Systemic effects and endometrial safety of local estrogen therapy


Systemic effects and endometrial safety of local estrogen therapy

November 2010 · Vol. 22, No. 11

Steven R. Goldstein, MD
Professor, Department of Obstetrics and Gynecology, New York University School of Medicine, Director, Gynecologic Ultrasound, Co-Director, Bone Densitometry, New York University Medical Center, New York, NY


  • Vaginal administration of estrogen is effective and well tolerated for treatment of symptoms of vulvovaginal atrophy
  • Estradiol tablets, estrogen creams, and estrogen rings are the three local estrogen formulations available in the United States
  • Relief of symptoms is achieved with low dosages of estrogen and limited systemic exposure
  • Vaginal administration is not associated with clinically important increases in serum estrogen levels or changes in endometrial proliferation

Vaginal atrophy is a prevalent condition resulting from estrogen deficiency that can occur at any time in a woman’s life but is more common after menopause.1 The precise prevalence of vaginal atrophy is difficult to ascertain. A recent review of vaginal atrophy found reports ranging from 4% of women in early perimenopause to 47% of postmenopausal women. Fortunately, in most women, local or systemic estrogen preparations relieve vaginal atrophy symptoms.2

Interest in the potential for lower systemic hormonal exposure with use of local vaginal estrogen therapy has grown since the results of the Women’s Health Initiative (WHI) were made public almost 10 years ago.3 Vaginal administration of low-dose estrogen provides sufficient estrogen to relieve symptoms and reverse the atrophic changes associated with menopause, with the added benefit of limited systemic absorption.4 Therefore, local vaginal treatment is typically recommended for women seeking estrogen therapy solely for the treatment of vaginal atrophy.5

Estradiol tablets, estrogen creams, and estrogen rings are the three local estrogen formulations available in the United States. This review presents the clinical evidence about the safety of these formulations.

SYSTEMIC ABSORPTION OF VAGINAL ESTROGEN THERAPY.  Absorption of estradiol and other steroid hormones is rapid, particularly through the thin vaginal epithelium characteristic of postmenopausal women.6 All three available formulations—the 17β-estradiol-releasing ring, 17β-estradiol tablets, and conjugated equine estrogen (CEE) and estradiol creams—are water-soluble and easily absorbed through the vaginal epithelium.7 Absorption with the ring or tablets may be slower than with creams.8 The concentration gradient across the epithelium determines the absorption rate; therefore, dosage may affect the extent of systemic exposure. Moreover, the distribution of absorbed estrogen within the pelvic region may differ depending on the anatomic position of administration. Some evidence suggests that delivery of estrogens to the lower one third of the vagina may limit distribution to the uterus, thereby lowering the risk of hyperplasia, and may be preferable for the treatment of vaginal atrophy.8,9

An important diference between local vaginal and oral administration of estrogen is that vaginal administration circumvents metabolic and physiologic barriers to estrogen absorption.6 Consequently, substantially lower dosages of estrogen are required when applying estrogen directly to the vagina, compared with oral administration.10 Although circulating levels of estrogen do increase with local administration, serum estrogen levels typically remain relatively low.


ESTROGEN CREAM. Several small studies have examined elevations in plasma estrogen concentrations with administration of low-dose vaginal creams containing either CEEs or estradiol across a range of doses.11,12 After 24 weeks of treatment at the highest dose of CEE cream used (1.25 mg/d), 21 of 59 (47%) women had a serum estradiol level outside the postmenopausal range (>49 pg/mL), although the magnitude of the elevation was not reported.12 In an other study,11 of 20 women treated for 6 months, CEE cream (0.3 g/d) produced only a minimal increase in estradiol and estrone levels.

Circulating levels of estradiol were measured in seven postmenopausal women treated with estradiol 10 µg vaginal cream for relief of symptoms of vaginal atrophy.13 After 3 weeks of daily administration, followed by an additional 9 weeks of twice-weekly treatment, circulating estradiol levels remained within the postmenopausal range.

No change in circulating mean estradiol (E2) levels have been reported with estriol cream, a vaginal estrogen therapy not available in the United States14,15; according to a Cochrane Review, this is the only cream not associated with systemic absorption.16

ENDOMETRIAL EFFECTS.   The primary concern regarding use of any estrogen therapy in women who have an intact uterus is the risk of endometrial hyperplasia and carcinoma associated with unopposed estrogen.

The endometrial safety of the 10-µg estradiol vaginal tablet was most recently evaluated for the treatment of vaginal atrophy in 336 non hysterectomized postmenopausal women.24 As shown in FIGURE 2,24 baseline endometrial thick ness was 2.04 mm as determined by transvaginal ultrasonography (double layer) compared with 1.94 mm after 52 weeks of treatment. At study’s end, there was no evidence of increased endometrial proliferation or hyperplasia.

A preliminary study35 on the use of local estrogen therapy in breast cancer survivors has been conducted. In this study, both low-dose vaginal estradiol tablet and estriol cream relieved vaginal atrophy, whereas a nonhormonal moisturizer provided only transient relief. Safety was evaluated by measuring serum estradiol levels and changes in endome-trial thickness, both of which were found to be minimal and clinically insignificant, although an evaluation of a longer duration of treatment is warranted. Because of the impact of moderate or severe vaginal atrophy on quality of life, women who do not respond to nonhormonal therapies may consider discussing the risks and benefits of local estrogen therapy.

SUMMARY AND CLINICAL IMPLICATIONS. Vaginal estrogen therapy is safe and well tolerated in postmenopausal women with vaginal atrophy, although these conclusions are based on experience in small trials, largely of short duration.

  • As with all forms of estrogen therapy, the Food and Drug Administration and NAMS have recommended the use of the lowest possible effective dose of vaginal estrogen for treating vaginal atrophy.5,39
  • Local estrogen treatments are associated with minimal systemic absorption.
  • Endometrial hyperplasia with local vaginal therapy is rare. Use of progestin therapy is generally not needed in patients using low-dose local vaginal estrogen therapy.4
  • In the absence of more rigorous studies suggesting otherwise, vaginal estrogens are not indicated for women receiving adjuvant AI therapy for breast cancer, and the potential for recurrence should be discussed with patients with a history of any hormone-sensitive cancer.
  • Because efficacy and safety of the local estrogen formulations appear to be similar, the preparation preferred by the patient and the provider should be used. Therapy should be continued as long as the troublesome symptoms remain.