Assessment of pituitary function in patients with serum prolactin levels greater than 100 ng/ml

Twelve women with galactorrhea-amenorrhea and prolactin levels greater than 100 ng/ml were evaluated with dynamic pituitary challenge testing. Forty-two per cent of the patients had positive findings on polytomography and subsequent surgical confirmation of a pituitary tumor. Patients with tumors had a delayed elevation of growth hormone (GH) and cortisol following induction of insulin hypoglycemia. Patients had increased thyroid-stimulating hormone levels after injection of thyrotropin-releasing factor, but showed blunting of prolactin secretion. Patients with tumors had decreased basal levels of GH and showed a blunted response to luteinizing hormone-releasing hormone (LRF) stimulation. These patients had normal elevations of follicle-stimulating hormone after LRF challenge. Patients with tumors showed a delay in elevation of GH levels following l-dopa treatment. They also failed to show prolactin suppression following this treatment. There are consistently predictive changes that occur in pituitary functions in the presence of a pituitary tumor. However, absolute prolactin levels and sellar polytomography are more reliable in diagnosing the presence of a pituitary tumor in the patient with galactorrhea-amenorrhea.     

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.     

Prolactin-secreting pituitary adenomas in women. II. Menstrual function, pituitary reserves, and prolactin production following microsurgical removal.

A prospective study of 46 women with prolactin-secreting pituitary adenomas and amenorrhea and/or galactorrhea was performed to determine the influence of the selective transsphenoidal removal of these tumors on pituitary and reproductive function. This procedure was effective in restoring menstrual function in 34 of 41 women and in eliminating lactation in 30 of 40 women. Tumor size and preoperative serum prolactin concentrations were the most important factors in predicting the postoperative disappearance of symptoms. Normal menstrual function returned in 33 of 34 women with tumors less than 2 cm in diameter but in only one of seven women with tumors greater than 2 cm. Similarly, galactorrhea disappeared in 29 of 34 women with tumors less than 2 cm but in only one of six women with larger tumors. Menses returned in 31 of 32 women and galactorrhea disappeared in 25 of 31 women with preoperative serum prolactin levels below 200 ng/ml; conversely, menses returned in only three of nine women and lactation ceased in one of six women with preoperative serum prolactin concentrations above 200 ng/ml. Prolactin concentrations decreased in 42 of 43 patients following the removal of pituitary adenomas and returned to normal in 30. Postoperative pituitary reserves of adrenocorticotropic hormone, growth hormone, luteinizing hormone, and follicle-stimulating hormone were normal in most patients. These data indicate that the removal of prolactin-secreting pituitary adenomas by a neurosurgeon accomplished in this surgical technique is effective in restoring menstrual function and eliminating lactation in most women, especially if the tumor is less than 2 cm in diameter and the preoperative serum prolactin concentration is less than 200 ng/ml.     

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.     

Dysfunction of dopaminergic regulation of prolactin in patients with functioning and nonfunctioning pituitary adenomas and craniopharyngiomas

The response to domperidone (a dopamine blocking agent) of serum prolactin (PRL) levels was compared in 3 patients with amenorrhea-galactorrhea without evidence of a pituitary tumor, 23 patients with prolactinomas (10 cases with histologic confirmation), 7 patients with histologically verified large nonfunctioning pituitary adenomas with normal or moderately elevated basal PRL levels, and 6 patients with histologically verified craniopharyngiomas (3 with normal basal PRL levels and 3 with elevated PRL levels). The response was compared with that of 10 patients with postpartum hyperprolactinemia and 14 normal women. Ten milligrams of intravenous domperidone induced a rapid rise in PRL that was maximal at 30 to 45 minutes in normal, postpartum, and amenorrhea-galactorrhea patients who had no sign of tumor. In contrast, domperidone failed to induce significant changes in PRL in cases of prolactinoma, nonfunctioning pituitary adenomas, and craniopharyngioma with or without elevated basal PRL levels. The results suggest that dopaminergic control on PRL secretion was impaired in all tumor cases. The mechanisms of this abnormal dopaminergic control, however, may be different. Whereas dopamine control in cases of prolactinoma is altered at the level of pituitary dopamine receptors, alternative explanations must be found for those tumors with normal basal PRL levels and lack of response to domperidone.     

