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)     

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.     

Conservative management of suspected prolactin secreting pituitary adenoma during pregnancy

Seventeen women with prolactin levels of 100 ng/ml and above suspected of harboring prolactin-secreting pituitary adenoma, form the basis of this study. Ten patients had radiological signs of an adenoma while in 7 the radiological criteria for such a diagnosis were not fulfilled. Ovulation and pregnancy were induced with bromocriptine in all 17 patients. They were carefully observed during pregnancy and following delivery. All gave birth to full-term babies after uneventful pregnancies, except for one patient who experienced intrauterine fetal death at 31 wk of gestation. It is our policy that women with suspected intrasellar prolactin-secreting pituitary adenoma be allowed to conceive and give birth without previous surgical intervention. The patient should be closely followed during pregnancy for clinical symptoms of enlargement of the tumor, including periodic visual field examinations. In cases of neurologic or ophthalmologic complications, surgery or bromocriptine administration without interruption of pregnancy is advocated, or if lung maturity is achieved, delivery should be induced.     

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.     

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.     

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.     

Pregnancy after treatment in patients with prolactinoma: operation versus bromocriptine

Prolactinoma was diagnosed in 190 women of the same age range, among whom 88 were treated with transsphenoidal microadenectomy and 102 with bromocriptine. The purpose of this study was to compare the two groups according to classification of the adenomas by size and invasiveness, pregnancy rates, prolactin levels after pregnancy, sella turcica changes after pregnancy, and serum prolactin levels and radiologic changes in patients who were operated on but did not become pregnant or did not desire pregnancy. In the group with operation, 91% of patients who had microadenoma and 88% of those with diffuse adenoma conceived, but none who had invasive tumors did so. In the bromocriptine-treated group, among patients with no visible microadenoma or with microadenoma seen radiologically 56% conceived; among those with diffuse adenoma 66% conceived; no patients with invasive adenoma were in this group. In the group with operation, 21% had higher serum prolactin levels and amenorrhea after pregnancy, compared with 19% in the medical treatment group and 19% in the group with operation who did not conceive. Of all patients studied, radiologic changes in the pituitary fossa were seen in only one patient undergoing operation.     

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.     

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.     

Bromocriptine treatment of hyperprolactinemic infertility with ovulatory disturbances

We studied 77 women with hyperprolactinemic infertility and possible ovulatory disturbances. Galactorrhea was present in 27. Ovulation was normal in 15, 21 were anovulatory and 41 had luteal phase deficiency. All patients received bromocriptine for three months, resulting in normal serum prolactin levels. After that time, if no pregnancy occurred, clomiphene (with or without human chorionic gonadotropin) or human menopausal gonadotropin and human chorionic gonadotropin were added to the treatment. The overall pregnancy rate was 65%. The incidence of hyperprolactinemia in infertile patients is higher than expected, and patients with luteal phase deficiency can benefit from treatment with bromocriptine and ovulatory agents.     

Subnormal postconceptional levels of prolactin do not interfere with the early events of human pregnancy.

To elucidate the role of bromocriptine treatment and serum prolactin levels in peri-implantational events, 30 healthy women asking for "morning after" type contraception were given bromocriptine. Treatment was started 30.6 +/- 18.4 (mean +/- SD) hours after unprotected intercourse and continued until the next menstruation. Blood samples were taken before and 1 and 2 weeks after initiation of treatment, and the samples were assayed for concentrations of prolactin, progesterone, human chorionic gonadotropin (hCG), and pregnancy-specific beta1-glycoprotein (PSBG) by radioimmunoassay. Prolactin concentrations fell significantly (P less than 0.001) from the pretreatment level of 11.4 +/- 7.9 ng/ml (mean +/- SD) to 2.8 +/- 2.3 ng/ml at 1 week and to 1.9 +/- 0.6 ng/ml after 2 weeks of treatment. Five women had demonstrable hCG in serum 8 to 15 days after unprotected intercourse, and one of them also had PSBG 14 days postcoitum. Pregnancy advanced normally until legal termination in three women, whereas menstruation-like bleeding ensued in two. Our results suggest that neither bromocriptine treatment nor a subnormal maternal serum prolactin level interferes with the early development of human pregnancy.     

Normalization of visual fields following bromocriptine treatment in hyperprolactinemic patients with visual field constriction

Two patients with galactorrhea-amenorrhea and bilateral visual field defects were studied. Routine radiologic examination of each patient revealed a normal sella turcica and no demineralization of the posterior clinoid process. Serum prolactin levels were elevated (patient V. G., 80 ng/ml; patient S. R., 204 ng/ml). Within 2 months of bromocriptine therapy, the serum prolactin levels were normal (patient V. G., 12.21 ng/ml; patient S. R., 8.25 ng/ml) and the bilateral visual field defects were corrected. Bromocriptine has been shown to control prolactin secretion in patients with prolactin-secreting pituitary tumors. Normalization of restricted visual fields following bromocriptine therapy indicates the possibility of an anatomical regression of pituitary hyperplasia or an underlying prolactin-producing microadenoma. It is speculated that the modality of functional galactorrhea reflects hyperplasia of the lactotrophs preceding a nodular and ultimately an adenomatous change. The continuous and prolonged administration of bromocriptine may prevent such a progressive sequence. Further experience is required to validate this possibility.     

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.     

