Deconstructing the androgen function in active perianal infection: Investigating inflammation-driven hypogonadal state

Abstract

Emerging evidence suggests that testosterone plays a more complex role in perianal infectious diseases than traditionally assumed. While early theories proposed that higher androgen levels may predispose individuals to anal gland obstruction, recent clinical data indicate that active perianal infections are frequently accompanied by reduced circulating testosterone compared to those with hemorrhoids or fistulas. This decline appears closely linked to systemic inflammatory stress, metabolic disorders, and obesity-factors known to suppress the hypothalamic-pituitary-gonadal axis and impair steroidogenesis. Inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and C-reactive protein may directly inhibit Leydig cell activity, whereas adiposity contributes additional endocrine disruption through reduced sex hormone-binding globulin and enhanced aromatization. Testosterone should be viewed as part of the inflammatory-metabolic response. This perspective provides an updated framework for understanding perianal sepsis. Future research should prioritize integration of inflammatory biomarkers and evaluation of endocrine or metabolic interventions as adjuncts to conventional surgical management.

Key Words: Testosterone; Perianal diseases; Systemic inflammatory stress; Metabolic disorders; Obesity

Core Tip: Acute perianal abscess is not only a localized infection but triggers a systemic inflammatory response that rapidly suppresses testosterone production. This inflammation-driven hypogonadal state challenges the traditional assumption that high androgen levels contribute to disease initiation and highlights the importance of integrating endocrine and metabolic factors into the understanding and management of perianal infections.

INTRODUCTION

Perianal infectious diseases remain common and clinically significant in colorectal practice[1]. Acute perianal abscess represents a rapid bacterial infection of the anal gland[2]. Anal fistula is the chronic stage that often follows an abscess[3]. Although incision and drainage is the standard treatment, recurrence is frequent[4,5], and clinical outcomes vary widely among patients[6]. These unresolved issues indicate that anatomical explanations alone are not sufficient[7,8] to understand the full course of disease development. There may be interactions between local infection, systemic inflammation, metabolic factors, and endocrine responses[9-11].

In this issue, Zhang et al[12] reported that patients with acute perianal abscess exhibited significantly reduced serum testosterone levels. Their study evaluates serum testosterone and other hormones in patients with acute perianal abscess and compares these values with those of patients with anal fistula and hemorrhoids[13]. The authors observed a significant decline in testosterone levels among patients with acute abscess[14]. This discovery suggests that acute perianal infection is associated with systemic endocrine changes[15,16]. It also challenges long-standing assumptions about the role of androgen in perianal disease[12]. In this editorial, we summarize the main observations, explain possible biological mechanisms, and consider the implications for clinical practice and future research.

OVERVIEW OF THE STUDY

Zhang et al[12] conducted a cross-sectional study involving 249 male patients. The cohort consisted of patients with acute perianal abscess, anal fistula, and hemorrhoids. Blood samples were taken before surgery to measure testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol. The authors aimed to determine whether acute inflammation affects androgen levels.

The study showed that serum testosterone was significantly lower in the acute abscess group[17]. The difference remained clear after adjusting for body mass index (BMI) and age. LH, FSH, and estradiol levels were not significantly different among the groups. Multivariable regression analysis revealed that abscess diagnosis was an independent predictor of lower testosterone (β = -2.999, P < 0.001). BMI was also a negative predictor (β = -0.368, P < 0.001). Within the abscess subgroup, higher white blood cell was linked to further testosterone reduction[18].

These findings indicate that acute infection may lead to rapid suppression of the hypothalamic-pituitary-gonadal (HPG) axis. This hormonal change may be part of a systemic inflammatory response rather than an underlying endocrine disorder. The study provides the first clinical evidence that acute perianal abscess can disrupt androgen function.

BIOLOGICAL INTERPRETATION OF TESTOSTERONE DECLINE

This editorial provides a focused conceptual interpretation rather than a comprehensive mechanistic review[19]. In many inflammatory conditions, cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α) suppress Leydig cell steroidogenesis[20-23]. Acute infection can also alter hypothalamic and pituitary signaling[24,25]. These mechanisms act together to reduce testosterone production during systemic inflammation[26,27]. Evidence from sepsis and endotoxin exposure supports this pattern[28-30]. Testosterone may decrease within hours after exposure to inflammatory stimuli[31].

We propose a conceptual model specific to acute perianal infection[32]. Local infection may trigger regional and systemic inflammatory responses[33]. These responses may increase circulating cytokines such as IL-6 and TNF-α[34]. Elevated cytokines may transiently suppress the HPG axis through central and peripheral mechanisms[35]. This suppression may reduce gonadotropin release and impair Leydig cell function[36]. This model is hypothesis-generating and requires further validation (Figure 1).

Figure 1 Proposed conceptual model linking acute perianal infection, systemic inflammation, and transient testosterone suppression. Acute perianal infection may trigger a systemic inflammatory response, leading to increased circulating cytokines, including interleukin-6 and tumor necrosis factor-α. Elevated cytokines may suppress the hypothalamic-pituitary-gonadal axis. This suppression may reduce testosterone production. Obesity and metabolic factors may further modify this process by promoting chronic inflammation, reducing sex hormone-binding globulin levels, and increasing aromatase activity, thereby amplifying testosterone suppression. All pathways shown are conceptual and hypothesis-generating and should not be interpreted as established causal relationships. IL: Interleukin; TNF-α: Tumor necrosis factor-α; HPG: Hypothalamic-pituitary-gonadal; SHBG: Sex hormone-binding globulin.

