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Menopause Matters

Vaginal Estrogen Therapy: The Question of Systemic Absorption

JoAnn V. Pinkerton, MD

Low-dose vaginal estrogen products have proven effectiveness for treating vaginal atrophy in postmenopausal women, but concern lingers about possible systemic absorption leading to endometrial hyperplasia.

In postmenopausal women, symptoms of vaginal atrophy occur when the lower estrogen levels associated with menopause lead to thinning of the vaginal epithelium, diminished vaginal secretions, and an increase in vaginal pH. Clinically, this can be recognized by pallor and petechiae of the vagina, cervix, and urethra; decreased moisture; and/or an alkaline pH (> 6.5). Symptoms may consist of vulvovaginal dryness, itching, dyspareunia, urinary frequency/ urgency, and vaginal infections. If left untreated, vaginal atrophy can progress to atrophic vaginitis.

Nonprescription vaginal moisturizers and lubricants, which can improve vaginal secretions and decrease symptoms of itching and dryness, are acceptable first-line treatments. However, if symptoms persist, prescription estrogen therapy (ET) may be indicated. When ET is considered solely for treating vaginal atrophy, products formulated for vaginal administration are generally recommended. A number of estrogen products have been approved by the US Food and Drug Administration (FDA) for this indication (Table).

Table not available online

Table. Vaginal Postmenopausal Estrogen Therapy

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THERAPEUTIC OPTIONS

Vaginal Cream

Low-dose, estrogen-containing vaginal creams can be used to control some menopause-related atrophic effects. Research has documented that in postmenopausal women, such creams are effective for treating various conditions associated with atrophic vaginitis.1

Disadvantages of creams include irregular application intervals; bolus systemic absorption; and stickiness and messiness from the emollient, which can lead to compliance issues.

The FDA-approved doses of vaginal estrogen creams have been found to increase plasma estrogen levels in a dose-dependent fashion.2,3 At the highest dose evaluated (1.25 g/d conjugated equine estrogens [CEE]), systemic estradiol levels rose to 60 pg/mL—ie, comparable to oral CEE. The lowest doses (0.3 g/d) produced only minimal increases in plasma estrone and estradiol levels.

Vaginal Ring

Estrogen can also be delivered locally via vaginal rings. The vaginal ring containing estradiol acetate (Table) delivers systemic levels of estrogen and, thus, is not included in this discussion.

Data indicate minimal systemic absorption from the 17β-estradiol vaginal ring.4,5 In these studies, only 4% of women using this ring had endometrial thickness > 5 mm after 36 weeks, as measured ultrasonographically, compared with 10% using vaginal cream. In all, 3% experienced vaginal withdrawal bleeding from the ring versus 21% using cream. However, the vaginal ring was associated with an increase in bone density, suggesting some degree of systemic absorption.

Vaginal Tablet

The vaginal tablet containing 17β-estradiol, provides a localized effect without appreciable systemic absorption. In a study comparing systemic absorption in postmenopausal women with atrophic vaginitis, after 12 weeks of treatment, 74% of women receiving 25 mcg and 96% of those receiving 10 mcg demonstrated low systemic absorption.6 The absorption patterns remained consistent over time, and there was no evidence of accumulation of circulating estradiol.

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DISCUSSION

The amount of systemic absorption from estrogen-containing vaginal creams, rings, and tablets depends on the type of hormone used and the dosage. Generally, vaginal administration results in lower levels of circulating hormones than an equivalent oral dose. It is reassuring that low doses of estradiol given vaginally achieve local vaginal effects without detectable systemic absorption. However, radioimmunoassays for estradiol may have not been sufficiently sensitive to detect minor increments in plasma estradiol with vaginal rings or creams.7 For example, one study using an ultrasensitive estradiol bioassay detected small increases in plasma estrogen values after administration of 10-mcg vaginal cream—but levels remained within the postmenopausal range of 3 to 10 pg/mL.7 By contrast, Rioux et al3 found no detectable increments in estradiol levels with the 25-mcg vaginal estradiol tablet.

In general, low-dose vaginal estrogen is not accompanied by a progestogen to prevent estrogen-induced endometrial hyperplasia because very little estrogen is systemically absorbed. With vaginal estrogen tablets, placement may be important for uterine safety. A first-pass uterine effect has been observed when estradiol tablets were placed in the upper 33% of the vagina, but not in the lower 33%.8 Thus, to optimize the efficacy of vaginal tablets while minimizing the risk of endometrial hyperplasia, placement is recommended in the lower 33% of the vagina.

A small number of endometrial hyperplasia cases have been reported with both vaginal cream and the vaginal estradiol ring.9 Although the risk of endometrial cancer is higher in the setting of unopposed vaginal estrogen, the magnitude of the risk remains low. Preventive options include periodic progestin-challenge therapy or endometrial observation with ultrasonography or endometrial biopsy.

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CONCLUSION

Although systemic absorption of estrogen can occur with locally applied vaginal formulations, data are insufficient to recommend annual endometrial surveillance in asymptomatic women using local vaginal estrogens.9,10

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JoAnn V. Pinkerton, MD, is professor, Department of Obstetrics and Gynecology, and medical director, The Womanês Place, Midlife Health Center, University of Virginia Health Sciences Center, Charlottesville, Va; and member, board of trustees, The North American Menopause Society. Disclosures available upon request.

References

1. Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1998;92(4 pt 2): 722-727.
2. Handa VL, Bachus KE, Johnston WW, Robboy SJ, Hammond CB. Vaginal administration of low-dose conjugated estrogens: systemic absorption and effects on the endometrium. Obstet Gynecol. 1994;84(2):215-218.
3. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS. 17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause. 2000;7(3):156-161.
4. Eriksen BC. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180(5):1072-1079.
5. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol. 1996; 174(1 pt 1):85-92.
6. Notelovitz M, Funk S, Nanavati N, Mazzeo M. Estradiol absorption from vaginal tablets in postmenopausal women. Obstet Gynecol. 2002;99(4):556-562.
7. Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy with low-dose estradiol: preliminary results. Menopause. 2002;9(3):179-187.
8. Cicinelli E, De Ziegler D, Morgese S, Bulletti C, Luisi D, Schonauer LM. –First uterine pass effect” is observed when estradiol is placed in the upper but not lower third of the vagina. Fertil Steril. 2004;81(5):1414-1416.
9. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2003;(4): CD001500.
10. Johnston SL, Farrell SA, Bouchard C, et al. The detection and management of vaginal atrophy. J Obstet Gynaecol Can. 2004;26(5):503-515.

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