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.

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.

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.