Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation.

Cyclic and individualized administration of gonadotropin-releasing hormone agonists plus progestogens: an alternative protocol for contraception.

Twenty-one women presenting with different diseases, with absolute or relative contraindications to hormonal contraception or the use of intrauterine devices, received 300-600 micrograms/day buserelin intranasally from the 1st to the 21st day, and 5 mg/day norethisterone acetate orally from the 16th to the 23rd day of the cycle for a total of 245 cycles. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and testosterone were determined on days 3-5 and 13-15 of the cycle, while progesterone determinations and ovarian sonography were performed during the second half of the cycle. According to progesterone values, 92.7% of the treatment cycles were anovulatory, while in one cycle pregnancy was detected (0.4%). Values of serum LH, FSH and estradiol were low, and in most of the cycles ovarian follicular development was limited to follicles < or = 11 mm. In 21 treatment cycles (9%), statistically significant increases in FSH (p < 0.0001) and LH (p < 0.02), as well as ovarian proliferation to preovulatory follicles or luteinized follicles, were found. It appears that in spite of the high cost of medication and monitoring of patients, this regimen could be useful as an alternative in cases where other forms of contraception are contraindicated or have failed.

Cyclic progestin administration brings about luteinization during continuous antiprogestin treatment.

The antiprogestin RU 486 has been proposed for use as a contraceptive because it disturbs folliculogenesis and inhibits ovulation when given continuously. In order to achieve regular and predictable withdrawal bleeding and to counteract the continuous influence of estrogen on the endometrium, a sequential, cyclic progestin regimen has been added. The drawback has been the frequent rise in the concentration of serum P, suggesting ovulation. The present pilot study with three subjects was carried out to test whether simultaneous administration of RU 486 and progestin during the second half of the cycle would eliminate the rise in serum P concentrations. Based on elevated serum P values, five of the seven cycles were apparently ovulatory. RU 486 alone, when given throughout the cycle at a dose of 8 mg per day without added progestin, resulted in anovulatory cycles, but the lengths of these cycles were prolonged. We conclude that both simultaneous and sequential cyclic co-administration of progestin with RU 486 abolishes the antiovulatory action of RU 486. This decreases the possibility of using antiprogestins in non-estrogenic contraceptive regimens (unless contraceptive effects of RU 486 exist at the endometrial level).

Clinical efficacy of the antiprogesterone RU486 in the treatment of endometriosis and uterine fibroids.

To evaluate the long-term effects of treatment with RU486 and to test its efficacy in endometriosis, a 3-month trial was conducted to evaluate the effects of daily administration (100 mg/day or approximately 2 mg/kg/day) on the functional activity of the reproductive axis, as well as implants, in patients with symptomatic pelvic endometriosis. All women became amenorrhoeic and acyclic. However, ovarian suppression was incomplete. In 24 h sampling studies, mean luteinizing hormone (LH) and LH pulse amplitude were increased without a change in LH pulse frequency. Additionally, an antiglucocorticoid effect was demonstrated. Treatment resulted in improvement in pelvic pain in all subjects without significant changes in the extent of disease as evaluated by laparoscopy. We also attempted to reduce the growth of uterine fibroids by using 50 mg/day of RU486 for 3 months in 10 patients. Myoma size decreased approximately 22% at 4 weeks, 39% at 8 weeks and 49% at 12 weeks. Serum concentrations of LH, androstenedione and testosterone increased in the first 3 weeks of treatment and then returned to baseline. In conclusion, daily administration of RU486 resulted in ovarian inhibition and menstrual acyclicity and in an improvement in the pain associated with pelvic endometriosis and decreased the size of uterine fibroids. This ovarian inhibition was achieved without oestrogen deprivation and may provide a novel long-term approach to the treatment of ovarian steroid-dependent disease processes.

The response of the pituitary-ovarian axis to pulsatile administration of gonadotropin-releasing hormone in long-term oral contraceptive users.

