Comparison of vaginal misoprostol and gemeprost as pre-treatment in first trimester pregnancy interruption.

OBJECTIVE: To compare the effectiveness of vaginal misoprostol pre-treatment with standard gemeprost pre-treatment in first trimester pregnancy termination. DESIGN: A prospective randomised study. POPULATION: One hundred and ninety-nine women scheduled for day case termination of pregnancy during the first trimester. METHODS: Cervical priming with a vaginally applied 200 microg tablet of misoprostol for at least four hours, compared with a 1.0 mg vaginal suppository of gemeprost for at least three hours before vacuum aspiration. MAIN OUTCOME MEASURES: The prostaglandin effect on baseline cervical dilatation was the main outcome. Others were occurrence of pre-operative pain and need for analgesia, pre-operative side effects such as nausea, vomiting and diarrhoea, presence of blood in the vagina and blood loss during the operation. RESULTS: There was no significant difference in the dilatation ability of misoprostol or gemeprost, nor in the pre-operative use of analgesics. The frequency of nausea and diarrhoea was significantly less common in the misoprostol treated women. CONCLUSIONS: Vaginally applied misoprostol is as effective as gemeprost in cervical priming prior to first trimester vacuum aspiration. Misoprostol was associated with fewer side effects than gemeprost.

PIP: The effectiveness of vaginal misoprostol pretreatment in first-trimester abortion was compared with that of the standard gemeprost pretreatment regimen in a prospective randomized study conducted at Helsinki City Maternity Hospital (Finland) during 1996-97. 188 women scheduled for vacuum aspiration abortion were assigned to undergo cervical priming with a vaginally applied 200 mcg tablet of misoprostol for at least 4 hours (n = 95) or a 1 mg gemeprost vaginal suppository for at least 3 hours (n = 93). The mean duration of prostaglandin pretreatment was 221 minutes in the gemeprost group and 288 minutes in the misoprostol group. 14% of women in the gemeprost group and 5% in the misoprostol group needed pain medication. There were no uterine perforations, cervical ruptures, or incomplete evacuations in either group. Nausea and diarrhea were significantly more frequent in the gemeprost group. The effects of the two analogues were similar in terms of cervical softening, as determined by baseline cervical dilatation, and the presence of blood in the vagina. Overall, the misoprostol treatment was found to be as effective as the more costly gemeprost regimen, with even fewer side effects. Use of a 400 mcg vaginal dose of misoprostol could be considered to reduce the time required to reach peak plasma concentrations.

Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy.

OBJECTIVES: To assess whether the levonorgestrel intrauterine system could provide a conservative alternative to hysterectomy in the treatment of excessive uterine bleeding. DESIGN: Open randomised multicentre study with two parallel groups: a levonorgestrel intrauterine system group and a control group. SETTING: Gynaecology departments of three hospitals in Finland. SUBJECTS: Fifty six women aged 33-49 years scheduled to undergo hysterectomy for treatment of excessive uterine bleeding. INTERVENTIONS: Women were randomised either to continue with their current medical treatment or to have a levonorgestrel intrauterine system inserted. MAIN OUTCOME MEASURE: Proportion of women cancelling their decision to undergo hysterectomy. RESULTS: At 6 months, 64.3% (95% confidence interval 44.1 to 81.4%) of the women in the levonorgestrel intrauterine system group and 14.3% (4.0 to 32.7%) in the control group had cancelled their decision to undergo hysterectomy (P < 0.001). CONCLUSIONS: The use of the levonorgestrel intrauterine system is a good conservative alternative to hysterectomy in the treatment of menorrhagia and should be considered before hysterectomy or other invasive treatments.

[When there is no suitable contraceptive method]. / Kun sopivaa ehkäisymenetelmää el löydy.

Despite of the many possibilities there are some situations where no method of contraception seems to be suitable. The reasons for this may be medical and clear such as rise of blood pressure, which is an obstacle to using combination pills. Sometimes a question arises, whether the feelings are really caused by the contraceptive method, or does the woman possibly blame contraception for some other reason.

