Negative feedback effects of chlormadinone acetate and ethynylestradiol on gonadotropin secretion in patients with prostatic cancer and male rats.

Noguchi, Kazumi; Nishimura, Ryuichi; Takai, Shudo; Ai, Jun; Higuchi, Takashi; Kawakami, Michiyuki

doi:10.1507/endocrj1954.27.285

Cited by 3 publications

(3 citation statements)

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“…In the male rat, estrogens negatively feed back to central regulatory centres thereby reducing luteinizing hormone and testosterone release (Noguchi et al 1980;Anderson et al 1991). Accordingly, the atrophy of Leydig cells that occurred with high incidence at 0.2 mg ethinylestradiol/kg in both studies is readily explained as a consequence of reduced luteinizing hormone secretion (Wing et al 1985).…”

Section: Discussionmentioning

confidence: 83%

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Andrews

Freyberger

Hartmann

et al. 2002

Archives of Toxicology

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Groups of five male and female Wistar rats were treated by gavage with 0, 0.01, 0.05 or 0.2 mg/kg body weight of the known synthetic estrogen ethinylestradiol for 28-32 days according to a modified enhanced OECD Test Guideline no. 407 in order to investigate which of the current and/or additional parameters would detect effects on the endocrine system reliably and sensitively and to provide data on intra-laboratory variability. Two identical studies (A and B) were run concurrently. The modified enhanced protocol requests the additional determination of triiodothyronine, thyroxine and thyroid-stimulating hormone (TSH), of the stage of the estrous cycle to ensure necropsy of all females in diestrus, of the number and morphology of cauda epididymal spermatozoa, and of additional organ weights (ovaries, uterus, thyroid, and male accessory reproductive organs), and histopathology of additional organs (pituitary, epididymides, coagulation glands, pancreas, and vagina). There were no treatment-related mortalities, clinical signs or changes in behavioral parameters. In male rats, 0.2 mg/kg was the maximum tolerated dose (MTD) resulting in reduced body weight gain. The only treatment-related alteration in hematological parameter was prolonged blood clotting time in high-dose females of both studies. Changes in clinical chemistry observed in study A were elevated alkaline phosphatase activity (high-dose females) and triglyceride levels (mid- and high-dose females and high-dose males). Changes in thyroid hormones and TSH of treated animals showed high variability with no clear dose-dependency, and could not be clearly related to estrogenic activity. In accordance to a suppression of the hypothalamic-pituitary-gonadal axis, decreased relative organ weights of the male accessory reproductive organs were obtained in both studies at the high dose. Corresponding histological changes were degeneration of the testicular germinal epithelium and atrophy of Leydig cells and of all accessory sex glands. Atrophy of the coagulating gland (study A) and seminal vesicles (study B) was also seen at 0.05 mg/kg. A marked increase in relative adrenal weight in male rats, accompanied by decreased vacuolization of zona fasciculata cells observed in both studies at the high dose seems to reflect an activation of the hypothalamic-pituitary-adrenal axis. The male mammary gland was sensitively affected. Increased numbers of small basophilic over large acidophilic cells indicated an estrogen-mediated feminisation and were detected at the low (study A) or mid dose (study B). Co-mitogenic properties of estrogens in rat liver were reflected by increased relative liver weights in females at the mid and high dose of study A and also at the high dose in study B. No treatment-related changes in endocrine organ weights were observed in treated females. Histological changes in the ovaries were increased numbers of apoptotic corpora lutea (from mid dose, study B) and of early stage follicles at the high dose in both studies. Classical direct estrogenic effects...

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Section: Discussionmentioning

confidence: 83%

Untitled

Andrews

Freyberger

Hartmann

et al. 2002

Archives of Toxicology

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“…This suggests that our results were relatively higher than those of their report. The relatively low levels of LH and FSH in their report may be related to the negative feedback effect of the estrogen contained in COC on gonadotropin‐releasing hormone secretion 25,26 …”

Section: Discussionmentioning

confidence: 93%

“…The relatively low levels of LH and FSH in their report may be related to the negative feedback effect of the estrogen contained in COC on gonadotropin-releasing hormone secretion. 25,26 A phase I/II study in Europe reported that the 24/4 dosing of DRSP did not reinstate ovulation until 9 days after the end of the dosing. 27 DRSP has also been shown to suppress ovulation even with intentional 24 h intake delay.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II study evaluating the pharmacokinetics, pharmacodynamics, and safety of drospirenone as an oral contraceptive in Japanese women

