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    J Korean Med Sci. 2023 Dec 18;38(49):e377. English.
    Published online Nov 14, 2023.
    https://doi.org/10.3346/jkms.2023.38.e377
    © 2023 The Korean Academy of Medical Sciences.
    Original Article

    Hormone Replacement Therapy and Psoriasis Risk: A Nationwide Population-Based Cohort Study

    Gang Min Go,1 Hyun Ju Oh,2 Kyungdo Han,3 Yeong Ho Kim,2 Hyun Ji Lee,1 and Ji Hyun Lee2
      • 1Department of Dermatology, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
      • 2Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
      • 3Department of Statistics and Actuarial Science, Soongsil University, Seoul, Korea.
    • Address for Correspondence: Ji Hyun Lee, MD, PhD. Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Email: ejee@catholic.ac.kr
    Received June 01, 2023; Accepted September 24, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    Hormone replacement therapy (HRT) is used to relieve menopause symptoms, but has been reported to be associated with coronary heart disease and cancers in women. However, a link between HRT and psoriasis has yet to be established. The aim of this study was to determine the association between HRT and the risk of psoriasis.

    Methods

    We executed a nationwide population-based study. A total of 1,130,741 post-menopause women were enrolled in the national health care insurance database based on the enrollment criteria. The study population was classified into four groups based on the duration of the HRT, and the risk of psoriasis was analyzed.

    Results

    The incidence rates of psoriasis per 1,000 person-years were 3.36 and 4.09 in the no history of HRT and ≥ 5 years of HRT, respectively. After adjustment for age, smoking, alcohol intake, regular exercise, body mass index, diabetes mellitus, hypertension, and dyslipidemia, the most prolonged duration of the HRT group (≥ 5 years) exhibited significantly increased risk of developing psoriasis (hazard ratio, 1.22; 95% confidence interval, 1.16–1.29).

    Conclusion

    We propose that HRT in post-menopausal women is associated with an increased likelihood of psoriasis development.

    Graphical Abstract

    Keywords
    Cohort Study; Epidemiological Study; Hormone Replacement Therapy; Psoriasis; Risk Factor

    INTRODUCTION

    Psoriasis is a chronic systemic inflammatory disease that affects not only the skin but the nails, joints, and other visceral organs. In the pathogenesis of psoriasis, helper T cell type 1 (Th1) and Th17/Th22 both play important roles.1, 2 Inflammation in psoriasis is not confined to the skin and can infiltrate the entire body with various comorbidities such as metabolic syndrome, Crohn’s disease, depression, and cancer.3, 4, 5 From the perspective of systemic disease, the pathophysiology mechanism of psoriasis outbreaks can be affected by multiple conditions including smoking, obesity, anemia, and even cancer.6, 7, 8 For instance, extrinsic factors including air pollution, drugs, vaccinations, and infections exhibited an association with psoriatic risk, while various intrinsic factors such as diabetes mellitus (DM), dyslipidemia, hypertension (HTN), and mental stress were connected with increased psoriasis risk.9 Hormone replacement therapy (HRT) has been used widely in menopausal women, exhibiting several benefits such as a decreasing menopause symptoms and the risk of osteoporotic fractures.10, 11 However, HRT may be associated with an increased risk of coronary heart disease, stroke, and breast cancer.12 Estrogen is the primary and essential component of diverse HRT regimens with conjugated equine estrogen and synthetic 17β-estradiol with or without progestin being the most commonly used, and is known to act as both an immunomodulator and immunostimulator depending on the cell types and cell membrane receptors. Consequently, the overall outcomes of estrogen and HRT on the immune system vary among different inflammatory diseases and even within the course of individual diseases.13, 14

    Thus far, the effect of HRT on psoriasis has not been fully understood. Therefore, we evaluated the risk of psoriasis in patients with HRT using a Korean National Health Insurance Service (KNHIS) database.