PIP: In Finland, all known combined oral contraceptives (OCs), minipills, implants, IUDs, and condoms are available, yet there are situations when none of these is suitable. For instance, OCs are contraindicated in the case of high blood pressure and problems can be encountered with fitting IUDs if an inflammation is present, or on account of irritability, weight gain, libido change, and depression. Solving psychological problems is arduous and time-consuming; these may include the desire to get pregnant, religious grounds for refusing to use OCs, and the mindset which opposes the introduction of any foreign hormone into the body. Another cause for nonuse of contraception is the unfounded fear of the risk of cancer. That is why the role of counseling is paramount in finding the appropriate contraceptive method for every individual situation.

Selection and performance of the levonorgestrel-releasing intrauterine system.

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNg IUS) is a hormonal contraceptive that is used in the uterine cavity. To determine whether the reasons for choosing LNg IUS vs. copperreleasing intrauterine devices (Cu IUDs) differ and whether their performances are comparable, we carried out a retrospective study in Finland during the first years of LNg IUS use. METHODS: Gynecological and contraceptive histories of 626 LNg IUS and 626 Cu IUD users and the performance of the device were reviewed from patient records. RESULTS: Women who accepted the LNg IUS were more likely than Cu IUD acceptors to have a history of menstrual bleeding of 6 days or more (44.4% vs. 28.4%), heavy bleeding (44.8% vs. 8.4%) and moderate or severe dysmenorrhea (15.9% vs. 7.5%). In both groups, 70% of the women had used Cu IUDs earlier. However, the LNg IUS acceptors had had more side effects during previous use of CU IUDs (58.2% vs. 28.8%). They also reported more side effects that resulted in discontinuation of a previous Cu IUD (39.4% vs. 10.1%). However, the 12-month life-table continuation rates of 80.6 (SE 1.9)% vs. 83.4 (SE 1.8)% were alike. Cu IUD users discontinued the current method more often because of problems of bleeding and unwanted pregnancy. Among those women who had previously discontinued a hormonal method because of hormonal side effects, there were no differences in the continuation rates of the two groups. CONCLUSIONS: LNg IUS can be successfully used by women who cannot use a CU IUD or who have experienced hormonal side effects with oral contraceptives.

Endometrial response to hormone replacement therapy as assessed by expression of insulin-like growth factor-binding protein-1 in the endometrium.

OBJECTIVE: To assess endometrial response to parenteral levonorgestrel in hormone replacement therapy by means of morphological criteria and immunohistochemical staining of insulin-like growth factor-binding protein-1 (IGFBP-1). DESIGN: Endometrial samples were collected from 35 postmenopausal women after 12 to 22 months of continuous combined estrogen-progestin therapy. All subjects were treated with parenteral progestin. A group of 8 women was treated with a subdermal levonorgestrel-releasing implant, and 27 women had a levonorgestrel-releasing intrauterine device (IUD). Sections of formalin-fixed paraffin-embedded biopsies were used for immunohistochemistry and after hematoxylin-eosin staining for routine histologic examination. RESULTS: Atrophic epithelium with pronounced decidual reaction in the stroma was detected by histologic examination in all endometrial samples obtained from 27 women treated with the levonorgestrel-releasing IUD. In contrast, the endometrium was proliferative in seven of eight (87.5 percent) biopsies obtained from women treated with the levonorgestrel-releasing implant. Immunoreactive IGFBP-1 was detected in decidualized stromal cells in all endometrial samples obtained during intrauterine levonorgestrel therapy, whereas only one of eight samples obtained from women treated with subdermal levonorgestrel exhibited weak staining for IGFBP-1. CONCLUSIONS: Our data show that both the morphological and biochemical response of post- menopausal endometrium to parenteral levonorgestrel was strikingly different, depending on the route of progestin administration, and that the decidual reaction and epithelial atrophy induced by intrauterine levonorgestrel were associated with expression IGFBP-1 in decidualized stromal cells.

The progestin ST 1435--rapid metabolism in man.

