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.     

Mild endometriosis and luteal function

The luteal function of 27 patients with mild endometriosis and infertility was compared with that of 50 infertile patients without endometriosis. The incidence of endometrial luteal phase deficiency was similar in both groups of patients. Luteal phase length and plasma levels of progesterone (P), estradiol (E2) and prolactin (PRL) in infertile patients (both groups) were similar to those in a group of 10 fertile women. We conclude that luteal phase defects should not be considered as a primary cause of infertility in mild endometriosis.     

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.     

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.     

Nocturnal prolactin levels in infertile women with endometriosis

Both hyperprolactinemia and endometriosis are associated with infertility. A study was performed to ascertain whether sleep-related prolactin (PRL) hypersecretion was present in endometriosis. Fifty-five consecutive infertile women with regular menstrual cycles and admitted for diagnostic laparoscopy were studied. Blood samples were drawn throughout the night preceding surgery. Serum PRL, estradiol and progesterone levels were measured with radioimmunoassays. Nocturnal patterns of PRL secretion may be altered in infertile women with endometriosis, with an exaggerated and prolonged nocturnal peak. This alteration in PRL dynamics may contribute to infertility in women with endometriosis and may be a part of the pathophysiology of this disease.     

Luteal phase hyperprolactinemia during ovulation induction with human menopausal gonadotropins: incidence, recurrence, and effect on pregnancy rates

Hyperprolactinemia may develop during ovulation induction with human menopausal gonadotropins and hCG (hMG/hCG). Because elevated serum prolactin (PRL) has several adverse effects on female reproductive function, this event has been implicated as a factor to explain the difference between ovulation and pregnancy rates in hMG/hCG treatment cycles. The incidence and severity of hyperprolactinemia in the luteal phase of hMG/hCG-stimulated cycles was investigated in a large series of patients. We analyzed 240 consecutive, ovulatory hMG/hCG cycles in 96 women from July 1984 to January 1986. All women had failed to conceive with clomiphene citrate, and had normal luteal phase PRL levels during unstimulated cycles. Daily serum total estrogens were determined during hMG administration. Serum progesterone and PRL were determined in the mid-luteal phase (7 days post-hCG administration). In 7.5% of the cycles, luteal phase PRL elevations were greater than 25 ng/mL. Only 2.5% of cycles had levels of PRL greater than 35 ng/mL. Hyperprolactinemia infrequently recurred in different cycles of the same patient (two of 16 patients, 12.5%). Cycles with hyperprolactinemia were found to have significantly higher preovulatory estrogen levels. Serum progesterone levels were not significantly decreased in cycles with elevated PRL. Pregnancy rates in cycles with and without hyperprolactinemia were similar (7.7 versus 11.1%, respectively; P greater than .05). We conclude that the development of luteal phase hyperprolactinemia during ovulation induction with hMG/hCG is an isolated event. High preovulatory estrogen levels may predispose to its development. Because hyperprolactinemia is uncommon and is usually mild, other factors must be responsible for the difference between ovulation and pregnancy rates using hMG/hCG.     

Superovulation-induced transient hyperprolactinemia in human in vitro fertilization and embryo transfer

To examine the effects of transient hyperprolactinemia on in vitro fertilization and embryo transfer, 61 cycles in 50 euprolactinemic ovulatory women with irreparable tubal diseases were stimulated with clomiphene (CC) alone or CC and human menopausal gonadotropin followed by human chorionic gonadotropin (hCG). Serum prolactin (PRL) increased after hCG administration with peak values of 45.4 +/- 4.2 ng/ml on the day of laparoscopic oocyte aspiration. The highest serum estradiol (E2) concentration was found on the day before PRL peak and serum progesterone (P) began to increase after hCG injection concomitant with the PRL rise. The group having 50 ng/ml or more of PRL (34 cycles) had significantly higher levels of E2 during preovulatory and early luteal phase compared to those of the group having less than 50 ng/ml of PRL (27 cycles) but there was no significant difference between the P levels in the two groups. In the higher PRL group 72 (62.1%) of 116 collected oocytes were fertilized and 6 (20.0%) conceived. In the lower PRL group 45 oocytes (58.4%) of 77 were fertilized and 3 (12.5%) became pregnant. These data suggest that elevated serum PRL concentrations may have no effect on fertilization of oocytes in vitro or embryonic development.     

