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.     

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.     

Prolactin secretion and menstrual function after long-term bromocriptine treatment

Long-term bromocriptine treatment was discontinued in 75 hyperprolactinemic women. Bromocriptine had been given for up to 65 months (median, 24 months). Treatment was reinstituted in 42 women (56%) after 1 to 3 months, mainly because of increasing prolactin levels. Thirty-three women (44%) were followed up for 6 months or more without treatment. Menstrual bleeding occurred in 19 of the 33 women (58%) after 6 months without treatment. The mean prolactin concentration in this group had decreased more than 60% compared with pretherapy concentrations. In 18 of the 42 women who had bromocriptine therapy again, treatment was discontinued a second time. Six of these patients have regular menstrual bleeding. Long-term bromocriptine treatment seems to induce long-standing normalization of prolactin secretion in patients with hyperprolactinemia.     

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.     

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

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

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.     

Borderline hyperprolactinemia in infertile women: evaluation of the prolactin response to thyrotropin releasing hormone and double-blind placebo-controlled treatment with bromocriptine

Twenty-two women with on average more than 3 years unexplained infertility including normal menstrual cycles were studied because of borderline hyperprolactinemia (repeated serum prolactin concentrations 400-1000 mU/l). Randomized double-blind treatment with bromocriptine 5 mg daily (leading to adequate prolactin suppression) or matching placebo, each for 4 cycles, resulted in a cumulative rate after 4 months of 14.3 +/- 10.6% (SE) in both groups. Also, the results of treatment were not significantly related to the serum prolactin response to an intravenous injection of thyrotropin releasing hormone, whether the response was blunted (ratio of peak to basal prolactin within 60 minutes of injection no greater than 2), intermediate (greater than 2 to 4) or normal (greater than 4).     

Studies of prolactin secretion in human pregnancy

Recent studies have confirmed the presence of a separate (HPr) human prolactin molecule. Measurement of HPr concentrations has been performed in normal and abnormal gestation and during the menstrual cycle. HPr rises throughout gestation with a return to prepregnant concentrations by the 7th postpartum day. Variable increases in plasma prolactin were observed after intravenous administration of arginine, especially after the 30th week of gestation. Puerperally, prolactin rises in response to sucking. Amniotic fluid prolactin levels are 100 times those of maternal or fetal blood. No significant change in basal HPr is seen during the menstrual cycle. The ability to measure this new pituitary polypeptide by radioimmunoassay permits investigation of its role in human gestation.     

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.     

Borderline hyperprolactinemia in infertile women: Evaluation of the prolactin response to thyrotropin releasing hormone and double-blind placebo-controlled treatment with bromocriptine

Twenty-two women with on average more than 3 years unexplained infertility including normal menstrual cycles were studied because of borderline hyperprolactinemia (repeated serum prolactin concentrations 400–1000 mU/l). Randomized double-blind treatment with bromocriptine 5 mg daily (leading to adequate prolactin suppression) or matching placebo, each for 4 cycles, resulted in a cumulative rate after 4 months of 14.3 ± 10.6% (SE) in both groups. Also, the results of treatment were not significantly related to the serum prolactin response to an intravenous injection of thyrotropin releasing hormone, whether the response was blunted (ratio of peak to basal prolactin within 60 minutes of injection no greater than 2), intermediate (>2 to 4) or normal (>4).     

Rapid re-enlargement of a macroprolactinoma after initial shrinkage in a young woman treated with bromocriptine.

We report the case of a macroprolactinoma in a 32-year-old woman, who presented with secondary amenorrhea, galactorrhea, increased plasma prolactin level (3259 ng/ml), headache and bi-temporal visual field defect. Magnetic resonance imaging showed a large pituitary tumor. The patient responded well to bromocriptine (7.5 mg/day) with improvement of clinical symptoms and normalization of plasma prolactin within a few weeks. After 4 months of treatment, tumor size was also reduced markedly. During continued treatment at the same dose of bromocriptine the plasma prolactin level remained normal, but after 8 months of treatment the patient suddenly complained of worsening of her visual fields, and magnetic resonance imaging indicated re-enlargement of the tumor. Bromocriptine was discontinued and transsphenoidal pituitary surgery was performed. After surgery the visual field defect improved, but postoperative plasma prolactin level (1104 ng/ml) and magnetic resonance imaging indicated a residual tumor. Postoperative treatment with quinagolide (0.15 mg/day) resulted in disappearance of all clinical symptoms, normalization of prolactin level and a reduction in size of the residual tumor. This case demonstrates that a dissociation of the inhibitory effect of bromocriptine on tumor size and prolactin level may rarely develop during the course of drug treatment in a patient with macroprolactinoma.     

Rapid re-enlargement of a macroprolactinoma after initial shrinkage in a young woman treated with bromocriptine

We report the case of a macroprolactinoma in a 32-year-old woman, who presented with secondary amenorrhea, galactorrhea, increased plasma prolactin level (3259?ng/ml), headache and bi-temporal visual field defect. Magnetic resonance imaging showed a large pituitary tumor. The patient responded well to bromocriptine (7.5?mg/day) with improvement of clinical symptoms and normalization of plasma prolactin within a few weeks. After 4 months of treatment, tumor size was also reduced markedly. During continued treatment at the same dose of bromocriptine the plasma prolactin level remained normal, but after 8 months of treatment the patient suddenly complained of worsening of her visual fields, and magnetic resonance imaging indicated re-enlargement of the tumor. Bromocriptine was discontinued and transsphenoidal pituitary surgery was performed. After surgery the visual field defect improved, but postoperative plasma prolactin level (1104?ng/ml) and magnetic resonance imaging indicated a residual tumor. Postoperative treatment with quinagolide (0.15?mg/day) resulted in disappearance of all clinical symptoms, normalization of prolactin level and a reduction in size of the residual tumor. This case demonstrates that a dissociation of the inhibitory effect of bromocriptine on tumor size and prolactin level may rarely develop during the course of drug treatment in a patient with macroprolactinoma.     

