Management of patients with hyperprolactinemia and normal or abnormal tomograms

Forty women with hyperprolactinemia with and without radiologic evidence of prolactin-secreting pituitary adenoma were prospectively treated with bromocriptine. On the basis of tomographic studies, the patients were divided into either a microadenoma group (N = 19) or no adenoma group (N = 21). Both groups had similar distributions as to obstetric history, menstrual abnormalities, levels of baseline serum luteinizing hormone, follicle-stimulating hormone, and thyrotropin. Patients in the adenoma group had significantly higher (p less than 0.001) baseline serum prolactin levels (173 +/- 4.4 ng/ml) than those of patients without adenoma (61.1 +/- 4.5 ng/ml). Patients without an adenoma required significantly less bromocriptine (5 to 7.5 mg) (p less than 0.005) to normalize serum prolactin or establish a pregnancy than did those who had an adenoma (5 to 20 mg). Similarly, patients with adenoma resumed ovulatory cycles (8.7 +/- 1.2 versus 5.7 +/- 0.06 weeks), had their galactorrhea disappear (11.3 +/- 2.1 versus 5.6 +/- 1.1 weeks), and become pregnant (16.2 +/- 2.5 versus 9.8 +/- 1.5 weeks) in a significantly longer time (p less than 0.01) than did those who had no adenomas. There was no significant difference in the pregnancy rate between the groups, and the overall rate was 86% of 28 patients desiring pregnancy. No complications were observed during pregnancy. The conclusion is that both patients with and those without radiologic evidence of a prolactin-secreting pituitary adenoma can be safely treated with bromocriptine. In addition, the resumption of ovulatory cycles is more important than the absolute normalization of serum prolactin.     

The incidence of complications during pregnancy after treatment of hyperprolactinemia with bromocriptine in patients with radiologically evident pituitary tumors.

The course of pregnancy achieved after bromocriptine therapy is described in nine patients with radiologically evident prolactin-secreting pituitary tumors. In six patients no complications occurred. No changes in sellar size or secondary endocrine deficiencies developed. In three patients, however, complications developed between the 22nd and 24th weeks of pregnancy. Despite prior external pituitary irradiation, one patient developed transient bitemporal hemianopsia and one patient had apoplexy of the pituitary tumor with transient paresis of the left abducens nerve. A third patient developed parasellar expansion of the pituitary tumor with bone destruction and paresis of the right abducens and oculomotor nerves. After transsphenoidal surgery the paresis of both nerves disappeared. Microscopically, the tissue removed at surgery was a chromophobe adenoma with focal fibrosis and calcifications without recent hemorrhages. In the course of more than 100 pregnancies achieved in The Netherlands after bromocriptine therapy, five patients reportedly developed complications of the pituitary tumor. At present, patients in whom complications can be expected cannot be predicted by the size or configuration of the sella turicica or the magnitude of elevation of the plasma prolactin level. In two patients external pituitary irradiation did not prevent complications during pregnancy.     

Outcome of Treatment with Bromocriptine in Patients with Hyperprolactinaemia

Results in 136 hyperprolactinaemic women who presented with infertility, amenorrhoea, menstrual irregularities and/or galactorrhoea are reported. There was radiographic evidence of pituitary microadenoma in 21 (15.4%) patients and 5 (3.7%) had macroadenoma. Four patients were taking antidepressants, 2 antihypertensive drugs and 7 had taken oral contraceptives for a period of 6 months to 5 years. The remaining patients had no obvious cause for elevated prolactin levels. Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy. The patients without an adenoma required a significantly smaller dose of bromocriptine (2.5-5.0 mg) (p less than 0.005) than those with an adenoma. Galactorrhoea disappeared in all 64 patients within 2-4 months of treatment, sixty-six (71%) of the 93 patients who desired pregnancy achieved it within 3 to 8 months of bromocriptine therapy; 32 of these patients received additional treatment with clomiphene and human chorionic gonadotrophins for induction of ovulation. In the remaining 70 patients menstruation became regular and ovulation was evident in 40% of them. There was no significant difference in the pregnancy rate between the patients with or without pituitary adenoma. Similarly, presence of galactorrhoea or a high level of prolactin did not influence the pregnancy rate. No complications were observed during pregnancy related to pituitary adenomas; 8 (12%) pregnancies ended in first trimester abortion. No lethal congenital fetal abnormalities were observed in the patients treated with bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Outcome and long-term effects of pregnancy in women with hyperprolactinaemia.

