Oral vs Transdermal Hormone Therapy after Menopause Linked to Increased Risk of NAFLD

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Among postmenopausal women receiving oral menopausal hormone therapy (MHT) for 12 months, the prevalence of nonalcoholic fatty liver disease (NAFLD) increased from 25.3% at baseline to 29.4% at 12 months, according to new research. Conversely, the prevalence of NAFLD decreased from 24% at study entry to 17.3% among women who received hormone therapy via transdermal delivery.

In addition, according to investigators from the department of obstetrics and gynecology at Sungkyunkwan University School of Medicine in Seoul, Korea, serum levels of both total and LDL cholesterol decreased while levels of triglycerides and HDL cholesterol increased in the group taking oral estrogen. The team observed negligible change in laboratory tests among women in the transdermal estrogen group.

The researchers say the study findings suggest that transdermal delivery of estrogen may protect against the development or progression of NAFLD in women after menopause. The study was published in Nature Scientific Reports.

“Because hepatic effects differ based on the route of estrogen administration, the effects of MHT on NAFLD can also differ between transdermal and oral NHT treatment,” wrote investigators. Transdermal delivery avoids first-pass hepatic metabolism, they point out, which in turn reduces the hormonal effects on lipid metabolism, and particularly on triglycerides, elevated levels of which are consistently associated with NAFLD.

“However, the effects of MHT on the prevalence of NAFLD based on the route of estrogen administration have not been evaluated to date,” wrote corresponding author Dong-Yun Lee, PhD, and colleagues.

Because hepatic effects differ based on the route of estrogen administration, the effects of MHT on NAFLD can also differ between transdermal and oral NHT treatment. Transdermal delivery avoids first-pass hepatic metabolism, they point out, which in turn reduces the hormonal effects on lipid metabolism, and particularly on triglycerides, elevated levels of which are consistently associated with NAFLD.

Methods, participants

For their evaluation of the prevalence and progression of NAFLD after MHT based on estrogen delivery route and dosage, the research team compared data from consecutive postmenopausal women who received 12 months of MHT at the Menopause Clinic at the Samsung Medical Center, Seoul, Korea, from January 2016 to December 2020.

Study inclusion required participants be aged 45 to 60 years, be postmenopausal (at least 12 months of amenorrhea), have consistently used the same menopausal hormone therapy regimen for at least 12 months, and have undergone a general health screening including abdominal ultrasonography before and after menopausal hormone therapy.

Potential participants were excluded for reasons including a change in therapy regimen within 12 months, positive serology for hepatitis B or C, daily consumption of more than 10 g of alcohol, and use of drugs that could significantly affect hepatic metabolism or body weight.

The final cohort numbered 368 women who were divided by route of estrogen administration into the oral MHT group (n=293) and the transdermal MHT group (n=75). The mean age in the former group was 53.7 years and, in the latter, 54.3 years. The investigators observed no relevant differences between the groups in reproductive or menstrual history, body mass index, blood pressure, or history of chronic medical diseases before initiation of MHT.

Investigators compared prevalence of NAFLD between the transdermal and oral administration groups at baseline and after 12 months of MHT. They also assessed differences in progression of NAFLD after beginning MHT based estrogen dose and type of progestogen in the oral administration group.

FINDINGS

Among the full cohort, 24.7% of patients had preexisting NAFLD. Of those with NAFLD at baseline, 24.0% were in the transdermal group and 25.3% were in the oral group, according to the study.

NAFLD prevalence, progression

The researchers reported that after 12 months of MHT, the prevalence of NAFLD decreased from 24% to 17.3% in the transdermal group but increased from 25.3% to 29.4% in the oral group, a difference that reached statistical significance (P = .036).

The proportion of participants that experienced NAFLD progression after initiation of MHT was significantly lower in the transdermal group than in the oral group (2.7% vs 11.3%; P = .024), whether NAFLD was newly diagnosed or was preexisting and had worsened, according to the study. When the investigators analyzed progression by baseline NAFLD status, they found it more prominent among those with preexisting (16.2%) than without preexisting (9.6%) NAFLD in the group taking oral MHT; the difference did not reach statistical significance.

Laboratory values

The investigators’ analysis of laboratory values over the 12 months found negligible differences in clinical characteristics or laboratory values in the transdermal MHT group.

In the oral MHT group, however, who et al reported decreases in serum total cholesterol (202.3 to 195 mg/dL) and LDL cholesterol (119.7 to 114.6 mg/dL) and increases in triglycerides (104.4 to 118.4 mg/dL) and in HDL cholesterol (59.9 to 70.5 mg/dL). Serum fibrinogen also was significantly increased at 12 months in the oral MHT group.

Finally, the team found no differences in NAFLD progression among women taking oral MHT based on estrogen dose (low-dose vs standard-dose, 7.1% vs 13.0%; P = .146) or between natural and synthetic progestogen (14.5% vs 9.9%; P = .295).

“The findings can help healthcare providers and patients in decision-making regarding choosing the best MHT option, especially in postmenopausal women who already have pre-existing NAFLD or who are at high risk of developing NAFLD,” investigators concluded.

Source: Kim SE, Min JS, Lee S, Choi D. Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration. Nature Sci Rep. Published online September 19, 2023. doi:10.1038/s41598-023-42788-6