# Sex and menopause-based differences in presentation of early Lyme disease: A prospective cohort study

## TL;DR

This study found that males and post-menopausal females with early Lyme disease show more severe symptoms and higher antibody positivity compared to pre-menopausal females.

## Contribution

The study reveals sex and menopausal status influence early Lyme disease presentation and severity, highlighting a novel biological or social behavioral link.

## Key findings

- Males had higher odds of two-tier antibody positivity and higher disease severity compared to pre-menopausal females.
- Post-menopausal females showed disease patterns more similar to males than to pre-menopausal females.
- Females reported more heart palpitations and vomiting, while males reported more sleep difficulty.

## Abstract

Although prior research has established sex and menopausal status-based differences in immune response, susceptibility, and severity to a variety of pathogens, their relevance in early Lyme disease is understudied. We examined the clinical and serologic presentation of patients with early Lyme disease, stratified first by sex then by menopausal status. We also explored the hypothesis that males would present with more severe early Lyme disease. In this prospective cohort study from the Mid-Atlantic US, 243 adult, antibiotic-naïve patients were enrolled with a diagnostic erythema migrans rash present. Demographic, physical exam, symptom, laboratory, and two-tier serology data were collected at a baseline, and a post-treatment visit 3 weeks later. Lyme disease severity was operationalized through six indicators: rash size, number of acute symptoms, dermatologic dissemination, positive serology, liver function elevation, and elevated neutrophil-lymphocyte ratio. Unadjusted group comparisons and multivariate regression adjusting for potential confounders were used to assess difference. In logistic models adjusted for age, Lyme disease duration, systemic steroid use, and co-morbid thyroid disease, males had higher odds of testing two-tier positive (OR = 1.77 [1.03, 3.04], p = 0.039). This difference was more pronounced between males and pre-menopausal females (OR = 2.93 [1.26–6.79], p = 0.012) and no significant difference was found comparing males to post-menopausal females. In ordinal logistic models with Lyme disease severity as the outcome adjusted for age and Lyme disease duration, males had higher odds of being in a higher disease severity score category (OR = 1.94 [1.20,3.15], p = 0.028); again, particularly in comparison to pre-menopausal females (OR = 2.26 [1.13,4.58], p = 0.044). Heart palpitations (p = 0.023), vomiting (p = 0.007), and photophobia (p = 0.057) trended towards higher reporting among females, while sleep difficulty (p = 0.010) was higher among males. No differences were found on non-dermatologic components of the physical exam. We found sex and menopausal status to be relevant in accounting for variability in two-tier serologic status and severity of early Lyme disease in a well-characterized group of patients. Lower rates of seroreactivity among females is unexpected but may be consistent with lower acute severity of disease. Our clinical findings underscore the need for additional research to understand possible contributing biologic and/or social behavioral factors, as well as their impact on timely diagnosis and post-treatment conditions.

The online version contains supplementary material available at 10.1007/s10238-026-02063-0.

Lyme disease is a bacterial infection obtained through a tick bite. The goal of this study was to look at whether male and female patients with early Lyme disease show up to the doctor with different signs of their disease in terms of the symptoms they report, their physical exams, and the results of their laboratory tests. We also examined whether females who had gone through menopause would be different on these factors compared to those who had not. We studied data from 243 adults (118 females and 125 males) with early Lyme disease before and after treatment. We found that at diagnosis, males were more likely to have a positive test and more obvious findings of severe disease, yet there were no differences in how long males and females had been sick. For both of these findings, the male group was more similar to females who had undergone menopause and was more different than females who had not. We found a small number of Lyme disease symptoms that were reported more frequently among females (heart palpitations, vomiting, eyes sensitive to light, neck pain, nausea) and two symptoms (sleep difficulty and irritability) reported more frequently among males. These findings suggest that sex and menopause status are important to consider in understanding early Lyme disease. More research is needed to determine the cause of these differences and their impact on time to diagnosis and risk of later conditions after treatment.

The online version contains supplementary material available at 10.1007/s10238-026-02063-0.

Male sex was associated with significantly higher odds of two-tier antibody positivity in early Lyme disease.

Severity of early Lyme disease, based on objective markers of disease impact, was higher among males.

When stratified by menopausal status, post-menopausal females appeared more similar to males in disease severity and two-tier antibody reactivity than pre-menopausal females.

The overall number of symptoms reported was not associated with patient sex, however heart palpitations and vomiting were significantly more common among females and sleep difficulty was significantly more commonly reported among males.

The online version contains supplementary material available at 10.1007/s10238-026-02063-0.