Early follicular phase luteinizing hormone-releasing hormone agonist administration - effects on follicular maturation and corpus luteum function in women

The potent luteinizing hormone-releasing hormone (LRH) agonist D-Ser(TBU)6-EA10-LRH was administered in a daily subcutaneous dose of 5 or 25 microgram for 1, 3 or 5 consecutive days to twelve regularly menstruating women in the early follicular phase of the menstrual cycle in an attempt to disturb follicular maturation and induce luteolysis. The treatment was monitored by clinical examinations, basal body temperature recordings, bleeding patterns and frequently taken peripheral venous blood samples for analyses of gonadotropins and ovarian steroids. The luteal phase during the LRH agonist treatment cycles did not differ in length from that of the control cycles before and after the treatment (p greater than 0.05). The maximal progesterone concentration during the luteal phase exceeded 32 nmol/l in all but one of the treatment cycles. The follicular phase of the treatment cycle was prolonged in comparison with that of the control cycles (p less than 0.01). Thus, administration of high doses of a superactive LRH agonist during the early follicular phase of the menstrual cycle prolonged the follicular phase and postponed ovulation but did not interfere with corpus luteum function in normally ovulating women.     

Hormone levels before and after tubal sterilization

OBJECTIVE: The aim of this study was to determine whether women experience significant luteal phase hormonal changes following interval tubal sterilization. DESIGN: This is a partly randomized, prospective clinical study. SETTING: This study involved healthy volunteers in an academic research environment. PATIENTS: This study involved 118 fertile women seeking tubal sterilization and 57 fertile controls with at least three normal cyclic menstrual periods before entry into the study. INTERVENTIONS: The patients were randomized to bipolar cautery or Hulka clip as sterilization methods. Barrier contraception or abstinence was used by controls. MAIN OUTCOME MEASURES: The main outcome measures are serum estradiol and progesterone levels and urinary estradiol and pregnanediol levels obtained during the luteal phase before, 1 year and 2 years after sterilization. RESULTS: The women randomized to the bipolar cautery group had higher midluteal progesterone levels measured between Days 5 and 11 postovulation (15.5 ng/mL before sterilization, 14.5 ng/mL at 1 year and 14.5 ng/mL at 2 years) than did the other two groups. The clip group had progesterone levels of 14.1, 12.0 and 12.5 ng/mL at baseline, 1 year and 2 years, respectively, and the control group had levels of 12.0, 11.9 and 11.3 ng/mL for the same periods. Serum estradiol and progesterone and urinary pregnanediol and estradiol were not significantly changed over the 2-year period, nor were there significant differences between the two groups. CONCLUSIONS: There were no significant hormonal changes in sterilized women over a period of 2 years when compared with their baseline levels or when compared with unsterilized age-matched controls.     

Assessment of luteal function after surgical tubal sterilization

To evaluate ovarian luteal function after tubal occlusion, a group of women who underwent Pomeroy sterilization were studied. A prospective group I (n=16) were followed for one year and scheduled for blood sampling every other day during their luteal phase before surgical procedure and at 3 and 12 months thereafter. Group II (n=15) included women who were studied during their luteal phase at 1 or 5 years post-surgery. Mid-luteal progesterone and estradiol serum levels were calculated by estimating the average of at least 3 values of serum samples obtained in days 20–25 of a menstrual cycle. The data suggest that no major changes occur in ovarian function after surgical tubal occlusion, as assessed by the mid-luteal hormone serum levels, and underscore the safety of this procedure.     

Menstrual cycle effects on the metabolism of tryptophan loads

The metabolism of tryptophan (Trp) was examined during the follicular and luteal phases of the human menstrual cycle. Eight healthy women were administered capsulated Trp (3 g) or placebo (3 g lactose) during two follicular and two luteal phases of their menstrual cycles. Trp loading resulted in increased plasma concentrations of Trp and kynurenine, in an increase in the ratio of Trp to neutral amino acids in plasma, and in an increase in urinary excretion of Trp and kynurenine at both phases of the menstrual cycle. However at 3 h after Trp ingestion, plasma kynurenine levels in the luteal phase (23.6 +/- 3.1 mumol/L) were 40% higher than in the follicular phase (16.7 +/- 1.1 mumol/L) (p less than 0.05). Urinary kynurenine excretion in the luteal phase (81.6 +/- 14.4 mumol/24 h) was 28% greater than in the follicular phase (63.9 +/- 13.0 mumol/24 h) (p less than 0.05). The results indicate that the catabolism of Trp via the kynurenine pathway is affected by the phase of the human menstrual cycle.     

