Three Giants in the Cradle of Reproductive Medicine; Reproduction Theories of the Seventeenth Century as Discerned by Pregnancy Portraiture in the Oeuvre of Jan Vermeer.

Portraits of pregnant women are rare in Catholic Renaissance art. In seventeenth-century Holland, the Catholic rule of Spain had been thrown off and a Protestant Calvinistic republic emerged, freeing Dutch artists to choose an unorthodox subject matter for their paintings. The Golden Age of Holland was characterized by extreme wealth, originating from overseas trade, which fostered a marked interest in philosophy, science, medicine, as well as art. Despite this, portraiture of pregnancy remained uncommon. An exception to this rule was Jan Vermeer of Delft, who lived during the zenith of this era. Jan Vermeer painted fewer than 40 pictures, fathered 15 children, and died bankrupt and little appreciated at the age of 43. Vermeer confined himself almost entirely to images of women in various domestic situations, including three figures of pregnant women. In this framework, pregnancy could be viewed as an icon for fidelity and conformism to social expectations. In this paper we investigate the roots of this unusual icon in Vermeer's oeuvre, and suggest that the use of pregnancy in his paintings could have been inspired by his Delft-resident contemporaries Antony van Leeuwenhoek and Reinier de Graaf, fathers of well-known and opposing theories of reproduction. These eminent scientists and Vermeer's pregnant wife, who frequently served as his model, might have made pregnancy less mysterious and more realistic to the painter.

Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century.

Administration of mifepristone followed by the prostaglandin, misoprostol, has been used successfully in the medical termination of pregnancy for over 25 years, and the method is registered in 35 countries. Single doses of mifepristone are also effective as an emergency postcoital contraceptive. Mifepristone administered for 3 months or longer to women with uterine leiomyomas, is associated with a reduction in pain and bleeding with improvement in quality of life and decrease in fibroid size. Mifepristone is also effective in decreasing pain in women with endometriosis. In both these conditions, serum estradiol levels are in the range of those in the early follicular phase. A daily dose of at least 2 mg mifepristone blocks ovulation. In contrast, weekly administration of 25 or 50 mg does not consistently block ovulation but has contraceptive potential by delaying endometrial development. Mifepristone in a dose of 200 mg, administered 48 h after the Luteinizing Hormone (LH) surge, also acts as a contraceptive, but this strategy is not practical for widespread use. Administration of mifepristone for 4-6 months or longer may lead to endometrial thickening. Endometrial histology reveals cystic glandular dilation together with admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histological pattern does not represent endometrial hyperplasia.

Free alpha-subunit is the most sensitive marker of gonadotropin recovery after treatment of central precocious puberty with the histrelin implant.

BACKGROUND: Gonadotropin free alpha-subunit (FAS) levels paradoxically increase during GnRH agonist (GnRHa) treatment of central precocious puberty (CPP). The histrelin implant suppresses gonadotropins and estradiol (E(2)) levels for 1 yr, but effects on FAS have not been described. OBJECTIVES: We aimed to determine whether FAS levels remain elevated during treatment with the implant, to assess the dynamics of FAS after removal, and to ascertain the reliability of FAS for monitoring gonadotropin secretion. METHODS: Ten girls with CPP were studied. In eight, monthly im GnRHa preparations were given until implant insertion. Two naive girls did not receive prior GnRHa. Duration of implant treatment ranged from 18-63 months with repeated implant removals and insertions of new implants. LH, FSH, E(2), and FAS were measured before implant insertion in the two naive patients and during treatment, and in all girls before and after implant removal. RESULTS: FAS levels were 0.2 and 0.4 ng/ml (normal, <0.6 ng/ml) in the two naive girls and increased to 2.4 and 5.1 ng/ml within 2-5 d of insertion. FAS level (mean +/- SD) in all 10 girls during histrelin implant treatment was 1.19 +/- 0.49 ng/ml and rapidly decreased to 0.31 +/- 0.12 ng/ml within 1 wk of implant removal (P < 0.03). In contrast, significant increases in LH (P < 0.05) and FSH (P < 0.02) were observed at 3 wk and E(2) (P < 0.05) at 6 wk after implant removal. CONCLUSIONS: Compared to LH, FSH, and E(2), FAS responds more rapidly to implant removal and represents the most sensitive indicator of gonadotropin recovery after histrelin implant treatment.

