Evaluation of a pen device for self-administration of recombinant human FSH in clomiphene citrate-resistant anovulatory women undergoing ovulation induction.

This open-label multicentre study evaluated ease of use, safety, and efficacy of a pen device for self-administration of recombinant follicle-stimulating hormone (rFSH) in 43 subjects undergoing ovulation induction. Follitropin beta was administered subcutaneously with the Follistim Pen within 3 days of onset of menses. A 75 IU starting dose could be increased by 25 or 50 IU on days 8 and 15 if no ovarian response was observed. Human chorionic gonadotrophin (HCG; 10,000 IU) was administered when one follicle > or =18 mm or two to three follicles > or =15 mm were observed. Subjects received standardized instruction for the pen device and subject comprehension was recorded as subjects practised and prepared injections. Ease of use was also evaluated by questionnaire. Forty-four subjects enrolled; 43 were treated with rFSH and 41 were treated with HCG. The comprehension questionnaire revealed that during the mock injection, 100% of subjects properly loaded the cartridge into the pen device, while 95% selected the correct dose and 100% self-injected the medication prescribed. During the second actual injection, 100% of subjects comprehended these pen-related steps. The ease-of-use questionnaire showed that 100% of the subjects rated the overall experience of self-administering with the pen as 'very good' to 'good'. Mean duration and total amount of follitropin beta were 11.4 +/- 4.2 days and 1070.3 +/- 580.3 IU respectively. Ovulation rate was 95%. Biochemical and ongoing pregnancy rates per attempt were 34.9 and 30.2% respectively. Three subjects experienced serious adverse events [asthma; ovarian hyperstimulation syndrome (OHSS) and pain; OHSS]. In conclusion, the pen device provides an easy, safe, and effective way for women to self-administer follitropin beta during ovarian stimulation.

Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486).

OBJECTIVE: We have previously shown that treatment with mifepristone, 50 to 100 mg daily, results in amenorrhea, anovulation, and symptomatic improvement in women with endometriosis. In this study we lowered the dose to 5 mg daily to determine whether clinical efficacy is altered without other adverse actions. STUDY DESIGN: After a baseline cycle, seven women with endometriosis were given mifepristone, 5 mg daily, for 6 months. Daily symptom inventories were recorded. Laparoscopy was performed during the sixth month of therapy. RESULTS: Pelvic pain improved in six of seven patients. Cyclic bleeding ceased in all patients, but four of the seven patients complained of irregular bleeding. Surgical staging at the conclusion of the study (five of seven patients) did not detect a change in endometriosis. CONCLUSIONS: Mifepristone, 5 mg daily, resulted in symptomatic improvement, but did not stabilize the endometrium. From our experience with three doses of mifepristone, we would recommend a dose of 50 mg be used for continued investigations.

PIP: The authors' previous research has demonstrated that treatment with 50-100 mg/day of mifepristone produces symptomatic improvement of endometriosis. The present study assessed the efficacy of a substantially reduced antiprogesterone dose. After a baseline cycle, 7 US women with pelvic pain caused by endometriosis were administered 5 mg of mifepristone daily for 6 months. Clinical responsiveness was evaluated in daily symptom inventories completed by study participants. Pelvic pain improved significantly within 1 month of treatment initiation in 6 of 7 patients. Cyclic bleeding ceased in all 7 patients, but 4 women complained of irregular bleeding that begin 3-5 months into treatment. Menstrual cyclicity returned 23-37 days after study completion. 2 women did not complete the study--1 because of continued pelvic pain and 1 because of heavy bleeding during the fifth cycle. Surgical staging through laparoscopy in the 5 remaining women failed to document a significant change in endometriosis. 1 woman had a slight increase in endometriosis score compared to baseline, 1 had no change, and the remaining 3 women showed decreases from 32-45%. Given the failure of the 5 mg dose to stabilize the endometrium and the high rate of uterine bleeding, a dose of 50 mg of mifepristone is recommended for future investigations.

