The Biology of ACRD: Impaired Hormone Conversion

To understand Apparent Cortisone Reductase Deficiency (ACRD), it helps to think of the body’s hormone system as a recycling center. In a typical person, the body does not just make cortisol and throw it away; it converts inactive cortisone back into active cortisol when needed ^[1]. ACRD is what happens when this conversion process is impaired.

The Impaired Conversion Loop

The conversion of cortisone to cortisol is handled by an enzyme called 11β-HSD1. For this enzyme to do its job, it needs a constant supply of energy (a cofactor called NADPH), which is provided by a second enzyme called H6PD ^[1].

ACRD occurs because of a genetic mutation in either of these two parts:

• HSD11B1 mutations: The enzyme itself is defective ^[1].
• H6PD mutations: The “generator” is defective, so the enzyme does not have the NADPH it needs to run ^[1].

Because the body cannot efficiently convert cortisone back to cortisol, it loses active cortisol much faster than normal—a process called increased cortisol clearance ^[2].

Why This Leads to High Androgens

When the brain senses that cortisol is being cleared too fast, it releases a signal called ACTH (adrenocorticotropic hormone) to tell the adrenal glands to work harder to maintain normal cortisol levels ^[1].

The adrenal glands respond by going into overdrive (adrenocortical hyperactivity). While they successfully pump out more cortisol to keep up, they also produce high amounts of “byproducts”—specifically, androgens (such as testosterone) and 17-hydroxyprogesterone (17-OHP) ^[1][2]. It is these excess androgens that cause the early hair growth in children and irregular cycles or skin issues in adult women ^[2].

It’s important to clarify that having ACRD does not necessarily mean your body cannot make cortisol at all (unlike untreated classic adrenal insufficiency). You are usually making it, but clearing it away too quickly.

Differentiating ACRD from Other Conditions

Because ACRD is rare and causes high androgens, it is frequently confused with more common conditions. Doctors look for specific biological clues to tell them apart.

Note: A person can have both PCOS and an adrenal disorder, and they are diagnosed using a combination of clinical signs and lab tests.

A Key Test: The Urinary Steroid Profile

Because blood tests for ACRD can be misleading (for example, 17-OHP can be high in both ACRD and NCCAH), a key specialized test to support an ACRD diagnosis is a 24-hour urinary steroid profile using a technology called GC-MS or LC-MS/MS ^[2][8].

This test looks at the ratio of THF and 5α-THF (or allo-THF) (cortisol leftovers) to THE (cortisone leftovers). In a healthy person, this ratio is higher (often reported around 0.7 to 1.2, depending on the lab). In someone with ACRD, the ratio is drastically lower—sometimes reported in case studies as low as 0.021—because the body isn’t making enough “cortisol leftovers” from cortisone ^[2]. While this test helps distinguish the mechanism of the disorder, the diagnosis is made by integrating these results with your clinical picture, other hormone tests, and sometimes genetics.