Relationships between FSH, inhibin B, anti-Mullerian hormone, and testosterone during long-term treatment with the GnRH-agonist histrelin in patients with prostate cancer.

OBJECTIVES: Medical castration with long-acting GnRH-agonist (GnRHa) is a well-established treatment for metastatic prostate cancer. Our aim was to explore the relationships between FSH, inhibin B, anti-Mullerian hormone (AMH), and testosterone during treatment with an implant releasing GnRHa. DESIGN: Analysis of hormone levels in frozen serum samples. METHODS: Ten patients aged 77+/-7 (means+/-S.E.M.) years with prostate cancer were treated with the GnRHa histrelin for at least a year. Two weeks prior to insertion and for 3-4 months following removal the patients were treated with the antiandrogen flutamide. Serum inhibin B, FSH, testosterone, and AMH levels were measured retrospectively. RESULTS: FSH, inhibin B, and testosterone increased during antiandrogen administration and levels fell after implant insertion. Four weeks post insertion, FSH gradually increased while inhibin B and testosterone remained fully suppressed. AMH levels did not change during antiandrogen treatment, but increased following implant insertion and remained elevated for the duration of implant use. Following removal, FSH and testosterone increased, inhibin B remained low, while AMH decreased. CONCLUSIONS: The secondary increase in FSH following initial suppression with the implant is probably related to impaired inhibin B secretion. The lack of inhibin B response to the secondary increase in FSH suggests that long-term exposure of Sertoli-cells to GnRHa impairs their function. This effect appears to be selective since unlike inhibin B, AMH increased. In the absence of testosterone, FSH has a role in AMH regulation.

Clinical utility of progesterone receptor modulators and their effect on the endometrium.

PURPOSE OF REVIEW: In view of the spate of recent publications related to mifepristone and some second generation progesterone receptor modulators (PRMs), this appears to be an opportune time to view the clinical status of these compounds. RECENT FINDINGS: Randomized double-blind placebo-controlled trials have been conducted with mifepristone, CDB-4124 (Proellex), CDB-2914 (VA 2914, Ulipristal) and asoprisnil (J867). All these PRMs are effective in the treatment of uterine fibroids where they are associated with a reduction in pain, bleeding and improvement in quality of life and decrease in fibroid size. CDB-4124 is also efficacious in endometriosis. Long-term treatment with PRMs may be associated with endometrial thickening on ultrasound and there have been reports of endometrial hyperplasia. Several reassuring recent publications have done much to explain the mechanism underlying these endometrial changes. The most common histological finding is cystic glandular dilatation often associated with both admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histology has not been previously encountered in clinical practice and should not be confused with endometrial hyperplasia. The endometrial thickness is related to this cystic glandular dilatation. SUMMARY: At this stage of development, PRMs cannot be administered for longer than 3 or 4 months. Even over this time, there is improvement of symptoms associated with fibroids and endometriosis. Clinicians and pathologists need to be aware that the endometrial thickening and histological appearance do not represent endometrial hyperplasia.

Is sildenafil citrate associated with an amelioration of the symptomatology of androgen decline in the aging male?

