Partial androgen suppression consequent to increased secretion of adrenal androgens in a patient with prostate cancer treated with long-acting GnRH agonists.

We present a case report of a patient with prostate cancer who failed to demonstrate consistent testosterone suppression to castration levels and incomplete suppression of serum prostate-specific antigen, although treated with gonadotropin releasing hormone agonists for 48 months. Serum dehydroepiandrosterone, dehydroepiandrosterone sulphate, as well as the androgen metabolite, androsterone glucuronide, were elevated compared to the other patients. The present data suggest that those prostate cancer patients who have even marginally elevated adrenal androgens may especially benefit from combined androgen blockade.

Estradiol/progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal women.

In order to investigate whether vaginal rings delivering estradiol and progesterone could prevent endometrial hyperplasia and relieve climacteric symptoms, two variants of rings were used in 20 postmenopausal women with intact uteri for 4 months. One ring designated as PI-002 (n = 8) delivered in vitro estradiol 160 microg/day and progesterone 20 mg/day, while the other (PI-003; n = 12) delivered the same dosage of estradiol but only half the progesterone (10 mg/day). Serum estrone, estradiol and progesterone were measured at pretreatment, weekly for 4 weeks, and then monthly for 4 months. The incidence of hot flushes, frequency of night sweats, mood scores, vaginal discharge and bleeding profiles were recorded. Endometrial thickness was monitored by ultrasonography. The mean estrone level was 50 pg/ml for 16 weeks. The mean serum estradiol level was 75 pg/ml for the first 4 weeks and gradually decreased to 50 pg/ml at 16 weeks. The mean progesterone level with the PI-002 ring was 5 ng/ml for the first 4 weeks and decreased to 3.5 ng/ml at 16 weeks. With the PI-003 ring, the mean progesterone level was initially 3.5 ng/ml and then decreased to 2.5 ng/ml thereafter. Significant decreases in the incidence of hot flushes and night sweats as well as a striking improvement in mood scores were noted as early as 2 weeks after insertion. Three of the 20 women discontinued the treatment, owing to ring expulsion. Increased vaginal discharge was observed with both rings in the first 6 weeks. Vaginal bleeding was more frequently apparent among users of the PI-002 ring, although bleeding and spotting were confined to the first 6 weeks. Ultrasonographic monitoring of the endometrium constantly revealed a thickness of < 3 mm for both variants throughout use for 16 weeks. An estradiol/progesterone-releasing vaginal ring is a potential alternative to long-term hormone replacement therapy with minimum attention required. It provides effective protection against endometrial hyperplasia.

Effects of levonorgestrel-releasing intra-uterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium in adenomyosis.

BACKGROUND: The levonorgestrel-releasing intra-uterine system (LNg-IUS) has been used to control menorrhagia, but irregular bleeding during the first 3 months of use was the most notable side effect. Endometrial angiogenesis is believed to be regulated by angiogenic factors. The study aim was to evaluate the effects of LNg-IUS on vascular endothelial growth factor (VEGF) and adrenomedullin (AM) expression in the endometrium. METHODS: VEGF and AM expression were analysed using the avidin-biotin immunoperoxidase method on endometrial curettage specimens from menorrhagic women associated with adenomyosis before and 3 months after LNg-IUS insertion. RESULTS: VEGF expression was abundant both in the endometrial glands and stroma before LNg-IUS insertion, but became scanty 3 months after insertion. No immunostaining for AM was noted in the endometrial glands and stroma before LNg-IUS insertion, whereas AM immunostaining became prominent in the endometrial glands and stroma 3 months after LNg-IUS use. CONCLUSIONS: This is the first study to demonstrate that LNg-IUS insertion results in decreased expression of VEGF and increased expression of AM in the endometrial glands and stroma after 3 months of use. The results obtained suggest that the increase in AM expression in the endometrium may be responsible for the frequent occurrence of irregular bleeding during the initial 3 months of LNg-IUS use.

Serum inhibin B levels measured early during FSH administration for IVF may be of value in predicting the number of oocytes to be retrieved in normal and low responders.

