Species: mouse
Mutation name: None
type: null mutation
fertility: None
Comment: Lubahn et al. (1993) described the pleiotropic effects of disruption of the ER-alpha gene in knockout mice. The findings included absence of breast development in females and infertility caused by reproductive tract and gonadal and behavioral abnormalities in both sexes. Schomberg et al. (1999)( found that in the adult null mice the major cause of the estrogen receptor knock out phenotype is high circulating LH interacting with functional LH receptor of the theca and granulosa cells. These features result in a failure of the normal maturational events leading to successful ovulation and luteinization and presumably involve both hypothalamic-pituitary and intraovarian mechanisms dependent upon ER alpha action.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues (Couse et al ). Both sexes of alpha beta estrogen receptor knockout (alpha beta ERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alpha beta ERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Mullerian inhibiting substance, sulfated glycoprotein-2, and Sox9, Therefore, Loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary. Rosenfeld CS et al tested whether ER alpha is required for ovarian folliculogenesis, ovulation, and CL formation, eCC and hCG were used to ovulate 3- to 5-wk-old ER alpha KO and wildtype (WT) sibling mice. Gonadotropin administration resulted in ovulation in both ER alpha KO and WT mice. Gonadotropin-treated ER alpha KO females that ovulated produced 7.09 +/- 0.77 oocytes per mouse, whereas gonadotropin-treated WT female mice had 16.17 +/- 0.84 oocytes. Surprisingly, ruptured ER alpha KO ovarian follicles developed into CL that had normal morphology. Gonadotropin-treated ERaKO mice had 3-fold higher concentrations of serum progesterone than did control ER alpha KO mice that had been administered saline rather than gonadotropins. Thus, the CL in gonadotropin-treated ER alpha KO mice appeared to be steroidogenically functional. On the basis of these findings, ovarian folliculogenesis, ovulation, and CL formation can occur in the absence of ER alpha, although to a lesser extent than in WT mice.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Weel et al investigated whether genetic variation at the estrogen receptor (ER) gene contributes to the variability in the onset of menopause in 900 postmenopausal women, aged 55-80 yr, of the Rotterdam Study, a population-based cohort study in The Netherlands. Gynecological information was obtained, and if women reported surgical menopause, validation of type and indication of surgery was accomplished by checking medical records. The ER genotypes (PP, Pp, and pp) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1-yr (P < 0.02) earlier onset of menopause. Furthermore, an allele dose effect was observed, corresponding to a 0.5-yr (P < 0.02) earlier onset of menopause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5-3.8) times higher for women carrying the PP genotype compared to those in the pp group, with the most prominent effect in women who underwent hysterectomy due to fibroids or menorrhagia.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Generation of Cyp17iCre transgenic mice and their application to conditionally delete estrogen receptor alpha (Esr1) from the ovary and testis. Bridges PJ et al. A transgenic mouse line that expresses iCre under regulation of the Cytochrome P(450) 17alpha-hydroxylase/17, 20-lyase (Cyp17) promoter was developed as a novel transgenic mouse model for the conditional deletion of genes specifically in the theca/interstitial cells of the ovary and Leydig cells of the testis. In this report, we describe the development of Cyp17iCre mice and the application of these mice for conditional deletion of the estrogen receptor alpha (Esr1) gene in the theca/interstitial and Leydig cells of the female and male gonad, respectively. These mice will prove a powerful tool to inactivate genes in the gonad in a cell-specific manner. genesis 46:499-505, 2008. (c) 2008 Wiley-Liss, Inc.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Developmental phenotype of a membrane only estrogen receptor alpha (MOER) mouse. Pedram A et al. Estrogen receptors (ER) Estrogen receptors (ER) alpha and beta exist as nuclear, cytoplasmic, and membrane cellular pools in a wide variety of organs. The relative contributions of each ERalpha pool to in-vivo phenotypes resulting from estrogen signaling have not been determined. To address this, we generated a transgenic mouse expressing only a functional E domain of ERalpha at the plasma membrane (MOER). Cells isolated from many organs showed membrane only-localized E domain of ERalpha and no other receptor pools. Liver cells from MOER and wild type (WT) mice responded to E2 with comparable activation of ERK and PI3K, not seen in cells