Skip to content
How It Works
Explore
Ask a Question Resources Pricing
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Sign Up
PubMed This is a summary of 5 peer-reviewed journal articles Updated
Endocrinology · Apparent Cortisone Reductase Deficiency

Diagnosis and Deciphering Your Lab Results

At a Glance

Apparent cortisone reductase deficiency is evaluated with a 24-hour urinary steroid profile, especially the THF plus 5α-THF to THE ratio. A markedly low ratio supports impaired cortisone-to-cortisol conversion, while genetic testing may assess HSD11B1 and H6PD.

The journey to a diagnosis of Apparent Cortisone Reductase Deficiency (ACRD) often begins with a series of blood tests that may leave you with more questions than answers. Because ACRD is so rare, standard screening tests can sometimes lead doctors toward more common conditions, like Polycystic Ovary Syndrome (PCOS) or Congenital Adrenal Hyperplasia (CAH). Confirming ACRD requires a deep dive into how your body processes and clears its stress hormones [1][2].

A Specialized Test: Urinary Steroid Profiling

While most hormone tests use blood, a key specialized test for ACRD is a 24-hour urinary steroid profile. This test provides a “map” of how your adrenal glands have been working over a full day [3].

To get an accurate map, labs use a technology called Gas Chromatography-Mass Spectrometry (GC-MS) or LC-MS/MS [3]. These methods are highly sensitive and can tell the difference between hormones that look nearly identical. Standard blood tests (immunoassays) can “cross-react,” meaning they might mistake one hormone for another, leading to an incorrect diagnosis [3].

Proper 24-Hour Urine Collection:
An incomplete collection can make the results unreliable. Generally, the process is:

  1. Wake up and urinate into the toilet (discard this first void). Note the exact time.
  2. Collect every single drop of urine for the next 24 hours in the provided container.
  3. Keep the container stored as instructed by the lab (often refrigerated).
  4. Exactly 24 hours after the start time, urinate one last time and add it to the container.

The Key Number: The Ratio

When you look at a specialized urinary lab report, you will see a list of metabolites—the “leftovers” created when the body breaks down hormones. The most important calculation for ACRD is the ratio between cortisol leftovers (THF and 5α-THF, also called allo-THF) and cortisone leftovers (THE) [1].

  • Normal Ranges Vary: In a healthy individual, this ratio is higher (literature often cites 0.7 to 1.2, but this varies based on laboratory method, age, and sex) [1][4].
  • The ACRD “Fingerprint”: In someone with ACRD, this ratio is markedly low. Because the body cannot convert cortisone into cortisol, it produces very few cortisol leftovers and a massive amount of cortisone leftovers. In documented cases, patients have had ratios reported as low as 0.021 [1]. Your endocrinologist will interpret this number in the context of your specific lab’s reference ranges and your overall clinical picture.

Avoiding the “17-OHP Trap”

One of the most common reasons ACRD is misdiagnosed is the 17-hydroxyprogesterone (17-OHP) level. In many adrenal conditions, an elevated 17-OHP in the blood is a sign of 21-hydroxylase deficiency (the most common form of CAH) [5].

However, in ACRD, 17-OHP can also be elevated [1]. This happens because the brain is constantly signaling the adrenal glands to work harder to make up for the rapidly cleared cortisol. The adrenal factory revs up and spills out extra 17-OHP as a byproduct [2]. If a doctor only looks at the 17-OHP blood test, they might suspect CAH. The urinary steroid profile helps distinguish that the real problem is impaired cortisone conversion [1][3].

Genetic Confirmation and Counseling

Once biochemical clues are found, doctors may recommend genetic testing to look for pathogenic variants (mutations) in two specific genes:

  1. HSD11B1: This gene provides the instructions for the enzyme itself [2].
  2. H6PD: This gene provides the instructions for the NADPH “power generator” that allows the enzyme to work [2].

Because genetics can be complex (e.g., finding a “variant of uncertain significance” or not finding a mutation despite having symptoms), you should consult with a genetic counselor. They can explain whether your results are homozygous (two identical mutations) or compound heterozygous (two different mutations), and what that means for your family and future children.