OBJECTIVE: Our purpose was to differentiate between pituitary and hypothalamic feedback effects of oral contraceptives. STUDY DESIGN: Twenty micrograms of gonadotropin-releasing hormone was administered intravenously at 90-minute intervals for 4 days to 14 long-term users of a combined oral contraceptive (30 micrograms of ethinyl estradiol and 150 micrograms of levonorgestrel), starting at different moments in the pill cycle. On the fourth day of administration the pulsatile release of luteinizing hormone was determined by blood sampling every 10 minutes for 6 hours. The sensitivity of the pituitary was determined before, during, and after treatment with gonadotropin-releasing hormone by a 100 micrograms gonadotropin-releasing hormone challenge test. On each sampling day serum estradiol, progesterone, and prolactin levels were measured, and ovarian ultrasonography was performed. RESULTS: After 4 days of pulsatile gonadotropin-releasing hormone administration every exogenous gonadotropin-releasing hormone bolus was followed by an endogenous luteinizing hormone pulse of high amplitude (median 3.30 U/L). Both serum luteinizing hormone and follicle-stimulating hormone levels increased significantly (p < 0.001). The increase in follicle-stimulating hormone levels was accompanied by an increase in serum estradiol (p < 0.01). The luteinizing hormone response to a 100 micrograms bolus of gonadotropin-releasing hormone decreased during gonadotropin-releasing hormone treatment (p < 0.01), whereas the follicle-stimulating hormone response did not change. CONCLUSION: Pituitary sensitivity is not impaired during oral contraceptive use, suggesting that oral contraceptives exert their negative feedback effects predominantly at the hypothalamic level.

The effects of levonorgestrel, desogestrel and gestodene on the pulsatile release of luteinizing hormone in oral contraceptive users.

The dynamics of luteinizing hormone (LH) and follicle stimulating hormone (FSH) release were investigated in 60 long-term oral contraceptive (OC) users. Five different types of OC, all containing the same amount of estrogens were studied: three monophasic preparations containing levonorgestrel, desogestrel and gestodene, respectively, and two triphasic formulations, containing levonorgestrel or gestodene. Thirteen healthy, normally cycling volunteers served as controls. Blood sampling was performed at 10-min intervals during a 6-h period to determine the pulsatile release of LH. LH and FSH were measured using a sensitive immunoradiometric assay. Pulse patterns were classified on the basis of the overall LH level, as well as on the character of the LH pulses, according to both frequency and amplitude characteristics. Pulsatile LH release was maintained during OC use. After the 7-day pill-free interval, FSH levels as well as the LH pulse patterns were comparable to those of early follicular-phase controls. FSH levels and FSH release in response to a gonadotropin releasing hormone (GnRH) challenge were profoundly suppressed in all OC users, as early as day 8 of the pill cycle. LH release during the pill cycle was characterized by either a low frequency (median 1 pulse/6 h), high amplitude (median 2.5 IU/l) pulse pattern or by a pattern of low-amplitude pulses (median 0.2 IU/l) and low basal LH levels (median 0.2 IU/l). The distribution of these pulse patterns showed marked differences between different OC preparations and depended on both the type and dose regimen of the gestagenic component of the OC.

Pulsatile luteinizing hormone patterns in long term oral contraceptive users.

