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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 proved 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). [ABSTRACT FROM PUBLISHER]

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.

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Intrauterine contraception is a widely used, highly effective method of birth control. Uterine perforation is a serious albeit rare complication with the use of an intrauterine device (IUD). Although uterine perforation by the levonorgestrel-releasing intrauterine system (LNG-IUS) has already been described, no plasma LNG concentrations in this setting were reported. Neither has the management of LNG-IUS been commented on to date. Two months after insertion of an LNG-IUS into a 33-year-old woman, it was noted to be in the peritoneal cavity. Laparoscopy for IUD removal was conducted 5 months after insertion. LNG and sex hormone-binding globulin plasma concentrations were measured prior to and following the laparoscopic removal of the IUD. Intra-peritoneal dislocated LNG-IUS resulted in plasma LNG levels 10 times higher (4.7 nmol/l) than the plasma level of LNG observed with LNG-IUS placed in utero. This high plasma LNG level suppresses ovulation. Therefore a misplaced LNG-IUS should be removed when pregnancy is desired.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.

Mifepristone administration to women in the mid- or late follicular phase delays the luteinizing hormone (LH) surge and prolongs the follicular phase. Since the resumption of follicular growth commences following mifepristone cessation, the drug must be given either continuously or at repeated intervals in order to block ovulation. Using various regimens with or without exogenous progestins, ovulation was inhibited in the majority of subjects. However, this was not consistent and in several instances, LH surges and a rise in plasma progesterone were suggestive of ovulation and corpus luteum function. Therefore, mifepristone cannot be used as a contraceptive which will reliably inhibit ovulation. With low-dose mifepristone administration, alterations in endometrial morphology were characterized by a delay in maturation despite the presence of ovulation. This suggests that the endometrium displays a greater sensitivity to mifepristone than does the pituitary, a finding that may have important contraceptive implications. Late luteal-phase mifepristone administration to women who were not sexually active did not alter their menstrual rhythm, bleeding patterns or steroid and gonadotrophin concentrations. However, when used in unprotected women in the late luteal phase, mifepristone did not uniformly terminate all pregnancies. On the other hand, when used within 72 h of intercourse, mifepristone was as effective a post-coital agent as the standard high-dose oestrogen-progestin combination.

In primates, the LH surge that triggers ovulation is induced by an increase in circulating estradiol (E2) levels. Although several studies suggest that E2 acts on the pituitary, it is still not clear whether GnRH is involved. We investigated the role of GnRH during the periovulatory period in normal women by treating them with the GnRH antagonist Nal-Glu ([Ac-D2Nal1,D4-ClPhe2,D3Pal3,Arg5,DGlu6 (AA),DAla10] when E2 levels exceeded 550 pmol/L. In the first study (A), Nal-Glu was administered in five regimens (n = 4 in each group): a single sc injection of 10 mg (group 1), a single injection of 20 mg (group 2), and an injection of 10 mg, sc, on 2 (group 3), 3 (group 4), and 5 consecutive days (group 5). In the second study (B; n = 4), Nal-Glu (10 mg, sc, on 3 consecutive days) was coadministered with E2 benzoate (EB; 0.5 mg, im, every 12 h on 3 consecutive days). Controls (n = 4) were treated with EB alone at the same stage of the cycle. In the third study (C), three women received 10 mg/day Nal-Glu, sc, on 3 consecutive days together with pulsatile GnRH therapy (25 micrograms/pulse, one pulse every 90 min, sc, for 3 days); the first pulse was given 12 h after the first Nal-Glu injection. In study A, gonadotropin suppression resulted in a transient decline in E2 in groups 1 and 2. Relative to control cycles, the LH surge occurred with a delay of 24-48 h in group 1 and 24-120 h in group 2. In groups 3, 4, and 5, Nal-Glu administration resulted in the demise of the dominant follicle in half of the women in each group. The remaining women showed a profile similar to that of groups 1 and 2, i.e. a transient decline in E2 levels followed by a recovery, and a LH surge occurring 4 +/- 0.3 days after the last Nal-Glu injection. In study B, simultaneous administration of Nal-Glu and EB induced a rise in E2 levels from 951.3 +/- 79.6 to 4000.1 +/- 772.5 pmol/L 24 h after the beginning of treatment. Serum LH and FSH levels both decreased and remained low throughout Nal-Glu treatment. None of the women showed a LH rise in response to the EB injection. In controls, however, EB administration was followed by a significant gonadotropin discharge 48 h after the first EB injection.(ABSTRACT TRUNCATED AT 400 WORDS)

To evaluate the role of altered luteinizing hormone (LH) release in the mechanism of polycystic ovarian disease (PCOD) anovulation, we have co-administered a gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH therapy to two clomiphene citrate-resistant PCOD patients. The aim was to correct their inappropriate gonadotrophin secretion. Nal-Glu was administered s.c. every 72 h to both subjects for 3 weeks. On day 7 after commencing the study, intravenous pulsatile GnRH therapy was initiated (10 micrograms/pulse) every 90 min for 15 days to both subjects. In one subject, Nal-Glu treatment was continued and the GnRH dose was increased to 20 micrograms/pulse for 10 additional days. Prior to Nal-Glu, mean serum LH levels were 10.4 +/- 1.6 and 9.3 +/- 1.3 mIU/ml (mean +/- SEM) and mean interpulse intervals were 67.1 and 60 min in patients 1 and 2, respectively. Mean serum FSH levels were 4.9 +/- 0.4 and 4.2 +/- 0.2 mIU/ml for patients 1 and 2, respectively. LH pulsatility was abolished following Nal-Glu, mean serum LH decreased to 1.1 +/- 0.1 and 1.3 +/- 0.5 mIU/ml and mean FSH to 1.8 +/- 0.1 and 2 +/- 0.1 mIU/ml in the two subjects. On the 4th day of the combined therapy, mean serum LH increased to 5.4 +/- 1.3 and 3.9 +/- 0.9 mIU/ml with a mean interpulse interval of 72 and 80 min, respectively. Mean FSH levels increased to 3 +/- 0.1 and 2.8 +/- 0.1 mIU/ml, respectively and to 5.5 +/- 0.2 mIU/ml after the GnRH dose was increased in patient 2.(ABSTRACT TRUNCATED AT 250 WORDS)