Suppression of luteal phase, but not midcycle, prolactin levels by chronic follicular phase opiate antagonism

Objective: To investigate whether establishment and maintenance of chronic opioid blockade throughout the follicular phase of the menstrual cycle influences midcycle and luteal phase prolactin levels.Design: Randomized, double-blind, crossover study.Setting: Academic research environment.Patient(s): Volunteers, aged 21–35 years, with regular menstrual cycles.Intervention(s): Naltrexone (50 mg) or placebo were administered on cycle days 2–14. Blood samples were obtained in the early follicular phase and in the periovulatory and midluteal phases of the menstrual cycle.Main Outcome Measure(s): Serum prolactin levels.Result(s): In the early follicular phase, serum prolactin levels were equivalent in naltrexone (12.0 ± 2.7 μg/L; mean ± SE) and placebo (12.1 ± 2.9 ug/L) cycles. A statistically significant increase in serum prolactin was observed on the day of the LH surge (naltrexone: 22.6 ± 3.7 μg/L; placebo: 21.7 ± 2.7 μg/L; P < 0.05 versus early follicular phase), but no difference between treatments was observed. However, midluteal prolactin levels were statistically significantly lower in naltrexone cycles compared with placebo cycles (12.6 ± 3.3 versus 15.4 ± 3.0 )ug/L; P < 0.05).Conclusion(s): Chronic blockade of opioid activities during the follicular phase does not affect midcycle prolactin increments, but withdrawal of opioid blockade may enhance opioid effects on prolactin levels in the luteal phase.     

Follicular phase treatment of luteal phase defect with follicle-stimulating hormone in infertile women

Fifteen infertile women diagnosed by endometrial dating to have a luteal phase defect were treated with human pituitary follicle-stimulating hormone (hFSH) for 45 cycles. Human follicle-stimulating hormone was administered intramuscularly in a dose of 50 IU/day (group 1) for 35 cycles and 100 IU/day (group 2) for ten cycles from either the third or fifth day of the cycle for five days. Plasma estrogen was measured daily during drug injection. Plasma progesterone was measured on the fourth, seventh, and tenth days after ovulation by basal body temperature during 11 pretreatment control cycles and 39 treatment cycles. Endometrial biopsies were performed on the seventh day after ovulation. The daily estrogen levels increased gradually during hFSH treatment. There was no significant difference between the two dosage groups. The mean progesterone levels were: 1) significantly (P less than .02) greater in the treatment cycles than in the control cycles, 2) significantly (P less than .05) greater in the pregnancy cycles than in the nonpregnancy cycles, 3) significantly (P less than .01) greater in the cycles with normal endometrial dating than in the cycles with abnormal endometrial dating after treatment, and 4) significantly (P less than .05) greater in group 1 than in group 2. After treatment, the endometrial biopsy specimens were improved to normal in 20 of 38 cycles. Five patients became pregnant during the treatment. The authors have concluded that hFSH may be useful in treatment of luteal phase defect.     

Prolactin production by explants of normal, luteal phase defective, and corrected luteal phase defective late secretory endometrium

The production of prolactin by explants of late secretory endometrium has been correlated with the extent of decidual differentiation. This correlation is strengthened by the observation that luteal phase defective endometrium produces less prolactin than normal control endometrium in a 24-hour in vitro culture system. In the present study the prolactin production by explants of normal, luteal phase defective, progesterone-corrected luteal phase defective, and clomiphene- or follicle-stimulating hormone/luteinizing hormone-corrected luteal phase defective late secretory endometrium was measured over 96 hours at 24-hour intervals. Progesterone in physiologic concentrations was added to the culture medium to maintain tissue integrity and prolactin synthesis. The prolactin production of normal late secretory endometrium rose over 96 hours under progesterone stimulation. The luteal phase defective endometrium produced significantly less prolactin under the same conditions. Histologically proven corrected luteal phase defective endometrium, regardless of treatment method, produced prolactin not different from the normal controls of the same dates. From these results it is concluded that histologic correction of luteal phase defective endometrium is associated with a corresponding biochemical correction with use of prolactin as a metabolic marker. The findings also strongly support timed endometrial biopsy as the method of diagnosis and evaluation of treatment of luteal phase defect.     

