levels in the two other cases. One woman became pregnant during CV 205-502 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal response of luteinizing hormone beta subunit to thyrotrophin-releasing hormone in patients with non-functioning pituitary adenoma

OBJECTIVE it has been suggested that the response of free β-subunit of LH (LHβ) to TRH Is the most useful in-vivo marker of gonadotroph adenomas in patients with non-functioning pituitary adenomas (NFPA). The aim of the present study was to investigate LHβ secretion in patients with NFPA in whom other markers of gonadotroph adenomas, such as supranormal basal concentrations or responses of intact gonadotrophins to TRH, were absent. DESIGN AND PATIENTS Serum basal levels Of LHβ, LH and FSH were evaluated in 80 patients with NFPA showing normal levels of intact gonadotrophin, 20 with PRL-secreting adenomas, 25 with OH-secreting adenomas and 58 healthy subjects. Moreover, LHβ, LH, FSH and alpha-subunit (α-SU) were evaluated in 27 patients with NFPA In whom intact gonadotrophin responses to TRH were absent, 8 with PRL-oma, 7 with GH-oma and 17 healthy subjects before and 20,30 and 60 minutes after the intravenous administration of either 200 μg TRH or placebo. A response was considered present when serum LHβ increased by at least 50% above basal levels. MEASUREMENTS LHβ was evaluated using a new assay based on the sequestration of the combined and free α-SU by an anti α-SU blotinylated monoclonal antibody (MAb) and the subsequent measurement of the LHβ by an IFMA method employing two MAbs directed towards two different epitopes on LHβ. intact LH and FSH were assayed with an IFMA method and α-SU with an IRMA method. RESULTS in basal conditions, no significant difference in the mean values of LHβ was observed among patients with different types of tumour and normal controls. In 9 of 27 (33%) patients with NFPA, TRH caused an abnormal elevation of serum LHβ (net increase 410 ± 403%, range 71-1300) which was completely dissociated from changes in intact gonadotrophins. Of the 5 patients who had a TRH test repeated after transsphenoidal surgery, abnormal LHβ responses disappeared in 2 and were maintained in 3. Disappearance of LHβ response occurred only in patients in whom improvement of visual field and radiological imaging after adenomectomy was observed. in contrast, in ail patients with pituitary tumours other than NFPA and healthy subjects a response to TRH was absent (net increase ranging from 0 to 23%). immunofluorescence, performed on 14 NFPA removed from patients either responsive or unresponsive to TRH, showed a variable proportion of cells positive for LHβ, without a significant difference between the two groups. CONCLUSIONS These results indicate that measurement of basal LHβ is of poor value in the diagnosis of non-functioning pituitary adenomas and the identification of gonadotroph adenomas among non-functioning pituitary adenomas. Conversely, an abnormal response of free LHβ to TRH occurs in about a third of patients with low/normal basal gonadotrophins unresponsive to TRH stimulation.     

Bromocriptine increasingly suppresses the in vitro gonadotropin and alpha-subunit release from pituitary adenomas during long term culture

Prolonged treatment with bromocriptine may lead to a decrease in tumor size in patients with a gonadotroph, alpha-subunit-secreting, or clinically nonfunctioning pituitary adenoma. The effectiveness of the treatment, however, may depend on its duration. We investigated the effects of prolonged incubation with bromocriptine on the release and intracellular hormone and alpha-subunit concentrations in 10 such adenomas in vitro. The release of FSH, LH, alpha-subunit, or a combination of these was demonstrated in 7 tumors. Bromocriptine significantly suppressed this release in 6 tumors. In 5 tumors bromocriptine had an inhibitory effect on gonadotropin and/or alpha-subunit release which increased with duration of culture. Withdrawal of bromocriptine during the culture period led to a recovery of gonadotropin or alpha-subunit release in the 2 tumors in which it was tested. Intracellular hormone and alpha-subunit concentrations in 3 of 4 tumors cultured for 4 or more weeks were significantly lower in bromocriptine-treated than in untreated cells. We conclude that 1) bromocriptine can suppress the in vitro release of gonadotropins and alpha-subunit from the majority of clinically nonfunctioning, gonadotroph, and alpha-subunit-secreting pituitary adenomas; 2) during prolonged incubation of these tumors with bromocriptine, this drug has a time-dependent increasing inhibitory effect on the release and synthesis of gonadotropins and alpha-subunit, which eventually may lead to decreased intracellular concentrations of these glycoproteins.     

