Elevation of plasma immunoreactive luteinizing hormone releasing hormone in hyperprolactinemic-amenorrheic women on bromocriptine therapy

There is evidence to suggest that abnormalities in the secretion of prolactin (PRL) in patients with the hyperprolactinemia-amenorrhea syndrome are due to hypothalamic dysfunction. In an attempt to further define the inhibitory effect of excessive PRL release on luteinizing hormone releasing hormone (LHRH) and luteinizing hormone (LH) secretory patterns in human plasma, four amenorrheic women with known hyperprolactinemia were studied before and during bromocriptine (BRCR) therapy. Ten-minute blood samples collected with a continuous withdrawal pump for two hours were analyzed for immunoreactive LHRH (IR-LHRH), LH and PRL using previously established radioimmunoassay procedures. Three patients showed a significant rise in mean IR-LHRH plasma levels coincident with a significant decrease in mean PRL concentrations five days to two weeks following BRCR therapy, whereas mean LH titers increased significantly in only one patient. One patient showed no increase in IR-LHRH or LH with BRCR therapy and failed to show a decrease in serum PRL to normal levels after five days of this treatment. A defect in the control of PRL release in these patients seemed to result from the inability of dopaminergic inhibition to be mediated effectively and seemed to be associated with altered secretion of LHRH.     

Effect of clomiphene citrate on serum prolactin in infertile women with ovarian dysfunction.

Serum prolactin (PRL) levels were determined by radioimmunoassay in 12 normal, menstruating women and in 26 infetile women with ovarian dysfunction for one cycle or for about 30 days in amenorrheic women. Galactorrhea was not observed. No significant change in serum PRL levels was observed throughout the normal, menstrual cycle. Of the 26 patients with ovarian dysfunction, seven showed PRL levels higher than normal. Twelve of the 26 patients were treated with clomiphene citrate (Clomid), 100 mg, daily for 5 days. Ovulation occurred in seven, and pregnancy was achi-ved in two of them. Serum PR;, follicle-stimulating hormone, and luteinizing hormone were measured for a preceding control cycle and during the cycle following Clomid treatment in the 12 patients. The serum PRL levels were normal during the control cycle in five of the patients who ovulated with Clomid and high in four patients who failed to ovulate. Although serum PRL levels were not significantly changed by Clomid in the patients who ovulated with the drug, they were markedly decreased during and immediately after Clomid treatment in patients who failed to ovulate with Clomid.     

Evaluation of dopaminergic activity of the hypothalamus in patients with polycystic ovarian syndrome]

To evaluate the hypothalamic dopaminergic activity in patients with polycystic ovary syndrome (PCOS), we studied the PRL, TSH, LH and FSH responses to i.m. administration of sulpiride in five euthyroid women affected by PCOS and in five normal women. The mean basal PRL and TSH plasma levels resulted significantly higher (p less than 0.01) in PCOS subjects with respect to normal subjects. The incremental area under PRL and TSH profiles, after sulpiride administration, were significantly lower (p less than 0.05) in PCOS patients than in the control group; no significant variation of LH and FSH plasma levels resulted. Our data suggest a decrease dopaminergic activity in PCOS.     

Serum prolactin and ovarian function after discontinuation of drug treatment for hyperprolactinaemia: a study with bromocriptine and metergoline

Serum prolactin (PRL) was estimated for up to 2 months after discontinuation of therapy with either bromocriptine (n = 33; 15 with idiopathic disease, 12 with pituitary microadenoma, and six with macroadenoma) or metergoline (n = 23; 11 with idiopathic disease, and 12 with microadenoma) that had been administered for 8-30 months. Only five patients treated with bromocriptine and two treated with metergoline had PRL levels that remained normal or below 50% of pretreatment values. Among the patients followed-up for up to 12 months, four showed a fall in PRL at 3-4 months, but this was followed by a rise in one patient. Five patients showing persistently lower or normal PRL after drug withdrawal were retested with thyrotrophin-releasing hormone; the two responsive women also had a normal response before treatment. Of 10 patients followed for 9 months, three had persistently normal PRL levels. Amenorrhoea and anovulation recurred, with some delay, in all the patients showing PRL rebound except one. Medical treatment of hyperprolactinaemia only rarely results in permanent benefit.     

