Estrogen receptor‐ and aromatase‐deficient mice provide insight into the roles of estrogen within the ovary and uterus*

Rosenfeld, Cheryl S.; Roberts, R. M.; Lubahn, Dennis B.

doi:10.1002/mrd.1039

Cited by 34 publications

(17 citation statements)

References 86 publications

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“…Knockout of either ESR1 or ESR2 altered but did not completely prevent follicle growth. However, double ab ERKO mice showed dramatically impaired follicular growth with some ovarian Sertoli-like seminiferous tubules indicating a partial reversal of the female phenotype in the ovaries [3,12,13]. In AromKO mice, follicular development was initially arrested shortly before ovulation, but in 1-year-old AromKO mice, secondary and antral follicles were absent [13,14].…”

Section: Introductionmentioning

confidence: 99%

Distinct Regulation by Steroids of Messenger RNAs for FSHR and CYP19A1 in Bovine Granulosa Cells

Luo

Wiltbank

2006

Biology of Reproduction

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Steroidal regulation of gene expression in follicular cells is not completely defined. Granulosa cells from 5 mm bovine follicles were cultured and treated and steady-state mRNA levels determined for FSHR (follicle-stimulating hormone receptor) and CYP19A1 (aromatase). Cells were treated for 5 days with (0.1-300 ng/ml) 17beta-estradiol (E2), testosterone (T), or 5alpha-dihydrotestosterone (DHT). FSHR mRNA was increased by T and DHT but not E2. In contrast, CYP19A1 mRNA was induced by all doses of E2 but only high doses of T and DHT. Similarly, varying treatment duration (1-5 days) showed that FSHR was increased by T and DHT and CYP19A1 mRNA increased by E2 and T at all times. Synergism between steroid hormones and FSH or forskolin was also evaluated. FSH or E2 did not alter FSHR mRNA and did not enhance DHT stimulation of FSHR mRNA. In contrast, DHT alone had no effect on CYP19A1 mRNA but synergized with FSH plus E2 to increase CYP19A1 mRNA, probably due to induction of FSHR by DHT. Effects of E2 and T on CYP19A1 were blocked by ICI 182,780, indicating mediation by estrogen receptors. However, the specific androgen receptor antagonist bicalutamide did not block E2 or T effects on CYP19A1 but did block T and DHT stimulation of FSHR. Thus, FSHR is specifically regulated through androgen receptor, whereas CYP19A1 is regulated by multiple pathways, including estrogen receptors and cAMP/protein kinase A induced by FSHR activation in granulosa cells. These inter- and intracellular regulatory mechanisms may be critical for normal follicle growth and dominant follicle selection.

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Section: Introductionmentioning

confidence: 99%

Distinct Regulation by Steroids of Messenger RNAs for FSHR and CYP19A1 in Bovine Granulosa Cells

Luo

Wiltbank

2006

Biology of Reproduction

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“…Estrogen signal receptors including estrogen receptor α (ER-α) play an important role in mediating the specific effects of the estrogen on development, proliferation and differentiation of reproductive tissues [10] . In addition, mice deficient in ER-α are infertile and exhibit atrophy of the oviduct and uterus [11] . Thus, the ER-α gene may be a candidate gene for the onset of menstruation.…”

Section: Introductionmentioning

confidence: 99%

Interaction effects between estrogen receptor alpha and vitamin D receptor genes on age at menarche in Chinese women

Long

et al. 2005

Acta Pharmacologica Sinica

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Aim: To evaluate whether estrogen receptor α(ER‐α) and vitamin D receptor (VDR) genes are associated with the age at menarche in Chinese women. Methods: A total of 390 pre‐menopausal Chinese women were genotyped at the ER‐αPvuII, XbaI, and VDR ApaI loci using polymerase chain reaction (PCR)‐restriction fragment length polymorphism (RFLP). Results: Neither the ER‐αgene nor the VDR gene individually had significant effects on the age at menarche in our subjects (P > 0.10). However, evidence of interaction effects between the two genes were observed: with the aa genotype at the VDR ApaI locus, subjects with haplotype PX at the ER‐αgene had, on average, 6 months later onset of menarche than the non‐carriers (P=0.01). Conclusion: We found that neither the ER‐αgene or the VDR gene had a significant association with the age at menarche individually. However, potential interaction effects between the two genes were observed in Chinese women.

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“…Reports of osteopenia and osteoporosis in animals and humans with gene defects in the estrogen receptor (3)(4)(5) and both in females and males with aromatase deficiency (6 -9) have called attention to the importance of estrogen for skeletal maturation (10). The precise role of estrogen in human male physiology remains largely unknown, especially which effects on bone mineralization and metabolism in the male are mediated by estrogens derived from the aromatization of androgens.…”

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confidence: 99%

Impact of Estrogen Replacement Therapy in a Male with Congenital Aromatase Deficiency Caused by a Novel Mutation in the CYP19 Gene

Herrmann¹,

Saller²,

Janßen³

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

214

186

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Recent reports of the impact of estrogen receptor ␣ and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position ؊3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 g transdermal estradiol twice weekly for 3 months, followed by 25 g twice weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months; normal range, 10 -50) and estrone levels (17 and 34 ng/ml; normal range, 30 -85) had normalized. Bone maturation progressed and the initially unfused carpal and phalangeal epiphyses began to close within 3 months and were almost completely closed after 6 months. I N A WIDE VARIETY of tissues, including testis, ovary, placenta, and adipose tissue, the aromatase cytochrome P450, as the product of the CYP19 gene, catalyzes the conversion of androgens to estrogens (1, 2). Reports of osteopenia and osteoporosis in animals and humans with gene defects in the estrogen receptor (3-5) and both in females and males with aromatase deficiency (6 -9) have called attention to the importance of estrogen for skeletal maturation (10). The precise role of estrogen in human male physiology remains largely unknown, especially which effects on bone mineralization and metabolism in the male are mediated by estrogens derived from the aromatization of androgens. Many studies have demonstrated that gonadal failure in males is associated with a decrease in bone mass, but less is known about the role of genetic disorders associated with estrogen resistance or deficiency (11). First descriptions of young men affected by congenital estrogen deficiency have shed new light on the importance of estrogen for bone formation in man (7,8,11,12). These findings suggest that epiphyseal closure does not develop without the action of estrogen even in males and that androgen alone is not sufficient to promote normal skeletal mineralization. Recently two mutations in the CYP19 gene in males have demonstrated the role of estrogen on bone mineralization and their effect on glucose and lipid metabolism (6 -9, 13, 14).We now present the third case of a 27-yr-old man with open epiphysis caused by a new mutation in the CYP19 gene (aromatase deficiency), the effect of estrogen replacement on bone mineralization/maturation and glucose and lipid metabolism. Subjects and Methods Case reportThe propositus was the only child of consanguineous parents (second cousins, Fig. 1). His mother d...

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Estrogen receptor‐ and aromatase‐deficient mice provide insight into the roles of estrogen within the ovary and uterus*

Cited by 34 publications

References 86 publications

Distinct Regulation by Steroids of Messenger RNAs for FSHR and CYP19A1 in Bovine Granulosa Cells

Distinct Regulation by Steroids of Messenger RNAs for FSHR and CYP19A1 in Bovine Granulosa Cells

Interaction effects between estrogen receptor alpha and vitamin D receptor genes on age at menarche in Chinese women

Impact of Estrogen Replacement Therapy in a Male with Congenital Aromatase Deficiency Caused by a Novel Mutation in the CYP19 Gene

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