Andropause part 6 - Lab Reference Ranges

Welcome to part 6 of the ODX Andropause & Low T Syndrome Series. In this post, the ODX research team reviews the reference ranges for the most common male sex hormones: Total Testosterone, Free Testosterone, Bioavailable Testosterone, and Sex Hormone Binding Globulin. We will also review additional biomarkers that will give you a full picture of what’s going on.

Andropause - Lab Reference Ranges

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

The ODX Male Andropause Series

1. Andropause Part 1 – An Introduction
2. Andropause Part 2 – Biology & Physiology
3. Andropause Part 3 – How to identify it
4. Andropause Part 4 – Lab Assessment and Biomarker Guideposts
5. Andropause Part 5 – Clinical Determination
6. Andropause Part 6 – Lab Reference Ranges
7. Andropause Part 7 – How do we treat and counteract andropause?
8. Andropause Part 8 – Lifestyle approaches to addressing Andropause
9. Andropause Part 9 – Optimal Takeaways
10. Optimal The Podcast – Episode 9: Andropause

Labs have different reference ranges for Total Testosterone, Free Testosterone, Bioavailable Testosterone and Sex Hormone Binding Globulin.Below are the ranges, organized by age, for the main labs here in the US and the optimal ranges employed by Optimal DX:

Quest male[i]

 Labcorp male[ii]

Laposata[iii]

Optimal DX Male

Additional testing[iv]

• Elevated LH and FSH are likely associated with primary hypogonadism
• Low to low normal LH and FSH are likely associated with secondary hypogonadism
• Age-related changes may be seen in other biomarkers though their significance to LOH has not been fully determined (e.g., estradiol, growth hormone, insulin-like growth factor-1, DHEA/S, thyroid hormone, melatonin)
• Assess FT or BAT if TT is in the low normal range or if alterations in SHBG are suspected:
  • Decreased SHBG in chronic illness, moderate obesity, diabetes, hypothyroidism, glucocorticoid use
  • Increased SHBG suspected in advanced age, cirrhosis, hepatitis, HIV, hyperthyroidism, estrogen use
• If TT is below 150 ng/dL (5.2 nmol/L), assessment of prolactin levels is recommended as well in the event a prolactinoma is present.[v]

Estradiol

Though considered primarily a female hormone, estradiol (E2) has important functions in men including prevention of body fat accumulation, limiting of vasomotor symptoms, and maintenance of bone mineral density and sexual function (in conjunction with testosterone).[vii]

Though conversion of testosterone to estradiol tends to increase with age, levels of both hormones can decrease with age.

Standard estradiol level in adult men is 39 pg/mL (143 pmol/L) or less.[viii] However, levels of bioavailable estradiol below 11 pg/mL (40 pmol/L) may be associated with accelerated loss of bone density.[ix] [x]

 Obesity is associated with an increase in estrogen production in adipose tissue which in turn can inhibit pituitary luteinizing hormone release and testicular T release. However, low serum estradiol, along with low serum T and elevated SHBG, increases the risk of non-vertebral fracture.[xi] This balancing act exemplifies the importance of hormonal harmony in both men and women.

Total T to Estradiol Ratio

Investigation into the ratio of total testosterone to estradiol in 611 post-endarterectomy patients revealed that those with the lowest TT/E2 ratio had significantly higher[xii]

• C-reactive protein: 2.81 v 1.22 ug/mL (27 vs. 11.6 nmol/L)
• White blood cell count: 8.98 vs. 7.75 109/L (especially higher neutrophils and monocytes)
• Atherosclerotic plaque neutrophils, IL-6, IL-6 receptors, plaque calcification
• BMI
• Risk of major cardiovascular events/MACE (MI, stroke, CVD death)
• Negative effects were worse in men with an elevated BMI (aromatase activity is high in white adipose tissue)

Optimal Takeaways for lab evaluation of Andropause / Low T syndrome Measurement

• Testosterone should be measured in the fasting state in the morning between 7 and 11 am.
• Repeat levels should be taken 30 days apart
• Symptoms of LOH may persist with a “normal” TT level if SHBG is elevated
• Free testosterone should be measured using equilibrium dialysis or calculation using TT, SHBG, and albumin (most common), not direct analog-based immunoassays.
• Bioavailable T should be measured using ammonium sulfate or calculated using TT, SHBG, and albumin

Clinical determination

LOH/Andropause is likely when[xiii] [xiv] [xv] [xvi]

• Three primary sexual symptoms (e.g., erectile dysfunction, morning erection, decreased libido) are present along with laboratory confirmation
• Total testosterone below 320 ng/dL (11 nmol/L) (repeated 30 days apart)
• Free testosterone below 64 pg/mL (220 pmol/L)

