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Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo-controlled trial with 600-mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14. Rifampicin increased urine pentaporphyrin concentration 3.7-fold (mean 1.80 ± 0.6 vs. 6.73 ± 4.4 nmol/L, p = 0.003) in comparison with placebo. Urine coproporphyrin I increased 23% (p = 0.036). Faecal protoporphyrin IX decreased (mean 31.6 ± 23.5 vs. 19.2 ± 27.8 nmol/g, p = 0.023). The number of blood erythrocytes was slightly elevated, and plasma bilirubin, catabolic metabolite of haem, was decreased. In conclusion, rifampicin dosing elevated the excretion of certain urinary porphyrin metabolites and decreased faecal protoporphyrin IX excretion. As urine pentaporphyrin and coproporphyrin I are not precursors in haem biosynthesis, increased excretion may serve as a hepatoprotective shunt when haem synthesis or porphyrin levels are increased.

The HCR gene, officially called Coiled-Coil alpha-Helical Rod protein 1 (CCHCR1), located within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene for the risk effect. Recently, CCHCR1 was shown to promote steroidogenesis by interacting with the steroidogenic acute regulator protein (StAR). Here, we examined the role of CCHCR1 in psoriasis and cutaneous steroid metabolism. We found that CCHCR1 and StAR are expressed in basal keratinocytes in overlapping areas of the human skin, and CCHCR1 stimulated pregnenolone production in steroidogenesis assay. Overexpression of either the CCHCR1*WWCC risk allele or the non-risk allele enhanced steroid synthesis in vitro. Furthermore, the cytochrome P450scc enzyme was expressed in human keratinocytes and was induced by forskolin, a known activator of steroidogenesis, and forskolin also upregulated CCHCR1. CCHCR1 has an altered expression pattern in lesional psoriatic skin compared to normal healthy skin, suggesting its dysregulation in psoriasis. We found that the expression of CCHCR1 is downregulated twofold at the mRNA level in cultured non-lesional psoriatic keratinocytes when compared to non-psoriatic healthy cells. Our results also suggest a connection between CCHCR1 and vitamin D metabolism in keratinocytes. The expression of the vitamin D receptor (VDR) gene was lower in non-lesional psoriatic keratinocytes than in healthy cells. Furthermore, Vdr expression was downregulated in the keratinocytes of mice overexpressing the CCHCR1*WWCC risk allele when compared to keratinocytes from mice with the non-risk allele of CCHCR1. Finally, we demonstrate that other agents relevant for psoriasis and/or the regulation of steroidogenesis influence CCHCR1 expression in keratinocytes, including insulin, EGF, cholesterol, estrogen, and cyclosporin A. Taken the role of steroid hormones, including vitamin D and estrogen, in cell proliferation, epidermal barrier homeostasis, differentiation, and immune response, our results suggest a role for CCHCR1 in the pathogenesis of psoriasis via the regulation of skin steroid metabolism.

Objective: Low dose mifepristone (RU486) is highly effective in emergency post-coital contraception (EC), although the mechanism(s) of action remains unclear. We studied the endocrine actions of 10 mg mifepristone administered orally as a single dose to eight healthy volunteers (aged 20–45 years) during the late follicular phase. Methods: Serum levels of LH, FSH, oestradiol, progesterone, leptin, mifepristone, cortisol, and gluco-corticoid bioactivity (GBA) were measured before and 1, 2, 4 and 8 h after ingestion of mifepristone on cycle day 10 or 11 (study day 1), and follow-up was continued for 10 days. Ovarian ultrasonography was performed on study days 1 and 7. Similar measurements were carried out during a control cycle. Results: Mifepristone postponed ovulation, as evidenced by a 3.4±1.1 day (means±s.d.) delay (P < 0.005) in the LH surge and 3.6±4.0 day prolongation of the treatment cycle (P = 0.08). During the mifepristone cycle, an LH surge was displayed by five subjects when serum mifepristone levels had declined to 9.5±7.1 nmol/l. During the day of mifepristone administration, circulating GBA (P < 0.001) and leptin (P < 0.001) levels declined. On the day after mifepristone administration, mean serum FSH and leptin levels were lower than pretreatment values (3.8±1.8 IU/l vs 5.2±1.1 IU/l, n = 7, P < 0.05; 28.9±6.7 μg/l vs 33.2±9.0 μg/l, n = 7, P < 0.05 respectively), and the corresponding difference in the mean serum oestradiol concentration was borderline (452±252 pmol/l vs 647±406 pmol/l, n = 7, P = 0.056). In contrast to the control cycle, individual leptin levels declined during the follow-up after ingestion of mifepristone (n = 8, P < 0.01). Conclusions: These data showed that the commonly employed dose of mifepristone for EC delays ovulation and prolongs the menstrual cycle, when given during the late follicular phase. The mechanism of action of mifepristone may include a reduction of FSH secretion via a decrease in circulating leptin.