    METHODS

    Data source and study population

    We analyzed the KNHIS database which is maintained by the Korean Government and contains almost all of the Korean population. The computerized KNHIS database included information about age, sex, socioeconomic variables, diseases diagnosed based on the International Statistical Classification of Disease and Related Health Conditions, 10th revision (ICD-10) codes, medical treatments, and procedures. In addition, a regular health examination was conducted every 1–2 years for adults over 40. Korea’s National Health Examination database contains anthropometric data, responses to questionnaires, and blood test findings. These data findings can be merged with KNHIS claim data (REQ202102009-001).

    All included patients were ≥ 40 years old and in menopausal status confirmed by questionnaire, underwent regular health examination and female cancer screening by NHIS in 2009. A total of 1,130,741 post-menopausal women were analyzed (Fig. 1). According to the survey results about the total duration HRT history, subjects with no history of HRT (n = 918,980), < 2 years of HRT (n = 122,879), 2–5 years of HRT (n = 50,630), and ≥ 5 years of HRT (n = 38,252) were divided into groups. The primary endpoint was newly developed psoriasis which was identified by the registration of ICD-10 code (L40) in the Korean NHIS database. The patients with a history of psoriasis prior to study enrollment which were affirmed by questionnaire and previous registration of L40 and with missing data were excluded. Also, we excluded the patients with a history of secondary menopause and ≥ 69 years old to minimize possible confounding factors that may affect female hormone status. The study population was tracked from 2010 to 2018.

    Fig. 1
    Flowchart of the enrollment of the study population in this study.
    KNHIS = Korean National Health Insurance Service.

    Clinical parameters and biochemical analyses

    Information on female reproductive factors including menarche age, menopause age, menstruation duration, oral contraceptive history, parity, breast feeding history, and HRT history were extracted from questionnaires during the regular Korean national health examinations. Information on smoking, alcohol intake, and physical activity was also taken from questionnaires during health examination. Smoking history was divided into none, ex, and current smoker. Alcohol intake was classified as none (no alcoholic drinks consumed within the past year), moderate (< 30 g pure alcohol per day), or heavy drinking (≥ 30 g of pure alcohol per day). The history of comorbidities including DM, HTN, and dyslipidemia was confirmed by ICD-10 codes and prescribed medications. History of stroke and heart disease was evaluated by self-reported questionnaires. Body mass index (BMI) (kg/m2) was calculated as the weight (kg) divided by the square of the height (m).

    Statistical analysis

    We analyzed continuous variables using analysis of variance (ANOVA) and dichotomous variables using the χ2 test. We also analyzed variables with skewed distributions after logarithmic transformation. The data were presented as means ± standard deviations (continuous variables), numbers and percentages (dichotomous variables), or geometric means and 95% confidence intervals (CIs) (continuous variables with skewed distributions). The incidence rate of psoriasis was calculated by dividing the total number of incident cases of psoriasis by the entire follow-up duration (person-years). We performed multivariate Cox proportional hazard regression analyses to evaluate the associations of HRT with the risk of psoriasis. The multivariate model was adjusted for age, smoking, alcohol intake, regular exercise, BMI, diabetes, HTN, and dyslipidemia. All statistical analyses were performed using SAS software (version 9.4, SAS Institute, Cary, NC, USA). P values < 0.05 were considered statistically significant.

    Ethics statement

    This study was approved by the Ethics Committee of Seoul St. Mary’s Hospital, The Catholic University of Korea (IRB No. KC21ZASI0058) and was conducted in accordance with the principles of the Declaration of Helsinki. The informed consent was waived by the Ethics Committee due to anonymity of data.

    RESULTS

    Baseline demographic features of the study population

    The baseline characteristics of the study population according to the duration of HRT are summarized in Table 1. Average age was the highest in the group with ≥ 5 years of HRT (59.77 ± 5.05). Average BMI was the highest in the group with no history of HRT (24.32 ± 3.16). Similar to the BMI, the proportion of subjects with regular exercise was the lowest in the group with no history of HRT (18.96%). Interestingly, HTN, DM, dyslipidemia, and stroke were the highest in the group with no history of HRT (42.11%, 8.31%, 34.21%, and 1.7%, respectively). However, for comorbidities, only the history of heart disease was highest in the group with ≥ 5 years of HRT (4.99%).

