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.     

Relationship between luteal function and prolactin in infertile women with endometriosis

Luteal function in 44 infertile women with endometriosis were studied with reference to prolactin (PRL) and compared with 34 unexplained infertile women without endometriosis. To assess luteal function, serum progesterone (P4) levels were measured on the 3rd, 7th and 10th days of the luteal phase. On the 7th day, serum estradiol (E2) levels and PRL levels were also determined. The response of PRL secretion to TRH was examined at 30 and 60 after following TRH (500 micrograms, im.) administration. The incidence of hyperprolactinemia (basal PRL level greater than or equal to 25 ng/ml) and latent hyperprolactinemia (peak PRL level in TRH challenge test greater than or equal to 150 ng/ml) were 19% and 31%, respectively, in the endometriosis group and 14% and 33%, respectively in the control group. At the midluteal stage, serum P4 levels in endometriosis group were decreased significantly (p less than 0.05), whereas no difference was found between the serum E2 levels in the endometriosis group and the control. In the endometriosis group, there was no correlation between P4 and E2 levels and abnormal secretion of PRL such as hyperprolactinemia and latent hyperprolactinemia. These results indicate the close association of endometriosis with an inadequate luteal phase. However, it seems that the aberrant secretion of PRL has no relation to the impared luteal function in endometriosis.     

A study on pathogenesis and treatment of normoprolactinemic galactorrhea syndrome

To investigate the pathogenesis of the normoprolactinemic galactorrhea syndrome, the response of prolactin secretion to TRH administration and the circadian profile of serum prolactin levels were examined in 13 women with galactorrhea whose resting levels of serum prolactin were lower than 25 ng/ml. Bromocriptine (5mg/day) was administered for 30 days and the mid-luteal serum estradiol and progesterone levels, as indicators of luteal function, were also measured before and after the administration. The basal levels of serum prolactin in these patients were significantly higher than those of the control (p less than 0.05), and the response of prolactin secretion also increased significantly at 30, 60, 90 and 120 min. after TRH administration compared to those of the control (p less than 0.005). The circadian profile of serum prolactin showed significantly higher levels from 22 to 8 o'clock compared to the control (p less than 0.05 approximately 0.005). And serum prolactin levels of these patients were higher than 25 ng/ml during the nocturnal period. When bromocriptine was administered, serum prolactin levels of these patients dropped conspicuously, and the nocturnal surges of prolactin also suppressed. Serum estradiol and progesterone levels in the mid-luteal phase normalized apparently due to the administration of bromocriptine (p less than 0.005, p less than 0.005), and galactorrhea also disappeared. These facts suggested that the normoprolactinemic galactorrhea syndrome might be caused by transient occulted hyperprolactinemia, and the treatment with bromocriptine was useful not only in suppressing galactorrhea but also in improving the luteal function in these patients.     

Clinical evaluation of the prolactin secreting capacity for the diagnosis of occult hyperprolactinemia

To clarify the diagnostic criteria of occulted or transient hyperprolactinemia, the resting prolactin level and the prolactin secreting capacity of normal women, which were tested with a 500 micrograms of TRH injection, were compared with those of patients with occulted hyperprolactinemia. Results revealed that: resting levels of prolactin in normal women were 13.4 +/- 4.4 ng/ml (mean +/- S.D.) in the follicular phase and 13.4 +/- 5.6 ng/ml in the luteal phase, which overlapped those of occulted hyperprolactinemia. the prolactin secreting capacity of occulted hyperprolactinemia was significantly greater than that of the normal women. These results indicated that it was impossible to distinguish the occulted hyperprolactinemia from the normal by the measuring the resting prolactin level, but possible by the evaluating the prolactin secreting capacity. If the serum prolactin was more than 150 ng/ml at 15 min. after TRH administration, occulted hyperprolactinemia was strongly suggested.     

Correlation of prolactin-secreting-capacity to circadian profile of prolactin in euprolactinemic women with ovulatory disturbances

Circadian profile and responsiveness of prolactin to TRH administration were examined in 21 women with ovulatory disturbances. The data were analyzed with reference to the clinical effectiveness of bromocriptine administration. Resting levels of serum prolactin in the patients studied were lower than 25 ng/ml. 14 patients out of 16 cases (Group A) responded to bromocriptine, whose prolactin levels were more than 30 ng/ml during the night in the circadian studies. On the other hand, none of 5 patient (group B) responded to bromocriptine, whose prolactin levels were not more than 30 ng/ml during the night. Group A showed hyper-responsiveness of prolactin to TRH higher than that of Group B. These results suggested that 1) In euprolactinemic ovulatory disturbances there are cases with nocturnal hyperprolactinemia, whose prolactin levels are normal during the day time. These cases will be referred to as occult hyperprolactinemia. 2) Those with occult hyperprolactinemia show increased prolactin-secreting-capacity, which is able to be diagnosed by the hyper-responsiveness of prolactin to TRH administration. 3) The effectiveness of bromocriptine in treating euprolactinemic ovulatory disturbances is due to the suppressive effect of bromocriptine on the hyperprolactinemic states of occult hyperprolactinemia.     