Lab Report Checklist

When reviewing your lab results with your doctor, look for these key elements:

  • Methodology: Confirm the test was performed using GC-MS or LC-MS/MS [3].
  • The Big Three Metabolites: The report must list values for Tetrahydrocortisol (THF), 5α-Tetrahydrocortisol (5α-THF or allo-THF), and Tetrahydrocortisone (THE) [1].
  • Calculated Ratio: The ratio of (THF + 5α-THF) / THE should be clearly stated and interpreted by your doctor [1].
  • Creatinine Correction: In some cases, the levels should be corrected for creatinine to ensure the concentration of the urine didn’t skew the results [3].
  • Age and Sex Specific: The lab should provide reference intervals that are specific to the patient’s age and sex [3].

Common questions in this guide

What test is usually used to evaluate apparent cortisone reductase deficiency?
A 24-hour urinary steroid profile is a key test because it measures hormone breakdown products collected over a full day. Laboratories commonly use GC-MS or LC-MS/MS to distinguish closely related hormones more accurately than some standard blood tests.
What does a low THF plus 5α-THF to THE ratio mean?
A markedly low ratio means there are relatively few cortisol breakdown products compared with cortisone breakdown products. This is the characteristic laboratory pattern of impaired cortisone-to-cortisol conversion, but your doctor must interpret it using the laboratory’s reference range and your clinical findings.
Why can 17-OHP be elevated in ACRD?
When cortisol is cleared rapidly, the brain can signal the adrenal glands to work harder. This increased activity may raise 17-OHP and make ACRD resemble congenital adrenal hyperplasia, so the urinary steroid profile helps clarify the cause.
How should I collect a 24-hour urine sample for ACRD testing?
Discard the first urine passed when you begin, then collect every subsequent sample for the next 24 hours, including the final sample at the exact end time. Keep the container as the laboratory instructs, often refrigerated, because an incomplete collection can make the results unreliable.
Why are GC-MS or LC-MS/MS used instead of a standard blood hormone test?
GC-MS and LC-MS/MS can separate hormones and their breakdown products that have very similar chemical structures. Some blood immunoassays can mistake one hormone for another, so specialized testing may provide a more reliable picture of cortisone and cortisol processing.
Which genes may be checked when ACRD is suspected?
Genetic testing may examine HSD11B1, which provides instructions for the cortisone-converting enzyme, and H6PD, which helps that enzyme function. A genetic counselor can explain positive, negative, or uncertain findings and discuss what they may mean for relatives and future children.

Get notified when new evidence is published on Hyperandrogenism due to cortisone reductase deficiency.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

References

References (5)
  1. 1

    A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis.

    Zajkowska A, Rydzewska M, Wojtkielewicz K, et al.

    Pediatric endocrinology, diabetes, and metabolism 2017; (23(1)):42-48 doi:10.18544/PEDM-23.01.0073.

    PMID: 29073307
  2. 2

    Alterations of Cortisol Metabolism in Human Disorders.

    White PC

    Hormone research in paediatrics 2018; (89(5)):320-330 doi:10.1159/000485508.

    PMID: 29843121
  3. 3

    Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: Tracing the complexity of human postnatal steroidogenesis.

    Dhayat NA, Frey AC, Frey BM, et al.

    The Journal of steroid biochemistry and molecular biology 2015; (154()):226-36.

    PMID: 26297192
  4. 4

    Lower Renal Function Is Associated With Derangement of 11-β Hydroxysteroid Dehydrogenase in Type 2 Diabetes.

    Gant CM, Minovic I, Binnenmars H, et al.

    Journal of the Endocrine Society 2018; (2(7)):609-620 doi:10.1210/js.2018-00088.

    PMID: 29942925
  5. 5

    Assisted Reproduction in Congenital Adrenal Hyperplasia.

    Chatziaggelou A, Sakkas EG, Votino R, et al.

    Frontiers in endocrinology 2019; (10()):723 doi:10.3389/fendo.2019.00723.

    PMID: 31708872

This page explains ACRD urinary steroid profiles and related genetic tests for informational purposes only and does not constitute medical advice. Your endocrinologist, laboratory team, and genetic counselor should interpret your specific results.

Guide contents Hyperandrogenism due to cortisone reductase deficiency
Research & Literature
03 The Biology of ACRD 05 Treatment and Balancing Hormone Management