Twenty-four women with high circulating prolactin became pregnant on 39 occasions, of which 32 ended in delivery. Sixteen patients showed radiological evidence of pituitary tumour, 6 exhibited a normal CT and 2 had an empty sella. The pregnancies were induced in 4 patients after successful pituitary surgery, in 3 after surgery and medical treatment, and in the rest by bromocriptine (16) long-acting repeatable bromocriptine (1) and methergoline (1). No major complications related to hyperprolactinaemia or its treatment were observed during pregnancy in the patients or offspring. Prolactin after pregnancy was lower than before (basal 95 micrograms/l, after 1st pregnancy 38 micrograms/l P < 0.002, after 2nd pregnancy 24 micrograms/l P < 0.005 compared to basal prolactin); this prolactin reduction tended to be greater in the 9 multiparous patients, but did not attain statistical significance, probably because the number of multiparous patients was too small. A new empty sella developed after delivery in 4 women and persisted in another 2, all of which were medically treated; prolactin fell in all 6 cases normalizing in 3; 4 of these patients had undergone two or more pregnancies. The mean period of follow-up from the last pregnancy was 41.6 months (8-101). These data suggest that pregnancy may hasten a tendency to spontaneous improvement of hyperprolactinaemia, and multiparity may be beneficial in this way.     

Hyperprolactinemia and pregnancy. Clinical series

We report 15 cases of pregnancy in 11 patients with hyperprolactinemia. These patients initially went to our Gynecologic Endocrinology Center for various menstrual troubles. They were all treated with bromocriptine, except one whose hyperprolactinemia was diagnosed when she had already started a gonadotropin therapy, since HPRL assays performed elsewhere had given normal results. In 6 patients we diagnosed prolactin-secreting pituitary adenoma. Only two patients underwent adenomectomy. All patients gave up bromocryptine as soon as their pregnancy was detected. Two patients had two subsequent pregnancies, another one had three. All pregnancies were single. The only twin pregnancy followed a gonadotropin therapy. One of the 15 pregnancies ended with abortion at the 12th week; another one (twin) with spontaneous delivery at the 37th week; 13 with term-delivery. They all had physiologic courses, except for one case of threatened abortion and one case of diabetes insipidus at the 9th month. None of the 15 newborns (7 SGA and 8 AGA) showed malformations. No sign or symptom of tumour growth was detected in the patients affected by pituitary adenoma.     

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.     

Chronic treatment with 2-alpha-bromocriptine in women with the hyperprolactinemic syndrome

Seventeen hyperprolactinemic patients with or without radiological evidences of a pituitary adenoma, were submitted to a long term (7-36 months) suppressive treatment with bromocriptine. Nine patients conceived during the treatment. All of them had a normal pregnancy and delivered normal babies. In all patients (with the exception of one-patient Z.S.) the post treatment prolactin levels were significantly lower than the pre-treatment values suggesting a long lasting suppressive effect of this dopamine agonist on the pituitary lactotrophs. Three of the patients followed throughout a whole menstrual cycle (3-10 months after discontinuation of therapy) showed presumptive signs of ovulation in spite of relatively elevated circulating immuno-reactive prolactin concentrations. These observations might suggest a modification of the biological activity of the hormone, possibly related to the chronic treatment with bromocriptine.     