Oral contraceptives (OC) inhibit folliculogenesis by a central suppressive action on the release of gonadotropins. To characterize the nature of these central effects, we studied 40 long term OC users on 3 different OCs: two monophasic preparations with 30 micrograms ethinyl estradiol and 150 micrograms l-norgestrel (group 1; n = 15), 150 micrograms desogestrel (group 2; n = 10), and a triphasic formulation containing 30-40 micrograms ethinyl estradiol and 50, 75, and 125 micrograms l-norgestrel (group 3; n = 15). Blood sampling at 10-min intervals during 6-h periods was performed at different moments in the pill cycle. Thirteen healthy volunteers with regular ovulatory cycles served as normal controls. FSH and LH were measured by a sensitive immunoradiometric assay. Pulsatile LH release was observed in all OC users. Mean serum LH and FSH levels, number of LH pulses per 6 h, and the amplitude of LH pulses on day 1 of the pill cycle did not differ from early follicular phase control values. FSH levels were rapidly suppressed from day 2 onward in all three groups, whereas LH levels progressively declined in groups 1 and 2 from day 8 onward. In group 3, however, LH levels were only significantly suppressed after day 13. The number of LH pulses per 6 h decreased in all groups starting on day 2, whereas the amplitude of LH pulses increased. A substantial percentage of LH pulses observed in OC users after day 1 were of low amplitude (< 0.75 IU/L). From these results, we conclude that 1) pulsatile release of LH is maintained during OC use; 2) FSH levels are suppressed equally early and equally effective by all OCs studied; 3) during OC use, the number of LH pulses per 6 h is reduced; 4) modulation of LH pulse amplitudes, and subsequently of serum LH levels, is mainly mediated by a dose- and time-dependent effect of the gestagenic component of the OC; and 5) after the 7-day pill-free interval, a normal early follicular phase pulse pattern is found, even in long term OC users, suggesting that in this period, most of the steroidogenic feedback effects wear off.

PIP: Oral contraceptives (OCs) inhibit folliculogenesis by a central suppressive action on the release of gonadotropins. To characterize the nature of these central effects, the authors studied 40 long-term OC users different OCs: 2 monophasic preparations with 30 mcg ethinyl estradiol and 150 mcg 1-norgestrel (group 1, n + 15), 150 mcg desogestrel (group 2; n = 10), and a triphasic formulation containing 30-40 mcg ethinyl estradiol and 50, 75, and 125 mcg 1-norgestrel (group 3; n = 15). Blood sampling at 10-minute intervals during 6-hour periods was performed at different moments in the pill cycle. 13 healthy volunteers with regular ovulatory cycles served a normal controls. FSH and LH were measured by a sensitive immunoradiometric assay. Pulsatile LH release was observed in all OC users. Mean serum LH and FSH level,s number of LH pulses per 6 hours, and the amplitude of LH pulses on day 1 of the pill cycle did not differ from early follicular phase control values. FSH levels were rapidly suppressed from day 2 onward in all 3 groups, whereas LH levels progressively declined in groups 1 and 2 from day 8 onward. In group 3, however, LH levels were only significantly suppressed after day 13. The number of LH pulses per 6 hours decreased in all groups starting on day 2, whereas the amplitude of LH pulses increased. A substantial percentage of LH pulses observed in OC users after day 1 were of low amplitude (0.75 IU/L). From these results, the authors conclude that 1) pulsatile release of LH is maintained during OC use; 2) FSH levels are suppressed equally early and equally effective by all OCs studied; 3) during OC use, the number of LH pulses per 6 hours is reduced; 4) modulation of LH pulse amplitudes, and subsequently of serum LH levels, is mainly mediated by a dose--and time-dependent effect of the gestagenic component of the OC; and 5) after the 7-day pill-free interval, a normal early follicular phase pulse pattern is found, even in long-term OC users, suggesting that in this period, most of the steroidogenic feedback effects wear off.

Comparison of a gonadotropin releasing-hormone antagonist plus testosterone (T) versus T alone as potential male contraceptive regimens.

Efforts to develop a hormonal contraceptive regimen for men have focused on administration of testosterone (T), alone or together with other agents. Previous regimens have successfully induced azoospermia in only 50-70% of subjects, however. GnRH antagonists, alone or in combination with T, have been shown to induce azoospermia in a very high percentage of nonhuman primates. We tested the hypothesis that the addition of a GnRH antagonist to a high-dose T regimen would lead to a higher percentage of men developing azoospermia than would T alone. We administered the GnRH antagonist, Nal-Glu (100 micrograms/kg.day sc), plus T enanthate, 200 mg im weekly or placebo sc injections daily plus T enanthate, 200 mg im weekly, to separate groups of healthy men for 16-20 weeks. Seven of 10 men who received Nal-Glu plus T and 6 of 9 men who received T alone became azoospermic; gonadotropin levels were suppressed and T levels were increased similarly in both groups. There was a trend toward higher pretreatment gonadotropin levels and lower sperm counts in men who became azoospermic. Weight gain, development of acne, and increases in hematocrit and hemoglobin were similar in the two groups. In the majority of the men, sperm counts returned to the baseline levels within 4-5 months after treatment ended. We conclude that with the dosages of Nal-Glu and T we used in this study, the addition of GnRH antagonist to a high-dose T regimen does not increase the ability of T to suppress spermatogenesis in healthy men. Use of a higher dose of Nal-Glu, a lower dose of T, delaying the start of T replacement until several weeks after Nal-Glu injections are initiated, or prolonged hormonal administration might lead to a combination regimen that will suppress spermatogenesis more fully than does T alone.

