Prolactin hyperstimulation in response to thyrotropin-releasing hormone in patients with endometriosis

In order to clarify the role of hyperprolactinemia as a possible cause of infertility in patients with endometriosis, baseline serum prolactin (PRL) concentrations and the PRL response to thyrotropin-releasing hormone (TRH) stimulation were measured in 14 infertile women with endometriosis and in 13 normal, fertile women. Baseline PRL concentrations were 2-fold greater in the endometriosis group than in normal subjects, but the mean values did not differ significantly. Following TRH administration, a significant increase in peak PRL concentrations was observed in patients with endometriosis (211.5 +/- 34.9 ng/ml) when compared with corresponding values in control subjects (117.1 +/- 14.9 ng/ml, P less than 0.05). This hypersecretory state was selective for PRL because no significant differences between the baseline and TRH-stimulated thyroid-stimulating hormone (TSH) concentrations or total serum thyroxine concentrations were observed. In summary, some infertile women with endometriosis exhibit a greater capacity for PRL secretion than normal women. These results suggest that relative hyperprolactinemia may be responsible for the infertility associated with endometriosis, and that PRL suppression may be indicated in these patients.     

Exaggerated prolactin response to thyrotropin-releasing hormone in infertile women with the luteinized unruptured follicle syndrome

Summary Ten cases of luteinized unruptured follicle (LUF) syndrome out of 250 women with unexplained infertility were detected on ultrasonography, giving a frequency of 4%. Hormonal analysis revealed lower serum progesterone levels at mid-luteal phase in LUF cases, suggesting a link between LUF syndrome and inadequate luteal phase. Prolactin response to thyrotropin-releasing hormone was exaggerated in LUF cases as compared with ovulatory cases. Aberrant prolactin release may be a contributory factor in the pathophysiology of the LUF syndrome.     

Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamic-pituitary disease

The prolactin (PRL) response to thyrotropin-releasing hormone (TRH) was evaluated in 686 patients over a 4-year period. Of the 170 control subjects tested, none had a blunted PRL response to TRH. Eighty patients with prolactinomas documented by surgery were tested. Ninety-five percent (76 of 80) of these patients had an abnormally blunted PRL response to TRH. Of the 87 patients with a prolactinoma who did not undergo surgery, 98% (85 of 87) had a blunted PRL response to TRH. Many patients with other pituitary and hypothalamic diseases (pituitary tumors other than prolactinomas [Cushing's disease, acromegaly, chromophobe adenoma], craniopharyngioma) also had an abnormal PRL response to TRH (79 of 153, 52%). In the majority of patients with hyperprolactinemia due to dopamine antagonist medications, TRH stimulation did not produce a normal rise in PRL. The TRH test may be helpful in confirming the diagnosis of prolactinoma, but it is not a decisive factor in the diagnosis or management of this entity.     

Prolactin response to thyrotropin-releasing hormone in normal and complicated late pregnancies.

Maternal serum prolactin level (PRL) was determined with radioimmunoassay in normal and complicated late pregnancy. The mean basal PRL levels were not statistically different among normal (179.3 ng/ml), preeclamptic (169.7 ng/ml), hypertensive (171.4 ng/ml), twin (194.8 ng/ml), or diabetic pregnancies (134.4 ng/ml), although 3 of 17 diabetic women had abnormally low PRL levels. The PRL response to 200 micrograms of intravenously administered thyrotropin-releasing hormone (TRH) was investigated and found similar in normal, preeclamptic, hypertensive, and twin pregnancies. There was no response to TRH in 2 of 3 diabetics with a low basal PRL level. One of these diabetic patients experienced an unexplained intrauterine death 4 weeks later; the others delivered term infants, 1 of whom died of respiratory distress syndrome (RDS). These preliminary results suggest that low basal PRL levels and unresponsiveness to TRH may be related to a poor fetal or neonatal prognosis in diabetic pregnancies.     

