Estrogen for vulvovaginal symptoms: how low can you go?

I n the most recent position statement of The North American Menopause Society (2008), we read that BI When HT is considered solely for the indication of vaginal atrophy, local vaginal ET is generally recommended. [ In view of recently accumulating data, including the data presented in this issue of the journal by Bachmann et al, this sentence might be rephrased in the next position statement. Vaginal atrophy, the loss of estrogen-dependent cellular maturation in the vagina, is manifested as a thin, friable vaginal epithelium, with symptoms of dryness, soreness, irritation, and dyspareunia. The vaginal pH becomes less acidic, altering the normal vaginal flora, with the vaginal and bladder epithelium becoming more susceptible to infection and inflammation. Estrogen therapy can counteract many of these changes and reduce associated complications. When vulvovaginal atrophic symptoms are the only bothering symptoms, it is (still) generally thought that vaginal administration of estrogen is the preferred method. A review including 19 randomized controlled trials with 4,162 women concluded that the available topical estrogen preparations, including creams, pessaries, tablets, and rings, are equally effective for treating vaginal atrophy and associated symptoms. It was suggested that local effects of vaginal delivery may vary, based on the location of absorption, because Doppler flow studies showed an increased flow in the uterine arteries when an estradiol (E2) tablet was applied near the cervix and posterior fornix, whereas little change was noted when it was applied to the distal vagina. However, women did not feel any difference in symptom relief based on the site of vaginal application. Lowering the dose of hormone therapy (HT) to reduce the incidence of side effects such as irregular bleeding, nausea, and breast pain, while still retaining the positive therapeutic effects, has become a key aim of treatment development. Data also suggest that lower-dose formulations minimize risks such as venous thromboembolism and stroke and perhaps cancer. Regulatory authorities, menopause societies, and many clinicians are increasingly recommending the use of the lowest effective dose of HT. The new data on dosedependent side effects and risks highlighted the need for further research into ultraYlow-dose estrogen therapy. A low-dose estrogen vaginal tablet containing 25 Kg of 17A-E2 was first introduced in 1988 as a hydrophilic cellulose-based matrix and has been shown to provide continuous release of E2 in an atrophic vaginal vault, with transient absorption being significantly reduced after maturation of the epithelium. It was initially believed that the 25Kg E2 dose would be necessary for the effective treatment of vaginal atrophy. However, it was recently shown that a lower-dose tablet may also be effective for the relief of vaginal atrophy symptoms. Simon et al evaluated the efficacy and safety of an ultraYlow-dose estrogen vaginal tablet in a placebo-controlled, 52-week, double-blind clinical trial. The researchers reported that an ultraYlow-dose 10-Kg E2 vaginal tablet, compared with placebo, demonstrated significant improvement in vaginal cytology and pH and most bothersome urogenital symptoms score. It is commonly believed that estrogen administered intravaginally is not absorbed systemically. Apparently, this is not the case. The absorption is determined by the formulation, the dose, and method of administration. In fact, it has been known for many years that estrogen in creams and vaginal tablets is absorbed very rapidly from an atrophic vagina with thin, friable vaginal epithelium and can cause significant elevation of serum E2 (and, to a lesser degree, estrone) levels. 9 More recently, using sensitive mass spectrometry assays of estrogens, it was shown that the Vagifem pill (25 Kg 17AE2) and Premarin cream, after 1 week of daily treatment, cause an approximately fivefold increase in serum E2 in postmenopausal women, thus indicating that the effects are unlikely to be limited to the vagina and that systemic actions are expected after application of these intravaginal estrogen preparations. However, it should be noted that as the vaginal mucosa cornifies, absorption decreases. This decline takes approximately 3 to 4 months, after which lesser but still significant absorption takes place. It is important to note that in a meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women, oral estriol had no effect on serum levels of E2 or estrone, and vaginal estriol had the least systemic absorption of estrogen as compared with other E2 and conjugated estrogens preparations. 11 The health values of tiny amounts of E2 for late postmenopausal women have been repeatedly demonstrated. The ultraYlow-dose transdermal estradiol assessment trial recently showed that systemic administration of approximately one quarter the usual daily dose of estrogen protects against bone loss despite producing only modest increases in serum E2 levels. Two-year treatment of women who were 5 years postmenopausal, with 0.014 mg/day transdermal E2, raised mean serum E2 levels from 4.5 to only 8.5 pg/mL. Nevertheless, the treatment resulted in a 2.0% mean increase in lumbar spine bone mineral density (BMD) and 1.2% mean increase in total hip BMD relative to placebo, along with significant decreases in the levels of several serum bone