Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys

Satoru Sasagawa, Yutaka Shimizu, Taiji Nagaoka, Hiroshi Tokado, Kazunori Imada, Kiyoshi Mizuguchi
In: Journal of Endocrinological Investigation · 2008 · vol. 31(7) , pp. 636–641 · doi:10.1007/bf03345616 · PMID:18787383 · W2007232511
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Dienogest reduced plasma estradiol by inducing apoptosis in granulosa cells of the dominant follicle without suppressing FSH in monkeys.

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The paper investigated whether dienogest’s antifolliculogenic effects involve suppression of gonadotropins or a direct ovarian action, using female cynomolgus monkeys given a single oral 0.1 mg/kg dose on day 7 of the menstrual cycle. Plasma FSH, estradiol (E2), and progesterone were followed for up to 15 days, and ovaries were excised 24 h after dosing for histology. Dienogest caused a rapid decline in plasma E2 within 24 h while FSH levels did not decrease prior to the E2 drop, with sustained low E2 for more than 11 days; histology showed apoptotic changes in granulosa cells of the dominant follicle in 2 of 3 animals. The authors’ limitation is the small histological sample size (two responders out of three), leaving mechanistic conclusions constrained. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Dienogest is a selective progestin that has been shown to arrest ovarian follicular development in women, without affecting gonadotropin secretion. As luteal progesterone or exogeneous progestins are known to suppress ovarian folliculogenesis via the inhibition of gonadotropin secretion, this action of dienogest on ovaries seems to be unique. To examine the underlying mechanism of the antifolliculogenic effect of dienogest, female cynomolgus monkeys were treated with a single oral dose of 0.1 mg/kg dienogest on day 7 of the menstrual cycle. Plasma FSH, estradiol (E2), and progesterone levels were measured up to 15 days after dosing. In an additional experiment, ovaries were excised 24 h after dosing for histological examinations. As a result, plasma E2 level declined within 24 h after dosing, while dienogest did not decreased FSH level prior to E2 decline. After decline of E2 level, the low level of E2 was sustained for more than 11 days. It is considered that a single oral dose of dienogest induced atresia of the dominant follicle. In the histological examination, two out of three animals showed decline in E2 level. The ovarian dominant follicles from these animals showed apoptotic changes in granulosa cells with scattered aromatase expression within 24 h after dosing. These results indicate that the induction of atresia of the ovarian dominant follicle by direct action would be a possible mechanism of dienogest to inhibit plasma E2 level.
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Abstract

Dienogest is a selective progestin that has been shown to arrest ovarian follicular development in women, without affecting gonadotropin secretion. As luteal progesterone or exogeneous progestins are known to suppress ovarian folliculogenesis via the inhibition of gonadotropin secretion, this action of dienogest on ovaries seems to be unique. To examine the underlying mechanism of the antifolliculogenic effect of dienogest, female cynomolgus monkeys were treated with a single oral dose of 0.1 mg/kg dienogest on day 7 of the menstrual cycle. Plasma FSH, estradiol (E2), and progesterone levels were measured up to 15 days after dosing. In an additional experiment, ovaries were excised 24 h after dosing for histological examinations. As a result, plasma E2 level declined within 24 h after dosing, while dienogest did not decreased FSH level prior to E2 decline. After decline of E2 level, the low level of E2 was sustained for more than 11 days. It is considered that a single oral dose of dienogest induced atresia of the dominant follicle. In the histological examination, two out of three animals showed decline in E2 level. The ovarian dominant follicles from these animals showed apoptotic changes in granulosa cells with scattered aromatase expression within 24 h after dosing. These results indicate that the induction of atresia of the ovarian dominant follicle by direct action would be a possible mechanism of dienogest to inhibit plasma E2 level. Similar content being viewed by others

References

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Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys. J Endocrinol Invest 31, 636–641 (2008). https://doi.org/10.1007/BF03345616 Accepted: Published: Issue date: DOI: https://doi.org/10.1007/BF03345616

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