Parenterally administered ST 1435 (Nestorone) is highly potent for contraception, and ovulation can be inhibited with very low serum levels of ST 1435. Orally administered ST 1435 is ineffective in various laboratory animals, presumably due to extensive first-pass metabolism. Thus, ST 1435 has been proposed for lactational contraception, to be metabolized by the suckling infant. We have studied the metabolism of ST 1435 in female volunteers following oral (10 mg), intravenous (iv) (0.1 mg) and transdermal (4.5-9.0 mg) routes of ST 1435 administration. Preliminary studies using rats were performed to develop the methodology of high performance-liquid chromatography (HPLC) fractionation and ST 1435-RIA detection. Rat portal serum revealed 4 distinct peaks of immunoreactive material with the retention times (Rt's) of 7.5, 10, 14.5 and 17.5 min (ST 1435 = 10 min). In systemic serum, only the peak with the Rt of 7.5 min could be detected. Therefore, orally administered ST 1435 is very effectively metabolized by the rat liver; this also explains the previously observed lack of biological effects of oral ST 1435. Following oral administration of ST 1435 to two women, the Rt of the major peak was 10 min. The magnitude of the ST 1435 peak decreased rapidly, and at 24h following ingestion, no ST 1435 could be detected by this method. The t1/2 of ST 1435 was approximately 1-2h. In addition, two minor peaks with Rt's of 4.5 and 16 min could be detected with the ST 1435 RIA at 1-4h following oral ingestion. Competitive receptor binding assays using the human uterine progesterone receptors (hPR) revealed that the ST 1435 fraction exhibits strong binding affinity towards the hPR; thus, in the human, a small fraction of biologically active ST 1435 seems to escape from the first-pass metabolism following oral intake. Following iv and transdermal administration of ST 1435, the only detectable peak with ST 1435-RIA was that of ST 1435. Similar magnitude of the ST 1435 peaks following oral administration of 10 mg and iv administration of 0.1 mg indicated that the bioavailability of ST 1435 is low. These data seem to confirm the suspicion that orally administered ST 1435 is also rapidly metabolized in the human, therefore encouraging further evaluation of ST 1435 during lactation. However, the rapid metabolism seen after oral intake can be successfully circumvented by sustained parenteral administration of ST 1435.

A contraceptive subdermal implant releasing the progestin ST-1435: ovarian function, bleeding patterns, and side effects.

OBJECTIVE: To study ovarian function, bleeding patterns, and side effects during the 1-year use of a new modified contraceptive subdermal implant releasing the progestin ST-1435 with a lifetime of 2 years. DESIGN, PATIENTS: The effect on ovarian function and bleeding patterns of one contraceptive implant releasing the progestin ST-1435 was studied in 26 healthy women who volunteered. Side effects were recorded. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: One ST-1435 contraceptive implant was inserted subcutaneously into the ventral aspect of left upper arm. MAIN OUTCOME MEASURES: The women attended the clinic at half-year intervals. Records of bleeding were kept. Blood samples were collected from 5 women before insertion of an implant, from 12 women during the first 5 to 6 weeks of use, and from 10 women during the 6th and 12th month of use. Serum concentrations of ST-1435, progesterone, and estradiol were determined. Side effects were reported. RESULTS: The study covered 302 woman-months. The implant gave serum concentrations of ST-1435 high enough to inhibit ovulation in all of the 37 analyzed cycles. No pregnancies occurred. Irregular bleeding or spotting was the main event observed, especially during the 1st year of use. One half of the users had irregular cycles. None of the women's implants was removed during 1 year of use because of irregular bleeding. The implant was well accepted and tolerated by the women; no hormonal side effects were reported. CONCLUSIONS: One single 4-cm subdermal ST-1435 implant with a lifetime of 2 years showed good contraceptive efficacy and led to suppression of ovulation. No hormonal side effects were reported. Irregular bleeding patterns were common but well-tolerated, and the implant had a high continuation rate.

PIP: Physicians inserted a new 4-cm subdermal implant releasing the progestin ST-1435 (78 mg) into the ventral area of the left upper arm in 26 healthy 20-36 year old women at the outpatient clinic at the City Maternity Hospital in Helsinki, Finland, and followed them for 12 months (total of 302 woman months) to examine its side effects, ovarian function, and bleeding patterns. (This implant has a lifetime of 2 years.) The implant released ST-1435 at serum levels high enough to suppress ovulation in all 37 analyzed menstrual cycles. None of the women became pregnant. Irregular bleeding occurred in 11 women. Even though a high proportion of women experienced irregular bleeding, it did not lead any women to request removal of the implant. The total spotting days decreased significantly between the first 6 months and the last 6 months (24-16 days; p .05). None of the women experience hormonally induced side effects, other than irregular bleeding. After 1 year of use, the continuation rate stood at 89%. 2 women wanted the implant removed so they could become pregnant. 1 woman wanted it removed for personal reasons. In conclusion, the women tolerated this implant well. Moreover, it was effective in preventing pregnancy.