Assisted reproductive technology: the state of the ART.

At least one in ten couples of reproductive age is affected by infertility. Tubal disease, ovulatory defects, endometrosis and abnormal sperm physiology are the most common causes of failure to conceive. Many of these disorders can be treated successfully with surgery, ovulation induction or intrauterine insemination, but in selected cases, or where there is long-standing intractable infertility, assisted reproductive technology (ART) becomes the treatment of choice. We provide an overview of the techniques for assisted reproduction, including in vitro fertilization, gamete intrafallopian transfer and other related procedures. Indications for treatment, patient evaluation and advances in reproductive technology including embryo cryopreservation, micromanipulation and donor gametes are also reviewed.

Modern medical management of endometriosis.

The modern medical management of endometriosis has changed considerably since the first attempts were made to control this disease hormonally over four decades ago. Currently, there are multiple choices for the clinician and patient, including oral contraceptives, danazol, GnRH agonist analogues, and gestrinone. Several advances have been made in the use of GnRH agonists in preventing some of the untoward effects of prolonged hypoestrogenism. These add-back regimens provide the best therapy available today for prolonged medical control of endometriotic symptoms. The antiprogesterones (RU-486) hold promise for the future, but are still in the investigational stage of development.

Ovulation induction in the estrogenized anovulatory patient.

Ovulation induction is one of the greatest success stories in reproductive endocrinology. With appropriate therapy in properly f1p4cted patients, the conception and live birth-rates in treated patients are almost indistinguishable from normal. In the estrogenized woman there are many different techniques to reverse the condition of chronic anovulation. With clomiphene citrate, up to 80% of patients will ovulate, and approximately half will conceive. In women who fail clomiphene therapy, injectable gonadotropins are usually successful in inducing ovulation. New protocols for administering these powerful agents have minimized the risk of ovarian hyperstimulation and multiple pregnancy. When medical therapy fails to result in successful ovulatory cycles, surgical treatments can be considered. Laparoscopic ovarian ablation has been shown to be effective treatment. Whether this less invasive surgery results in fewer adhesions than conventional ovarian wedge resection remains to be proven. By carefully considering each patient and individualizing treatment based on a full knowledge of alternatives, ovulation induction remains one of the most challenging and rewarding treatments in reproductive endocrinology.

Mifepristone: clinical application in general gynecology.

PIP: RU-486, the first clinically available antiprogestin, has numerous gynecologic applications beyond first-trimester pregnancy termination. Long-term administration of 2 mg/day of RU-486 suppresses ovulation while maintaining serum estrogen levels and ovarian follicular activity. In the endometrium, long-term RU-486 administration results in significant endometrial dysynchrony and stromal compaction. RU-486 has been demonstrated to relieve pain in women with symptomatic endometriosis and decrease the size of uterine leiomyomata by about 50%. There are preliminary findings indicating that RU-486 is effective in the treatment of premenstrual syndrome, ectopic pregnancy, and anovulatory uterine bleeding. In need of further investigation is the RU-486 dosage that can treat pathophysiologic states while minimizing the endometrial effects.^ieng

Quality of life assessment.

Quality of Life (QOL) is a generic term covering a wide variety of end points. It generally refers to a multitude of subjective experiences important to people's lives. Four domains contribute to this overall effect: physical and occupational function, psychological state, social interaction, and economic status/factors. Quality of life has emerged as an important outcome measure of optimal medical care, particularly for the treatment of chronic conditions. Four types of clinical trials in which QOL should be evaluated are: (1) the intervention has an effect on symptoms but not mortality or complication rates; (2) the intervention causes a high frequency of side effects; (3) prevention trials, and (4) trials designed to lower cost or rate of adverse effects. Standards for such trials are currently being developed. The one area of current agreement is the need for the use of validated scales of measurement. The use of both a general scale and a disease- (or age group) specific scale may provide the best assessment of overall QOL.

Circulating levels of follistatin from puberty to menopause.

