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Cyclic progestin administration brings about luteinization during continuous antiprogestin treatment.

The antiprogestin RU 486 has been proposed for use as a contraceptive because it disturbs folliculogenesis and inhibits ovulation when given continuously. In order to achieve regular and predictable withdrawal bleeding and to counteract the continuous influence of estrogen on the endometrium, a sequential, cyclic progestin regimen has been added. The drawback has been the frequent rise in the concentration of serum P, suggesting ovulation. The present pilot study with three subjects was carried out to test whether simultaneous administration of RU 486 and progestin during the second half of the cycle would eliminate the rise in serum P concentrations. Based on elevated serum P values, five of the seven cycles were apparently ovulatory. RU 486 alone, when given throughout the cycle at a dose of 8 mg per day without added progestin, resulted in anovulatory cycles, but the lengths of these cycles were prolonged. We conclude that both simultaneous and sequential cyclic co-administration of progestin with RU 486 abolishes the antiovulatory action of RU 486. This decreases the possibility of using antiprogestins in non-estrogenic contraceptive regimens (unless contraceptive effects of RU 486 exist at the endometrial level).

Adult↗

The recovery of ovarian function during breast-feeding.

The pattern of breast-feeding was daily recorded and the serum concentrations of prolactin (PRL), FSH, LH, estradiol (E2) and progesterone (prog) were measured at weekly intervals in 26 breast-feeding mothers from the time of delivery and up to the resumption of regular ovulation or to the end of the first postpartum year. Twelve postpartum non-breast-feeding women were similarly studied as controls. An algorithm was used to characterize ovulatory events into three types: the first, with evidence highly suggestive of normal ovulation (EHSO), the second, with evidence of probable ovulation (EPO) and the third with evidence indicating questionable ovulation or deficient corpus luteum function (QO/DCT). Pregnancy preceded the first menstruation in one woman in each of the breast-feeding and control groups. Of the 19 breast-feeding women who started to menstruate during the first postpartum year, five had EHSO, one had EPO, 5 had EQO/DCL and 7 had anovulatory (AO) menstruation. The corresponding figures in the 11 controls were 6, 2, 3 and 0. Pregnancy occurred before a second menstruation in one woman in both the study group and the controls. In 18 breast-feeding women observed, the second menstruation was preceded by EHSO in 7, by EPO in 3, by EQO/DCL in one and AO in 7. In 10 controls the corresponding figures were 7, 3, 0 and 0. Out of a total of 79 menstruations observed during breast-feeding the incidence of AO was 30% and of QO/DCL was 15%. In actively breast-feeding mothers, hyperprolactinemia persisted for more than 1 yr. However, menstruation and ovulation occasionally occurred before the drop of PRL to concentrations seen during the normal menstrual cycle. In the majority of women, low E2 levels were present during lactational amenorrhea, but with occasional spikes in some. A few women maintained somewhat high values of E2 for several weeks before the resumption of menstruation. The implications of these hormonal findings to the attempts to improve on the contraceptive effect of breast-feeding are discussed.

Adult↗

The in-vitro and in-vito effects of diethylstilbestrol on testicular synthesis of testosterone.

The effect of diethylstilbestrol (DES) on the percent conversion of a 14C-progesterone (14C-P) substrate to 14C-testosterone (14C-T) when added to incubates fo rat testicular homogenates has been measured. Similarly the effect of DES administered parenterally to intact adult rats at 9 dose regimens on such conversion has been evaluated. In addition, in the latter group serum luteinizing hormone (LH) levels were assessed simultaneously. DES added in-vitro significantly reduced T formation at every level. Only the large parenteral dose of DES affected T synthesis after 24 hours, while every parenteral dose significantly reduced T synthesis with 4 and 8 day regimens. Mean serum LH levels failed to reflect a significant decrease at the 1 and 4 day dose level, but did decrease significantly in 2 of 3 groups on the 8 day regimen. These results suggest that there is a direct effect of DES at a testicular level inhibiting T synthesis not associated with a simultaneous drop in mean serum LH levels. A measurable decrease in LH concentration does occur with continued treatment.

Animals↗

Estrogen-induced sexual receptivity and localization of 3H-estradiol in brains of female mice: effects of 5 alpha-reduced androgens, progestins and cyproterone acetate.

Sexual receptivity induced in ovariectomized CD-1 mice with chronic daily administration of estradiol benzoate (E2 B) was blocked by concurrent administration of the 5 alpha-reduced androgen, dihydrotestosterone (DHT). Receptivity was restored in these females with progesterone-, but not with dihydroprogesterone-priming 6 hr prior to testing. Delaying the DHT injections until 12 hr after the E2 B injections greatly reduced its inhibitory properties. Receptivity in E2 B-primed females was also blocked by concurrent treatment with cyproterone acetate and 3 alpha-, but not 3 beta-adrostanediol. Pretreatment with DHT, or 3 alpha- or 3 beta-androstanediol failed to consistently affects 3H-estradiol accumulation in crude nuclear and supernatant fractions from brain and pituitary.

20-alpha-Dihydroprogesterone↗

Ovulation inhibition with nafarelin acetate nasal administration for six months.