Effects of prune consumption on the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone

BACKGROUND: A higher urinary ratio of the biologically inactive estrogen metabolite, 2-hydroxyestrone (2OHE1), to the biologically active metabolite, 16alpha-hydroxyestrone (16alphaOHE1), may be associated with a lower risk of breast cancer. High fiber intake is also associated with decreased breast cancer risk. OBJECTIVE: We investigated the effects of prunes, which are naturally rich in both soluble and insoluble fiber, on the concentrations of 2OHE1 and 16alphaOHE1 and on the ratio of 2OHE1 to 16alphaOHE1. DESIGN: Nineteen healthy premenopausal women consumed their habitual diets for 3 menstrual cycles and then consumed 100 g prunes/d for the next 3 cycles. Concentrations of urinary 2OHE1 and 16alphaOHE1 were determined during the follicular and luteal phases. RESULTS: Prune supplementation increased total and soluble fiber intakes by 4 and 2 g/d, respectively (P < 0.001). Mean (+/- SEM) luteal 2OHE1 excretion decreased from 3.92 +/- 0.79 to 2.20 +/- 0.40 nmol/mmol creatinine during the third cycle (P = 0.017). Luteal 16alphaOHE1 excretion decreased from 1.38 +/- 0.24 to 0.87 +/- 0.10 and 0.87 +/- 0.15 nmol/mmol creatinine during the first and third cycles, respectively (P = 0.018 for both values). Follicular 16alphaOHE1 excretion decreased significantly only during the first cycle (from 0.82 +/- 0.12 to 0.45 +/- 0.09 nmol/mmol creatinine; P = 0.005). The 2OHE1-16alphaOHE1 ratio did not change significantly after prune supplementation. CONCLUSIONS: Prune supplementation significantly decreased the excretion of 16alphaOHE1 during the follicular phase of the first menstrual cycle and during the luteal phases of both the first and third menstrual cycles. The 2OHE1-16alphaOHE1 ratio did not change significantly. The potential significance of the decrease in 16alphaOHE1 excretion, without a change in the 2OHE1-16alphaOHE1 ratio, on the prevention of estrogen-dependent cancers remains to be determined.     

Levonorgestrel administration in emergency contraception: bleeding pattern and pituitary-ovarian function

BACKGROUND: This study was conducted to evaluate the effects of levonorgestrel administration for emergency contraception (EC) on bleeding pattern and pituitary-ovarian function. STUDY DESIGN: In 69 women with a reported stable menstrual cycle length of 24-34 days, we investigated bleeding patterns following EC administration in the follicular (n=26), periovulatory (n=14) and luteal (n=29) phase. In a subgroup of 8 women, hormonal evaluation and ultrasonography were performed. RESULTS: EC taken in the follicular, but not in the periovulatory or luteal phase, significantly shortened cycle length by 10.9+/-1 days. The subsequent cycle was not affected. EC taken in the late preovulatory phase, prior to the gonadotrophin surge, suppressed ovulation (n=7), while ovulation was not blocked when EC was given during an ongoing luteinizing hormone (LH) pulse (n=1). CONCLUSIONS: Our data indicate that EC given before the onset of the luteinizing hormone (LH) surge inhibits ovulation and hastens the end of the current menstrual cycle. Subsequently, the length of the following menstrual cycle returned as prior to treatment. By contrast, levonorgestrel administered after the expected ovulation has no effect on menstrual cycle length.     

Inhibition of luteal phase progesterone levels in the rhesus monkey by epostane

This study examined the effect of epostane, a new antifertility drug, on normal and hCG-stimulated progesterone production during the luteal phase of the menstrual cycle in rhesus monkeys. When administered once each day for five days, epostane inhibited normal luteal phase progesterone levels in a dose-related fashion. Epostane also reduced the elevated luteal phase progesterone levels of animals treated with hCG indicating that the drug acts directly on the corpus luteum. These data suggest that epostane interferes with corpus luteum function in a primate and that the drug would be effective as an interceptive agent during early pregnancy.     

Effect of continuous oral administration of estriol on corpus luteum function.

Estriol, 6 mg per day, administered orally to six normal women, caused a statistically significant reduction in plasma LH levels in the follicular phase and during and immediately after ovulation as compared to control cycles. In the luteal phase, a highly significant increase in estradiol production and a reduction in progesterone production, as judged from the plasma levels of these hormones, was observed. The mean length of the menstrual cycle was not significantly altered and no pregnancy occurred in this small group of women. It is concluded that estriol administration significantly influences corpus luteum function perhaps by affecting steroid biosynthesis. It is suggested that the remarkable increase in plasma estradiol levels which results from estriol administration cause a reduction in the functional life-span of the corpus luteum. However, the significantly lower plasma LH level seen during and immediately after ovulation may also be partly responsible for the luteolytic effect observed.     