Gonadotroph cell pituitary adenomas

The frequency of gonadotroph cell adenomas among all unselected pituitary adenomas is likely much higher than previously suspected. The prevalence in one series of 139 men with pituitary macroadenomas was 17 per cent (24 per cent if adenomas secreting only alpha subunit are included). The clinical characteristics of patients with gonadotroph cell adenomas are similar. Most are middle-aged men who have a history of normal pubertal development and a normal fertility history and by examination are normally virilized and have testes of normal size. They are brought to medical attention because of visual impairment, which is the result of the enormous size of the adenoma. The most common hormonal characteristics of gonadotroph cell adenomas in vivo is hypersecretion of FSH, which is often accompanied by hypersecretion of FSH-beta and alpha subunits and less often by hypersecretion of LH-beta or intact LH. Another common characteristic is secretion of FSH and/or LH-beta in response to TRH. A few patients with gonadotroph cell adenomas hypersecrete intact LH and therefore have supranormal serum testosterone concentrations. A larger number have secondary hypogonadism, because the adenomas are not secreting intact LH but are compressing the normal gonadotroph cells and impairing LH secretion. These patients have concentrations of intact LH that are not elevated, despite subnormal testosterone concentrations. The testosterone increases markedly in response to human chorionic gonadotropin. Both the clinical and hormonal characteristics of gonadotroph cell adenomas usually make them readily distinguishable from pituitary enlargement due to long-standing primary hypogonadism. Most gonadotroph cell adenomas are now managed first by transsphenoidal surgery to attempt to restore vision as quickly as possible, and then by supervoltage radiation to prevent regrowth of the remaining adenomatous tissue. Surgery usually does improve vision, as well as the pretreatment hormonal abnormalities, and radiation reduces FSH hypersecretion further. Dopamine agonist therapy is experimental but warrants further trial. The hormonal abnormalities detected prior to treatment, such as supranormal basal concentrations of FSH, alpha, and FSH-beta and the FSH and LH-beta responses to TRH, can be used to monitor the response to therapy.     

Postpartum return of pituitary and ovarian activity during lactation inhibition with the new dopamine agonist CV 205-502 and during normal lactation

The new nonergot dopamine agonist CV 205-502 appears to be a promising alternative in the treatment of hyperprolactinemia. Regarding the potential use of CV 205-502 in infertility practice, we studied the influence of CV 205-502 on the return of endocrine fertility parameters during the physiological hyperprolactinemia of the puerperium. The resumption of pituitary and ovarian activity in 18 CV 205-502 treated women was compared with that in 10 bromocriptine-treated women. LH was measured by a new specific assay, which does not cross-react with hCG. This assay was also used in a second part of the study in which the pituitary function of 10 breast-feeding women was investigated. Both dopamine agonists adequately suppressed PRL. Pituitary secretion returned in the second week and was initially characterized by a high FSH/LH ratio. There were no major differences between CV 205-502 and bromocriptine. Ovulations occurred from day 18 on. The PRL rebound at the end of treatment seemed to play a role in the ovulation process. An acute increase of PRL just before midcycle was able to prevent ovulation. Breastfeeding women showed a delayed return of pituitary secretion: after a hypogonadotropic period, FSH returned in the third week and was followed by a period with a high FSH/LH ratio and follicular inactivity.     

