On the frequency of intercourse around ovulation: evidence for biological influences

BACKGROUND: Intercourse in mammals is often coordinated with ovulation, for example through fluctuations in libido or by the acceleration of ovulation with intercourse. Such coordination has not been established in humans. We explored this possibility by examining patterns of sexual intercourse in relation to ovulation. METHODS: Sixty-eight sexually active North Carolina women with either an intrauterine device or tubal ligation provided data for up to three menstrual cycles. These women collected daily urine specimens and kept daily diaries of intercourse and menstrual bleeding. Major estrogen and progesterone metabolites excreted in urine were used to identify the day of ovulation. The fertile days of the cycle were defined as the 6 consecutive days ending with ovulation. Women contributed a total of 171 ovulatory cycles. Menstrual bleeding days were excluded from analysis. RESULTS: The frequency of intercourse rose during the follicular phase, peaking at ovulation and declining abruptly thereafter. The 6 consecutive days with most frequent intercourse corresponded with the 6 fertile days of the menstrual cycle. Intercourse was 24% more frequent during the 6 fertile days than during the remaining non-bleeding days (P < 0.001). CONCLUSIONS: There apparently are biological factors that promote intercourse during a woman's 6 fertile days.     

Basal and day 12 inhibin concentrations in the prediction of ovarian response to gonadotrophins in women with PCOS

BACKGROUND: In this study, we aimed to investigate whether basal and day 12 serum total inhibin concentrations in women with polycystic ovarian syndrome (PCOS) were of predictive value for the estimation of the ovarian response to gonadotrophins. METHODS: Ovulation induction with a very low dose gonadotrophin protocol, starting with 37.5 IU/day, was performed for 40 cycles on 35 patients with PCOS. Day 3 (basal) serum total inhibin, FSH and oestradiol concentrations; day 12 dominant follicle diameter, inhibin and oestradiol concentrations and midluteal serum progesterone concentrations were measured during the 40 cycles. The correlations between basal and day 12 inhibin concentrations and some critical ovulation monitoring parameters were investigated. RESULTS: Ovulation was obtained in 14 out of 40 cycles: 21% of cycles with basal inhibin <1.0 IU/ml; 33.3% of cycles with basal inhibin between 1.0-1.9 IU/ml; and 83.3% of those with inhibin concentrations > or =2 IU/ml were ovulatory (P < 0.05). Ovulation was achieved in 91.6% of the cycles with a day 12 inhibin concentration > or =4 IU/ml. CONCLUSIONS: Basal inhibin concentrations may determine poor and good responders to ovulation induction with very low dose gonadotrophin protocol in patients with PCOS. The day 12 inhibin concentration was found to be a more sensitive parameter than the oestradiol concentration in the prediction of follicular maturation.     

Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study

BACKGROUND: Previous data on the efficacy of clomiphene citrate, the most commonly used drug for treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS), have shown a discrepancy between ovulation and pregnancy rates. In the present subanalysis (of a larger previously published randomized controlled trial), the effect of clomiphene citrate on several ultrasonographic markers of uterine receptivity in PCOS patients who ovulated under treatment was studied. METHODS: Thirty-three PCOS women who ovulated under 150 mg daily clomiphene citrate and 33 healthy controls were studied. Uterine, subendometrial and endometrial blood flows, endometrial thickness and pattern were assessed using serial ultrasonographic assessments. The data were analysed before and after grouping the clomiphene citrate-stimulated ovulatory cycles for reproductive outcome [unfavourable (ovulation alone or early pregnancy loss) or favourable outcome (clinical pregnancy and/or live birth)]. RESULTS: Both before and during treatment, uterine vascularity assessed at all sites was significantly lower in the PCOS group than in controls. Endometrial thickness and pattern were impaired in the PCOS group under clomiphene citrate treatment. A significant difference in all ultrasonographic parameters was observed between cycles ending in unfavourable versus those ended in favourable outcome. CONCLUSIONS: Clomiphene citrate administration alters several surrogate ultrasonographic parameters of uterine receptivity, and this effect could be crucial for its efficacy.     

