title: Protective effect of dienogest on chemotherapy-induced reduced fertility in female rats.
abstract: Reduced fertility is one of the main long-term consequences of chemotherapy given for lymphoma, leukemia, and other malignancies in young women. We examined with a female rat model whether and how dienogest, a fourth-generation progestin, modulates reduced fertility following exposure to gonadotoxic chemotherapy. Female rats were administered cyclophosphamide with or without GnRH agonist and different concentrations of dienogest for 20 days. Animals were sacrificed on Day 29, and the numbers of follicle at primordial, preantral and antral stage in the ovaries were counted histologically. Rats treated with sterile saline solution (as control), cyclophosphamide, cyclophosphamide plus GnRH agonist, and cyclophosphamide plus dienogest were also mated with male rats to evaluate their fertility and pregnancy outcomes. Cyclophosphamide significantly reduced the number of primordial follicles, whereas dienogest suppressed depletion of primordial follicle pool induced by chemotherapy. Although the rats exposed to cyclophosphamide alone failed to deliver live births, co-treatment with dienogest improved the pregnancy outcomes of treated rats. The protective effect of dienogest on chemotherapy-induced ovarian damage and reduced fertility was comparable to that of GnRH agonist. The present results suggest that the co-administration of dienogest and chemotherapy may be a useful strategy in preserving ovarian function and fertility in premenopausal women facing gonadotoxic chemotherapy.
authors.affiliation: Department of Obstetrics and Gynecology, University of Fukui, Fukui, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tsuyoshi
authors.affiliation: Department of Obstetrics and Gynecology, University of Fukui, Fukui, Japan. Electronic address: orisaka@u-fukui.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Orisaka
authors.affiliation: Department of Obstetrics and Gynecology, University of Fukui, Fukui, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Obstetrics and Gynecology, University of Fukui, Fukui, Japan.
authors.forename: Katsushige
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Departments of Obstetrics & Gynecology and Cellular & Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
authors.affiliation: Department of Obstetrics and Gynecology, University of Fukui, Fukui, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D003520:Cyclophosphamide / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005299:Fertility Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D007247:Infertility, Female / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006080:Ovarian Follicle / Q000187:drug effects; D010053:Ovary / Q000187:drug effects; D011247:Pregnancy; D017207:Rats, Sprague-Dawley
chemical_list: D018906:Antineoplastic Agents, Alkylating; D005299:Fertility Agents; D007987:Gonadotropin-Releasing Hormone; C023635:dienogest; D009277:Nandrolone; D003520:Cyclophosphamide
keywords: Chemotherapy; Cyclophosphamide; Dienogest; Ovary; Primordial follicle