Hyperprolactinemia associated with clinically silent adenomas: endocrinologic and pathologic studies; a report of two cases

Pituitary adenomas containing adrenocorticotropic hormone (ACTH) in one case, and ACTH, beta-lipotropin, and beta-endorphin in the other, were demonstrated in two patients who had amenorrhea-galactorrhea and hyperprolactinemia with no manifestation of Cushing's disease. Neither adenoma contained prolactin (PRL). Initial bromocriptine therapy resulted in cessation of amenorrhea-galactorrhea and normalization of PRL levels. However, there was radiologic evidence of tumor enlargement in both patients. After pituitary adenomectomy, the two patients resumed regular menses and normal PRL dynamics. These patients illustrate the need for bromocriptine therapy for possible enlargement of their pituitary adenomas. The diagnosis of silent corticotroph adenoma should be kept in mind.     

Prolactin response to the dopamine antagonists sulpiride and domperidone. Further evidence for pituitary dopamine deficiency in hyperprolactinemic disorders of different etiology

The PRL response to the dopamine antagonists sulpiride (100 mg i.m.) or domperidone (2 or 8 mg i.v.) was evaluated in healthy controls and in 148 patients with different hyperprolactinemic disorders (50 with idiopathic hyperprolactinemia, 58 with microprolactinoma, 19 with macroprolactinoma, 2 with empty sella, 8 with acromegaly, 7 with organic lesions of the hypothalamus, and 4 with idiopathic hypopituitarism of presumed hypothalamic origin). Mean PRL response to both drugs was significantly lower in all groups of patients than in controls, and significantly higher in subjects with idiopathic hyperprolactinemia than in those with pituitary adenomas or hypothalamic disease. Absent or impaired PRL responses were found in 38% of idiopathic patients, in 91.5% of microprolactinomas and in all of the patients with either macroprolactinoma, acromegaly, or hypothalamic disorders. Since the PRL response to dopamine antagonists depends on the presence of an endogenous dopaminergic tone, it is suggested that these figures reflect the incidence of major dopamine deficiency at pituitary lactotrophs in different hyperprolactinemic states. These data suggest that the pathophysiology of hyperprolactinemia in many patients with idiopathic disease is different from that of microprolactinoma. However, the finding of a normal PRL response to sulpiride in some subjects with radiologically or surgically proven microprolactinoma indicates that this test has no diagnostic value in the individual case.     

Antecedent factors and outcome in amenorrhea-galactorrhea

One hundred seventeen patients with amenorrhea and galactorrhea or hyperprolactinemia were evaluated with regard to antecedent factors, results of investigations, and management. Full details of the outcome of prolonged follow-up were available for 104 patients. Patients who developed amenorrhea-galactorrhea after withdrawal of oral contraceptives or postpartum had a lower incidence of pituitary adenomas than did those who developed amenorrhea-galactorrhea spontaneously. Six of a total of 40 tumors were detected only during the follow-up period. This study suggests that patients with spontaneous amenorrhea-galactorrhea have a greater risk of developing a detectable pituitary adenoma than do those with postpill or postpartum symptoms. However, patients with a microadenoma are more likely to have had postpill onset of hyperprolactinemia. Plasma prolactin (PRL) in patients with postpill amenorrhea-galactorrhea increased in proportion to the duration of oral contraceptive use.     

Integrity of central dopaminergic system in women with postpartum hyperprolactinemia

In order to elucidate the role of elevated prolactin (PRL) on the central dopaminergic systems, the suppressive effects of PRL were studied after the administration of l-dopa and l-dopa plus carbidopa on consecutive days to the following three groups: 10 normoprolactinemic subjects, six nonnursing normal puerperal women, and seven hyperprolactinemic women without any evidence of pituitary tumor. In the normoprolactinemic subjects (basal PRL 13 ± 2 ng/ml mean ± SE), the suppressive effects of l-dopa alone and l-dopa plus carbidopa were similar (48% ± 4% and 58% ± 6%, respectively). In puerperal hyperprolactinemic subjects, the basal PRL (116.8 ± 16.4 ng/ml) was suppressed 77% ± 2% after administration of l-dopa and 51% ± 7% after l-dopa plus carbidopa, significantly different from that of l-dopa alone (p < 0.005), but similar to that observed in normal subjects. In the patients with idiopathic hyperprolactinemia, the baseline PRL (131 ± 38 ng/ml) decreased 56.3% after the administration of l-dopa. In the presence of peripheral dopa decarboxylase inhibition, the administration of l-dopa decreased plasma PRL values 30%, a drop significantly different from that of l-dopa alone (p < 0.02). Women with idiopathic hyperprolactinemia exhibit reduced central dopaminergic inhibition of PRL secretion similar to that in patients with pituitary tumor; whereas the response to central dopaminergic inhibition in postpartum women with comparable baseline PRL levels is similar to that in normoprolactinemic subjects. This indicates that hyperprolactinemia per se is not associated with a state of reduced central dopaminergic inhibition. The increased pituitary sensitivity to l-dopa observed in puerperal women may be due to alterations in PRL receptors or vascularity.     