正常早期妊娠妇女以β-hCG为参照的催乳素曲线研究

目的:探讨正常早期妊娠妇女催乳素(PRL)随不同水平血清人绒毛膜促性腺激素β亚单位(β-hCG)的变化规律。方法:采用化学发光免疫测定法检测正常早期妊娠妇女不同孕龄血清β-hCG、PRL水平。结果:当β-hCG≤80 000 IU/L时,PRL随着β-hCG上升同样呈直线上升趋势,其中当β-hCG为70 000￣80 000 IU/L时PRL达到高峰,为76.04±38.97μg/L,提示妊娠早期血清PRL水平随血清β-hCG浓度增高而增加;当β-hCG>80 000 IU/L之后,PRL的变化趋于平稳,无明显的直线上升趋势。结论:建立了正常早期妊娠妇女以β-hCG为参照的PRL变化曲线,为正常早期妊娠妇女的PRL水平提供了合适参考范围。     

Maternal and fetal prolactin in pregnancy-induced hypertension

Summary In plasma from 35 women with pregnancy-induced hypertension (PIH) and 35 normal pregnant women both at 39 weeks of gestation, plasma prolactin levels were measured at 8.30 a.m. (PRL1) and 9.30 a.m. (PRL2) under basal conditions. At delivery umbilical cord blood samples were taken for measurement of fetal prolactin (PRLF). PRL1 and PRL2 were higher in women with PIH, but no significant relations were found betwen PRL1/PRL2 and blood pressure. PRLF did not differ when infants of mothers with PIH and infants of normal pregnant women were compared, but PRLF had a significant direct independent relation with PRL2. The latter relation may be due to the increase in placental oestrogens during pregnancy, which stimulate both the maternal and fetal hypophyses and their prolactin secretion. PRLF did not show any relation with neonatal morbidity, but PRL1 showed a significant direct relation with the Apgar score at 5 min.     

Prolactin response to thyrotropin-releasing hormone in women with infertility and/or randomly elevated serum prolactin levels

Infertile women with normal serum prolactin (PRL) levels have been known to establish a pregnancy after the use of bromocriptine, a dopamine agonist. These data imply that there may be a group of women with a slight but significant increase in PRL secretion that may have resulted in their infertility. This study evaluates the thyrotropin-releasing hormone (TRH)-induced PRL and thyroid-stimulating hormone (TSH) response in normal women (NL, n = 6), women with anovulation and/or inphase endometrial biopsies (AN/IN, n = 12), and women with histologic evidence of luteal phase deficiency (LPD, n = 12). Most of these women were found to have elevated serum PRL values on random testing. There was a statistically significant increase in PRL response at all time intervals after TRH between the NL and AN/IN groups compared with the group with LPD on the basis of repeated measures analysis (P = 0.0013). There was no statistical difference in the TSH response between these three groups. Although the PRL response was statistically different, individual PRL response patterns were not diagnostic. It appears from these data that there is an increased PRL secretion in infertile women who have histological evidence of a LPD.     

Does transient hyperprolactinemia during ovarian hyperstimulation interfere with conception or pregnancy outcome?

The significance of transiently increased serum prolactin (PRL) levels on pregnancy rates in in vitro fertilization (IVF) is unknown. The aim of this study was to evaluate PRL levels in IVF patients who conceived and in matched controls who did not. Thirty-seven IVF cycles resulting in pregnancy and 74 nonpregnant cycles were compared. Prolactin was measured before ovarian stimulation with clomiphene citrate, and human menopausal gonadotropin and estradiol (E2) and PRL were measured 8 hours after human chorionic gonadotropin (hCG) administration at midcycle. Before ovarian stimulation, serum PRL levels were not different in the pregnant and nonpregnant women (11.1 +/- 0.6 [mean +/- standard error] micrograms/l and 10.1 +/- 0.4 micrograms/l, respectively). After hCG, PRL levels were significantly higher in the pregnant women than in the nonpregnant women (20.8 +/- 1.6 and 16.0 +/- 0.9 micrograms/l, respectively; P less than 0.005) and more pregnant than nonpregnant women had elevated PRL levels (49% versus 28%, respectively; P less than 0.05). There was no correlation between PRL and E2 in either group. The abortion rate was not different between the women with elevated PRL (22.2%) and the normoprolactinemic women (31.6%). These results do not support treatment of transient hyperprolactinemia with dopamine agonists in IVF patients.     

