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.     

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.     

Antecedent factors and outcome in amenorrhea-galactorrhea

One hundred seventeen patients with amenorrhea and galactorrhea or hyperprolactinemia were evaluated with regard to antecedent factors, results of investigations, and management. Full details of the outcome of prolonged follow-up were available for 104 patients. Patients who developed amenorrhea-galactorrhea after withdrawal of oral contraceptives or postpartum had a lower incidence of pituitary adenomas than did those who developed amenorrhea-galactorrhea spontaneously. Six of a total of 40 tumors were detected only during the follow-up period. This study suggests that patients with spontaneous amenorrhea-galactorrhea have a greater risk of developing a detectable pituitary adenoma than do those with postpill or postpartum symptoms. However, patients with a microadenoma are more likely to have had postpill onset of hyperprolactinemia. Plasma prolactin (PRL) in patients with postpill amenorrhea-galactorrhea increased in proportion to the duration of oral contraceptive use.     

Dysfunction of dopaminergic regulation of prolactin in patients with functioning and nonfunctioning pituitary adenomas and craniopharyngiomas

The response to domperidone (a dopamine blocking agent) of serum prolactin (PRL) levels was compared in 3 patients with amenorrhea-galactorrhea without evidence of a pituitary tumor, 23 patients with prolactinomas (10 cases with histologic confirmation), 7 patients with histologically verified large nonfunctioning pituitary adenomas with normal or moderately elevated basal PRL levels, and 6 patients with histologically verified craniopharyngiomas (3 with normal basal PRL levels and 3 with elevated PRL levels). The response was compared with that of 10 patients with postpartum hyperprolactinemia and 14 normal women. Ten milligrams of intravenous domperidone induced a rapid rise in PRL that was maximal at 30 to 45 minutes in normal, postpartum, and amenorrhea-galactorrhea patients who had no sign of tumor. In contrast, domperidone failed to induce significant changes in PRL in cases of prolactinoma, nonfunctioning pituitary adenomas, and craniopharyngioma with or without elevated basal PRL levels. The results suggest that dopaminergic control on PRL secretion was impaired in all tumor cases. The mechanisms of this abnormal dopaminergic control, however, may be different. Whereas dopamine control in cases of prolactinoma is altered at the level of pituitary dopamine receptors, alternative explanations must be found for those tumors with normal basal PRL levels and lack of response to domperidone.     

Hyperprolactinemia and hypophyseal tumors--results of treatment with bromocriptine

Forty-one patients with hyperprolactinemia are presented. They were divided into two groups. In the first group, 11 or 27% women had radiological evidence of a pituitary tumour. Seven of 11 patients conceived by means of the bromocryptine treatment. The visual impairment in one patient in the tenth week of pregnancy disappeared after the re-institution of bromocryptine. The values of prolactin in this group varied between 4000 and 7000 mIE/ml. In the second group, 30 or 73% women were without radiological evidence of a pituitary tumour. The values of prolactin in this group ranged from 1200 to 5000 mIE/ml. Fourteen of 30 patients conceived by means of the bromocryptine treatment.     

Spontaneous pregnancy in women with a prolactin-producing pituitary adenoma

The occurrence of spontaneous pregnancy in patients with amenorrhea-galactorrhea, hyperprolactinemia, and radiographic evidence of a pituitary tumor is unusual. We present here two patients who conceived spontaneously. One had an uneventful pregnancy. Following delivery, transsphenoidal pituitary surgery was performed, confirming the presence of a prolactin-producing adenoma. The second patient had an early pregnancy termination (at 12 weeks of gestation). These patients provide evidence that ovulation and pregnancy can occur in spite of elevated prolactin levels.     

Treatment of hyperprolactinemic amenorrhea by intermittent administration of bromocryptine (CB 154)

The results obtained with intermittent bromocryptine treatment from the fifth day after the beginning of menstruation until the second day after the basal temperature rise, in 14 women with hyperprolactinemic amenorrhea-galactorrhea and in whom menses had previously been induced by continuous treatment, are presented. All women had menses without reappearance of galactorrhea; serum FSH, LH, estradiol, and progesterone followed a normal physiologic trend. Only prolactin rose again in the second phase of the cycle, in which lower levels of progesterone were also found, but without any significant interference in the clinical and hormonal trend. It is stressed that administration of bromocryptine during the first part of the cycle might substitute for continuous administration, thereby reducing drug consumption and hence possible side-effects as well as the cost of treatment.     

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.     

Primary amenorrhea-galactorrhea with hyperprolactinemia and huge pituitary enlargement in juvenile primary hypothyroidism.

We report a girl with juvenile primary hypothyroidism revealed by growth retardation and a syndrome of primary amenorrhea-galactorrhea with hyperprolactinemia and suprasellar pituitary enlargement. Resolution of the pituitary enlargement and the amenorrhea-galactorrhea syndrome occurred after thyroid hormone replacement. No similar observation has been reported earlier in juvenile hypothyroidism.     