Exaggerated prolactin response to thyrotropin-releasing hormone and metoclopramide in primary testicular failure

Twenty-eight severely oligospermic and azoospermic men aged 20 to 42 years were challenged with luteinizing hormone (LH)-releasing hormone (LHRH), thyrotrophin-releasing hormone (TRH), and the dopaminergic antagonist, metoclopramide, given at 30-minute intervals. According to basal gonadotropin levels, the patients were subdivided into three groups: those with severe testicular failure (basal LH > 20 mIU/ml and FSH > 14 mIU/ml); those with moderate testicular failure with predominant seminiferous tubule involvement (LH < 20 mIU/ml and FSH > 14 mIU/ml) and those with mild testicular failure (LH < 20 mIU/ml and FSH < 14 mIU/ml. With one exception, mean basal prolactin (PRL) levels were normal in all patients. In all three groups, however, there was an exaggerated PRL response to TRH, the response in severe and moderate testicular failure being greater than that in mild testicular failure. The response to metoclopramide was increased only in the first two groups, not in the group with mild testicular failure. When individual patients and control subjects were considered together, the peak PRL response to TRH correlated with both basal and peak gonadotropin responses to LHRH. However, the PRL responses did not correlate with 17 beta-estradiol, estrone, testosterone, or the estradiol-testosterone ratio. It is concluded that oligospermic and azoospermic subjects with the most severe testicular failure and the highest gonadotropin levels have the greatest PRL increases after TRH and metoclopramide, indicating that the PRL response is related to the degree of testicular failure.     

Dissociation of serum prolactin response to sequential thyrotropin-releasing hormone and chlorpromazine stimulation in patients with primary empty sella syndrome

The presence of galactorrhea and/or hyperprolactinemia in patients with the primary empty sella syndrome (PESS) has been proposed to be of hypothalamic etiology. To further elucidate this possible mechanism, sequential testing of 19 subjects with PESS with 500 micrograms thyrotropin-releasing hormone (TRH), followed by the injection of 0.7 mg/kg chlorpromazine (CPZ) 150 minutes later, was compared with results obtained in 6 patients with idiopathic galactorrhea (IG) and 3 normal adult women in the early follicular phase of the menstrual cycle. The thyroid-stimulating hormone and prolactin (PRL) response to TRH was similar in all three groups. The mean maximal increase of serum PRL following CPZ, however, was 16.1 +/- 18.5 ng/ml (standard deviation) in the PESS group, whereas the mean maximal PRL response was 68.6 +/- 40.9 ng/ml in subjects with IG and 67.7 +/- 48.1 ng/ml in the seven normal women. The impaired responsiveness of CPZ in the PESS group was significant (P less than 0.05) when compared with the normal CPZ response in the other two groups. The results of this study suggest that patients with PESS may have hypothalamic dysfunction, and that sequential testing of subjects with TRH and CPZ may be of value in differentiating patients with PESS from those with IG.     

Effect of epimestrol on gonadotropin and prolactin plasma levels and response to luteinizing hormone-releasing hormone/thyrotropin-releasing hormone in secondary amenorrhea and oligomenorrhea.

The effects of epimestrol (5 mg every 6 hours for 5 days) on basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (Prl), estradiol, progesterone, and dehydroepiandrosterone sulfate, and on the response to LH-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) stimulation, were studied in 18 cases of secondary amenorrhea and oligomenorrhea of hypothalamic-pituitary origin, in three cases of anorexia nervosa, in two cases of long-lasting progestin-induced amenorrhea, and in one case of precocious menopause. The results in the first 18 patients indicate that epimestrol treatment induces a significant increase in LH and Prl levels after 24 hours, while the FSH increase becomes significant only after 4 days of therapy. Twelve hours after discontinuation of treatment, all three hormone levels decreased significantly to values similar to the basal levels, while the pituitary response to LH-RH indicated a much more marked LH secretion than before treatment. A second test, performed 36 hours after the last drug administration, again showed a significantly higher LH response than that found under basal conditions. No significant variations were observed in the FSH response to LH-RH, nor in the Prl response to TRH. These data suggest that epimestrol interferes at the level of the centers responsible for Prl and gonadotropin secretion in the manner of a weak estrogen.     

