Cases in Menopause

Your menopausal patient’s breast biopsy reveals atypical hyperplasia

OBG Manag. 2013 May;25(5):36-41

References

1. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11(1):11-33.

2. Pinkerton JV, Stovall DW, Kightlinger RS. Advances in the treatment of menopausal symptoms. Womens Health (Lond Engl). 2009;5(4):361-384.

3. Ghaleiha A, Jahangard L, Sherafat Z, et al. Oxybutynin reduces sweating in depressed patients treated with sertraline: a double-blink, placebo-controlled, clinical study. Neuropsychiatr Dis Treat. 2012;8:407-412.

4. Hall E, Frey BN, Soares CN. Non-hormonal treatment strategies for vasomotor symptoms: a critical review. Drugs. 2011;71(3):287-304.

5. Pinkerton JV, Archer DF, Guico-Pabia CJ, Hwang E, Cheng RF. Maintenance of the efficacy of desvenlafaxine in menopausal vasomotor symptoms: a 1-year randomized controlled trial. Menopause. 2013;20(1):38-46.

6. Simon JA, Sanacora G, Bhaskar S, Lippman J. Safety and efficacy of low-dose mesylate salt of paroxetine (LDMP) for the treatment of vasomotor symptoms (VMS) associated with menopause: a 24-week randomized, placebo-controlled phase 3 study. Menopause. 2012;19(12):1371.-

7. Freeman EW, Guthrie KA, Caan B, et al. Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. JAMA. 2011;305(3):267-274.

8. Pinkerton JV, Kagan R, Portman D, Sathyanarayan RK, Sweeney M. Efficacy of gabapentin extended release in the treatment of menopausal hot flashes: results of the Breeze 3 study. Menopause. 2012;19(12):1377.-

9. MacBride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85(1):87-94.

10. Bedell S, Nachtigall M, Naftolin F. The pros and cons of plant estrogens for menopause [published online ahead of print December 25 2012]. J Steroid Biochem Mol Biol. 2012. doi: 10.1016/j.jsbmb.2012.12.004.

11. Moegele M, Buchholz S, Seitz S, Ortmann O. Vaginal estrogen therapy in postmenopausal breast cancer patients treated with aromatase inhibitors. Arch Gynecol Obstet. 2012;285(5):1397-402.

12. North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007;14(3 Pt 1):355-371.

13. Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy. Menopause. 2010;17(1):194-203.

14. Simon JA. Vulvovaginal atrophy: new and upcoming approaches. Menopause. 2009;16(1):5-7.

15. Kaunitz AM. Transdermal and vaginal estradiol for the treatment of menopausal symptoms: the nuts and bolts. Menopause. 2012;19(6):602-603.

16. Pruthi S, Simon JA, Early AP. Current overview of the management of urogenital atrophy in women with breast cancer. Breast J. 2011;17(4):403-408.

17. Menes TS, Kerlikowske K, Jaffer S, Seger D, Miglioretti D. Rates of atypical ductal hyperplasia declined with less use of postmenopausal hormone treatment: findings from the Breast Cancer Surveillance Consortium. Cancer Epidemiol Biomarkers Prev. 2009;18(11):2822-2828.

18. Santen RJ, Mansel R. Benign breast disorders. N Engl J Med. 2005;353(3):275-285.

19. Pinkerton JV, Shapiro M. The North American Menopause Society. Overview of available treatment options for VMS and VVA. Medscape Education Web site. http://www.medscape.org/viewarticle/763413. Published May 24 2012. Accessed February 23, 2013.

Many small trials have assessed other medications and complementary and alternative therapies regarding management of menopausal symptoms. Most, however, are limited by small numbers of enrolled participants and shorter study duration (≤12 weeks). In addition, enrolled participants have variable numbers of hot flashes, often less than 14 per week.^2,4