    Table 1
    Baseline characteristics of the study population according to the duration of HRT (N = 1,130,741)

    Incidence and risk of psoriasis in HRT received post-menopause women

    The overall incidence rates of psoriasis according to the duration of HRT are analyzed in Table 2. In the no history of HRT group, the incidences of psoriasis were 3.36 per 1,000 person-years. The incidences of psoriasis in < 2 years of HRT, < 5 years of HRT, and ≥ 5 years of HRT were 3.75, 4.00, and 4.09 per 1,000 person-years, respectively.

    Table 2
    The risk of psoriasis according to the duration of HRT

    In model 1 analysis, which was a crude investigation, the group with ≥ 5 years of HRT had the greatest increase in the risk of psoriasis (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.16–1.28) compared to the no history of HRT group as a control. In addition, the < 2 years of HRT group and 2–5 years of HRT group also exhibited significantly increased risk of psoriasis (HR, 1.19; 95% CI, 1.14–1.25 and HR, 1.22; 95% CI, 1.16–1.28).

    In model 4 analysis adjusting for age, smoking, alcohol intake, regular exercise, BMI, DM, HTN, and dyslipidemia, there was a significantly increased risk of psoriasis in the < 2 years of HRT and 2–5 years of HRT groups (HR, 1.13 95% CI, 1.09–1.17 and HR, 1.21; 95% CI, 1.15–1.26), respectively. The group with ≥ 5 years of HRT still exhibited the highest increased risk of psoriasis (HR, 1.22; 95% CI, 1.16–1.29).

    Interestingly, in all types of model analysis, the risk of psoriasis tended to increase with the duration of HRT (Fig. 2).

    Fig. 2
    Risk of psoriasis according to HRT duration. Model 1: non-adjusted, Model 2: age, Model 3: age, smoking, alcohol intake, regular exercise, and BMI, Model 4: age, smoking, alcohol intake, regular exercise, BMI, diabetes mellitus, hypertension, and dyslipidemia.
    HRT = hormone replacement therapy, BMI = body mass index.

    DISCUSSION

    In our nationwide population-based cohort study, HRT in post-menopausal women significantly increased the risk of psoriasis and exhibited a positive correlation with the elongation of total HRT duration, suggesting HRT as an independent risk factor of psoriasis.

    Inflammatory cytokines such as interleukin (IL)-17 and IL-23 play a central role in multi-organ-involving inflammation that occurs in psoriasis. There are several comorbidities like HTN, obesity, type 2 DM, dyslipidemia and even cardiovascular disease (CVD) that have been identified through several studies.15 On the other hand, based on the association of various diseases related to psoriasis, studies have been performed to investigate the effects of numerous clinical factors such as smoking, alcohol, drugs, and sex hormones on psoriasis.9 Among these clinical factors, sex hormones are attracting attention because they have several advantages including the alleviation of hot flashes, the most common menopausal symptom in post-menopausal women, and the prevention of osteoporotic fractures due to reduced osteoporosis.16, 17

    Estrogen, which is the major sex hormone of females, plays various roles beyond the reproductive cycle. For instance, estrogen can affect systemic inflammatory activity. Kanda et al.18, 19 suggested that estradiol (E2), which is natural estrogen of humans, has anti-inflammatory effects by inhibiting interferon (IFN)-γ induced CXCL10 expression. As evidence to support estrogen’s anti-inflammatory features, it has been reported that psoriatic lesions improve during pregnancy when estrogen levels reach their peak. Kanda et al.20 suggested that estrogen reduces psoriatic inflammation by decreasing neutrophil blood levels and keratinocyte production. In addition, Mashiko et al.21 reported the accentuation of psoriasis severity after menopause. However, estrogen not only exhibited positive effects, but also had negative effects on psoriatic inflammation such as increasing the proliferation of keratinocytes and endothelial cells, producers of macrophage/fibroblast growth factors.13 In line with two-sided effects in psoriasis, estrogen influenced both sides of the inflammatory spectrum depending on the timing. In the early phase of atherosclerosis, estrogen decreased inflammatory activation, but in the chronic and established stages of the disease, estrogen promoted the contradictory acceleration of inflammation.12, 14, 22 Furthermore, the possible mechanisms of estrogen promoting inflammation in arthritis, systemic lupus erythematosus (SLE), thyroiditis, and visceral organ inflammation have been suggested from previous studies.14