A group of 24 women with normal menstrual cycles were treated with nafarelin acetate administered in doses of either 125 micrograms or 250 micrograms daily intranasally for 6 months. Each subject was studied for one ovulatory control cycle, six treatment cycles, and post-treatment until the return of ovulation was documented. Once a week progesterone, estradiol, follicle stimulating hormone, and luteinizing hormone were measured in the serum. Acute hormone responses to nafarelin acetate were determined on day 1, day 98 and day 186 of treatment. Two subjects failed to complete the treatment phase. One subject using the 250 micrograms daily dose of nafarelin acetate discontinued treatment on the sixth day because of heavy uterine bleeding. One subject using the 125 micrograms daily dose of the study drug terminated treatment on day 126 because of a 21-pound weight gain. There were significantly less presumed ovulatory cycles at the higher dose (2 out of 60 cycles) than at the lower dose (10 out of 54 cycles) (p less than 0.01). On the average menstrual cycles were reestablished 28.5 +/- 8.3 (S.D.) days after discontinuing the 125 micrograms daily dose and 33.7 +/- 17.9 (S.D.) days after terminating the 250 micrograms daily dose. With the higher dose of nafarelin acetate there were significantly fewer bleeding episodes, less number of days of bleeding, and longer cycles. During the treatment phase the area under the LH curve was significantly less and the acute response of LH in the last week of treatment was significantly less with the higher dose of drug. With both doses of nafarelin acetate the acute responses of LH, FSH and estradiol were significantly greater on day 1 than on either day 98 or day 186. Side effects observed during this study included galactorrhea (2 subjects) and vasomotor symptoms (7 subjects).

Administration, Intranasal↗

Interleukin-6 and tumor necrosis factor-alpha concentrations in the intrauterine cavity of postmenopausal women using an intrauterine delivery system releasing progesterone. A possible mechanism of action of the intrauterine device.

Intrauterine devices (IUD) provide effective contraception. The current study evaluates the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the intrauterine fluid of postmenopausal women using an intrauterine delivery system releasing progesterone (IDS-P). Intrauterine fluid was obtained by lavage, and IL-6 and TNF-alpha were analyzed using an enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed with a one-way analysis of variance (ANOVA). Intrauterine fluid IL-6 levels were 33.6 vs 6.09 pg/sample IDS-P vs no IDS-P (p = 0.0301). Intrauterine TNF-alpha levels for women using the IDS-P were higher than in nonusers, but the differences did not reach statistical significance. IL-6 and TNF-alpha levels were increased in the intrauterine cavity of postmenopausal women with an IDS-P. These data suggest that secreted cytokines could be a potential mechanism of IUD contraceptive efficacy.

Enzyme-Linked Immunosorbent Assay↗

The effect of intrauterine progesterone treatment on the endometrial prostaglandin F content in the rabbit.

The effect on rabbit endometrial prostaglandin F caused by progesterone delivered directly to the uterus was investigated. Four groups of animals were used in the experiment: (1) no treatment (control); (2) an empty Silastic capsule (as an intrauterine device [IUD]) was inserted in one horn and the other horn was sham-operated; (3) a Silastic capsule releasing 150 microng of progesterone/day was placed in one horn and the other horn was sham-operated; (4) a Silastic capsule releasing progesterone was placed in one horn and the opposite horn received an empty Silastic capsule. In group 1, which received no treatment, no difference was noted. In group 2, the prostaglandin content of the horn containing an empty IUD was significantly higher than that of the sham-operated horn. In group 3, the same significant difference was noted between the prostaglandin content of the IUD-containing, progesterone-treated horn and the sham-operated horn. In group 4, no significant difference was observed between the horn containing an inert IUD and that containing a progesterone-releasing device. The addition of progesterone to an IUD does not significantly affect the elevated prostaglandin content of the endometrium caused by an inert IUD.

Animals↗

Induction of ovulation in patients with normoprolactinemic amenorrhea by combined therapy with bromocriptine and clomiphene.

Bromocriptine is known to be effective in the treatment of women with hyperprolactinemic anovulation or amenorrhea-galactorrhea. A new schedule of combined treatment with bromocriptine and clomiphene citrate was applied to 23 patients with normoprolactinemic amenorrhea who failed to respond to clomiphene alone. Ovulation was restored by treatment in 14 of these patients (60.9%), resulting in pregnancy in 3 women. Treatment resulted in immediate suppression of serum prolactin levels and a gradual increase in serum luteinizing hormone levels and estradiol levels followed by a luteinizing hormone surge. The present results indicate that bromocriptine/clomiphene combination therapy is effective in the treatment of amenorrheic patients with normoprolactinemia who do not respond to clomiphene alone, and suggest that bromocriptine restores the responsiveness of the hypothalamic-pituitary-ovarian system to clomiphene.

Adult↗

Facilitation of receptivity in estrogen-primed rats during successive mating tests with progestins and methysergide.

The role of hormonal and experiential variables in mediating the gradual increase of receptivity occurring during weekly tests was evaluated in adult ovariectomized females. Hormone treatment consisted of estradiol benzoate (EB) injection followed by progesterone (P), 20alpha-hydroxyprogesterone (20alpha-OHP), methysergide maleate (Me), or oil during weekly mating tests. The experiential conditions were vaginal stimulation, mounts only, or no interaction with males. There was a gradual increase in receptivity in all groups even en the one receiving oil. Progressive facilitation occurred even when no interaction with the male was permitted. Interchanging the synergists on the sixth and seventh tests was not detrimental to the display of receptivity attained with synergists given previously. Thus, we concluded that successive injections of EB rather than synergists or experience mediate this increase in receptivity.

Animals↗