Background. To study the role of progesterone (P4) in the regulation of circulating leptin in early human pregnancy, we measured the levels of leptin before and after administration of the antiprogestin mifepristone, followed by misoprostol in early pregnancy. Methods. Thirty-four women requesting termination of pregnancy, with ≤63 days of amenorrhea, received 200 mg of mifepristone on day 0, followed by either oral or vaginal administration of 0.8 mg of misoprostol on day 2. Five serial serum samples were assayed for leptin, human chorionic gonadotrophin (hCG), P4, estradiol (E2), cortisol, and mifepristone. Results. Circulating leptin concentrations decreased by 8.7 ± 29.7% (mean ± standard deviation) ( p < 0.05) following the ingestion of mifepristone. After misoprostol administration on day 2, a decrease of 12.6 ± 17.0% ( p < 0.05) was followed by a rebound on day 3 to 87.6 ± 25.7% of the pretreatment values. Two weeks after mifepristone, leptin levels had declined by 25.4 ± 30.4%. In contrast, E2, P4...

A 2-year trial of a single Nestorone® (NES) rod implant was conducted at three Latin American centers, each enrolling 100 women. We studied the safety, effectiveness and acceptability of this progestin-releasing contraceptive implant. Three pregnancies occurred, the last at 18 months of use. Because no pregnancies were expected in the first 18 months, the trial was halted. At that time, 224 women had completed at least 18 months of use, and 99 women had used the implant for more than 24 months. Few participants used adjunctive contraception between the time the study was halted and the time they had their implant removed. No additional pregnancies occurred before the removal of the last implant. The 2-year cumulative pregnancy rate was 1.7 per 100 with a Pearl index of 0.6 per 100 for the 2-year period. The 1-year and 2-year continuation rates were 80.5 and 66.7 per 100, respectively. Menstrual and medical disturbances were the principal reasons for discontinuation, followed by planned pregnancy. Headache and weight gain frequently led to discontinuation. The NES implant had little important effect on most clinical chemistry and lipid parameters. Over the study course, the mean change in hemoglobin was

Mifepristone is a potent antiglucocorticoid, the administration of which results in a dose-dependent activation of the hypothalamic-pituitary-adrenal axis. However, the net effect of this compound on circulating glucocorticoid activity is not known. We have used a recombinant cell bioassay to study glucocorticoid bioactivity (GBA), measured directly from serum, in 18 women undergoing medical termination of an early pregnancy with 200 mg mifepristone, followed by 0.8 mg misoprostol, a prostaglandin. Increased serum mifepristone was accompanied by an increase in serum cortisol that was insufficient to maintain circulating GBA within the normal (pre-mifepristone) range (34.7-93.8 nM cortisol equivalents); after approximately 43, 46, and 68 h of mifepristone ingestion, the mean serum GBA levels were much lower than the mean pre-mifepristone level (P0.0001). At the corresponding times, 16, 13, and 12 women displayed subnormal serum GBA levels (ranges,15.6-23,15.6-25.6, and15.6-32.5 nM cortisol equivalents, respectively). Altogether 11 subjects displayed subnormal serum GBA (range,15.6-32.5 nM cortisol equivalents) continuously in the presence of high concentrations of mifepristone. Two weeks after mifepristone administration, circulating GBA had returned to normal levels in all subjects. We conclude that 200 mg mifepristone elicits a significant suppression of serum GBA, to one third of the pretreatment value, despite the compensatory increase in the serum cortisol concentration.

