Dr. Ron’s Research Review – August 2, 2017

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This week’s research review focuses on Cyclic (Sequential) and Continuous HRT

Cyclic or Sequential Hormone Replacement Therapy

Cyclic (sequential) hormone therapy consists of four weeks of estrogen with progesterone added for the last 10 to 13 days of each month. Cyclical HRT is often recommended for women taking combined HRT who have menopausal symptoms but still have their periods. There are two types of cyclical HRT: monthly and three-monthly. In the later, the combination is taken every three months. Monthly HRT is usually recommended for women having regular periods. Three-monthly HRT is usually recommended for women experiencing irregular periods.

Continuous Combined Hormone Replacement Therapy

In continuous HRT, estrogen and progesterone are taken every day without a break. Estrogen-only HRT is usually taken continuously. Continuous combined HRT is recommended in later postmenopausal women as it is a general understanding that early initiation of continuous combined HRT after menopause is associated with an increased risk of sporadic bleeding.

Cyclic Transdermal Estrogen and Vaginal Progesterone

Transdermal 17beta-estradiol replacement therapy (Dermestril 50 µg/day) combined with 100 mg of micronized natural progesterone (Prometrium) administered per vagina from the 14th day to the 25th day of each 28-day cycle leads to good cycle control and provides excellent patient satisfaction without serious side effects. (Di Carlo et al., 2010)

Cardiovascular Risk

A Danish study featured in European Heart Journal suggests that women taking hormone replacement therapy (HRT) should cycle their hormones to have a menstrual bleed. A combined cyclic regiment with monthly bleeding creates a lower cardiovascular risk for women than continuous-combined estrogen/progesterone therapy, which does not cause a menstrual bleed. (Lokkegaard et al., 2008)

Breast Cancer Risk

A study published in the International Journal of Cancer found increased breast cancer risk with estrogen-only and combined menopausal hormone therapy (MHT). Continuous combined preparations were associated with the highest risk. (Bakken et al., 2010)

Dr. Ron


Articles

 

Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European prospective investigation into cancer and nutrition (EPIC)
            (Bakken et al., 2010) Download
BACKGROUND: Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. METHODS: 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country-specific self-administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow-up (mean 8.6 years). Overall relative risks (RR) and 95 % confidence interval (CI) were derived from country-specific Cox proportional hazard models estimates. RESULTS: A total of 4,312 primary breast cancers were diagnosed during 1,153,747 person-years of follow-up. Compared to MHT never-users, breast cancer risk was higher among current users of estrogen-only (RR 1.42, 95 % CI 1.23-1.64) and higher still among current users of combined MHT (RR 1.77, 95 % CI 1.40-2.24; p=0.02 for combined vs. estrogen-only). Continuous combined regimens conferred a 43 % (95 % CI 19%-72 %) greater risk compared to sequential regimens. There was no significant difference between progesterone- and testosterone-derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration, nor for estradiol compounds vs. conjugated equine estrogens. CONCLUSIONS: Estrogen-only and combined MHT were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component. (c) 2010 UICC.

Transdermal estradiol and oral or vaginal natural progesterone: bleeding patterns.
            (Di Carlo et al., 2010) Download
OBJECTIVE:  To evaluate the effects on bleeding pattern of two different doses of natural progesterone (NP) administered per os or per vagina in association with transdermal estradiol in a continuous, sequential estrogen-progestin therapy. METHODS:  A prospective, randomized trial was conducted on 100 patients randomized into four groups. Each group received transdermal 17beta-estradiol treatment at the dose of 50 microg/day. Groups A and B received NP per os at the dose of 100 mg/day and 200 mg/day, respectively. Groups C and D received NP per vagina at the dose of 100 mg/day and 200 mg/day, respectively. RESULTS:  After 12 cycles of treatment, no significant differences were observed in endometrial thickness between groups, suggesting that all treatments are effective in balancing the effects of estradiol on endometrium. Regarding bleeding control, patients in Groups C and D showed a higher number of episodes of regular bleeding than patients in Groups A and B and fewer episodes of spotting. The better control of bleeding was associated with a higher treatment compliance in patients who received vaginal NP, with a larger percentage of women completing the study. CONCLUSION:  Transdermal estrogen replacement therapy combined with 100 mg of micronized NP administered per vagina from the 14th day to the 25th day of each 28-day cycle leads to good cycle control and provides excellent patient satisfaction without serious side-effects. This therapy could be a treatment of first choice in early postmenopausal patients.

Hormone therapy and risk of myocardial infarction: a national register study
            (Lokkegaard et al., 2008) Download
AIM: To assess the risk of myocardial infarction (MI) as a result of hormone therapy (HT), with focus on the influence of age, duration of HT, various regimens and routes, progestagen type, and oestrogen dose. METHODS AND RESULTS: All healthy Danish women (n = 698,098, aged 51-69) were followed during 1995-2001. On the basis of a central prescription registry, daily updated national capture on HT was determined. National Registers identified 4947 MI incidents. Poisson regression analyses estimated rate ratios (RRs). Overall, we found no increased risk [RR 1.03 (95% CI: 0.95-1.11)] of MI with the current HT compared with women who never used HT; age-stratified RR among women aged 51-54, 55-59, 60-64, and 65-69 years were 1.24 (1.02-1.51), 0.96 (0.82-1.12), 1.11 (0.97-1.27), and 0.92 (0.80-1.06), respectively. An increasing risk with longer duration was found for younger women, which was not observed with older age groups. In all age groups, the highest risk of MI was found with continuous HT regimen. No increased risk was found with unopposed oestrogen, cyclic combined therapy, or tibolone. Significantly lower risk was found with dermal route than oral unopposed oestrogen therapy (P = 0.04). No associations were found with progestagen type or oestrogen dose. CONCLUSION: In a National cohort study, we found that HT regimen and route of application could modify the influence of HT on the risk of MI.

References

Bakken, K., et al. (2010), ‘Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European prospective investigation into cancer and nutrition (EPIC)’, Int J Cancer, PubMed: 20232395
Di Carlo, C, et al. (2010), ‘Transdermal estradiol and oral or vaginal natural progesterone: bleeding patterns.’, Climacteric, 13 (5), 442-46. PubMed: 20575654
Lokkegaard, E., et al. (2008), ‘Hormone therapy and risk of myocardial infarction: a national register study’, Eur Heart J, 29 (21), 2660-68. PubMed: 18826989