Pituitary hormone response to thyrotropin-releasing hormone in secondary amenorrheic women associated with simple weight loss

OBJECTIVE: To investigate endocrine dysfunction in simple weight loss amenorrhea. DESIGN: We studied pituitary hormone responses to thyrotropin-releasing hormone (TRH) in 10 women with simple weight loss amenorrhea. SETTING: Department of Obstetrics and Gynecology, University Hospital, University of Tokushima at Tokushima, Japan. PATIENTS, PARTICIPANTS: Secondary amenorrheic women associated with simple weight loss who did not have anorexia nervosa. INTERVENTIONS: Intravenous injection of 500 micrograms of synthetic TRH. MAIN OUTCOME MEASURE: Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin, and prolactin were measured before and 15, 30, and 60 minutes after TRH injection. RESULTS: In normally menstruating women on day 7 of the cycle TRH did not affect serum LH and FSH levels. In women with simple weight loss amenorrhea, however, TRH raised serum LH and FSH levels significantly (P less than 0.01, respectively). Prolactin response to TRH was significantly (P less than 0.05) lower in women with simple weight loss amenorrhea than in normally menstruating women. CONCLUSIONS: These results indicate that TRH causes a significant rise in serum LH and FSH and the impaired prolactin response in women with simple weight loss amenorrhea.     

Evaluation of serum prolactin levels in patients with endometriosis and infertility.

The aim of this study was to clarify the significance of serum prolactin concentrations in patients with infertility and endometriosis. Forty patients with infertility and laparoscopically proven endometriosis were recruited into the study. Basal serum prolactin levels and prolactin levels after TRH administration were measured. The mean basal serum prolactin concentrations were 12.5, 16.5, 19.5, and 26.5 ng/ml and those after thyrotropin-releasing hormone (TRH) administration were 88.3, 114.2, 125.3 and 138.8 ng/ml in patients with stages I, II, III and IV endometriosis, respectively. A statistically significant relationship was found between the basal serum prolactin levels as well as those after TRH injection and the stage of the endometriosis. The patients were divided in two groups. Group I consisted of 20 patients who did not receive any treatment, while group II consisted of 20 patients who were initially treated with GnRH analogues for 24 week and subsequently with several therapeutic schemes in order to improve their fecundity. The pregnancy rate was not different between the two groups. The patients, however, who did not become pregnant had higher serum prolactin concentrations after TRH administration as compared to those who conceived. We conclude that occult hyperprolactinemia may be a cause of infertility in patients with endometriosis.     

Fetal sex dependent hormone levels in early pregnant women with elevated maternal serum alpha-fetoprotein

Maternal serum and amniotic hormone levels have been investigated in two groups of women in pregnancy weeks 18-21. One group (B) was composed of women with high alpha-fetoprotein levels in serum without fetal abnormality, and a matched control group (A) with normal alpha-fetoprotein levels in serum. Amongst group B women were four pregnancy complications: two spontaneous abortions, one premature delivery, and one cesarean section due to fetal asphyxia. Group B women were significantly different from group A women. Thus, higher maternal serum levels of total estriol (P = 0.030), testosterone (P = 0.016), and alpha-fetoprotein (P = 0.018) were noted in the presence of male fetuses; and higher hPL (P = 0.004), FSH (P = 0.037), and alpha-fetoprotein (P = 0.002) concentrations in women carrying female fetuses, who were accompanied by lower total estriol concentrations (P = 0.045). Differences between groups B and A in terms of amniotic fluid analyses were only related to female fetal sex. Thus, group B showed higher hPL (P = 0.028), testosterone (P = 0.020), and FSH (P = 0.006) levels, and lower alpha-fetoprotein (P = 0.013) concentrations. It is concluded that elevated maternal serum levels of alpha-fetoprotein are accompanied in female fetuses by an endocrine milieu different from that of matched controls. This difference may put the conceptus at a disadvantage, but the majority of the girls were born on time without signs of small-for-date.     