BACKGROUND: Misoprostol is widely used in combination with mifepristone for medical termination of pregnancy. We studied the endocrine parameters of trophoblast function during medical termination of early pregnancy using mifepristone in combination with oral or vaginal misoprostol. The effect of prolonged misoprostol administration was also examined. METHODS: Thirty-four women, requesting termination of pregnancy and with ≤63 days of amenorrhoea, received 200 mg of mifepristone on day 0, followed by either oral (n 13) or vaginal (n 21) administration of 0.8 mg of misoprostol on day 2. In 23 cases misoprostol administration was continued orally for an additional 7 days. Serum samples, collected up to 14 days following the beginning of the treatment, were analysed for hCG, progesterone and mifepristone. RESULTS: hCG and progesterone concentrations continued to increase until day 2. Following misoprostol, hCG and progesterone levels declined by 70.5 8.8% and 61.3 16.3% (mean SD) respectively, in 24 h. The percentage decline in hCG correlated inversely (P < 0.05) with the time taken to abort. The peak level of mifepristone measured on day 2 did not correlate with the decline in serum hCG or progesterone. The kinetics of hCG, progesterone and mifepristone were similar in the different treatment groups. CONCLUSIONS: The route and duration of misoprostol administration have no effect on the kinetics of serum hCG or progesterone during medical termination of early pregnancy.

Background: Levonorgestrel (LNG) is a commonly used progestin for emergency contraception; however little is known about its pharmacokinetics and optimal dose for use. Methods: Serum levels of LNG and sex hormone-binding globulin (SHBG) were measured in five women who received three different regimens: A: 0.75 mg LNG twice with a 12 h interval; B: 0.75 mg twice with a 24 h interval; and C: 1.50 mg in a single dose with a washout period of 28 days between each treatment. Blood samples were taken before pill intake and at 1 2 4 8 and 12 h after each dose every 12 h up to day 4 and every 24 h until day 10. LNG and SHBG were measured in all samples. Results: Maximum LNG concentrations were of -27 nmol/l for treatments A and B and close to 40 nmol/l for treatment C. The area under the curve was significantly higher for treatment C during the first 12 h and significantly lower for treatment B during the first 24 h. After 48 h and up to 9 days from onset of treatment serum LNG levels were similar in all three regimens. SHBG levels remained stable for 24 h decreasing to 60% of the initial value from day 5 until day 10 with no difference between regimens. Conclusions: The similarity of LNG serum levels obtained with one single dose of 1.5 mg or two doses of 0.75 mg with a 12 h interval justify a clinical comparison of these two regimens. (authors)

Using steady-state conditions the authors aimed to test if administration of oral activated charcoal affects the bioavailability of norethisterone acetate (NET Ac) and gestodene (GEST) by inhibiting their enterohepatic recirculation. 13 volunteers received in a randomized order Minulet (75 mcg GEST and 30 mcg ethinyl estradiol [EE2]) and Econ/30 (1 mg NET Ac and 30 mcg EE2) each for 4 months. Serum GEST and NET levels were evaluated with respect to concentration maximum times of concentration maximum and 24-hour area under the curve (AUC0-24-hour) in the middle of the control (3rd) cycle and the charcoal treatment (4th) cycle during both pill treatments. No statistically significant difference was seen in any of the aforementioned variables between the control and charcoal treatment cycles of either pill. Neither was a difference seen in the bioavailability of GEST and NET as evaluated by the ratios of two 24-hour AUCs calculated in the control and charcoal cycles of each pill treatment (p = 0.29). The results suggest that enterohepatic circulation of GEST and NET is not of clinical importance. The authors conclude that women on oral contraceptives can take activated charcoal for the treatment of diarrhea when administered 3 hours after at least 12 hours before pill intake. (authors)