Clinical history and outcome of 59 patients with idiopathic hyperprolactinemia.

OBJECTIVE: To investigate the clinical course of hyperprolactinemia without demonstrable cause. DESIGN: Prospective study of all patients with idiopathic hyperprolactinemia first seen between 1974 and 1985. SETTING: Outpatient Department of University Hospital. PATIENTS: Fifty-nine patients followed for 6 to 190 months (median 78 months). Medical treatment given only in case of anovulatory infertility or hypogonadism. OUTCOME MEASURES: Development of pituitary (micro)prolactinoma, prolactin (PRL) levels, and clinical signs of menstrual dysfunction. RESULTS: With exception of one woman in whom it probably had been missed by hypocycloidal tomography, no demonstrable prolactinoma developed. Prolactin levels rose in two patients, one using oral contraceptives and the other with prolactinoma. At the end of follow-up, 15 of 16 patients using a dopaminergic drug had a normal cycle; 13 had normal final PRL levels. From the 43 patients off medication, 28 (66%) had normal PRL levels and 23 (54%) had a normal cycle. There were no significant differences between women who had and had not been pregnant. Dopaminergic medication had no appreciable influence on the course of the disease. CONCLUSION: In idiopathic hyperprolactinemia, progression to pituitary prolactinoma seldom, if ever, occurs. There is a high tendency to spontaneous cure, and pregnancy or medication have no apparent effect. Frequent pituitary imaging was found to be not necessary in our patient population. It may best be reserved for situations in which the PRL level in symptomatic hyperprolactinemia is inconsistent with pituitary imaging results.     

Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamic-pituitary disease

The prolactin (PRL) response to thyrotropin-releasing hormone (TRH) was evaluated in 686 patients over a 4-year period. Of the 170 control subjects tested, none had a blunted PRL response to TRH. Eighty patients with prolactinomas documented by surgery were tested. Ninety-five percent (76 of 80) of these patients had an abnormally blunted PRL response to TRH. Of the 87 patients with a prolactinoma who did not undergo surgery, 98% (85 of 87) had a blunted PRL response to TRH. Many patients with other pituitary and hypothalamic diseases (pituitary tumors other than prolactinomas [Cushing's disease, acromegaly, chromophobe adenoma], craniopharyngioma) also had an abnormal PRL response to TRH (79 of 153, 52%). In the majority of patients with hyperprolactinemia due to dopamine antagonist medications, TRH stimulation did not produce a normal rise in PRL. The TRH test may be helpful in confirming the diagnosis of prolactinoma, but it is not a decisive factor in the diagnosis or management of this entity.     

Primary empty sella syndrome with elevated serum prolactin

A young, adult, white female with long-standing amenorrhea-galactorrhea syndrome and known pituitary enlargement since 1969 is presented. Further evaluation revealed PRL levels elevated in the microadenoma range and an empty sella. The presence of a pituitary adenoma, however, could not be confirmed by our studies. The question now arises--in a young woman desirous of pregnancy, should an induction of ovulation be attempted in view of the elevated serum PRL and an empty sella?     

Hyperprolactinemia: pathophysiology and therapeutic approach

Abstract

Prolactin (PRL) is a hormone, mainly secreted by lactotroph cells of the anterior pituitary gland. Recent studies have shown it may also be produced by many extrapituitary cells. Its well-recognized PRL plays an important role in lactation during pregnancy, but it is involved in other biological functions such as angiogenesis, immunoregulation and osmoregulation. Hyperprolactinemia is a typical condition producing reproductive dysfunction in both sexes, resulting in hypogonadism, infertility and galactorrhea. It may be also asymptomatic. Lactotroph adenomas (prolactinoma) is one of the most common cause of PRL excess, representing approximately 40% of all pituitary tumors. Several other conditions should be excluded before a clear diagnosis of hyperprolactinemia is made. Hyperprolactinemia may be secondary to pharmacological or pathological interruption of hypothalamic–pituitary dopaminergic pathways or idiopathic. Stress, renal failure or hypothyroidism are other frequent conditions to exclude in patients with hyperprolactinemia. We will review biochemical characteristics and physiological functions of that hormone. Clinical and pharmacological approach to hyperprolactinemia will also be discussed.     

