Diagnosis of prolactin-secreting pituitary microadenoma.

Four women with secondary amenorrhea associated with hyperprolactinemia were studied. Baseline hormonal evaluation, including serum FSH, serum LH, TSH, T3, T4, and plasma cortisols were normal. Plain sella turcia x-rays were also normal. Prolactin-secreting pituitary microadenomas were found in all of the patients only after further diagnostic studies were done. These studies included polytomography of the sella turcia, dynamic pituitary testing of growth hormone reserve, ACTH reserve, gonadotropin reserve, and prolactin suppression with L-dopa. The early diagnosis of a small prolactin-secreting adenoma may be possible if several diagnostic criteria are ulilized. The most sensitive techniques available are: (1) polytomography, (2) the magnitude of plasma prolactin evaluation, and (3) the failure of suppression of prolactin secretion with L-dopa. Our findings emphasize the importance of an extensive evaluation of all women with amenorrhea associated with hyperprolactinemia.     

Evaluation and treatment of patients with prolactin-secreting pituitary tumors

Six women with secondary amenorrhea and hyperprolactinemia, four of whom had associated galactorrhea, were studied. Four were found to have prolactin-secreting pituitary microadenomas and two had macroadenomas. Suppression of prolactin secretion and stimulation of prolactin, serum growth hormone and thyroid-stimulating hormone secretion were studied, and gonadotropin and adrenocorticotropic hormone reserves were evaluated. The most sensitive techniques available for the diagnosis of pituitary adenomas in patients with amenorrhea and hyperprolactinemia appear to be the measurement of the magnitude of plasma prolactin elevation and hypocycloidal tomography of the sella turcica. The dynamic function tests proved to be of little diagnostic, but of great prognostic, value for patients with small pituitary tumors.     

Coexistent empty sella and prolactin-secreting microadenoma

The empty sella turcica may be found in people with no antecedent history of intracranial disease, as well as in those with known pituitary pathology or following therapy to the pituitary gland. We have evaluated 3 women with galactorrhea and hyperprolactinemia, 2 of whom had amenorrhea. Each had an empty sella. In all cases polytomograms demonstrated asymmetry of the sella floor with focal bony erosion, conventional pneumoencephalography showed intrasellar air, and polytomographic pneumoencephalography confirmed air limited to one side of the pituitary fossa with tumor and/or residual normal tissue on the opposite side. In 2 patients who had extensive endocrine evaluation, pituitary function was normal with the exception of hyperprolactinemia. Transsphenoidal excision of microadenomas resulted in postoperative normalization of the serum prolactin concentration and resumption of regular menses in the previously amenorrheic women.     

Spontaneous regression of prolactin-producing pituitary adenomas

Two women evaluated for amenorrhea, galactorrhea, and hyperprolactinemia had radiographic changes of the sella turcica (localized erosion on trispiral tomography) suggestive of a pituitary tumor. Both patients experienced spontaneous regression of apparent prolactin-secreting adenomas with a marked decrease in the quantity of galactorrhea and a reduction of serum prolactin concentrations to the normal range. One patient noted a marked improvement of headaches and spontaneous menses resumed in the other patient.     

Hyperprolactinemia: comparison of thyrotropic-releasing hormone and tomography

A group of 95 women with unexplained hyperprolactinemia (over 20 ng/mL) underwent radiologic examination of the sella turcica with hypocycloidal polytomography (N = 58), computed axial tomography (N = 8), or both (N = 29). All patients also underwent a thyrotropin-releasing hormone (TRH) stimulation test, with serum prolactin (PRL) measurement before and 20 and 30 minutes after a 500-micrograms intravenous bolus of TRH. Their PRL responses were compared with those of two control groups, nine normal women in the follicular phase of the menstrual cycle, and 13 women in the first five months of gestation with pregnancy-related hyperprolactinemia. Both control groups exhibited PRL increases with 95% confidence limits at least 200% above baseline levels. In all, 12 patients from the study group also had a normal PRL response (more than a 200% increase) to TRH, and none of these women had tomographic findings consistent with a pituitary tumor. The remaining 83 women all had diminished or absent PRL increases after TRH administration; 46 (55%) of these patients had radiographic evidence of an adenoma, whereas 37 (45%) had no clear signs of a tumor on either polytomography or computed axial tomography. No patient with a baseline PRL level in excess of 60 ng/mL had a normal PRL response to TRH. The results of the study indicate that 1) in patients with PRL between 20 and 60 ng/mL, a normal TRH test can be relied upon to avoid the expense and radiation of tomography (computed axial tomography or polytomography), 2) there is no benefit to be obtained in performing a TRH test in patients with a baseline PRL level over 60 ng/mL, and 3) about 45% of patients with hyperprolactinemia and an abnormal TRH test have a normal computed tomography or polytomography. These patients may have a small adenoma, and thus warrant closer follow-up than patients with a normal TRH test.     