Gonadotropin-secreting pituitary adenoma with concomitant hypersecretion of testosterone and elevated sperm count. Treatment with LRH agonist

Hypersecretion of both FSH and LH was demonstrated in a man with pituitary macroadenoma, who also presented elevated levels of blood testosterone and an increased sperm count. The patient underwent transsphenoidal surgery followed immediately by cranial irradiation. Immunocytochemical analysis of the tumour revealed the presence of FSH, LH, TSH and the alpha-subunit. Gel chromatography of the serum on Sephadex G-100 revealed immunoactive FSH, LH and the alpha-subunit which coeluted with the labelled standards of corresponding hormones. Blood levels of both gonadotropins and testosterone remained persistently elevated up to one year following surgical decompression of the tumour and radiotherapy. It was decided to treat this patient with sc administration of 100 micrograms D-Trp6-LRH biweekly. After 20 weeks, LRH-analogue treatment resulted in the reduction of serum FSH and LH levels and a diminishing in tumour size as assessed by computed tomography scan of the pituitary. This report shows that in a patient with clinically and biochemically documented gonadotropin-secreting adenoma, inducing a state of persistent gonadal hyperfunction, pituitary surgery and cranial irradiation failed to normalize the biochemical abnormality; however, therapy with D-Trp6-LRH agonist induced clinical, biochemical and radiologic improvement.     

Value of alpha subunit assay in pituitary pathology]

We evaluated serum alpha-subunit concentrations in 72 patients bearing pituitary adenomas. We conclude that: 1) alpha-subunit hypersecretion is found in all patients with TSH secreting pituitary adenoma (n = 10). Two patients have a predominant secretion of alpha-subunit as compared to TSH secretion. 2) As concerns gonadotropin secreting pituitary adenomas (n = 3), all patient have elevated serum alpha-subunit levels with increased FSH and LT concentrations in 2 cases and 1 case respectively. 3) In prolactinomas (n = 14), alpha-subunit concentrations are not significantly different from that of normal subjects. 4) In 11 acromegalic patients, alpha-subunit hypersecretion is found in 2 patients only with GH-alpha and GH-PRL-alpha secreting pituitary adenomas. 5) Among 34 patients with nonsecreting adenomas, 8 have elevated alpha-subunit concentrations (24%). Positive immunocytochemical staining is found in 70% most often with gonadotropins (55%). Only a few pituitary tumors with positive alpha-subunit immunocytochemical staining have elevated serum alpha-subunit levels. At least, the measurement of basal circulating alpha-subunit levels is very useful in the follow-up of patients with nonsecreting adenomas. In our study, medical treatments including bromocriptine and somatostatin analogues have been found effective in patients with alpha-subunit hypersecretion. Further investigations are necessary to prove if such treatments could control tumoral growth and could prevent recurrences.     

Clinically nonfunctioning pituitary adenoma and octreotide response to long term high dose treatment, and studies in vitro.

We have studied seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary macroadenoma, four of whom received long term, high dose octreotide treatment. We have attempted to correlate the presence of somatostatin receptors (SS-R) in the adenomas and the outcome of octreotide treatment, as measured by tumor size, improvements in visual field defects, and hormonal response. The presence of SS-R in the pituitary adenomas was demonstrated in vivo using [111indium]octreotide scintigraphy and in vitro by autoradiography of tissue fragments obtained after transsphenoidal surgery. Adenomas from six of the seven subjects were SS-R positive. High dose (1200 micrograms, sc, daily) octreotide treatment was given to four subjects, three of whom were SS-R positive. Improvement of the visual field defects was observed in three of four patients (including the SS-R-negative subject), although no computed tomographic scan-assessed tumor size reduction was found. Two of four patients showed small but significant reductions in serum FSH concentrations (to 83% and 93% of initial values) with treatment. These in vivo responses to high dose octreotide treatment could not be predicted by pretreatment responses to 200 micrograms TRH or 100 micrograms octreotide. Tissue fragments for cell culture were obtained from six patients, and in vitro release of gonadotropins and/or alpha-subunit could be demonstrated in five cultures. In vitro, octreotide (10 nmol/L) significantly decreased gonadotropiin or subunit release in three of five cultures, whereas bromocriptine (10 nmol/L) significantly reduced the release in four of five cultures and to a significantly greater extent than octreotide. In conclusion, in six of seven patients with a clinically nonfunctioning or alpha-subunit-secreting pituitary adenoma, SS-R were demonstrated in the tumor. In vitro incubation of adenoma cells with octreotide resulted in mild inhibition of gonadotropin or alpha-subunit release. Although in vivo long term treatment with high doses of octreotide did not result in substantial tumor size reduction, improvement of visual field defects was observed in three of four subjects.     

