Nontumoral Hyperprolactinemia Research Articles

Bilateral Galactorrhea Revealing Idiopathic or Non-Tumoral Hyperprolactinemia: A Case Report and Review of the Literature

Prolactin is a polypeptide hormone that is synthesized in the anterior pituitary gland and secreted in a pulsatile manner. It plays central role in a variety of reproductive functions and lactation. Prolactin release in humans depends on physiological state and varies in response to different stimuli. Hyperprolactinemia is a common endocrinological disorder; it could be physiological, pathological or idiopathic in origin. In several respects prolactin is unique among anterior pituitary hormones. We report the case of a 25-year-old woman who came to the endocrinology department with galactorrhea. The history revealed spontaneous and provoked galactorrhea, with secondary amenorrhea that had been going on for 05 years and had been neglected by the patient. The questioning did not reveal any particular medication being taken. Our examination revealed induced lactescent galactorrhea and moderate hirsutism with a Ferriman score of 18. Pregnancy was ruled out, Prolactin=148.1 ng/mL (6xN), the rest of the hypophysiogram was unremarkable (no associated hypogonadism). A pituitary magnetic resonance imaging (MRI) revealed no pituitary adenoma or interruption of the pituitary stalk! We adopted the diagnosis of symptomatic non-tumor hyperprolactinemia. Cabergoline was introduced at 0.5 mg per week. The course of the disease was favorable, with a reduction in galactorrhea and normalization of the menstrual cycle.

True hyperprolactinemia in men without visible pituitary adenoma.

Men with mild to moderate hyperprolactinemia rarely present with normal pituitary on MRI with no visible adenoma, a condition entitled also "idiopathic hyperprolactinemia" or "non-tumoral hyperprolactinemia". We have characterized a cohort of hyperprolactinemic men with normal pituitary imaging. We have identified 13 men with true hyperprolactinemia and normal pituitary MRI. Baseline clinical and hormonal characteristics and response to medical treatment were retrospectively retrieved from medical records. Mean age at diagnosis was 51 ± 16 years (range, 20-77); mean serum prolactin level at presentation was 91 ng/ml (range, 28-264), eight men presented with low baseline testosterone. Initial complaints leading to diagnosis included sexual dysfunction in ten men and gynecomastia in five. All patients were treated with cabergoline, except for one who was given bromocriptine; none required pituitary surgery. All patients normalized prolactin and testosterone with subsequent clinical improvement reported by most men. Currently, after a mean follow-up of 72 months, ten patients continue treatment with caborgoline (median weekly dose, 0.25 mg), whereas three men discontinued treatment. Men with symptomatic hyperprolactinemia may rarely present with normal pituitary imaging. Medical treatment can lead to hormonal improvement with clinical benefit.

Results of a Single-Center Observational 10-Year Survey Study on Recurrence of Hyperprolactinemia after Pregnancy and Lactation

The current survey study investigated the recurrence rate of hyperprolactinemia after cabergoline (CAB)-induced pregnancy and after lactation as well as safety of CAB exposure during early gestation. From 1997-2008, 143 pregnancies were recorded in 91 patients with hyperprolactinemia (age 30.4 ± 4.7 yr, 76 microadenomas, 10 macroadenomas, and five nontumoral hyperprolactinemia). CAB therapy was discontinued within wk 6 of gestation in all. Pregnancies were monitored until delivery or termination, during and after lactation, twice yearly up to 60 months. The incidence of abortions, premature delivery, and fetal malformations was also analyzed. Pregnancies resulted in 13 (9.1%) spontaneous abortions and 126 (88.1%) live births. No neonatal malformations and/or abnormalities were recorded. In 29 of 91 patients (three with macroadenomas), treatment with CAB had to be restarted within 6 months after lactation because of hyperprolactinemia recurrence, whereas in 68% of cases, no additional therapy was required up to 60 months. No tumor mass enlargement was observed. All patients but three were breastfeeding, 35 (38.5%) for less than 2 months and 56 (61.5%) for 2-6 months. Three months after cessation of lactation and 60 months after pregnancy, no difference in prolactin levels was found between patients nursing for less than 2 months and 2-6 months. Fetal exposure to CAB at conception does not induce any increased risk of miscarriage or malformations. Pregnancy is associated with normalization of prolactin levels in 68% of patients. Breastfeeding does not increase the recurrence rate of hyperprolactinemia.

