What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.
FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY
Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.
Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.
In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.
Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).
Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical trials, the longest of which was 12 months.
Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms (3.2% vs 0.9%).
VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.
Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.
What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.
UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST
Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.
As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.7 Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.
They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.