OBJECTIVE: To determine the changes in circulating levels of follistatin, a binding protein for activin and inhibin, through the reproductive life cycle in women. DESIGN: An open, prospective descriptive study. SETTING: An academic endocrine research unit. PATIENTS: Prepubertal (n = 10), midpubertal (n = 7), and postpubertal (n = 25) (early adolescent) girls, normal cycling adult women (n = 8), postmenopausal women (n = 17), and men (n = 13) were studied. INTERVENTIONS: Normal cycling women were given Nal-Glu GnRH antagonist for 3 days in the follicular phase of the cycle. MAIN OUTCOME MEASURE: Serum concentrations of follistatin determined in a heterologous RIA. RESULTS: Mean follistatin levels did not change during puberty but were higher in adult and postmenopausal women. Levels of immunoreactive follistatin in men were lower than levels found in normal cycling women and postmenopausal women. Daily immunoreactive follistatin levels during the menstrual cycle remained constant and did not change significantly after ovarian suppression with GnRH antagonist. CONCLUSION: Because dynamic changes of serum immunoreactive follistatin do not occur during ovarian activation (puberty), suppression, and age-related ovarian failure, the increase in immunoreactive follistatin levels in adult and postmenopausal women may implicate sources of follistatin other than the ovary.

Treatment of endometriosis with the antiprogesterone mifepristone (RU486)

OBJECTIVE: To evaluate the safety and efficacy of an antiprogesterone (mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis. DESIGN: An open, prospective clinical trial. SETTING: The clinical practice of an academic faculty. PATIENTS: Nine women with endometriosis were studied. INTERVENTIONS: RU486 (50 mg/d) was administered for 6 months. MAIN OUTCOME MEASURES: Daily symptom inventories and urinary steroid metabolites were assessed before, during, and after treatment. Blood for hormone analysis was obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis, bone mineral density, circadian rhythm of cortisol, and LH pulsatility were determined before and after treatment. Safety laboratory measurements were made before and at 1, 2, and 6 months of treatment. RESULTS: Pelvic pain and uterine cramping improved in all patients. Endometriosis regressed by 55%. All patients exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism. A rise in serum LH and T levels was observed during the first month of treatment and one patient developed an elevation of liver transaminases during the last month of treatment. All other measurements were unchanged. CONCLUSION: RU486 appears to be effective in improving the symptoms and causing regression of endometriosis in the absence of significant side effects.

Successful pregnancy outcome after cryopreservation of all fresh embryos with subsequent transfer into an unstimulated cycle.

OBJECTIVE: To assess the pregnancy outcome of freezing and storing all fresh embryos produced in a stimulated IVF cycle and replacing them in a subsequent nongonadotropin-stimulated cycle. DESIGN: Retrospective study. SETTING: University-associated assisted reproductive technology program. PATIENTS: We studied 36 patients (age range 23 to 44 years) who underwent cryopreservation of all fresh embryos in a controlled ovarian hyperstimulation (COH) cycle because of either the risk of severe ovarian hyperstimulation (24 patients, group 1) or the presence of an endometrial lining < 8 mm in thickness (12 patients, group 2). Five hundred fifty-five embryos were generated for replacement in 63 cycles. All embryos were cryopreserved in 1.5 M propanediol at the pronuclear or two-cell stage, and 264 embryos subsequently were transferred into a hormone replacement cycle (70%) or natural ovulatory cycle (30%). The average number of embryos transferred per patient was 4.2. RESULTS: Twenty-one clinical pregnancies were achieved, giving a pregnancy rate (PR) of 58.3% per patient (33.3% per cycle). The live birth rate was 50% per patient (28.6% per cycle). The implantation rate was 9.1%. Groups 1 and 2 had a similar PR per patient (58.3%). With 208 cryopreserved embryos remaining and considering the 33.3% PR per cycle, we expect the overall extrapolated PR to be 63.9%. CONCLUSIONS: This is the first series showing that freezing and storing all fresh embryos produced in a stimulated IVF cycle and replacing them in a subsequent nongonadotropin-stimulated cycle results in successful PRs. These results underlie the importance of a successful cryopreservation program in IVF and could be a possible approach to overcoming the alleged adverse effects of COH on the endometrium, thereby improving the chances of pregnancy when numerous embryos are obtained simultaneously.

Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response effect.

OBJECTIVE: To study the response of uterine leiomyomata to three daily doses of RU486 (5, 25, and 50 mg). DESIGN: Prospective nonrandomized trial of women with symptomatic leiomyomata. SETTING: Patients from the clinical practice of the authors at the University of California, San Diego Medical Center. PATIENTS: Ten patients with symptomatic leiomyomata previously reported after treatment with 50 mg of RU486 daily for 3 months. Eleven patients treated with 25 mg of RU486 daily and nine patients placed on 5 mg of RU486 daily for 12 weeks. MAIN OUTCOME MEASURES: Changes in leiomyomata volume as measured with vaginal ultrasounds at baseline and monthly thereafter. Frequent blood samples for hematology, chemistry, and hormone levels were obtained. Twenty-four-hour urine collections for free cortisol and creatinine were obtained at baseline and at 12 weeks. RESULTS: All three doses induce ovarian acyclicity. Administration of 50 mg of RU486 decreases leiomyomata volume to 78.1% +/- 4.8% of baseline at 4 weeks, 60.5% +/- 6.6% at 8 weeks, and 51.0% +/- 9.2% after 12 weeks of treatment. Regressive response in patients treated with 25 mg of RU486 daily was 76.3% +/- 5.0% of baseline at 4 weeks, 54.0% +/- 5.1% at 8 weeks, and 44.0% +/- 5.0% after 12 weeks. At 5 mg of RU486 leiomyomata volume was 80.6% +/- 8.3% of baseline after 4 weeks, 63.7% +/- 14.6% after 8 weeks, and 74.4% +/- 19.8% after 12 weeks of therapy. CONCLUSIONS: Although acyclicity is seen at all three doses, an effective dose to cause a clinically significant (50%) decrease in leiomyomata volume appears to be 25 mg daily.

PIP: The author report their findings from a study of the effect of RU486 on uterine leiomyomata volume. The authors previously reported an inhibitory effect of RU486 on the growth of uterine leiomyomata in 10 patients with symptomatic leiomyomata receiving 50 mg daily for 12 weeks. Findings are now reported on the effect of 5 mg and 25 mg daily doses of RU486 in 9 and 11 patients, respectively. Subjects were patients at the University of California, San Diego Medical Center. Vaginal inhibitory at baseline and monthly thereafter were used to measure changes in leiomyomata volume. Frequent blood samples for hematology, chemistry, and hormone levels were obtained, as well as 24-hour urine collections to assess free cortisol and creatinine at baseline and 12 weeks. All three doses induce ovarian acyclicity. Administration of 50 mg of RU486 decreases leiomyomata volume to 78.1% of baseline at 4 weeks, 60.5% at 8 weeks, and 51.0% after 12 weeks of treatment. Administration of 25 mg of RU486 decreases leiomyomata volume to 76.3% of baseline at 4 weeks, 54.0% at 8 weeks, and 44.0% after 12 weeks of treatment. Administration of 5 mg of RU486 decreases leiomyomata volume to 80.6% of baseline at 4 weeks, 63.7% at 8 weeks, and 74.4% after 12 weeks of treatment. 25 mg daily appears to be the effective dose to cause a clinically significant 50% decrease in leiomyomata volume.

Clomiphene citrate reduces serum insulin-like growth factor I and increases sex hormone-binding globulin levels in women with polycystic ovary syndrome.