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

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

Long-term treatment with a new repeatable injectable form of bromocriptine, Parlodel LAR, in patients with tumorous hyperprolactinemia

A new long-acting repeatable injectable form of bromocriptine, (Parlodel LAR, Sandoz, Basle, Switzerland) has recently been developed. We studied the clinical, hormonal and radiological changes in six female patients with microprolactinomas and eight (3 female and 5 male) with macroprolactinomas receiving monthly injections of Parlodel LAR 50 to 100 mg for 6 months. Five patients with microadenomas and 4 with macroadenomas had normal prolactin (PRL) levels with Parlodel LAR 50 mg after one (5 patients), two (2 patients), or five (2 patients) injections; two patients with macroadenomas had normal or near normal PRL levels only after 4 monthly injections of 100 mg. Clinical improvement paralleled the changes in serum PRL. A complete normalization of a visual field defect occurred in one patient after 5 months of therapy. Marked shrinkage of the adenoma was shown by magnetic resonance and/or computed tomographical imaging in three patients with macroadenomas after 1 week. Side-effects were mild and usually transient. Parlodel LAR represents a novel treatment of hyperprolactinemic states which is both effective and well tolerated, and appears to be a useful alternative to oral therapy for long-term treatment.     

Prolactin responsiveness to TRH in amenorrheic women with and without galactorrhea.

Sixty women were given intravenous injection of 200 microgram TRH to assess its diagnostic potential as a stimulus to PRL release. Following the administration of TRH, there was a prompt increase in serum PRL to 614.6%, to 296%, to 282.1%, and 34% in normal women, amenorrheic patients, non tumoral galactorrheic cases, and patients with pituitary tumors respectively. The TRH response above baseline of PRL levels was statistically significant in all groups, but the women with pituitary tumors which showed a blunted response. The per cent of increment of PRL levels after TRH was similar in amenorrheic women regardless the presence or not of galactorrhea; this increase was significantly greater than in patients with pituitary tumors (p less than 0.01). The per cent of increment above baseline of PRL was significantly greater in menstruating women than in amenorrheic patients (p less than 0.001). In basis of present data: 1) there is a diminished PRL secretion after TRH in amenorrheic women regardless the presence of galactorrhea or hyperprolactinemia; 2) a blunted response to TRH in hyperprolactinemic women may be indicative of a pituitary tumor.     

Defective natural killer cell activity in puerperal hyperprolactinemia

Prolactin (PRL) influences immune reactivity in animals and in humans and both T-cell abnormalities and reduced natural killer (NK) cell activity have been reported in women with pathological hyperprolactinemia. To investigate further the possible interactions between PRL and the immune system in humans, we analysed T-cell phenotypes and NK cell activity in 15 women with physiological hyperprolactinemia of the puerperium and in 45 age-matched healthy normal cycling women. Puerperal women displayed a normal T-cell phenotype but a significant reduction in the number of Leu-7+ and Leu-11+ cells, associated with a decreased NK cell activity, as measured against K-562 target cells. There was a significant inverse correlation between the raised serum PRL levels and both the number of Leu-7+ cells and NK cell activity. These data confirm an important immunoregulatory role for PRL in humans and suggest a direct inhibitory effect of the chronically raised PRL concentrations on the maturation of NK cells.     

Further evidence that big,big prolactin is preferentially secreted in women with hyperprolactinemia and normal ovarian function

The heterogeneity of human serum prolactin (PRL) in 12 women with hyperprolactinemia and different derangements of the hypothalamic-pituitary-ovarian axis was studied. The patients were subdivided into three groups: four women with hyperprolactinemia and normal ovarian function (group I), four women with hyperprolactinemia associated with sporadic endometrial bleedings and a positive progestin test (group II), and four women with amenorrhea and a negative progestin test (group III). Gel filtration chromatography of serum samples from patients in group I revealed in three of them that most (80%) of their immunoreactive PRL eluted as big,big PRL (Mr greater than 100,000); whereas the rest of the patients, including those from groups II and III, exhibited a distribution pattern similar to that obtained in normal menstruating women. All PRL species had similar affinities for the antibody, as disclosed by the slopes generated in dose-response curves. These results indicate that ovarian function in hyperprolactinemia might be dependent upon PRL heterogeneity and suggest that big,big PRL may have, under in vivo conditions, a low degree of biologic activity.     