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.     

Increased prolactin response to TRH in polycystic ovary syndrome with low basal prolactin values

An intravenous TRH loading test with 200 micrograms TRH was carried out in 9 hypoprolactinemic (serum prolactin less than 100 mIU/ml) and 6 normoprolactinemic PCO patients and 6 normal subjects. Basal and stimulated prolactin and TSH levels were measured. The latter were within normal values. Prolactin responses to TRH were exaggerated in PCO patients, irrespective of the basal prolactin values. According to literary data, these results indicate that increased prolactin response to TRH in PCO is independent of the basal prolactin values and suggest disturbed tuberoinfundibular dopaminergic function.     

Prolactin secretion in benign breast diseases

In order to evaluate the importance of prolactin in the pathogenesis of benign breast diseases (BBD), serum prolactin (PRL) levels were determined before and during a TRH challenge test in 50 patients affected by various BBD studied during the luteal phase of their cycle. They were compared to 15 normal women also studied during the luteal phase. In all the subjects estradiol (E2) and progesterone (P) were also measured. The patients were studied as a total group and in different subgroups according to the type of their disease, before and after 3 months of treatment with a potent progestin, lynestrenol. No significant differences appeared between any group of patients and the control group either on the basal prolactin secretion or on its dynamic secretory pattern after TRH injection before and during treatment. The only significant difference observed between patients and controls was the progesterone values, respectively 6.86 +/- 0.9 ng/ml and 21.2 +/- 1.4 ng/ml. It can therefore be concluded that benign breast diseases are more likely to be related to an inadequate luteal phase than to any abnormality of prolactin secretion.     

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.     

Prolactin secretion in benign breast diseases

In order to evaluate the importance of prolactin in the pathogenesis of benign breast diseases (BBD), serum prolactin (PRL) levels were determined before and during a TRH challenge test in 50 patients affected by various BBD studied during the luteal phase of their cycle. They were compared to 15 normal women also studied during the luteal phase. In all the subjects estradiol (E²) and progesterone (P) were also measured. The patients were studied as a total group and in different subgroups according to the type of their disease, before and after 3 months of treatment with a potent progestin, lynestrenol. No significant differences appeared between any group of patients and the control group either on the basal prolactin secretion or on its dynamic secretory pattern after TRH injection before and during treatment. The only significant difference observed between patients and controls was the progesterone values, respectively 6.86 ± 0.9 ng/ml and 21.2 ± 1.4 ng/ml. It can therefore be concluded that benign breast diseases are more likely to be related to an inadequate luteal phase than to any abnormality of prolactin secretion.     

TRH-induced hyperprolactinemia and pituitary-ovarian function

To elucidate the role of prolactin in the control of pituitary-ovarian function, eight healthy women were given 80 mg of synthetic thyrotropin-releasing hormone (TRH) orally on two consecutive days during the luteal phase of their menstrual cycle. TRH elevated serum prolactin to a mean concentration of 43.8 ng/ml on the first day and to 15.5 ng/ml on the second day. The reduced response to the second TRH dose was statistically significant (p < 0.05). Accompanying changes in concentrations of gonadotropins or ovarian steroids were not consistent. Short-term oral administration of TRH and/or the temporary hyperprolactinemia induced by its use do not modify the pituitary-ovarian function during the luteal phase of the menstrual cycle.     

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.     

Hyperandrogenemia as a cause of primary infertility

A total of 205 female infertility patients were investigated for hormonal causes of infertility after other factors such as tubal dysfunction or andrologic disorders had been ruled out. Increased androgen serum levels were found in 72/205 (35.1%) of females. In 28/205 (13.7%), elevated prolactin serum levels were noted. 119/205 (58%) of patients suffered from primary infertility versus 86/205 (42%) with secondary infertility. The incidence of hyperandrogenemia was higher in the primary infertility group (p less than 0.0015). No differences relative to hyperprolactinemia were noted between the two groups. Computerized tomography and sonographic methods did not reveal tumors in any of the subjects where serum concentrations of testosterone and dehydroepiandrosterone sulfate were greater than 2 ng/ml and 7 micrograms/ml, respectively. Present data combine to suggest that the determination of androgen serum levels is of major importance when investigating infertile patients.     

Prolactin concentrations in preterm and term pregnancy and labour

Maternal plasma and amniotic fluid (AF) were obtained for measurement of prolactin concentrations from: 1) 20 patients with preterm labor and intact membranes who delivered within one week of amniocentesis; 2) 20 patients with preterm labor who responded to tocolysis and delivered at term; 3) 20 women at term who were not in labor and 4) from 20 women in active labor at term. No significant differences were found between: 1) maternal plasma prolactin concentrations in women with preterm labor who delivered prematurely and those who delivered at term (155 ng/ml vs 176.5 ng/ml); 2) patients at term who were not in labor (188 ng/ml) and those who were in labor (155 ng/ml); 3) AF prolactin concentrations in the two preterm labor groups (1987.5 vs 1282.5 ng/ml) and 4) AF prolactin concentration in the two term groups (562 ng/ml vs 701 ng/ml). Prolactin concentrations were generally significantly higher preterm than at term. We concluded that no significant changes in maternal plasma and amniotic fluid prolactin levels were found in preterm and term parturition.     