Effects of nocturnal hyperprolactinemia on ovarian luteal function and galactorrhea

To determine the effects of nocturnal hyperprolactinemia on luteal function and galactorrhea we studied six diurnal normoprolactinemic women with regular menstrual cycles. The diurnal serum levels of prolactin (PRL), luteinizing hormone (LH) and progesterone (Prog) and the nocturnal PRL levels at 1 h intervals were determined throughout the first menstrual cycle. Four of the women were nocturnally normoprolactinemic and two showed nocturnal hyperprolactinemia and low luteal progesterone values. In the second menstrual cycle, they were given metoclopramide (10 mg) at midnight before sleep every day, and their serum levels of PRL, LH and Prog were determined by the same protocol as in the first cycle. During treatment with metoclopramide, all the women showed nocturnal hyperprolactinemia, but their diurnal PRL levels remained within the normal range. Low luteal Prog values were observed in all of them and the peak LH levels decreased in all four nocturnally normoprolactinemic women. They had galactorrhea but neither of the nocturnally hyperprolactinemic women had galactorrhea. These results suggest that nocturnal hyperprolactinemia is a cause of luteal insufficiency and galactorrhea.     

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.     

Physiopathological aspects of corpus luteum defect in infertile patients with mild/minimal endometriosis

Purpose: We describe a physiopathological model to the luteal insufficiency of infertile patients with mild/minimal endometriosis with normal hormone measurements in the early follicular phase. Methods: We designed a case-control study with 24 patients, 14 fertile with in-phase endometrium (control group) and 10 infertile with mild/minimal endometriosis and luteal insufficiency (study group). The histologic dating of endometrium was performed during cycle days 23–25 and serum TSH, FSH, LH, prolactin, and estradiol levels were measured during the early follicular phase (cycle day 3). Progesterone serum levels were measured in three different occasions during the luteal phase. Results: Patients with out-of-phase endometrium have lower estradiol levels (P = 0.031) and decreased progesterone secretion (P = 0.012) during the late luteal phase. Serum prolactin, TSH, FSH, and LH levels were similar between the groups (P > 0.05). Conclusions: The physiopathology of luteal phase defect in infertile patients with mild/minimal endometriosis is associated with a small and large luteal cells dysfunction, characterized by abnormal follicular phase (lower estradiol serum levels) and lower progesterone LH-dependent secretion.     

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.     

Transient hyperprolactinemia in infertile women with luteal phase deficiency

This study was conducted to evaluate the prevalence of transient hyperprolactinemia in infertile women with luteal phase deficiency. One hundred fifty-one luteal phase deficiency patients and 11 controls had serum prolactin (PRL) measured daily for 3-4 days near ovulation. Thirty-three subjects (21.9%) had transient hyperprolactinemia, with PRL above 20 ng/mL for 1 or 2 days, and were studied further. The blood samples of these 33 subjects and of the controls were also analyzed for LH and FSH. Plasma progesterone was measured on the fourth, seventh, and tenth days after ovulation in both groups. The mean (+/- SD) of the mid-cycle integrated LH surge (125.0 +/- 23.0 mIU/mL; N = 26) and the sum of three plasma progesterone levels (23.8 +/- 4.5 ng/mL; N = 21) in the luteal phase deficiency women were significantly (P less than .001) lower than those of the controls (LH 158.7 +/- 13.8 mIU/mL; progesterone 33.8 +/- 6.5 ng/mL). All 33 luteal phase deficiency subjects with transient hyperprolactinemia were treated with bromocriptine at a dose ranging from 1.25-5 mg/day to maintain mid-cycle PRL levels between 5-15 ng/mL. Both the integrated LH surge and the sum of three progesterone levels increased significantly (P less than .05) during bromocriptine treatment, to 142.6 +/- 22.4 mIU/mL (N = 20) and 28.2 +/- 6.2 ng/mL (N = 18), respectively. Fourteen of the 33 patients conceived. The cumulative probability of conception was 31% for six cycles and 45% for 12 cycles of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endometrial estradiol and progesterone receptors in patients with luteal phase defects and endometriosis