Bromocryptine therapy in cases of amenorrhea-galactorrhea

Of 28 patients presenting with amenorrhea-galactorrhea, pituitary tumors were confirmed in eight. Six patients had occult hypothyroidism and the rest had an endocrine profile suggestive of pituitary tumor or of an idiopathic etiology. Treatment with bromocryptine resulted in suppression of the inappropriate lactation and restoration of regular menstrual function. In five cases, however, the galactorrhea was only diminished and in four of these cases, normal ovarian function did not return. Of the 19 patients that were seeking fertility and continued the medication for at least 20 days, nine pregnancies resulted. A similar response to bromocryptine was observed regardless of the underlying cause of the amenorrhea-galactorrhea.     

Macroprolactinomas with suprasellar extension: effect of bromocriptine withdrawal during one or more pregnancies.

OBJECTIVE: To investigate the effects of bromocriptine withdrawal during one or more pregnancies in patients who presented with pituitary macroprolactinomas with suprasellar extension. DESIGN: Four infertile patients presenting with a macroprolactinoma with suprasellar extension conceived during treatment with bromocriptine on 10 occasions resulting in eight full-term normal deliveries. Treatment was withheld shortly after conception in each pregnancy. RESULTS: Serum prolactin (PRL) levels fell initially from a mean of 2,776 (range 1,682 to 4,515) to 27 micrograms/L (range 1 to 71) with the development of a partially empty sella in all patients. Recovery of visual field defects occurred in the only affected individual. In case 1, PRL levels remained within the normal range, after bromocriptine withdrawal in the first pregnancy, with the development of an empty sella. Prolactin levels, however, increased substantially in cases 2 to 4. An asymptomatic suprasellar tumor extension returned in cases 2 and 3. After two or more pregnancies (cases 1, 3, and 4), there was a progressive decline in the serum PRL levels. Although still elevated in cases 3 and 4, the PRL levels were considerably below those obtained at presentation or in the first pregnancy. Tumor regression with the development of an empty sella was observed in both these patients as well in their pregnancy or postpartum period. CONCLUSIONS: Bromocriptine may be safely withdrawn during pregnancy in patients presenting with a macroprolactinoma. With multiple bromocriptine induced pregnancies, PRL levels and tumor size may progressively decrease with the eventual development of an empty sella.     

Maternal prolactin secretion during labor. The role of dopamine

BACKGROUND: To investigate the role of dopamine on the mechanisms of maternal prolactin secretion during labor and in the first six hours following delivery. METHODS: The study included 30 pregnant women with normal pregnancies, who were meeting the same criteria. They were divided into three subgroups of 10 patients each and they delivered healthy newborns. Group A was the control group. Metoclopramide 10 mg/h intravenously was given in Group B, while bromocryptine 5 mg per os was given in Group C. Maternal blood samples were obtained every hour during labor and in the six hours postpartum. Prolactin values were determined by using a radioimmunoassay method. RESULTS: Metoclopramide infusion caused an initial significant (p<0.01) rise in PRL level in Group B. Prolactin levels showed the same multiphasic pattern during labor and first h postpartum in both Groups A and B. PRL levels decreased until 1-2 h antepartum, then increased for about 3 h and they finally decreased, starting at 2 h postpartum and reaching values lower than the basic at 6 h postpartum. However, absolute PRL values were higher in Group B (where metoclopramide was given) than in Group A, in every time point. Bromocryptine (Group C) markedly lowered PRL levels, but PRL fluctuation still followed the same trends as in the other two groups. CONCLUSIONS: The different PRL values between the three groups show that maternal PRL is still under dopaminergic influence during labor. However, the fact that PRL levels exhibit the same multiphasic pattern, suggests that there are factors other than dopamine, which strongly influence this pattern.     