Infertility: Corpus luteum function and pregnancy rates with clomiphene citrate therapy: comparison of human chorionic gonadotrophin-induced versus spontaneous ovulation

A total of 508 clomiphene citrate cycles with intra-uterineinsemination (IUI) performed in 233 consecutive patients werestudied. In 247 cycles insemination was performed 36–38h after human chorionic gonadotrophin (HCG)-triggered ovulation;in the remaining 261 cycles IUI was performed 18–20 hafter urinary luteinizing hormone (LH) kit detection of a spontaneousLH surge. Corpus luteum function, as determined by luteal phaselength and midluteal progesterone concentrations, together withpregnancy rates were analysed. There was no difference in lutealphase parameters between spontaneous and HCG-triggered cycleswhen adjusting for patient age. Furthermore, the pregnancy ratesdid not differ between the HCG and LH kit groups, even afteradjusting for patient age and number of motile spermatozoa inseminated.Additionally, the large numbers of cycles analysed providedsufficient power to detect increases in clinical pregnancy ratesin spontaneous ovulatory cycles and HCG-induced ovulation of10.1 and 2.4% respectively, using the customary significancelevel (alpha-type error) of 0.05. These findings indicate thatpregnancy rates and corpus luteum function in carefully monitoredclomiphene citrate/IUI cycles do not differ between HCG-triggeredand spontaneous ovulatory cycles.     

Folliculogenesis and ovulation in infertile women with mild endometriosis

Twenty-one infertile women with laparoscopically documented minimal-mild endometriosis (AFS score 2-10) were studied during 27 cycles (six women had two cycles each) to investigate follicular development and ovulation. Of the 27 cycles studies, 24 (89%) appeared to be endocrinologically normal and ovulatory. Luteinized unruptured follicle (LUF) occurred in only one cycle (4%). One further patient exhibited abnormal endocrinology with evidence of premature ovulation over two (8%) consecutive cycles. This study indicates that the majority of women with minimal-mild endometriosis have endocrinologically normal menstrual cycles and that luteinized unruptured follicles occur infrequently.     

Validating signals of ovulation: Do women who think they know,really know?

This study was carried out to test whether women who think they know when they ovulate, really know. Fifty-three women of age 18.7 to 46.1 (mean age 28.4 years) participated in initial interviews about ovulation. Criteria for recruitment included perceived ovulation, regular menstrual cycles, and not using hormonal contraception. Women collected and refrigerated urine samples from day 5 until they thought they ovulated. Samples collected within 48 h of the perceived signal were then tested for a pre-ovulatory LH surge. Of the 53 original participants, 36 women provided urine samples for 1-6 cycles, so that 87 cycles were tested. Subjective signals of ovulation varied between women and between cycles but included abdominal pain and changes in cervical discharge, libido, and mood. Of the 87 cycles tested, during which women identified one or multiple signals of ovulation, 37 of the 87 urine specimens tested positive for an LH surge for a concordance rate of 42.5%. Using the first tested cycle from the 36 women who provided urine specimens, 13 of those specimens demonstrated an LH surge, for a concordance rate of 36.1%. That rate dropped to 28% (7/25) when women who used basal body temperature as an ovulatory signal were excluded. Finally, the mean level of accuracy among the 15 women who contributed 3-6 urine specimens for testing was 48.9%. The results of this study demonstrate a low degree of concordance between LH surge and perceived ovulation among women who think they know when they ovulate. The most motivated study participants were right about half of the time. Although there is variation among women in their ability to know when they ovulate, this study suggests that, for most women, ovulation is concealed.     