Endometrial cytosol estrogen receptors (ERs) and progesterone receptors (PgRs) were quantitated in postovulatory endometrial biopsy samples of patients with luteal phase defect (LPD), those with endometriosis, and normal control subjects. Serum levels of estradiol (E2) and progesterone (P), obtained on the day of the biopsy, were also measured. No significant differences among endometrial ER, PgR, serum E2, and P levels were detected between the patients with endometriosis and normal control subjects. Although ER concentrations in the luteal defect group did not differ from those of control subjects, the PgR levels in day 20 to 23 endometrium were significantly higher. Mean serum E2 and P levels in the group with luteal insufficiency were significantly lower than those of the control subjects. Our data suggest that in patients with LPD the increase in PgR levels during the midluteal days is compatible with a relative deficiency of P secretion by the corpus luteum.     

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.     

Thyrotropin-releasing hormone and gonadotropin-releasing hormone test to predict effectiveness of bromocriptine therapy in infertile women

Sixty-four infertile women presenting with luteal phase defect, anovulatory cycle, and secondary amenorrhea were compared with 15 normal cycling women with bolus injections of thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH) before bromocriptine (BCPT) therapy. All of the women had normal baseline prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) concentrations. Responses of PRL, LH, and FSH levels were measured. PRL responses in BCPT responders were markedly greater than in controls and nonresponders. A better responder rate to BCPT therapy was observed in patients with apparent (88.9%) or borderline (69.2%) exaggerated responses of PRL to TRH than in normal patients (41.7%). Further, in patients with normal PRL responses, the inappropriately enhanced LH responses were seen in BCPT responders but not in nonresponders. These findings suggest that TRH and GnRH tests are worthwhile in predicting the outcome of BCPT therapy in infertile patients.     

Prolactin in the evaluation of luteal phase in infertility

Hyperprolactinemia was detected in 15 of 130 infertile patients (11.5%) with regular menstrual cycles and no galactorrhea who underwent luteal phase evaluation by basal body temperature (BBT), plasma estradiol (E2), and progesterone (P) determination, and endometrial biopsy (repeated in a later cycle when the first was defective). Luteal phase length and plasma levels of P and E2 were similar in the hyperprolactinemic and normoprolactinemic patients. Moreover, a significantly higher incidence of inadequate luteal phase, histologically documented, was found in the normoprolactinemic group. It is concluded that the usefulness of plasma prolactin (PRL) determination in the evaluation of luteal function in infertility is scanty and that most histologically documented cases of luteal phase defects occur with euprolactinemia.     

Oxytocin enhances thyrotropin-releasing hormone-induced prolactin release in normal menstruating women

The effects of oxytocin (OT) on basal thyrotropin-releasing hormone (TRH)-stimulated thyrotropin (TSH) and prolactin (PRL) secretion were evaluated in normal menstruating women during follicular, periovulatory, and luteal phases. Two different studies were performed. In one study, 15 subjects were treated with OT or saline; in the other study, 20 women were tested with TRH alone or in combination with OT. Results during follicular, periovulatory, and luteal phases were similar. OT did not produce any effect on basal serum TSH and PRL levels and on the TRH-stimulated TSH secretion, whereas it significantly enhanced the PRL response to TRH. At all examined phases during the menstrual cycle, the mean peak PRL response was reached within 20 minutes after TRH injection, and the peak was about three times higher than basal value when TRH was given alone and about four times when OT was present. These data suggest that in normal women OT is not involved in the control of basal and TRH-stimulated TSH secretion and of basal PRL release. In contrast, the enhancement of the TRH-induced PRL release suggests that OT plays a role in the control of the acutely stimulated PRL secretion. Because results were similar regardless of the phase of the menstrual cycle, estrogen and/or progesterone do not appear to be involved in the effect of OT on the TRH-induced PRL release.     