Etiology, clinical features and prognosis in secondary amenorrhea.

A clinical investigation of 356 patients with secondary amenorrhea revealed that 95% of patients with postpill amenorrhea and 56% of patients with anorexia nervosa recovered in 6 years. The corresponding recovery rates for patients with psychogenic amenorrhea and amenorrhea following self-induced weight loss were 72% for both groups, and in patients with the amenorrhea-galactorrhea syndrome and idiophatic functional amenorrhea the recovery rates at 6 years were 64 and 61% respectively. Unlike the other groups with functional amenorrhea, patients with the amenorrhea-galactorrhea syndrome had impaired ovarian responsiveness to exogenous gonadotropins. Bromocriptine treatment resulted in disappearance of the galactorrhea and restoration of the menses and/or ovulation in nine of 18 patients; of these three became pregnant. The effect of bromocriptine did not persist for long after treatment ceased, and permanent recovery was recorded only in four patients. The group with functional amenorrhea included 34 patients who wished to become pregnant. Gonadotropin treatment was successful in 20 patients, clomiphene-hCG in two, tamoxifen in two, bromocriptine in two, and combined bromocriptine and clomiphene in one. Thus, the overall pregnancy rate in patients with functional amenorrhea was 79%. The groups with ovarian amenorrhea inclutients with assumed ovarian failure responded to large doses of exogenous gonadotropins by ovulation and three became pregnant. Ovarian wedge resection was ineffective in all five cases with polycystic ovaries, but two patients became pregnant after treatment with clomiphene and chorionic gonadotropin, and one with exogenous gonadotropins.     

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.     

Current management of the amenorrhea-galactorrhea syndrome

Management of the amenorrhea-galactorrhea syndrome has changed considerably in the last 5 years. Better understanding of the neuroendocrine physiology of the central nervous system in general, and of the hypothalamic-pituitary region in particular, have contributed significantly to our understanding of the pathophysiology of this syndrome. Greater awareness by physicians, improved neuroradiologic techniques, and the development of immunoassays for prolactin have markedly improved our diagnostic abilities. Many more patients are being diagnosed as having a pituitary tumor. The recent introduction of microneurosurgical techniques and the new medications (ergolines) are changing the treatment of this syndrome. Women in the childbearing age--who are affected most often--can expect successful treatment in the majority of cases with resumption of normal menstrual function and fertility. However, certain risks are still posed, particularly during pregnancy. In spite of improved diagnosis and treatment, the natural history of prolactin-secreting pituitary tumors and the long-range effects are still not fully appreciated. More experience in time will be needed before the indications for and the efficacy of various treatment regimens are fully known.     

Clinical and therapeutical study of the post-pill galactorrhea-amenorrhea syndrome (author's transl)

Post pill amenorrhea-galactorrhea syndrome is one of the most common side effects of OC (oral contraception) treatment. The authors observed 112 nulliparous, and 71 multiparous patients on OC treatment for over 1 year. Of these 17, i.e. 9.29% presented galactorrhea-amenorrhea syndrome, with a higher incidence in patients on higher estroprogestinic dosages. Treatment was by administration of 7.5 mg pro die of 2bromo-alpha-ergocriptine for 38-90 days. Prolactin values decreased from 50.6 to 23.2 ng/ml; menstruation returned in 53% of patients, with 7 pregnancies; side effects were reported in 23.5% of cases, but only for the first few days of treatment.     

Primary empty sella syndrome with elevated serum prolactin

A young, adult, white female with long-standing amenorrhea-galactorrhea syndrome and known pituitary enlargement since 1969 is presented. Further evaluation revealed PRL levels elevated in the microadenoma range and an empty sella. The presence of a pituitary adenoma, however, could not be confirmed by our studies. The question now arises--in a young woman desirous of pregnancy, should an induction of ovulation be attempted in view of the elevated serum PRL and an empty sella?     

Combined bromocryptine and hMG treatment in hyperprolactinemic infertility

Ten women with hyperprolactinemic sterility, which had lasted for 2-8 years, did not conceive under bromocryptine alone or combined with clomiphene, with or without hCG. Two of the patients were anovulatory, while in eight the main problem seemed to be an unreceptive cervix. They were all treated with bromocryptine combined with menotropin (hMG) and hCG for one to four cycles. Seven became pregnant after one to two cycles. Three remained unresponsive even after four cycles of treatment. It is proposed that in hyperprolactinemic infertility a combination of bromocryptine with hMG-hCG may give good results when other regimens of treatment have failed.     

The therapeutic value of low-dosage irradiation of the pituitary gland and ovaries in functional menstrual disorders and sterility

Low-dosage irradiation of the pituitary gland and ovaries resulted in restoration of the menstrual function in 59 per cent of 106 cases of amenorrhea, 89 per cent of 18 cases of dysfunctional metrorrhagia during the childbearing age and in 57 per cent of 26 cases of dysfunctional menorrhagia. It had no effect in 3 cases of hypomenorrhea. The amenorrhea of 2 patients was presumably aggravated by the treatment.Low-dosage irradiation of the putuitary gland and ovaries in 26 women with normal menstrual cycles resulted in temporary amenorrhea of one who, however, had in the past shown a tendency to amenorrhea.Low-dosage irradiation of the pituitary gland and ovaries is highly effective in sterility of women with functional menstrual disorders but has very little, if any, effect in those who menstruate normally.     