The effect of oxytocin on the corpus luteum of the monkey

The effect of a pharmacologic dose of synthetic oxytocin on corpus luteum function was evaluated in rhesus monkeys during normal menstrual cycles, or during menstrual cycles in which the corpus luteum was concomitantly stimulated by injections of human chorionic gonadotropin (hCG). Oxytocin administered by intramuscular injection at a total dose of 4.5 milligrams (2250 I.U.) on Day +6 of the normal luteal phase (Day 0 is the day of the midcycle LH surge) did not change the concentrations of progesterone in the peripheral serum of monkeys or alter the duration of the luteal phase. The same dose of oxytocin, administered to monkeys on Day 22 of menstrual cycles in which hCG was also given on Days 20-22, caused a small, but statistically significant, reduction in serum progesterone values. The results indicate that oxytocin does not alter luteal life span or markedly change blood progesterone concentrations in primates.     

On the mechanisms of action of short-term levonorgestrel administration in emergency contraception.

The effects of short-term administration of levonorgestrel (LNG) at different stages of the ovarian cycle on the pituitary-ovarian axis, corpus luteum function, and endometrium were investigated. Forty-five surgically sterilized women were studied during two menstrual cycles. In the second cycle, each women received two doses of 0.75 mg LNG taken 12 h apart on day 10 of the cycle (Group A), at the time of serum luteinizing hormone (LH) surge (Group B), 48 h after positive detection of urinary LH (Group C), or late follicular phase (Group D). In both cycles, transvaginal ultrasound and serum LH were performed from the detection of urinary LH until ovulation. Serum estradiol (E2) and progesterone (P(4)) were measured during the complete luteal phase. In addition, an endometrial biopsy was taken at day LH + 9. Eighty percent of participants in Group A were anovulatory, the remaining (three participants) presented significant shortness of the luteal phase with notably lower luteal P4 serum concentrations. In Groups B and C, no significant differences on either cycle length or luteal P4 and E2 serum concentrations were observed between the untreated and treated cycles. Participants in Group D had normal cycle length but significantly lower luteal P4 serum concentrations. Endometrial histology was normal in all ovulatory-treated cycles. It is suggested that interference of LNG with the mechanisms initiating the LH preovulatory surge depends on the stage of follicle development. Thus, anovulation results from disrupting the normal development and/or the hormonal activity of the growing follicle only when LNG is given preovulatory. In addition, peri- and post-ovulatory administration of LNG did not impair corpus luteum function or endometrial morphology.     

Hormonal profile of the menstrual cycle in chinese women after tubal sterilization

Ten women after tubal sterilization were studied for the hormonal profile of the menstrual cycle. They had undergone sterilization procedures, on the average 5.3 years (range 1.5–10 years) earlier. The serum concentrations of LH, FSH, prolactin, estradiol and progesterone were measured by RIA in daily blood samples of a complete menstrual cycle. Another ten normal women were studied at the same time and were used as the control group. There were no significant differences in the hormonal patterns of the menstrual cycle between the two groups. There was a significantly lower LH level in the early luteal phase of the tubal ligation group compared to the control group. Also, a significantly lower E2 luteal peak compared to the preovulatory peak was observed in the tubal ligation group. The physiological significance of these minor changes is not clear.

Only one out of ten women in the tubal ligation group, who had undergone sterilization 1.5 years prior, showed a deficiency in luteal function, but her ovulatory function and menstrual cycle appeared normal. This study indicates that normal hormonal profiles are retained after tubal sterilization.     

A single dose of mifepristone (200 mg) in the immediate preovulatory phase offers contraceptive potential without cycle disruption

A single dose of mifepristone is an effective emergency contraceptive and has potential as a regular "once-a-month" pill. If given in the early luteal phase, the formation of a secretory endometrium is inhibited or delayed and implantation of the embryo prevented. We have explored the effect of giving the mifepristone just prior to ovulation on the ovarian and endometrial cycle. Seven women with regular menstrual cycles were studied during a control cycle and then in a second cycle when 200 mg mifepristone was given within 24 h of ovulation, i.e., when luteinizing hormone (LH) in serum was >15 IU/L and the dominant follicle was >18 mm. Ovulation was confirmed within 48 h by ultrasound in five of the seven women. The remaining two women had luteinized unruptured follicle. Following mifepristone, menses occurred after a normal luteal phase compared to control cycle (13.7 +/- 0.7 vs. 13.7 +/- 0.9 days). In all subjects the endometrium on LH + 6 in the treatment cycle showed no, or very little, secretory changes, suggesting it was unlikely that pregnancy would have occurred. We conclude that mifepristone could be given as a "once-a-month" contraceptive pill without causing significant disruption in the menstrual cycle in the majority of women for a 4-day period from just prior to ovulation until LH + 3.     

