Takahiro Mizutani

Danazol concentrations in ovary, uterus, and serum and their effect on the hypothalamic-pituitary-ovarian axis during vaginal administration of a danazol suppository *

OBJECTIVE To determine danazol concentrations in the ovary, uterus, and serum during daily vaginal administration of a danazol suppository and to examine its effect on the hypothalamic-pituitary-ovarian axis. DESIGN Sampling of tissues after vaginal or oral administration of danazol and sampling of blood during control and danazol-administration menstrual cycles. SETTING Outpatient volunteers and inpatients at a public hospital. PARTICIPANTS Thirty patients who were to undergo hysterectomy and oophorectomy because of uterine leiomyoma and eight regularly menstruating volunteers. INTERVENTIONS Danazol was administered as a vaginal suppository (100 mg) or orally (400 mg). MAIN OUTCOME MEASURE Danazol concentrations in the ovary, uterus, and serum, and serum E2 and P levels. RESULTS Danazol concentrations in the ovary and uterus after daily vaginal administration of a suppository containing 100 mg danazol were comparable to those after daily oral administration of 400 mg danazol, but the serum danazol concentration was much lower. Menstrual cycle patterns of serum E2 and P levels were normal during daily vaginal administration of a danazol suppository. CONCLUSION Daily administration of a suppository containing 100 mg danazol produces high ovarian and uterine concentrations but low serum concentrations, and no effect was detected on the hypothalamic-pituitary-ovarian axis.

Effects of danazol, gonadotropin-releasing hormone agonist, and a combination of danazol and gonadotropin-releasing hormone agonist on experimental endometriosis

Effects of danazol, gonadotropin-releasing hormone agonist (leuprolide), and danazol-leuprolide combination on experimental endometriosis were evaluated in female rats. A complete resorption of the fluid and a marked decrease in the volume of endometrium autotransplanted under the renal capsule were found after castration (1.4 +/- 0.1 mm3 in castrated, n = 14, vs 26.7 +/- 5.6 mm3 in intact control, n = 16). Histologic examination indicated atrophy and regression of the endometrial explant. These atrophic changes of endometrial explant were also induced by danazol, leuprolide, and the combination treatment. However, the volume of explants after combination therapy with danazol and leuprolide (1.8 +/- 1.0 mm3, n = 17) was significantly less than that after therapy with danazol (11.6 +/- 2.8 mm3, n = 20) or leuprolide alone (5.9 +/- 1.4 mm3, n = 24). The combination therapy (16/17) was also shown to be superior to danazol (9/20) or leuprolide alone (14/24) to induce the regression of fluid in experimental endometriosis. As expected, administration of leuprolide decreased the serum estradiol level, but use of danazol did not. These findings suggest that a combination therapy of danazol and gonadotropin-releasing hormone agonist, which show different modes of action, may be a potential modality in treatment of patients with advanced endometriosis.

Impact of prepregnant body mass index and maternal weight gain on the risk of pregnancy complications in Japanese women

Background. To analyze the association of pregnancy complications with prepregnant body mass index and weight gain during pregnancy in Japanese women. Methods. A retrospective cohort study was conducted with 21,718 Japanese women with a singleton pregnancy. Pregnant women were grouped by prepregnant body mass index and evaluated for association with pregnancy complications using multivariate logistic regression analysis. The women in each body mass index group were then divided into groups by weight gain during pregnancy using intervals of 0.05 kg/week to analyze the relationship between the weight gain and pregnancy complications by multivariate logistic regression association analysis. Results. In both nulliparous and parous women, the least pregnancy complications were found among women with medium prepregnant body mass indexes (18–23.9). Significant risks of pregnancy complications were associated with low (<18) and high (≥24) prepregnant body mass indexes, particularly high prepregnant body mass indexes. In nulliparous women, the optimal weight gain was 0.25–0.4 kg/week for low (<18) prepregnant body mass index, 0.20–0.30 kg/week for medium (18–23.9) prepregnant body mass index, and ≥0.05 kg/week for high (≥24) prepregnant body mass index. In parous women, the corresponding values were ≥0.20, 0.20–0.30, and 0.05–0.30 kg/week. Conclusions. Japanese women with prepregnant body mass indexes from 18 to 23.9 are least associated with pregnancy complications, although there is a broad range of prepregnant body mass indexes associated with few pregnancy complications. Optimal weight gain is roughly inversely related to prepregnant body mass index.

Preliminary Report on the Use of Danazol in the Treatment of Endometrial Adenomatous Hyperplasia

Since the authors recently reported that danazol inhibits the growth of human endometrial cancer cells in vitro, a clinical trial was initiated to examine whether danazol can regress adenomatous hyperplasia, a precursor of endometrial adenocarcinoma. Danazol was used for 3 months in the treatment of five patients with a history of hypermenorrhea and irregular uterine bleeding. Within a 9‐month follow‐up period, all patients were symptom‐free, and none of the specimens obtained by endometrial biopsy showed the presence of adenomatous hyperplasia. These findings suggest that danazol has a potential application in the treatment of patients with endometrial adenomatous hyperplasia. A possible mechanism of action of the compound in adenomatous hyperplasia is also discussed.

Ovariectomy increases the level of estrogen receptor mRNA and estrogen receptor binding sites in female rat adipose tissue

The roles of estrogen in the changes in estrogen receptor (ER) mRNA and ER binding sites in rat adipose tissue were studied in female rats. To elucidate the mechanism(s) behind ovariectomy (OVX)-induced obesity, the levels of ER mRNA and ER binding sites in adipose tissue were analyzed three weeks after OVX using Northern blot analysis of ER mRNA and the [3H]E2 binding assay, respectively. OVX induced an increase in body weight, and replacement of estradiol (E2) prevented that increase. Significant increases in the amounts of ER mRNA and in [3H]E2-specific binding were observed after OVX, and E2 replacement reduced both of those increases. These results suggest that E2 may regulate rat obesity directly through ER in adipose tissues.