BACKGROUND: In a previous study we have found that in normal ovulatory women, serum inhibin B levels on days 4-6 of FSH administration correlated with the number of oocytes retrieved. In the current study we examined the significance of earlier inhibin B measurements in predicting the oocyte number, in both normal and low responders. METHODS: Study A consisted of 19 patients undergoing their first IVF cycle (n = 10) or had a normal response ( vertical line 6 oocytes retrieved, n = 9), while study B consisted of 15 patients with a previous low ovarian response (16. Study B: oocyte number correlated significantly with inhibin B and inhibin A on all days of FSH treatment, even on day 2 (r = 0.90, P < 0.001 and r = 0.65, P < 0.05 for inhibin B and A respectively). No significant correlation was found with E(2) levels. In both studies, all patients with inhibin B >100 pg/ml on treatment day 2 had >6 oocytes. CONCLUSIONS: Our data suggest that serum inhibin B measured early during FSH stimulation may indicate whether sufficient oocytes will be retrieved, in both normal and low responders. Serum inhibin B measured during early FSH treatment may be of predictive value in monitoring ovarian stimulation treatment for IVF.

Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.

BACKGROUND: Activin promotes ovarian follicular development, inhibits androgen production and increases FSH and insulin secretion. Follistatin, an activin-binding protein, neutralizes activin bioactivity. Therefore, a decrease in the ratio of activin/follistatin might encourage characteristic features of polycystic ovary syndrome (PCOS). We investigated whether women with PCOS showed disordered follistatin and/or activin serum concentrations. METHODS: The study group included 24 obese and 20 non-obese (body mass index vertical line and <27 kg/m2 respectively) clomiphene-failure PCOS patients. The control group included 16 obese and 46 non-obese patients with normal ovulatory cycles. Blood samples were obtained from the patients on day 3-5 of a progesterone-induced or spontaneous cycle and were assayed for LH, FSH, testosterone, 17-hydroxy-progesterone, androstenedione, follistatin, activin A, fasting glucose and insulin. RESULTS: Follistatin concentrations were comparable between obese and non-obese PCOS patients (mean +/- SE; 1171 +/- 103 and 1045 +/- 159 pg/ml respectively) and significantly higher than their respective controls (628 +/- 61 and 592 +/- 49 pg/ml, P < 0.0001 and P < 0.02 respectively). Activin A concentrations were comparable between the four groups (590 +/- 35, 513 +/- 74, 661 +/- 87 and 595 +/- 43 pg/ml in obese and non-obese PCOS and controls respectively). Stepwise regression analyses for relationships between follistatin or activin A levels and all other variables indicated that follistatin was significantly and independently positively affected by PCOS (P < 0.0001), age (P < 0.02), androstenedione (P < 0.03) and weight (P < 0.05). Activin A was significantly and independently negatively affected by PCOS (P < 0.003) and FSH (P < 0.03), and positively affected by weight (P < 0.009) and androstenedione (P < 0.02). CONCLUSIONS: Serum follistatin is increased in PCOS patients, regardless of obesity. PCOS is the most significant variable that relates to high follistatin and low activin A serum concentration. A high follistatin/activin ratio could well contribute to the pathophysiology of PCOS.

Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium.

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNg-IUS) has been shown to be effective in the management of menorrhagia. In order to evaluate the effects of LNg-IUS on endometrial proliferation and apoptosis, proliferating cell nuclear antigen (PCNA) expression, apoptosis, Fas and Bcl-2 protein expression in the endometrium were determined at the early proliferative phase of the menstrual cycle before and 3 months after LNg-IUS insertion. METHODS: PCNA, Fas and Bcl-2 protein expression were analysed using an avidin-biotin immunoperoxidase method. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labelling (TUNEL) method. RESULTS: PCNA, immunolocalized both in the nuclei of endometrial glands and stroma was less abundant 3 months after insertion (P < 0.05). Bcl-2 protein, immunolocalized in the cytoplasm of endometrial glands but not in the stroma, became scanty 3 months after insertion. Fas antigen, immunolocalized only in endometrial glands before insertion, became prominent in both endometrial glands and stroma 3 months after insertion. The apoptosis-positive rate of the nuclei in both endometrial glands and stroma was significantly higher 3 months after insertion relative to that before insertion (P < 0.05). CONCLUSIONS: LNg-IUS resulted in a decrease in endometrial proliferation and an increase in apoptosis in endometrial glands and stroma. The increase in apoptosis associated with increased Fas antigen expression and decreased Bcl-2 protein expression in the endometrium may be one of the underlying molecular mechanisms by which LNg-IUS insertion causes the atrophic change of the endometrium.

Long-term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia.

Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long-term safety profile of mifepristone, especially at high doses, is less well-established. Long-term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25--100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium. We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6-month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment. In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long-term mifepristone may be prudent.

Effects of progesterone on uterine leiomyoma growth and apoptosis.

Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. Recently we have found that the use of levonorgestrel-releasing intrauterine system (IUS) is effective in the long-term contraception and management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. These clinical experiences prompted us to characterize the effects of progestin on the proliferation and apoptosis of leiomyoma cells cultured in vitro. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either E(2) (10 ng/ml) or P(4) (100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells; whereas in cultures of normal myometrial cells, the addition of E(2) augmented PCNA expression in the cells, but P(4) did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P(4) treatment resulted in an increase in EGF expression in the cells. In contrast, E(2) treatment augmented EGF-R expression in cultured leiomyoma cells, but P(4) did not. These results indicate that P(4) up-regulates the expression of PCNA and EGF in leiomyoma cells, whereas E(2) up-regulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P(4) and E(2) act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium, suggesting that the abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of leiomyoma relative to that of normal myometrium in the uterus. Furthermore, Bcl-2 protein expression in leiomyoma cells was up-regulated by P(4), but down-regulated by E(2). Therefore, it seems likely that P(4) may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells.

Progesterone receptor modulators and progesterone antagonists in women's health.

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are terminated with prostaglandins or surgery. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death and promotes dilation of the non-pregnant primigravid uterus. It is also effective in the treatment of missed abortion. Together with methotrexate, mifepristone can be used in the medical treatment of ectopic pregnancy. Both PAs and PRMs display antiproliferative effects on the endometrium. Because of this, they have application in the treatment of endometriosis, an estrogen-dependent condition. They may also be utilized to reduce myoma size, acting as both a PA and antiproliferative agent. Unlike GnRH agonists, long-term use in endometriosis and myoma is not associated with loss of bone and hypoestrogenism. PRMs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. Some PRMs have potential use as hormone replacement therapy in women during menopause or in those with dysfunctional uterine bleeding.

The use of progesterone antagonists and progesterone receptor modulators in contraception.

Progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) have contraceptive potential by suppressing follicular development, delaying the surge of luteinizing hormone (LH), retarding endometrial maturation, and promoting endometrial bleeding. Mifepristone, in daily doses of 2-10 mg, blocks the LH surge and ovulation. Many of the studies were conducted in women not at risk of pregnancy, and thus the contraceptive efficacy is not yet known. Nevertheless, there is evidence that daily doses of 2 or 5 mg of mifepristone have contraceptive potential. Because of anovulation, there may be an unopposed estrogen effect on the endometrium, although this risk may be mitigated by the noncompetitive anti-estrogenic activity exhibited by both PAs and PRMs. Low doses of PAs and PRMs, which do not affect ovulation, retard endometrial maturation, indicating that the endometrium is exquisitely sensitive to these compounds. This raises the prospect of endometrial contraception, i.e. prevention of endometrial maturation without disturbing ovulation or producing alterations in bleeding patterns. This approach works well in monkeys but was not found to be very promising when given to women not using contraception. On the other hand, 200 mg mifepristone administered 48 h after the LH surge, which has minimal or no effect on ovulation and bleeding patterns, is an effective contraceptive; yet, it is not a practical approach to contraception. Late luteal phase administration of mifepristone produces menstrual bleeding. However, when mifepristone was administered every month at the end of the cycle either alone or together with prostaglandins, it was not very effective in preventing pregnancy. In contrast, a mifepristone-prostaglandin combination has been shown to be a very effective treatment for occasional menstrual regulation, with vaginal bleeding induced in 98% of pregnant women, with menses delay of 11 days or less. Mifepristone is an excellent agent for emergency contraception when used within 120 h of unprotected intercourse. It is also possible that PAs and PRMs may be used to reduce the occurrence of bleeding irregularities induced by progestin-only contraceptive methods. Both classes of progesterone receptor ligands may also have contraceptive efficacy by having a pharmacological effect on the embryo or altering tubal transport or other aspects of tubal physiology.

Alterations in sex steroids and gonadotropins in post-menopausal women subsequent to long-term mifepristone administration.

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 (P < 0.05), 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.

Medical termination of pregnancy.

