A New Frontier in Diagnosing Low Testosterone: The CAG Repeat Game-Changer

[Nelson Vergel]

Imagine going to your doctor, complaining of fatigue, low libido, and mood swings, only to be told your testosterone levels are "normal." Frustrating, right? Well, a groundbreaking study from the University of Sheffield and Barnsley Hospital might just change the game for millions of men struggling with these symptoms.

The Testosterone Puzzle​

Let's face it, diagnosing low testosterone (or male hypogonadism, if we're being fancy) has always been a bit of a head-scratcher. Doctors have traditionally relied on measuring total testosterone levels in the blood, but here's the kicker: not all testosterone is created equal.

The Three Musketeers of Testosterone:

1. Free Testosterone: The maverick, ready for action
2. Albumin-bound Testosterone: The sidekick, also pretty active
3. SHBG-bound Testosterone: The lazy one, just hanging around

Only the first two really matter when it comes to how testosterone affects your body. But even then, something was missing from the picture.

Enter the CAG Repeat: The Hidden Player​

Here's where things get interesting. Researchers have discovered that it's not just about how much testosterone you have, but how well your body responds to it. The androgen receptor (AR), which is in charge of controlling this response, can vary greatly between men in terms of sensitivity. The secret? It's all in your genes, specifically the number of CAG repeats in the AR gene. Think of it like a volume knob for testosterone:

• Fewer CAG repeats = AR turned up to 11, super sensitive to testosterone
• More CAG repeats = AR with the volume down, less responsive to testosterone

The Study: Putting It All Together​

The clever folks at Sheffield and Barnsley decided to combine testosterone measurements with this CAG repeat information. They looked at 40 men, some with symptoms of low testosterone and some without.

The Big Discovery:
When they factored in the CAG repeat length, their ability to accurately diagnose low testosterone skyrocketed. The best performer? A ratio they called FT*, which combines free testosterone levels with CAG repeat information.

What This Means for You​

1. More Accurate Diagnosis: If you're experiencing symptoms of low testosterone but your levels come back "normal," this new approach might finally explain why.
2. Personalized Treatment: Understanding your AR sensitivity could lead to more tailored treatment plans. One-size-fits-all might become a thing of the past.
3. Hope for the Borderline Cases: Men who fall into that frustrating gray area of "maybe low testosterone" might finally get some clarity.

The Road Ahead​

While this study is exciting, it's just the beginning. More research is needed to fully understand how we can use this information in everyday clinical practice. But for men struggling with unexplained fatigue, low libido, and other symptoms of low testosterone, this could be the light at the end of the tunnel.So, the next time you're discussing testosterone with your doctor, you might want to bring up the CAG repeat test. It could be the key to unlocking a more vibrant, energetic you.Remember, when it comes to your health, sometimes it pays to dig a little deeper. The answer might just be hiding in your genes.

Source: 8567 Clinical Use of the Androgen Receptor Sensitivity CAG Repeat Polymorphism to Refine and Improve the Diagnosis of Male Hypogonadism

 

[Nelson Vergel]

Based on the search results, here are the key points about how CAG repeats in the AR gene are measured:

1. PCR-based methods are commonly used:
- Fragment length analysis: The CAG repeat region is amplified by PCR and then analyzed by capillary electrophoresis to determine fragment size[1][3].
- Fluorescence-labeled PCR: Uses fluorescent primers to amplify the CAG repeat region, allowing for more precise sizing[1][3].

2. The specific process often involves:
- Isolating DNA from blood samples[1][4].
- Using PCR with forward and reverse primers to amplify the region containing the CAG repeats[1].
- Separating the amplified fragments using capillary electrophoresis[1].
- Analyzing the fragment lengths to determine the number of CAG repeats[1][3].

3. The normal range of CAG repeats in the AR gene is typically:
- Between 9-35 repeats in most individuals[3][4].
- A mean of 21-23 repeats is common in normal populations[3].

4. There can be ethnic variations in CAG repeat lengths[2]:
- Different populations may have slightly different ranges and distributions of repeat lengths.

5. In some studies, the CAG repeat length is categorized into groups (e.g., <19, 19-28, >28) for analysis of its effects[5].

6. For accurate clinical diagnosis or research, multiple methods may be used in combination to verify results[1][2][3].

7. The CAG repeat length can be analyzed in relation to various factors like androgen sensitivity, semen quality, and certain health conditions[1][2][5].