PURPOSE: We examined whether treatment of erectile dysfunction with sildenafil citrate is associated with amelioration of the symptomatology of androgen decline in the aging male, and whether this alters the endocrine pattern. MATERIALS AND METHODS: A double-blind, randomized, placebo controlled, crossover study with sildenafil citrate was conducted in 60 men (age range 47 to 75 years old) who presented with erectile dysfunction and screened positively for androgen decline in the aging male by the questionnaire of the same name. The patients were randomized to receive sildenafil citrate or placebo in a 1:1 ratio and were crossed over after 3 months of treatment for an additional 3 months. The evaluation included International Index Erectile Function and Aging Male Symptoms questionnaires, hormonal profiles, total testosterone, and bioavailable testosterone. RESULTS: A total of 40 patients completed the study. Compared to placebo, sildenafil citrate improved erectile function (52.7 +/- 2 vs 39 +/- 1.9, p <0.001) and Aging Male Symptoms score (33.5 +/- 1.3 vs 28.6 +/- 1.3, p <0.001) in the total group. Breakdown into hypogonadal and normal men showed that the International Index of Erectile Function score improved more in normal (Delta 18.5 +/- 3.6) than in hypogonadal men (Delta 6.7 +/- 2.7). There were no differences in improvement on the Aging Male Symptoms questionnaire between hypogonadal and normal men. No treatment changes were observed in total testosterone and bioavailable testosterone. CONCLUSIONS: In the total group of patients sildenafil citrate was associated with expected improvement in erectile function and in the Aging Male Symptoms questionnaire without any alteration in hormonal pattern. The available questionnaires for androgen decline in the aging male are not specific for the diagnosis of biochemical androgen decline in the aging male, although the suboptimal response to sildenafil citrate suggests the presence of hypogonadism.

Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma.

BACKGROUND: Mifepristone (RU486) is an oral antiprogestational and, to a lesser extent, antiglucocorticoid agent commonly used for short-term (single-day) therapy. However, treatment of neoplasms or chronic conditions will require long-term administration. Meningioma is a benign central nervous system tumor that is often progesterone-but not estrogen-receptor positive, making long-term antiprogestational therapy a logical treatment strategy. METHODS: Patients with unresectable meningioma were treated with oral mifepristone 200 mg/day. This dose was selected to provide significant antiprogestational but not antiglucocorticoid activity. Patients also received oral dexamethasone 1 mg/day for the first 14 days. Serial follow-up allowed evaluation for tolerability and side effects of long-term therapy as well as observation for efficacy (tumor shrinkage or improvement in visual fields). RESULTS: Twenty-eight patients received daily oral mifepristone for a total of 1,626 patient-months of treatment. The median duration of therapy was 35 months (range 2-157 months). Repeated oral administration was well tolerated with mild fatigue (22 patients), hot flashes (13 patients), and gynecomastia/breast tenderness (6 patients) being the most common side effects. However, endometrial hyperplasia or polyps were documented in 3 patients and one patient developed peritoneal adenocarcinoma after 9 years of therapy. Minor responses (improved automated visual field examination or improved CT or MRI scan) were noted in 8 patients, 7 of whom were male or premenopausal female. CONCLUSIONS: Long-term administration of mifepristone is feasible and clinically well tolerated, with generally mild toxicity. However, endometrial hyperplasia was noted in several patients. In view of the association between long-term treatment with tamoxifen (another agent that can induce an unopposed estrogen effect) and endometrial cancer, this observation will require further investigation and screening. Minor regression of meningioma that can result in significant clinical benefit is suggested in the male and premenopausal female subgroups of patients.

Progesterone receptor antagonists.

Since the discovery of the progesterone receptor antagonist mifepristone, numerous additional compounds, which display a spectrum of biological actions ranging from full antagonist to those with mixed agonist/antagonist activity, have been synthesized. The latter are referred to as selective progesterone receptor modulators. Long-term administration of these agents is associated with an antiproliferative action on the endometrium as well as amenorrhea and often inhibition of ovulation. Thus far, the majority of clinical data have been obtained with mifepristone but studies are currently underway with other compounds. These compounds have application in the treatment of uterine myoma, endometriosis, dysfunctional uterine bleeding, as potential contraceptives and in steroid responsive tumors.

Management of patients receiving long-term treatment with mifepristone.