The Dilemma of Mild Hyperprolactinaemia

Summary: Ninety-eight women with mild hyperprolactinaemia (<4N) were followed for a mean duration of 5.5 years. Where pregnancy was desired treatment with bromocriptine (pM clomiphene) was effective in 87%. Following cessation of bromocriptine therapy almost one-third had a 'spontaneous' resolution of hyperprolactinaemia and resumed cyclical menstrual activity and fertility.
Pituitary tumours were identified on coned-view assessment in 9% of patients at the time of presentation and a further 10% during follow-up. Although some of these latter tumours may have been diagnosed earlier had CAT scans been performed routinely in all hyperprolactinaemic patients, such a policy would be hard to justify for those with mild hyperprolactinaemia as the tumours were small, produced no harmful effects, and would almost certainly have responded to bromocriptine should this have been administered.
All patients found to have pituitary tumours and given bromocriptine, showed no evidence of tumour progression subsequently, even where pregnancy occurred and the bromocriptine therapy was ceased. In addition, patients without pituitary tumours who were given bromocriptine to achieve pregnancy, were less likely to develop tumours during follow-up even when pregnancy had occurred.
Bromocriptine therapy can thus be justified in mildly hyperprolactinaemic patients to reduce troublesome galactorrhoea, achieve pregnancy, improve the chance of 'spontaneous' resolution of the menstrual problem and infertility, control or reduce tumour growth where a pituitary tumour has been identified, and reduce the risk of tumour development in patients with normal radiographs at the time of presentation.     

Spontaneous pregnancy after a pregnancy induced by treatment in hyperprolactinemic women

The relationship between spontaneous pregnancy of hyperprolactinemic patients after a first pregnancy induced by treatment and their serum prolactin levels was examined. Of the 100 patients with hyperprolactinemia studied, 74 became pregnant after treatment; namely, 20 transsphenoidal adenomoidectomy for pituitary prolactinoma (group 1), 26 on treatment with bromocriptine for pituitary prolactinoma (group 2), and 28 on treatment with bromocriptine for hyperprolactinemia without prolactinoma (group 3). After delivery in the first pregnancy, the rates of menstrual restoration and subsequent spontaneous pregnancy in group 1 (72.2% and 75.0%) were significantly (p less than 0.05) higher than those in group 2 (32.0% and 25%) and group 3 (13.6% and 18.2%). The serum levels of prolactin after the first pregnancy and weaning were significantly (p less than 0.05) lower in patients with subsequent spontaneous pregnancy than in patients without spontaneous pregnancy in each group, and the levels in patients with spontaneous pregnancy were significantly (p less than 0.05) lower in group 1 (15.2 +/- 8.8 ng/ml) than in group 2 (46.6 +/- 2.9 ng/ml). These data suggest that the transsphenoidal adenomoidectomy for pituitary prolactinoma may be better than bromocriptine treatment for recovery of reproductive function.     

Treatment with hachimijiogan, a non-ergot Chinese herbal medicine, in two hyperprolactinemic infertile women

Two hyperprolactinemic infertile women, one with and one without a pituitary adenoma, who were resistant to bromocriptine treatment, were treated orally with Hachimijiogan, a Chinese herbal medicine. This treatment reduced the serum prolactin level, resulting in a normal ovulatory cycle and pregnancy, without side effects.     

Clinical course and outcome of pregnancy in twenty-five patients with pituitary microadenomas

Twenty-five patients, aged 23-39, with amenorrhea of 18 to 168 months' duration, galactorrhea, hyperprolactinemia (prolactin levels of 45 to 370 ng/ml), and radiologic evidence of a pituitary microadenoma, were treated with bromocriptine or lergotrile, 7.5 mg daily for 2 to 16 weeks until conception occurred. All conceived and were delivered of infants. Follow-up during pregnancy included frequent office visits and monthly visual field examinations from the sixth month until delivery. All the pregnancies resulted in single infants and uneventful and no neurological or visual symptoms developed. All infants born were normal. Twelve patients breast-fed while the others did not by choice. Menstrual function resumed in two patients after delivery and one of them subsequently conceived spontaneously. We believe that the presence of a pituitary microadenoma without neurological or visual symptoms should not be a contraindication to ovulation induction and pregnancy. Most of such pregnancies are uneventful. If symptoms arise during pregnancy, they can be treated medically or, in extreme emergencies, surgically.     