A practical approach for the evaluation of women with abnormal polytomography or elevated prolactin levels

Based upon the experience gained in the evaluation of 60 patients with abnormal polytomography and/or elevated prolactin levels, the following observations can be made: Patients with amenorrhea, amenorrhea and galactorrhea, galactorrhea alone, or anovulatory cycles and infertility may or may not have pituitary tumors. Clinical symptoms do not always correlate with the prolactin level, and patients with normal prolactins may have pituitary tumors. The incidence of empty sella is significant (15.8% in this series). Visual field examination is not a useful screening procedure, but evaluation of thyroid function is important to detect the occasional patient with hypothyroidism (3.5% in this series). The insulin tolerance test is not helpful in detecting the presence of pituitary tumors or in guiding management decisions, and the CT scan contributes little and should be omitted from the evaluation process. A straightforward, economical, and efficient approach to this clinical problem is presented.     

Prolactin secretion in Sheehan's syndrome. Responses to thyrotropin-releasing hormone and metoclopramide

The prolactin response to thyrotropin-releasing hormone (TRH) and metoclopramide was studied in 16 patients with Sheehan's syndrome and 16 matched controls in the follicular phase. Metoclopramide resulted in a greater prolactin response than TRH did in the controls. However, both stimuli failed to evoke any appreciable prolactin response in the patients with Sheehan's syndrome. Since metoclopramide is generally free of side effects and far cheaper than TRH, we recommend the prolactin response to metoclopramide as the preferred screening test in the diagnosis of Sheehan's syndrome.     

Prolactin molecular heterogeneity. Response to thyrotropin-releasing hormone stimulation of concanavalin A-bound and -unbound immunoassayable prolactin during human pregnancy

Since the milieu of pregnancy stimulates physiologic hyperprolactinemia, we questioned whether prolactin secreted during normal pregnancy contains a large-molecular weight component that binds to concanavalin A and whether this large-molecular weight prolactin contributes to the thyrotropin-releasing hormone (TRH)-releasable pool. Serum was collected from pregnant patients (n = 28) undergoing TRH stimulation tests. This serum was passed through a concanavalin A column and eluted with 0.2M alpha-methylmannoside. Concanavalin A-bound prolactin, as determined by radioimmunoassay, ranged from 10% to 30% of the total immunoassayable prolactin. An increase in the basal serum concentration of both concanavalin A-bound and -unbound prolactin occurred as pregnancy progressed. However, throughout gestation, only the concanavalin A-unbound prolactin increased after TRH stimulation. The concanavalin A-bound prolactin was found to have a molecular weight of 60,000 by means of Sephadex G-100 permeation chromatography.     

Exaggerated prolactin response of thyrotropin-releasing hormone in women with anovulatory cycles: possible role of endogenous estrogens and effect of bromocriptine

Twenty-one women 18 to 36 years old, presenting with chronic anovulation, were compared with 10 normally cycling women. The patients were characterized by low progesterone (P) levels (0.93 +/- 0.14 ng/ml versus 15.5 +/- 1.4 in controls), whereas 17 beta-estradiol (E2) was moderately decreased (110.2 +/- 8.3 pg/ml versus 162.8 +/- 14.5 in controls) realizing a relative hyperestrogenism. Basal prolactin (PRL) levels were not elevated (12.1 +/- 0.97 ng/ml versus 9.2 +/- 0.7 in controls), but after thyrotropin-releasing hormone (TRH) stimulation an exaggerated response was observed (114.5 +/- 7 ng/ml versus 55.8 +/- 9 in controls). Patients were treated with bromocriptine (1.25 mg 2 times a day) for 3 months. Fifteen responded with ovulatory cycles, and five became pregnant. Progesterone increased significantly (10.2 +/- 1.3 ng/ml), whereas in patients who did not ovulate P increased only slightly (1.56 +/- 0.18 ng/ml). The particular endocrine profile of these patients (P/E2 imbalance) realizing relative hyperestrogenism may be responsible for the exaggerated PRL response to TRH. Bromocriptine, in reducing this transient, or masked, hyperprolactinemia, allows in many patients the return to ovulatory cycles. This mechanism may be one of the possible pathways leading to chronic functional or organic hyperprolactinemia.     