Is the contraceptive effect of 300 micrograms of norethisterone mainly peripheral or central?

The effect of norethisterone (NET) on pituitary function was evaluated by measuring circulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) during the mid follicular phase as well as before and after removal of the corpus luteum (CL) in 30 untreated women and 43 women treated with 300 micrograms of NET daily for three months. All untreated women exhibited significantly elevated FSH levels after removal of the CL irrespective of the stage of the luteal phase. In the NET-treated women, the levels of FSH were significantly raised in women with luteal activity but these levels were not influenced by the operative procedure in those women without luteal activity. The LH levels remained unchanged after removal of the CL in both untreated and NET-treated women. The results suggest that a low dose of gestagen exerts variable effects on pituitary function. The main contraceptive effect seems to be through direct interference with ovarian function.     

Clitoral artery blood flow in healthy young women: preliminary report on menstrual cycle and hormonal contraception

The aim of the present study was to measure clitoral artery blood flow throughout the menstrual cycle and in oral contraceptive users. We recruited healthy young women (n = 19, age range: 21-28 years; body-mass index: 18-23 kg/m2) without sexual dysfunction (Female Sexual Functioning Index criteria; Rosen et al., 2000). Clitoral arterial peak systolic velocity (PSV) in at least two phases of the same ovulatory cycle or during the second week of the pill was measured by doppler ultrasonography. Clitoral arterial PSV measures (cm/s) were superimposable during the follicular and the luteal phase of the menstrual cycle (10.4 +/- 1.2 versus 10.2 +/- 1.6), whereas a slight but significant increase (12.2 +/- 1.2, f = 3.99; p < 0.04) was evident at the time of ovulation. In addition, PSV measures were significantly higher in women taking hormonal contraception compared to women studied throughout the menstrual cycle (14.2 +/- 2.7 versus 10.8 +/- 1.5; p < .001). Whether or not these preliminary data may be of any significance to female sexual arousal throughout the menstrual cycle remains to be established.     

24-hour energy expenditure and the menstrual cycle

To determine whether 24-h energy expenditure changes during the menstrual cycle, 10 normally menstruating women in their 20s and 40s were measured repeatedly for periods of 36 and 46 h by simultaneous direct and indirect calorimetry. A standardized sedentary daily schedule included three meals to provide food intake equal to expenditure. Eight of the 10 women showed increases of 8-16% during the 14-day luteal phase following ovulation, a significant increase (p less than 0.00002 by direct calorimetry, p less than 0.001 by indirect calorimetry). One subjects, whose increase was 14% following ovulation, showed no significant change during a month when she took an oral contraceptive. Progesterone from the corpus luteum is the likely cause of a 9% increase in 24-h energy expenditure in normally menstruating women.     

Menstrual cycle and voluntary food intake in young Chinese women.

The effect of menstrual cycle phase on energy and macronutrients intakes was assessed in 20 university students (21.2+/-1.3 years) all of whom experienced ovulatory cycle as documented by a surge in urinary luteinizing hormone. Three-day food intake records, which consisted of one weekend day, were kept in both mid-follicular and mid-luteal phases. Mean daily energy intake was higher (p=0.02) in the luteal phase (6978+/-1847 kJ) than in the follicular phase (6095+/-1174 kJ). Intakes of carbohydrate and fat were also significantly elevated (by 15 and 21%, respectively) in the luteal phase. The menstrual phase effect on energy intake was attributed to the substantially higher intakes from Thursday through Sunday in the luteal phase. The proportion of energy from the three macronutrients was not affected by menstrual phase nor day of the week.     