Ovulatory potential was studied during the use of two oral contraceptive pill preparations, after repeated mid-cycle administration of activated charcoal. Eleven women used monophasic pills containing gestodene, 75 microgram, plus ethinyl oestradiol, 30 microgram, or norethisterone acetate, 1 mg, plus ethinyl oestradiol, 30 microgram, for 4 months each, in randomized order. During both pill treatments the third cycle was a control cycle, and during the fourth cycle of both pill types, 5 g of activated charcoal was ingested four times a day, starting 3 h after pill intake, on cycle days 12, 13 and 14. Ovarian activity was monitored by intravaginal ultrasonography of follicles and by measurements of serum concentrations of LH, FSH, oestradiol and progesterone throughout the control and charcoal-treatment cycles of both pill treatments. None of the women ovulated. Follicular activity seen in two women did not correlate with charcoal administration. It is concluded that the possible enterohepatic recirculation of gestodene and norethisterone is not of clinical importance. Repeated charcoal treatment, when administered 3 h after but at least 12 h before pill intake, can be used to treat diarrhoea in women taking oral contraceptives.

Long-term administration of progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) has been proposed as a novel hormonal therapy for various hormone dependent maladies. We studied the long-term endocrine effects of mifepristone on the kinetics of estradiol (E(2)) and its precursors, and on gonadotropin levels in five postmenopausal women treated for unresectable meningioma with mifepristone [200 mg/day] for at least 15 months. Serum samples were analyzed for LH, FSH and SHBG with fluoroimmunoassay; androstenedione (A), testosterone (T), estrone (E(1)) and E(2) were measured with radioimmunoassay (RIA). Serum levels of mifepristone were measured using both RIA and high performance-liquid chromatography (HPLC). Serum levels (mean +/- SD) of LH and FSH were suppressed from pretreatment values of 32 +/- 16 and 65 +/- 30 IU/l to 13 +/- 7 and 33 +/- 16 IU/l at 6 months (P0.05), respectively. Serum (mean +/- SD) A, T, E(1), and E(2) were increased from initial values of 6.9 +/- 0.9 nmol/l, 1.2 +/- 0.3 nmol/l, 77 +/- 25 pmol/l, and 29 +/- 14 pmol/l to 6 month values of 13.1 +/- 5.6 nmol/l, 1.8 +/- 0.6 nmol/l, 178 +/- 60 pmol/l, and 45 +/- 22 pmol/l (n.s.). The correlation coefficients between the levels of A, T, E(1), and E(2) were statistically significant, whereas the ratios of T/A, E(1)/A, E(2)/E(1), and E(2)/T remained unchanged. The levels of SHBG remained stable, and ranged from 48 +/- 10 to 65 +/- 9 nmol/l (mean +/- SD). Thus, prolonged mifepristone treatment marginally increased the serum levels of A, T, E(1) and E(2). These effects of mifepristone are likely due to its antiglucocorticoid effect and thus increased secretion of adrenal A. Serum levels of LH and FSH declined. The serum levels of gonadotropins and those of T, E(1) and E(2) were inversely, yet significantly, correlated. Therefore the decrease in LH and FSH might reflect the slightly increased levels of T, E(1) and E(2). However, the lack of change in SHBG and the low E(2) levels suggest that enhanced systemic estrogen effects are unlikely during long-term mifepristone treatment.