The effect of contraceptive steroids on hypothalamic-pituitary function.

A study was performed to obtain additional information about the effects of oral contraceptives on pituitary function. A sequential pituitary stimulation test (SST) was used to study normal control women who then received either a combination pill with 50 mug of ethinyl estradiol or an injectable or oral progestin for three weeks, after which the test was repeated. The same test was also performed on five long-term oral contraceptive users. The SST consists of measurement of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at frequent intervals after stimulation by hypoglycemia, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. GH and TSH release following stimulation were unaffected by the use of contraceptive steroids, while PRL release was increased by both the combination pill and the progestin alone. LH and FSH release was decreased in the three short-term and most of the long-term users of the combination pills but was not decreased in two of the long-term users as well as in those receiving the progestin alone. These results indicate that the combination oral contraceptives have a direct effect upon the pituitary gland, causing an increase in prolactin release and a decrease in gonadotropin release. This effect varies among individuals receiving the same formulation and may be related to the development of syndrome of postpill amenorrhea-galactorrhea.     

Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results

OBJECTIVES: A high proportion of women with persistent low levels of hCG, in the absence of pregnancy or any evidence of tumor, have received chemotherapy and hysterectomy for assumed malignancy. Such chemotherapy and surgery were ineffective and unwarranted. This study identifies the causes of persistent low level of hCG and provides guidelines for the management of these patients, preventing unnecessary treatment in the future. METHODS: The USA hCG Reference Service has consulted on 170 women with low levels of hCG persisting for 3 months or longer. Serum total hCG was measured in the Diagnostic Products Corporation (DPC) Immulite assay and hyperglycosylated hCG in the Nichols Advantage test. RESULTS: Among these 170 patients, the average persistent hCG result was 102 +/- 152 mIU/ml, with a range of 6.1-900 mIU/ml. Thirteen (7.6%) of the 170 patients had true malignancy, 5 had placental site trophoblastic tumor, 3 had other gestational trophoblastic neoplasms (GTN), and 5 had non-trophoblastic malignancies. The remaining 157 patients had false-positive hCG, quiescent gestational trophoblastic disease (quiescent GTD), or pituitary hCG (hCG of pituitary origin). Of 71 patients with false-positive hCG, 47 patients received chemotherapy and 9 had surgery that had no effect on the level of hCG. Five of these patients with false-positive hCG were being monitored for hydatidiform mole or GTN. The majority of these cases were first investigated following an incidental pregnancy test. Of 69 patients who had quiescent GTD, 41 received chemotherapy and 9 underwent hysterectomy. All these therapies were unnecessary and ineffective. While 21 patients with quiescent GTD followed incidental pregnancy tests, the majority were discovered while monitoring patients after treatment for hydatidiform mole or GTN/choriocarcinoma (n = 48). Seventeen cases of pituitary hCG were found among those women who were peri- or post-menopause. Two patients also received chemotherapy for assumed malignancy which was not present. CONCLUSION: Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis. In most of these cases of persistent low hCG etiologies, all therapies were found unnecessary and ineffective. Guidelines are proposed for managing these patients. It is essential to demonstrate a malignancy clinically and with readily available biochemical tests before initiating therapy. This applies whether the patient is identified by an incidental pregnancy test or is actively being monitored for gestational trophoblastic disease.     

Ovulation induction in amenorrheic women

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

An endocrinological study of hyperprolactinemia and its treatment (author's transl)

Twenty-six cases of women with pituitary adenoma and seven cases of women with functional hyperprolactinemia were studied to evaluate the effects of neurosurgery and Bromocriptine treatment. In the patients with pituitary adenoma, the mean serum PRL level was significantly higher than that in the functional cases. Among the patients with pituitary adenoma, the serum PRL levels were roughly correlated to the size of the tumors. Basal serum LH, FSH and 17 beta-estradiol levels were lower in the patients with pituitary macroadenoma than in those with microadenoma. Neurosurgery was performed on fourteen patients of pituitary adenoma. Of ten cases with visual disturbance, it was necessary to use Bromocriptine to reduce the serum PRL to the normal level after operation. In the treatment of sixteen patients with microadenoma, Bromocriptine alone was used for eight of them and surgery was performed on four. As a result, there was a significant lowering of the serum PRL level and induction of regular menses in ten patients. Regular menses were induced by means of Bromocriptine treatment in all of the patients with functional hyperprolactinemia. Our data indicate that neurosurgery, either selective or combined with Bromocriptine, can normalize PRL levels and induce regular menses in patients with hyperprolactinemia.