Recurrence of Hyperprolactinemia After Withdrawal of Long-Term Cabergoline Therapy

The dopamine agonist cabergoline (CAB) may produce a long-term normalization of serum prolactin and maintain markedly reduced tumor size in most patients with hyperprolactinemia. Long-term therapy is problematic from both a clinical and economic perspective. A previous study using criteria for CAB withdrawal based on multiple parameters obtained remission rates in hyperprolactinemia patients selected for withdrawal of 32% and rates in unselected patients of 70% to 90%. Specific criteria for selecting patients for withdrawal were recommended by the Pituitary Society in its 2006 guidelines. However, treatment outcomes using these guidelines have not been critically examined in a clinical setting. This retrospective study determined the rate of recurrence of hyperprolactinemia in 46 selected patients who met these guidelines (normoprolactinemic and with marked tumor volume reduction after 2 or more years of treatment) and investigated clinical predictors of recurrence. The study was conducted between 2002 and 2007 at a pituitary center. All patients were followed from the date of CAB withdrawal to either recurrence of hyperprolactinemia, or the day of last available prolactin test extracted from patient histories. Following withdrawal, prolactin measurements were obtained monthly, then quarterly in the first year and at 6-month intervals and 1-year intervals, thereafter. If a prolactin value was above the reference range, another prolactin measurement was obtained within 1 month, and if abnormal, an MRI was performed. Symptoms of hyperprolactinemia were assessed by use of a short questionnaire. The median age of patients was 45 years (range: 18-50) and 70% were women. Of the 46 patients, 31 (67%) had microprolactinomas, 11 (24%) had macroprolactinomas, and 4 (9%) had nontumoral hyperprolactinemia. At the time of study completion, 54% of all patients had recurred. At 18 months, the estimated risk of recurrence was 63%. Ninety-one percent of recurrences occurred within 1 year of CAB withdrawal at a median time of 3 months (range, 1-18 months). Recurrence after CAB withdrawal was predicted by the size of the tumor remnant: Each millimeter of size reduction from the original tumor size was associated with an 18% decrease in risk. At the time of recurrence, none of the residual tumors showed evidence of enlargement or regrowth on the MRI and overt symptoms of hypogonadism were reported by 28% of patients. The investigators conclude from these findings that CAB withdrawal in a subset of patients according to Pituitary Society guidelines is safe and effective. However, the risk of recurrence is high, especially during the first year, and frequent monitoring is important.

Recurrence of Hyperprolactinemia after Withdrawal of Long-Term Cabergoline Therapy

Recurrence of hyperprolactinemia after cabergoline withdrawal ranges widely from 36 to 80%. The Pituitary Society recommends withdrawal of cabergoline in selected patients. Our aim was to evaluate recurrence of hyperprolactinemia in patients meeting The Pituitary Society guidelines. Patients were followed from the date of discontinuation to either relapse of hyperprolactinemia or the day of last prolactin test. We conducted the study at an academic medical center. Forty-six patients meeting Pituitary Society criteria (normoprolactinemic and with tumor volume reduction after 2 or more years of treatment) participated in the study. After withdrawal, if prolactin returned above reference range, another measurement was obtained within 1 month, symptoms were assessed by questionnaire, and magnetic resonance imaging was performed. We measured risk of and time to recurrence estimates as well as clinical predictors of recurrence. Mean age of patients was 50 +/- 13 yr, and 70% were women. Thirty-one patients had microprolactinomas, 11 had macroprolactinomas, and four had nontumoral hyperprolactinemia. The overall recurrence was 54%, and the estimated risk of recurrence by 18 months was 63%. The median time to recurrence was 3 months (range, 1-18 months), with 91% of recurrences occurring within 1 yr after discontinuation. Size of tumor remnant prior to withdrawal predicted recurrence [18% increase in risk for each millimeter (95% confidence interval, 3-35; P = 0.017)]. None of the tumors enlarged in the patients experiencing recurrence, and 28% had symptoms of hypogonadism. Cabergoline withdrawal is practical and safe in a subset of patients as defined by The Pituitary Society guidelines; however, the average risk of long-term recurrence in our study was over 60%. Close follow-up remains important, especially within the first year.

