Low testosterone and your genes

While bodybuilding and athletes may come to mind with the word testosterone, it is actually an essential hormone for men and women of all ages and athletic abilities. As with most hormones, balance is key for testosterone levels – not too low and not too high.

This article looks at testosterone and the genetic variations that can affect your natural “T” levels. I’ll explain some of the background science and then wrap up with Lifehacks for increasing testosterone levels.

Testosterone Levels:

In men, low serum testosterone levels are linked to an increased risk of:

  • metabolic syndrome
  • type-2 diabetes
  • atherosclerosis
  • heart disease mortality[ref][ref]

In women, increased testosterone levels are a risk factor for:

  • fatty liver disease[ref]
  • PCOS, insulin resistance, and higher fasting glucose levels[ref]
  • type 2 diabetes[ref]

In men, the testes release testosterone when stimulated by luteinizing hormone. In women, the adrenals and the ovaries produce small amounts of testosterone.

Most testosterone, about 98%, that circulates in the bloodstream is bound to either albumin or sex-hormone-binding globulin (SHBG). The 2% that is ‘free’ testosterone is the biologically active form that can act on receptors on cells.

Your circulating testosterone levels depend on many factors, including genetics.

How do your genes influence testosterone levels?

While age, diet, and lifestyle choices play a role in testosterone levels, there is also a fairly strong genetic factor at play. Studies of male siblings estimate that the genetic component of testosterone levels is ~70%.[ref]

Genetic studies can now use the known variants linked to testosterone levels to see if those variants are related to other conditions.

For example, studies on the SHBG gene variants show an association with facial characteristics such as jaw shape, which is connected to testosterone levels.[ref]

Other studies link genetic variants impacting testosterone levels to an increased risk of prostate cancer, increased bone mineral density, and lower body fat.[ref]

What if you’re XXY?

Klinefelter syndrome is caused by having two X chromosomes and the Y chromosome.

In general, Klinefelter syndrome is linked to lower testosterone levels. Men with XXY genotypes may have less body hair, lower muscle mass, and possibly abnormal development of the testicles.

Klinefelter syndrome is one of the most common chromosomal abnormalities, with an estimated 1 in 500 men having an extra X chromosome.


Testosterone Genotype Report:

Below are the genetic variants that have been linked in multiple studies to testosterone levels.

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SHBG gene variants:

Sex hormone-binding globulin (SHBG) binds to testosterone (and other sex hormones) in the bloodstream, making it biologically inactive and unable to enter the cells. Often SHGB levels are tested along with total testosterone levels to determine what part of the total testosterone is ‘free’ and available to be used by the cells.

Adding up your variant: A large-scale study of 14,000+ men found the following SHBG variants were associated with testosterone levels, and the association is additive. The more minor alleles the men carried, the likelier they were to have low testosterone levels (<300ng/dl in this study).[ref]

Check your genetic data for rs12150660 (23andMe v4 only):

  • G/G: Lower average free testosterone[ref]
  • G/T: lower average free testosterone levels
  • T/T: typical testosterone levels

Members: Your genotype for rs12150660 is .

Check your genetic data for rs6258 (23andMe v4, v5; AncestryDNA):

  • T/T: lower free testosterone, decreased SHBG binding affinity for testosterone[ref] (rare genotype)
  • C/T: lower free testosterone, decreased SHBG binding affinity for testosterone
  • C/C: typical testosterone

Members: Your genotype for rs6258 is .

Check your genetic data for rs6259 (23andMe v4, v5):

  • A/A: increased SHBG levels[ref][ref]
  • A/G: increased SHBG levels
  • G/G: typical SHBG

Members: Your genotype for rs6259 is .

Check your genetic data for rs1799941 (23andMe v4, v5; AncestryDNA):

  • A/A: higher SHBG levels, higher total testosterone levels[ref]
  • A/G: somewhat higher SHBG levels, testosterone
  • G/G: typical SHBG

Members: Your genotype for rs1799941 is .

FAM9B gene variants:

The FAM9B gene encodes a protein expressed in the testes that is thought to be related to the formation of sperm.[ref] Note that the FAM9B gene is on the X-chromosome, so males will only have one copy. Yes, guys, you can blame your mom for this one.