Treatment of prolactin-secreting pituitary macroadenomas with the long-acting non-ergot dopamine agonist CV 205-502

STUDY OBJECTIVE: Evaluation of the effects of an experimental long-acting non-ergot dopamine agonist, CV 205-502, on serum prolactin, tumor size, gonadal function, visual abnormalities, and tolerability in patients with macroprolactinomas. DESIGN: Prospective, unblinded, dose escalation as needed. SETTING: Four university medical centers; patients referred for treatment. PATIENTS: Twenty-six hyperprolactinemic patients (prolactin greater than 150 micrograms/L) with a pituitary macroadenoma were treated for 24 weeks with CV 205-502 given once daily. MEASUREMENTS AND MAIN RESULTS: Serum prolactin was measured at regular intervals. Prolactin levels decreased in all patients during treatment (mean pretreatment level, 2051.7 +/- 1077 micrograms/L [+/- SE]; 24 weeks, 39.0 +/- 11.3 micrograms/L; P = 0.0001); normal prolactin levels were achieved in 15 (58%). Tumor size decreased in 21 of 26 patients and ranged from 6% to 67% (mean, 19.2% +/- 3.4%). Onset or return of regular menses occurred in 11 of 15 premenopausal women, accompanied by an increase in estradiol concentrations (pretreatment, 186.5 +/- 25.0 pmol/L; on treatment, 690.9 +/- 104.3 pmol/L; P = 0.0003). Serum testosterone increased in 6 of 8 men; sexual function improved in 5 of 7 with pretreatment abnormalities. Two patients with reversible visual abnormalities improved within 2 weeks of starting treatment. Side effects occurred in 11 patients and abated over 1 to 2 weeks or after the dose was reduced. There was no evidence of toxicity as indicated by serial serum chemistries, liver function tests, hematologic profiles, thyroxine levels, and electrocardiogram studies. CONCLUSIONS: CV 205-502 reverses hyperprolactinemia and promotes reduction in tumor size with reversal of visual abnormalities and restoration of gonadal function in most patients. This compound will probably be useful in treating prolactinomas.     

Specific effect of CV 205-502, a potent nonergot dopamine agonist, during a combined anterior pituitary function test

CV 205-502, an octahydrobenzo[g]quinoline, is a dopamine agonist compound that is not an ergot or ergoline derivative. To investigate the site of action of CV 205-502, three groups of five men were given single daily doses of CV 205-502 (0.04, 0.06, or 0.08 mg/day, doses that suppress plasma PRL by 60-80% for 24 h) for 5 days; on day 6 a combined anterior pituitary function test using iv administration of four hypothalamic releasing hormones (TRH, 200 micrograms; GHRH, 100 micrograms; CRH, 100 micrograms; LHRH, 100 micrograms) was performed. One month later the challenge tests were repeated to obtain control values. The following hormones were measured by RIA in plasma: TSH, ACTH, cortisol, PRL, GH, LH, FSH, and testosterone. With the exception of plasma PRL levels, basal and releasing hormone-stimulated values were similar after CV 205-502 administration and after the 1-month washout period. Basal plasma PRL was lower after CV 205-502 administration, and the response to TRH was attenuated by all three doses of CV 205-502 (the mean percent inhibition values were 76%, 93%, and 94%, respectively). All three doses of CV 205-502 were well tolerated, and another group of men well tolerated 0.1 mg daily. The results confirm that CV 205-502 is a potent dopamine agonist, which directly inhibits lactotropic cells but has no effect on other pituitary cell types.     

