Prolactin-secreting pituitary tumor associated with von Recklinghausen's disease.

A prolactin-secreting pituitary tumor, manifesting as galactorrhea and amenorrhea, was detected in association with multiple neurofibromatosis (von Recklinghausen's disease) in a young woman. The patient showed an excellent symptomatic response to bromocriptine mesylate treatment. To our knowledge, this association has never before been reported and may represent a new endocrine tumor association.

Cushing's syndrome associated with galactorrhea, amenorrhea, and hypothyroidism: a primary hypothalamic disorder.

A 19-year-old woman presented with a unique constellation of endocrinopathies, including Cushing's disease, post-partum galactorrhea, hypothalamic hypothyroidism and hypothalamic amenorrhea. There was no evidence of granulomatous or neoplastic disease in pituitary or hypothalamus. The potential role of excess glucocorticoids and disturbances in normal hypothalamic regulation of anterior pituitary function in the pathophysiology of this syndrome is discussed.

Decrease of prolactin by methysergide in amenorrheic hyperprolactinemic women.

The effect of methysergide (MES), a serotoninergic antagonist on prolactin (PRL) blood levels was studied in five hyperprolactinemic amenorrheic women. The drug was administered for five days at a daily dosage of 11.2 mg. MES decreased significantly the PRL blood levels in all subjects (p less than 0.01). Since the MES has been shown to have antiserotoninergic effects and since serotonin has been thought to be involved in the control of PRL release, the effects of MES in lowering PRL might be due to a decrease of serotonin tone.

Neurogenic galactorrhea-amenorrhea.

Neuroendocrine function in two women with galactorrhea-amenorrhea arising from abnormalities in the PRL reflex arc was compared to that of normal women. Basal gonadotropins were lower than normal, and one patient lacked episodic secretion of LH; however, the serum gonadotropin rise after iv LRH was in the normal range in both patients. Mean basal PRL levels were slightly elevated in one patient and were normal in the other, and the PRL levels after TRH, chlorpromazine, and levodopa testing were similar to those seen in normal women. Breast stimulation did not increase PRL levels in either patient. PRL levels fell with bromergocryptine therapy, galactorrhea ceased, and normal menses resumed. These studies indicate that chronic afferent impulses originating in the PRL reflex arc can result in galactorrhea and amenorrhea and that bromergocryptine therapy in such patients can restore normal menses.

Hyperprolactinemia and galactorrhea: spontaneous versus iatrogenic hypothyroidism.

Although hyperprolactinemia and galactorrhea occur in primary hypothyroidism, factors influencing their presence are not well established. To further define these factors, the duration of illness and serum levels of PRL and TSH were investigated in a group of 50 patients with spontaneous (27 females and 7 males) and iatrogenic (16 females) primary hypothyroidism. To test the hypothesis of reduced hypothalamic dopamine content in over long-standing primary hypothyroidism, the percent increase in serum PRL after the administration of metoclopramide, a dopamine blocker (2.5 mg, iv bolus), was studied in 13 women with spontaneous primary hypothyroidism and compared with that in 10 euthyroid women. While 88.2% of the patients with spontaneous primary hypothyroidism were hyperprolactinemia, only 31% of those with iatrogenic disease had elevated PRL levels. Women with spontaneous primary hypothyroidism had a longer duration of illness (72 +/- 12 vs. 6.7 +/- 1.8 months; P less than 0.001) and higher serum TSH (189 +/- 32 vs. 68 +/- 14 microunits/ml; P less than 0.01) and PRL levels (49.8 +/- 5.6 vs. 20.9 +/- 0.8 ng/ml; P less than 0.001) than women with iatrogenic hypothyroidism. A linear correlation existed between PRL and duration of illness (r = 0.53; P less than 0.001), while a logarithmic correlation was found between PRL and TSH levels (r = 0.44; P less than 0.01). Even though the duration of illness and TSH levels were similar in women with spontaneous disease with (n = 7) or without (n = 20) galactorrhea, the former were significantly younger (39.3 +/- 1.8 vs. 56.6 +/- 3 yr; P less than 0.001), and their PRL levels were significantly higher (69.3 +2- 8.9 vs. 42.9 +/- 2.2 ng/ml; P less than 0.001). The PRL response to metoclopramide in women with spontaneous disease was significantly smaller than that in controls (194 +/- 39% vs. 446 +/- 40%; P less than 0.001) and inversely correlated with basal PRL levels (r = -0.55; P less than 0.05). These data indicate that in primary hypothyroidism 1) the duration of illness is important in the development of hyperprolactinemia, 2) galactorrhea is more common in young women with spontaneous disease and high PRL levels, and 3) hypothalamic dopamine appears reduced in spontaneous disease.

