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Anna L Goldman, Shalender Bhasin, Frederick C. W. Wu | Endocrine Reviews | (2017)
Primary Link Pubmed DOI Openalex Full text (OA)

Abstract

In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant.

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Sample Definition And Size

This paper is a narrative review and does not involve a primary study sample; instead, it critically appraises existing literature and experimental data regarding testosterone binding in circulation. No specific sample size is applicable.

Study Type

Review article (narrative review with appraisal of historical and experimental literature).

Conflicts Of Interest

No conflicts of interest are declared in the available metadata (PubMed entry does not list any).

Results Summary

Key findings: The review challenges prevailing assumptions about stoichiometry, binding dynamics, and affinity in models of testosterone binding to sex hormone-binding globulin (SHBG) and human serum albumin (HSA), showing they are not supported by experimental data. It highlights that only 1–4% of circulating testosterone is free, and that free plus albumin-bound testosterone constitutes bioavailable testosterone. The review presents a revised model incorporating allosteric, multistep binding dynamics of testosterone to SHBG, which better aligns with equilibrium dialysis measurements. It emphasizes the clinical importance of accurate free testosterone measurement for diagnosing and treating androgen disorders. (Endocr Rev. 2017;38(4):302–324) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/28673039/?utm_source=openai))

Referenced In

William Fan
6 months ago
William Fan's 2025 91 Day Weight Loss Challenge

Week 9: Thinking Long-term and TRT

  • Weight (7d avg): 186.4lbs/84.5kg, from peak -13.3lbs/-6.1kg

  • RHR (7d avg): 62.0bpm

  • Calories In (7d avg): 2057kcal

  • Exercise (7d avg): 550kcal

  • Net Deficit (total): -1500kcal

  • 2x4x500m row: 1:51.0, 1:51.3

Notes:

As I began to recover from my surgery, I began thinking about my long-term fitness goals. While getting lean and healthy in my mid 30s was still feasible, what would my capability be like in my 40's, 50's, and 60's. Muscle loss becomes a larger factor as we age. Less time and energy means less exercise leading to loss of bone density and mobility.

This is why I found it so important to continue to challenge myself on this weight loss journey. To create personal benchmarks and also learn how to optimize my nutrition and exercise. Experimenting is easier now and the gains are build on themselves.

Peter Attia: Testosterone Replacement Therapy

Testosterone Replacement Therapy (TRT)

TRT has been a growing topic of interest as an intervention not just for people with specific hormonal disruptions but simply as a health promoting measure for men in their later years. Joe Rogan and the manosphere of health influencers have put TRT in the forefront of many men's minds including myself. What I'd like to understand is how much reduced free testosterone would warrant TRT and the potential risks and benefits if used correctly.

Total testosterone can be understood in three broad categories:

  • Free testosterone (1-4%): bio-available to the body to be used

  • Albumin bound testosterone: loosely bound, held as a reservoir

  • Sex Hormone Binding Globulin (SHBG) bound testosterone: tightly bound for hormone regulation

These three types in sum are your total testosterone and what is most often measured in clinics. However, free testosterone is the only measure that is generally considered valuable for deciding on TRT. Most labs will use a calculated free testosterone (cFT) rather than measure free testosterone due to the complexities of direct measurement. That being said, many guidelines still use total testosterone to determine cutoffs despite free testosterone being a more accurate measure.

As an example, normal amounts of total testosterone are shown in this study:

Our final analytic cohort contained 1,486 men. Age-specific middle tertile levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359-498 ng/dL (30-34 years old), 352-478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively.

When making the decision on whether TRT is right for you, its best to consider these factors and the impact some lifestyle changes like exercise can make not just on your total testosterone, but also how it may liberate additional free testosterone from your other bounded reservoirs.

This 2017 study reviewed the impact of various exercise types on elderly men's testosterone levels:

TT was significantly increased following HIIT (~17%; P < 0.001) with most increase occurring during preconditioning (~10%; P = 0.007). Free-T was unaffected by conditioning exercise (P = 0.102) but was significantly higher following HIIT compared to baseline (~4.5%; P = 0.023). Cortisol remained unchanged from A to C (P = 0.138). The present data indicate a combination of preconditioning, and HIIT increases TT and SHBG in sedentary older males, with the HIIT stimulus accounting for a small but statistically significant increase in free-T.

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6
William Fan
6 months ago
Health, Fitness, and Nutrition

Testosterone Replacement Therapy (TRT)

Peter Attia: Testosterone replacement therapy TRT has been a growing topic of interest as an intervention not just for people with specific hormonal disruptions but simply as a health promoting measure for men in their later years. Joe Rogan and the manosphere of health influencers have put TRT in the forefront of many men's minds including myself. What I'd like to understand is how much reduced free testosterone would warrant TRT and the potential risks and benefits if used correctly.

Total testosterone can be understood in three broad categories:

  • Free testosterone (1-4%): bio-available to the body to be used

  • Albumin bound testosterone: loosely bound, held as a reservoir

  • Sex Hormone Binding Globulin (SHBG) bound testosterone: tightly bound for hormone regulation

These three types in sum are your total testosterone and what is most often measured in clinics. However, free testosterone is the only measure that is generally considered valuable for deciding on TRT. Most labs will use a calculated free testosterone (cFT) rather than measure free testosterone due to the complexities of direct measurement. That being said, many guidelines still use total testosterone to determine cutoffs despite free testosterone being a more accurate measure.

As an example, normal amounts of testosterone are shown in this study:

Our final analytic cohort contained 1,486 men. Age-specific middle tertile levels were 409-558 ng/dL (20-24 years old), 413-575 ng/dL (25-29 years old), 359-498 ng/dL (30-34 years old), 352-478 ng/dL (35-39 years old), and 350-473 ng/dL (40-44 years old). Age-specific cutoffs for low testosterone levels were 409, 413, 359, 352, and 350 ng/dL, respectively.

When making the decision on whether TRT is right for you, its best to consider these factors and the impact some lifestyle changes like exercise can make not just on your total testosterone, but also how it may liberate additional free testosterone from your other bounded reservoirs.

This 2017 study reviewed the impact of various exercise types on elderly men's testosterone levels:

TT was significantly increased following HIIT (~17%; P < 0.001) with most increase occurring during preconditioning (~10%; P = 0.007). Free-T was unaffected by conditioning exercise (P = 0.102) but was significantly higher following HIIT compared to baseline (~4.5%; P = 0.023). Cortisol remained unchanged from A to C (P = 0.138). The present data indicate a combination of preconditioning, and HIIT increases TT and SHBG in sedentary older males, with the HIIT stimulus accounting for a small but statistically significant increase in free-T.

Read Full Post
0