Forty-two healthy women volunteered to have blood samples drawn at 2, 4, 8, 24, 48, and 168 h (7 days) following placement of levonorgestrel-releasing rod (LNG rod) or of Norplant capsule implants to permit measurement of drug concentrations. Three clinics recruited 10 women each, half of whom used each type of implant. Twelve additional subjects were later enrolled at one site to provide greater detail for the capsule implants. Throughout the week, women with Norplant implants had apparently higher mean drug concentrations than did women with LNG rod implants, but the differences were significant only in the first 48 h after placement (p0.05). Maximum levels for capsule implants were found at the 24-h sample (mean, 1358 to 1474 pg/mL) and for the LNG rod implants at 48 h (772 pg/mL). Body weight was negatively correlated with levonorgestrel concentrations at all times (p0.05). For several sampling times, differences between clinics in mean concentrations were statistically significant after weight adjustment. Despite differences by implant type, weight, or clinic location, drug concentrations compatible with contraceptive effect were attained within 24 h in users of LNG rod or of Norplant implants, insofar as all women had levonorgestrel concentrations above 250 pg/mL at the 24-h sample.To establish the minimum times required for contraceptive implants to achieve serum concentrations compatible with contraceptive action, drug concentrations were measured in blood samples collected from 42 women at 2, 4, 8, 24, and 168 hours after implant insertion. 15 volunteers from three centers (US, Chile, and the Dominican Republic) were fitted with a levonorgestrel (LNG)-releasing rod and 27 received Norplant implants. An LNG concentration of 250 pg/ml and above was considered indicative of contraceptive action. By 8 hours, all Norplant subjects but only 40% of the LNG rod subjects had achieved this serum level. By 24 hours, however, all women in both groups had LNG concentrations above 250 pg/ml. The maximum mean LNG level was recorded in the 24-hour sample (1358 pg/ml) in the Norplant group and at 48 hours (772 pg/ml) in the LNG rod group. Consistent with earlier investigations, LNG concentrations demonstrated strong and significant negative correlations with body weight at all time points. The paucity of pregnancies recorded in large-scale clinical trials in the first month of use of contraceptive implants supports the rapid attainment of effective LNG concentrations. It remains unclear, however, precisely how late in the menstrual cycle implants can be inserted and still prevent follicular development or halt ovulation. Until more information is available, continuation of the policy of implant placement in the first few days after the onset of menstruation is recommended.

To study the role of progesterone (P4) in the regulation of circulating leptin in early human pregnancy, we measured the levels of leptin before and after administration of the antiprogestin mifepristone, followed by misoprostol in early pregnancy.Thirty-four women requesting termination of pregnancy, withor =63 days of amenorrhea, received 200 mg of mifepristone on day 0, followed by either oral or vaginal administration of 0.8 mg of misoprostol on day 2. Five serial serum samples were assayed for leptin, human chorionic gonadotrophin (hCG), P4, estradiol (E2), cortisol, and mifepristone.Circulating leptin concentrations decreased by 8.7 +/- 29.7% (mean +/- standard deviation) (p0.05) following the ingestion of mifepristone. After misoprostol administration on day 2, a decrease of 12.6 +/- 17.0% (p0.05) was followed by a rebound on day 3 to 87.6 +/- 25.7% of the pretreatment values. Two weeks after mifepristone, leptin levels had declined by 25.4 +/- 30.4%. In contrast, E2, P4, and hCG concentrations continued to increase following mifepristone, followed by rapid declines from day 2 to day 3. Serum cortisol concentrations increased by 89.7% +/- 82.7% in response to mifepristone, but this increase did not correlate with the decrease in leptin. The decrease in leptin levels on day 2 correlated with the decreases in P4 (r = 0.37, p0.05) and in E2 (r = 0.44, p0.05) levels.The fall in leptin levels following mifepristone implies a role for P4 in the regulation of leptin in early pregnancy. Moreover, the significant correlation between the changes in leptin and those of P4 and E2 at the time of luteolysis suggests that corpus luteum may also play a role in the regulation of circulating leptin in early pregnancy.

Objective To determine the pharmacokinetics and endometrial tissue levels of levonorgestrel when taken as a single dose of 1.5 mg either orally or vaginally by healthy women in the periovulatory phase of their menstrual cycle. Design Prospective randomized study. Setting Academic research institution. Patient(s) Thirty women with regular cycles allocated to control (n = 5), oral (n = 13), and vaginal (n = 12) groups. Intervention(s) Blood samples were drawn before (0 time) and at 0.5, 1, 2, 4, 6, 8, 24, 48, and 168 hours after levonorgestrel administration. Endometrial samples were collected 24 and 168 hours after levonorgestrel administration. Main Outcome Measure(s) Plasma and endometrial tissue levels of levonorgestrel. Result(s) Plasma concentrations of levonorgestrel were significantly greater during the first 48 hours after oral administration. However, 7 days after levonorgestrel administration, the plasma levels were similar for both treatments (3–5 nmol/L). Compared with vaginal administration, oral administration resulted in higher peak plasma concentrations (C max 64 vs. 10.7 nmol/L), with a shorter time to reach the maximal concentrations (T max 1.4 vs. 6.6 hours) and with a greater AUC (509 vs. 175 nmol/L). Interestingly, the half-life of levonorgestrel was shorter after oral administration (25 hours vs. 32.6 hours). Levonorgestrel tissue concentrations were not related to the plasma levels. Levonorgestrel values tended to be higher in endometrial tissue after vaginal administration. The ratio between plasma and endometrial concentrations of levonorgestrel differed significantly between the groups. Conclusion(s) These data indicate that orally administered levonorgestrel achieves higher plasma levels sooner than vaginally administered levonorgestrel. However, plasma levels after vaginal administration are more sustained and were likely to be sufficient for ovarian suppression. Therefore, the vaginally administered levonorgestrel could be considered as an alternative option for emergency contraception.