Enlargement of a prolactin-secreting pituitary microadenoma during bromocriptine treatment

Summary. A patient with prolactin-secreting pituitary microadenoma was treated with bromocriptine, 5 mg daily for 1 year. Despite normalization of prolactin levels throughout the treatment period, partial destruction of the sellar floor with growth of the adenoma into sphenoidal sinus were evident in a control tomography performed at the end of the treatment.     

The effects of pregnancy on patients with hyperprolactinemia

Seventy women with amenorrhea with or without galactorrhea associated with high serum prolactin levels and radiologic evidence of pituitary tumors were treated with transsphenoidal tumor resection. The prolactin level was measured in 29 patients before pregnancy, at 3 months post partum or cessation of lactation, and at 6-month intervals thereafter. The results were compared to those of 18 patients who had hyperprolactinemia but no demonstrable radiologic evidence of a pituitary tumor and who responded to bromocriptine and conceived. Our investigations showed that operation resulted in normalization of serum prolactin levels in 74% of patients. Forty of the 49 patients less than 36 years old conceived (80%). Five of 29 patients who were studied before and after operation as well as after delivery showed an increase in serum prolactin levels post partum and persistent amenorrhea suggesting recurrence. Six of the 18 patients who became pregnant after bromocriptine also showed a significant rise in serum prolactin levels above the treatment level. None of the patients in the two groups developed visual changes or symptoms or radiologic changes during pregnancy. These results showed that transsphenoidal operation has a high incidence of success, but some patients may show a rise of serum prolactin levels and persistent amenorrhea after pregnancy or passage of time, suggesting recurrence. Some patients who become pregnant after bromocriptine therapy may have further rises in prolactin greater than pretreatment levels. Follow-up of these patients is indicated.     

Pregnancy in hyperprolactinemic infertile women treated with vaginal bromocriptine: report of two cases and review of the literature.

Vaginal bromocriptine has proven safe and effective in treating hyperprolactinemic women. However, there has been no long-term clinical assessment regarding the influence of daily vaginal bromocriptine administration on the ability to conceive. This article presents two cases of successful pregnancy resulting from this alternative treatment. An infertile woman with an empty sella and hyperprolactinemia was treated with vaginal bromocriptine because of intolerance to oral administration. Prolactin levels were quickly normalized and no side effects occurred. Repeated postcoital tests during treatment proved normal. Twelve months later, the patient conceived. The therapy was discontinued during pregnancy, without complications. Although bromocriptine treatment was not resumed after delivery, postpartum prolactin levels were lower than before treatment and magnetic resonance imaging revealed an unchanged empty sella. Another patient with infertility and pituitary microadenoma with intolerance to oral dopaminergic agonists received the same treatment. Prolactin quickly fell to within the normal range. Vaginal bromocriptine was well tolerated and postcoital test results were not impaired. Tumor regression occurred and 10 months later the patient conceived. Despite bromocriptine withdrawal, no significant complications occurred during pregnancy. It can therefore be concluded that a couple's fertility does not appear to be significantly affected by the persistent local presence of bromocriptine.     

An acromegalic woman first diagnosed in pregnancy

Background: Reports of pregnancy in acromegalic women are uncommon, numbering less than 100, in which a case of acromegaly first diagnosed in pregnancy is rare. Case: A 40-year-old woman in 19-week gestation was presented with a 10-week history of photophobia and visual disturbance. Elevated growth hormone (GH) levels in the serum, an inadequate suppression of GH secretion with glucose administration and a mass image in the pituitary fossa confirmed the diagnosis of acromegaly. We initiated dopamine agonist treatment, bromocriptine at a weekly dose of 1 mg at 27-week gestation. Ten weeks after the start of the bromocriptine treatment, the GH levels gradually decreased to a normal range, and visual symptoms were improved. Enlargement of the tumor was not observed throughout the pregnancy and the patient delivered a healthy infant following an eventful pregnancy. At 3 weeks after delivery, she underwent a transsphenoidal resection of a pituitary adenoma. Conclusion: Pregnancy may lead to pituitary tumor growth and increase the risk of developing loss of vision. It is important to take pituitary tumors into consideration when encountering gravida with visual disturbance.     