Obesity adds another layer of complexity. High BMI is known to reduce sex hormone-binding globulin, increase aromatase activity, and promote chronic low-grade inflammation[37-39]. These factors lower total and free testosterone[40,41]. Because obesity is a known risk factor for perianal abscess recurrence, the metabolic-endocrine relationship may influence disease severity and outcomes[42].

The differences between acute abscess and chronic fistula are also consistent with known biology. Acute abscess triggers strong inflammation[43], while chronic fistula is characterized by low-grade, localized inflammation[44]. Therefore, the endocrine response is more pronounced in acute settings[45,46].

RECONSIDERING THE TRADITIONAL VIEW OF ANDROGEN AND ANAL GLAND OBSTRUCTION

A traditional explanation for the higher incidence of perianal abscess in men is that higher androgen levels stimulate anal gland secretion[47,48] and increase the risk of obstruction[49]. However, direct evidence for this hypothesis is limited[50]. Zhang et al’s findings suggest that androgen levels during active infection are lower, not higher[12]. This observation challenges the classical explanation and suggests that the association between androgen and perianal disease is more complex[51].

A two-phase model may help reconcile these ideas[52]. In the early stage before infection, some individuals may have higher androgen activity that promotes glandular secretion[53,54]. After infection begins, systemic inflammation rapidly suppresses testosterone[55,56]. Another possibility is that chronic low testosterone weakens mucosal immunity[57,58] and increases susceptibility to infection[59]. Both hypotheses require further testing but are biologically reasonable.

COMPARISON ACROSS DISEASE TYPES

To better interpret the findings, Table 1 summarizes testosterone changes across acute and chronic perianal inflammatory conditions[60,61].

Table 1 Testosterone changes in acute and chronic perianal inflammatory diseases.

Disease	Pathophysiological features	Testosterone alteration	Proposed mechanisms	Clinical implications
Acute perianal abscess	Acute suppurative infection; strong systemic inflammation[60]; elevated WBC, CRP, IL-6, TNF-α	Significant decrease; inflammation-induced hypogonadism	Cytokine-mediated Leydig cell suppression; acute HPG axis inhibition; obesity-related effects	Reduced testosterone may reflect inflammatory burden and systemic stress
Complex anal abscess (horseshoe, ischiorectal)	Extensive multi-space infection; higher inflammatory load	Marked decrease	Higher inflammatory stress amplifies endocrine suppression	May assist in risk stratification
Simple Intersphincteric abscess	Localized infection; moderate systemic response	Moderate decrease	Cytokine-driven but less severe	Distinguishes simple vs complex abscess inflammation
Cryptoglandular anal fistula (chronic)	Chronic low-grade inflammation[61]; persistent tract	Generally unchanged or mildly reduced	Low-grade inflammation insufficient for HPG suppression	Limited endocrine involvement
High-transsphincteric/suprasphincteric fistula	Higher internal opening; more complex anatomy	Mild decrease in selected cases	Subtle endocrine modulation with chronic inflammation	May correlate with fistula complexity

All concepts presented in this table are hypothesis-generating. WBC: White blood cell; CRP: C-reactive protein; IL: Interleukin; TNF-α: Tumor necrosis factor-α; HPG: Hypothalamic-pituitary-gonadal.

STRENGTHS OF THE STUDY

This study has several strengths. First, the authors used a clear three-group comparison, which helps reduce disease-related bias. Second, hormone samples were taken before surgery, minimizing external influence on hormone levels. Third, the study used full endocrine profiling and multivariable analysis. Fourth, the biological pattern observed in testosterone matches known inflammatory mechanisms. Finally, the findings open a new perspective in a field that traditionally focuses on anatomy and surgery.

LIMITATIONS

This study has several limitations. The cross-sectional design does not allow temporal or causal inference. The absence of cytokine measurements limits mechanistic interpretation. In addition, the male-only cohort restricts generalizability to female patients. The lack of longitudinal follow-up prevents assessment of testosterone recovery after treatment. These limitations introduce uncertainty in temporal interpretation and prevent direct confirmation of inflammatory-endocrine mechanisms.

CLINICAL IMPLICATIONS

The findings support a broader view of perianal abscess. It is not only a local infection but also a systemic inflammatory condition that affects endocrine function. Reduced testosterone levels should be interpreted as an epiphenomenon of acute systemic inflammation[62,63]. Obesity and metabolic dysfunction may influence risk and postoperative recovery[64]. Understanding the endocrine response may help improve treatment planning, risk stratification, and postoperative care.

For surgeons, recognizing hormonal changes may help explain variations in recovery. For researchers, the findings highlight interactions among inflammation, endocrine pathways, and metabolism. These factors may influence recurrence and long-term outcomes.

FUTURE DIRECTIONS

Future studies should adopt longitudinal designs. Testosterone and inflammatory markers may be measured at diagnosis, after drainage, and during recovery. These studies may clarify temporal hormonal changes during acute inflammation. All proposed approaches remain exploratory.

CONCLUSION

Zhang et al[12] provide new evidence that acute perianal abscess is associated with significant testosterone decline. This finding challenges traditional explanations of disease formation and highlights important interactions between inflammation and endocrine function. Perianal infection should be viewed as a condition influenced by anatomical, inflammatory, metabolic, and endocrine factors. Integrating these areas may help improve outcomes and reduce recurrence.