The results of several randomized studies have verified the efficacy of 10 mg mifepristone in emergency contraception. In the present study we characterized the pharmacokinetics of 10 mg mifepristone. Eight healthy female volunteers received a single oral dose of mifepristone on the day 10 or 11 of their menstrual cycle. Blood samples were collected at 0, 1, 2, 4 and 8 h, daily for the next 6 days and on day 10 after mifepristone. Mifepristone concentrations were determined by radioimmunoassay preceded by column chromatography. A peak level of 1.41 +/- 0.31 micromol/L (mean +/- SD) was measured at 1 h. Individual elimination phase half-lives varied from 15.3 to 26.8 h, the mean (+/- SD) value being 19.6 +/- 4.50 h. Serum mifepristone concentrations exceeded 10 nmol/L in all volunteers for an average of 4.9 days. The pharmacokinetic data on 10 mg mifepristone are in line with previous pharmacokinetic and clinical data, and encourage further development of the 10-mg dose in emergency contraception.

Serum levonorgestrel concentrations were assayed in a multicenter, 7-year study of 199 users of Jadelle rod implants. We examined drug levels, patterns of changes, factors affecting drug levels, and concentrations at which pregnancies occurred. Mean levonorgestrel concentrations declined from 435 pg/mL at 1 month of use to 64% of that value (280 pg/mL) at the end of 3 years. Between the end of the third and fifth years neither mean nor median serum levels varied markedly. At 5 years the mean concentration was again 64% of the first month’s mean. Declining levels were observed thereafter through the end of 7 years when the mean, 224 pg/mL, was 52% of the 1-month value. Last measured drug concentrations of women who became pregnant during Jadelle use had mean and median values of 152 and 144 pg/mL, respectively, and a maximum value of 180 pg/mL. Analyses indicated ponderal index, body weight, duration of use, and a single clinical center were the most important variables affecting measured levonorgestrel levels. Approximately one-third of assays in the sixth and seventh years were found to be below 180 pg/mL, suggesting that Jadelle levonorgestrel implants would not maintain sufficiently high levels of effectiveness against pregnancy after 5 years and that heavier women would then be at greater risk of pregnancy.

Nestorone (NES) progestin is highly effective for contraception following parenteral administration, but ineffective after oral ingestion due to rapid first-pass metabolism. Thus, NES might be ideal for lactational contraception; possible NES in milk should be metabolized by the nursing infant. We evaluated the distribution of NES, its endocrine effects and infant weight gain in five cynomolgus monkeys and their nursing infants. Nestorone implants, releasing approximately 40 microg NES/day in vitro, were placed s.c. in the mothers 3-4 months following delivery, where they remained in situ for 4 weeks. Sampling (blood daily from the mother; milk and blood from the infant at 3 day intervals) was initiated at 2 weeks prior to insertion, and continued for 2 weeks following removal of the implant. NES, oestradiol, progesterone and prolactin were measured by radioimmunoassays and the infants were weighed weekly. The (mean +/- SD) maternal serum and milk concentrations of NES were 337 +/- 90 and 586 +/- 301 pmol/l during the use of the implants. The ratio of milk/serum NES was 1.68 +/- 0.12 (mean +/- SE), and the serum and milk concentrations were significantly correlated (r = 0. 75, P0.001). NES was not detectable (13 pmol/l) in any infant serum samples. Concentrations of prolactin (mean +/- SD) were 41.1 +/- 32, 26.7 +/- 7.6 and 26.3 +/- 9.5 ng/ml before, during and after the use of the implants respectively. The (mean +/- SE) infant weight increased from 643 +/- 54 g 1 week prior to insertion to 713 +/- 54 g 1 week following removal. These data confirm that NES in milk is rapidly metabolized by the suckling infant. Therefore, NES appears to be an ideal hormonal contraceptive for use during lactation.