OBJECTIVES: To evaluate the effect of clomiphene citrate (CC) on circulating levels of insulin-like growth factor I (IGF-I) and sex hormone-binding globulin (SHBG) in patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective open trial. PATIENTS: Eight women with clinical and biochemical evidence of PCOS. INTERVENTION: One hundred fifty milligrams CC was administered orally for 5 days. MAIN OUTCOME MEASURES: Serum IGF-I, SHBG, LH, FSH, and E2 levels were determined for 8 days, beginning 3 days before CC treatment. RESULTS: A progressive decline in serum IGF-I levels was observed in all subjects reaching a maximum of 30% on the 5th day of therapy (40.6 +/- 5.1 to 28.7 +/- 4.0 nmol/L [conversion factor to SI unit, 0.13]). This was correlated inversely with the expected rises in LH, FSH, and E2 levels. Concomitantly, there was a 23% rise in SHBG levels. The absolute decrease of IGF-I levels was negatively correlated with age and was independent of body mass index. CONCLUSIONS: These observations suggest that oral administration of CC has an impact on the IGF-I and SHBG systems, which may be involved in the initiation of ovulatory function in PCOS.

Expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane) is superior to oxidized regenerated cellulose (Interceed TC7+) in preventing adhesions.

OBJECTIVE: To compare the impact of expanded polytetrafluoroethylene (PTFE; Gore-Tex Surgical Membrane; W. L. Gore & Associates, Inc., Flagstaff, AZ) and oxidized regenerated cellulose (Interceed TC7, Johnson & Johnson Medical, Inc., Arlington, TX) on the development of postsurgical adhesions. DESIGN: A multicenter, nonblinded, randomized clinical trial. SETTING: University medical centers. INTERVENTIONS: Each barrier was allocated randomly to the left or right sidewall of every patient. PATIENTS: Thirty-two women with bilateral pelvic sidewall adhesions undergoing reconstructive surgery and second-look laparoscopy. MAIN OUTCOME MEASURES: Adhesion score (on a 0- to 11-point scale), the area of adhesion (cm2), and the likelihood of no adhesions. RESULTS: The use of both barriers was associated with a lower adhesion score and area of adhesion postoperatively. However, those sidewalls covered with PTFE had a significantly lower adhesion score (0.97 +/- 0.30 versus 4.76 +/- 0.61 points, mean +/- SEM) and area of adhesion (0.95 +/- 0.35 versus 3.25 +/- 0.62 cm2). Overall, more sidewalls covered with PTFE had no adhesions (21 versus 7) and, when adhesions were present on the contralateral sidewall, the number of sidewalls covered with PTFE without adhesions was greater than those covered with oxidized regenerated cellulose (16 versus 2). CONCLUSION: Expanded polytetrafluoroethylene was associated with fewer postsurgical adhesions to the pelvic sidewall than oxidized regenerated cellulose.

Endometrial effects of long-term low-dose administration of RU486.

OBJECTIVE: To examine endometrial response to long-term low-does RU486 administration. DESIGN: Retrospective controlled study of women with endometriosis treated for 6 months with 50 mg RU486 daily for 6 months. Controls consisted of women in the follicular phase of a spontaneous cycle undergoing endometrial biopsy. SETTING: Patients from the clinical practice of the authors at the University of California, San Diego Medical Center. PATIENTS AND INTERVENTIONS: Nine patients treated with long-term low-dose RU486 and nine normal cycling controls undergoing hysterectomy or endometrial biopsy for benign disease. MAIN OUTCOME MEASURES: Changes in endometrial morphology and immunohistochemical analysis for estrogen receptor (ER) and progesterone receptor (PR) protein. RESULTS: All patients treated with RU486 exhibited abnormal endometrial morphology. The endometrial glands were irregular in size and shape. The stroma was varied but consisted predominantly of dense cellular stroma with frequent mitotic figures. The glands were lined by a combination of epithelial types some of which were secretory. No cytologic atypia was seen. Levels of ER immunoreactivity, as determined by image analysis, were greater in the stroma with no difference in PR immunoreactivity compared with controls. No difference in ER and PR immunoreactivity were seen in the glands compared with normal controls. CONCLUSION: The generalized cystic changes demonstrated are consistent with a chronic unopposed estrogen effect and are concordant with hormonal data showing early to midfollicular phase levels of estrogens. They also are consistent with our findings of increased ER immunoreactivity in the stroma. Evidence of minimal P agonist effect was noted.

