The results of this study conducted at a medical center in Slovenia show that the number of females diagnosed with EM or ACA exceeded the number of males with these cutaneous manifestations of Lyme borreliosis. The opposite was found for non-cutaneous manifestations, where the number of males diagnosed with LNB or Lyme arthritis exceeded the number of females. A female predominance among patients with ACA is quite consistent among case series of ACA reported from other European countries 
. There has also been a female predominance among EM cases in many case series of adult patients from other European countries 
, with an especially high proportion of females in patients with recurrent EM in Sweden 
. Similarly, a male predominance for LNB or Lyme arthritis in Europe is by no means unique to Slovenia 
. A particular strength of our study is that we had data on a large number of patients with different clinical manifestations of Lyme borreliosis who were diagnosed at a single medical center, thus avoiding confounding variables that may be present when comparisons are made between medical centers.
To our knowledge, this is the first report to document at the same medical center that the proportion of ACA patients who are female is substantially greater than those diagnosed with EM. The difference in the proportion who were females between patients with ACA and EM, however, can be explained almost entirely by differences in the ages of these patients. ACA is a late manifestation of Lyme borreliosis, and patients with ACA were about 15 years older than those with EM. The sex ratio in Slovenia is increasingly biased toward females in older age groups 
, and the difference between ACA and EM patients becomes marginal after controlling for this trend. The observed differences in the proportions of females with EM or ACA, compared with those with either LNB or Lyme arthritis, however, cannot be accounted for by the ages of the patient groups.
Although the patient groups in this study were not from identical time periods, this could only substantively influence the results if there were marked time-related shifts in the sex ratio of the general Slovenian population between 1990 and 2012. Census data, however, indicate that females accounted for 51.5%, 51.1% and 50.5% of the Slovenian population in 1990, 2000, and 2010 respectively, underscoring that there have been no major shifts in the sex ratio 
. In addition, if we had limited our analysis of EM cases to the 5,049 cases (48%) occurring during the overlapping years of 2000–2009, the female preponderance was essentially unchanged at 58%. Thus, time-related changes in the sex ratio cannot account for the observed gender differences between cutaneous and non-cutaneous clinical manifestations of Lyme borreliosis.
What might account for the male predominance among patients with LNB and Lyme arthritis? One possibility is that strains of B. garinii
and B. burgdorferi
sensu stricto, the Lyme borrelial species thought to be most closely associated with LNB and Lyme arthritis respectively 
, are less likely to infect women than men. This would be plausible if the ticks infected with these species of Lyme borrelia were preferentially found in geographic areas frequented more by men than women, or alternatively, if men were more susceptible to developing infection with these species after being bitten by an infected tick. With either of these scenarios, one might expect, relative to B. afzelii
infection, that there would be a lower proportion of women with EM who had a positive skin culture for B. garinii
or for B. burgdorferi
sensu stricto. shows the available Slovenian data on gender for the patients with a positive culture of a skin biopsy sample of an EM skin lesion 
. In support of these hypotheses, a higher percentage of patients with B. afzelii
infection were female compared with those infected with B. garinii
(62.2% vs. 53.3%, p
0.06), and this difference was statistically significant when the rates were adjusted for the age of the patients (59.1% vs. 44.1%, p
0.003). Indeed, after the age correction there was a male predominance for B. garinii
infections. However, this pattern was not found for B. burgdorferi
Correlation between the Species of Lyme Borrelia Isolated from the Skin of Patients with Erythema Migrans and the Gender of Infected Slovenian Patients.
Since LNB and Lyme arthritis presumably arise in most cases through hematogenous dissemination 
, it may be that the likelihood of spirochetemia with highly neurotropic strains of B. garinii
, or with strains of B. burgdorferi
sensu stricto with the strongest propensity to infect joints 
, is greater in males than females. Possible differences between females and males in the immunologic response to borrelia has been discussed by others in trying to explain the much greater likelihood of recurrent episodes of EM in females from Sweden compared with men 
. In the experience at the University Medical Center Ljubljana with patients found to have a positive blood culture for B. garinii
, there were 12 females compared with 10 males; among patients with a positive blood culture for B. burgdorferi
sensu stricto, there were 3 females and no males to date. Clearly the available data are too limited to exclude the possibility that gender might influence the risk of hematogenous dissemination with certain strains of B. garinii
or B. burgdorferi
Perhaps the explanation is purely behavioral. It could be argued that Slovenian men are simply less likely than Slovenian women to seek health care for EM skin lesions, and thus they become at higher risk for dissemination of Lyme borrelia to extracutaneous sites. Available data in Slovenia on utilization of health care indicate among individuals aged ≥20 years that women had more outpatient primary care visits in 2010 than men with a ratio of 1.3 visits for women to 1 for men 
. A counter-argument against this hypothesis, however, is the clear female predominance among patients with ACA, which is also a late manifestation of Lyme borreliosis 
. However, it may be that men are simply less likely than women in Slovenia to seek medical care for any kind of skin lesion including both EM and ACA.
The potential for biologic significance of gender in infectious diseases is not unique to Lyme borreliosis. For example, it has been previously demonstrated in a murine model of Borrelia hermsii
infection that males have a significantly higher initial peak level of spirochetemia than females 
. In another example, it has been observed in patients with Coxiella burnetii
infection (Q fever) that men are 2.5 times more likely to be symptomatic than women 
, and experimental studies in mice have confirmed that sex hormones play a role in the pathophysiology of this infection 
In conclusion, in this study performed at a single medical center in Slovenia, patients with the cutaneous manifestations of Lyme borreliosis, EM and ACA, were predominantly female, while those with LNB or Lyme arthritis were predominantly men. This pattern of gender distribution has been noted in other 
, but not all 
, case series from Europe of these particular clinical manifestations of Lyme borreliosis. Elucidation of the mechanism(s) involved may provide useful insights into the pathogenesis of Lyme borreliosis in Europe.