EndoAxis Clinical Team
Reframing the Conversation
In part 1, we have defined the role of adipose as an endocrine tissue and outlined when adipose can be a healthy buffer to hormone balance, and when adipose can become an unhealthy villain in metabolic inflammation.
If you missed part 1, check it out here
This week, we will delve into urinary metabolites that may help point to whether adipose is a partner in health or going rogue to promote inflammation.
Adipose and Sex Hormone activity
When adipose tissue becomes metabolically unstable, it releases inflammatory cytokines and adipokines that interfere with normal insulin signaling. This promotes insulin resistance and compensatory hyperinsulinemia, which has downstream effects on sex hormone regulation. Elevated insulin alters hepatic production of sex hormone–binding globulin (SHBG), often lowering it, which increases the amount of free, biologically active sex hormones in circulation. Insulin and inflammatory signaling also influence key steroidogenic enzymes, including CYP19A1 (aromatase), which is expressed in adipose tissue.
Aromatase converts androgens into estrogens, and its activity is upregulated by inflammatory cytokines commonly produced by inflamed fat tissue. In men, increased aromatase activity within adipose tissue shifts testosterone toward estrogen production. Rising estrogen levels signal the hypothalamus and pituitary that sufficient sex hormones are present, suppressing luteinizing hormone (LH) output. Reduced LH leads to decreased testicular testosterone synthesis, reinforcing a cycle of relative estrogen dominance and functional hypogonadism. Clinically, this pattern is associated with increased central adiposity, gynecomastia, mood changes, fatigue, and reduced libido.
In women, adipose tissue acts both as a site of estrogen production and a storage reservoir for estrogens. As adiposity and inflammation increase, so does the total estrogen burden that must be metabolized and cleared by hepatic detoxification pathways. When this burden exceeds the capacity of Phase I and Phase II estrogen metabolism (including enzymes such as CYP1A1, COMT, UGTs, and SULTs), estrogen clearance may be delayed. This can contribute to symptoms of estrogen excess, including heavy or painful menstrual bleeding, breast tenderness, weight gain, and mood changes. Insulin resistance further compounds this issue by disrupting ovarian steroidogenesis and altering SHBG levels, increasing free estrogen exposure at the tissue level.
Beyond aromatase, inflamed adipose tissue can influence additional enzymes involved in sex steroid balance, including 17β-hydroxysteroid dehydrogenases/17bHSD (which regulate interconversion between active and less active estrogens and androgens) and steroid sulfatase (STS), which reactivates stored estrogen conjugates.
In men, higher 17b-HSD can increase conversion of testosterone to DHT, primarily within the prostate, increasing concern for higher oxidative damage within the prostate, while STS can increase active estrone, which may also impact growth of the prostate.
In women, higher 17bHSD can push preference toward higher androgens, even in the absence of conditions like PCOS. Often there will be a pattern of both elevated testosterone AND estradiol when influenced by metabolic dysfunction of adipose.
Together, these mechanisms help explain how excess or dysfunctional adipose tissue can drive hormonal imbalance in both men and women, linking metabolic dysfunction directly to reproductive and endocrine symptoms.
Adipose can be a problem regardless of actual body habitus. If a patient is leptin or insulin resistant, regardless of the actual amount of adipose present, they may still reveal inflammatory dysfunction driven by metabolically unstable adipose. Often the culprits to adipose dysregulation are high stress, poor sleep, environmental xenoestrogen exposures, alcohol use, poor nutrition, and genetics.
Adipose and Cortisol
While adipose tissue is increasingly recognized as a driver of endocrine and inflammatory signaling, its behavior does not occur in isolation. Cortisol dynamics, particularly cortisol metabolism, play a critical role in determining whether adipose tissue remains protective or becomes inflammatory.
Assessment tools such as the DUTCH test allow clinicians to move beyond serum cortisol snapshots and evaluate patterns of cortisol production, clearance, and tissue-level exposure. Of particular relevance is the balance between tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF), which reflects 5α- and 5β-reductase activity and influences both inflammatory tone and adipose signaling.
A preferential shift toward elevated THF and increased total cortisol metabolites may indicate enhanced cortisol turnover often seen in insulin resistance, central adiposity, and chronic inflammatory states. Conversely, impaired cortisol clearance may prolong tissue exposure despite “normal” daily output, contributing to immune activation, altered adipokine signaling, and worsened metabolic inflexibility.
In this context, cortisol is not simply a stress hormone: it becomes a metabolic regulator capable of shaping adipose behavior. Patterns observed on DUTCH testing can therefore provide valuable insight into whether adipose tissue is operating in a resilient, adaptive state or functioning as an inflammatory endocrine organ. When interpreted alongside glucose regulation, sex hormone patterns, and clinical presentation, these markers help clinicians identify the upstream drivers sustaining adipose dysfunction and guide more precise, physiology-based interventions.
Adipose dysfunction rarely exists in isolation and is profoundly influenced by the surrounding hormonal environment, particularly cortisol metabolism. Evaluation of urinary cortisol patterns, such as those assessed through DUTCH testing, provides insight beyond daily cortisol output by illuminating tissue exposure, clearance, and metabolic preference. Shifts in cortisol metabolites, including THF dominance and altered reductase activity, may reflect inflammatory signaling, insulin resistance, and sustained adipose stress despite otherwise unremarkable serum findings.
When interpreted alongside sex hormone patterns and metabolic markers, these data help clinicians identify whether adipose tissue is functioning adaptively or contributing to chronic inflammatory burden. In this way, cortisol metabolism becomes not merely a stress metric, but a window into the endocrine behavior of fat itself. Our EndoAxis report highlights these sex hormone and adrenal considerations to ensure providers do not miss these important and impactful insights.
