Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review.

OBJECTIVE: Menopause and its transition represent significant risk factors for the development of vulvovaginal atrophy-related sexual dysfunction. The objective of this study was to review the hormonal and nonhormonal therapies available for postmenopausal women with vulvovaginal atrophy-related sexual dysfunction, focusing on practical recommendations through a literature review of the most relevant publications in this field. METHODS: This study is a literature review. RESULTS: Available vaginal estrogen preparations are conjugated equine estrogens, estradiol vaginal cream, a sustained-release intravaginal estradiol ring, or a low-dose estradiol tablet. Vaginal estrogen preparations with the lowest systemic absorption rate may be preferred in women with history of breast cancer and severe vaginal atrophy. Vaginal lubricants and moisturizers applied on a regular basis have an efficacy comparable with that of local estrogen therapy and should be offered to women wishing to avoid the use of vaginal estrogens. CONCLUSIONS: Oral, transdermal, or vaginal estrogen preparations are the most effective treatment options for vulvovaginal atrophy-related sexual dysfunction. Selective estrogen receptor modulators such as lasofoxifene and ospemifene showed a positive impact on vaginal tissue in postmenopausal women. Vaginal dehydroepiandrostenedione, vaginal testosterone, and tissue selective estrogen complexes are also emerging as promising new therapies; however, further studies are warranted to confirm their efficacy and safety.

Molecular mechanism for repression of 17alpha-hydroxylase expression and androstenedione production in granulosa cells.

CONTEXT: According to the traditional two-cell two-gonadotropin model of follicular steroidogenesis, androgen production arises exclusively from theca cells. The granulosa cells, in turn, utilize androstenedione and testosterone, which are aromatized into estrone and estradiol, respectively. Differential expression of the activator protein-1 (AP-1) transcription factor, c-fos, has been postulated to result in distinct patterns of steroidogenesis in the theca and granulosa cell compartments. We hypothesize that c-fos functions to inhibit the production of 17alpha-hydroxylase 17,20 lyase (CYP17) in granulosa cells, thereby suppressing androgen synthesis. OBJECTIVE: Our objective was to define the role of c-fos in the regulation of CYP17 production in granulosa cells. DESIGN AND METHODS: Human luteinized granulosa (HGL5) cells were utilized for all experiments. The following techniques were used: mRNA extraction, steroid quantification, small interfering RNA silencing, microarray analysis, and immunohistochemistry. RESULTS: Immunohistochemistry studies demonstrated significant staining of c-fos in the granulosa cell layer, but absent staining for CYP17. Conversely, the theca cell layer did not stain for c-fos, but staining was evident for CYP17. Treatment of HGL5 cells with the MAPK kinase inhibitor PD98059 resulted in an 11-fold increase in CYP17 mRNA levels. In c-fos gene silenced cells, CYP17 mRNA levels increased 8-fold. Androstenedione production was increased 13-fold after treatment with PD98059. CONCLUSIONS: These results suggest that the AP-1 transcription factor, c-fos, may be one of the factors responsible for CYP17 repression and hence suppression of androstenedione production in granulosa cells. This may provide an explanation for the lack of CYP17 in granulosa cells.

The mechanism for protein kinase C inhibition of androgen production and 17alpha-hydroxylase expression in a theca cell tumor model.

INTRODUCTION: In polycystic ovary syndrome (PCOS), there is increased formation of androgens by thecal cells. Moreover, PCOS ovaries have been shown to have decreased levels of c-fos transcription factor. We hypothesize that c-fos expression inhibits 17alpha-hydroxylase 17,20 lyase (CYP17) activity in the human ovary, and its decreased expression seen in PCOS may lead to elevated CYP17 transcription, resulting in increased androgen production. OBJECTIVE: Our objective was to define the role of the activator protein-1 transcription factors, namely c-fos, in the regulation of CYP17 expression in theca cells. METHODS: Human ovarian thecal-like tumor cells were used for all experiments. The following techniques were used: steroid quantification, mRNA extraction, microarray analysis, transfection, small interfering RNA, and immunohistochemistry. RESULTS: Stimulation of human ovarian thecal-like tumor cells with the protein kinase A pathway activator forskolin resulted in stimulation of C19 androgen production. In contrast, treatment with the protein kinase C pathway activator tetradecanoylphorbol acetate (TPA) resulted in decreased androgen production with a shift toward C21 progesterone production. TPA also led to complete inhibition of CYP17. Microarray data showed a 37-fold increase in c-fos after treatment with TPA. Transfection with steroidogenic factor 1 resulted in an increase in CYP17 promoter activity, which was significantly inhibited in the presence of c-fos. c-fos gene silencing led to an increase in CYP17 mRNA levels. Immunohistochemical staining for c-fos in ovaries demonstrated strong staining in granulosa cells, but not theca. CONCLUSIONS: The activator protein-1 transcription factor c-fos plays a role in the inhibition of CYP17 expression. The decreased levels of c-fos expression in polycystic ovaries may be responsible for increased CYP17 levels in PCOS.

Effect of vitamin E supplementation with and without hormone therapy on circulatory inflammatory markers in postmenopausal women.

OBJECTIVE: To investigate the effect of vitamin E with and without estrogen replacement therapy or hormone therapy (HT) on inflammatory markers in postmenopausal women. DESIGN: Prospective, observational study, followed by a randomized, prospective, double-blind study. SETTING: Healthy volunteers in an academic medical referral center in Dallas, Texas. PATIENT(S): Seventy-five postmenopausal healthy women, ages 40 to 65 years, with follicle-stimulating hormone (FSH) levels greater > or =30 mIU/mL and a serum estradiol level < or =30 pg/mL. INTERVENTION(S): After enrollment, all women were studied at baseline and received vitamin E for 4 weeks. They were then randomized from week 4 to week 12 to receive vitamin E in conjunction with conjugated equine estrogen (CEE) (0.625 mg), CEE (0.625 mg) plus medroxyprogesterone acetate (MPA) (2.5 mg), or placebo. MAIN OUTCOME MEASURE(S): Change from baseline and between groups effects of vitamin E with and without estrogen or hormone therapy on seven circulatory inflammatory markers in postmenopausal women. RESULT(S): Vitamin E levels increased to a similar extent in all three groups compared with baseline at weeks 4 and 12. Vitamin E increased serum interleukin-6 levels. Combination CEE plus MPA significantly increased C-reactive protein levels. However, there were no consistent statistically significant effects on six other inflammatory markers. CONCLUSION(S): Vitamin E attenuated C-reactive protein increases in postmenopausal women treated with estrogen replacement therapy but not with HT. Because there was no other persistent effect on six additional inflammatory markers, it can be concluded that vitamin E and HT do not play a major role in promoting a change in cardiovascular inflammatory markers.