PIP: At the University of California, San Diego, Medical Center during laparoscopy, reproductive specialists examined samples of endometrial tissue from 9 women being treated for endometriosis with 50 mg/day of RU-486 for 6 months and from 9 untreated women (controls) in the follicular phase of the cycle to determine whether or not low-dose RU-486 affected the endometrium. All 9 women treated with RU-486 had abnormal endometrial morphology. Mild hyperplasia was evident in the functional tissues, especially in the stromal compartment. The cellular stroma were dense and had many mitotic figures. The shape of endometrial glands was not regular in size or shape. RU-486 patients exhibited significantly more estrogen receptor (ER) immunostaining than controls (122.93 vs. 103.2; p 0.002), but progesterone receptor (PR) immunostaining was essentially the same. On the other hand, there were no differences in ER and PR in the endometrial glands. These findings suggest that RU-486 acts as a progesterone antagonist and has a chronic unopposed estrogen effect. They also show that the effect of RU-486 is associated with early to midfollicular phase levels of estrogens.

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.

Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist.

OBJECTIVE: The efficacy of acute and sustained pituitary gonadotropin down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the treatment of uterine leiomyomas. DESIGN: Prospective, open clinical trial. PATIENTS: Seven normally cycling women with symptomatic leiomyomas. INTERVENTIONS: Nal-Glu (50 micrograms/kg per day) was administered subcutaneously for 3 months. MAIN OUTCOME MEASURES: Baseline ultrasound examinations were obtained and repeated monthly throughout treatment. Each leiomyoma was mapped and measured in three dimensions. Blood samples were drawn daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months. RESULTS: Mean leiomyoma size decreased 52.8 +/- 7.3% (means +/- SD) after 1 month of therapy and remained unchanged for the remainder of the study. Serum levels of E2 (35.9 +/- 11.8 to 9.3 +/- 0.8 pg/mL, 131.7 +/- 43.3 to 34.0 +/- 1.4 pmol/L), estrone (37.3 +/- 7.5 to 13.0 +/- 2.5 pg/mL, 138.1 +/- 27.7 to 48.1 +/- 9.1 pmol/L), and P (1.6 +/- 1.1 to 0.3 +/- 0.01 ng/mL, 5.0 +/- 3.6 to 0.9 +/- 0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed throughout treatment. Serum LH, FSH, androstenedione, T, and DHEA levels did not change significantly. In two subjects who did not have surgical removal, leiomyomas grew to original size within the 1st month off drug. Six patients remained amenorrheic and the other subject spotted during the last 2 months of therapy. CONCLUSIONS: Continuous treatment with Nal-Glu induces immediate and sustained pituitary-gonadal down-regulation that results in regression in leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian up-regulation, GnRH antagonists may prove to be superior tools in the medical management of leiomyomas.

Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome.

OBJECTIVE: To examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Prospective controlled trial. PATIENTS, PARTICIPANTS: Seventeen women with PCOS and 9 normal-cycling women. INTERVENTIONS: Subjects with PCOS received CC, 150 mg/d for 5 days. MAIN OUTCOME MEASURES: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 micrograms) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n = 8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling. RESULTS: Thirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E2), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E2 increased initially and then returned to baseline and remained unchanged for the ensuring 40 days. CONCLUSIONS: Clomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.

Regression of uterine leiomyomata in response to the antiprogesterone RU 486.