Suppression of ovarian function with the transdermally given synthetic progestin ST 1435.

OBJECTIVE: To study transdermal administration of the synthetic progestin ST 1435 and effectiveness of the steroid in suppression of ovarian function. DESIGN, PATIENTS: The effect of transdermal administration of the synthetic progestin ST 1435 in suppression of ovarian function was studied in a short term (17 to 93 days) study in healthy regularly menstruating women. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: Nine women used the progestin ST 1435 transdermally during a total of 21 menstrual cycles. Treatment was started on the 5th day of the menstrual cycle and continued for 17 to 93 days. Three different daily doses (0.5, 0.8, and 1.0 mg) were tested. The steroid was applied to the periumbical area once a day in a gel. MAIN OUTCOME MEASURES: Serum concentrations of ST 1435, progesterone, and estradiol (E2) were determined during the luteal phase of control cycles and in a total of 16 treatment cycles. Bleeding records were kept and side effects registered. RESULTS: Transdermal absorption of the progestin ST 1435 resulted in relatively constant serum concentrations in each subject, depending on the dose used. All doses caused changes in ovarian function. With the 0.5-mg/d dose, inhibition of ovulation was observed in three of five treatment periods. The 0.8-mg/d dose was high enough to inhibit ovulation in 7 of 10 cycles analyzed. With the 1.0-mg/d dose, the serum concentrations of the progestin were high, and anovulation was seen. Serum E2 concentrations were variable in all cases; occasional high peak values were seen, typical of progestin treatment. Bleeding control was variable; irregular bleeding was seen, especially in anovulatory cases. CONCLUSIONS: A 0.8-mg dose of the progestin ST 1435 administered transdermally once a day appeared to suppress ovulation, if properly applied, and excessive suppression of ovarian function was not seen. The steroid was well accepted. The synthetic progestin ST 1435 given transdermally represents an effective alternative for inhibition of ovulation and for progestin therapy.

PIP: Physicians monitored serum concentrations of the synthetic progestin ST 1435, progesterone, and ethinyl estradiol in 9 healthy 28-42 year old women attending the outpatient clinic at City Maternity Hospital in Helsinki, Finland who agreed to apply ST 1435 gel to the periumbilical area daily for 21 menstrual cycles. They 1st applied it on day 5 of the menstrual cycle and continued treatment for 17-93 days. The physicians wanted to examine the daily dose of ST 1435 needed to suppress ovarian function and ovulation. A daily dose of 0.8 mg ST 1435 achieved the optimal serum concentration of ST 1435 (112-278 pmol/L) to inhibit ovulation. Each woman tended to have constant serum concentrations and those concentrations depended on the dose. All 3 different doses (0.5, 0.8, and 1 mg) affected ovarian function. The 0.5 mg/day dose prevented ovulation in 3 of 5 treatment periods while the 0.8 mg/day dose did in 7 of 10 cycles. Anovulation occurred in the only women who used the 1 mg/day dose. ST 1435 levels (mean 691 pmol/L) were high at this dose. Serum ethinyl estradiol levels differed among the women in each dose group and between dose groups. A few women even had very high levels which typifies progestin treatment. Irregular bleeding occurred in some women especially during the anovulatory cycles. Bleeding control was the only side effect. 0.8 mg/day of ST 1435 applied transdermally appeared to be an effective and acceptable contraceptive. Researchers should conduct more studies on transdermal ST 1435 to account for the interindividual differences in ST 1435 serum levels and to determine ST 1435's efficacy.

Intrauterine progestin induces continuous insulin-like growth factor-binding protein-1 production in the human endometrium.