Long-term follow-up of 246 hyperprolactinemic patients

BACKGROUND: We wanted to evaluate the very long-term effects of bromocriptine on prolactin (PRL) levels and pituitary tumor size in a large cohort of hyperprolactinemic patients. METHODS: We conducted a retrospective cohort study in the Department of Endocrinology from Necker Hospital in Paris, France. Two hundred and forty-six patients consulted primarily for menstrual disorders, with diagnosis of hyperprolactinemia. Patients were followed-up for 99.9+/-3.6 months. One hundred and ninety-one were treated with bromocriptine, 32 underwent surgery, and 23 received no treatment. RESULTS: The mean initial plasma PRL level was 135.0+/-20.2 ng/ml. Presence of an adenoma was detected in 60% of our patients and comprised a microadenoma in 64% of cases. Compared to oligomenorrheic women, amenorrheic patients had significantly higher levels of PRL and larger pituitary tumor size. In the bromocriptine group, PRL levels decreased from 99.6+/-7.9 to 20.0+/-1.5 ng/ml (p=0.00001). The medical treatment was associated with disappearance of the adenoma in 45% of the women and with stabilization of pituitary tumor size in 40% of patients. Surgery led to disappearance of the adenoma in almost all cases, but failed to definitively cure hyperprolactinemia. CONCLUSION: In this large-scale retrospective study, the medical treatment of mild hyperprolactinemia was shown to be effective and sufficient after 9 years of follow-up.     

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

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

Hypothalamic-pituitary function following bromocriptine therapy in patients with prolactinomas

Bromocriptine in a dose of 5 mg daily was given to 18 patients with prolactinomas to promote resumption of menses, to overcome infertility and as a primary treatment for the tumor. Serum prolactin levels fell to within the normal range in 95% of the patients by 12 weeks of therapy. The prolactin response to TRH stimulation was significantly less than before treatment; however, the percent maximum increment was significantly higher. There was no significant change in pituitary reserve of the other hormones. Seven pregnancies occurred during treatment. All the pregnancies have been progressing normally. All patients have already been delivered of healthy babies, including one set of twins. It is suggested that follow-up studies of the various pituitary hormones be conducted on patients on maintenance bromocriptine treatment. In addition, bromocriptine treatment might be used to promote fertility in patients with prolactin-secreting microadenomas.     

Effects of therapy and pregnancy on hyperprolactemia caused by a pituitary adenoma. A clinical case

A woman who presented with amenorrhea and galactorrhea with a large prolactinoma (8.5 mm) which regressed on bromocriptine therapy is described. When treatment with bromocriptine was instituted (10 mg/daily) mean serum prolactin concentration fell from 490 ng/ml to 108 ng/ml. Despite a progressive reduction in size up to disappearance of the adenoma after the first 5 years of therapy, prolactin levels remained high. Bromocriptine treatment was stopped after 6 years, when pregnancy was diagnosed. Pregnancy proceeded without complications and lactation was initiated and maintained. After 8 months of breast-feeding, menstrual function resumed spontaneously and bromocriptine therapy was no longer required. Bromocriptine can cause not only a decrease in serum prolactin levels but also a regression in the size of prolactinomas in hyperprolactinemic women. No problems associated with pregnancy and/or breast-feeding were noted in these patients.     

A study of the effects of bromocriptine on serum prolactin, follicle stimulating hormone and luteinizing hormone and on ovarian responsiveness to exogenous gonadotrophins in anovulatory women

Twelve anovulatory patients with normal serum prolactin values and six with elevated values were treated with bromocriptine and the effects on serum prolactin, FSH and LH levels were recorded. Ovulation resulted in one patient who had normal prolactin values and in all six who had raised values. No patient with normal basal prolactin values showed an increase in serum FSH during therapy with bromocriptine, whereas 5 of the 6 patients with elevated values showed significant increases. Similar results were obtained for LH. Although these differences were highly significant (P less than 0-005) the majority of the serum FSH and LH values remained within the normal ranges. Five patients with normal basal prolactin values and one with elevated values were also treated with human pituitary gonadotrophin (HPG). An increase in ovarian responsiveness to HPG during therapy with bromocriptine was recorded in the one patient with initially elevated prolactin values. It was concluded that bromocriptine acts by allowing FSH to rise above threshold requirements for follicular stimulation.     

The influence of gestational age and preeclampsia on the presence and magnitude of serum endogenous digoxin-like immunoreactive substance(s)

Digoxin-like immunoreactive substance(s) has been measured in serum during pregnancy. Because of its presence in pregnancy, investigators have suggested that digoxin-like immunoreactive substance may play an etiologic role in the development of preeclampsia. The objectives of this study were to evaluate the relationship between maternal digoxin-like immunoreactive substance and gestational age and compare digoxin-like immunoreactive substance concentrations in patients with and without preeclampsia who were in the third trimester. Two hundred twenty patients were studied during either the first (n = 53), second (n = 56), or third (n = 111) trimester of pregnancy. Digoxin-like immunoreactive substance was undetectable in the serum of patients during the first trimester; however, 11% of second-trimester and 96% of third-trimester patients had measurable levels of serum digoxin-like immunoreactive substance (p less than 0.05). The mean +/- SEM concentration of digoxin-like immunoreactive substance in serum in third-trimester patients was 0.29 +/- 0.01 ng/ml (range 0 to 0.58 ng/ml). Gestational age at delivery was significantly lower in patients with preeclampsia than in those without preeclampsia (36.3 +/- 0.6 versus 38.8 +/- 0.4 weeks; p less than 0.001). In addition, there was no statistical difference in mean +/- SEM concentration of digoxin-like immunoreactive substance between 27 patients without preeclampsia (0.32 +/- 0.02 ng/ml) and 27 patients with preeclampsia (0.30 +/- 0.02 ng/ml; p = 0.47) matched for gestational age. We conclude that (1) digoxin-like immunoreactive substance appearance and increasing serum concentration during pregnancy are correlated with increasing gestational age and (2) there is no difference in digoxin-like immunoreactive substance values between patients with and without preeclampsia, which may exclude digoxin-like immunoreactive substance as a predictor of preeclampsia.     

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.