Study on the hypothalamic dopaminergic activity in different stages of pregnancy and non-pregnancy

The purpose of this study was to investigate hypothalamic dopaminergic activity in pregnant women after the administration of metoclopramide (MCP), a dopamine receptor blocker, and to investigate the effects of MCP on the placental steroid and peptide hormones, and to clarify the prolactin (PRL) releasing mechanism in the hypothalamo-pituitary axis during pregnancy using dopaminergic agents and TRH. The following results were obtained. The plasma PRL levels following intravenous MCP remained significantly elevated for 180 minutes (p less than 0.001-0.05) in all groups as compared to the control group, but there were no significant differences between early and late pregnant groups, and between pregnant and nonpregnant groups. Therefore, the dopaminergic activity of the hypothalamus remained unchanged during pregnancy as well as in the nonpregnant state. The administration of MCP or a sudden increase in plasma PRL had no effect on the maternal plasma estradiol-17 beta, progesterone, HCG or HPL during pregnancy. PRL release from the pituitary by MCP was suppressed significantly (p less than 0.01) by pretreatment with bromocriptine. PRL releasing activity of MCP 10mg was significantly higher (p less than 0.01-0.05) than that of TRH 500 micrograms in the pregnant women.     

A prospective,double-blind,randomized, placebo-controlled clinical trial of bromocriptine in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level

OBJECTIVE: To evaluate the effects of administration of bromocriptine combined with clomiphene citrate (CC) in CC-resistant patients with polycystic ovary syndrome (PCOS) and normal prolactin (PRL) level. DESIGN: Prospective double-blind, placebo-controlled, randomized. SETTING: Referral university hospitals. PATIENTS: One hundred women with PCOS and normal PRL who failed to ovulate with a routine protocol of CC. INTERVENTIONS: Treatment group received 150 mg of CC from day 5 to 9 and 7.5 mg bromocriptine continuously, with hCG 10,000 units on day 16 or 17. Control group received the same protocol of CC combined with placebo. MAIN OUTCOME MEASURES: Follicular development, hormonal changes, ovulation rate, pregnancy rate. RESULTS: Follicular development (follicular size greater than 15 mm) was observed in 12 (25.5%) and 8 (15.1%) women in the treatment and placebo group, respectively (p = 0.29). The serum prolactin level was within normal limits in all patients before treatment. After 3 and 6 months of treatment with bromocriptine, there was a significant decrease in serum level of prolactin (p = 0.000001). No significant differences were seen in ovulation, pregnancy rate, or serum levels of FSH, LH, DHEAS, and progesterone between treatment and placebo groups after treatment. CONCLUSIONS: The only significant effect of long-term bromocriptine therapy in CC-resistant women with PCOS was to lower the serum PRL concentration. It is also concluded that 10%-15% of patients with PCOS experienced occasional ovulatory cycles and pregnancy whether or not they were on treatment.     

The arylsulphatase A (EC 3.1.6.1) activity in serum, urine and amniotic fluid from pregnant women with EPH-gestosis

In serum, urine and amniotic fluid obtained from the 52. women divided into three groups the arylsulphatase A (EC 3.1.6.1) activity was measured by the modified Lee-Vaupel and Conzelmann method. It was noticed in serum from the pregnant women with EPH-gestosis the statistically significant (p < 0.05) increase in the enzyme activity comparing to the results from non-pregnant women and pregnant with normal course of pregnancy. It was no statistically significant differences in the urine from pregnant with EPH-gestosis and from the healthy pregnant, but there was the increase (p < 0.01) in the enzyme activity in amniotic fluid from pregnant women with EPH-gestosis comparing to the physiological course of pregnancy. According to our data, the arylsulphatase A activity assay could be recommended as a diagnostic marker in the EPH-gestosis.     