PIP: This review focuses on advances in the medical termination of pregnancy during the early period of the first trimester, when most abortions are performed. The drugs are used to terminate pregnancy act by inhibiting the synthesis of progesterone, inducing myometrial contractions, antagonizing the action of progesterone, or inhibiting trophoblast development. Among the drugs used in medical abortion are epostane, prostaglandins (including misoprostol and gameprost), combined methotrexate and misoprostol, tamoxifen-misoprostol regimen, mifepristone and prostaglandin, and antiprogestin and prostaglandins. The efficacy, side effects, and contraindications of these drugs in the medical termination of pregnancy are discussed. In general, medical abortion is associated with higher rates of prolonged bleeding, nausea, vomiting, and pain as compared to surgical abortion. However, medical termination of pregnancy has a high rate of efficacy in women with early pregnancies. In addition, medical abortion is safe and acceptable to women, and it does not require anesthesia. Lastly, women who choose medical abortion must have access to a center where suction curettage is available, should heavy bleeding occur and blood transfusion is required.^ieng

An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer.

PURPOSE: The administration of gonadotropin hormone-releasing hormone agonists is well established for treating metastatic prostate cancer. In an ongoing study we evaluated the effect of a long acting implant that releases the gonadotropin hormone-releasing hormone agonist histrelin ([ImBzl]D-His6,Pro9-Net) in 15 patients with disseminated prostate cancer. MATERIALS AND METHODS: The 2.6 cm. implant releasing 60 microg. histrelin daily is inserted subcutaneously into the upper arm using local anesthesia. Of the patients 8 received 1 and the remainder received 2 implants. Treatment with the antiandrogen flutamide or cyproterone acetate began 2 weeks before implant insertion and continued for up to 12 weeks. Testosterone, luteinizing hormone (LH) and prostate specific antigen were determined monthly, and a metastatic evaluation was performed every 6 months. RESULTS: LH and testosterone increased after flutamide administration and decreased after implant insertion. By day 28 LH and testosterone were completely suppressed. LH and testosterone decreased immediately after cyproterone acetate administration. Prostate specific antigen began to decrease during antiandrogen therapy and decreased further after implant insertion. One patient requested implant removal after 1 year for personal reasons and 1 died of an unrelated cause 18 months after insertion. Escape was demonstrated in 4 cases at 5, 10, 12 and 19 months, although LH and testosterone remained suppressed. Duration of treatment in the remaining 9 patients was between 21 and 30 months. LH and testosterone remained completely suppressed and prostate specific antigen levels were in the normal range. The clinical and biochemical response was identical in those who received 1 or 2 implants. At 12 months 8 patients were challenged at intermittent intervals for up to 24 months with a bolus of 100 microg. gonadotropin hormone-releasing hormone followed by 2 weeks of flutamide. The response was compared with that in untreated controls recently diagnosed with prostate cancer. Unlike controls there was complete LH suppression in the 8 challenged patients. CONCLUSIONS: A histrelin implant suppresses LH and testosterone in prostate cancer for up to 30 months. This finding represents a significant improvement over existing preparations, which must be administered at 1 to 3-month intervals.

Use of various ultrasonographic criteria to evaluate the efficacy of mifepristone and misoprostol for medical abortion.

OBJECTIVE: This study was undertaken to determine whether applying modern formulas for mean sac diameter and crown-rump length to data from the recently published US mifepristone-misoprostol abortion trial would result in differences in assigned gestational ages and a higher rate of complete abortion. STUDY DESIGN: Data from the US mifepristone-misoprostol trial were reanalyzed. The ultrasonographic findings at baseline examination of the 2121 participants were used to estimate gestational age according to criteria established by Rossavik et al for mean sac diameter and by Robinson and Fleming, Hadlock et al, and Goldstein and Wolfson for embryonic pole. The gestational ages as assigned by the different criteria were then compared and the treatment outcomes at various gestational ages were calculated for each of the dating criteria. These findings were compared with those reported in the original study. RESULTS: Fourteen percent of study subjects were assigned to the incorrect gestational age group according to the criteria used for the original report. Still, outcomes according to gestational age group were similar regardless of which ultrasonographic gestational age criteria were used and were comparable to those calculated in the original report. Overall efficacy for subjects at

Early pregnancy termination with mifepristone and misoprostol in the United States.