OBJECTIVE: To determine clinical side effects and biochemical and hematological abnormalities in patients with nonresectable meningioma on long-term mifepristone (RU 486) therapy. DESIGN: Long-term mifepristone administration in patients with meningioma. SETTING: Outpatient clinic of a university hospital. PATIENT(S): Sixteen women and 9 men aged 22-80 years with nonresectable meningioma. INTERVENTION(S): Mifepristone (200 mg daily). One patient received treatment for more than 13 years; six received treatment for 10-12 years; five received treatment for 4-9 years; eight received treatment for 1-4 years; and the remainder received treatment for 4-10 months. MAIN OUTCOME MEASURE(S): Evaluation of side effects and of hematological and biochemical abnormalities. RESULT(S): Fatigue was observed in 22 of 25 patients. Endometrial hyperplasia occurred in one premenopausal woman and one postmenopausal woman. Another two women had endometrial thickening without hyperplasia. There were no consistent abnormalities in liver or renal function or in any other biochemical or hematological parameters. One subject (on long-term dexamethasone) developed hypoadrenalism, which responded to treatment. CONCLUSION(S): Mifepristone can be administered for prolonged periods. Ultrasound should be performed if irregular vaginal bleeding occurs. In asymptomatic women, it should be performed annually. If endometrial thickening is observed, then endometrial biopsy is recommended. Because biochemical hypothyroidism has been reported during long-term mifepristone therapy, thyroid function tests should be performed annually.

The histrelin implant: a novel treatment for central precocious puberty.

OBJECTIVE: Standard treatment of central precocious puberty (CPP) consists of intramuscular or subcutaneous administration of a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) at 3- to 4-week intervals. Although generally effective in suppressing clinical and laboratory parameters of puberty, GnRHa injections are painful, and the need for monthly clinic visits may contribute to poor compliance. Recently, a subcutaneous implant was developed that releases the GnRHa histrelin at an average rate of 65 microg/day. The aims of this study were to determine if a histrelin implant would suppress gonadotropin and estradiol (E2) in girls with CPP for 1 year and to compare the suppression to standard treatment. METHODS: We studied 11 girls with CPP to determine if the histrelin implant can maintain long-term gonadotropin suppression. Mean age at diagnosis was 6 years (range: 2-9 years). GnRH (100 microg intravenously) stimulation tests (GnRH-STs) showed peak luteinizing hormone and follicle-stimulating hormone responses of 23 +/- 28 (mean +/- SD) and 20 +/- 25 mIU/mL, respectively. All subjects were initially treated with depot intramuscular GnRHa triptorelin embonate. Implants were inserted subcutaneously under local anesthesia, and depot GnRHa treatment was discontinued. Six girls were followed for 15 months after insertion (group A). For the remaining 5 girls, the implant was removed after 9 months, and a new implant was inserted at the same incision site (group B). GnRH-STs were performed before depot GnRHa treatment, immediately before implant insertion, at the 6- and 9-month visits for each patient and the 12- and 15-month visit for those girls followed for 15 months. RESULTS: In all girls, breast development regressed, growth velocity decreased, and bone-age advancement was slowed. Basal gonadotropins and their responses to GnRH-STs and E2 levels were suppressed. Peak luteinizing hormone and follicle-stimulating hormone responses to GnRH-STs at preinsertion versus 9 months were 1.30 +/- 1.34 vs 0.25 +/- 0.08 and 1.68 +/- 1.08 vs 1.13 +/- 0.55 mIU/mL, respectively. Basal and stimulated gonadotropin levels and E2 level remained suppressed in all 6 patients followed for 15 months after implant insertion. Patients and parents reported less pain and discomfort and less interference with school activity and work with the implant compared with standard monthly injections. CONCLUSIONS: The histrelin implant consistently suppresses clinical and laboratory parameters of puberty for 1 year and is a promising new technique for treating CPP without the pain and inconvenience of monthly injections.

Dynamic assays of inhibin B, anti-Mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome.