Effect of tamoxifen alone and in combination with RU 486 on the endometrium in the mid-luteal phase.

The effects of RU 486 combined with tamoxifen and tamoxifen alone on hormonal parameters and endometrial development at the time of implantation were studied. Measurements of cytosolic oestrogen and progesterone receptors in endometrium and placental protein 14 (PP14) in plasma were also included. Three dosage schedules were used: single oral dose of 40 mg tamoxifen alone and in combination with 200 mg RU 486, and 40 mg tamoxifen for three consecutive days starting on the first day after the luteinizing hormone (LH) surge. The combined treatment prolonged the luteal phase (P < 0.05) and increased the plasma levels of progesterone. A single dose of tamoxifen did not affect the bleeding pattern and plasma hormone levels, but raised plasma oestradiol and LH with the 3-day treatment. The endometrium was retarded after the combined and the 3-day treatment with tamoxifen. Concentrations of cytosolic progesterone receptors were higher after the combined therapy, but were unaffected after tamoxifen only. PP14 levels were higher (P < 0.05) after repeated tamoxifen doses than in controls, but were lower with combined treatment. Progesterone and oestrogen are evidently necessary for endometrial maturation during the secretory phase of the menstrual cycle. PP14 levels in plasma cannot be used for clinical assessments of endometrial function because high levels coincide with disturbed endometrial development.

Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle.

The effects of continuous low dose mifepristone (RU 486) 10, 5 or 1 mg/day on the menstrual cycle were assessed in groups of five volunteers, who were treated for 30 days from the beginning of the cycle. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on day 22-29 of treatment were used to monitor the cycle. Pre- and post-treatment cycles presented a normal profile. During treatment, concentrations of RU 486 in plasma ranged from 65 nmol/l with 1 mg/day to 1000 nmol/l with 10 mg/day. With 10 or 5 mg/day, all treated cycles were prolonged as a result of arrested or slower follicular growth during treatment. Gonadotrophins, sex steroids and their urinary metabolites remained at early follicular phase levels throughout treatment, whereas androstenedione, prolactin and cortisol were unaffected. Follicular maturation resumed after discontinuation of treatment and several days later a luteinizing hormone surge followed by a luteal phase was observed in all cases. Ovulation was suppressed during treatment only in one of the five cycles treated with 1 mg/day. Endometrial maturation was disturbed by all doses. These data demonstrate a differential threshold of the follicle and the endometrium to mifepristone. This finding has potential application in the contraceptive field.

Hormone levels and anogenital swelling of female chimpanzees as a function of estrogen dosage in a combined oral contraceptive.

A combined oral contraceptive consisting of ethinyl estradiol (EE2) in three dosages (50, 100, and 400 micrograms) and norethindrone (0.5 mg) was given to female chimpanzees to determine the effect on endogenous sex hormone levels and anogenital swelling. Serum levels of EE2 increased with increasing dosages of EE2, estradiol decreased, and luteinizing hormone, progesterone and testosterone were maintained at approximately midfollicular phase levels. Urinary levels of EE2 glucuronide increased with the increasing dosages of EE2, whereas estrone and pregnanediol glucuronide were essentially undetectable. The cyclic increase in female anogenital swelling was abolished when the norethindrone was combined with 50 micrograms of EE2 and relatively constant and low levels of swelling were recorded. Relatively constant but successively higher levels of swelling were recorded when the norethindrone was combined with the higher dosages of EE2. These effects of oral contraceptives on female genital tissues are relevant to our laboratory studies of sexual behavior in chimpanzees given oral contraceptives and could also have implications for women taking oral contraceptives.

Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of luteal phase of the menstrual cycle: a contraceptive potential.

OBJECTIVE: To examine hormonal and endometrial responses to intermittent low-dose RU486 administration in the luteal phase of the menstrual cycle. DESIGN: Prospective open trial in which subjects serve as their own controls. PATIENTS/PARTICIPANTS: Eight normal cycling women. INTERVENTIONS: RU486 (10 mg, orally) was administered 5 and 8 days after urinary luteinizing hormone (LH) surge of treatment cycle. MAIN OUTCOME MEASURES: Daily serum concentrations of LH, follicle-stimulating hormone, estradiol (E2), and progesterone (P) were determined in control, treatment, and recovery cycles (n = 5) or treatment and recovery cycles (n = 3). Changes in endometrial morphology and immunohistochemical staining for P receptor (PR) and E2 receptor (ER) were determined during control (or recovery) and treatment cycles. RESULTS: Cycle length and hormonal patterns were unaltered after treatment with RU486. As demonstrated by reduced stromal edema and delayed glandular development, endometrial dyssynchrony occurred in all eight treatment cycles. In addition, seven of eight treatment cycle endometria demonstrated a decrease in PR staining without consistent change in ER staining. CONCLUSIONS: Two low doses of RU486 given 72 hours apart during the luteal phase of the cycle disrupted ongoing endometrial maturation without altering the hormonal and time course of the menstrual cycle. This study provides a basis for the development of a novel form of luteal contraception.

PIP: This study sought to examine hormonal and endometrial responses to intermittent low-dose RU486 administration in the luteal phase of the menstrual cycle. 8 normally cycling women participated in this prospective open trail in which the subjects served as their own controls. RU486 (10 mg, orally) was administered 5 and 8 days after urinary luteinizing hormone (LH) surge of treatment cycle. Daily serum concentrations of LH, follicle stimulating hormone, estradiol (E2), and progesterone (P) were determined in control, treatment, and recovery cycles (n=5) or treatment and recovery cycles (n=3). Changes in endometrial morphology and immunohistochemical staining for P receptor (PR) and E2 receptor (ER) were determined during control (or recovery) and treatment cycles. Cycle length and hormonal patterns were unaltered after treatment with RU486. As demonstrated by reduced stromal edema and delayed glandular development, endometrial dyssynchrony occurred in all 8 treatment cycles. In addition, 7 of 8 treatment cycle endometria demonstrated a decrease in PR staining without consistent change in Er staining. The authors conclude that 2 low doses of RU486 given 72 hours apart during the luteal phase of the cycle disrupt ongoing endometrial maturation without altering the hormonal and time course of the menstrual cycle. This study provides a basis for the development of a novel form of luteal contraception.

Nonpregnant women with a history of habitual abortion have normal and luteal function independent production of prostacyclin and thromboxane A2.

OBJECTIVE: To see if changes in prostacyclin and thromboxane A2 (TXA2) production during early pregnancy in women with habitual abortion is a pregnancy-induced change, we compared the production of these prostanoids in habitual aborters and in healthy controls in nonpregnant state and related it to luteal function. DESIGN: Comparison between patients (n = 16) with a history of at least three consecutive miscarriages and healthy controls without a history of abortions (n = 11). SETTING: Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland. RESULTS: Habitual aborters and control women exhibited no change in the urinary output of the stable degradation products of prostacyclin and TXA2 when studied between 0 and 2 and 5 and 8 days after the luteinizing hormone peak. Habitual aborters as a whole, or when subgrouped to those with normal (10 cycles) or defective luteal function (12 cycles) did not differ from the control series with regard to prostacyclin and TXA2 production. CONCLUSIONS: Productions of prostacyclin and TXA2 are not relative to the luteal function and are normal in nonpregnant women with a history of habitual abortion.