Heterogeneous distribution of serum prolactin values in apparently healthy young women, and the effects of oral contraceptive medication

Controversy over effects of oral contraceptives (OCs) on serum prolactin (PRL) levels from retrospective studies suggested performing a prospective study. Statistical analyses of PRL levels in 552 reproductive-age, nonmedicated women indicated a provisionally lognormal distribution of values less than 15 ng/ml, contaminated by a small number of abnormally high values less than or equal to 90 mg/ml. Truncated samples were used to estimate a "normal range" of PRL levels for three subsets of the study sample, classified according to number of weeks after pregnancy. Fifty-microgram estrogen-containing OCs doubled basal PRL levels at 5 to 8 weeks in those whose initial control values fell below 15 ng/ml, but the PRL elevation was no longer evident at 6 months of drug use. These OCs induced a small but significant lowering of PRL at 5 to 8 weeks in those with control levels of 15 ng/ml or higher. Thirty-five-microgram estrogen-containing OCs failed to alter PRL levels at 5 to 8 weeks in those with control values less than 15 ng/ml.     

Prolactin response after gonadotropin-releasing hormone in the polycystic ovary syndrome

The administration of gonadotropin-releasing hormone (GnRH) has been shown to stimulate prolactin (PRL) release under certain conditions. The authors compared PRL responses after GnRH in normoprolactinemic patients with the polycystic ovary syndrome (PCO) with those of normal ovulatory women in the follicular phase. Seven of 15 patients had a significant increase in PRL after GnRH, whereas none of the control subjects had a positive response. After 1 week of oral L-dopa, the responders no longer exhibited this positive response. Baseline PRL levels in responding patients with PCO were similar to levels in control subjects, whereas nonresponding patients with PCO had higher PRL levels. Baseline follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratios were higher in patients with a positive response. The positive PRL response after GnRH was not correlated with baseline serum LH, the LH/FSH ratio, delta maximum LH responses, serum testosterone (T), unbound T, or baseline PRL. The positive response correlated positively with serum levels of unbound estradiol (P less than 0.05) and serum unbound estradiol/unbound T ratios (P less than 0.01). These data suggest that under certain conditions a subgroup of patients with PCO may demonstrate a positive PRL response after GnRH. Dopamine, gonadotropins, and estrogen may play a role in this interaction.     

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.     

A study of alpha-human atrial natriuretic peptide in normal pregnancy and in pre-eclampsia.

The object of this study was to compare plasma levels of alpha-human atrial natriuretic peptide (ANP) in patients with pre-eclampsia, normal pregnant women, and healthy non-pregnant women. This was an observational study carried out at Llandough Hospital, Cardiff, Wales on 85 age-matched women divided into three groups (30 patients with pre-eclampsia, 30 healthy pregnant women in the third trimester and 25 healthy non-pregnant women). Plasma ANP concentration was measured between 14.00 and 16.00 hours, in the recumbent position using pre-extraction radioimmunoassay. The following measurements were also performed: blood urea, serum creatinine, serum uric acid and serum sodium in all study subjects and 24-hour urinary protein in pregnant women. All women were eating a normal diet. It was shown that plasma ANP levels were significantly higher in healthy pregnant women in the third trimester of pregnancy than in non-pregnant women (18.12 +/- 7.36 vs. 13.68 +/- 6.41 pmol/l, P < 0.05). This difference was also observed in pre-eclamptic women (17.6 +/- 12.06 pmol/l vs. 13.68 +/- 6.41 pmol/l, P < 0.05) but the plasma hormone levels were not significantly different from healthy pregnant women. In all pregnant women, plasma ANP level was related to the gestational age and birth weight as shown by the regression coefficient (+ 0.39,-0.26 respectively, P < 0.05). In pre-eclamptic patients, there was no relationship between the severity of hypertension, assessed by the level of systolic and diastolic blood pressure, serum uric acid level and amount of proteinuria, and log (plasma) ANP levels. There was a significant negative correlation between serum sodium level and log (plasma) ANP level in all pregnant subjects (r=- 0.51, P < 0.05). Compared with non-pregnant women, plasma ANP levels are increased during the third trimester of normal pregnancy and in pregnancies complicated by pre-eclampsia. A relationship between ANP and pre-eclampsia seems unlikely but ANP is probably involved in the regulation of sodium and water balance in normal pregnancy and in pre-eclampsia.