Understanding the Steroidogenesis Cascade: A Visual Guide
What Is Steroidogenesis?
Steroidogenesis is the biochemical process by which your body manufactures steroid hormones from cholesterol. Every hormone in this cascade—from cortisol managing your stress response to testosterone driving muscle protein synthesis to estradiol protecting your bones—originates from a single molecule of cholesterol undergoing a series of enzymatic transformations.
The process begins in the mitochondria, where the enzyme CYP11A1 performs the rate-limiting first step: cleaving cholesterol's side chain to produce pregnenolone. From there, pregnenolone branches into multiple pathways depending on which tissue it's in and which enzymes are present. The adrenal cortex produces cortisol and aldosterone. The gonads produce testosterone and estradiol. Each pathway is defined by specific enzymes—most notably the cytochrome P450 family (CYP17A1, CYP19A1, CYP21A2) and hydroxysteroid dehydrogenases (3β-HSD, 17β-HSD)—that determine which hormones a given cell can synthesize.
Click any hormone to highlight its complete biosynthetic lineage—both upstream precursors and downstream metabolites. This reveals the interconnected nature of the system: testosterone doesn't exist in isolation, but sits downstream of DHEA and androstenedione while serving as the direct precursor to both DHT and estradiol.
Implications for Hormone Supplementation
Understanding steroidogenesis has practical consequences for anyone using exogenous hormones, whether for hormone replacement therapy (HRT), testosterone replacement therapy (TRT), or performance enhancement.
Downstream Conversion Is Inevitable
When you introduce a hormone exogenously, it doesn't simply remain as that hormone. Testosterone will aromatize to estradiol via the aromatase enzyme (CYP19A1), particularly in adipose tissue. It will also convert to DHT via 5α-reductase in androgen-sensitive tissues like the prostate and hair follicles. This is why TRT patients often need to monitor not just testosterone levels, but also estradiol and DHT—the downstream effects are baked into the biochemistry.
The same principle applies in reverse: taking a precursor hormone like DHEA or pregnenolone doesn't guarantee it will convert to your target hormone. Conversion depends on enzyme availability, which varies by tissue and individual genetics. DHEA supplementation, for instance, may preferentially convert to androgens in some individuals and estrogens in others.
Upstream Suppression Is Real
Exogenous hormones create negative feedback on the hypothalamic-pituitary axis, suppressing endogenous production of upstream hormones. Testosterone administration suppresses LH and FSH, which in turn reduces testicular production of not just testosterone but also the intratesticular precursors. This is why fertility preservation during TRT often requires additional intervention.
For those on feminizing HRT, exogenous estradiol suppresses gonadotropins and consequently reduces endogenous testosterone production—a feature, not a bug, of the therapy. But it also means that if estradiol is discontinued abruptly, the upstream machinery may take time to recover.
Enzyme Inhibitors Reshape the Cascade
Many adjunct medications work by blocking specific enzymes in the cascade. Finasteride inhibits 5α-reductase, reducing DHT production from testosterone—useful for hair loss but with implications for neurosteroid production (since 5α-reductase also processes other substrates). Aromatase inhibitors block the testosterone-to-estradiol conversion, which can be beneficial for managing elevated estrogen but risks bone density loss and lipid profile changes if estradiol is suppressed too aggressively.
Anastrozole, letrozole, and exemestane each inhibit aromatase with different potencies and mechanisms. Understanding where aromatase sits in the cascade—and how broadly expressed it is in peripheral tissues—helps explain why these drugs have systemic effects beyond just lowering serum estradiol.
Context Matters: Tissue-Specific Expression
The visualizer shows the complete theoretical cascade, but no single cell expresses every enzyme. The zona glomerulosa of the adrenal cortex lacks CYP17A1, so it produces aldosterone rather than cortisol. The testes express high levels of 17β-HSD, driving testosterone production. Adipose tissue expresses aromatase, making it a significant site of peripheral estrogen synthesis—one reason body composition influences hormone profiles.
This tissue specificity means that systemic hormone levels only tell part of the story. Local hormone concentrations can differ dramatically from serum measurements, and local enzyme expression determines which metabolites predominate in a given tissue.
The Takeaway
Steroid hormones don't exist as isolated compounds—they're nodes in a dynamic, interconnected network. Introducing any hormone exogenously creates ripple effects both upstream (via feedback suppression) and downstream (via enzymatic conversion). Effective hormone management requires understanding not just your target hormone, but its relationship to the entire cascade.
Whether you're optimizing a TRT protocol, managing side effects of gender-affirming hormone therapy, or simply trying to understand your lab work, the steroidogenesis cascade provides the map. The enzymes are the roads, the hormones are the destinations, and cholesterol is where every journey begins.