One of the primary objectives of the Women's Health Initiative was to see if postmenopausal hormone replacement therapy (HRT) improved long-term risk of coronary heart disease, among other chronic diseases.
However, the combined estrogen/progestin (Prempro) arm was halted in 2002, citing that the participants’ risk of cardiovascular disease outweighed any potential benefit of HRT in the prevention of colorectal cancer and bone fracture . The conjugated equine estrogen (CEE)-only arm was also halted in 2004 citing no improvement in heart disease risk but an increased incidence of stroke, and no benefit in terms of fractures, although there was a reduced breast cancer risk .
Yet the WHI investigators published a report this week  after a cumulative follow-up of 18 years finding that there was no overall increase in all-cause, cardiovascular, or cancer mortality as a result of either Prempro or CEE-only treatment during their participation in the trial.
Much debate has ensued since the WHI was halted regarding the type of HRT used, and whether or not the same effects could be extrapolated to all forms of hormone therapy, including bioidentical hormone replacement therapy (BHRT). However, one important criticism of WHI was that it enrolled women aged anywhere from 50 to 79 years old, and the bulk of the study participants were starting HRT well over a decade after entering menopause.
In an attempt to address this problem with the study design, two new trials were started which specifically looked at the long-term vascular effects of hormone therapy started early in the postmenopausal period. These trials were ELITE (Early versus Late Intervention Trial with Estradiol) and KEEPS (Kronos Early Estrogen Prevention Study). In Menopause Month, it would be interesting to see what the current news is on those two trials of menopause research.
Early versus Late Intervention Trial with Estradiol – ELITE
This study compared women who started HRT within 6 years of menopause with women who started more than 10 years after entering menopause. The HRT consisted of 1 mg/day oral 17β-estradiol plus 45 mg/day progesterone vaginal gel for 10 days each month for the women who had a uterus, or placebo plus placebo gel. Vascular health was determined by measuring carotid intima-media thickness (CIMT) every 6 months as an indicator of subclinical atherosclerosis, as well as CT scans to assess any actual coronary atherosclerosis.
Results after a median of 5 years since starting treatment were published in 2016 , and these showed that there was a clear difference in the outcome between the early and late menopausal groups. Women treated within 6 years of menopause had less progression of subclinical atherosclerosis, as indicated by a small increase in CIMT compared to the placebo group. In contrast, women who started HRT more than 10 years after menopause were not protected from atherosclerosis, as they showed no improvement in CIMT progression compared to the corresponding placebo group. Neither early nor late menopausal groups had any improvement in atherosclerosis evident on CT scans.
Kronos Early Estrogen Prevention Study (KEEPS)
When interpreting results of the above-mentioned and other studies, it is important to take into consideration the route of administration, the dose of hormone used, and the outcomes measured.
Like ELITE, KEEPS studied women using HRT in the early stages of menopause, but was designed to determine whether a very low, physiological dose of estrogen would be beneficial in preventing atherosclerosis. Women within 3 years of their final menstrual period were randomized to a weekly 50 µg/day estradiol transdermal patch or 0.45 mg/day oral CEE (conjugated equine estrogens), both combined with 200 mg oral micronized progesterone for 12 days/month, or placebo.
Unlike ELITE, the KEEPS results announced in 2012 were disappointing in that they showed no significant effect of either of the estrogen treatments on CIMT progression, suggesting that the lower estrogen dose was insufficient to produce a change at the arterial wall level. However, the active treatment groups receiving HRT did have substantial reductions in hot flashes and night sweats and some improvement in bone density compared to placebo.
Recently, a group of publications have appeared giving further data on additional quality of life benefits to the women in the KEEPs trial. Let's take a look at these recent publications.
Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS) 
This ancillary study assessed measures of sexual function including desire, arousal, lubrication, orgasm, sexual satisfaction, and dyspareunia (pain) scored using the Female Sexual Function Inventory (FSFI). FSFI scores were moderately, but with statistical significance, improved in women using the estradiol transdermal patch compared with placebo, while there was no significant difference in score between the women using low-dose oral CEE and those using placebo. The main contributors to the improved FSFI score in the transdermal estradiol group were increased lubrication and decreased pain on intercourse.
Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) 
Using the Pittsburgh Sleep Quality Index, KEEPS participants recorded various aspects of sleep quality on entry to the trial and at 6, 18, 36, and 48 months during treatment. Sleep quality index scores improved in both treatment groups (oral low-dose CEE and estradiol patch) compared to placebo, and scores correlated with severity of hot flashes and night sweats. While most of the individual aspects of sleep quality recorded were similar in both treatment groups, the score for sleep disturbances improved to a greater extent in the estradiol patch users than the CEE users.
Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study 
Menopausal symptoms (hot flashes, night sweats, insomnia, and irritability) were recorded in KEEPS participants at screening and at 6, 12, 24, 36, and 48 months after starting treatment. Substantial reductions in hot flashes and night sweats were reported by women using either low-dose oral CEE or a low-dose transdermal estradiol patch compared to placebo, and these reductions were seen at 6 months and sustained during all 4 years of follow-up. Reported insomnia was reduced intermittently in both treatment groups compared to placebo; CEE was more effective than placebo at 36 and 48 months, while the estradiol patch was more effective than placebo at 48 months. Irritability was not reported to improve with either estrogen treatment compared to placebo.
Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study 
This ancillary study looked at measures of mood and cognition, including the Modified Mini-Mental State examination, cognitive factors, verbal learning/memory, auditory attention/working memory, visual attention/executive function, mental flexibility, and the Profile of Mood States (POMS). Neither treatment group showed an improvement in any of the cognitive outcomes. Regarding mood, the low-dose oral CEE group showed improved depression and anxiety symptoms during the 4 years of follow-up compared to placebo, while the estradiol patch had similar mood scores to the placebo group.
When interpreting results of the above-mentioned and other studies, it is important to take into consideration the route of administration, the dose of hormone used, and the outcomes measured. The rule of thumb is that physiologic dosing of hormones, mimicking endogenous production, is recommended when trying to achieve normal, pre-menopausal levels. Balancing estrogen with progesterone is important, both when symptoms of estrogen dominance are present and to protect the uterus from endometrial proliferation. In order to ensure balance in the hormonal milieu, saliva testing is best for assessing the free, bioavailable fraction of hormone and urine is best for assessing total levels and metabolite status.
- Blog: Learning the Nuts & Bolts of BHRT
- Blog: Menopause – Is It All In Your Head?
- Web: Simple Testing for Menopause
 Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
 Taylor HS, et al. Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017 Aug 28. [Epub ahead of print]
 Cintron D, et al. Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Menopause. 2017 Aug 21. [Epub ahead of print]
 Santoro N, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. 2017;24(3):238-246.
 Gleason CE, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015;12(6):e1001833; discussion e1001833.