BACKGROUND: Mifepristone and a prostaglandin have been used successfully to terminate pregnancy in Europe and China. We report the results of a large U.S. study of mifepristone and misoprostol in women with pregnancies of up to nine weeks' duration. METHODS: We administered 600 mg of mifepristone and then 400 microg of misoprostol two days later to 2121 women seeking termination of their pregnancies at 17 centers. The women were observed for four hours after the administration of misoprostol and returned on day 15 for final assessment. RESULTS: Two thousand fifteen women completed the final assessment. Among them, pregnancy was terminated in 762 of the 827 women pregnant for < or =49 days (92 percent), 563 of the 678 women pregnant for 50 to 56 days (83 percent), and 395 of the 510 women pregnant for 57 to 63 days (77 percent) (P<0.001). Termination occurred within 4 hours after the administration of misoprostol in 49 percent of the women and within 24 hours in 75 percent. Failures, defined as cases requiring surgical intervention for medical reasons or because the patient requested it, the abortion was incomplete, or the pregnancy was ongoing, increased with increasing duration of pregnancy. The largest increase was in failures representing ongoing pregnancy, which increased from 1 percent in the < or =49-days group to 9 percent in the 57-to-63-days group (P<0.001). Abdominal pain, nausea, vomiting, diarrhea, and vaginal bleeding also increased with advancing gestational age. Two percent of the women in the < or =49-days group, as compared with 4 percent in each of the other two groups, were hospitalized, underwent surgical interventions, and received intravenous fluids (P=0.008). CONCLUSIONS: This mifepristone-misoprostol regimen is effective in terminating pregnancies, especially in women with pregnancies of 49 days' duration or less.

PIP: The availability of medical abortion in the US and elsewhere could lead to greater access to safer abortion services. This study assessed the capability of mifepristone (600 mg) and misoprostol (400 mcg 2 days later) to terminate pregnancies of up to 63 days' duration. Enrolled were 2121 US women recruited from 17 Planned Parenthood, university hospital, and free-standing abortion clinics. Among the 2015 women who returned for the follow-up visit at day 15, the rates of pregnancy termination were 92% in women with pregnancies of durations of 49 days or under, 83% in the 50-56 days group, and 77% in the 57-63 days group (p 0.001). Abortion occurred within 4 hours of misoprostol administration in 49% of women and within 24 hours in 75%. Termination rates were higher for women with no previous induced abortions. Side effects such as abdominal pain, nausea, vomiting, diarrhea, and vaginal bleeding were frequent and increased with gestational age. 2% of women with pregnancies of 49 days' gestation or less, compared with 4% in both the 50-56 days and 57-63 days groups, were hospitalized, underwent surgical intervention, and received intravenous fluids. The success rate in this study was lower than that reported by other researchers. This may be related, in part, to the lack of experience with medical abortion in the US.

Mechanism of action and clinical effects of antiprogestins on the non-pregnant uterus.

Considerable progress has been made in elucidating the mechanism of action of antiprogestins. The biological response to a progesterone antagonist depends on many factors. The usual effect is that of an antagonist, but progesterone agnostic or even antioestrogenic or oestrogenic effects have also been observed. The present review focuses on the clinical applications of antiprogestins in the non-pregnant uterus. Whereas high doses of antiprogestins block ovulation, low doses impair endometrial development without affecting ovulation, hormonal levels or bleeding patterns Indeed, the endometrium is the tissue which is the most sensitive to antiprogestins. The effect of antiprogestins is to produce a delay in endometrial maturation and to postpone the appearance of the implantation window. This concept of 'endometrial contraception' requires further testing in humans, although the principle has been proven in monkeys. In contrast to the low doses of mifepristone which delay endometrial maturation, a minimum dose of 50 mg is required to produce endometrial bleeding. Late luteal phase antiprogestin administration does not disturb ovulation, hormonal levels or bleeding patterns. This has clinical application, and mifepristone has been used together with prostaglandins in women with delayed menses to successfully prevent implantation. Mifepristone has also been shown to be an effective post-coital agent. However, when used on a regular basis once monthly at the end of the cycle as a potential contraceptive, the results are disappointing. Because of their antiproliferative and anti-oestrogenic effects on the endometrium, antiprogestins are also used in the treatment of oestrogen-dependent conditions such as endometriosis and fibromyomas. In humans, chronic administration of high doses of antiprogestins has on rare occasions been associated with endometrial hyperplasia, presumably a consequence of unopposed oestrogen activity. This does not occur with low doses (1 mg daily for 5 months).

Alterations in the pituitary-thyroid and pituitary-adrenal axes--consequences of long-term mifepristone treatment.

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.