Serum allopregnanolone levels relate to FSFI score during the menstrual cycle

The aim of this study was to measure serum allopregnanolone levels and other hormones in women who completed the Female Sexual Function Index (FSFI; Rosen et al., 2000) during the follicular or the luteal phase of the menstrual cycle. Twenty-nine women with a regular menstrual cycle completed the FSFI during days 5-7 and days 19-21 of their menstrual cycles. We collected a blood sample on the same days so that we could determine levels of allopregnanolone (AP), dehydroepiandrosterone (DHEA), free testosterone (FreeT), androstenedione (A), and estradiol (E2); we stored serum at--20 degrees C until we assayed it. We performed statistical analyses by parametric and nonparametric comparisons and correlations, as appropriate. We found that the full FSFI score was 23 +/- 11.3 (mean +/- SD; 31% under 95% confidence interval = 18.7) in our study population. We also found a significant positive correlation between serum allopregnanolone levels and each FSFI domain, including full scale score (r = 0.47, p < 0.01), with the exception of pain. Similarly, we found a positive correlation between FreeT and each FSFI domain and full scale score (r = 0.55, p < 0.002). We found no significant correlation among FSFI scores and DHEA, A, or E2 plasma levels. It is interesting to note that FSFI full score was significantly higher (p < 0.04) in women tested in the luteal phase compared to women tested in the follicular phase. Serum allopregnanolone may be relevant to female sexuality directly or by its influence on a woman's general sense of well-being during the menstrual cycle. Further studies are required to test the hypothesis that high serum allopregnanolone levels in the luteal phase play a role in women's attitudes toward self-report questionnaires on sexual function.     

黄体期避孕对月经影响的临床研究

目的:评估当妇女在月经周期有无保护性生活超过120h,或多次无保护性生活后于黄体期避孕对月经的影响。方法:在黄体期1次性服用米非司酮100mg并在36~48h后服用米索前列醇400μg,服药后观察月经情况。结果:100例受试者中4例妊娠,在成功避孕的96例中,月经提前68例(70·83%),延期15例(15·6%),无改变13例(13·5%)。服药前后比较,月经周期缩短,差异有显著性意义(P<0.01),服药后月经出血天数5·76±1·18天,与妇女原来出血天数比较差异有显著性意义(P<0.05),与服药前自身经量比较,经量减少1例,相似90例,增多5例,经量与服药前差异无显著性意义(P>0.05)。服药距下次月经时间为6·85±1·88天,服药距下次月经9~7天组和6~4天组月经周期缩短,与服药前相比差异均有显著性意义(P<0.05),而3~1天组月经周期改变不明显(P>0.05);出血天数及经量3组间无显著性差异(P>0.05)。结论:黄体期避孕有效率为96%,该方法可使妇女月经周期缩短,经期延长,且服药距下次月经时间长对月经周期影响较大。     

The influence of oxymetholone on the HCG stimulated corpus luteum

To determine whether HCG administration during the luteal phase will counteract the “luteolytic” effects of oxymetholone in humans (shortening of luteal phase length and decrease of blood progesterone), five women were studied during a total of 15 cycles. Blood progesterone levels were estimated during treatment with oxymetholone only, with HCG only, and with HCG employed simultaneously with oxymetholone.

In the presence of HCG, oxymetholone did not evoke precipitous menstrual bleeding; on the contrary, the luteal phase length was extended in the same way as with HCG treatment only. The ovarian progesterone output was increased: by an average of 70 percent over the control values, and by an average of 105 percent over values in the cycles with oxymetholone treatment only.

It is concluded that although oxymetholone interferes with the corpus luteum function of the normal luteal phase, this action is insufficient to interfere with the HCG stimulated corpus luteum. It is suggested that the HCG test be performed with compounds designated for post-conceptional fertility control.     

黄体期使用米非司酮配伍米索前列醇避孕对月经影响的临床研究

目的:探讨妇女在无保护性生活超过120h,或多次无保护性生活后在黄体期使用米非司酮配伍米索前列醇避孕对月经的影响。方法:观察对象在黄体期一次性服用米非司酮100mg并在36～48h后服用米索前列醇400μg,服药后随访2个月经周期。结果:在成功避孕的289例(98.6%)中,服药前月经周期29.36±2.14d,服药当月月经周期26.15±3.68d,差异有统计学意义(t=15.498,P<0.05);服药前经期5.42±1.02d,服药后当月经期5.61±1.09d,差异有统计学意义(t=-4.143,P(0.05);服药后当月经量与自身既往经量比较,无变化215例(74.4%),减少59例(20.4%),增多15例(5.2%)。服药后次月月经周期为29.65±2.82d,与服药前相比差异无统计学意义(t=-1.922,P>0.05);经期5.46±1.03d,与服药前比较差异无统计学意义(t=-1.609,P>0.05);经量无变化273例(94.5%),减少10例(3.5%),增多6例(2.1%)。服药距预计月经时间越长月经提前的时间就越长(F=3.445,P<0.05)。结论:妇女黄体期使用米非司酮配伍米索前列醇避孕有效率高,可使服药当月月经周期缩短、经期延长,且服药距预计月经时间越长对月经影响越大,但对以后月经无影响。