Effects of transdermal versus oral hormone replacement therapy in postmenopause: a systematic review

Abstract

Purpose To summarize available evidence comparing the transdermal and the oral administration routes of hormone replacement therapy (HRT) in postmenopausal women. Methods We performed a systematic review of the literature on multiple databases between January 1990 and December 2021. We included randomized controlled trials and observational studies comparing the transdermal and oral administration routes of estrogens for HRT in postmenopausal women regarding at least one of the outcomes of interest: cardiovascular risk, venous thromboembolism (VTE), lipid metabolism, carbohydrate metabolism, bone mineral density (BMD), and risk of pre-malignant and malignant endometrial lesions, or breast cancer. Results The systematic literature search identified a total of 1369 manuscripts, of which 51 were included. Most studies were observational and of good quality, whereas the majority of randomized controlled trials presented a high or medium risk of bias. Oral and transdermal administration routes are similar regarding BMD, glucose metabolism, and lipid profile improvements, as well as do not appear different regarding breast cancer, endometrial disease, and cardiovascular risk. Identified literature provides clear evidence only for the VTE risk, which is higher with the oral administration route. Conclusions Available evidence comparing the transdermal and oral administration routes for HRT is limited and of low quality, recommending further investigations. VTE risk can be considered the clearest and strongest clinical difference between the two administration routes, supporting the transdermal HRT as safer than the oral administration route.

Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long?

“…Eleven randomized trials have compared lipid effects of oral versus transdermal HT. 41 These trials have consistently found that, in contrast with oral HT, which increases triglycerides by 5% to 15%, transdermal HT decreases triglyceride levels by 5% to 30% 41,60,61 (Table 5). In this context, we recommend the transdermal route of ET for symptomatic menopausal women with dyslipidemia, particularly those with a tendency toward hypertriglyceridemia.…”

“…No randomized controlled trials have compared VTE risk with oral versus transdermal versus placebo therapy. However, observational studies have consistently observed lower rates of VTE with transdermal compared with oral HT 39–41 (Table 3). Moreover, in 11 randomized controlled studies of lipid metabolism, transdermal HT has shown neutral effects on triglycerides, in contrast with oral HT, which increases triglyceride levels.…”

“…Moreover, in 11 randomized controlled studies of lipid metabolism, transdermal HT has shown neutral effects on triglycerides, in contrast with oral HT, which increases triglyceride levels. 41 In a randomized trial of 196 women, oral HT significantly increased C-reactive protein levels compared with placebo. 42 However, at 6 months, transdermal estrogen had no significant effect on C-reactive protein levels compared with placebo.…”

Management of Menopausal Symptoms

“…The determination of whether vasomotor symptoms are moderate to severe is based on each patient’s assessment of their symptoms and whether they are bothersome, interfere with daily activities, or both. Because of the potential adverse effects of hormone therapy (eg, increased risk of venous thromboembolism, stroke, and breast cancer with combined estrogen plus progestogen therapy) (Table 2 and eTables 17-23 in the Supplement), vasomotor symptoms should only be treated if they are bothersome. Clinicians should prescribe the lowest effective dose of hormone therapy for the shortest duration consistent with the patient’s needs, with periodic reevaluation of the need for continued hormone therapy to control symptoms.…”

Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches

“…In the wake of the Women's Health Initiative study, the use of ET initially decreased and then began to transition from oral to transdermal formulations, presumably because of a hypothesized lower risk of adverse outcomes 3-6 . However, the risk difference between formulations has yet to be fully elucidated 7-10 . Much of the risk (and benefit) associated with the use of ET is thought to be related to the amount and duration of estrogen exposure 11,12 .…”