TABLE 1

Nonhormonal treatment of vasomotor symptoms

Treatment	Study Design*	Findings
Complementary/alternative medicines (black cohosh, St. John’s Wort, red clover, acupuncture, exercise)	Duration: 4–52 wk; OL and RPL trials; entry criteria for most trials: >14 hot flashes/wk	Mixed results, mostly with no sustained improvement
SSRIs** (paroxetine, fluoxetine, sertraline, citalopram, escitalopram)	Duration: 4–36 wk; RPL trials with all agents; N = 20–90 in active arms; entry criteria for most trials: >14 hot flashes/wk	Reduction in vasomotor symptoms (frequency, composite scores): 28%–55%
SNRIs** (venlafaxine, desvenlafaxine)	Duration, 12–52 wk; RPL trials with all agents; N = 20–65 in VEN; N = 120–200 in DVS; Entry criteria >14 hot flashes/wk for VEN; >50/wk for DVS	Reduction in VMS (frequency, composite scores): 35%–58% for VEN, 55%–68% for DVS
Gabapentin**	Duration: 4–12 wk; RPL trials; N = 20–100; entry criteria for most trials: >14–50 hot flashes/wk	Reduction in vasomotor symptoms (frequency, composite scores): 50%–70%
All studies of menopausal, nondepressed women. *Treatment is off label. Hall E, et al. Drugs. 2011;71:287-304. Reprinted with permission. Pinkerton JV, Shapiro M. The North American Menopause Society. Overview of available treatment options for VMS and VVA. Medscape Education Web site. http://www.medscape.org/viewarticle/763413. Published May 24, 2012. Accessed February 23, 2013.¹⁹

Can your patient restart HT? If so, should HT be offered vaginally or systemically?

Non-HT may be enough for vaginal dryness. Benefit has been shown with the use of vaginal moisturizers twice weekly and lubricants as needed for sexual activity.⁹ Therefore, the local application of daily lubricants, such as olive oil, along with the use of moisturizers with regular sexual intercourse may be enough to maintain vaginal health and function.

In randomized trials, phytoestrogens lack benefit data for vaginal atrophy. Small pilot studies of the effect of oral/ vaginal phytoestrogens on vaginal atrophy do not show any benefit on vaginal pH or vaginal maturation index and mixed improvement in vaginal dryness. In addition, no clear effect of these agents has been seen compared with placebo, except that there may be less progression of vaginal atrophy over time with phytoestrogens.¹⁰ It is possible that the benefits of phytoestrogens may take longer to take effect than the 12 weeks required to see an effect with HT.

Vaginal estrogen: limited safety data. No published clinical trials have assessed the impact of topical vaginal estrogen on risk of recurrence in breast cancer survivors, and concern exists because detectable estradiol levels have been reported in women who take aromatase inhibitors and have very atrophic vaginal mucosa.¹¹ NAMS recommends that the discussion about vaginal estrogen be individualized between the patient, her provider, and her oncologist.¹²

Vaginal estrogen creams and tablets (Vagifem 10 μg per tablet) are often started daily for 2 weeks for a “priming dose” then dosed twice per week. To minimize systemic absorption, creams may be used externally or with smaller doses vaginally. The higher the dose or more frequent the use, the greater the risk of significant systemic absorption, particularly when the vagina is atrophic.¹³

Another option is the vaginal estradiol ring, which delivers a low dose (7.5 μg per day) for 90 days.^14,15

James A. Simon, MD:
When you want the lowest dose of vaginal estradiol, consider Vagifem; the total dose of estrogen is lower over 90 days than with the vaginal ring.¹⁶

Progestogen therapy is generally not needed when low-dose estrogen is administered locally to treat vaginal atrophy.¹²

A new oral option. In February 2013, ospemifene, a selective estrogen receptor modulator (SERM), was approved for pain with intercourse and vaginal dryness.

Related article: “New treatment option for vulvar and vaginal atrophy,” by Andrew M. Kaunitz, MD (May 2013)

There is concern with systemic estrogen use

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered. However, data from the Breast Cancer Surveillance Consortium⁹ showed that as postmenopausal HT use decreased (from 35% to 11% between 1999 and 2005), rates of ADH decreased from a peak of 5.5 per 10,000 mammograms in 1999 to 2.4 per 10,000 mammograms in 2005. Similarly, rates of invasive cancer with ADH decreased from a peak of 4.3 per 10,000 mammograms in 2003 to 3.3 per 10,000 mammograms in 2005. This finding—that rates of ADH and invasive breast cancer were significantly linked to postmenopausal use of HT—raises concern about using HT in women with prior ADH. Of note, the cancers linked with ADH were of lower grade and stage and more estrogen receptor–positive than cancers not linked with ADH.¹⁷