BACKGROUND: We evaluated basal and dynamic hormonal markers [(FSH, inhibin B, estradiol and anti-Mullerian hormone (AMH)] during the follicular phase and luteal phase of the menstrual cycle and ultrasonic ovarian morphology as predictors of IVF outcome. METHODS: Fifty-six women, aged <38 years, with normal day 3 FSH levels were included prospectively. Serum estradiol, inhibin B and AMH were measured before and 24 h after administration of 300 IU of recombinant FSH on cycle day 3-4 and during the luteal phase. Ovarian volume and antral follicle count (AFC) were evaluated on cycle day 3-4. The predictive value of oocyte number and pregnancy were assessed using uni- and multivariate analysis. RESULTS: Poor responders (<6 oocytes) had significantly lower luteal AMH levels, while high responders (>20 oocytes) had significantly higher AFC, AMH and luteal stimulated inhibin B and estradiol than normal responders. Multivariate regression analyses showed that the best models for predicting oocyte number included AFC, follicular phase AMH and stimulated inhibin B. Only AMH showed a significant difference between pregnant and non-pregnant women at both cycle phases. CONCLUSIONS: In young women (<38 years), AFC or basal AMH and stimulated inhibin B predict ovarian response for IVF. The only predictor for pregnancy is follicular or luteal phase AMH.

Vaginal ring delivering estradiol and progesterone: a possible alternative to relieve climacteric symptoms.

BACKGROUND: Relief of climacteric symptoms is currently the main role of hormone therapy. However, vaginal bleeding complicating this therapy is among the leading causes for its early discontinuation. OBJECTIVES: To assess the effect of a vaginal ring delivering estradiol and progesterone in postmenopausal women and to determine whether continuous administration can relieve climacteric symptoms, produce an acceptable pattern of vaginal bleeding and control endometrial proliferation. METHODS: Twenty-nine postmenopausal women with an intact uterus were studied. All had climacteric symptoms. The vaginal rings contained 0.36 g estradiol and either 3.6 g progesterone (high dose progesterone) or 1.8 g (low dose progesterone), and were kept in place for 4-6 months. Serum progesterone, estradiol and estrone were measured and endometrial thickness determined. All women kept a daily diary of bleeding/spotting and completed a questionnaire on climacteric symptoms at monthly intervals. The low dose progesterone group comprised 14 women and the high dose progesterone group 15 women. RESULTS: A total of 18 patients (9 in each group) completed the study. Mean levels of estradiol, estrone and progesterone were at their peak after 2 to 4 weeks. All rings were effective in alleviating vasomotor symptoms, although there was evidence of "escape from effect" in month 6. Endometrial thickness increased in 6 of the 29 women but biopsy in each case showed no evidence of hyperplasia. Of the 18 women who completed the study, 5 had amenorrhea throughout, 7 had amenorrhea after 3 months, and the remainder had one or two bleeding episodes after 3 months. Therapy was discontinued in 11 women. CONCLUSIONS: A vaginal ring delivering estradiol and progesterone controlled climacteric symptoms, prevented endometrial proliferation, and provided an acceptable bleeding pattern. It should be viewed as a possible alternative for short-term estrogen-progesterone therapy.

Serum anti-Mullerian hormone levels during controlled ovarian hyperstimulation in women with polycystic ovaries with and without hyperandrogenism.

BACKGROUND: Anti-Mullerian hormone (AMH) is expressed in pre- and small-antral follicles. High serum levels are found in women with polycystic ovaries (PCO), accordant with their increased content of small follicles. To evaluate the relationship between AMH, folliculogenesis and hyperandrogenism, we compared serum AMH levels between women with PCO with and without hyperandrogenism and normal controls during controlled ovarian hyperstimulation (COH). METHODS: Nineteen women with PCO and hyperandrogenism (group A), 10 women with PCO but no hyperandrogenism (group B) and 23 ovulatory women with normal ovarian morphology (group C, controls) underwent COH with the long protocol. Serum levels of AMH, estradiol, androstenedione and follicular tracking were determined before gonadotropins treatment (day 0) and every 2-4 days up to the day of HCG administration. RESULTS: AMH levels declined gradually throughout COH in the three groups, but remained higher in groups A and B compared with the controls. Significantly higher levels were found in group A compared with group B, despite comparable numbers of small follicles. Multiple regression analysis revealed that both the number of small follicles and serum androgens were correlated to AMH. CONCLUSIONS: Women with PCO have higher serum AMH levels during COH than controls. Hyperandrogenism is associated with an additional increase in AMH. It is conceivable that hyperandrogenism may reflect more severe disruption of folliculogenesis in women with PCO or may affect AMH secretion.

Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.

Since the discovery of the antiprogestin mifepristone, hundreds of similar compounds have been synthesized, which can be grouped in a large family of progesterone receptor ligands. This family includes pure agonists such as progesterone itself or progestins and, at the other end of the biological spectrum, pure progesterone receptor antagonists (PA). Selective progesterone receptor modulators (SPRM) have mixed agonist-antagonist properties, and occupy an intermediate position of the spectrum. These compounds have numerous applications in female health care. Mifepristone is used to terminate pregnancy, and as such is commercially available in many countries. The negative abortion-related image of mifepristone has clearly limited the involvement of the major pharmaceutical companies in the development of PA and SPRM. Many PA and SPRM display direct antiproliferative effects in the endometrium, although with variable actions which seem product- and dose-dependent. This property justifies their use in the treatment of myomas and endometriosis. PA also suppress late follicular development, block the LH surge and retard endometrial maturation, which renders them potential estrogen-free contraceptive drugs. SPRM such as asoprisnil are not as effective in blocking the LH surge and appear to target the endometrium directly and produce amenorrhoea. Interestingly, clinical data show that treatment with these compounds is not associated with hypo-estrogenism and bone loss. The potential clinical applications of these compounds cover a broad field and are very promising in major public health areas. These include emergency contraception, long-term estrogen-free contraception (administered alone, or in association with a progestin-only pill to improve bleeding patterns), myomas (where they induce a marked reduction in tumour volume and produce amenorrhoea) and endometriosis. Further developments might also include hormone replacement therapy in post-menopausal women, as well as the treatment of hormone-dependent tumours.

Reversibility of androgen deprivation therapy in patients with prostate cancer.

PURPOSE: We determined the duration of testosterone suppression and recovery in patients with prostate cancer treated with a hydrogel implant releasing the gonadotropin releasing hormone (GnRH) agonist histrelin or treated with a depot GnRH agonist. MATERIALS AND METHODS: Luteinizing hormone (LH) and testosterone (T) responses were monitored in 3 groups. Group 1 comprised 7 patients treated with histrelin implant, which is inserted into the arm of the patient while under local anesthesia, and suppresses LH and testosterone. Following implant removal antiandrogens (flutamide or bicalutamide) were administered. Group 2 comprised 8 patients treated with long-term depot GnRH super agonists which were later withheld and patients were given bicalutamide. Group 3 consisted of 7 patients treated with bicalutamide. RESULTS: In group 1 LH and T were in the castration range while implants were in place. LH increased 1 to 6 weeks after implant removal followed by an increase in T. In 7 of 8 patients in group 2, LH, T and prostate specific antigen remained suppressed for 9 months. In 6 of 7 group 3 patients LH and T increased with a decrease in prostate specific antigen. CONCLUSIONS: Despite continuous prolonged T suppression for up to 3 years due to histrelin implant, LH and T increased rapidly following implant removal, indicating that suppression is reversible. In view of the 9-month suppression of LH and T after the last depot GnRH injection in 7 of 8 patients, it is possible to space GnRH agonist administration at longer intervals. However, T must be monitored to determine that suppression is maintained.

Mifepristone does not induce cervical softening in non-pregnant women.

BACKGROUND: Many techniques have been developed to soften the cervix to reduce complications following surgical dilatation. Progesterone inhibits myometrial contractility and its secretion during pregnancy ensures cervical competence. We used the progesterone antagonist mifepristone as a cervical ripening agent and evaluated its effect prior to office hysteroscopy. METHODS: Fifty-eight healthy non-pregnant women aged 18-50 were studied in a randomized double-blind study. They received mifepristone (200 mg) or placebo 30 h prior to hysteroscopy. A Hegar test was performed prior to drug administration and again before hysteroscopy. A visual analogue pain scale was used to assess pain. RESULTS: Medical history, physical examination and blood tests were similar in both groups, except for serum progesterone which was higher in the study group. Hegar measurement prior to drug ingestion was similar in both groups and after a mean time of 30.3 h increased in both groups. Neither the DeltaHegar measurement nor the pain scale was different in the two groups. There was also no effect of the high progesterone levels. CONCLUSIONS: Unlike its dramatic effect in the pregnant uterus, mifepristone administered 30 h prior to hysteroscopy was not effective in ripening the cervix of non-pregnant women.