Luteal function in infertile patients with endometriosis.

OBJECTIVE: Our purpose was to determine whether infertile patients who have endometriosis show luteal phase defects. STUDY DESIGN: The luteal function in 24 infertile patients who had endometriosis was compared with the luteal function in 20 patients who had unexplained infertility and did not have endometriosis (control). In both groups serum luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol were assayed every day throughout the menstrual cycle. Endometrial biopsy specimens were obtained from eight patients of the endometriosis group for histologic dating of the endometrium. RESULTS: No significant differences in progesterone levels were observed between these two groups during the mid and late luteal phase. Seven of the eight patients who underwent histologic dating showed a luteal phase pattern, whereas only one patient was out of phase. CONCLUSION: Infertile patients who have endometriosis do not always have luteal phase defects.     

Hyperprolactinemia: comparison of thyrotropic-releasing hormone and tomography

A group of 95 women with unexplained hyperprolactinemia (over 20 ng/mL) underwent radiologic examination of the sella turcica with hypocycloidal polytomography (N = 58), computed axial tomography (N = 8), or both (N = 29). All patients also underwent a thyrotropin-releasing hormone (TRH) stimulation test, with serum prolactin (PRL) measurement before and 20 and 30 minutes after a 500-micrograms intravenous bolus of TRH. Their PRL responses were compared with those of two control groups, nine normal women in the follicular phase of the menstrual cycle, and 13 women in the first five months of gestation with pregnancy-related hyperprolactinemia. Both control groups exhibited PRL increases with 95% confidence limits at least 200% above baseline levels. In all, 12 patients from the study group also had a normal PRL response (more than a 200% increase) to TRH, and none of these women had tomographic findings consistent with a pituitary tumor. The remaining 83 women all had diminished or absent PRL increases after TRH administration; 46 (55%) of these patients had radiographic evidence of an adenoma, whereas 37 (45%) had no clear signs of a tumor on either polytomography or computed axial tomography. No patient with a baseline PRL level in excess of 60 ng/mL had a normal PRL response to TRH. The results of the study indicate that 1) in patients with PRL between 20 and 60 ng/mL, a normal TRH test can be relied upon to avoid the expense and radiation of tomography (computed axial tomography or polytomography), 2) there is no benefit to be obtained in performing a TRH test in patients with a baseline PRL level over 60 ng/mL, and 3) about 45% of patients with hyperprolactinemia and an abnormal TRH test have a normal computed tomography or polytomography. These patients may have a small adenoma, and thus warrant closer follow-up than patients with a normal TRH test.     

Alterations in progesterone metabolism and luteal function in infertile women with endometriosis

The concentrations of pregnanediol-3-glucuronide (PGD) and pregnanolone (PN) were measured in daily morning urine specimens from 66 infertile women (40 with varying degrees of endometriosis and 26 control subjects) and correlated with daily changes in basal body temperature (BBT) and with midluteal levels of serum progesterone (P). PN and BBT rose at midcycle in women with endometriosis, as expected, indicating secretion of some P at that time. However, PGD, the major endpoint of P metabolism, was delayed in its excretion. Endometrial biopsies were similarly delayed (out of phase) in women with endometriosis, and a significantly higher incidence of follicular luteinization was seen. It appears that while P secretion begins at midcycle, the bulk of P secretion is delayed, perhaps because of the process of follicular luteinization, and that a shortened functional luteal phase thus exists in women with endometriosis.