Treatment of functional amenorrhea-galactorrhea with 2-bromoergocryptine.

The present study was undertaken to investigate not only the effectiveness of bromoergocryptine therapy in 13 women with amenorrhea-galactorrhea and hyperprolactinemia without evidence of organic pathology, but also to assess the value of pretreatment evaluation in predicting the response to therapy. Sella turcica tomography, base line serum follicle-stimulating hormone, luteinizing hormone (LH), thyroid-stimulating hormone, T4, plasma cortisol levels, and the growth hormone reserve were normal in all patients. The pretreatment administration of LH-releasing factor (LRF) (100 microng subcutaneously) resulted in either a normal or excessive release of LH. On bromoergocryptine therapy, cyclic menses were reintiated in 10 of the women, while conception occurred prior to reinitiation of menses in the remaining three women. The time required for resumption of menses or conception on therapy correlated well with the magnitude of gonadotropin response to LRF. No correlation was seen with pretreatment prolactin levels nor with the degree of suppression of prolactin during bromoergocryptine therapy. In four women the mean prolactin levels during therapy were above normal, and in one patient prolactin levels approached pretreatment values during therapy. The initiation of cyclic menses despite continued hyperprolactinemia may indicate a possible direct effect of bromoergocryptine on hypothalamic LRF secretion as a partial explanation for its therapeutic action. On discontinuation of bromoergocryptine therapy, serum prolactin levels rapidly returned to pretreatment values or higher in all of the patients studied. In contrast to previous studies in which amenorrhea recurred in all patients after discontinuation of therapy, three of our patients maintained cyclic menses despite continued hyperprolactinemia. The recurrence of hyperprolactinemia after discontinuation of bromoergocryptine would indicate a persistent autonomy of the mechanisms involved. Periodic endocrine evaluation will be necessary to substantiate the presence or absence of pituitary microadenoma in these women.     

Evaluation of the pituitary. Patients with suspected prolactin-producing tumors

We have reviewed our experience in the radiographic and ophthalmologic evaluation of 1001 patients with symptoms suggesting the presence of a pituitary, prolactin-secreting adenoma. Twenty-seven patients had abnormal or suspicious radiographic examination of the sella turcica. Twenty-two of those had hyperprolactinemia. In only one instance was an abnormality noted on polytomography that was not seen on a conventional four-view study of the skull. Based on these findings, a four-view plain conventional radiographic assessment of the skull suffices as a screening procedure in patients with amenorrhea, galactorrhea, or both. Thin section tomography should be reserved to more thoroughly evaluate those patients with elevated serum prolactin concentrations and/or abnormal conventional radiographs. We found visual field testing to be of little value as an initial screening procedure in these patients.     

Nonfunctioning pituitary macroadenoma presenting with mild hyperprolactinemia and amenorrhea.

OBJECTIVE: To describe a patient with a clinically nonfunctioning pituitary macroadenoma who presented with mild hyperprolactinemia and amenorrhea. DESIGN: Case report. SETTING: Tertiary care medical facility. PATIENT(S): A 44-year-old woman with a 6-month history of amenorrhea. INTERVENTION(S): Pituitary testing, magnetic resonance imaging of the sella turcica, and transsphenoidal surgery. MAIN OUTCOME MEASURE(S): Pituitary function testing, magnetic resonance imaging, and return of menstrual cycles. RESULT(S): Baseline laboratory data revealed a serum prolactin level of 34 ng/mL (normal range, 3-20 ng/mL), normal thyroid function test results, and an FSH level of 6.7 mIU/mL. A second fasting prolactin level was 48 ng/mL. Magnetic resonance imaging of the sella turcica revealed a pituitary macroadenoma measuring 1.4 x 3.2 cm. Further testing of baseline pituitary function revealed normal findings. The patient underwent an uncomplicated transsphenoidal resection of the pituitary tumor and maintained normal pituitary function. Pathologic evaluation revealed a pituitary adenoma that stained positive for FSH and focally for the alpha subunit. The adenoma stained negative for GH, prolactin, ACTH, LH, and TSH. CONCLUSION(S): This patient had a nonsecreting gonadotroph macroadenoma that resulted in hypogonadotropic hypogonadism along with mild hyperprolactinemia, presumably secondary to interruption of normal transport down the pituitary stalk.     