Prolactin and thyrotropin responses to thyrotropin-releasing hormone during the peripartal period

To investigate the changes in pituitary responsiveness to hypothalamic releasing hormones during the periparturitional period, women undergoing labor and vaginal delivery were stimulated with thyrotropin-releasing hormone. The percentage of incremental changes in prolactin and thyroid-stimulating hormone were significantly lower in pregnant women at term than in nonpregnant control subjects. Evidence of augmented release of prolactin was disclosed after the onset of active labor. The percent increases in prolactin and thyroid-stimulating hormone were significantly higher at 24 hours post partum than at term. Administration of thyrotropin-releasing hormone to the gravid patient in active labor caused a brisk response in fetal thyroid-stimulating hormone, although the increase in fetal prolactin remained low. These findings suggest that the changes in serum triiodothyronine (T3) significantly influence the release of prolactin and thyroid-stimulating hormone in response to thyrotropin-releasing hormone during the periparturitional period.     

Prolactin and thyroid-stimulating hormone responses to thyrotropin-releasing hormone in cases of hyperprolactinemia with normal and abnormal sella tomograms

An intravenous bolus of 500 micrograms of thyrotropin-releasing hormone (TRH) was used to test prolactin and thyroid-stimulating hormone (TSH) responses in normoprolactinemic patients and in hyperprolactinemic patients with normal and abnormal sella turcica. The prolactin response showed a mean increment of 64.1 +/- 46.3 ng/ml in normoprolactinemic women. In patients with hyperprolactinemia, the mean increment was 14.1 +/- 22.4 ng/ml and 13.8 +/- 33.1 ng/ml for patients with normal and abnormal sella, respectively. The difference in the prolactin response between the normoprolactinemic patients and either group of hyperprolactinemic patients is significant (P less than 0.005). The mean baseline TSH in normoprolactinemic patients is significantly higher than in patients with hyperprolactinemia with normal and abnormal sella. The mean increment of TSH after TRH stimulation is significantly higher in normoprolactinemic patients than in either group of patients with hyperprolactinemia (P less than 0.005). These results suggest an inhibitory action of hypothalamic dopamine on the response of both prolactin and TSH to TRH in patients with hyperprolactinemia. The hypothalamic dopamine mechanism might also be the factor leading to suppression of baseline TSH levels in hyperprolactinemic patients. In addition, these results suggest that patients with hyperprolactinemia, with or without changes in the sella turcica, might have various degrees of the same pathology affecting the lactotropes.     

Prolactin and its response to the luteinizing hormone-releasing hormone thyrotropin-releasing hormone test in patients with endometriosis before, during, and after treatment with danazol