Insuffisance aortique sous faibles doses de cabergoline pour hyperprolactinémie non tumorale

Used in its neurological indication, cabergoline is known to induce cardiac valve regurgitations, essentially mitral and aortic valvular diseases, by its action on the 5HT2b receptors. Until now, it was assumed that the dose and the duration of exposure were the major factors of appearance. We describe a case of aortic insufficiency which developed in a patient given low doses of cabergoline (0.5 mg weekly) for non-tumoral hyperprolactinemia. Because of previous use of appetite suppressants and of bromocriptine, the exclusive responsibility of cabergoline remained uncertain. The potential gravity of these valvular heart diseases emphasizes the importance of careful cardiologic examination before and during treatment.

Withdrawal of Long-Term Cabergoline Therapy for Tumoral and Nontumoral Hyperprolactinemia

Although dopamine agonist treatment is preferred to surgery for prolactinoma, observations suggest that hyperprolactinemia recurs more often when medical treatment is withdrawn than after surgery, with or without radiotherapy. This prospective observational study focused on the effects of withdrawing treatment with the dopamine-receptor agonist cabergoline. The study group included 105 patients with microprolactinomas, 70 with macroprolactinomas, and 25 with nontumoral hyperprolactinemia. Treatment began with 0.5 mg orally in the first week and the dose was increased to 5 to 7 mg per week. Withdrawal was considered if prolactin levels were normal and magnetic resonance imaging showed a lack of tumor or tumor reduction of at least 50%, providing that the tumor was more than 5 mm from the optic chiasm. In addition, there could be no invasion of the cavernous sinuses or other important regions. It was expected that patients would be followed up for at least 2 years. The dose was lowered to 0.5 mg per week before withdrawal. In 25 women with nontumoral hyperprolactinemia, cabergoline was withdrawn after a median treatment time of 3 years. Six patients (24%) had a recurrence after a median of 18 months, but none became symptomatic. The other patients were followed up for a median of 4 years. Patients with microprolactinomas received cabergoline for a median of 4 years before withdrawal. Hyperprolactinemia recurred in 30% of patients after a median period of 1 year, but no patient had magnetic resonance imaging evidence of a recurrent tumor. Five of 25 women became oligomenorrheic but none had galactorrhea. Three of 7 men had decreased libido and potency; their testosterone levels did not change. In 73 patients, hyperprolactinemia remained controlled for a median of 3 years of follow up. Cabergoline was withdrawn after a median of 42 months in patients with macroprolactinoma. The recurrence rate was 36% and the median time to recurrence was 18 months. Five of 14 women became oligomenorrheic and 1 had recurrent galactorrhea. Four of 11 men reported decreased sexual potency and libido, and their testosterone levels declined. The other patients remained controlled a median of 4 years after drug withdrawal. The best predictor of the prolactin level at last follow up was the maximum diameter of a tumor during cabergoline therapy. Hyperprolactinemia remitted after withdrawal of cabergoline therapy in a majority of all groups, and there was no evidence of renewed tumor growth. Nevertheless, patients must be closely followed up to detect a delayed increase in tumor size. Periodic attempts at withdrawal seem warranted, particularly in patients having normal magnetic resonance imaging findings during treatment.

Colao A, Di Sarno A, Cappabianca P, et al: Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 349:2023–2033, 2003

