PMID- 10579351
OWN - NLM
STAT- MEDLINE
DCOM- 19991220
LR  - 20131121
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 140
IP  - 12
DP  - 1999 Dec
TI  - Prevention of the polycystic ovarian phenotype and characterization of ovulatory 
      capacity in the estrogen receptor-alpha knockout mouse.
PG  - 5855-65
AB  - Ovarian-derived estradiol plays a critical endocrine role in the regulation of 
      gonadotropin synthesis and secretion from the hypothalamic-pituitary axis. In 
      turn, several para/autocrine effects of estrogen within the ovary are known, 
      including increased ovarian weight, stimulation of granulosa cell growth, 
      augmentation of FSH action, and attenuation of apoptosis. The estrogen 
      receptor-alpha (ERalpha) is present in all three components of the 
      hypothalamic-pituitary-ovarian axis of the mouse. In contrast, estrogen 
      receptor-beta (ERbeta) is easily detectable in ovarian granulosa cells but is low 
      to absent in the pituitary of the adult mouse. This distinct expression pattern 
      for the two ERs suggests the presence of separate roles for each in the 
      regulation of ovarian function. Herein, we definitively show that a lack of 
      ERalpha in the hypothalamic-pituitary axis of the ERalpha-knockout (alphaERKO) 
      mouse results in chronic elevation of serum LH and is the primary cause of the 
      ovarian phenotype of polycystic follicles and anovulation. Prolonged treatment 
      with a GnRH antagonist reduced serum LH levels and prevented the alphaERKO cystic 
      ovarian phenotype. To investigate a direct role for ERalpha within the ovary, 
      immature alphaERKO females were stimulated to ovulate with exogenous 
      gonadotropins. Ovulatory capacity in the immature alphaERKO female was reduced 
      compared with age-matched wild-type (14.5+/-2.9 vs. 40.6+/-2.6 oocytes/animal, 
      respectively); however, oocytes collected from the alphaERKO were able to undergo 
      successful in vitro fertilization. A similar discrepancy in oocyte yield was 
      observed after superovulation of peripubertal (42 days) wild-type and alphaERKO 
      females. In addition, ovaries from immature superovulated alphaERKO females 
      possessed several ovulatory but unruptured follicles. Investigations of the 
      possible reasons for the reduced number of ovulations in the alphaERKO included 
      ribonuclease protection assays to assess the mRNA levels of several markers of 
      follicular maturation and ovulation, including ERbeta, LH-receptor, cyclin-D2, 
      P450-side chain cleavage enzyme, prostaglandin synthase-2, and progesterone 
      receptor. No marked differences in the expression pattern for these mRNAs during 
      the superovulation regimen were observed in the immature alphaERKO ovary compared 
      with that of the wild-type. Serum progesterone levels just before ovulation were 
      slightly lower in the alphaERKO compared with wild-type. These studies indicate 
      that treatment of alphaERKO females with a GnRH antagonist decreased the serum LH 
      levels to within the wild-type range and concurrently prevented development of 
      the characteristic ovarian phenotype of cystic and hemorrhagic follicles. 
      Furthermore, a lack of functional ERalpha within the ovary had no effect on the 
      regulation of several genes required for follicular maturation and ovulation. 
      However, the reduced numbers of ovulations following the administration of 
      exogenous gonadotropins in the alphaERKO suggests an intraovarian role for 
      ERalpha in follicular development and ovulation.
FAU - Couse, J F
AU  - Couse JF
AD  - Receptor Biology Section, Laboratory of Reproductive and Developmental 
      Toxicology, National Institute of Environmental Health Sciences, National 
      Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
FAU - Bunch, D O
AU  - Bunch DO
FAU - Lindzey, J
AU  - Lindzey J
FAU - Schomberg, D W
AU  - Schomberg DW
FAU - Korach, K S
AU  - Korach KS
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Chorionic Gonadotropin)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Gonadotropins, Equine)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Estrogen)
RN  - 33515-09-2 (Gonadotropin-Releasing Hormone)
RN  - 4G7DS2Q64Y (Progesterone)
RN  - 9002-67-9 (Luteinizing Hormone)
SB  - IM
MH  - Animals
MH  - Chorionic Gonadotropin/pharmacology
MH  - Estrogen Receptor alpha
MH  - Female
MH  - Fertilization in Vitro
MH  - Gonadotropin-Releasing Hormone/antagonists & inhibitors
MH  - Gonadotropins, Equine/pharmacology
MH  - Hypothalamus/physiopathology
MH  - Luteinizing Hormone/blood
MH  - Mice
MH  - Mice, Knockout
MH  - Oocytes/physiology
MH  - Ovary/pathology
MH  - *Ovulation
MH  - Phenotype
MH  - Pituitary Gland/physiopathology
MH  - Polycystic Ovary Syndrome/*genetics/pathology/physiopathology
MH  - Progesterone/blood
MH  - RNA, Messenger/metabolism
MH  - Receptors, Estrogen/*deficiency/*genetics/physiology
MH  - Superovulation
EDAT- 1999/12/01 00:00
MHDA- 1999/12/01 00:01
CRDT- 1999/12/01 00:00
PHST- 1999/12/01 00:00 [pubmed]
PHST- 1999/12/01 00:01 [medline]
PHST- 1999/12/01 00:00 [entrez]
AID - 10.1210/endo.140.12.7222 [doi]
PST - ppublish
SO  - Endocrinology. 1999 Dec;140(12):5855-65. doi: 10.1210/endo.140.12.7222.