The effect of local intrauterine progestin on endometrial insulin-like growth factor-binding protein-1 (IGFBP-1) production was studied in 60 women using a levonorgestrel-releasing intrauterine device (IUD). Intrauterine progestin was a potent stimulator of stromal cell IGFBP-1 production, with 97% of endometrial specimens showing positive staining by immunohistological methods. After 5 yr or more of intrauterine progestin exposure, 100% (n = 20) of the tissues remained strongly positive for IGFBP-1. The IGFBP-1 content in endometrial tissue homogenates reached values as high as 10 micrograms/mg protein when measured by immunoradiometric assay. In contrast to the continuous endometrial IGFBP-1 production induced by local progestin, no such effect could be found in endometria from subjects with sc progestin-releasing implants or copper IUDs. Although the levonorgestrel-releasing IUD had a striking effect on local endometrial IGFBP-1 production, it had no effect on serum IGFBP-1 levels. By Western ligand blot analysis, the domainating IGF-binding species in endometria exposed to intrauterine progestin was of 28K mol wt, corresponding to IGFBP-1, whereas no IGFBP species of 31-43K, corresponding to IGFBP-2 or IGFBP-3, were detected.

Endometrial effect of transdermal estradiol and progestin ST-1435 in postmenopausal women.

OBJECTIVE: To study the endometrial effect of the transdermal synthetic progestin ST-1435. DESIGN: Prospective. SETTING: City Maternity Hospital, Helsinki, Finland. PATIENTS: Eleven postmenopausal women used transdermal estradiol (E2) patches for 6 weeks immediately before a vaginal operation for prolapse. For the last 10 days, 1 mg of ST-1435 transdermally in a gel was combined to the treatment. MAIN OUTCOME MEASURES: Blood samples were taken to follow serum concentrations of E2, follicle-stimulating hormone, and ST-1435. Endometrial samples for histologic examination were collected during the operation to evaluate the effect of the progestin. RESULTS: Transdermal absorption of ST-1435 resulted in reasonably constant serum concentrations of ST-1435 in each subject. A progestin effect on the endometrium was seen in 9 of 10 samples obtained. One sample did not show any progestin effect in spite of adequate ST-1435 levels, but this patient's E2 concentrations were low. CONCLUSIONS: When the estrogen stimulation was adequate, the transdermal ST-1435 induced a progestin effect on the endometrium, i.e., it had an end-organ effect.

Contraception with subdermal implants releasing the progestin ST-1435: a dose-finding study.

A new modified subdermal implant releasing the potent progestin ST-1435 was studied in eleven fertile-aged women. These implants have been developed for contraception and they have a life-time of two years. Three implant lengths of 4, 6 and 8 cm were tested to find the optimal steroid dose for inhibition of ovulation. Serum samples were collected twice per week during a six-week period every six months. The concentrations of serum ST-1435, estradiol and progesterone were determined by RIA. Ovulation was inhibited by all ST-1435 doses tested. The concentration of serum progesterone was below 6 nmol/l in all samples tested showing the absence of luteinization. The concentration of serum ST-1435 increased with increasing ST-1435 dose. Serum estradiol concentrations were quite variable, showing wide range and occasional high peak values typical of progestin treatment; the mean value of serum estradiol concentrations measured did not differ with different ST-1435 doses. The results of steroid determinations led to the conclusion that a single 4 cm subdermal implant is optimal for contraception. With this dosage level, ovulation is inhibited and side effects are minimized. Bleeding control was variable. No hormonal side effects due to the progestin ST-1435 were reported. This method, using a single 4 cm subcutaneous implant releasing the progestin ST-1435 with a life-time of two years, represents a promising alternative for inhibition of ovulation and contraception.

Transdermal absorption of the progestin ST-1435: therapeutic serum steroid concentrations and high excretion of the steroid in saliva.

The synthetic progestin ST-1435 was administered transdermally to six healthy women during the late luteal phase. The steroid was applied to the periumbilical area in a commercial gel ("Progestogel"), also containing progesterone. Single doses of 2.3, 4.5 and 9.0 mg of ST-1435 were given in three experiments and repeated doses of 2.3 mg of ST-1435 for five days were given in another three experiments. Samples of serum and saliva were collected and the concentrations of ST-1435 and progesterone were determined by radioimmunoassays. Transdermal absorption of the synthetic progestin ST-1435 was shown to result in serum steroid concentrations high enough for therapeutic purposes. The concentration of ST-1435 in serum was still high 24 hours after application, reflecting sustained release of the steroid from the skin. In the five-day experiments, relatively constant serum levels were achieved in different individuals, and a single dose per day seems sufficient. High excretion of ST-1435 in saliva was found two hours after gel application. However, the concentrations of serum and salivary ST-1435 were not directly correlated in different individuals. Transdermal application of ST-1435 might offer a good alternative for systemic progestin treatment.