Further evaluation

• Total T below 400 ng/dL warrants further evaluation
• Free T should be evaluated when TT is 250-350 ng/dL (8-12 nmol/L) or in conditions of altered SHBG.[xvii]
• SHBG should be evaluated in obesity, diabetes, chronic illness, and the elderly, especially when TT is in the low to normal range.[xviii]
• Researchers suggest a cutoff for SHBG of 4.99 ug/mL (44.4 nmol/L) when diagnosing LOH.[xix]
• Symptoms may coincide with specific serum levels of testosterone

Additional testing

• Elevated LH and FSH are likely associated with primary hypogonadism
• Decreased or low normal LH and FSH are associated with secondary hypogonadism
• Estradiol has important functions in men though levels that are too high can feedback to decrease T release. Levels that are too low are associated with reduced bone mineral density.
• A low estradiol to testosterone ratio was associated with significantly higher CRP, WBC, and inflammatory atherosclerotic plaque. [xx]

NEXT UP:Andropause Part 7 – Treating and Counteracting Andropause

Research

[i] Quest. Testosterone Total. Free, Bioavailable. SHBG

[ii] Labcorp Testosterone Total, Free. Bioavailable.

[iii] Laposata, Michael. Laboratory Medicine Diagnosis of Disease in Clinical Laboratory 2/E. McGraw-Hill Education, 2014.

[iv] Singh, Parminder. “Andropause: Current concepts.” Indian journal of endocrinology and metabolism vol. 17,Suppl 3 (2013): S621-9. doi:10.4103/2230-8210.123552.

[v] Guidelines on the management of sexual problems in men: the role of androgens A statement produced by: British Society for Sexual Medicine. 2010.

[vi] Swee, Du Soon, and Earn H Gan. “Late-Onset Hypogonadism as Primary Testicular Failure.” Frontiers in endocrinology vol. 10 372. 12 Jun. 2019, doi:10.3389/fendo.2019.00372

[vii] Bhasin, Shalender et al. “Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.” The Journal of clinical endocrinology and metabolism vol. 103,5 (2018): 1715-1744. doi:10.1210/jc.2018-00229

[viii] Karakas, Sidika E, and Prasanth Surampudi. “New Biomarkers to Evaluate Hyperandrogenemic Women and Hypogonadal Men.” Advances in clinical chemistry vol. 86 (2018): 71-125. doi:10.1016/bs.acc.2018.06.001

[ix] Orwoll, Eric et al. “Testosterone and estradiol among older men.” The Journal of clinical endocrinology and metabolism vol. 91,4 (2006): 1336-44. doi:10.1210/jc.2005-1830

[x] Gennari, Luigi et al. “Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men.” The Journal of clinical endocrinology and metabolism vol. 88,11 (2003): 5327-33. doi:10.1210/jc.2003-030736

[xi] Decaroli, Maria Chiara, and Vincenzo Rochira. “Aging and sex hormones in males.” Virulence vol. 8,5 (2017): 545-570. doi:10.1080/21505594.2016.1259053

[xii] van Koeverden, Ian D et al. “Testosterone to oestradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis.” Cardiovascular research vol. 115,2 (2019): 453-462. doi:10.1093/cvr/cvy188

[xiii] Wu, Frederick C W et al. “Identification of late-onset hypogonadism in middle-aged and elderly men.” The New England journal of medicine vol. 363,2 (2010): 123-35. doi:10.1056/NEJMoa0911101

[xiv] Bhasin, Shalender et al. “Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.” The Journal of clinical endocrinology and metabolism vol. 103,5 (2018): 1715-1744. doi:10.1210/jc.2018-00229

[xv] Singh, Parminder. “Andropause: Current concepts.” Indian journal of endocrinology and metabolism vol. 17,Suppl 3 (2013): S621-9. doi:10.4103/2230-8210.123552.

[xvi] Swee, Du Soon, and Earn H Gan. “Late-Onset Hypogonadism as Primary Testicular Failure.” Frontiers in endocrinology vol. 10 372. 12 Jun. 2019, doi:10.3389/fendo.2019.00372

[xvii] Karakas, Sidika E, and Prasanth Surampudi. “New Biomarkers to Evaluate Hyperandrogenemic Women and Hypogonadal Men.” Advances in clinical chemistry vol. 86 (2018): 71-125. doi:10.1016/bs.acc.2018.06.001

[xviii] Lawrence, Kristi L et al. “Approaches to male hypogonadism in primary care.” The Nurse practitioner vol. 42,2 (2017): 32-37. doi:10.1097/01.NPR.0000511774.51873.da

[xix] Liang, Guoqing et al. “Serum sex hormone-binding globulin is associated with symptomatic late-onset hypogonadism in aging rural males: a community-based study.” Sexual health, 10.1071/SH20201. 15 Mar. 2021, doi:10.1071/SH20201

[xx] van Koeverden, Ian D et al. “Testosterone to oestradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis.” Cardiovascular research vol. 115,2 (2019): 453-462. doi:10.1093/cvr/cvy188