The effects of ketoprofen on ovarian function in dairy cows

Two experiments were conducted to investigate the effects of ketoprofen on ovarian function in dairy cows. In experiment I, eight non-milking dairy cows were administered a 0.9% saline solution daily from day 8 (day −3) of ensuing synchronized estrous cycle at 24-h intervals over 4 days (control observation). After an estrous cycle rest, the cows were given the recommended daily therapeutic dose (3 mg/kg, i.m.) of ketoprofen (Ketofen 100; 10%, Merieux/Webster, Australia) from day 8 (day −3) of the synchronized estrous cycle at 24-h intervals over 4 days. All cows received an intramuscular injection of prostaglandin (30 mg, Lutalyse) either 6 h before the first treatment of saline solution or 6 h before the first injection of ketoprofen. Ultrasonography of the ovaries was performed daily from the day before (day −4) experimental treatments until day 2 after induced estrus, to monitor the growth of the ovulatory follicle and ovulation, and then on day 9 after estrus to determine the presence and the size of the corpus luteum. In experiment II, five non-milking dairy cows were used in two successive observations. The plasma preovulatory estradiol-17β peak and progesterone concentrations were determined, and ovarian ultrasonography was performed to determine ovulation and corpus luteum development. Results obtained from experiment I showed that the diameter of dominant ovulatory follicle on day of estrus was significantly (p<0.05) higher in saline-treated estrous cycle compared to that of ketoprofen-treated cycles (13.8±1.3 vs 10.9±0.4 mm). Furthermore, by 48 h after standing estrus, ovulation had taken place in seven of eight saline-treated estrous cycles, whereas only three ketoprofen-treated cows had ovulated by 48 h after standing estrus (p<0.05). A significantly (p<0.05) higher mean estradiol-17β peak was observed in ketoprofen-treated estrous cycles at estrus compared to that of the control estrous cycles (experiment II). Additionally, a significant (p<0.05) daily increase in the mean plasma progesterone concentration was observed after ketoprofen treatment beginning from day 0 to 6 of the subsequent estrous cycle (p<0.05). The results of the present study demonstrate that administration of ketoprofen during the pre- and periovulatory period of the estrous cycle in dairy cows impairs final growth of ovulatory follicle, leading to a disturbance in the normal process of ovulation.     

The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain.

BACKGROUND: Until recently, human menopausal gonadotrophin (HMG), a urinary extract containing a fixed combination of LH and FSH, was the only source of exogenous LH for women with hypogonadotrophic hypogonadism undergoing ovulation induction with gonadotrophins. Recombinant human LH (rLH) is now available for clinical use, providing a new treatment option but clinical data on its use are scanty. Therefore, the aim of the present study was to investigate the efficacy and safety of rLH combined with recombinant FSH (rFSH) to induce follicular development and ovulation in World Health Organization (WHO) group I anovulatory women. METHODS: We included in this multicentre study 38 hypogonadotrophic anovulatory (WHO group I) women. Patients received 150 IU/day rFSH and 75 IU/day rLH (with the possibility of dose adjustment) as a single s.c. injection for up to three cycles with a total of 84 treatment cycles. RESULTS: Sufficient follicular growth was observed in 79 (94%) out of 84 initiated cycles. The 75 IU rLH dose was found to be effective in most treatment cycles (94%) and only five cycles in three patients required daily dose increase. Overall, HCG was administered to trigger ovulation in 67 (80%) of the 84 cycles while it was withheld in 12 cycles (14%) due to ovarian hyper-response and five cycles (6%) were cancelled for insufficient follicular growth. The pregnancy rate per started treatment cycle and per cycle given HCG was 18 and 22.4% respectively. Pregnancy was achieved by 15 (39.5%) of the 38 patients. Mild to moderate ovarian hyperstimulation syndrome occurred in three patients. Local tolerance was good. CONCLUSIONS: This study confirms that combined rFSH and rLH treatment induces follicular growth, ovulation and pregnancy in a good proportion of hypogonadotrophic anovulatory patients and is well tolerated. The doses of 150 IU rFSH and 75 IU rLH daily seem the most appropriate but in a small minority of patients doses >75 IU rLH/day may be necessary.     

The role of pre-ovulatory progesterone in the midcycle gonadotrophin surge, ovulation and subsequent luteal phase: studies with RU486 in rhesus monkeys