The value of prolactin dynamics as a predictor of ovulation with bromocriptine in patients with polycystic ovary syndrome

Six euprolactinemic polycystic ovary syndrome (PCOS) patients were subjected to a 24-hour study with serum sampling every 30 minutes and a perphenazine stimulation test. The serum prolactin (PRL) levels were compared with those of five healthy normoprolactinemic women whose cases were evaluated in a similar fashion. In addition to evaluating the PRL secretory pattern and lactotroph response, the PCOS individuals were given dopamine agonist therapy in a graduated dosage schedule, increasing each month, over a 3-month interval. The PCOS patients exhibited parallel but lower PRL levels than the control subjects during the late evening and early morning hours (P less than 0.0001) and were less responsive to perphenazine at the 6-hour sampling (P less than 0.05). Only one PCOS individual had suggestive evidence of ovulation over the 15 cycles the group was monitored. Therefore, we conclude that euprolactinemic PCOS patients who are nocturnal hyposecretors of PRL and who hyporespond to a perphenazine stimulation test are not likely to ovulate on bromocriptine in the dosages used in this study.     

Ectopic human chorionic gonadotropin: Gynecological tumors and nonmalignant conditions

Four groups of patients have been studied for the presence of serum human chorionic gonadotropin-like materials. The groups included benign and malignant tumors of the corpus of the uterus and of the ovary. A high frequency of human chorionic gonadotropin production has been found in patients with malignant tumors. However multiple measurements of hormone levels among these patients did not reflect the presence of tumor and the amount of the tumor present. In addition we report the presence of detectable levels of human chorionic gonadotropin in sera of patients without malignancies and the presence of different human chorionic gonadotropin-like entities in an extract from normal human pituitaries and in an ovarian cystic fluid. The finding that the presence of human chorionic gonadotropin in pituitary tissue, ovarian fluid, and blood from nonpregnant subjects or subjects without clinical evidence of neoplasm suggests that the hormone is not a unique secretory product of trophoblast and tumor. These findings reduce the usefulness of radioimmunological measurement of human chorionic gonadotropin in the diagnosis and in the management of nontrophoblastic tumors.     

Response of serum prolactin to exogenous stimulation.

Previous observations by other workers indicating suppression of serum prolactin (hPRL) by water loading could not be confirmed. Sequential testing using an acute water load in patients with various clinical diagnoses did not aid conclusively in differentiating functional hyperlactinemic states from pituitary adenoma. It was of interest that the acute ingestion of water resulted in a triphasic response in serum hPRL levels. The response to breast stimulation was more marked in patients with excessive breast hypertrophy and galactorrhea. This was in contrast to patients with hypo- or hyperthyroidism, anorexia nervosa, and our normal subjects. In response to breast stimulation, there was no difference among the normal group, women with functional hyperlactinemia, and patients with proven pituitary adenoma. When they were compared with other patient groups in this study, marked responsiveness was found in patients with amenorrhea and galactorrhea, amenorrhea with elevated hPRL levels without galactorrhea, breast hypertrophy, and adrenal overactivity in response to these two stimuli. The physiologic mechanisms resulting in the increase in serum hPRL levels seen in these patients remain unclear at the present time.     

Serum prolactin levels in galactorrhea.

Some patients with galactorrhea will have normal serum prolactin levels but many will have elevated serum prolactin levels. The galactorrhea may be due to drug ingestion, nipple afferent nerve stimulation, nonneoplastic disease or injury, and intracranial tumors. Serum prolactin levels were measured by radioimmunoassay in 17 women with galactorrhea. Levels 5 and 6 times normal values were found in two women who had proved pituitary adenomas. The latter conditions must be strongly considered and functional tests may help in diagnosis prior to enlargement of a prolactin-secreting tumor to the size where changes in the sella are seen on x-ray or visual field changes occur. If galactorrhea persists when no evidence of tumor can be found, the patient must be periodically re-evaluated, as the tumor may have been too small for detection at the time of the previous examination.     