Galactorrhea and hyperprolactinemia associated with chest wall injury.

A 48 year old premenopausal woman presented with galactorrhea and amenorrhea associated with chest wall burns. Basal serum prolactin levels were raised, and were further elevated by the administration of L-dopa, chlorpromazine and TRH. Intercostal nerve block and bromocryptine treatment reduced prolactin levels to normal, but did not noticably reduce milk secretion.

The natural history of idiopathic hyperprolactinemia.

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

A comparison of the efficacy and safety of pergolide and bromocriptine in the treatment of hyperprolactinemia.

UNLABELLED: Pergolide is a synthetic ergoline derivative with highly potent long-acting PRL-lowering activity, allowing therapy of hyperprolactinemia with a once daily administration of the drug. The results of two open-label, randomized controlled multicenter clinical trials are reported. Pergolide (taken once a day), was compared with bromocriptine (taken two to four times daily) regarding efficacy and safety in the reduction of PRL levels, the cessation of galactorrhea and amenorrhea, the improvement in sexual function, and tumor shrinkage in hyperprolactinemia without (trial I; 61 patients) and with radiologically evident pituitary tumors (trial II; 96 patients). Both drugs were equally effective in lowering PRL levels in both trials. A median optimal dose of 50 micrograms pergolide and 5 mg bromocriptine/day suppressed PRL levels in the 61 patients of trial I by more than 80%. During the 24-week investigational period galactorrhea disappeared in 96% and 87% of patients, whereas menstruation returned in 90% and 96% of patients, respectively. An equally high efficacy (optimal median dose: 75-100 micrograms pergolide, 7.5-10 mg bromocriptine daily) was observed in trial II, although the resumption of menses was less frequent than in the patients of trial I (50% and 58% of patients, respectively). Sexual dysfunction improved similarly on both drugs in about half the patients. In addition, tumor shrinkage occurred to a similar extent with both drugs. A high incidence of adverse events was noted especially at the initiation of therapy with both compounds: nausea, dizziness, vomiting, asthenia, headache, and decrease in blood pressure occurred at a similar incidence and extent during the use of pergolide and bromocriptine. Patients in trial I treated with pergolide reported a slightly higher incidence of fever, vasodilatation, and flu syndrome. CONCLUSIONS: in these 24-week studies comprising a total of 157 hyperprolactinemic patients, a once daily administration of pergolide was shown to be as safe and effective as the two to four times daily ingestion of bromocriptine. Longer-acting dopamine agonists like pergolide that can be taken once daily, are likely to increase the ease to adherence to the therapeutic regimen. This might result in a higher compliance to medical treatment of hyperprolactinemia.

Persistent defect in regulation of prolactin secretion after successful pituitary tumor removal in women with the galactorrhea-amenorrhea syndrome.

TRH, metoclopramide (MCP), chlorpromazine (CPZ), and insulin (ITT) stimulation tests of PRL secretion were carried out in age-matched controls and before and after successful removal of pituitary prolactinomas in women with the galactorrhea-amenorrhea syndrome. In preoperative patients there was a blunted or absent PRL response to TRH in 87%, to MCP in 100%, to CPZ in 100%, and to ITT in 93%. Two to 6 months after successful tumor removal, serum PRL rose 2-fold (the usual criterion for a normal response) in 73% after TRH, in 100% after MCP, but in only 13% after CPZ and in only 14% on ITT. However, the PRL increment with all four tests was significantly lower than that in normal controls. One to 8 yr after successful surgery, the PRL increments after TRH and MCP were returning to normal, but the PRL responses to CPZ and ITT remained blunted. GH, ACTH, and TSH reserves were intact in all patients. The diminished PRL response to all stimulation tests observed up to 6 months postoperatively might be explained by the persistence of a negative feedback effect from high PRL levels associated with the tumor. The more persistent impairment of the PRL response to CPZ and ITT is unexplained but suggests a hypothalamic defect.

Effect of triiodothyronine treatment on prolactin secretion in patients with amenorrhea-galactorrhea.