Immunoperoxidase localization of prolactin in endometrium during normal menstrual, luteal phase defect, and corrected luteal phase defect cycles

An avidin-biotin immunoperoxidase staining technique for human prolactin (hPRL) was developed for determination of the location of PRL-producing cells in the endometrium of women with normal menstrual cycles (NMC), luteal phase defects (LPD), and corrected LPD cycles (CLPD). One hundred eight biopsy specimens were studied. Fifty-six patients had NMC, 29 had LPD, and 23 had CLPD. Only decidualized stromal cells stained specifically for hPRL. There was no specific staining in specimens dated earlier than day 25. All specimens dated later than day 25 exhibited decidual cell staining. In specimens dated day 25, 15 of 20 NMC, 5 of 11 CLPD, and 6 of 10 LPD demonstrated decidual staining (P greater than 0.1). These findings suggest that decidual cells are responsible for hPRL production in late secretory endometrium and that the ability of decidual cells to stain for hPRL is dependent on the histologic date of the endometrium and not on the diagnosis of LPD or CLPD.     

黄体功能不全患者月经期子宫内膜细胞凋亡的研究

目的：探讨黄体功能不全（luteal phase defect LPD)患者月经期子宫内膜细胞的凋亡及意义。方法：应用免疫组织化学S－P方法,测定35例黄体功能不全患者和19例对照组月经期子宫内膜bcl-2和bax蛋白的表达,同时应用脱氧核糖核苷酸末端转移酶介导的缺口末端标记法（TUNEL）测定二组月经期子宫内膜的细胞凋亡。结果：LPD组患者子宫内膜bcl-2表达较对照组高（P＜0．01）,而bax表达较对照组（P＜0．05）,凋亡指数（apoptotic index AI）对照组高于LPD组（P＜0．01）,且随着bcl-2的表达强度增加而减少（Ｐ＜０．０１）,而随着bax的表达强度增加而增加（P＜0．01）,结论：LPD组患者月经期子宫内膜 bcl-2表达增高bax表达降低,从而抑制LPD患者子宫内膜细胞凋亡,对其子宫内膜的异常变改变起一定作用。     

Treatment of luteal phase inadequacy with bromocriptine.

A group of 15 women diagnosed as having luteal phase inadequacy (LPI) and a history of 1--2 years of infertility were treated with bromocriptine continuously for 4 months. Plasma levels of prolactin, progesterone, 17 alpha-hydroxy-progesterone and estradiol were measured by radioimmunoassay in a control month and each of the treatment months. There was no significant improvement in the levels of the steroids over the 4-month period, although the prolactin levels were depressed, and 2 subjects became pregnant during the study.     

Induction of luteal phase defect with clomiphene citrate

The effect of clomiphene citrate and progesterone on luteal function in infertile women was studied. Endometrial biopsies were performed in 103 women immediately prior to menstruation. Group 1 (n = 62) had secretory endometrium with a histologic lag time of ≥48 hours with respect to the subsequent menses, that is, luteal phase defect. Group 2 (n = 10) had normal histologic characteristics of the secretory phase. Group 3 (n = 31) had anovulatory endometrium. The last group was subdivided into those with polycystic ovary syndrome (n = 9) and those without the characteristic gonadotropin pattern of polycystic ovary syndrome (n = 22). Clomiphene citrate at doses of 50 to 250 mg daily for 5 days was administered for induction of ovulation, timing of ovulation, or treatment of luteal phase defect. An endometrial biopsy was obtained after three ovulatory treatment cycles. Only one fourth of the women with prior luteal phase defect had normalization of the biopsy specimen with clomiphene citrate, while one half of those treated with progesterone had normal specimens. Half of the normally ovulating women had induction of a luteal phase defect with clomiphene citrate. Only women with polycystic ovary syndrome had consistently well-timed endometrial histologic features with clomiphene citrate therapy. Despite successful induction of ovulation, 16 of the other 22 previously anovulatory women had endometrial histologic findings compatible with luteal phase defect. Increasing the clomiphene citrate dosage was unsuccessful in improving endometrial maturation. These results suggest that the use of clomiphene citrate may be associated with a high rate of luteal phase defect induction, except among women with polycystic ovary syndrome. Clomiphene citrate, even at high doses, appears to be ineffective therapy for luteal phase defect.     