Studies on the capillary permeability of experimental liver metastases

By using a quantitative Evans blue technique, vascular permeability of Walker carcinosarcomas implanted in the liver was compared with that of the host liver tissue. Rats were sacrificed at intervals from one minute to 96 hours after the intravenous injection of the dye. Permeability activity curves were significantly different for tumors and normal liver. Permeability activity was lower in the tumor at one and five minutes, approximately the same in the tumor and liver from 15 minutes to one hour but, from two hours to 48 hours, the permeability activity was significantly higher in the tumor. The peak tumor-liver permeability activity ratio of 1.87 occurred at six hours, and the highest tumor permeability activity values were seen at 18 hours. Liver permeability activity, in contrast, increased gradually after dye injection, reading peak levels at 24 to 72 hours. At 96 hours, both tumor and liver permeability activity were lower and equal. The differences in permeability activity may be explainable on the basis of structural differences in normal and tumor vessels or may be due to chemical substances released as a result of the presence of the tumor. The differences in permeability activity of tumors and normal tissues may be an important factor in determining the effectiveness of diagnostic and therapeutic techniques.     

The outcome of pregnancy in patients with treated and untreated prolactin-secreting pituitary tumors

Few data document pregnancy risks in patients with prolactin-secreting pituitary tumors, particularly risks relating to the likelihood and severity of increased tumor size. This study presents three groups of women with such lesions. Group 1 consisted of 47 women with transsphenoidal resection who were euprolactinemic postoperatively. Of this group 20 of 22 previously infertile women conceived 25 pregnancies. Group 2 was composed of 17 women who were operated upon but in whom prolactin was still raised (greater than 50 ng/ml) postoperatively and bromocriptine was subsequently used. Seven of these 17 patients were previously infertile, and six of the seven have conceived. In group 3 22 infertile women with small pituitary tumors were not operated upon but received bromocriptine. Eighteen of these patients have achieved 24 pregnancies. Methods of diagnosis, surveillance during pregnancy, and medical and surgical management are presented. Only two patients, both in group 3, developed signs of expanding tumor size in pregnancy.     

Variation of serum prolactin-releasing activity in women with the galactorrhea-amenorrhea syndrome after bromocriptine treatment

Serum methanol extracts were obtained from nine women with the galactorrhea-amenorrhea syndrome, 24 pregnant women in the third trimester, and 18 normal men and women. The serum extract released prolactin (PRL) in significant amounts from rat anterior pituitary in vitro. The extracts from patients with galactorrhea-amenorrhea released PRL in large quantities. A significant positive correlation was observed between the PRL-releasing activity and serum PRL levels in individual samples from the pregnant women and normal subjects but not from the patients with galactorrhea-amenorrhea. Bromocriptine therapy suppressed serum PRL levels of five patients without tumors but increased the PRL-releasing activity in three out of five patients after treatment for 1 or 2 months. Apparently hypothalamic regulation of PRL secretion was disrupted in these three patients after bromocriptine therapy.     

An endocrinological study of hyperprolactinemia and its treatment (author's transl)

Twenty-six cases of women with pituitary adenoma and seven cases of women with functional hyperprolactinemia were studied to evaluate the effects of neurosurgery and Bromocriptine treatment. In the patients with pituitary adenoma, the mean serum PRL level was significantly higher than that in the functional cases. Among the patients with pituitary adenoma, the serum PRL levels were roughly correlated to the size of the tumors. Basal serum LH, FSH and 17 beta-estradiol levels were lower in the patients with pituitary macroadenoma than in those with microadenoma. Neurosurgery was performed on fourteen patients of pituitary adenoma. Of ten cases with visual disturbance, it was necessary to use Bromocriptine to reduce the serum PRL to the normal level after operation. In the treatment of sixteen patients with microadenoma, Bromocriptine alone was used for eight of them and surgery was performed on four. As a result, there was a significant lowering of the serum PRL level and induction of regular menses in ten patients. Regular menses were induced by means of Bromocriptine treatment in all of the patients with functional hyperprolactinemia. Our data indicate that neurosurgery, either selective or combined with Bromocriptine, can normalize PRL levels and induce regular menses in patients with hyperprolactinemia.     

