title: 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.
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.
authors.affiliation: Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka 412-8524, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sasagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Shimizu
authors.forename: T
authors.initials: T
authors.lastname: Nagaoka
authors.forename: H
authors.initials: H
authors.lastname: Tokado
authors.forename: K
authors.initials: K
authors.lastname: Imada
authors.forename: K
authors.initials: K
authors.lastname: Mizuguchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004958:Estradiol / Q000097:blood*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood*; D005496:Follicular Atresia / Q000378:metabolism; D006107:Granulosa Cells / Q000187:drug effects / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008597:Menstrual Cycle / Q000502:physiology; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D011374:Progesterone / Q000097:blood; D011372:Progestins / Q000494:pharmacology
chemical_list: D006727:Hormone Antagonists; D011372:Progestins; C023635:dienogest; D011374:Progesterone; D004958:Estradiol; D009277:Nandrolone; D005640:Follicle Stimulating Hormone
references.citation: Indian J Exp Biol. 1989 Apr;27(4):324-8
references.pmid: 2530166
references.citation: Endocrinology. 1980 Jun;106(6):1820-6
references.pmid: 6768544
references.citation: Mol Cell Endocrinol. 1993 Nov;97(1-2):135-43
references.pmid: 8143896
references.citation: Rev Reprod. 1997 Sep;2(3):139-46
references.pmid: 9414477
references.citation: Endocrinology. 1983 Jun;112(6):2076-80
references.pmid: 6406208
references.citation: Fertil Steril. 2006 Jul;86(1):27-35
references.pmid: 16764869
references.citation: Endocrinology. 1979 Jul;105(1):69-79
references.pmid: 109289
references.citation: Fertil Steril. 1983 Nov;40(5):688-92
references.pmid: 6628715
references.citation: J Clin Endocrinol Metab. 1971 Mar;32(3):309-16
references.pmid: 5541341
references.citation: Maturitas. 2004 Apr 15;47(4):277-83
references.pmid: 15063480
references.citation: J Clin Endocrinol Metab. 1977 Oct;45(4):837-40
references.pmid: 410825
references.citation: Drugs Exp Clin Res. 1997;23(2):45-62
references.pmid: 9309380
references.citation: Am J Physiol. 1982 Nov;243(5):E387-97
references.pmid: 6814263
references.citation: Fertil Steril. 2001 Apr;75(4):744-8
references.pmid: 11287029
references.citation: Am J Physiol. 1981 May;240(5):E489-92
references.pmid: 6786104
references.citation: Zentralbl Gynakol. 1997;119(12):597-606
references.pmid: 9483810
references.citation: Proc Soc Exp Biol Med. 1977 Sep;155(4):479-81
references.pmid: 408814
references.citation: Biol Reprod. 1981 Sep;25(2):332-41
references.pmid: 6796137
references.citation: Biol Reprod. 2007 Oct;77(4):743-50
references.pmid: 17582010
references.citation: J Clin Endocrinol Metab. 1984 Feb;58(2):378-83
references.pmid: 6420438
references.citation: Contraception. 1980 Jan;21(1):61-9
references.pmid: 7357870
references.citation: Mol Cell Endocrinol. 2007 Jan 29;264(1-2):197-203
references.pmid: 17116363
references.citation: Reproduction. 2006 Aug;132(2):191-206
references.pmid: 16885529
references.citation: J Clin Endocrinol Metab. 1980 Oct;51(4):903-7
references.pmid: 7419672
references.citation: Acta Eur Fertil. 1979 Mar;10(1):29-33
references.pmid: 121012
references.citation: Endocrinology. 1994 Aug;135(2):569-75
references.pmid: 8033804