Background Whether the withdrawal of treatment in patients with nontumoral hyperprolactinemia, microprolactinomas, or macroprolactinomas is safe and effective has been unclear. We performed an observational, prospective study of cabergoline (a dopamine-receptor agonist) withdrawal in such patients. Methods The study population included 200 patients—25 patients with nontumoral hyperprolactinemia, 105 with microprolactinomas, and 70 with macroprolactinomas. Withdrawal of cabergoline was considered if prolactin levels were normal, magnetic resonance imaging (MRI) showed no tumor (or tumor reduction of 50 percent or more, with the tumor at a distance of more than 5 mm from the optic chiasm, and no invasion of the cavernous sinuses or other critical areas), and if follow-up after withdrawal could be continued for at least 24 months. Results Recurrence rates two to five years after the withdrawal of cabergoline were 24 percent in patients with nontumoral hyperprolactinemia, 31 percent in patients with microprolactinomas, and 36 percent in patients with macroprolactinomas. Renewed tumor growth did not occur in any patient; in 10 female patients (22 percent) and 7 male patients (39 percent) with recurrent hyperprolactinemia, gonadal dysfunction redeveloped. In all diagnostic groups, prolactin levels at the time of recurrence were significantly lower than at diagnosis (p < 0.001). The Kaplan–Meier estimated rate of recurrence at five years was higher among patients with macroprolactinomas and those with microprolactinomas who had small remnant tumors visible on MRI at the time of treatment withdrawal than among patients whose MRI scans showed no evidence of tumor at the time of withdrawal (patients with macroprolactinomas, 78 percent vs. 33 percent, P = 0.001; patients with microprolactinomas, 42 percent vs. 26 percent, P = 0.02). Conclusions Cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor. However, because the length of follow-up in our study was insufficient to rule out a delayed increase in the size of the tumor, we suggest that patients be closely monitored, particularly those with macroprolactinomas, in whom renewed growth of the tumor may compromise vision.

Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia

Gender differences in tumor size are supposed to exist in hyperprolactinemia since microadenomas are more commonly found in women and macroadenomas in men. Whether this reflects only a delay in diagnosis in men or a true gender difference in tumor pathogenesis is still unclear. To prospectively analyze gender differences in the presentation and response to cabergoline treatment in 219 consecutive newly diagnosed patients with hyperprolactinemia. An open prospective design. Of the 219 patients of which 145 were women; 107 patients had macroprolactinoma, 97 had microprolactinoma, and 15 had non-tumoral hyperprolactinemia. Presenting clinical symptoms, prolactin levels and tumor size at magnetic resonance imaging were measured before and 3-6 Months after cabergoline therapy. Prevalence of microprolactinomas (56% vs 22%, P=<0.0001) and non-tumoral hyperprolactinemia (10% vs 0%, P=0.01) was higher in women than in men. Men and women were of similar age (median 32 vs 29 Years; P=0.2) and a similar number had gonadal/sexual dysfunction (85 vs 83%, P=0.6); weight gain (70 vs 46%; P=<0.0001) and galactorrhea (52 vs 19%; P=<0.0001) were more common in women. Prolactin levels were higher in men than in women, whether exhibiting macro- (2848+/-2954 vs 1132+/-2351 microg/l, P=<0.0001) or microadenomas (187.8+/-51.8 vs 135.4+/-60.5 microg/l, P=0.009) and the size of the adenoma was larger in men than in women irrespective of macro- (25.8+/-12.4 vs 17.2+/-7.2 mm, P=<0.0001) or microadenoma diagnosis (8.0+/-1.4 vs 7.1+/-1.6 mm, P=0.04). After treatment, prolactin levels decreased by 89.2-96.4% in all groups, and normalized more frequently in micro- than in macroadenoma patients (86 vs 64%, P<0.0001), regardless of gender (70% vs 69%, P=0.9). Menses resumed in 82% of women, libido disturbances improved in 57% of men. Tumor size was reduced by 45+/-25% and 52+/-24% in macroprolactinoma patients and by 44+/-31 and 38+/-29% in microprolactinoma patients in women and men respectively. Visual field defects disappeared in 61% of women and in 71% of men (P=0.6). Prevalence of macroprolactinomas was similar in men and women; microprolactinomas and non-tumoral hyperprolactinemia were more frequent in women. Clinical symptoms at presentation differed according to gender, with galactorrhea and weight gain more frequent in women. The successful response to cabergoline treatment for 6 Months was higher in micro- than in macroprolactinoma patients and was similar in women and men.