Citations:
[1] Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals - PMC
[2] Androgen Receptor Gene CAG Repeat Length Varies and Affects Semen Quality in an Ethnic-Specific Fashion in Young Men from Russia - PMC
[3] Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility
[4] AR gene: MedlinePlus Genetics
[5] Frontiers | Size Matters: The CAG Repeat Length of the Androgen Receptor Gene, Testosterone, and Male Adolescent Depression Severity

 

[Wilson7]

Carruthers hit on this topic among a large number of other variables that can drive sensitivity to testosterone in a 2008 paper. Carruthers M. The paradox dividing testosterone deficiency symptoms and androgen assays: A closer look at the cellular and molecular mechanisms of androgen action. J Sex Med 2008;5:998–1012

 

[SparkyNeuron]

As far as this stuff goes, we live in a really cool time. The price of Whole Genome Sequencing WGS is becoming more affordable. I came across this list for anyone that's interested. Average price I've found for 30X WGS is around $400-$500.

Genome Services

Geo.Church.

arep.med.harvard.edu

30X seems to be the standard from what I understand. WGS will also let you search for SNP's Single Nucleotide Polymorphisms in the SHBG gene area, plus whatever else you want to look for. MTHFR gene mutation comes to mind if fatigue is a concern. Really cool times, I just sent my sample in, should have results in about 12 weeks. I'll post what I find when I get the results back.

 

[SparkyNeuron]

Imagine going to your doctor, complaining of fatigue, low libido, and mood swings, only to be told your testosterone levels are "normal." Frustrating, right?

Testosterone Replacement Therapy for Male Hypogonadism

Testosterone deficiency, or male hypogonadism, is a clinical syndrome that can be defined as persistently low serum testosterone levels in the setting of symptoms consistent with testosterone deficiency. Studies suggest that testosterone replacement therapy may improve sexual function...

www.aafp.org

I emailed the author of the 2024 American Family Physician guidelines. I also CC'd the AAFP, the Endocrine Society, and the author of the 2017 AFP guidelines. He responded that he received my emails and is looking in to it.

The 2024 AFP guidelines use a diagnostic flow chart from the 2017 article. That flow chart is referenced as being from the 2010 endocrine guidelines.

The 2010 guidelines have been retired and replaced with the 2018 endocrine guidelines.

Testosterone Therapy in Men With Hypogonadism: An Endocrine Society* Clinical Practice Guideline

This update to the Endocrine Society’s 2010 testosterone guideline, prepared by an expert panel, describes the diagnosis, screening, treatment, and monitor

academic.oup.com

Scroll down to the diagnostic flow chart, it mentions SHBG and free T levels, the notes under the flow chart are an important read.

Personally, I like the VA (Veteran's Affairs) criteria. They are short and to the point. Here's a copy of part of the email that I sent.

"Veteran Affairs Guidelines
Guidelines are listed under “Documents & Links”
Criteria for Use: Testosterone Replacement Therapy in Adult Men [Mar-19]
VA Formulary Advisor

Things to note:
Page 1: 3rd line from the bottom of the page – “Free (or bioavailable) testosterone levels are acceptable alternatives to total testosterone”
Page 4: Free Testosterone Levels – 2nd bullet from the top of the page
Page 5: Reference #3 is the 2018 Endocrine guidelines (2010 guidelines have been retired). Interestingly, there’s no reference to the AUA guidelines. I imagine that was purposely done because the current AUA guidelines are written similarly to the retired 2010 Endocrine guidelines.

This is important because Free T levels are showing to be a better metric for testosterone therapy. Patients with Normal Total T and Low Free T are often highly symptomatic but are being denied care due to the use of outdated guidelines. Crucially, they are also being excluded in research because they do not fit the criteria of outdated guidelines.

This is an interesting read.
Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone
The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 7, 1 July 2016, Pages 2647–2657, Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone
Of particular note, Page 2650 Table 1 - Normal TT/Low cFT Group:
-Highest SHBG
-Lowest overall sexual function score
-Highest Beck depression inventory score
-BMI similar to the Normal TT/Normal cFT group
-Lowest Bone mineral density

 

[Systemlord]

I fully expect to have fewer AR CAG repeats if my experience with very low Total and Free T is any indication.

I’ve continued to lose weight (186->169 lbs) with a later afternoon (3:40 pm) Total T @104 ng/dL and a Free T <2.0. I don’t have any symptoms of low testosterone.

Muscle mass if there, muscle definition, energy is increasing. Muscle recovery time, same as TRT. I work 8-10 hour days and still have energy to spare. Full throttle energy all day.

Well, my break is over, time to get back to work.

 

[Kenp]

Damn this could also be interesting for PFS, PSSD, etc