PIP: To examine if changes in prostacyclin and thromboxane A2 (TXA2) production during early pregnancy in women with habitual abortion are pregnancy-induced the authors compared the production of these prostanoids in habitual aborters with those in healthy controls in a nonpregnant state and related it to luteal function. Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Finland, were the setting of this comparison between patients with a history of at least 3 consecutive miscarriages (n=16) and healthy controls without a history of abortions (n=11). Habitual aborters and control women exhibited no change in urinary output of the stable degradation products of prostacyclin and TXA2 when studied between 0 and 2 and 5 and 8 days after the luteinizing hormone peak. Habitual aborters as a whole, or when subgrouped to those with normal (10 cycles) or defective luteal function (12 cycles), did not differ from the control series with regard to prostacyclin and TXA2 production. Productions of prostacyclin and TXA2 are not relative to the luteal function and are normal in nonpregnant women with a history of habitual abortion.

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.

PIP: 10 women were studied poststerilization for the hormonal profile of the menstrual cycle. They had undergone the procedures on an average of 5.3 years earlier (range 1.5-10 years). The serum concentrations of luteinizing hormone (LH), follicle stimulating hormone, prolactin, estradiol, and progesterone were measured by radioimmunoassay in daily blood samples of a complete menstrual cycle. Another 10 normal women were studied at the same time and were used as a control group. There were no significant differences in the hormonal patterns of the menstrual cycle between the 2 groups. There were significantly lower LH levels in the early luteal phase of the tubal ligation group as compared to the controls. 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 1 of 10 women in the tubal ligation group who had undergone sterilization 1.5 years earlier showed a deficiency in luteal function however, her ovulatory function and menstrual cycle appeared normal. This study indicates that normal hormonal profiles are retained after tubal sterilization.

[Ovarian suppressive activity of a low dose monophasic oral contraceptive during correct and incorrect pill intake]. / Etude de l'activite contraceptive d'une pilule minidosee lors de son utilisation correcte ou incorrecte.

PIP: A systematic study was undertaken in order to evaluate the consequences of missing oral contraceptives (OCs) at different times in the cycle. 39 young, healthy, normally menstruating patients were voluntarily enrolled in this study and all were given Cilest (ethinyl estradiol 35 mcg + norgestimate 250 mcg, Cilag, France) for 21 days without any gaps. Then, after a 7-day interval, they were prescribed 1 (group 1), 2 (group 2), 3 (group 3), or 4 (group 4) days of OC misses. These occurred on day 1 (class a), day 6 (class b), day 12 (class c), or day 18 (class d) of a 21 day Cilest cycle. In addition, supplementary contraceptive measures were recommended to those participating. With 47 cycles examined, 5 patients had no miss prescribed and this group served as the controls. Ovarian function was evaluated with daily estrogen monitoring (E1 + E2 enzymatic dosage, Bio Merieux, France) and ultrasound examination. When necessary, due to a significant estrogen increase or follicular growth detected on ultrasound, progesterone and LH were measured. 9 patients showed a follicular image on ultrasound. 4 patients (1 control, 3 others ) had a significant increase in estrogens and 2 others had no secretions. All the others had no manifestation of restoration of ovarian function. None of the 9 patients had a normal ovulation (no LH surge or increase in progesterone). Blockage of ovarian function by OCs remains efficient even after several days of OC missing. (author's modified)^ieng

Immunochemical tests of potential fertility.