A phase II trial of oral capecitabine in patients with platinum--and taxane--refractory ovarian, fallopian tube, or peritoneal cancer

PURPOSE: To determine the efficacy, toxicity, and quality of life of capecitabine (Xeloda), an oral 5-fluorouracil derivative, in patients with chemorefractory recurrent mullerian cancers. PATIENTS AND METHODS: Patients with chemorefractory persistent or recurrent ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled. Capecitabine was administered beginning at 2000 mg/m2/day orally in two divided doses with meals on a 21-day cycle: 14 days of capecitabine followed by a 7-day rest period. One dose escalation or reduction was allowed. Response was assessed after cycle 2 and cycle 4 and every third cycle thereafter. Standard evaluation included two-dimensional measurement of evaluable disease. Standard criteria for response were used. Therapy was discontinued if progression occurred after at least two cycles of therapy. Quality of life and symptoms were assessed. RESULTS: Forty-one patients were enrolled. Ninety-two percent of patients had >2 previous chemotherapy regimens. All patients had platinum- and taxane-resistant disease. Thirty-six patients were evaluable for response. Three patients had a partial response, with a median response duration of five cycles. Twenty-two patients had stable disease for 3 to 11 cycles (median, 6 cycles). Eleven had progressive disease. The only grade 4 toxicity was abdominal pain (n = 2). The most common grade 3 toxicities were fatigue (n = 19), hand-foot syndrome (n = 11), abdominal pain (n = 7), and diarrhea (n = 4). One patient had a grade 3 hematologic toxicity (anemia). CONCLUSION: Capecitabine at the dosages used in this study is well tolerated and has minimal hematologic toxicity.     

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.     

A phase II trial of arzoxifene,a selective estrogen response modulator,in patients with recurrent or advanced endometrial cancer

OBJECTIVES: The goal of this study was to determine response rate and evaluate toxicity of LY353381 (arzoxifene) in patients with recurrent or advanced endometrial cancer (EC). METHODS: A phase II, open-labeled study with arzoxifene was performed at 13 centers. Patients with measurable recurrent/advanced EC not amenable to curative therapies were eligible if either the primary tumor or recurrent tumor was ER+ and/or PR+. If receptor status could not be determined, patients with well or moderately well-differentiated EC were also permitted. Prior use of salvage chemotherapy was not allowed; however, prior use of progestagens was permitted and patients were stratified by prior exposure to progestagen. Patients received 20 mg/day PO, and were treated for at least 8 weeks in the absence of disease progression or unacceptable toxicity. Efficacy was based on the frequency of complete (CR) and partial (PR) responses, and a 95% confidence interval (CI) was calculated. The Kaplan-Meier method was used to analyze time to progression and duration of response. RESULTS: From February 1999 through April 2001, 37 patients were entered of whom 34 received treatment. Efficacy was evaluated for the 29 patients who received at least 4 weeks of therapy and at least one tumor response assessment. Safety was assessed in all 34 patients who received any drug. Thirty patients were defined as progestagen sensitive, and 4 patients were defined as progestagen failures. Twenty-six patients were ER+, and 22 were PR+. Nine (1 CR + 8 PR) of 29 patients responded (31%, CI 25-51%), with a median duration of response of 13.9 months. All 9 responses occurred in progestagen-sensitive patients. Two additional patients (one from each progestagen cohort) had stable disease for >or=6 months. The median progression-free interval was 3.7 months (CI 1.9-6.6 months) for all 29 patients. Toxicity was minimal with no grade 3-4 toxic effects, and 9 patients had only grade 1-2 toxic effects (7 grade 1, 2 grade 2). Hot flashes were the most common toxic effect and, in all 3 reported cases, were grade 1. CONCLUSIONS: Arzoxifene has demonstrated a high response rate with the longest median duration of response reported in a phase II trial of this patient population. The ease of administration and extremely favorable toxicity profile make this an agent warranting further evaluation.     

Hormonal profiles in the follicular phase, luteal phase and first trimester of pregnancies arising from in-vitro fertilization

The hormonal profiles for oestradiol-17 beta, progesterone, prolactin and beta-human chorionic gonadotrophin (beta-hCG) are documented for the first 24 pregnancies arising from in-vitro fertilization during a collaborative project between the University of Western Australia and PIVET Laboratory. All patients had ovarian follicle stimulation with clomiphene citrate, sometimes combined with human menopausal gonadotrophin and all had oocyte recovery undertaken 36 h after injection of 5000 i.u. hCG. The follicular phase profile indicated that patients were admitted for the hCG injection when oestradiol-17 beta levels were around 1500 pmol/l per follicle with a dimension of greater than or equal to 1.6 cm on ultrasound. Luteal phase data indicated that oestradiol-17 beta and progesterone levels were two to three times higher than that expected during spontaneous conception cycles and those pregnancies which subsequently aborted had significantly lower levels in the late luteal phase. During pregnancy elevated oestradiol-17 beta and progesterone levels were maintained through the early weeks during organogenesis while the beta-hCG profile was similar to that reported for spontaneous pregnancies arising without ovarian stimulation. Six women aborted and the other 18 pregnancies have generated 22 infants.     