In order to determine the role of thyroid hormone in prolactin (PRL) secretion in patients with amenorrhea-galactorrhae, PRL response to 500 mug of iv thyrotropin-releasing hormone (TRH) was studied before and after the administration of triiodothyronine (T3) in 10 patients with amenorrhea-galactorrhea. Seven of these patients were euthyroid and the other 3 had hypothyroidism. The patients in the euthyroid group received 50 mug of T3 daily for 7 days and 75 mug q.d. for the ensuing 14 days. The hypothyroid patients received T3 at progressively increasing doses from 10 mug q.d. to 75 mug q.d. during 34 to 68 days. In the initial test, the elevated basal levels of PRL, 61.9 +/- 9.8 ng/ml (Mean +/- SE) exhibited a slight but insignificant net increase (7.7 +/- 2.1 ng/ml) after TRH injection in the euthyroid group. However, a marked response to TRH with a net increase of 147.2 +/- 26.3 ng/ml from the basal level of 47.3 +/- 11.2 ng/ml was observed in the hypothyroid patients. After treatment with T3, both the basal level (56.9 +/- 8.3 ng/ml) and the net increase (9.9 +/- 3.6 ng/ml) of PRL following TRH stimulation remained virtually unchanged in the euthyroid group. The hypothyroid group, in contrast, displayed a significant depression of both the basal level (26.1 +/- 13.0 ng/ml) and the net increase (33.8 +/- 6.5 ng/ml) of PRL to TRH stimulation. The diminution of the basal levels and responses of thyroid-stimulating hormone (TSH) to TRH stimulation was observed in all cases of both groups. These results suggest that the level of thyroid hormone has little pathogenic role in PRL secretion in euthyroid patients with amenorrhea-galactorrhea, in contrast to its marked effect in hypothyroid patients with amenorrhea-galactorrhea.

Lack of demonstrable tumor growth in progressive hyperprolactinemia.

Prolactin has been regarded as an excellent tumor marker for patients harboring prolactinomas, and a significant rise in the basal prolactin level is generally regarded as being commensurate with tumor growth. This report describes a case in which the basal serum prolactin level rose from 250 ng/ml to 1,528 ng/ml over a 10-year follow-up period in the absence of definitive therapy. Three sequential contrast-enhanced direct coronal computed tomographic scans obtained over a four-year period failed to demonstrate any evidence of growth of the 5 mm microprolactinoma. Progressive hyperprolactinemia may not be synonymous with tumor growth in patients with microprolactinomas.

Primary empty sella, galactorrhea, hyperprolactinemia and renal tubular acidosis.

Discussed here is a 41 year old woman with galactorrhea associated with the empty sella syndrome and mild renal tubular acidosis. Basal serum prolactin (PRL) levels were normal, but a 24 hour serum PRL secretory profile demonstrated an increased mean PRL concentration. Serum PRL was appropriately suppressed by the administration of L-dopa; however, chlorpromazine stimulation resulted in a blunted serum PRL response. Pituitary luteinizing hormone, follicle stimulating hormone, ACTH and thyroid stimulating hormone levels were normal. Thus, galactorrhea associated with an enlarged sella does not establish the diagnosis of a pituitary tumor, and pneumoencephalography must be performed to exclude the empty sella syndrome.

Use of bromocriptine in hyperprolactinaemic anovulation and related disorders.

Bromocriptine has been successfully used to treat hyperprolactinaemic disorders of ovulation; treatment with 5.0 to 7.5 mg daily results in normalisation of serum prolactin concentration and restoration of ovulatory menstruation in most patients with hyperprolactinaemic amenorrhoea or oligomenorrhoea. It is equally effective in hyperprolactinaemic patients with pituitary tumours as in those with normal pituitary x-rays, but the choice of bromocriptine as primary treatment in the former group (especially in those patients who desire pregnancy) is a matter of some controversy and requires careful judgement. Bromocriptine has also been used, with reported success, in infertility associated with luteal insufficiency, the polycystic ovary syndrome, normoprolactinaemic amenorhoea and ovulatory infertility. However, its role in the treatment of these disorders will remain uncertain until more extensive, adequately controlled clinical trials are availabe.

Galactorrhea and amenorrhea in a patient with an empty sella.

A report of a patient with amenorrhea and galactorrhea who was shown, by tomopneumoencephalogram, to have an empty sella is presented. Endocrinologic testing revealed only a blunted human growth hormone response to insulin-induced hypoglycemia and acyclicity of plasma gonadotropins. Thyroid testing, ACTH, and metopirone responses were normal. In addition, plasma prolactin levels were found to be within the normal range. Most significantly, after the pneumoencephalogram the patient's menses returned and have continued at regular monthly intervals for 6 months. During this time there has been a significant decrease in the galactorrhea. This is the first patient described with an empty sella and galactorrhea. The clinical and endocribologic aspects of the empty sella are discussed.

Intrasellar subarachnoid herniation or empty sella associated with galactorrhea.

Eight of 115 patients with empty sella had concurrent galactorrhea. All 8 patients had abnormal sellae, and the diagnosis of empty sella was made by polytome pneumoencephalography. There were no obvious endocrine dysfunctions, but 2 patients had elevated prolactin levels. One mechanism for production of galactorrhea may involve compression of the hypothalamus and/or pituitary stalk; this was suggested by most of our observations. There may be a coincidental association of empty sella with galactorrhea, and this association is probably more common than previously noted. Evaluation of patients with galactorrhea and abnormal sellae by polytome pneumoencephalography is emphasized.