    Along with the complexity of estrogen effects on inflammation, the impact of HRT on systemic conditions involved in areas other than the reproductive system have been studied. Interestingly, contrary to the natural anti-inflammatory effects of sex hormones, HRT in post-menopausal women promoted T cell proliferation, the stimulation of tumor necrosis factor (TNF) secretion, and increased levels of IL-6 and C-reactive proteins, ultimately triggering pro-inflammatory effects.23, 24, 25 In terms of disease pathophysiology, studies from Meier et al.26 and Buyon et al.27 reported increased risk of developing SLE in post-menopausal women with chronic HRT. In addition, HRT raised the possibility of acute flare ups in pre-diagnosed patients.

    In our study, consistent with the influence on SLE, HRT increased the risk of developing psoriasis in post-menopausal women. Based on this finding, we propose the following mechanism.

    First, HRT not only increases estrogen serum level to a relatively low point where the hormone acts as a pro-inflammatory agent, but also other types of sex hormones resulting in elevated inflammation. As we mentioned above, estrogen has both anti-inflammatory and pro-inflammatory features. In post-menopausal women with HRT, serum estrogen is relatively low compared to the average level of menstruating women, and low doses of estrogen could invoke Th1-mediated immunity with the secretion of IL-1, IL-6, TNF, and IFN-γ.28, 29 Additionally, Verthelyi and Klinman30 examined the reduced levels of dehydroepiandrosterone (DHEA) in post-menopausal women, which is raised after HRT and proliferates IFN-γ secreting cells with pro-inflammatory effects. This hypothesis may be consistent with several reports that found increased risk of coronary heart disease and stroke events, which are associated with chronic inflammation of vessel walls.12

    Second, different effects on inflammation depending on the timing of estrogen administration by HRT may influence psoriatic inflammation. For instance, in the pathophysiology of atherosclerosis, female endogenous estrogen exhibits a protective role against atherosclerotic plaque formation. On the other hand, HRT in women older than 60 years of age who possibly have established vessel narrowing may have an increased possibility of atherosclerosis with inflammatory activation.22 Likewise, HRT in post-menopausal women whose average age was > 58 years in our study may potentiate the pre-existing chronic inflammation course of psoriasis to ultimately provoke the disease outbreaks.

    In previous study investigating hormonal factors and risk of psoriasis in women, Wu et al.31 analyzed 163,763 female nurses and confirmed 1,253 incident psoriasis cases. They reported statistically insignificant increased risk of psoriasis according to HRT. However, the duration of HRT and risk of developing psoriasis showed positive correlation (HR in current user of HRT = 1.22, HR in < 5 years of HRT = 1.14, HR in 5-9 years of HRT = 1.19, HR in ≥ 10 years of HRT = 1.27).31 Although the statistical insignificance was probably resulted from relatively small number of study population confined to specific occupational group with lower age (mean age of population with psoriasis = 48.5 years, mean age of population without psoriasis = 48.9 years), the risk of psoriasis was increased as the duration of HRT extends which is consistent with our study result.

