According to L’Hermite et al (2008), HRT in young postmenopausal women is a safe and effective tool to counteract menopause symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment.

The decision whether to take HRT, the dose of HRT used and the duration of its use should be made on an individualised basis after discussing the benefits and risks with each patient. The different types of HRT may offer comparable efficacies on symptoms control. However, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages.

WHAT THE GUIDELINES SAY

According to the NICE guideline’s (2015), assessment of the long-term benefits and risks of hormone replacement therapy:

• The risk of venous thromboembolism (VTE) associated with HRT is greater for oral than transdermal preparations
• The risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline population risk for VTE
• Consider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30kg/m².

In a Position Statement on menopause by the American Association of Clinical Endocrinologists and American College of Endocrinology, Cobin et al (2017) recommend:

• The use of menopausal hormone therapy in symptomatic postmenopausal women should be based on consideration of all risk factors for cardiovascular disease, age, and time from menopause.
• The use of transdermal as compared with oral estrogen preparations may be considered less likely to produce thrombotic risk and perhaps the risk of stroke and coronary artery disease.
• When the use of progesterone is necessary, micronised progesterone is considered the safer alternative.

The 2016 International Menopause Society’s Recommendations on women’s midlife health and menopause hormone therapy, states the risk of ischaemic stroke with MHT may be related solely to oral therapy, with lower doses having a smaller risk and no significant risk occurring with transdermal therapy, suggesting a primary thrombotic mechanism. Epidemiological studies have not found any increased risk of VTE with use of transdermal estrogen. Meta-analyses of these epidemiological studies have shown that transdermal estrogen did not increase the risk of VTE. Oral estrogen therapy is contraindicated in women with personal history of VTE.

“Transdermal estrogen therapy should be the first choice in obese women suffering from climacteric symptoms,” the authors stated.

THE BENEFITS OF MICRONISED PROGESTERONE

Studies suggest that micronised progesterone or dydrogesterone could be associated with a lower risk than synthetic progestogen. A large European observational study suggested that micronised progesterone or dydrogesterone used in association with oral or percutaneous estradiol may be associated with a better risk profile for breast cancer than synthetic progestogens.

To the same extent, a growing literature suggests that the progestins used in association with estrogens may not be equivalent. Micronised progesterone displays a favourable action on the vessels and on the brain, while this might not be true for some synthetic progestins. Compelling evidence also exists that differences might also be present for the risk of developing breast cancer, with trials indicating that the association of progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins.

“MHT continuously combining oral micronised progesterone with transdermal estradiol can presently be considered as the optimal MHT. It is not only safer than custom-compounded bioidentical hormones but also than oral conventional MHT and has the best breast profile; registered products for such optimal MHT are available around the world and must be preferred,” Simon (2014) stated.

This was echoed by Newson et al (2018) who stated: “There is robust evidence demonstrating that transdermal oestrogen in association with natural MP could represent the optimal HRT regimen, particularly in women at risk of cardiovascular events. This combination should ideally be initiated by healthcare professionals at a primary care level. The costs of these products are comparable with other types and formulations of HRT.”

THE BENEFITS OF TRANSDERMAL ESTROGEN

L’Hermite et al (2008), described how non-orally administered estrogens, minimise the hepatic induction of clotting factors and other proteins associated with the first-pass effect. There is compelling data that avoiding the first-pass liver metabolism by transdermal oestrogen therapy offers safety advantages over oral HRT, associated with potential advantages for the cardiovascular system. In particular, the risk of developing DVT or pulmonary thromboembolism (PE) is negligible in comparison to that associated with oral estrogens. There are also potential advantages for blood pressure control with non-oral estrogens.

Simon et al (2016) examined VTE and cardiovascular disease complications in menopausal women using transdermal vs oral estrogen therapy. This large matched-cohort study based on real-world data showed that women receiving transdermal estrogen therapy have significantly lower incidences of CVD events compared with those receiving oral estrogen therapy, and that they also incur lower healthcare costs.