PIP: There are many methods of determining the physiological basis of cyclical periods of potential fertility: calculations, sensations, or physical or chemical biosensors. This article reviews the development of self-tests of potential fertility using immunoassay of hormone metabolites in urine. Indices of potential fertility in urine are the concentration of principal metabolites of steroid hormones and luteinizing hormone (LF). The ovaries produce an estimated 50-800 mcg of estradiol/day, the most active estrogen which is concentrated in the peripheral circulation during the preovulatory period of rapid follicular growth. Measurements may be taken from the blood, saliva, or cervico-vaginal fluid, and urine as estrogen-3 or 17 beta-glucuronide. The metabolism of progesterone shows changes at carbon atoms 3, 11, 17, and 20. Urine contains lower concentrations of 5 beta-pregnanediol-3 alpha-glucuronide (P3G), followed by 5 beta-pregnanediol glucuronide and 5 alpha-pregnanediol glucuronide. Methods of measurement are presented, including the mean changes in the urinary concentrations of estrogen 3-glucuronide (E3G) and P3G and their concentration ratio in relation to day 1 of menses, the day of luteinizing hormone LH peak, and the time limits for ovulation during menstrual cycle. A laboratory test of E3G in early morning urine (EMU) from 38 subjects showed that delineating a defined fertile period (day of maximum follicular diameter minus 3 to day plus 2) was possible in 89% of cases. New methods with immunotubes or immunostrips, novel antibodies, and idiometric assay attempt to improve the signal/background ratio; each method is described. Immunotubes for measuring steroid glucuronide may be light absorbing, light emitting (fluorescence polarization), and light emitting with time resolved fluorescence. Each procedure is described. The present technology demonstrates that immunoassays can be performed as self-tests, and what remains to be done is ascertaining the most appropriate one for determining potential fertility.^ieng

Comparative contraceptive efficacy and mechanism of action of the norgestimate-containing triphasic oral contraceptive.

Norgestimate (NGM), a derivative of 19-nortestosterone with very specific affinity for the progesterone receptor, has been used in combination with ethinyl estradiol (EE) at low doses in both monophasic and triphasic oral contraceptives (OCs). An open-label comparative clinical trial was conducted with 4,234 healthy women using comparative clinical trial was conducted with 4,234 healthy women using triphasic levonorgestrel (LUG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive (LUG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive efficacy was excellent with both preparations, with no statistically significant between-regimen differences in pregnancy rates. The theoretical Pearl index was the NGM/EE triphasic, and 0.34 for the LNG/EE triphasic. Adverse experiences in groups were typical of those that may occur among women taking low-dose OC agents. was similar with the two preparations: 8.6% for the NGM/EE triphasic and 6.8% for the LNG/EE triphasic. In a separate mechanism of action study, specific endocrine parameters were investigated in 20 subjects using the NGM/EE triphasic for 4 cycles. Ovulation suppression was demonstrated in statistically significant decreases from pretreatment values in serum levels of luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol. Significant on-treatment increases in serum levels of sex hormone binding globulin evidenced minimal androgenicity. All hormonal values returned to or toward normal in the post-treatment cycle. The study results support those obtained in large noncomparative studies of the NGM/EE triphasic. This phased-dose combination suppresses ovulation and is a very effective, minimally androgenic contraceptive agent with a good safety profile.

PIP: Norgestimate (NGM), a derivative of 19-nortestosterone with very specific affinity for the progesterone receptor, has been used in combination with ethinyl estradiol (EE) in low doses in both monophasic and triphasic oral contraceptives (OCs). An open-label comparative clinical trial was conducted with 4234 healthy women using triphasic levonorgestrel (LNG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive efficacy was excellent with both preparations with no statistically significant between-regimen differences in pregnancy rates. The theoretical Pearl index was 0.12 for the NGM/EE triphasic, and 0.34 for the LNG/EE triphasic. Adverse experiences in both groups were typical of those which could occur among women taking low-dose OCs. The % of subjects who discontinued treatment due to use-related adverse experiences was similar among the 2 preparations; 8.6% for the NGM/EE triphasic and 6.8% for the LNG/EE triphasic. In a separate mechanism of action study, specific endocrine parameters were investigated in 20 subjects who used the NGM/EE triphasic for 4 cycles. Ovulation suppression was demonstrated in statistically significant decreases from pretreatment values in serum levels of luteinizing hormone, follicle stimulating hormone, progesterone, and estradiol. Significant on-treatment increases in serum levels of sex hormone binding globulin evidenced minimal androgenicity. All hormonal values returned to or toward normal in the posttreatment cycle. The study results support those obtained in large noncomparative studies of the NGM/EE triphasic. This phased-dose combination suppresses ovulation and is a very effective, minimally androgenic contraceptive with good safety profile.

Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido.