Serum prolactin levels in patients with fibrocystic breast disease

In 193 patients suffering from fibrocystic breast disease, basal serum prolactin concentrations were determined and compared to serum prolactin levels in 193 healthy women. In 45 additional patients and 23 healthy control subjects, a thyrotropin-releasing hormone (TRH) stimulation test was performed. The response to TRH in seven healthy female volunteers and in one patient with fibrocystic breast disease, was correlated with the mean serum prolactin levels over 24 hours. Serum prolactin levels were above normal in 45.6% of the patients and in 21.2% of the control subjects. Mean values of the two groups were significantly different (P less than .001). The maximum prolactin response to TRH stimulation was significantly higher in the study patients than in the control subjects (P less than .001). The TRH-stimulated prolactin response correlated positively with the mean 24-hour level (P less than .01, r = 0.8705). These results indicate that a high proportion of patients with fibrocystic breast disease exhibit increased daily prolactin secretion.     

The effects of bromocriptine in normoprolactinemic anovulation and dysovulation: followed by pregnancy in 11 cases

The authors report the results of a study of 40 patients with normal serum prolactin levels who were treated with bromocriptine for sterility secondary to ovulatory disturbances. This therapy restored normal ovulatory cycling in 62.5% of cases with subsequent pregnancy in 27.5% of cases, in particular in patients with primary infertility of long duration. The course of "latent" hyperprolactinemia (peak of TRH, repeated dosages of PRL) was discovered in only one out of two patients who responded to treatment. In patients with "non-latent" normal serum prolactin levels, bromocriptine's mechanism of action is not always clear.     

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.     

Serum prolactin and thyroid stimulating hormone levels following thyreotropin releasing hormone stimulation in preeclamptic patients.

Serum prolactin and thyroid stimulating hormone (TSH) levels were measured following administration of thyreotropin releasing hormone (THR) in 17 preeclamptic patients and 18 normal pregnant controls. From the 31st to the 35th pregnancy week the preeclamptic patients showed increased basal serum prolactin and TSH levels compared to controls, but later in pregnancy the differences disappeared. Following TRH stimulation, the serum prolactin and TSH responses were similar in women with and without preeclampsia. A possible role of prolactin in the development of preeclampsia is discussed.     

Transient hyperprolactinemia during cycle stimulation: influence on the endocrine response and fertilization rate of human oocytes and effects of bromocriptine treatment

The effect of transient hyperprolactinemia and its treatment during cycle stimulation on the endocrine response and fertilization rate of human oocytes was studied. Fifty stimulated cycles were included in the study and divided into three groups: group I consisted of 18 cycles with serum prolactin (PRL) levels less than or equal to 25 ng/ml; group II contained 15 cycles, where patients developed PRL levels greater than 25 ng/ml; group III consisted of 17 cycles, where patients, who already developed hyperprolactinemia in a previous cycle, were treated by 3.75 mg bromocriptine daily. The serum estradiol (E2), progesterone (P) and PRL levels 1, 2, and 3 days before and at oocyte retrieval were evaluated. The E2 decrease at oocyte retrieval was significantly steeper in groups I and III. Follicular luteinization was more effective in groups I and III. The fertilization rate in groups I and III was significantly higher than in group II. High serum PRL levels seem to interfere in follicular and oocyte development. The treatment of transient hyperprolactinemia improved the patients' endocrine response and the fertilization rate of oocytes.     

Pituitary tumors associated with hyperprolactinemia and polycystic ovarian disease.

Galactorrhea and hyperprolactinemia, or both, have been described in some patients with polycystic ovarian disease. Three patients who had had previous bilateral wedge resection of the ovaries and who manifested persistent amenorrhea were found to have elevated levels of serum prolactin (180 to 540 ng/ml) 5 to 10 years later. All three patients initially demonstrated moderate hirsutism and failed to experience withdrawal bleeding after administration of progesterone or clomiphene citrate. Polytomographic evidence suggestive of an intrasellar tumor was present when elevated serum prolactin levels were noted. (Routine sellar roentgenograms prior to wedge resection had been reported as normal.) Two of the three patients underwent transsphenoidal surgery with removal of an 8-mm diameter chromophobe adenoma in each instance. Although serum prolactin levels decreased to 32 and 102 ng/ml, respectively, amenorrhea has persisted with gradual cessation of galactorrhea over a 1- to 2-year follow-up period. Our experience with the reported three cases supports the conclusion that in some cases an association may exist between polycystic ovarian disease and prolactin-producing adenomas.