Dr. Ron’s Research Review – July 15, 2020

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This week’s research review focuses on Premarin vs transdermal estradiol

Hormone Changes

A study found the principle estrogen measured in the serum of the CEE group was estrone, which is less biologically active than E2.
The CEE group had significantly higher levels of testosterone, as well as estrone and E2 than the placebo group.  The levels of FSH at month 48 were significantly lower for the CEE treatment group, but LH levels did not differ, compared to placebo. 
As seen in oral preparations, some of these components would undergo metabolism in the liver before reaching the peripheral circulation due to the gastric-hepatic circulation.
It is difficult to fully explicate the hormonal associations for the CEE group, given the inter-conversion between estrone and E2. (Kling et al., 2019)

Longitudinal Changes in Menopausal Symptoms  

A study compared the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. (Santoro et al., 2017)
A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 μg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months post-randomization
Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms.
Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004).
Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

WHO and Coronary Heart Disease

The Women's Health Initiative Observational Study directly compared different estrogen doses, routes of delivery, and hormone therapy (HT) formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality. This was a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women. The mean follow-up was 10.4 years. (Shufelt et al., 2014)
In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited.
Similarly, transdermal estradiol was associated with a moderate but non-significantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06).
In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality.
However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE.

Dr. Ron

 


Articles

 

Impact of menopausal hormone formulations on pituitary-ovarian regulatory feedback.
            (Kling et al., 2019) Download
Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of postmenopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45 ± 2.49 yr of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE; n = 109), transdermal 17β-estradiol (t-E2; n = 107), or placebo (n = 146). Androstenedione, testosterone, 17β-estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum before (baseline) and 48 mo after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE, t-E2, and placebo on these hormone levels at 48 mo, adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 mo within treatment groups. As expected, at 48 mo of treatment, hormone levels differed between women in the two active treatment groups compared with placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups compared with placebo. Associations among testosterone, 17β-estradiol, FSH, and LH differed between the o-CEE group compared with t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and interhormonal associations in recently menopausal women. These interactions provide the basis for future studies investigating the impact of hormonal modulation of aging, including cognitive decline in women.

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.
            (Santoro et al., 2017) Download
OBJECTIVE:  The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS:  A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 μg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS:  Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS:  Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women's Health Initiative Observational Study.
            (Shufelt et al., 2014) Download
OBJECTIVE: Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality. METHODS: The Women's Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009. RESULTS: The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women. CONCLUSIONS: In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses.

 


References

Kling, JM, et al. (2019), ‘Impact of menopausal hormone formulations on pituitary-ovarian regulatory feedback.’, Am J Physiol Regul Integr Comp Physiol, 317 (6), R912-20. PubMed: 31663769
Santoro, N, et al. (2017), ‘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.’, Menopause, 24 (3), 238-46. PubMed: 27779568
Shufelt, CL, et al. (2014), ‘Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women’s Health Initiative Observational Study.’, Menopause, 21 (3), 260-66. PubMed: 24045672