GnRH antagonists suppress pituitary and gonadal function by competing with endogenous GnRH for binding to receptors on pituitary gonadotrophs. We studied the effects of GnRH antagonist administration to men in a protocol simulating a likely male contraceptive regimen combined with a low dose of testosterone. The GnRH antagonist Nal-Glu was given daily (10 mg, sc) for 20 weeks to eight normal men, and a low dose of testosterone enanthate (25 mg, sc) was given every week. Sperm counts started declining during week 4, and complete azoospermia was reached within 6-12 weeks in six of the eight subjects. Subjects 7 and 8, whose sperm counts and serum gonadotropin levels were not suppressed after 10 weeks, were given 20 mg Nal-Glu starting at week 10. One became azoospermic at week 16, while the other's total sperm counts continued declining and reached a nadir of 1.4 million by week 20. Sperm motility and viability in this subject were completely suppressed after week 14. Sperm counts returned to baseline levels 12-14 weeks after the end of Nal-Glu administration. The mean serum LH level of the first six subjects decreased from 3 +/- 03. U/L at baseline to less than 0.1 U/L until week 20, and then levels returned to baseline. FSH levels similarly decreased from a combined mean of 3.6 +/- 0.9 U/L at baseline to below 0.3 U/L after 4 weeks of Nal-Glu administration. Serum mean testosterone levels between weekly injections of testosterone enanthate ranged from 27.4 +/- 5.9 to 4.8 +/- 1.4 nmol/L, but remained in the hypogonadal range (less than 10 nmol/L) for 4 of the 7 days. None of the subjects, however, complained of decreased libido or potency, as assessed by a questionnaire. No systemic or significant local side-effects were observed, other than a minimal reaction at the injection site. These data suggest that complete sustained azoospermia can be achieved in man, without loss of libido, by chronic administration of a GnRH antagonist plus testosterone.

Hirsutism: metabolic effects of two commonly used oral contraceptives and spironolactone.

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

PIP: 51 hirsute women were randomly treated for 9 months with ethinyl estradiol (EE) 35 mcg + norethindrone 0.4 mg or 30 mcg EE + 1.5 mg norethindrone acetate if contraception was necessary or spironolactone 200 mg daily if it was not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the 2 oral contraceptives (OCs) but not with spironolactone. While systolic blood pressure was lower with it, fasting insulin levels were higher as opposed to either low-dose OC preparation. EE 30 mcg + 1.5 mg norethindrone acetate lowered 3-alpha-diol-glucuronide levels; however, E 35 mcg + norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

Reversible azoospermia induced by an androgen-progestin combination regimen in Indonesian men.

The suppression of spermatogenesis by a combination of depot medroxyprogesterone acetate (DMPA) and testosterone enanthate (TE) was studied in Indonesian men. Twenty healthy, fertile volunteers were allocated randomly to either of two treatments each consisting of four intramuscular injections at monthly intervals. Group I (n = 10 men) received 100 mg DMPA plus 100 mg TE monthly while group II (n = 10 men) received 200 mg DMPA plus 250 mg TE monthly. Sperm concentration was suppressed markedly, with all men attaining azoospermia between the third and fourth month after the start of treatment. There was no significant difference in the suppression of spermatogenesis between the two dosage regimens. The median time to reaching azoospermia was 2.5 months from the onset of injections and the median time to recovery of sperm in the ejaculate was 2.0 months after cessation of treatment. Both steroid regimens were equally effective in suppressing LH, FSH and testosterone levels. Testosterone levels returned to baseline by the fourth post-treatment month while LH and FSH demonstrated significant rebound above baseline levels from 3 to 5 months after cessation of treatment. No serious clinical side effects were observed. Weight gain and increases in libido were reported during treatment by most volunteers. A transient decrease in libido was noted in 5/20 (25%) men between 1-2 months after cessation of injections, presumably due to the prolonged effects of DMPA relative to TE. These results indicate that uniform induction of reversible azoospermia with minimal side effects can be achieved in a non-Caucasian population.(ABSTRACT TRUNCATED AT 250 WORDS)