Pharmacological properties of mifepristone: toxicology and safety in animal and human studies.

Roussel Uclaf in partnership with the INSERM unit of Prof. E.E. Baulieu first discovered mifepristone (RU486) as part of a large research program on steroidal compounds with antihormone properties. Exhibiting a strong affinity to the progesterone and the glucocorticoid receptors, mifepristone exerted competitive antagonism to these hormones both in in vitro and in animal experiments. Due to its antiprogesterone activity, it was proposed that mifepristone be used for the termination of early human pregnancy. Mifepristone, at a dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandin that led to a success rate of 95% as a medical method for early termination of pregnancy (TOP). Its use was extended to other indications, such as cervical dilatation prior to surgical TOP in the first trimester, therapeutic TOP for medical reasons beyond the first trimester, and for labor induction in case of fetal death in utero. The efficacy and safety of this treatment has been confirmed based on its use for over a decade, with close adherence to the approved recommendations. This paper describes the safety studies conducted in animals as well as the safety follow-up and side effects reported with use of the compound in various indications either approved or unapproved. The rationale for warnings and contraindications for use of the product are also explained. At lower doses, the molecule has proven promising for contraceptive purposes with few reported side effects. However, development of the product for this indication would require long-term studies. Although political and philosophical obstacles have delayed research, the use of mifepristone for other potential indications in gynecology or oncology should be investigated.

Progesterone antagonists and progesterone receptor modulators: an overview.

Since the original description of the structure of the antiprogestin, mifepristone, was published, numerous related compounds have been synthesized which may function as progesterone antagonists (PAs) or progesterone receptor modulators (PRMs). The latter are mixed agonists-antagonists. Both PAs and PRMs have therapeutic applications in female health care. Mifepristone is predominantly a PA and displays only minimum agonist activity in certain systems. Together with a prostaglandin, mifepristone can terminate pregnancies of less than 9 weeks duration, and it may also be used at later gestational ages. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death. A mifepristone-prostaglandin combination has been shown to be very effective treatment in women with menses delay of 11 days or less. Many PAs and PRMs display antiproliferative effects in the endometrium. Serum estradiol levels however remain in the early to mid-follicular phase range. For this reason, they have application in the treatment of endometriosis and myoma without being associated with bone loss and hypoestrogenism. PRMs may also find application in the treatment of dysfunctional bleeding as well as an adjunct to estrogens in hormone replacement therapy in postmenopausal women. Many PAs have contraceptive potential by suppressing follicular development and blocking the LH surge. Low doses may also be potential contraceptives by retarding endometrial maturation without affecting ovulation or inducing bleeding. Mifepristone is an excellent agent for use as an emergency "postcoital" contraceptive. PAs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. In addition to their use in women's health care, mifepristone and several other PAs are potent antiglucocorticoid agents and may be used to treat ACTH-independent Cushing's syndrome. They may also be used in the treatment of tumors containing steroid receptors and in other situations which require suppression of the ACTH-cortisol axis.

Progesterone antagonists and progesterone receptor modulators.

Since the discovery of the antiprogestin RU 486 (mifepristone), other compounds have been synthesised that function as pure progesterone antagonists or progesterone receptor modulators. The latter are mixed agonists-antagonists. Mifepristone is usually used to terminate pregnancy but these compounds have numerous other applications in female healthcare. Mifepristone is an excellent agent for emergency contraception. Many progesterone antagonists and progesterone receptor modulators display antiproliferative effects on the endometrium and thus have application in the treatment of endometriosis and uterine myoma without being associated with hypoestrogenism and bone loss. They also have contraceptive potential by suppressing follicular development, blocking the luteinising hormone surge and retarding endometrial maturation. Finally, they have clinical application in GeneSwitch system, a plasmid-based method enabling controlled expression of specific genes (e.g., erythropoietin) using a progesterone antagonist as the inducer.