title: Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro.
abstract: OBJECTIVE
  What are the direct effects of progesterone (P4) and estradiol (E2) on the development and function of primate follicles in vitro from the pre-antral to early antral stage?
  
  
  CONCLUSIONS
  In a steroid-depleted milieu, E2 improved follicle survival, growth, antrum formation and oocyte health, whereas P4 exerted minimal beneficial effects on follicle survival and reduced oocyte health.
  
  
  BACKGROUND
  Effects of P4 and E2 on follicle development have been studied primarily in large antral and pre-ovulatory follicles. Chronic P4 exposure suppresses antral follicle growth, but acute P4 exposure promotes oocyte maturation in pre-ovulatory follicles. Effects of E2 can be stimulatory or inhibitory depending upon species, dose and duration of exposure.
  
  
  METHODS
  Non-human primate model, randomized, control versus treatment. Macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks.
  
  
  METHODS
  Adult rhesus macaque secondary follicles were encapsulated in 0.25% alginate and cultured individually in media containing follicle stimulating hormone plus (i) vehicle, (ii) a steroid-synthesis inhibitor, trilostane (TRL, 250 ng/ml), (iii) TRL + low E2 (100 pg/ml) or progestin (P, 10 ng/ml R5020) and (iv) TRL + high E2 (1 ng/ml E2) or P (100 ng/ml R5020). Follicles reaching the antral stage (≥750 µm) were treated with human chorionic gonadotrophin for 34 h. End-points included follicle survival, antrum formation, growth pattern, plus oocyte health and maturation status, as well as media concentrations of P4, E2 and anti-Müllerian hormone (AMH).
  
  
  RESULTS
  In a steroid-depleted milieu, low dose, but not high dose, P improved (P < 0.05) follicle survival, but had no effect (P > 0.05) on antrum formation and AMH production. Low-dose P increased (P < 0.05) P4 production in fast-grow follicles, and both doses of P elevated (P < 0.05) E2 production in slow-grow follicles. Additionally, low-dose P increased (P < 0.05) the percentage of no-grow follicles, and high-dose P promoted oocyte degeneration. In contrast, E2, in a steroid-depleted milieu, improved (P < 0.05) follicle survival, growth, antrum formation and oocyte health. E2 had no effect on P4 or E2 production. Follicles exposed to E2 yielded mature oocytes capable of fertilization and early cleavage, at a rate similar to untreated control follicles.
  
  
  CONCLUSIONS
  This study is limited to in vitro effects of P and E2 during the interval from the secondary to small antral stage of macaque follicles.
  
  
  CONCLUSIONS
  This study provides novel information on the direct actions of P4 and E2 on primate pre-antral follicle development. Combined with our previous report on the actions of androgens, our findings suggest that androgens appear to be a survival factor but hinder antral follicle differentiation, E2 appears to be a survival and growth factor at the pre-antral and early antral stage, whereas P4 may not be essential during early folliculogenesis in primates.
  
  
  BACKGROUND
  NIH P50 HD071836 (NCTRI), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), ONPRC 8P51OD011092. There are no conflicts of interest.
authors.affiliation: Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA ting@ohsu.edu.
authors.forename: A Y
authors.initials: AY
authors.lastname: Ting
authors.affiliation: Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Stouffer
mesh_terms: D000818:Animals; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D008253:Macaca mulatta; D006080:Ovarian Follicle / Q000187:drug effects* / Q000254:growth & development; D011374:Progesterone / Q000494:pharmacology*
chemical_list: D013196:Dihydrotestosterone; D011374:Progesterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone; C009954:trilostane
keywords: estrogen; follicle development; ovary; progesterone