Uterine leiomyomata are steroid hormone dependent tumors which possess receptors for estrogen (ER) and progesterone (PR). We reasoned that an antiprogesterone (RU 486) may induce regression of leiomyomata by withdrawal of progesterone action and/or by its interference of estrogen action. Accordingly, we examined the effects of daily administration of RU 486 (50 mg) for a period of 3 months in 10 patients with uterine leiomyomata and regular menstrual cycles. Baseline ultrasound examinations were obtained and repeated monthly during treatment as a measure of leiomyomata volume. Hormonal parameters were monitored by blood samples obtained prior to treatment and daily for 7 days, weekly for 4 weeks and monthly for the duration of therapy. Myomectomy or hysterectomy was performed in 6 of 10 patients at the end of treatment. Leiomyomata and myometrial tissue was obtained for immunocytochemical analysis of ER and PR protein. Amenorrhea was induced in all patients during treatment. Leiomyomata volume (mean +/- SE) decreased 21.9 +/- 4.8% after 4 weeks, 39.5 +/- 6.6% (P < 0.001) after 8 weeks, and 49.0 +/- 9.2% (P < 0.001) after 12 weeks of treatment compared to pretreatment measurements. Serum LH levels (P < 0.005), but not FSH levels, more than doubled during the first 3 weeks of treatment with a concomitant increase in serum androstenedione (P < 0.006) and testosterone (P < 0.0001) levels. These elevated hormonal levels returned to baseline at 4 weeks without further changes during the remainder of treatment. A significant rise in serum dehydroepiandrosterone sulfate (P < 0.0001) and cortisol (P < 0.01) was seen at 12 weeks, suggesting an antiglucocorticoid effect of RU 486 has occurred. Serum estradiol, estrone, progesterone, sex hormone binding protein, thyroid-stimulating hormone, and PRL were unchanged from early follicular phase values. PR but not ER immunoreactivity was significantly reduced in both leiomyomata and myometrium after RU 486 treatment compared with tissues from untreated patients, suggesting that regression of tumors may be attained through a direct antiprogesterone effect. However, an alteration in ER functionality cannot be excluded. We conclude that RU 486 is well tolerated, safe, and effective; thus, it may prove to be a novel mode of management for uterine leiomyomata.

PIP: Under the hypothesis that the antiprogesterone RU 486 may induce regression of leiomyomata by withdrawal of progesterone action and/or by its interference with estrogen action, the effects of daily administration of 50 mg RU 486 for 3 months were examined in 10 patients with uterine leiomyomata. Monthly ultrasound examinations measured volume of leiomyomata. Myomectomy or hysterectomy was performed in 6 of 10 patients at the end of the treatment. Leiomyomata and myometrial tissue were obtained for immunocytochemical analysis of estrogen receptor (ER) and progesterone receptor (PR) proteins. Amenorrhea was induced in all patients. Leiomyomata volume decreased 21.9 +or- 4.8% after 4 weeks, 39.5 +or- 6.6% (p 0.001) after 8 weeks, and 49.0 +or- 9.2% (p 0.001) after 12 weeks of treatment compared to pretreatment measurements. Serum luteinizing hormone (LH) levels (p 0.005), but not follicle-stimulating hormone (FSH) levels, more than doubled during the first 3 weeks of treatment, with a concomitant increase in serum androstenedione (p 0.006) and testosterone (p 0.0001) levels which returned to baseline at 4 weeks and remained unchanged afterwards. A significant rise in serum dehydroepiandrosterone sulfate (p 0.0001) and cortisol (p 0.01) was seen at 12 weeks, suggesting an antiglucocorticoid effect of RU 486. PR, but not ER, immunoreactivity was significantly reduced in both leiomyomata and myometrium after RU 486 treatment compared with tissues from untreated patients, suggesting the regression of tumors through a direct antiprogesterone effect. There was a significant decrease in PR staining in both leiomyomata and myometrium of RU 486-treated patients when compared to controls. Using image analysis, significantly (p 0.05) more PR immunoreactivity was seen in leiomyomata of treated or control patients when compared to their respective myometrium. ER immunoreactivity was significantly greater (p 0.05) in control leiomyomata when compared to control myometrium, while no difference in ER immunoreactivity was seen between leiomyomata and myometrium of treated patients. RU 486 proved to be safe and effective for a novel mode of management for uterine leiomyomata.

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.