Check your genetic data for rs5934505 (23andMe v4, v5):

  • T- allele: lower average serum and free testosterone levels[ref]
  • C-allele: typical testosterone

Members: Your genotype for rs5934505 is .

FSHB gene:

The FSHB gene codes for FSH (follicle-stimulating hormone) beta-subunit. This hormone is expressed by the pituitary gland and regulates the function of either the ovaries or the testes.

Check your genetic data for rs10835638 (23andMe v4, v5; AncestryDNA):

  • T/T: risk of low follicle-stimulating hormone levels, reduced free testosterone[ref], increased risk of male infertility[ref]
  • G/T: intermediate risk of low follicle-stimulating hormone levels
  • G/G: typical FSH

Members: Your genotype for rs10835638 is .

LIN28B gene:

The LIN28B gene codes for a cold-shock protein that is expressed in the testes and placenta.

Check your genetic data for rs7759938 (23andMe v5; AncestryDNA):

  • C/C: lower testosterone levels (compared to TT genotype)[ref][ref]
  • C/T: lower testosterone levels (compared to TT genotype)
  • T/T: typical (higher T compared to the minor allele)

Members: Your genotype for rs7759938 is .

 

Note: Other gene variants influence testosterone levels that aren’t available via 23andMe or AncestryDNA testing. Specifically, a commonly repeated section of the androgen receptor plays a significant role in testosterone levels.


Lifehacks:

What is the best way to know if your testosterone levels are normal? Get a blood test to see what your levels are. Your doctor should be able to run the test, or you can order your blood test online (in the US) through a place like UltaLab Tests.

Timing of Testing:
Testosterone levels fluctuate throughout the day in a circadian-controlled rhythm, with the highest levels in the morning for men.[ref] If you are going to test your testosterone periodically to see how it changes, always get the blood drawn around the same time.

Get enough sleep:
A study in healthy young men found that a short night (5 hours of sleep) decreased testosterone levels significantly (~13%) for the following day.[ref]

BPA:
Environmental exposure to BPA and phthalates is associated with increased SHBG levels and decreased testosterone (total and free) in children and teens.[ref]

Related article: BPA and your genes

Phthalates:
Another study looked at phthalate levels in a larger group and found that increasing phthalate levels were associated with decreased testosterone levels for boys and men and women ages 40-60.[ref]

Related article: Detoxifying Phthalates: Genes and Diet

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References:

Bogaert, Veerle, et al. “Heritability of Blood Concentrations of Sex-Steroids in Relation to Body Composition in Young Adult Male Siblings.” Clinical Endocrinology, vol. 69, no. 1, July 2008, pp. 129–35. PubMed, https://doi.org/10.1111/j.1365-2265.2008.03173.x.

El Tarhouny, S. A., et al. “Study of Sex Hormone-Binding Globulin Gene Polymorphism and Risk of Type 2 Diabetes Mellitus in Egyptian Men.” The West Indian Medical Journal, vol. 64, no. 4, Sept. 2015, pp. 338–43. PubMed, https://doi.org/10.7727/wimj.2014.088.

Ferguson, Kelly K., et al. “Prenatal and Peripubertal Phthalates and Bisphenol-A in Relation to Sex Hormones and Puberty in Boys.” Reproductive Toxicology (Elmsford, N.Y.), vol. 0, Aug. 2014, pp. 70–76. PubMed Central, https://doi.org/10.1016/j.reprotox.2014.06.002.

Fui, Mark Ng Tang, et al. “Lowered Testosterone in Male Obesity: Mechanisms, Morbidity and Management.” Asian Journal of Andrology, vol. 16, no. 2, 2014, pp. 223–31. PubMed Central, https://doi.org/10.4103/1008-682X.122365.

Grigorova, Marina, Margus Punab, Kristo Ausmees, et al. “FSHB Promoter Polymorphism within Evolutionary Conserved Element Is Associated with Serum FSH Level in Men.” Human Reproduction (Oxford, England), vol. 23, no. 9, Sept. 2008, pp. 2160–66. PubMed Central, https://doi.org/10.1093/humrep/den216.