Gonadotropin and alpha-subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting pituitary tumors

Pituitary tumors secreting intact glycoprotein hormones (LH, FSH, and TSH) and/or alpha-subunit are being increasingly recognized. Because chronic administration of GnRH analogs decreases gonadotropin secretion in normal subjects, we investigated gonadotropin and alpha-subunit responses to chronic GnRH analog administration in five men with glycoprotein hormone-secreting pituitary tumors. Two patients (patients A and B) received the GnRH agonist analog (D-Trp6-Pro9-NEt-LHRH) for 4 weeks as a daily sc dose (8 micrograms/kg.day). In both, secretion of LH and/or alpha-subunit increased markedly. Subsequently, three patients received a higher analog dose (32 micrograms/kg.day) for a longer duration (8 weeks). One patient with a LH- and FSH-secreting tumor (patient C) had a highly significant (P less than 0.001) fall in serum LH and FSH concentrations; however, alpha-subunit secretion increased. During a subsequent study, when this patient received a lower dose (8 micrograms/kg.day) for 8 weeks, gonadotropin suppression also occurred. In two additional patients who received this dose (32 micrograms/kg.day), it had a persistent agonist effect on FSH beta (patient D) and alpha-subunit secretion (patient E). A marked increase in alpha-subunit secretion occurred in all five patients, regardless of whether basal serum alpha-subunit concentrations were elevated. These patients received the GnRH analog at doses 2-8 times greater than those that suppress gonadotropin secretion in normal men. Serum LH and FSH concentrations decreased in only one patient with a gonadotropin-secreting adenoma. The serum LH and FSH responses to acute GnRH stimulation did not predict the gonadotropin responses to chronic GnRH analog administration. Thus, gonadotropin and alpha-subunit production by most pituitary adenomas is augmented during chronic GnRH analog administration, consistent with defective GnRH desensitization in the adenomatous tissue. Despite the heterogeneous gonadotropin responses to the GnRH analog in these patients, serum alpha-subunit levels increased in all patients, indicating dissociation in the secretion of intact gonadotropins and alpha-subunit.     

Acute effects of Parlodel-LAR and response to long-term treatment with bromocriptine in a patient with a follicle stimulating hormone-secreting pituitary adenoma

A 68-year-old male patient presented with visual impairment due to a large pituitary tumor. After transsphenoidal adenomectomy the elevated serum FSH levels were lowered but not normalized. Deterioration of the vision was detected five years later and tumor regrowth was evidenced. The patient was treated with the long-acting and repeatable form of bromocriptine (Parlodel-LAR). Three days after the first intramuscular injection it already resulted in an important improvement of the visual field defects. Serum FSH concentration was suppressed during a prolonged period, but no change in the size of the pituitary adenoma was recorded on CT scan. Long-term oral treatment with bromocriptine resulted in a sustained suppression of the serum FSH levels, without further visual improvement, but with a significant reduction of the volume of the adenoma. The rapid and prolonged effect of Parlodel-LAR upon the FSH secretion, with a possible correction of the visual field defects and a reduction of the tumor mass, could make this medication appropriate as adjunctive treatment in some gonadotroph cell adenomas.     

The stimulated C-kinase activity in estradiol-treated rat pituitaries is reduced by chronic treatment with the dopamine agonist CV 205-502

To investigate whether the modulation of lactotrope cell multiplication and prolactin secretion in rat pituitary glands implicated the phosphoinositide C-kinase system, female Wistar rats were treated or not-with the dopamine agonist CV 205-502 or 8 days or with estradiol cervical implants for 8 for 15 days, alone or in combination with CV 205-502 for the last 8 days. CV 205-502 treatment induced a significant reduction in plasma PRL levels and in pituitary weights, whereas estradiol treatment induced a significant increase in both parameters. CV 205-502, in association with estradiol, counteracted estradiol stimulation of PRL levels and of pituitary weights. Total C-kinase activity in controls was 29.8 +/- 9.9 pmol 32phosphorus/min (N = 7, mean +/- SEM), mainly found in the soluble fraction (84%). When administered alone, CV 205-502 induced a significant reduction (-58%, p less than 0.02) in C-kinase activity in the particulate fraction with no modification in the soluble fraction. Both 8 and 15 days estradiol treatment induced a significant stimulation of total C-kinase activity, 74% and 155% respectively. When combined with estradiol, CV 205-502 significantly (p less than 0.02) counteracted the estradiol increase in total C-kinase activity, which was only 45% over control values. We conclude that treatment with a dopamine agonist and estradiol, which have antagonistic effects on the pituitary, exerts an opposite regulation of C-kinase activity. Whether this may be one of the mechanisms involved in their interaction on pituitary lactotropes remains to be determined.