Galactorrhea-amenorrhea and hyperprolactinemia associated with pituitary tumors of growth-hormone- and adrenocorticotropic-hormone-secreting cells. A report of two cases

In women with galactorrhea, amenorrhea/oligomenorrhea, hyperprolactinemia and radiographic evidence of a pituitary tumor, the presumed etiology is usually a primary prolactin-secreting tumor. We treated two patients whose presenting symptoms (galactorrhea and oligomenorrhea) and initial investigation (which showed radiographic enlargement of the sella and hyperprolactinemia) suggested a prolactin-secreting pituitary tumor. However, after further endocrinologic investigation, transsphenoidal exploration and ultrastructural-immunohistologic evaluation of the excised pituitary tumors, the tumors were found to be composed of cells characteristic of growth-hormone and adrenocorticotropic-hormone production. These data are consistent with the hypothesis that any factor or factors increasing intrasellar pressure, including pituitary tumors originating in cells other than galactotrophs, can elevate serum prolactin and present clinically as galactorrhea-amenorrhea. They suggest further that a diligent search be done for elevations of other pituitary trophic hormones when a pituitary tumor is suspected in order not to overlook other kinds of serious endocrinopathy.     

Recovery of gonadotropin-secreting function of the pituitary in the puerperal women with eclampsia

Recovery of gonadotropin-secreting function of the pituitary has been studied in 4 puerperal women with episodes of eclampsia during the last pregnancy, delivery and/or the first 24 hours after delivery. On day 20 postpartum, hypertension, edema and proteinuria were improved in all the puerperal women. Serum FSH and LH responses to LH-RH on day 20 postpartum in 3 puerperal women with less than 6 eclamptic attacks during pregnancy or delivery were at a comparable level to those on day 20 postpartum in 4 puerperal women with premature labor between 31 and 33 weeks' gestation and in 9 normal puerperal women. Serum FSH response to LH-RH on day 20 postpartum in a puerperal woman with 10 eclamptic attacks during pregnancy and the first 24 hours after delivery was lower than those in 4 puerperal women with premature labor and in 9 normal puerperal women. In the puerperal woman with 10 eclamptic attacks, the lowered FSH response to LH-RH on day 20 postpartum was apparently improved on day 55 postpartum. However, the FSH response to LH-RH on day 55 postpartum was still lower in the puerperal woman with 10 eclamptic attacks than in 7 normal puerperal women. These results indicate that many eclamptic attacks during pregnancy, delivery and/or the first 24 hours after delivery may cause perturbation to some extent in recovery of FSH-secreting function of the pituitary during the puerperium.     

Elevated levels of plasma beta-endorphin and gamma 3-melanocyte stimulating hormone in the polycystic ovary syndrome

The authors have suggested that dysfunction of a central structure (above the pituitary level) is the primary etiologic factor responsible for the production of the polycystic ovary syndrome. To investigate further the functional integrity of the hypothalamic pituitary axis, plasma levels of beta-endorphin, gamma 3-melanocyte stimulating hormone, and gamma 1-melanocyte stimulating hormone-like immunoreactivity were measured in six patients with polycystic ovary syndrome, and in ten women with normal ovarian function. The limit of sensitivity for the radioimmunoassays was 20 pg/mL. Plasma beta-endorphin was significantly higher in polycystic ovary syndrome than in control subjects: (mean +/- SE) 60 +/- 10 versus 30 +/- 4 pg/mL, respectively (P less than .05). gamma 3-Melanocyte stimulating hormone was detectable in four of six patients with polycystic ovary syndrome (mean for the whole group: 45 +/- 15 pg/mL); it was undetectable in all the control subjects. Control of plasma beta-endorphin and gamma 3-melanocyte stimulating hormone secretion in PCO was evaluated with metyrapone and dexamethasone. Overnight administration of metyrapone to polycystic ovary syndrome patients resulted in rises of beta-endorphin and gamma 3-melanocyte stimulating hormone. Dexamethasone suppressed only partially (to basal concentrations) beta-endorphin and gamma 3-melanocyte stimulating hormone levels. Plasma adrenocorticotropic hormone concentrations were within the normal range and displayed the expected changes in response to metyrapone and dexamethasone. The present report presents an additional central (hypothalamic-pituitary) abnormality in patients with the polycystic ovary syndrome.     