The significance of galactorrhea in patients with normal menses, oligomenorrhea, and secondary amenorrhea

Thyroid-stimulating hormone and prolactin (PRL) were measured in a group of 149 women with galactorrhea. Three of these patients were found to have primary hypothyroidism. In the remaining 146 patients, the PRL assay was correlated with the menstrual history and the results of hypocycloidal polytomography. Sixty-two per cent of these patients had hyperprolactinemia and 35 per cent had abnormal tomograms. Nine patients with abnormal x-rays had normal prolactin levels. None of the patients with normal menses and normal PRL was found to have an abnormal x-ray. Fourteen of the 15 patients with PRL levels greater than 200 ng. per milliliter had abnormal tomograms. Almost 70 per cent of patients with secondary amenorrhea and low estrogen status had abnormal x-rays. In patients with oligomenorrhea and secondary amenorrhea with normal estrogen status, it was not possible to differentiate between patients with normal or abnormal tomograms based on the level of serum PRL. Polytomography remains the single most important diagnostic test in establishing the presence of a pituitary tumor.     

Prolactin and thyroid-stimulating hormone responses to thyrotropin-releasing hormone in cases of hyperprolactinemia with normal and abnormal sella tomograms

An intravenous bolus of 500 micrograms of thyrotropin-releasing hormone (TRH) was used to test prolactin and thyroid-stimulating hormone (TSH) responses in normoprolactinemic patients and in hyperprolactinemic patients with normal and abnormal sella turcica. The prolactin response showed a mean increment of 64.1 +/- 46.3 ng/ml in normoprolactinemic women. In patients with hyperprolactinemia, the mean increment was 14.1 +/- 22.4 ng/ml and 13.8 +/- 33.1 ng/ml for patients with normal and abnormal sella, respectively. The difference in the prolactin response between the normoprolactinemic patients and either group of hyperprolactinemic patients is significant (P less than 0.005). The mean baseline TSH in normoprolactinemic patients is significantly higher than in patients with hyperprolactinemia with normal and abnormal sella. The mean increment of TSH after TRH stimulation is significantly higher in normoprolactinemic patients than in either group of patients with hyperprolactinemia (P less than 0.005). These results suggest an inhibitory action of hypothalamic dopamine on the response of both prolactin and TSH to TRH in patients with hyperprolactinemia. The hypothalamic dopamine mechanism might also be the factor leading to suppression of baseline TSH levels in hyperprolactinemic patients. In addition, these results suggest that patients with hyperprolactinemia, with or without changes in the sella turcica, might have various degrees of the same pathology affecting the lactotropes.     

Pituitary responses to synthetic luteinizing hormone-releasing hormone in thirty-four cases of amenorrhea or oligomenorrhea associated with galactorrhea.

Pituitary responses to 100 mcg. of luteinizing hormone-releasing hormone (LH-RH) administered subcutaneously were studied in 34 cases of amenorrhea or anovulatory oligomenorrhea associated with galactorrhea. Twenty-six patients had pituitary prolactin-secreting tumors (group I); eight patients had a normal sella turcica and remission of the syndrome either spontaneously or after thyroid replacement therapy (group 2). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to LH-RH were variable in each group of patients, ranging from poor to exaggerated, and no statistically significant difference could be observed between the groups. A positive correlation was found between FSH pituitary responses and basal FSH levels (r=0.50; P less than 0.01). No positive correlation was observed between either LH responses and basal LH levels or the gonadotropin responses and plasma estradiol levels, serum prolactin concentrations, duration of amenorrhea, or size of the tumor.     

Clinical response to CB-154 and the pituitary response to thyrotropin-releasing hormone-gonadotropin-releasing hormone in patients with galactorrhea-amenorrhea.

Ten patients with galactorrhea and amenorrhea were treated with 2-bromo-alpha-ergocryptine (CB-154). All patients had normal anteroposterior and lateral x-rays of the sella turcica and normal or low gonadotropin levels. Before treatment, serum prolactin (PRL) levels were between 80 and 1575 ng/ml. Prior to initiating therapy, six patients were further evaluated by the intravenous administration of thyrotropin-releasing of a pituitary etiology in all patients. During treatment, PRL levels were measured at monthly intervals. After 1 month, serum PRL concentrations were reduced between 13% and 99%. In eight subjects there was complete cessation of galactorrhea. During treatment, nine patients resumed ovulatory menstrual cycles and three patients conceived. After discontinuing therapy, five of seven subjects had a recurrence of galactorrhea, amenorrhea, and hyperprolactinemia.     

Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea

Over a period of two and a half years, 34 women with galactorrhea or amenorrhea, all with an abnormal sellar polytomogram, underwent transsphenoidal microsurgical exploration of the sella. Eighteen women and microadenomas (less than or equal to 1 cm. in diameter), seven had macroadenomas (greater than than 1 cm. in diameter), and five had unidentified lesions. Only one women had a normal pituitary gland. Three women had cryosurgery without biopsy. Preoperatively, hyperprolactinemia occurred in 24 of 25 women with adenomas and two of five with nonadenomatous lesions. There were no operative deaths. Significant morbidity occurred in only three patients, none of whom had microadenomas. Postoperatively, menses resumed in 16 of the 17 women with microadenomas and in two of the seven with macroadenomas who presented with amenorrhea. Galactorrhea disappeared in 15 of the 17 women with microadenomas and in four of the seven with macroadenomas who presented with galactorrhea. In five patients with unidentified lesions, a return of menses occurred in two of four with previous amenorrhea, and galactorrhea abated in two of three who presented with lactation. We conclude that sellar polytomography in women with hyperprolactinemia is a useful technique technique for the diagnosis of pituitary adenomas, a lesion which may occur more frequently than previously realized. In addition, transsphenoidal microresection of microadenomas is safe and effective.     

Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.     

Hyperprolactinemia and polycystic ovarian syndrome.

Prolactin and pituitary gonadotropin levels were studied in eight patients with polycystic ovarian syndrome. All women were of reproductive age and had had menstrual disorders since menarche. Three patients had hyperprolactinemia with or without galactorrhea and tomograms of the sella turcica revealed pituitary microadenomas. The remaining five patients with normal baseline prolactin levels had a prolactin stimulation test which used 25 mg of thorazine per os, and a prolactin suppression test using l-dopa 500 mg per os. Analysis of the results of these tests and a comparison with tests performed in five normal individuals used as controls showed significantly different responses in the two groups of women. The preliminary information obtained indicates that an abnormal prolactin secretion status may exist in the polycystic ovarian syndrome.     

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.     

Hyperprolactinemia: etiology,diagnosis, and management

Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis. A prolactinoma is the most common cause of chronic hyperprolactinemia once pregnancy, primary hypothyroidism, and drugs that elevate serum prolactin levels have been excluded. Patients can present with hypogonadism, infertility, galactorrhea, osteopenia, and mass effects of the tumor. When hyperprolactinemia is confirmed, a cause for the disorder needs to be sought. This involves a careful history and examination, followed by laboratory tests and diagnostic imaging of the sella turcica. The goals of treatment are to normalize prolactin levels, restore gonadal function, and reduce the effects of chronic hyperprolactinemia. Dopamine agonists are the treatment of choice for the majority of patients. Transsphenoidal surgery is usually reserved for patients who are intolerant of or resistant to dopamine agonists or when hyperprolactinemia is caused by non-prolactin-secreting tumors compressing the pituitary stalk. Cabergoline has been shown to be more effective and better tolerated than bromocriptine. However, there are more data on the safety of the latter drug during pregnancy and bromocriptine, therefore, remains the treatment of choice in hyperprolactinemic women wishing to conceive.     

Treatment of hyperprolactinemia-anovulation syndrome

Twelve patients with amenorrhea-galactorrhea and hyperprolactinemia are presented. The mean serum prolactin level was 175 ng/ml (range, 37 to 575 ng/ml). Basal gonadotropin levels were normal in all patients. Serum estradiol levels were normal in three women and reduced in nine. The response to luteinizing hormone-releasing hormone was normal in 10 patients and the response to clomiphene citrate was reduced in all women. Radiologic evaluations of the sella turcica and neurologic examinations were performed in all cases. Patients were treated with bromocryptine (2-bromo-alpha-ergocryptine, CB-154), 2.5 to 10 mg/day, for 5 to 35 weeks. In 10 patients normalization of the menstrual cycle was restored, and 9 patients were ovulatory. The galactorrhea ceased or was improved in all cases. Four patients who were treated for infertility became pregnant after one to three treatment cycles. In all cases prolactin levels were normalized (mean level, 10 ng/ml). Side effects were slight and were experienced only on initiation of therapy. The role of prolactin and the significance of normalization of plasma prolactin levels are discussed. Lowering prolactin secretion with bromocryptine allows resumption of normal gonadal function.     

Galactorrhea and hyperprolactinemia during treatment of polycystic ovary syndrome

The serum concentration of prolactin and the presence of galactorrhea were evaluated systematically in a prospective study of the effect of medroxyprogesterone acetate (MPA) in polycystic ovary syndrome (PCO). In 21 patients, the diagnosis of PCO was made by laparoscopy. Three women presented with galactorrhea and increased prolactin levels, 2 had galactorrhea with normal prolactin levels, and 3 had an isolated elevation in the serum concentration of prolactin. Treatment with MPA induced galactorrhea in 10 additional patients. Elevated levels of prolactin were detected in 18 of the patients during treatment. There was no correlation between the score for galactorrhea and the level of prolactin. Tomograms of the sella turcica were abnormal in 3 of 8 patients with hyperprolactinemia. The authors conclude that galactorrhea and/or hyperprolactinemia are important side effects of MPA in patients with PCO.     

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.