from ERalphaKO mice. Matings of MOER female mice with proven male WT breeders produced no pregnancies since the uterus and vagina of the MOER female mice were extremely atrophic. Ovaries of MOER and homozygous Strasbourg ERalphaKO mice showed multiple hemorrhagic cysts and no corpus luteum, and the mammary gland development in both MOER and ER alphaKO mice was rudimentary. Despite elevated serum E2 levels, serum LH was not suppressed and prolactin levels were low in MOER mice. MOER and Strasbourg female mice showed plentiful abdominal visceral and other depots of fat and increased body weight despite comparable food consumption.These results provide strong evidence that the normal development and adult functions of important organs in female mice requires nuclear ERalphaand is not rescued by membrane ERalpha domain expression alone.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Theca-specific Esr1 knockout mice lose fertility prematurely. Lee S et al. Estrogen receptor alpha (ERalpha; Esr1) mediates estrogen action in regulating at all levels of the hypothalamic-pituitary-ovarian axis. While the importance of Esr1 in hypothalamus and pituitary has been demonstrated by loss of fertility in the neuron- and pituitary-specific Esr1 knockout mice, whether Esr1 plays a critical role in the ovary remains to be determined. In the ovary, Esr1 is mainly expressed in the theca/interstitial cells and germinal epithelium and thus is believed to mediate estrogen action in these cells. In this study, we assessed the importance of Esr1 in the ovarian theca cells in regulating female reproduction. The Cre-LoxP approach was employed to selectively delete the Esr1 gene in the theca cells, and the reproductive consequence of the deletion was measured. Adolescent theca-specific Esr1 knockout (thEsr1KO) mice (< 4 months of age) are fertile and cycling. However, they begin to display an erratic pattern of estrous cycles and become infertile before they reach the age of 6 months. The ovaries of thEsr1KOmice (>/= 4 months) have fewer corpora lutea, but more antral follicles than the age-matching wild type mice. The numbers of Cyp17-expressing cells are largely increased in the interstitium of the thEsr1KO mouse ovary. Interestingly, whereas basal levels of serum testosterone and FSH were mildly elevated, LH level was either markedly lower or undetectable in the thEsr1KO mice. When super-stimulated by exogenous gonadotropins, thEsr1KO mice released significantly fewer oocytes that WT littermates and developed multiple hemorrhagic cysts. Taken together, this study demonstrates that theca Esr1 plays a critical role in regulating female reproduction.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. Qin Y et al. ABSTRACT: BACKGROUND: : Premature ovarian failure (POF) is a complex and heterogeneous disorder that is influenced by multiple genetic components. Numerous candidate gene studies designed to identify POF susceptibility loci have been published, but most positive findings have not been confirmed in follow up studies. We sought to determine if sequence variants previously associated with age at natural menopause (AANM) or early menopause (EM) contribute as well to genetic susceptibility to POF. METHOD: S: Our study was performed on 371 unrelated idiopathic POF patients and 800 female controls, all Chinese Han. Thirty six SNPs from previous genome-wide association studies (GWAS) responsible for AANM or EM and 3 additional SNPs in ESR1, and 2 additional SNPs in PTHB1 were tested using the Sequenom MassARRAY iPLEX platform for genotyping. RESULTS: : Three SNPs rs2278493 in HK3, rs2234693 in ESR1 and rs12611091 in BRSK1 showed nominally significant association with POF. Thus, a plausible relationship could exist between ESR1, BRSK1, HK3 and POF. CONCLUSIONS: : This largest association study undertaken to determine correlation between POF and AANM / EM revealed three significant SNPs (rs2278493, rs2234693, and rs12611091). All are associated with not only AAWM and EM but also POF. Insights into shared genetic susceptibility between POF and AANM/EM will provide novel entry points for unraveling genetic mechanism involved in ovarian reserve and oocyte aging processes.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Generation of ERa-floxed and knockout mice using the Cre/LoxP system. Antonson P et al. Estrogen receptor alpha (ERa) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a floxed ERa mouse line that can be used to knock out ERa in selected tissues by using the Cre/LoxP system. In this study, we established a new ERa knockout mouse line by crossing the floxed ERa mice with Cre deleter mice. Here we show that genetic disruption of the ERa gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ERa is necessary for reproductive tract development and has important functions as a regulator of metabolism in females.