A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia

The return of menses in amenorrheic normoprolactinemic women after treatment with bromocriptine is well documented. To determine whether an increased pituitary prolactin-secreting capacity may be the underlying mechanism, 14 women with amenorrhea were studied. None complained of galactorrhea, but in all 14 it was possible to express a few drops of milk from the nipple. All women were normoprolactinemic and had normal sellar tomography. A standard thyrotropin-releasing hormone (TRH) test was performed and bromocriptine (2.5 mg twice daily) was administered. Within 8 weeks, 9 of 14 patients had return of menses. The second group of five patients did not respond to bromocriptine. The mean prolactin response to TRH was significantly greater in those women who experienced return of menses, although there was individual overlap between both groups. This finding suggests that enhanced prolactin secretory capacity may account for amenorrhea is some apparently normoprolactinemic patients. The TRH test may serve to identify those patients who may benefit from bromocriptine.     

Effects of pregnancy, delivery and lactation in hyperprolactinemia with prolactin producing pituitary adenoma

The effects of pregnancy, delivery and lactation on changes in serum prolactin (PRL) values were investigated in patients with hyperprolactinemia. Thirty-seven patients with hyperprolactinemia who wished to become pregnant were treated by transsphenoidal surgery, bromocriptine therapy, or a combination of the two. In 33 patients whose pre-pregnancy serum PRL concentration exceeded 30ng/ml, only in two did serum PRL return to the normal range below 30ng/ml after pregnancy, delivery and lactation. However, the serum PRL concentration was decreased in 28 patients. When classified according to the pre-pregnancy serum PRL concentrations, PRL less than or equal to 100 (Group A), 100 less than PRL less than or equal to 200 (Group B) and 200 less than PRL (Group C), patients with the greatest pre-pregnancy serum PRL concentration showed the greatest reduction. The ratios of post-pregnancy serum PRL to pre-pregnancy PRL in group A, B and C were 91.4 +/- 22.1%, 81.5 +/- 7.0% and 65.0 +/- 6.5% (Mean +/- SE), respectively. Group C with the highest pre-pregnancy serum PRL concentration consisted almost entirely of patients with macroadenoma. Thus, the reduction in serum PRL after pregnancy, delivery and lactation was considered to be the result of a decrease in the size of the adenoma due to adenoma enlargement over the sella turcica through the estrogen effects during pregnancy, and from impairment of pituitary circulation.     

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.     

Pregnancy-induced changes in prolactinomas as assessed with computed tomography

Seven women with prolactin-secreting pituitary microadenomas and three with persistent hyperprolactinemia after surgical adenomectomies were evaluated with computed tomography to assess the effect of pregnancy on the volume of pituitary prolactinomas and hyperfunctioning pituitary tissue. In one patient a microadenoma enlarged to become a macroadenoma. Tumor enlargement occurred in the remaining six patients with microadenomas. None of the patients with previously resected adenomas exhibited hypertrophy of residual pituitary tissue or tumor recurrence after pregnancy.     

Cushing Syndrome Complicating Pregnancy

Summary: A case of Cushing syndrome in a 25-year-old female diagnosed during pregnancy is presented. The pregnancy was complicated by diabetes mellitus, pregnancy induced hypertension, prematurity and intrauterine growth retardation. The patient underwent transphenoidal pituitary adenectomy after delivery for removal of a large pituitary adenoma. The mother and infant are well 10 months after delivery.