Hyperprolactinemia and associated pituitary prolactinomas

The association between serum prolactin (PRL) and the presence of pituitary tumors as determined by third generation computed tomography scan was studied in hyperprolactinemic patients. Patient charts from a four-year period were reviewed to identify those patients with elevated PRL (greater than or equal to 25 ng/mL). All patients with hyperprolactinemia underwent computed tomography scan evaluation of the pituitary gland. Hyperprolactinemia was identified in 79 patients, mean PRL 59 +/- 6.1 ng/mL SEM. Pituitary tumors were identified in 35 of these patients, mean PRL 65 +/- 11.9 ng/mL. This level was not significantly different from the level in 43 patients with normal computed tomography scans (52 +/- 5.7 ng/mL). This review found that computed tomography scan identified pituitary tumors in 44% (35 of 79) of patients with hyperprolactinemia. The likelihood of finding a pituitary tumor did not correlate with the level of hyperprolactinemia. Computed tomography scan is indicated for the diagnosis of prolactinomas in all hyperprolactinemic patients regardless of the serum PRL level.     

Pituitary tumors and pregnancy.

This paper contains a review of the natural history of pituitary tumors in nonpregnant and pregnant patients. Data were drawn from previously published reports and from responses to a questionnaire and were analyzed by life-table techniques. Follow-up of 62 nonpregnant patients with untreated pituitary tumors with and without visual field changes revealed a median time to treatment of 15 1/2 years and similar, relatively constant hazard functions. In 91 pregnancies occurring in 73 women with previously untreated pituitary tumors, ovulation had occurred spontaneously in 9 per cent, headache occurred in 23 per cent, and visual disturbances in 25 per cent with 61 per cent remaining asymptomatic. In those patients who developed symptoms, median time to headache was 10 weeks and to visual disturbance, 14 weeks. The hazard functions were relatively constant and similar. The relative risk of developing symptoms is independent of whether or not the first or second pregnancy occurred in the presence of the pituitary tumor. Of the pregnant patients with previously untreated pituitary tumors, 30 per cent required surgery or radiation therapy. Median time to treatment was 19 weeks. None of the 69 pregnant women without pituitary therapy had permanent sequelae. Only four patients who underwent surgery or received radiation treatment developed permanent symptoms and none was serious. In 78 pregnancies occurring in 73 women with previously treated pituitary tumors, headache occurred in 4 per cent and visual disturbances in 5 per cent. Only one patient required therapy. Treatment during pregnancy results in significantly increased prematurity rates but unchanged abortion and perinatal mortality rates. Small pituitary tumors do not constitute a contraindication to either induction of ovulation or pregnancy.     

A practical approach for the evaluation of women with abnormal polytomography or elevated prolactin levels

Based upon the experience gained in the evaluation of 60 patients with abnormal polytomography and/or elevated prolactin levels, the following observations can be made: Patients with amenorrhea, amenorrhea and galactorrhea, galactorrhea alone, or anovulatory cycles and infertility may or may not have pituitary tumors. Clinical symptoms do not always correlate with the prolactin level, and patients with normal prolactins may have pituitary tumors. The incidence of empty sella is significant (15.8% in this series). Visual field examination is not a useful screening procedure, but evaluation of thyroid function is important to detect the occasional patient with hypothyroidism (3.5% in this series). The insulin tolerance test is not helpful in detecting the presence of pituitary tumors or in guiding management decisions, and the CT scan contributes little and should be omitted from the evaluation process. A straightforward, economical, and efficient approach to this clinical problem is presented.     

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.