Ovulation induction in amenorrheic women.

Seventy-six patients with primary or secondary amenorrhea who wished to conceive were treated with clomiphene citrate, 2-Br-alpha-ergocryptine, and/or human menopausal gonadotropins (hMG). Of these 71 patients who received clomiphene citrate, 39 (55%) ovulated. Of these 71 patients, 52 had withdrawal uterine bleeding following IM progesterone, and 38 (73%) ovulated; only 1 of the 19 who did not bleed ovulated (P less than 0.001). Ovulation occurred in the former group of patients whether or not they had galactorrhea. Of the 32 patients who failed to ovulate despite treatment with the maximal dose of clomiphene, 250 mg/day for 5 days, 26 received hMG-hCG. All 26 ovulated and 15 conceived. All 8 patients with amenorrhea-galactorrhea who were treated either primarily or secondarily with bromergocryptine ovulated, and 4 conceived. Therefore, the drug of choice for ovulation induction in amenorrheic patients depends on 1) the presence of withdrawal bleeding after progesterone and 2) the presence of galactorrhea. In all patients with progesterone withdrawal bleeding with or without galactorrhea, the initial treatment of choice is clomiphene citrate. In the absence of withdrawal bleeding, hMG should be administered if galactorrhea is absent, and bromergocryptine should be administered if galactorrhea is present.

Galactorrhea, amenorrhea, hyperprolactinemia, and an empty sella.

Increased serum prolactin (hPRL) and increased volume of the sella turcica as detected by roentgenography are compatible with a pituitary adenoma. The empty sella syndrome can increase sella volume, but is usually associated with minimal, if any, endocrine dysfunction. The present case details a young woman with amenorrhea, galactorrhea, elevated serum hPRL, and roentgenographic evidence of an enlarged sella turcica. Pneumoencephalography with hypocycloidal polytomography is interpreted as both an empty sella, and evidence of a pituitary adenoma. The etiology and endocrine findings in the empty sella syndrome are discussed.

Sella turcica abnormalities in an anovulatory population.

In a series of 177 anovulatory patients, x-ray studies of sella turcica revealed 4 patients with pituitary adenomas and 1 with an empty sella. Galactorrhea was present in 15 patients (8.5%) of the total series, but 4 of the 5 patients with pituitary abnormalities also showed galactorrhea. As patients were frequently unaware of the presence of milk in their breasts, careful examination by the physician will delineate a population at high risk for pituitary abnormalities. Clinical and endocrinologic characteristics of the 5 patients with pituitary abnormalities are presented and their management is discussed.

Retrospective evaluation of human menopausal gonadotropin and human chorionic gonadotropin induction of ovulation in galactorrheic and hyperprolactinemic women.

A retrospective study on the success of induction of ovulation with human menopausal gonadotropin and human chorionic gonadotropin (hMG/hCG) in 267 women was performed. Galactorrheic women had a higher pregnancy rate (55%) than nongalactorrheic women (22%). Galactorrhea was a far better indicator of the success of the treatment than hyperprolactinemia at present. The results obtained may suggest that in "bromocriptine failure" it is not mandatory to lower prolactin levels prior to induction of ovulation with hMG/hCG, and these women may be treated with menotropins alone.

Dissociation of serum prolactin response to sequential thyrotropin-releasing hormone and chlorpromazine stimulation in patients with primary empty sella syndrome.

The presence of galactorrhea and/or hyperprolactinemia in patients with the primary empty sella syndrome (PESS) has been proposed to be of hypothalamic etiology. To further elucidate this possible mechanism, sequential testing of 19 subjects with PESS with 500 micrograms thyrotropin-releasing hormone (TRH), followed by the injection of 0.7 mg/kg chlorpromazine (CPZ) 150 minutes later, was compared with results obtained in 6 patients with idiopathic galactorrhea (IG) and 3 normal adult women in the early follicular phase of the menstrual cycle. The thyroid-stimulating hormone and prolactin (PRL) response to TRH was similar in all three groups. The mean maximal increase of serum PRL following CPZ, however, was 16.1 +/- 18.5 ng/ml (standard deviation) in the PESS group, whereas the mean maximal PRL response was 68.6 +/- 40.9 ng/ml in subjects with IG and 67.7 +/- 48.1 ng/ml in the seven normal women. The impaired responsiveness of CPZ in the PESS group was significant (P less than 0.05) when compared with the normal CPZ response in the other two groups. The results of this study suggest that patients with PESS may have hypothalamic dysfunction, and that sequential testing of subjects with TRH and CPZ may be of value in differentiating patients with PESS from those with IG.