Kitamura,

Colli,

Azuma

et al. 2024

J of Obstet and Gynaecol

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AimDrospirenone (DRSP) is a synthetic progestogen approved as a progestin‐only pill for contraception in both the United States and Europe. Herein, we conducted a phase I/II study to evaluate the pharmacokinetics, pharmacodynamics, and safety of DRSP in Japanese women.MethodsSingle and multiple doses of 4 mg of DRSP were orally administered to healthy premenopausal Japanese women. In the multiple‐dose period, 4 mg of DRSP was administered once daily for 24 days. Pharmacokinetics, hormone levels, and adverse events (AEs) were investigated.ResultsTwelve Japanese women participated in this study. The single‐ and multiple‐dose pharmacokinetics of DRSP was similar to that reported in previous studies in Caucasians. In the multiple‐dose period, no subject displayed a progesterone level of more than 5.03 ng/mL. AEs were observed in 11 (91.7%) subjects. The most common AE was genital hemorrhage, which was observed in six (50.0%) subjects, followed by diarrhea and acne in four (33.3%) subjects each. All AEs resolved or improved at the end of the study, and complete recovery was confirmed in all subjects at follow‐up.ConclusionsThe pharmacokinetics of DRSP in Japanese women was similar to that of previous studies performed in Caucasian women. Repeated administration of DRSP maintained low plasma progesterone levels indicating effective inhibition of ovulation. No notable safety concerns were observed. In this phase I/II study, DRSP had no obvious pharmacokinetic, pharmacodynamic, or safety issues to consider in Japanese women.

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Effects of Chlormadinone Acetate and Ethinylestradiol Treatment on Epididymal 5.ALPHA.-Reductase Activities in Patients with Prostate Cancer.

Nukui

1997

Endocr J

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Abstract. The difference between in vivo and in vitro inhibitory effects on epididymal 5a-reductase was investigated by using epididymides obtained from patients treated with chlormadinone acetate (6-chloro-3,20-dioxo-4,6-pregnadien-17-yl acetate, CMA) or ethinylestradiol (17a-ethynyl-1,3,5 (10)-estratriene-3,17-diol, EE2). In the in vitro study CMA exhibited competitive inhibition, whereas EE2 was a noncompetitive inhibitor of human epididymal 5a-reductase. Their in vitro inhibitory effects were weak compared with the effect of finasteride ((-)-N-tert-butyl-3-oxo-4-aza-5a-androst-1-ene-17f3 carboxamide), a steroidal 5a-reductase inhibitor. The Ki values for CMA, EE2, and finasteride were 1.4 x 10-5 M, 1.5 x 10-5 M, and 1.3 x 10-9 M, respectively. Despite their weak in vitro inhibitory potency, CMA and EE2 strongly inhibited testosterone 5a-reductase in vivo. There were regional differences in inhibitions by CMA and EE2 on human epididymal 5a-reductase activity depending on the site of the epididymis; the efferent ductules, the head, the body or the tail. In vivo administration of CMA reduced epididymal 5a-reductase activity by 49.7% to 89.4%. In vivo administration of EE2 reduced epididymal 5a-reductase activity by 82.7% to 96.3%. The apparent Km values for the enzyme in patients treated with CMA or EE2 and untreated patients did not differ significantly. The Vmax values were significantly decreased in treated patients. These findings suggest that the marked in vivo inhibition of 5a-reductase induced by CMA and EE2 was not related to the direct action of these compounds, but resulted from a reduction in the amount of the enzyme.

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Negative feedback effects of chlormadinone acetate and ethynylestradiol on gonadotropin secretion in patients with prostatic cancer and male rats.

Cited by 3 publications

References 3 publications

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A phase I/II study evaluating the pharmacokinetics, pharmacodynamics, and safety of drospirenone as an oral contraceptive in Japanese women

Effects of Chlormadinone Acetate and Ethinylestradiol Treatment on Epididymal 5.ALPHA.-Reductase Activities in Patients with Prostate Cancer.

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