Conflicting evidence exists on the possible physiological roleof progesterone in the regulation of the midcycle surge of gonadotrophinsduring the normal primate menstrual cycle. We designed the presentstudy based on the availability of a potent antiprogesterone,RU486, that acts by binding to the progesterone receptor withoutinducing progestational activity. Regularly cycling rhesus monkeysreceived daily administration of RU486,10 mg orally (n = 8)or vehicle (n = 5) from the day of the menstrual cycle in whichserum oestradiol was 130 pg/ml or more, and a laparoscopy revealedthe presence of a dominant follicle. While vehicle administrationdid not affect the normal ovulatory pattern nor the hormonalmilieu of the menstrual cycles, RU486 induced marked aberrationsduring the treated cycles. Delay of ovulation with a normalsubsequent luteal phase was observed in three animals. Threeanimals remained anovulatory until the following cycle and twoanimals that ovulated on days 14 and 16 of the treated cycleshad short luteal phases. Analysis of daily FSH, LH, oestradioland progesterone revealed that the administration of RU486 disruptedthe midcycle pattern of gonadotrophins by disrupting them afterthe surge was initiated. Oestradiol surges were not differentfrom controls and in all animals the ascendant levels of progesteronewere interrupted by the administration of the antiprogesterone.This study clearly shows that the pre-ovulatory administrationof RU486, a potent antiprogesterone, alters pre-ovulatory gonadotrophinsecretion, inducing different degrees of menstrual irregularitiessuch as anovulation, delayed ovulations and short luteal phases.Based on these results it is possible to speculate that progesteroneexerts a facilitatory effect (positive feed-back) on the midcyclegonadotrophin peak that induces ovulation in primates.     

Effect of long-term treatment with low-dose mifepristone on the endometrium

BACKGROUND: Mifepristone in low daily doses has contraceptive potential by inhibiting ovulation and menstruation. Because follicular development is maintained, the endometrium is exposed to estrogen for prolonged periods unopposed by progesterone. METHODS: Endometrial biopsies were collected from 90 women in Edinburgh and Shanghai before (late proliferative) and 60 and 120 days after taking 2 or 5 mg mifepristone per day for 120 days. RESULTS: Ovulation and menstruation were inhibited in >90% of cycles and estrogen production was similar to that observed during the follicular phase of the control cycle. By 120 days, endometrial thickness increased significantly in women in Edinburgh but decreased in Shanghai. Endometrial histology showed inactive proliferative or cystic changes with dense stroma. There was a significant decrease in markers of proliferation, i.e. mitotic index and Ki67 staining. There were no pregnancies in a total of 200 women-months in 50 sexually active women who used no other method of contraception. CONCLUSIONS: We confirm that ovulation and menstruation were suppressed in the majority of cycles and there was asynchrony between ovarian activity and endometrial histology, which showed no signs of hyperplasia or atypia. These preliminary data suggest that daily low-dose mifepristone is potentially a safe estrogen-free contraceptive pill which has the added health benefit of amenorrhoea.     

High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.

This preliminary report reviews our experience with 18 infertile patients with clomiphene-resistant polycystic ovary syndrome (PCOS). In the first treatment cycle, troglitazone was administered alone. During cycles 2-5, clomiphene was added with increments of 50 mg (up to 200 mg/day) if the previous cycle was anovulatory. Basal body temperature charts and serum progesterone were obtained to confirm ovulation. In a total of 66 treatment cycles, ovulation occurred in 44 (67%) and pregnancy in seven (11%). There were no significant changes in body weight, waist:hip ratio or liver enzymes during treatment. Troglitazone, alone or with clomiphene, induced ovulation in 15 of 18 patients (83%) and seven (39%) of them achieved pregnancy. This is the first report on ovulatory rates in clomiphene-resistant women with PCOS when troglitazone was used alone or with clomiphene. Recently, metformin and clomiphene were successfully used in women with PCOS. However, our patients represent a more resistant population of women with PCOS, with each patient serving as her own historical control by previous resistance to clomiphene. Although the pregnancy rate (39%) was promising for clomiphene-resistant women with polycystic ovary syndrome, it does not seem to have a definite advantage over gonadotrophins.     

Effect of cyclofenil on hormonal dynamics, follicular development and cervical mucus in normal and oligomenorrhoeic women.

Cyclofenil is a triphenylethylene derivative, similar in structure to clomiphene citrate, which is used to induce ovulation in anovulatory women. The effects of cyclofenil on a group of 10 normal cyclic and 10 oligomenorrhoeic subjects were examined in a double blind controlled cross-over study. Both groups of women were administered either cyclofenil or, following a washout cycle, a placebo in two treatment cycles. Urinary oestrone and pregnanediol excretion were measured daily and ultrasound scans performed to assess follicular development. Frequent sampling of blood was performed on day 6 to study luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile release. Cervical mucus changes and sperm-cervical mucus interaction were studied after identification of the LH peak. There were no significant differences between cyclofenil and placebo cycles in the following: ovulation rates, daily urinary oestrone and pregnanediol excretion, the number or size of developing follicles, LH pulsatility (parameters studied: number of peaks, pulse interval, pulse amplitude, pulse area and mean nadir LH), mean FSH level on day 6, cervical mucus and sperm-cervical mucus interaction. In view of our inability to demonstrate an effect on any parameter of endocrine function in normal and oligomenorrhoeic women, these results throw doubt on the therapeutic value of cyclofenil in its present dosage and formulation.     