According to L’Hermite (2017), the transdermal route of estrogen administration avoids excess venous thromboembolic and ischaemic stroke events. There is some indication that CEE are more thrombogenic and most likely induce some hypertensive responses. Estradiol might also be superior to CEE in terms of global cardiovascular health.

In fact, Simon (2014) hypothesised, what if the Women’s Health Initiative had been performed using transdermal estradiol plus micronised progesterone in women who need uterine protection? The findings probably would have been quite different from those initially reported in 2002 and 2004. The data suggest that women treated with transdermal estradiol (instead of conjugated equine estrogens [CEE]) and with oral micronised progesterone (instead of medroxyprogesterone acetate) would probably have fared better with regard to CVD risk, stroke risk, VTE risk, and BrCA risk. This conclusion is based on a review of the recent literature, with a specific focus on studies dealing with VTE risk.

Pinkerton’s (2020) key messages are that observational studies suggest that the risk of thromboembolism and stroke is lower with transdermal therapy than with oral hormone therapy. Note that compounded bioidentical hormone therapies that have not been approved by the US Food and Drug Administration are not recommended owing to safety concerns.

Closer to home, Davey (2014) found that transdermal estrogen has some clear advantages over oral estrogen, particularly in higher-risk patients such as the older woman who wishes to continue with HT, patients with mild hypertension, diabetes or metabolic syndrome, smokers, and in obese patients. “Given the many advantages of transdermal administration we should offer this form of HT as a first choice to all patients being considered for HT. In so doing we may lower the risk of adverse events and further increase the benefit vs risk profile with the use of HT in our management of menopausal patients,” he stated.

According to Martin et al, 2020, oral estrogens should be avoided in women with hypertriglyceridemia, active gallbladder disease, or known thrombophilias such as factor V Leiden (with or without a personal history of VTE).

“Transdermal estrogen is also preferred for women with migraine headaches with auras. First choice of progestin is oral natural micronised progesterone (200 mg/day for 12 days/month [ie, a cyclic regimen that is designed to mimic the normal luteal phase of premenopausal women] or 100 mg daily [continuous regimen]). We advise taking progesterone at bedtime as some of its metabolites are associated with somnolence. There are reasons to believe that natural progesterone is safer for the cardiovascular system (no adverse lipid effects) and possibly the breast,” the authors concluded.

REFERENCES:

• Hamoda H, Panay N, Arya R, Savvas M. The British Menopause Society & Women’s Health Concern 2016 recommendations on hormone replacement therapy in menopausal women. Post Reproductive Health. 2016;22(4):165-183. doi:10.1177/2053369116680501.
• L'Hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. Doi: 10.1016/j.maturitas.2008.07.007. Epub 2008 Sep 5.
  PMID: 18775609.
• National Institute for Health and Care Excellence. Menopause: diagnosis and management. NG23. London: NICE, 2015.
• Cobin RH, Goodman NF. AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Menopause-2017 Update. Endocr Pract 2017;23:869-880. Doi: 10.4158/EP171828.
• Baber RJ, Panay N & Fenton A. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy, Climacteric, 2016:19:2, 109-150, Doi: 10.3109/13697137.2015.1129166.
• Simon JA. What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause 2014;21:769-83. doi: 10.1097/GME.0000000000000169. PMID: 24398406.
• Newson LR, Lass A. Effectiveness of transdermal oestradiol and natural micronised progesterone for menopausal symptoms. British Journal of General Practice 2018; 68: 499-500. Doi: 10.3399/bjgp18X699353.
• Simon JA, Laliberté F, Duh MS, et al. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause 2016;23:600-10. Doi: 10.1097/GME.0000000000000590. PMID: 26953655.
• L’Hermite M. Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal. 2017 Climacteric DOI:10.1080/13697137.2017.1291607.
• Pinkerton JV. Hormone Therapy for Postmenopausal Women. N Engl J Med. 2020:30;382:446-455. doi: 10.1056/NEJMcp1714787. PMID: 31995690.
• Davey M. Transdermal estrogen - a first-choice option in hormone therapy. Menopause Focus 2014:3;12-14.
• Martin K, Robert B. Treatment of menopausal symptoms with hormone therapy. UpToDate, 2020.