Resistance to Cabergoline as Compared With Bromocriptine in Hyperprolactinemia: Prevalence, Clinical Definition, and Therapeutic Strategy

di Sarno, Antonella; Landi, Maria Luisa; Cappabianca, Paolo; Di Salle, Francesco; Rossi, Francesca W.; Pivonello, Rosario; di Somma, Carolina; Faggiano, Antongiulio; Lombardi, Gaetano; Colao, Annamaria

Resistance to Cabergoline as Compared with Bromocriptine in Hyperprolactinemia: Prevalence, Clinical Definition, and Therapeutic Strategy

To evaluate the prevalence of resistance to cabergoline treatment, we studied 120 consecutive de novo patients (56 macroadenoma, 60 microadenoma, 4 nontumoral hyperprolactinemia) treated with cabergoline (CAB) compared with 87 consecutive de novo patients (28 macroadenoma, 44 microadenoma, 15 nontumoral hyperprolactinemia) treated with bromocriptine (BRC) for 24 months. Resistance was evaluated as inability to normalize serum PRL levels (first end point) and to induce tumor shrinkage (second end point). After 24 months, PRL normalization and tumor shrinkage after CAB and BRC treatments, respectively, were obtained in 82.1% and 46.4% of macroprolactinomas (P < 0.001) and in 90% vs. 56.8% of microprolactinomas (P< 0.001). The median doses of CAB and BRC able to fulfill the two criteria of treatment success were 1 mg/wk and 7.5 mg/d in macroprolactinomas, 1 mg/wk and 5 mg/d in microprolactinomas, and 0.5 mg/wk and 3.75 mg/d in nontumoral hyperprolactinemia. Hyperprolactinemia persisted in 17.8% of macroprolactinomas, 10% of microprolactinomas, and after CAB at doses of 5–7 mg/wk and in 53.6% of macroprolactinomas, 43.2% of microprolactinomas, and 20% of nontumoral hyperprolactinemic patients, after BRC at doses of 15–20 mg/d. In these resistant macro- and microprolactinomas, the maximal tumor diameter was reduced by 43.7 ± 3.6% and 22.1± 3.7% and by 59.3 ± 7.1% and 4.3 ± 2.1% after CAB and BRC, respectively (P < 0.001). In conclusion, long-term CAB treatment induced the successful control of hyperprolactinemia associated with tumor shrinkage in a higher proportion of patients than did BRC treatment. In a small number of patients (i.e. 17.8% of macroprolactinomas and 10% of microprolactinomas), however, CAB treatment did not normalize serum PRL levels despite reducing tumor mass, even at very high doses. Therefore, an absence of tumor shrinkage cannot be considered as end point to indicate resistance to CAB, and increasing the dose of CAB higher than 3 mg/wk does not seem to be helpful in controlling PRL hypersecretion.

Adrenocorticotropic hormone and beta-endorphin concentrations in the inferior petrosal sinuses in Cushing's disease and other pituitary diseases.

Aim of the present study was the evaluation of ACTH and beta-endorphin-like-immunoreactivity (beta-ELI) in the inferior petrosal sinuses (IPS's) and in the peripheral blood of patients with Cushing's disease (Group 1), with GH- or PRL-secreting adenomas or nontumoral hyperprolactinemia (Group 2). These patients had undergone selective and bilateral simultaneous IPS sampling for diagnostic purposes or for neurosurgical indications. In the patients of Group 1, ACTH and beta-ELI levels were higher in the IPS ipsilateral than in the contralateral to the adenoma and in the periphery (p < 0.001). In the patients of Group 2 ACTH and beta-ELI levels were higher in the IPS's than in the peripheral blood (p < 0.001) and, in the 9 patients with GH- or PRL-secreting adenomas, they were higher in the IPS ipsilateral than in the contralateral to the adenoma and in the periphery (p < 0.05). A significant correlation exists between ACTH and beta-ELI in the periphery (p < 0.01; r = 0.72), in the IPS ipsilateral (p < 0.05; r = 0.54) and contralateral (p < 0.01; r = 0.66) to the adenoma in Group 1, but not in Group 2. In conclusion, higher beta-ELI levels were detected in the IPS's than in the peripheral blood not only in patients with Cushing's disease but also in those with other pituitary diseases not involving ACTH secretion. The absence of correlation between ACTH and beta-ELI in patients not bearing Cushing's disease suggests that in these conditions corticotrophs release ACTH and beta-endorphin in an independent manner.

