One of the primary objectives of the Women’s Health Initiative (WHI) 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 participants’ risk of cardiovascular disease outweighed any potential benefit [1]. 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 [2].
Yet the WHI investigators published a report 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 [3].
Much debate has ensued since the WHI was halted regarding the type of HRT used, and whether the same effects could be extrapolated to all forms of hormone therapy, including bioidentical hormone replacement therapy (BHRT). One important criticism of WHI was that it enrolled women aged anywhere from 50 to 79 years old, with the bulk of participants starting HRT well over a decade after entering menopause.
In an attempt to address this problem, two new trials were started which specifically looked at the long-term vascular effects of hormone therapy started early in the postmenopausal period: ELITE (Early versus Late Intervention Trial with Estradiol) and KEEPS (Kronos Early Estrogen Prevention Study).
ELITE: Early versus Late Intervention Trial with Estradiol
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 women who had a uterus, or placebo. 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 coronary atherosclerosis.
Results after a median of 5 years showed a clear difference in outcome between the early and late menopausal groups [4]. Women treated within 6 years of menopause had less progression of subclinical atherosclerosis compared to the placebo group. In contrast, women who started HRT more than 10 years after menopause showed no improvement in CIMT progression compared to placebo.
When interpreting results of these and other studies, it is important to take into consideration the route of administration, the dose of hormone used, and the outcomes measured.
KEEPS: Kronos Early Estrogen Prevention Study
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 randomised to a weekly 50 µg/day estradiol transdermal patch or 0.45 mg/day oral CEE, both combined with 200 mg oral micronised progesterone for 12 days/month, or placebo.
The KEEPS results announced in 2012 showed no significant effect of either estrogen treatment on CIMT progression, suggesting the lower estrogen dose was insufficient to produce a change at the arterial wall level. However, the active treatment groups did have substantial reductions in hot flushes and night sweats and some improvement in bone density compared to placebo.
Sexual Function
FSFI scores were moderately but significantly improved in women using the estradiol transdermal patch compared with placebo, while there was no significant difference between low-dose oral CEE and placebo. The main contributors to improved scores in the transdermal estradiol group were increased lubrication and decreased pain on intercourse [5].
Sleep Quality
Sleep quality index scores improved in both treatment groups compared to placebo, and scores correlated with severity of hot flushes and night sweats. The score for sleep disturbances improved to a greater extent in the estradiol patch users than the CEE users [6].
Menopausal Symptoms
Substantial reductions in hot flushes and night sweats were reported by women using either low-dose oral CEE or a low-dose transdermal estradiol patch compared to placebo, sustained during all 4 years of follow-up. Reported insomnia was reduced intermittently in both treatment groups compared to placebo [7].
Mood and Cognition
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 [8].
What This Means for Hormone Testing
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.
To establish a full hormonal baseline before starting HRT — or to monitor your levels during treatment — our Comprehensive Female Saliva Hormone Profile (LCMS) measures the free, bioavailable fraction of estradiol, progesterone, testosterone and DHEA using highly accurate LCMS analysis — the most clinically relevant measure for assessing and monitoring HRT.
For a deeper picture of how your body is processing and clearing hormones — including estrogen metabolites that influence cancer and cardiovascular risk — our Comprehensive Hormone Profile II assesses total hormone levels and metabolite status, giving you and your practitioner a complete view of your hormonal milieu.
For women experiencing weight gain, abdominal fat or metabolic changes alongside menopausal symptoms, our Female Weight Management Profile Test measures the key hormones linked to fat storage and metabolism — including cortisol, estradiol, testosterone, progesterone and DHEA — in a single at-home kit.
Hormone Lab UK is the official UK test provider of ZRT Laboratory.
References
- Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321–33.
- Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA. 2004;291(14):1701–12.
- Manson JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality. JAMA. 2017;318(10):927–938.
- Hodis HN, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016;374(13):1221–31.
- Taylor HS, et al. Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause. JAMA Intern Med. 2017.
- Cintron D, et al. Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains. Menopause. 2017.
- Santoro N, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral CEE or transdermal estradiol plus micronised progesterone versus placebo. 2017;24(3):238–246.
- Gleason CE, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: KEEPS-Cognitive and Affective Study. PLoS Med. 2015;12(6):e1001833.
Originally ZRT Laboratory. Reproduced with permission. Last reviewed: May 2026.