Prolactin levels and the response to central dopamine synthesis blockade in subjects on oral contraceptives

This study investigates whether oral contraceptive (OC) users have decreased central dopaminergic tone by the means of blocking hypothalamic dopamine (DA) synthesis with monoiodotyrosine (MIT). The prolactin (PRL) response that follows MIT would reflect the degree of central dopaminergic inhibition. 18 females on OC and 10 normal ovulating women were observed; of the OC users 5 had taken OCs for less than 1 year, and 6 for longer than 5 years. 1 g of MIT was given orally and blood samples were taken for assay of PRL. The mean basal PRL level in OC subjects was significantly higher than in controls, although both values were in the normal range. Normal females showed a 5-fold rise in PRL levels in response to MIT. OC subjects showed a significant increase in PRL response to MIT 45 minutes after MIT ingestion. The PRL response area in OC subjects was also significantly greater, but there was no difference in the basal level and the response to MIT in subjects on OC for less than 1 year, as compared to those on OC for more than 5 years. It can be concluded that OC therapy results in increased central dopaminergic inhibitory activity which acts to balance estrogen-induced lactotroph hyperplasia and increased prolactin production. MIT is an important tool for estimating central hypothalamic DA activity.     

Prolactin responsiveness to TRH in amenorrheic women with and without galactorrhea.

Sixty women were given intravenous injection of 200 microgram TRH to assess its diagnostic potential as a stimulus to PRL release. Following the administration of TRH, there was a prompt increase in serum PRL to 614.6%, to 296%, to 282.1%, and 34% in normal women, amenorrheic patients, non tumoral galactorrheic cases, and patients with pituitary tumors respectively. The TRH response above baseline of PRL levels was statistically significant in all groups, but the women with pituitary tumors which showed a blunted response. The per cent of increment of PRL levels after TRH was similar in amenorrheic women regardless the presence or not of galactorrhea; this increase was significantly greater than in patients with pituitary tumors (p less than 0.01). The per cent of increment above baseline of PRL was significantly greater in menstruating women than in amenorrheic patients (p less than 0.001). In basis of present data: 1) there is a diminished PRL secretion after TRH in amenorrheic women regardless the presence of galactorrhea or hyperprolactinemia; 2) a blunted response to TRH in hyperprolactinemic women may be indicative of a pituitary tumor.     

Laboratory and clinical significance of macroprolactinemia in women with hyperprolactinemia

The role of macroprolactinemia in women with hyperprolactinemia is currently controversial and can lead to clinical dilemmas, depending upon the origin of macroprolactin, the presence of hyperprolactinemic symptoms and monomeric prolactin (PRL) levels. Macroprolactinemia is mostly considered an extrapituitary phenomenon of mild and asymptomatic hyperprolactinemia associated with normal concentrations of monomeric PRL and a predominance of macroprolactin confined to the vascular system, which is biologically inactive. Patients can therefore be reassured that macroprolactinemia should be considered a benign clinical condition, resistant to antiprolactinemic drugs, and that no diagnostic investigations or prolonged follow-up should be necessary. However, a significant proportion of macroprolactinemic patients appears to suffer from hyperprolactinemia-related symptoms and radiological pituitary findings commonly associated with true hyperprolactinemia. The symptoms of hyperprolactinemia are correlated to the levels of monomeric PRL excess, which may be explained as coincidental, by dissociation of macroprolactin, or by physiological, pharmacological and pathological causes. The excess of monomeric PRL levels in such cases is of primarily importance and the diagnosis of macroprolactinemia is misleading or inadequate. However, macroprolactinemia of pituitary origin associated with radiological findings of pituitary adenomas may rarely occur with similar hyperprolactinemic manifestations, exclusively due to bioactivity of macroprolactin. Therefore, in such cases with hyperprolactinemic signs and pituitary findings, macroprolactinemia should be considered a pathological biochemical condition of hyperprolactinemia. Accordingly, individualized diagnostic investigations with the introduction of dopamine agonists, or other treatment with prolonged follow-up, should be mandatory. The review analyses the laboratory and clinical significance of macroprolactinemia in hyperprolactinemic women suggesting clinically useful diagnostic and treatment strategies.     

Prolactin and glucose tolerance in normal and gestational diabetic pregnancy

The relationship between the deterioration of glucose tolerance and plasma prolactin (PRL) levels was investigated in 15 normal pregnant women and in 15 women with gestational diabetes mellitus. Oral glucose tolerance tests were performed in late pregnancy and postpartum, and the insulin, glucagon, and PRL responses were measured. In late pregnancy the gestational diabetics revealed significantly elevated fasting glucose levels compared with the normal pregnant women and after the glucose challenge their insulin responses were significantly diminished and the suppression of glucagon less pronounced. These differences in glucose metabolism were markedly reduced early postpartum. There was no difference in basal PRL concentrations between the two groups neither in pregnancy nor postpartum. The PRL levels were not altered during the oral glucose tolerance tests and no correlation between the deterioration of glucose tolerance and the PRL concentrations could be demonstrated in either group. These results indicate that abnormal PRL levels are not of pathophysiologic importance for the development of gestational diabetes mellitus.     