Hormonal gradients between inferior petrosal sinuses in various pituitary diseases.

The aim of this retrospective study was to evaluate the existence of a multihormonal gradient between the inferior petrosal sinuses in various pituitary diseases: Cushing's disease (8 cases), acromegaly (4 cases), prolactinomas (7 cases), GH, PRL-secreting adenoma (1 case), functionless adenoma (2 cases), empty sella (3 cases) and in non-tumoral hyperprolactinemia (5 cases). A significant intersinus gradient (more than 1.4:1) was recorded for GH, ACTH and PRL in 16 patients (80%), but in only 9 patients (45%) out of the 20 with hormone-secreting tumors for TSH, FSH and LH. Moreover, of the 10 patients in the remaining groups, only in two cases was a significant intersinus gradient present: one for GH and one for LH. In conclusion, the finding of a multihormonal release in the inferior petrosal sinus ipsilateral to the adenoma is reported, for the first time, in patients with GH- and PRL-secreting adenomas. The possible explanation for such a finding may be either an increased blood flow in this site of sampling or a pituitary multihormone release through a paracrine mechanism primed by the tumoral hypersecreted hormone. In addition, the pulsatile secretory pattern and the short half-life of polypeptide hormones may contribute to better demonstrate this phenomenon in respect to glycoprotein hormones.

Effectiveness and long-term tolerability of the slow release oral form of bromocriptine on tumoral and non-tumoral hyperprolactinemia

The effectiveness and long-term tolerability of a new formulation of bromocriptine with slow gastrointestinal release (Parlodel SRO) has been evaluated on ten patients with macroprolactinoma, seven patients with microprolactinoma and five patients with nontumoral hyperprolactinemia during a period of 1-30 months. Six out of ten macroprolactinoma-bearing patients obtained a rapid normalization of plasma PRL levels with reduction of the tumor size recorded by CT scan follow-up. Four of six microprolactinomas and all the five nontumoral hyperprolactinemic patients became normoprolactinemic with recovery of gonadal functions while in two other microprolactinomas Parlodel SRO significantly reduced plasma PRL levels with restoration of menses. Only in two patients the treatment was withdrawn for the appearance of side effects. In conclusion, Parlodel SRO is an effective drug in the management of tumoral and nontumoral hyperprolactinemia. The good long-term tolerability together with the hypoprolactinemic activity makes this drug a very good choice therapy in hyperprolactinemic syndromes even in case of poor tolerability to the standard formulation of the drug.

Oral and injectable long-lasting bromocriptine preparations in hyperprolactinemia: Comparison of their prolactin lowering activity, tolerability and safety

Bromocriptine, a D2 receptor agonist, has been widely used in tumoral and non-tumoral hyperprolactinemia, in reducing both plasma prolactin levels and in restoring fertility and/or menses in most patients. In this study a comparison between the injectable repeatable and the oral slow release formulations of bromocriptine (Parlodel LAR and Parlodel SRO) is reported, with respect to their effectiveness, tolerability and safety. Eleven patients with hyperprolactinemia, submitted to both treatments, were studied for a period of 1-24 months. Among the four patients with macroprolactinoma, three reached normoprolactinemia without complaining of side-effects, with both formulations, while the remaining patient became intolerant of the oral form after 1 year, and is presently being treated with the injectable formulation without presenting any side-effects. Among the five patients with microprolactinoma, two patients had a good response to both drugs; two patients did not reach normoprolactinemia with the injectable formulations, but a progressive decrease of prolactin levels was obtained with Parlodel SRO therapy, and the remaining patient was completely intolerant of the oral form without complaining of side-effects with Parlodel LAR. Two patients had non-tumoral hyperprolactinemia: one was intolerant of both drugs and one tolerated both formulations very well. In conclusion, Parlodel LAR and Parlodel SRO are very effective compounds in the medical treatment of hyperprolactinemic syndromes. The availability of these differing formulations improves the medical therapy, allowing a better choice of therapeutic regimen according to the effectiveness of, and tolerability to, the different drug formulations. In this way also, with poorly tolerant patients, it is possible to choose the better tolerated and more effective formulation of the drug.