Estimated maximum failure rates of cycle monitors using daily conception probabilities in the menstrual cycle

BACKGROUND: A number of menstrual cycle monitors have been developed to detect the fertile window of the menstrual cycle, mainly for contraceptive purposes. Reliable data on most of these systems are still missing but are urgently needed because many women use them and the tested systems differ enormously in price and effectiveness. We suggest a new efficacy estimating method to evaluate cycle monitors prior to full prospective clinical trials. METHODS: Sixty-two women prospectively tested seven cycle monitors and the symptothermal method (STM) of natural family planning (NFP) but not more than two different systems at the same time. The clinical fertile window was determined by detecting the day of ovulation using daily urinary LH measurements and daily ultrasonic folliculometry. This was compared to the fertile phase predicted by the systems. Maximum failure rates were estimated for each cycle monitor and the STM, using the daily conception probability rates taken from the European Fecundability Study. Intercourse was assumed to occur on each of all falsely predicted days of infertility. RESULTS: Sixty-two women with a mean age of 31 years (range: 21-42 years) contributed a total of 122 cycles to this study. Monitors based on the microscopic evaluation of saliva or mucus had many more false infertile days than the other methods based on temperature or hormonal measurements (225 versus 42 days). The maximum unintended pregnancy rates per cycle for temperature computers were estimated to be 0.0134-0.0336, for the hormonal computer 0.1155 and for mini-microscopes 0.2313-0.2369. For the STM of NFP, there were no false infertile days. CONCLUSIONS: The STM of NFP proved to be the most effective contraceptive method to detect the fertile window among all the methods tested. The estimated efficacy of the other cycle monitors range from the temperature computers (upper level) to the hormonal computer (medium level) and the mini-microscopes with very low estimated contraceptive efficacy.     

Endocrinology: Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients

A total of 82 normogonadotrophic clomiphene-resistant anovulatorypatients were treated with exogenous gonadotrophins accordingto a step-down dose regimen during 234 cycles. In 43 (18%) cyclesco-treatment with gonadotrophin-releasing hormone analogueswas applied. The initial dose was between 1.5 and 2.5 ampoules(75 IU folliclestimulating hormone each) per day (dependenton body weight), and decreasing steps of 0.5 ampoules/day werebased on sonographic findings. The overall ovulation rate was91% (213 cycles). The median treatment period was 11 days anda total of 14 ampoules of gonadotrophin were needed. In 131(62%) of the ovulatory cycles not more than one, and in 208(98%) cycles not more than two, follicles 16 mm were presenton the day human chorionic gonadotrophin was given. A totalof 37 pregnancies occurred of which two were twins and one wasa triplet (multiple pregnancy rate 8%). The pregnancy rate percycle was 17% and the cumulative pregnancy rate after 7 monthswas 47%. The abortion rate was 19%. There were four (1.7%) casesof mild ovarian hyperstimulation, of which none became pregnant.In conclusion, this study shows that the applied step-down regimenfor gonadotrophin induction of ovulation can be a safe and effectivetreatment alternative for patients with clomiphene-resistantanovulation. The duration of ovarian stimulation and the amountof exogenous gonadotrophin required is limited. Pregnancy ratesare comparable with those reported for step-up regimens, anda low incidence of complications (i.e. multiple gestation andovarian hyperstimulation) was noted. Although data obtainedfrom this non-comparative study appear favourable, a prospectivecomparative trial is mandatory to confirm and extend these observations.     