A contraceptive vaginal ring releasing ethinyl estradiol and the progestin ST-1435: bleeding control, serum steroid concentrations, serum lipids and serum chemistry.

Four women used vaginal rings releasing the synthetic progestin ST-1435 and ethinyl estradiol for at least three 21-day cycles with a 7-day treatment-free period between intervals of use. Patterns of bleeding were evaluated and serum concentrations of ST-1435, estradiol, progesterone and ethinyl estradiol were measured by radioimmunoassay. Total serum cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and serum chemistry were determined before ring use and during the first and third treatment cycles. The women experienced no difficulties in using the vaginal ring and all continued to use the ring after the first three cycles. Bleeding control was good and hormonal side effects were minimal. Serum steroid concentrations were: ST-1435, 289 +/- 117 pmol/l (mean +/- SD); ethinyl estradiol, 172 +/- 108 pmol/l; and estradiol, 184 +/- 107 pmol/l. Concentrations of serum progesterone were low, indicating complete suppression of ovulation during treatment. Total serum cholesterol increased slightly during use of ring. However, this increase could be accounted for by an increase in serum HDL-cholesterol. Liver function tests were in the normal range during ring use and values of serum chemistry showed no significant changes. This contraceptive vaginal ring presents a good method of contraception, showing good bleeding control and no harmful metabolic effects.

Interference with ovulation by sequential treatment with the antiprogesterone RU486 and synthetic progestin.

Seven healthy women were treated with the antiprogesterone RU486, 25 mg/d, on days 1 to 14 of the follicular phase of the menstrual cycle, followed by the synthetic progestin NET in the luteal phase of the cycle. Venous blood samples were collected twice per week. Serum E2, P, and RU486 concentrations were determined by RIAs, and FSH and LH by immunofluorometric assays. Ultrasonography was used to measure the sizes of the follicles. Serum concentrations of FSH and LH were not suppressed during the treatment. Ovulation was apparently suppressed during RU486 treatment according to E2 and P concentrations and ultrasonography findings. During NET treatment, some evidence of ovulation and follicle growth were found during the first treatment periods. During the third treatment cycle, there was no evidence of ovulation (n = 2). Estradiol concentrations were sufficient to stimulate normal proliferative growth of the endometrium during the treatment. Control of bleeding was good. The exact mechanism of action of RU486 on steroid synthesis and ovulation is not clear, but it appears to act at the ovarian level. The evidence indicates that sequential RU486/progestin treatment could be developed to result in suppression of follicular growth and ovulation.

PIP: In Finland, physicians at the outpatient clinic at the Helsinki City Maternity Hospital followed 7 26-38 year old women who took 25 mg RU-486/day during days 1-14 (follicular phase) and 5 mg of norethindrone/day (NET) during days 15-24 (luteal phase) for 1 menstrual cycle or for 3 menstrual cycles to investigate the possibility of sequential use of an antiprogesterone and progestin as an oral contraceptive. They used ultrasonography to monitor follicular growth and obtained blood samples 2 times/week to do radioimmunoassays and immunofluorometric assays to measure estradiol, progesterone, RU-486, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels. They took endometrial biopsies at the end of RU-486 treatment (days 12- 13) and during NET treatment (days 21-22). Before RU-486/NET treatment the physicians performed various tests during a control cycle. RU-486 treatment did not alter FSH or LH levels. Progesterone and estradiol levels and ultrasonography indicated, however, that RU-486 did suppress ovulation. Ovulation and follicle growth did occur during NET treatment, yet during the third cycle no one ovulated. Bleeding control was adequate. It appeared that the mechanism of action of RU-486 on steroid synthesis and ovulation occurred at the ovarian level. Even though RU-486 at least partially inhibited estradiol synthesis, sufficient estradiol remained to stimulate normal proliferative growth of the endometrium. None of the women experienced steroidal side effects from the treatment. These findings indicated that further development of sequential RU-486/progestin treatment could suppress follicular growth and ovulation.

Distribution of RU 486 and its demethylated metabolites in humans.