A new oral slow release form of bromocriptine, Parlodel SRO, in the chronic treatment of 26 hyperprolactinemic patients

Parlodel SRO, a new slow release form of bromocriptine, was studied in 26 patients with tumoral and non-tumoral hyperprolactinemia. Prior to the treatment, serum prolactin (PRL) levels ranged from 45 ng/ml to 7000 ng/ml and they decreased to within the normal range in all but one patient after 7 days-1 year of treatment with this new formulation of bromocriptine. The clinical improvement paralleled the normalization of PRL secretion. Tolerability was rated good or very good in 24 patients, even in the three patients who had been intolerant of oral Parlodel. In conclusion, Parlodel SRO administered as a single daily dose resulted in very effective lowering of serum PRL in patients with hyperprolactinemic disorders.

Hypothalamic neurotransmitter function in experimentally induced hyperprolactinemia

It is known that animals or patients bearing a prolactin (PRL)-secreting tumor (PST) do not suppress PRL levels after administration of indirectly acting dopamine agonists, namely nomifensine (Nom), and are not responsive to the PRL releasing effect of antidopaminergic drugs and opioid peptides. Since the action of these drugs is mediated through the tuberoinfundibular dopaminergic (TIDA) system, these findings have been taken to indicate that animals and humans bearing prolactinomas have a defective TIDA function. Alternatively, PRL unresponsiveness to these drugs could be due to hyperfunction of TIDA system for the feedback action of high PRL levels. To clarify whether hypo- or hyperfunction of the TIDA system was responsible for such behaviour, we tested the effect of a synthetic opioid peptide (FK 33–824), a DA receptor antagonist, domperidone (Dom), and of Nom on PRL secretion in two experimental models of non-tumoral hyperprolactinemia, i.e. rats bearing ectopic pituitaries since 3 days (TP rats), or treated with ovine PRL (oPRL 250 μg, twice daily for 3 days), in which existence of an increased TIDA function has been demonstrated. FK 33–824 (0.5 mg/kg i.p.) increased significantly plasma PRL levels in control rats but failed to do so in TP rats and it elicited a significantly lower PRL response than in controls in rats treated with oPRL. In both experimental models, a PRL secretagogue, e.g. 5-hydroxytryptophan (50 mg/kg i.p.), elicited the same response as in controls, indicating that the pituitayr PRL pool was preserved. Kinetic characteristics of opioid binding sites in the hypothalamus of hyperprolactinemic rats did not differ from those of controls, and also hypothalamic Met-enkephalin concentrations were similar to those of controls. These findings would exclude a defect of endogenous opioid neurotransmission as responsible for the impaired PRL stimulation by the enkephalin analog. Supporting this were the findings that oPRL-treated rats exhibited a growth hormone response to FK 33–824 and a rise in plasma luteinizing hormone after naloxone (5 mg/kg s.c.) similar to those present in controls. These data indicate that the defective PRL responsiveness to opioids has to be attributed to the impairment of a neurotransmitter e.g. DA, functionally located at a site ‘downstream’ from opioid receptors. As already shown for oPRL-treated rats, TP rats exhibited a faster turnover rate of DA in the median eminence of the hypothalamus. In keeping with the idea that the hypothalamic dopaminergic system was involoved in the defective PRL responsiveness to opioids, Dom (50 μg/kg i.p.) induced aignificantly lower increase of PRL levels in TP and oPRL-injected rats than in controls. All these data demonstrate that opioid peptides and DA receptor antagonists are unable to discriminate the functional state of TIDA system. In fact, they fail to elicit a rise in plasma PRL in hyperprolactinemic states related to either TIDA hypo- (PST rats and humans) or hyperfunction (TP and oPRL-treated rats). In contrast to FK 33–824 and Dom, Nom (10 mg/kg i.p.), a drug which fails to lower PRL secretion in animals and patients with prolactinoma, did suppress plasma PRL levels of oPRL-treated rats as those of controls. The latter data indicate that indirectly acting DA agonists can discriminate the functional state of TIDA system; they fail to lower PRL secretion only when TIDA function is defective.