The effects of short-term administration of the antiprogestin and antiglucocorticoid, mifepristone, have been well characterized. However, little is known about the effects of prolonged administration of mifepristone. We analyzed hormonal parameters in four female and three male patients with unresectable meningioma who were treated with mifepristone (200 mg/d) for 20 to 40 months. Serum samples were collected at monthly intervals approximately 24 hours following mifepristone ingestion. Serum thyrotropin (TSH), thyroxine (T4), free T4 (fT4), 3,5,3-triiodothyronine (T3), prolactin, and cortisol were analyzed by fluoroimmunoassay, and androstenedione by radioimmunoassay (RIA). Levels of mifepristone and its three most proximal metabolites were measured by high-performance liquid chromatography. TSH values increased significantly (P < .005, one-way ANOVA), with the most pronounced increase evident during the first 3 months of mifepristone treatment. Despite these changes, concentrations of TSH remained within the normal range throughout the treatment period. There were no significant changes in serum T4, fT4, T3 or prolactin; however, a transient decrease in serum T4 was noted at 2 to 3 months. Cortisol and androstenedione values increased significantly and in parallel (P < .05), suggesting an adrenal origin also for androstenedione. As during short-term administration, levels of mifepristone and its metabolites remained stable in the micromolar range. Individual levels of mifepristone were significantly correlated with those of TSH and cortisol. This suggests that the alterations in the pituitary-thyroid and -adrenal axes occurred in a concentration-dependent manner. It is concluded that long-term mifepristone treatment results in resetting of the pituitary-thyroid balance. As in the case with cortisol and androstenedione, it is likely that the alterations in serum TSH are due to the antiglucocorticoid properties of mifepristone. The clinical significance of these biochemical alterations in thyroid homeostasis remains to be determined. However, monitoring thyroid function during long-term mifepristone treatment appears to be warranted.

The goal of this study was to observe if nitecapone protected against taurocholate-induced damage in primary cultured rat gastric mucosal cells, as well as in a well-differentiated human gastric epithelial cell line (MKN 28). Prostaglandins were measured to analyze the protection mechanism. In primary rat gastric mucosal cell culture, nitecapone 125-250 microM protected the cells significantly against damage induced by sodium taurocholate, increasing cell viability by 31-38%. In the human gastric epithelial cell line, in which mitochondrial activity was measured as an indication of cell viability, nitecapone (62.5-250 microM) protected the cells against sodium taurocholate-induced damage by 12-20%. Prostaglandin E2, thromboxane B2, and 6-keto-prostaglandin F1 alpha measurements in the primary cultured rat gastric mucosal cells showed that nitecapone (125 microM and 250 microM) significantly stimulated prostaglandin E2 production (84.7% and 61.0%, respectively), and inhibited thromboxane B2 formation (50% at 250 microM), while the 6-keto-prostaglandin F1 alpha formation was unaffected. Nitecapone had no effect on prostaglandin E2 production in the MKN 28 epithelial cell line. Indomethacin or aspirin, at concentrations that did not affect cell viability, antagonized the stimulative effect of nitecapone on prostaglandin E2 formation in the primary cultured rat gastric mucosal cells. Although the prostaglandin E2 synthesis was blocked, nitecapone still protected against cell damage induced by taurocholate. These results demonstrated the direct and efficacious protection of nitecapone on gastric cell level and suggest that the "cytoprotection" by nitecapone against taurocholate may not be mediated through the mechanism of stimulated synthesis of prostaglandin E2.