The concentrations of RU 486 and its demethylated metabolites were determined by RIA in samples of myometrium, abdominal adipose tissue, and serum, which were collected at hysterectomies performed 12-15 h after oral administration of 200 mg RU 486. The RU 486 concentrations in myometrium were similar in the five women studied, with a mean of 148 +/- 58 (+/- SD) ng/g (344 +/- 135 pmol/g). The adipose tissue RU 486 levels varied more, the mean concentration being 447 +/- 191 ng/g (1041 +/- 445 pmol/g). The serum RU 486 concentrations ranged from 175-899 ng/ml [mean, 396 +/- 259 ng/mL (922 +/- 603 nmol/L)]. In these women the nonprotein-bound fraction of [6,7-3H]RU 486 varied from 1.4-3.1% (mean, 2.3%). The approximate concentrations of the combined mono- and didemethylated metabolites of RU 486 were 1.4, 3.1, and 5.2 times higher in adipose tissue, myometrial tissue, and serum, respectively, than those of the parent RU 486. In vitro, rapid and nonsaturable accumulation of [6,7-3H]RU 486 from phosphate buffer into adipose tissue was inhibited by the addition of alpha 1-acid glycoprotein, the specific serum transport protein for RU 486, to the buffer medium. Accumulation of [6,7-3H]RU 486 in myometrial specimens was poor. The enterohepatic cycling of RU 486 was assessed in four normal subjects by repetitive intake of charcoal subsequent to ingestion of 200 mg RU 486. Compared to other normal subjects, the serum levels and areas under the concentration curves were lower and t1/2 values shorter in the group given charcoal, suggesting that in vivo RU 486 may be partly pooled in the enterohepatic cycle. Our studies suggest that despite the low volume of distribution and the effective serum binding of RU 486, the myometrial and adipose tissue concentrations of RU 486 and its metabolites were similar (approximately 10(-9)-10(-10) mol/g) after oral intake of RU 486.

Inhibition of folliculogenesis and ovulation by the antiprogesterone RU 486.

Healthy, regularly menstruating women were treated with the antiprogesterone RU 486, Mifepristone (Roussel-Uclaf, Romainville, France) during the follicular phase of the cycle. Three women were given 25 mg of RU 486 on days 1 to 14 of the cycle and five received 25 mg on days 1 to 21 of the cycle. Venous blood samples were collected three times per week during a control cycle and during one treatment cycle in each subject. Serum concentrations of estradiol (E2), progesterone (P), and RU 486 were determined by radioimmunoassays. No drug-related side effects and no spotting or bleeding during RU 486 treatment were observed. Menstrual bleeding was delayed by 8.7 +/- 3.8 days (mean +/- SD) after treatment over days 1 to 14 and by 12.6 +/- 3.2 days after treatment over days 1 to 21. During the treatment with RU 486, the serum concentrations of E2 remained low, indicating effective inhibition of folliculogenesis. After cessation of RU 486 treatment, serum E2 levels rose to similar values as in the control cycle, and subsequently serum P concentrations also reached ovulatory levels in six out of the eight volunteers. The results showed that the antiprogesterone RU 486 delayed folliculogenesis and luteinization even at low doses when given during the follicular phase of the menstrual cycle. It is speculated that this property of RU 486 could be utilized in the design of an estrogen-free combined oral contraceptives.

PIP: The antiprogesterone RU 486 (mifepristone, Roussel-Uclaf, Romainville, France) was taken by 3 women for days 1-14 of the menstrual cycle, and by 5 women on days 1-21, at a low dose of 25 mg/day, to see whether it would affect ovulation. There is normally a brief progesterone peak before the LH surge that precedes ovulation. To monitor the cycle, women reported bleeding symptoms, and their serum estradiol, progesterone and RU 486 levels were assayed. There were no side effects or bleeding or spotting reported. Serum estradiol levels remained below those recorded in the control cycle, indicating that development of the follicle was inhibited. Estradiol levels rose to follicular phase levels after discontinuation of the drug. Menstruation was delayed by 6, 6 and 14 (mean 8.7) days in the women who took RU 486 for 14 days, and by 8, 12, 12, 13 and 18 days (mean 12.6) days in those who took it for 21 days. The subsequent luteal phase was of normal duration and progesterone level. Based on progesterone level, 2 treatment cycles were anovulatory. Serum RU 486 concentrations ranged from 200 to 1400 ng/ml. It is conceivable that an estrogen-free combined oral contraceptive could be developed based on this property of RU 486.