A study of 17β-estradiol-regulated genes in the vagina of postmenopausal women with vaginal atrophy

Cotreau, Monette M.; Chennathukuzhi, Vargheese M.; Harris, Heather A.; Han, Lixin; Dorner, Andrew J.; Apseloff, Glen; Varadarajan, Usha; Hatstat, Ellyn; Zakaria, Marjorie; Strahs, Andrew; Crabtree, Judy S.; Winneker, Richard C.; Jelinsky, Scott A.

doi:10.1016/j.maturitas.2007.09.009

Cited by 37 publications

(49 citation statements)

References 34 publications

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“…Our gene array findings agree with data obtained by Cotreau et al [28] on vaginal biopsies from 19 women with vulvovaginal atrophy (VVA) before and after treatment with 17β-estradiol. The similarity in results suggests that many of the genes being differentially regulated between dryness and healthy women may be as a result of differential estrogen levels between the groups.…”

Section: Discussionsupporting

confidence: 92%

Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness

et al. 2011

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After menopause, many women experience vaginal dryness and atrophy of tissue, often attributed to the loss of estrogen. An understudied aspect of vaginal health in women who experience dryness due to atrophy is the role of the resident microbes. It is known that the microbiota has an important role in healthy vaginal homeostasis, including maintaining the pH balance and excluding pathogens. The objectives of this study were twofold: first to identify the microbiome of post-menopausal women with and without vaginal dryness and symptoms of atrophy; and secondly to examine any differences in epithelial gene expression associated with atrophy. The vaginal microbiome of 32 post-menopausal women was profiled using Illumina sequencing of the V6 region of the 16S rRNA gene. Sixteen subjects were selected for follow-up sampling every two weeks for 10 weeks. In addition, 10 epithelial RNA samples (6 healthy and 4 experiencing vaginal dryness) were acquired for gene expression analysis by Affymetrix Human Gene array. The microbiota abundance profiles were relatively stable over 10 weeks compared to previously published data on premenopausal women. There was an inverse correlation between Lactobacillus ratio and dryness and an increased bacterial diversity in women experiencing moderate to severe vaginal dryness. In healthy participants, Lactobacillus iners and L. crispatus were generally the most abundant, countering the long-held view that lactobacilli are absent or depleted in menopause. Vaginal dryness and atrophy were associated with down-regulation of human genes involved in maintenance of epithelial structure and barrier function, while those associated with inflammation were up-regulated consistent with the adverse clinical presentation.

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Section: Discussionsupporting

confidence: 92%

Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness

et al. 2011

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“…RNA extraction, isolation, and labeling was performed as previously described (18). For rat samples, 10 Ag of cRNA were fragmented and hybridized to GeneChip Rat Genome 230 Figure 1.…”

Section: Methodsmentioning

confidence: 99%

Comparison of Human and Rat Uterine Leiomyomata: Identification of a Dysregulated Mammalian Target of Rapamycin Pathway

Crabtree¹,

Jelinsky²,

Harris³

et al. 2009

Cancer Research

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Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyomata. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyomata. An unbiased pathway analysis using a method of gene-set enrichment based on the sigPathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly up-regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomata, preclinical studies were conducted in Eker rats. These rats develop uterine leiomyomata as a consequence of loss of Tsc2 function and up-regulation of mTOR signaling. Inhibition of mTOR in female Eker rats with the rapamycin analogue WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity, and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly show the dependence of uterine leiomyomata with activated mTOR on this signaling pathway for growth. [Cancer Res 2009;69(15):6171-8]

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“…Changes in gene expression after estrogen treatment of VA include genes involved in several signaling pathways that promote tissue repair, remodeling, vascularization and defense against microbes in the vagina. 101 Holistic therapy Psychological therapy including CBT, sex therapy, psychoeducation, couple communication and more recently, mindfulness, has been the mainstay of therapy for women's sexual dysfunctions. However, well-designed, controlled studies on these nonpharmalogic treatment modalities are few-for review, see Brotto.…”

Section: Investigational Drugsmentioning

confidence: 99%

Women's sexual function and dysfunction: current uncertainties, future directions

Basson

2008

Int J Impot Res

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There is increasing evidence that women at the outset of sexual activity do not need to have sexual desire, as in 'drive', and that many do not distinguish desire from arousal. Multiple modes of investigation confirm poor correlation between women's subjective arousal and measured genital congestion. Suggested revisions to the DSM-IV definitions of sexual disorder have been published: there is now need to align interview assessments and screening questionnaires with contemporary understanding of women's sexual response. Whereas the psychological factors associated with women's sexual function and resilience to biological insults and external stressors are well documented, the role of biological factors is less clear. Variations in the rate of decline of adrenal and ovarian pro-hormones, activity of converting enzymes in peripheral cells, sensitivity of androgen and estrogen receptors and cerebral production of sex steroids may all be involved. Thus there is great complexity underlying the question of sex hormone supplementation, and in particular, little clarity as to which women have decreased brain and/or peripheral androgen activity. When psychosexual etiological factors appear to be minimal and investigational testosterone supplementation is considered, it would be appropriate to target women with disordered arousal and desire in keeping with the recently recommended revised definitions.

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A study of 17β-estradiol-regulated genes in the vagina of postmenopausal women with vaginal atrophy

Cited by 37 publications

References 34 publications

Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness

Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness

Comparison of Human and Rat Uterine Leiomyomata: Identification of a Dysregulated Mammalian Target of Rapamycin Pathway

Women's sexual function and dysfunction: current uncertainties, future directions

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