Prolactin secretion in polycystic ovary syndrome: circadian rhythmicity and dynamic aspects

The circadian rhythms of plasma prolactin (PRL) and cortisol and of oral temperature were simultaneously studied in 24 women with polycystic ovary syndrome (PCOS). The PRL response to thyrotropin-releasing hormone (TRH) and domperidone was also evaluated in some of these patients. The physiological circadian chrono-organization of prolactin and cortisol secretion and of oral temperature was maintained in PCOS. The PRL responsiveness to the specific stimulations fell within normal limits. These results do not support the hypothesis of an impaired central dopaminergic regulation of prolactin secretion in PCOS.     

Long-term effects of time, medical treatment and pregnancy in 176 hyperprolactinemic women.

The changes in plasma prolactin (PRL) concentrations were studied in 176 hyperprolactinemic women over periods of 6-180 months, to evaluate the independent effects of time, drugs and pregnancy on the evolution of prolactinemia. CT scans showed pituitary adenoma in 87 (9 macroadenoma), the clinical presentations for 110 patients there amenorrhea, for 37 abnormal cycles and 29 had anovulatory sterility as an isolated symptom. 107 women underwent 191 cycles of dopaminergic treatment and 73 had pregnancies (86), either spontaneously or as a consequence of the treatment. Changes in prolactin induced by medical treatment and pregnancy were recorded and the spontaneous changes in prolactin in 38 patients (17 with adenoma) were followed over periods of 6-72 months. Final mean PRL concentrations were lower than basal though not significantly, in both 'functional' (54.4 vs. 79.2 ng/ml) and prolactinoma patients (87.3 vs. 116.4 ng/ml). Separate calculation of changes in prolactin after the course of medical treatment, pregnancies or 'just waiting' periods showed mean PRL concentrations to be significantly lower only for 'functional' patients after pregnancy. On the other hand, PRL variations in individual patients revealed that: (1) spontaneously, PRL rarely becomes lower over a few years; (2) dopaminergic treatment was associated with normalization of PRL in 13% of women; and (3) pregnancy normalized prolactin concentrations in 29% of the patients. Chi-square analysis of the PRL-lowering frequencies in functional patients showed a high cure rate for pregnancy (P less than 0.0001) and a lesser but still significant effect of drugs (P less than 0.025).     

Spontaneous pregnancy in women with a prolactin-producing pituitary adenoma

The occurrence of spontaneous pregnancy in patients with amenorrhea-galactorrhea, hyperprolactinemia, and radiographic evidence of a pituitary tumor is unusual. We present here two patients who conceived spontaneously. One had an uneventful pregnancy. Following delivery, transsphenoidal pituitary surgery was performed, confirming the presence of a prolactin-producing adenoma. The second patient had an early pregnancy termination (at 12 weeks of gestation). These patients provide evidence that ovulation and pregnancy can occur in spite of elevated prolactin levels.     

Evaluation of dopaminergic activity of the hypothalamus in patients with polycystic ovarian syndrome]

To evaluate the hypothalamic dopaminergic activity in patients with polycystic ovary syndrome (PCOS), we studied the PRL, TSH, LH and FSH responses to i.m. administration of sulpiride in five euthyroid women affected by PCOS and in five normal women. The mean basal PRL and TSH plasma levels resulted significantly higher (p less than 0.01) in PCOS subjects with respect to normal subjects. The incremental area under PRL and TSH profiles, after sulpiride administration, were significantly lower (p less than 0.05) in PCOS patients than in the control group; no significant variation of LH and FSH plasma levels resulted. Our data suggest a decrease dopaminergic activity in PCOS.     

Pergolide mesylate inhibits exercise-induced prolactin release in man

The effects of Pergolide, a potent dopamine agonist, on exercise-induced plasma prolactin (PRL) changes were studied in normal men. Exercises consisted of a graded bicycle ergometer test and of a 20-km endurance run. In both circumstances, treatment with Pergolide, when compared with placebo or control values, resulted in a significant suppression of basal PRL (P less than 0.001) as well as of exercise-induced PRL increase (P less than 0.01). From these experiments it was concluded that augmented levels of PRL in plasma, as seen during or after muscular exercise, are caused by increased pituitary secretion, rather than decreased elimination.