Basal levels of prolactin (PRL) were studied in 16 normal women and in 60 women with endometriosis, 37 of whom were infertile. In addition, the authors studied the response to an intravenous (IV) injection of luteinizing hormone-releasing hormone (LH-RH) (100 micrograms) plus thyrotropin-releasing hormone (TRH) (300 micrograms) in the 16 normal women and in 18 endometriosis patients, examining the basal PRL and thyrotropin, and at 15, 30, 45, 60, and 120 minutes after the IV bolus. After laparoscopy and/or conservative surgery, the patients were treated with danazol for 6 months and a second laparoscopy was performed. The LH-RH/TRH test was carried out in the third month of danazol treatment in 6 endometriosis patients and before the second laparoscopy in 11 patients. The results show that there was both an increase in the mean basal levels of PRL and in the percentage of cases of moderate hyperprolactinemia in endometriosis patients. There also was a greater rise in PRL with the LH-RH/TRH test in moderate and severe endometriosis. The PRL response was significantly greater in endometriosis than in normal women, and was not related to TSH response. Danazol treatment reduced significantly the PRL response. The PRL response before treatment was significantly higher in patients who after treatment showed persistent endometriosis at the second laparoscopy. This could suggest a lower effectiveness of danazol in patients with endometriosis and a PRL hyper-response to LH-RH/TRH.     

Plasma thyrotropin-releasing hormone, prolactin, thyrotropin, and thyroxine concentrations following the intravenous or oral administration of thyrotropin-releasing hormone.

In a further evaluation of the use of oral thyrotropin-releasing hormone (TRH) in puerperally lactating women, a radioimmunoassay for its measurement has been developed. Its concentration in plasma as well as that of prolactin (PRL), thyrotropin (TSH) and thyroxine (T4) were measured following either intravenous or oral administration of TRH. Basal concentrations of TRH in 14 normally cycling women ranged from less than 5 to 17 pg/ml. Two luteal phase studies produced peaks in plasma TRH 5 to 10 minutes after 100 micrograms of TRH administered intravenously with a return to basal concentrations within 2 to 3 hours. In 10 normally menstruating women, ingestion of 10 mg of TRH orally resulted in plasma TRH which peaked at 423 +/- 123 pg/ml (standard error of the mean) at 30-minutes. Plasma PRL, TSH, and T4 also increased and remained slightly elevated at 4 hours. These 8-hour studies were performed in a puerperal lactating woman who had ingested 10 mg of TRH orally twice a day for 7 days prior to blood sampling. TRH concentrations declined throughout each day while TSH rose slightly in the first 1 to 2 hours but remained within normal limits. The prolonged administration of 10 mg of TRH orally twice daily to three puerperally lactating women resulted in elevations in plasma TRH 2 to 3 hours following hormone administration, yet no significant increases in plasma TSH were observed. Both endogenous TRH and TSH were measured before and after 22 nursing events in nine puerperally lactating women. There was no change in the concentration of either substance and all values were similar to those obtained in normally menstruating women.     

Depot medroxyprogesterone acetate and basal serum prolactin levels in lactating women

OBJECTIVE: To study the effect of depot medroxyprogesterone acetate on basal serum prolactin levels in lactating women. METHODS: We compared basal serum prolactin levels in 25 lactating women after depot medroxyprogesterone acetate injection and in 25 lactating women of similar age who were using a copper T380A intrauterine device (control group). This sample size was required in order to have 95% power to detect a significant difference. Basal prolactin levels were evaluated by time-resolved fluoroimmunoassay three times (6 weeks postpartum and 3 and 6 weeks after beginning either contraceptive method). RESULTS: At 6 weeks postpartum, before beginning either contraceptive method, the mean prolactin levels in the study and control groups were 991.31 and 948.75 mU/L, respectively (P =.850, 95% confidence interval [CI] -407.57, 492.70). Three weeks later, the mean prolactin levels in the study and control groups were 1156.12 and 860.10 mU/L, respectively (P =.116, 95% CI -76.20, 668.26). At the last follow-up, the mean prolactin levels in the study and control groups were 1127.83 and 710.97 mU/L, respectively (P =.026, 95% CI 51.97, 781.73). There were no significant within-group differences at 6 weeks postpartum before contraception and at 6 weeks after beginning contraception in the study and control groups (P >.05, 95% CI -327.99, 243.02 and -46.76, 522.33, respectively). CONCLUSION: Contraception with depot medroxyprogesterone acetate in lactating women produced higher basal prolactin levels than contraception with copper T380A intrauterine device.