Grigorova, Marina, Margus Punab, Olev Poolamets, Mart Adler, et al. “Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age.” Journal of the Endocrine Society, vol. 1, no. 6, Apr. 2017, pp. 560–76. PubMed Central, https://doi.org/10.1210/js.2017-00050.

Grigorova, Marina, Margus Punab, Olev Poolamets, Piret Kelgo, et al. “Increased Prevalance of the −211 T Allele of Follicle Stimulating Hormone (FSH) β Subunit Promoter Polymorphism and Lower Serum FSH in Infertile Men.” The Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 1, Jan. 2010, pp. 100–08. PubMed Central, https://doi.org/10.1210/jc.2009-1010.

Jin, Guangfu, et al. “Genome-Wide Association Study Identifies a New Locus JMJD1C at 10q21 That May Influence Serum Androgen Levels in Men.” Human Molecular Genetics, vol. 21, no. 23, Dec. 2012, pp. 5222–28. PubMed, https://doi.org/10.1093/hmg/dds361.

Leinonen, Jaakko T., et al. “LIN28B Affects Gene Expression at the Hypothalamic-Pituitary Axis and Serum Testosterone Levels.” Scientific Reports, vol. 9, Dec. 2019, p. 18060. PubMed Central, https://doi.org/10.1038/s41598-019-54475-6.

Lerchbaum, Elisabeth, et al. “Hyperandrogenemia in Polycystic Ovary Syndrome: Exploration of the Role of Free Testosterone and Androstenedione in Metabolic Phenotype.” PLoS ONE, vol. 9, no. 10, Oct. 2014, p. e108263. PubMed Central, https://doi.org/10.1371/journal.pone.0108263.

Lopresti, Adrian L., et al. “A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Examining the Hormonal and Vitality Effects of Ashwagandha ( Withania Somnifera) in Aging, Overweight Males.” American Journal of Men’s Health, vol. 13, no. 2, Apr. 2019, p. 1557988319835985. PubMed, https://doi.org/10.1177/1557988319835985.

Meeker, John D., and Kelly K. Ferguson. “Urinary Phthalate Metabolites Are Associated With Decreased Serum Testosterone in Men, Women, and Children From NHANES 2011–2012.” The Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 11, Nov. 2014, pp. 4346–52. PubMed Central, https://doi.org/10.1210/jc.2014-2555.

Mohammadi-Shemirani, Pedrum, et al. “Effects of Lifelong Testosterone Exposure on Health and Disease Using Mendelian Randomization.” ELife, vol. 9, p. e58914. PubMed Central, https://doi.org/10.7554/eLife.58914. Accessed 19 May 2022.

Ohlsson, Claes, et al. “Genetic Determinants of Serum Testosterone Concentrations in Men.” PLOS Genetics, vol. 7, no. 10, Oct. 2011, p. e1002313. PLoS Journals, https://doi.org/10.1371/journal.pgen.1002313.

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Panizzon, Matthew S., et al. “Genetic and Environmental Influences of Daily and Intra-Individual Variation in Testosterone Levels in Middle-Aged Men.” Psychoneuroendocrinology, vol. 38, no. 10, Oct. 2013, pp. 2163–72. PubMed Central, https://doi.org/10.1016/j.psyneuen.2013.04.003.

Roosenboom, Jasmien, et al. “SNPs Associated With Testosterone Levels Influence Human Facial Morphology.” Frontiers in Genetics, vol. 9, Oct. 2018, p. 497. PubMed Central, https://doi.org/10.3389/fgene.2018.00497.

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Sarkar, Monika, et al. “Testosterone Levels in Pre-Menopausal Women Are Associated With Nonalcoholic Fatty Liver Disease in Midlife.” The American Journal of Gastroenterology, vol. 112, no. 5, May 2017, pp. 755–62. PubMed Central, https://doi.org/10.1038/ajg.2017.44.

Wankhede, Sachin, et al. “Examining the Effect of Withania Somnifera Supplementation on Muscle Strength and Recovery: A Randomized Controlled Trial.” Journal of the International Society of Sports Nutrition, vol. 12, 2015, p. 43. PubMed, https://doi.org/10.1186/s12970-015-0104-9.

Originally published 10/2018. Updated 3/2020.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.