Uterine leiomyomata are steroid hormone dependent tumors which possess receptors for estrogen (ER) and progesterone (PR). We reasoned that an antiprogesterone (RU 486) may induce regression of leiomyomata by withdrawal of progesterone action and/or by its interference of estrogen action. Accordingly, we examined the effects of daily administration of RU 486 (50 mg) for a period of 3 months in 10 patients with uterine leiomyomata and regular menstrual cycles. Baseline ultrasound examinations were obtained and repeated monthly during treatment as a measure of leiomyomata volume. Hormonal parameters were monitored by blood samples obtained prior to treatment and daily for 7 days, weekly for 4 weeks and monthly for the duration of therapy. Myomectomy or hysterectomy was performed in 6 of 10 patients at the end of treatment. Leiomyomata and myometrial tissue was obtained for immunocytochemical analysis of ER and PR protein. Amenorrhea was induced in all patients during treatment. Leiomyomata volume (mean +/- SE) decreased 21.9 +/- 4.8% after 4 weeks, 39.5 +/- 6.6% (P < 0.001) after 8 weeks, and 49.0 +/- 9.2% (P < 0.001) after 12 weeks of treatment compared to pretreatment measurements. Serum LH levels (P < 0.005), but not FSH levels, more than doubled during the first 3 weeks of treatment with a concomitant increase in serum androstenedione (P < 0.006) and testosterone (P < 0.0001) levels. These elevated hormonal levels returned to baseline at 4 weeks without further changes during the remainder of treatment. A significant rise in serum dehydroepiandrosterone sulfate (P < 0.0001) and cortisol (P < 0.01) was seen at 12 weeks, suggesting an antiglucocorticoid effect of RU 486 has occurred. Serum estradiol, estrone, progesterone, sex hormone binding protein, thyroid-stimulating hormone, and PRL were unchanged from early follicular phase values. PR but not ER immunoreactivity was significantly reduced in both leiomyomata and myometrium after RU 486 treatment compared with tissues from untreated patients, suggesting that regression of tumors may be attained through a direct antiprogesterone effect. However, an alteration in ER functionality cannot be excluded. We conclude that RU 486 is well tolerated, safe, and effective; thus, it may prove to be a novel mode of management for uterine leiomyomata.
Dynamic changes in serum immunoreactive (ir) inhibin levels during the transition from the luteal to the follicular phase (luteal-follicular transition) were characterized during 3 consecutive cycles in 12 cycling women. Both spontaneous (first to second cycle) and GnRH antagonist-imposed premature luteolysis (second to third cycle) were evaluated. Serum FSH, LH, estradiol (E2), and progesterone (P4) levels were monitored daily by RIA for the entire study. Daily ir-inhibit levels were determined from 7 days before until 7 days after the onset of menses and from 4 days before to 10 days after the GnRH antagonist-induced bleeding by a heterologous RIA. During spontaneous luteolysis, ir-inhibin levels peaked 7 days before menses and declined in a linear fashion (r = -0.99) thereafter, reaching a sustained low level 1 day after the onset of menses. The decline of P4 and E2 levels appears to be coupled to that of ir-inhibin (r = 0.98 and r = 0.95, respectively). FSH levels showed an inverse pattern, with an acute elevation unaccompanied by LH, for 5 days before the onset of menses and reaching a plateau 2 days after. ir-Inhibin and FSH were negatively correlated (r = -0.87; P less than 0.0001). Increased LH levels did not occur until the day of menses and were negatively correlated with ir-inhibin (r = -0.50; P less than 0.05), but not E2 and P4. During the second cycle, at the midluteal phase luteolysis was induced by a single (50 micrograms/kg) im injection of a potent GnRH antagonist, [Ac-D2Nal,D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),+ ++DAla10] GnRH; an acute decline of LH and FSH levels occurred, with maximal suppressions of 51% and 35%, respectively. ir-Inhibin levels decreased rapidly (40 +/- 2.8%) in parallel with E2 and P4 during the first 24 h and continued to decline for 4 days. The inverse relationship and time course of changes between FSH and ir-inhibin levels were similar to those of the spontaneous luteal-follicular transition. Six of the 12 subjects experienced partial reversal of luteolysis; the decline of ir-inhibin and the rise of FSH during the first 2 days were arrested for 4 days, which corresponded to the rebound increases in E2, P4, and LH. The subsequent fall of ir-inhibin was followed by a rise in FSH. Both the complete and incomplete luteolysis groups exhibited an orderly follicular maturation, LH surge, and luteal function during the ensuing cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
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