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.     

Amenorrhea with low normal thyroid function and thyroxine treatment

The effect of thyroxine treatment in cases of functional amenorrhea accompanied by low normally thyroid function was studied. During six months of follow-up, regular or single menstrual cycles were restored in ten of the 17 patients with thyroxine treatment and in four of the 11 patients without thyroxine treatment. During thyroxine treatment, thyroxine and free thyroxine index levels were elevated and serum testosterone levels decreased, but no significant changes were observed in serum estradiol, prolactin, follicle-stimulating hormone or luteinizing hormone levels. In the thyroid-releasing hormone/luteinizing-releasing hormone test, the thyroid-stimulating hormone response was markedly suppressed, but there were no changes in follicle-stimulating hormone, luteinizing hormone or prolactin responses. In one patient with primary hypothyroidism, regular menstrual cycles were restored and serum prolactin and thyroid-stimulating hormone levels normalized during thyroxine treatment. Thyroxine treatment seems to have benefits in some amenorrheic patients with low normal thyroid function.     

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

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

Computed tomography of the brain in patients with serum prolactin levels over 200 ng/ml.

We reviewed the computed tomographic (CT) findings of the sella turcica in 26 patients with a serum prolactin level of over 200 ng/ml. The interval between the dates of CT examination and checking of the serum prolactin level were within 2 months. There were 24 nonpregnant women with a mean age of 30 years and 2 men with a mean age of 28.5 years. None of them were taking medication known to cause an elevation in serum prolactin levels. Surgery was performed on 8 patients with chromophobe adenomas of the pituitary gland: 6 of them were proven to have prolactin-secreting tumors (prolactinomas) after performing a special stain, and the remaining 2 patients, clinically diagnosed as prolactinomas, showed extremely high serum prolactin levels (3,200 and 2,251 ng/ml, respectively). CT studies showed that the height of the pituitary gland in the coronal sections were more than 7 mm in 15 cases (58%) and more than 10 mm in 13 cases (50%); focal bulging of the diaphragma sellae in 16 cases (62%); erosion of the sellar floor in 20 cases (77%); deviation of the pituitary stalk in 19 cases (73%); and abnormal attenuation or enhancement of the pituitary gland in 18 cases (69%). Three patients (12%) showed no evidence of any abnormal CT finding despite a hyperprolactinemic state of over 200 ng/ml. Six histologically proven cases (23%) of prolactinomas and chromophobe adenomas showed radiologic evidence of cavernous sinus invasion. We conclude that patients with a serum prolactin level higher than 200 ng/ml generally show significant changes in the sella turcica in CT.     

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.     

Sheehan’s syndrome

Abstract

Sheehan’s syndrome (SS) is characterized by various degrees of hypopituitarism, and develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. Increased pituitary volume, small sella size, disseminated intravascular coagulation and autoimmunity are the proposed factors in the pathogenesis of SS. Hormonal insufficiencies, ranging from single pituitary hormone insufficiency to total hypopituitarism, are observed in patients. The ?rst most important issue in the diagnosis is being aware of the syndrome. Lack of lactation and failure of menstrual resumption after delivery that complicated with severe hemorrhage are the most important clues in diagnosing SS. The most frequent endocrine disorders are the deficiencies of growth hormone and prolactin. In patients with typical obstetric history, prolactin response to TRH seems to be the most sensitive screening test in diagnosing SS. Other than typical pituitary deficiency, symptoms such as anemia, pancytopenia, osteoporosis, impairment in cognitive functions and impairment in the quality of life are also present in these patients. Treatment of SS is based on the appropriate replacement of deficient hormones. Growth hormone replacement has been found to have positive effects; however, risk to benefit ratio, side effects and cost of the treatment should be taken into account.     

Long-term effects of time, medical treatment and pregnancy in 176 hyperprolactinemic women.

The changes in plasma prolactin (PRL) concentrations were studied in 176 hyperprolactinemic women over periods of 6-180 months, to evaluate the independent effects of time, drugs and pregnancy on the evolution of prolactinemia. CT scans showed pituitary adenoma in 87 (9 macroadenoma), the clinical presentations for 110 patients there amenorrhea, for 37 abnormal cycles and 29 had anovulatory sterility as an isolated symptom. 107 women underwent 191 cycles of dopaminergic treatment and 73 had pregnancies (86), either spontaneously or as a consequence of the treatment. Changes in prolactin induced by medical treatment and pregnancy were recorded and the spontaneous changes in prolactin in 38 patients (17 with adenoma) were followed over periods of 6-72 months. Final mean PRL concentrations were lower than basal though not significantly, in both 'functional' (54.4 vs. 79.2 ng/ml) and prolactinoma patients (87.3 vs. 116.4 ng/ml). Separate calculation of changes in prolactin after the course of medical treatment, pregnancies or 'just waiting' periods showed mean PRL concentrations to be significantly lower only for 'functional' patients after pregnancy. On the other hand, PRL variations in individual patients revealed that: (1) spontaneously, PRL rarely becomes lower over a few years; (2) dopaminergic treatment was associated with normalization of PRL in 13% of women; and (3) pregnancy normalized prolactin concentrations in 29% of the patients. Chi-square analysis of the PRL-lowering frequencies in functional patients showed a high cure rate for pregnancy (P less than 0.0001) and a lesser but still significant effect of drugs (P less than 0.025).