Implantation: Ovulation induction and endometrial steroid receptors

The endometrial morphology, endometrial steroid receptors andserum steroid hormone concentrations have been studied in 22infertile women participating in an in-vitro fertilization,gamete intra-Fallopian transfer programme, including nine casesfollowing treatment with gonadotrophin-releasing hormone analogue/humanmenopausal gonadotrophin/human chorionic gonadotrophin. Allpatients had normal ovulatory function before treatment andsatisfactory response to ovulation induction. Endometrial biopsieswere taken in spontaneous and treatment cycles on the fourthday after ovulation had been detected by ultrasound scanning,when endometrial receptors were measured using immunohisto-chemistry.Histological examination of biopsies in spontaneous cycles showedthe majority (20/22) to be ‘in-phase’, while intwo cases luteal phase defect was diagnosed. After ovulationinduction, all the biopsies were still morphologically ‘in-phase’,although a significant reduction had occurred in the nuclearreceptor level in both the glands and stroma for both progesteronereceptors (gland P = 0.030, stroma P = 0.012 using microscopicanalysis; gland P = 0.020, stroma P < 0.001 using a cellanalysis system) and oestrogen receptors (gland P = 0.017, stromaP = 0.002 using direct microscopic analysis). This suggeststhat a reduction in steroid receptors in the endometrium occursafter ovulation induction in the presence of supraphysiologicalamounts of steroids, which is not associated with detectablemorphological changes     

Changes with age in the level and duration of fertility in the menstrual cycle

BACKGROUND: Most analyses of age-related changes in fertility cannot separate effects due to reduced frequency of sexual intercourse from effects directly related to ageing. Information on intercourse collected daily through each menstrual cycle provides the data for estimating day-specific probabilities of pregnancy for specific days relative to ovulation, and these estimates allow unconfounded analysis of ageing effects. METHODS: A total of 782 healthy couples using natural family planning methods contributed prospective data on 5860 menstrual cycles. Day of ovulation was based on basal body temperature measurements. Estimates of day-specific probabilities of pregnancy and the length of the fertile window were compared across age groups. RESULTS: Nearly all pregnancies occurred within a 6 day fertile window. There was no evidence for a shorter fertile window in older men or women. On average, the day-specific probabilities of pregnancy declined with age for women from the late 20s onward, with probabilities of pregnancy twice as high for women aged 19-26 years compared with women aged 35-39 years. Controlling for age of the woman, fertility was significantly reduced for men aged >35 years. CONCLUSIONS: Women's fertility begins to decline in the late 20s with substantial decreases by the late 30s. Fertility for men is less affected by age, but shows significant decline by the late 30s.     

Uterus and endometrium: Effects of daily low dose mifepristone on endometrial maturation and proliferation

Following an ovulatory control cycle, six women took 2 mg ofmifepristone daily for 30 days. Endometrial biopsies were collectedin the control cycle between 7 and 11 days after the plasmaluteinizing hormone (LH) surge and on the corresponding dayof the treatment cycle (days 19–28). In order to investigatethe effects of unopposed oestrogen on the endometrium, persistentproliferative endometrium was obtained from six women with anovulatoryinfertility due to polycystic ovarian syndrome (PCOS) on a similarcycle day (days 21–23) following a progestogen-inducedwithdrawal bleed. Endometrium was evaluated for histology andimmuno-localization of oestrogen receptors (ER), progesteronereceptors (PR) and the cell proliferation markers [proliferatingcell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristoneinhibited ovulation in four of the six subjects. In the twosubjects in whom ovulation did occur, secretory transformationwas delayed, suggesting that successful implantation of a blastocystwould be unlikely. In subjects who remained anovulatory duringtreatment, the histology and pattern of steroid receptor expressionwas similar to proliferative phase endometrium. In women withPCOS, mitoses and intense immunostaining for ER, PR and cellproliferation markers were observed in both glands and stroma.Although PCNA and Ki67 immunostaining were also present in mifepristone-treatedendometrium from subjects who did not ovulate, there were nomitoses and significantly less ER immunostaining in spite ofexposure to unopposed oestrogen for a similar duration. SincePCNA and Ki67 detect cells throughout all stages of the cellcycle this would suggest that mifepristone might affect theentry of cells into the mitotic phase of the cell cycle and,therefore, might prevent endometrial hyperplasia. These findingsadd further evidence to support the contraceptive potentialand antiproUferative activity of daily low dose mifepristone.     

Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices,ovarian physiology and fertility rate induced by diet

BACKGROUND: This prospective study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome (PCOS). METHODS: Thirty-three anovulatory overweight patients with PCOS were enrolled in the study. All had patent Fallopian tubes and chronic anovulation: 27 of them were oligo-amenorrhoeic. The partners were normospermic. Patients were prescribed a 1200 kcal/day diet, and physical exercise was recommended. Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10%. RESULTS: Twenty-five patients (76%) lost at least 5% of their body weight. Eleven of these patients (33%) reached a 10% decrease in weight. Waist circumference at the umbilical level, hip circumference, four skin folds, body mass index and fatty mass ratio were significantly reduced after 5 and 10% weight loss. Ovarian morphology changed during the diet: we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary. Among the 27 patients with oligo-amenorrhoea, 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation; 10 spontaneous pregnancies occurred in patients who lost at least 5% of their weight. CONCLUSIONS: Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients, reduces ovarian volume and microfollicle number and can restore ovulatory cycles, allowing spontaneous pregnancy.     

Effect of low daily doses of mifepristone on ovarian function and endometrial development

The effects of low daily doses of the antiprogestin mifepristone (RU 486) on ovarian and endometrial function were studied. The study included one control cycle, three treatment cycles and one follow-up cycle. During the treatment cycles, either 0.1 (n = 5) or 0.5 (n = 5) mg of mifepristone was administered once daily. Urine samples were collected three times weekly during the control and treatment cycles and pregnanediol glucuronide and oestrone glucuronide and luteinizing hormone (LH) were quantified by radioimmunoassay. Blood samples for cortisol measurement were collected once weekly and for serum glycodelin at the onset of menstruation. An endometrial biopsy was obtained in the mid-luteal phase in the control cycle and in the first and third treatment cycles and analysed by morphometric and histochemical methods. Binding of Dolichus biflorus agglutinin (DBA) lectin was measured and expression of progesterone and oestrogen receptors and glycodelin were analysed immunohistochemically. All cycles studied were ovulatory with an LH peak and elevated pregnanediol glucuronide concentrations. Follicular development seemed normal as judged by ultrasound examination. The length of the menstrual cycle and the menstrual bleeding were not significantly altered. Following administration of 0.5 mg mifepristone/day, endometrial development appeared to be slightly retarded and glandular diameter was significantly reduced. Furthermore, significant decreases in DBA lectin binding and endometrial expression of glycodelin were observed. Daily doses of 0.1 mg did not have any significant effect on the endometrium. No differences in oestrogen or progesterone receptor immunoactivity between control and treatment cycles were seen. This study provides further evidence that endometrial function is sensitive even to doses of antiprogestin that are low enough not to disturb ovulation. It remains to be established whether these effects are sufficient to prevent implantation.      

Early luteal phase treatment with mifepristone (RU 486) for fertility regulation

Mifepristone (RU 486) is an antiprogestin which interacts withprogesterone at the receptor level. Administration of mifepristoneimmediately after ovulation does not upset the menstrual cycle.However, the maturation and function of the endometrium is inhibitedand uterine contractility is changed. To test if these effectsare sufficient to prevent implantation, 21 women agreed to useone single treatment with 200 mg mifepristone on day luteinizinghormone (LH) + 2 monthly as their only contraceptive method.The women were treated for 1– 12 months. The time of theLH peak was determined in the urine by the women themselvesusing a rapid LH test (Ovu-quick, Organon). The overall numberof cycles studied was 169. In 12 cycles the women were unableto detect the LH peak. In these cycles no treatment was givenand the women advised to use barrier methods during the timeto menstruation. The remaining 157 cycles with a detectableLH peak were all ovulatory based on plasma progesterone measurement.One pregnancy occurred. On the basis of the time of the LH peak,it was retrospectively calculated that in 124 cycles at leastone act of intercourse occurred during the period 3 days beforeto 1 day after ovulation. The probability of pregnancy in thisperiod of the menstrual cycle is thus 0.008. The women did notcomplain of any treatment-related side-effects apart from slightbleeding for 2–3 days starting a few days after the dayof treatment in 35% of the cycles. The results show that theeffect of mifepristone on the endometrium is sufficent to preventpregnancy and indicate that treatment with antiprogestin canalso be used for contraceptive purposes.