    Apart from the effect of HRT on psoriasis, HTN, DM, dyslipidemia and stroke were the highest in the group with no history of HRT in baseline. According to several studies investigating the association between HRT and CVD risk, HRT showed both positive and negative effects for various comorbidities depending on specific diseases or the timing of administration.32, 33 For instance, the previous studies reported that HRT decreased fasting glucose, fasting insulin, and insulin resistance.34, 35 Also, the favorable effect of HRT on low-density lipoprotein cholesterol, lipoprotein(a) levels, and high-density lipoprotein cholesterol was reported.32 In contrast, although some studies reported no clinically meaningful change in blood pressure after HRT on women with preexisting HTN, women’s health initiative identified increased blood pressure by 1–1.5 mmHg after HRT.36, 37, 38 Interestingly, the effect of HRT on stroke was dependent on the timing of treatment initiation, decreasing the risk of stroke in women < 60 years old which is consistent with our study population but increasing the risk in women > 60 years old.39, 40, 41, 42 Although HRT showed the complexity on its effects, HTN, DM, and dyslipidemia are well known risk factors of CVD which remains as the leading cause of morbidity and mortality in post-menopausal women over the age of 50 years worldwide and, thus, is the major concern of HRT.43 Also, stroke is the second leading cause of mortality among females globally and health conditions such as HTN, DM, and dyslipidemia are modifiable cause of stroke.43 As a result, HRT in clinical fields is recommended after comprehensive risk assessment with the identification of comorbidities including HTN, DM, dyslipidemia, and stroke which are markedly elevated CVD risk factors.33, 44 Along with the HRT effects on comorbidities, as a population-based retrospective study, we presumed that this risk assessment process for the initiation of HRT resulted in preferred selection of patients without HTN, DM, dyslipidemia and stroke in HRT group, which occurred already before study enrollment. Therefore, we additionally calculated the risk of psoriasis in Model4 analysis adjusting HTN, DM, and dyslipidemia as confounding factors and the increased risk of psoriasis was maintained (Table 2).

    As a retrospective study using survey information registered into the KNHIS database, our study has a limitation that the information about basal hormone levels including estrogen or progestin and the specific regimens of HRT was not evaluated in the analysis. Plus, there was statistically significant difference in oral contraceptive (OC) history between study groups but the risk of psoriasis according to OC history was not available in our analysis.

    Considering the diverse combination of HRT using various types of estrogen and progestins, the different HRT regimens could have different affects in certain situations. However, progestin can induce chronic inflammation by modulating various cytokines such as IL-1β, IL-6, IL-12, IFN-γ, NK cell, and even Th2.13, 45 However, as a population-based cohort study, our study secured a large sample size and different adjusting models for several confounding factors based on the information about diverse health factors.

    In conclusion, post-menopausal women who received HRT exhibited increased risk of psoriasis compared to those who did not in our nationwide population-based cohort study. The risk for the development of psoriasis after HRT seemed to increase with the duration of HRT. Hence, we propose that HRT in post-menopausal women may be associated with an increased likelihood of psoriasis development. Further investigation still needs for the mechanism of HRT on psoriasis development.

    Notes

    Funding:This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (No. NRF-2018R1D1A1B07044100).

    Disclosure:The authors have no potential conflicts of interest to disclose.

    Data Availability Statement:The data supporting the findings of our study are available from the corresponding author upon reasonable request.

    Author Contributions:

    • Conceptualization: Kim YH, Lee JH.

    • Data curation: Go GM, Oh HJ, Han KD, Lee JH.

    • Formal analysis: Han KD, Lee JH.

    • Funding acquisition: Lee JH.

    • Methodology: Go GM, Oh HJ.

    • Supervision: Kim YH, Lee HJ, Lee JH.

    • Validation: Lee HJ.

    • Visualization: Kim YH.

    • Writing - original draft: Go GM.

    • Writing - review & editing: Oh HJ, Han KD, Kim YH, Lee HJ, Lee JH.

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    MeSH Terms
    Alcohol Drinking
    Body Mass Index
    Cohort Studies*
    Coronary Disease
    Delivery of Health Care
    Diabetes Mellitus
    Dyslipidemias
    Epidemiologic Studies
    Exhibition
    Female
    Hormone Replacement Therapy*
    Humans
    Hypertension
    Incidence
    Insurance
    Menopause
    Postmenopause
    Psoriasis*
    Respect
    Risk Factors
    Smoke
    Smoking
    Metrics
    Share
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