Hormonal profiles in the follicular phase, luteal phase and first trimester of pregnancies arising from in-vitro fertilization

Summary. The hormonal profiles for oestradiol-17β, progesterone, prolactin and β-human chorionic gonadotrophin (β-hCG) are documented for the first 24 pregnancies arising from in-vitro fertilization during a collaborative project between the University of Western Australia and PIVET Laboratory. All patients had ovarian follicle stimulation with clomiphene citrate, sometimes combined with human menopausal gonadotrophin and all had oocyte recovery undertaken 36 h after injection o f 5000 i.u. hCG. The follicular phase profile indicated that patients were admitted for the hCG injection when oestradiol-17β levels were around 1500 pmol/l per follicle with a dimension of 1·6 cm on ultrasound. Luteal phase data indicated that oestradiol-17β and progesterone levels were two to three times higher than that expected during spontaneous conception cycles and those pregnancies which subsequently aborted had significantly lower levels in the late luteal phase. During pregnancy elevated oestradiol-17β and progesterone levels were maintained through the early weeks during organogenesis while the β-hCG profile was similar to that reported for spontaneous pregnancies arising without ovarian stimulation. Six women aborted and the other 18 pregnancies have generated 22 infants.     

Lipoprotein-cholesterol levels in infertile women with luteal phase deficiency

OBJECTIVE: To determine if reductions in plasma progesterone (P) secretion seen in luteal phase deficiency (LPD) might be because of reduced availability of circulating low-density lipoprotein (LDL) or high-density lipoprotein (HDL), known substrates for corpus luteum P synthesis. DESIGN: We measured plasma lipoproteins in the luteal phase of the menstrual cycle in 39 infertile women. These women were divided into two groups on the basis of endometrial biopsies; the LPD group had biopsies that were greater than or equal to 3 days out-of-phase. SETTING: All participants were recruited from the Reproductive Endocrinology and Infertility Clinic at the University of Washington, an institutional tertiary care center. PATIENTS, PARTICIPANTS: Eighteen women had in-phase and 21 had out-of-phase LPD biopsies. MAIN OUTCOME MEASURE: Lipoprotein levels were obtained in a fasted state on the day of the luteal phase on which the biopsy was performed. RESULTS: No difference in covariates that affect lipoprotein levels such as obesity, age, and alcohol use were observed between the two groups. No significant differences between groups were found for triglycerides, total cholesterol, very low density lipoprotein, LDL, HDL, HDL2, and HDL3 concentrations. However, LPD was associated with a reduction in the extent to which: age and obesity are associated with higher triglycerides; obesity is associated with a lower HDL2; and alcohol is associated with a higher HDL3-cholesterol. CONCLUSIONS: Lipoproteins on average are not different in LPD, suggesting reasons other than a deficient plasma lipoprotein cholesterol source as the explanation for decreased P secretion. A lesser interaction between LDL or HDL and obesity, age, and alcohol in LPD could signify an influence of the altered hormonal milieu of LPD on the way lipoproteins interact with covariates and could lead to differences in lipoproteins between normal and LPD subjects at the extremes of the lipoprotein distribution.     

Superovulation of habitual aborters with subtle luteal phase deficiency

Five habitual aborters without a known organic cause of their pregnancy losses were studied in detail by serial blood sampling for immunoreactive estrogen, progesterone, follicle-stimulating hormone, luteinizing hormone, and the ratio of the two. All patients had premenstrual spotting regularly. Luteal phase progesterone levels on the 6th postovulatory day were significantly lower (11.8 +/- 1.2 ng/mL, mean +/- SEM) than in control patients (20.8 +/- 3.5 ng/mL, mean +/- SEM). Results of immunoreactive estrogen, FSH, and LH assays and the FSH/LH ratio did not reveal a discernible pattern of deviation from normal. Indirect immunofluorescence of blood samples from all habitual aborters showed evidence of autoimmunity in three of five patients without clinical symptoms of autoimmune disease. Treatment by superovulation produced at least one living child in each couple. The balance of pregnancy outcome changed from 100% abortion (N = 31) before treatment to 31% (N = 13) after treatment. These results suggest that treatment with superovulation may be the treatment of choice for habitual aborters with a subtle luteal phase deficiency.     

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)