Intro
In a recent article I wrote about enclomiphene being used as an alternative to testosterone replacement therapy, which has become trendy. Today I wanted to give a breakdown on testosterone, it’s production and how to analyze it within a hormone panel.
How Testosterone is Produced
The majority (~95%) of testosterone is produced in the testicles by Leydig cells, with a small amount being produced by the adrenal gland. Testosterone production and regulation is the end result of a somewhat complex cascade of chemical processes. The hypothalamus secretes gonadotropin releasing hormone (GnRH) that binds the pituitary. The pituitary then secretes the gonadotropins which, ie leutinizing hormone (LH) and follicle stimulating hormone (FSH). LH signals for the leydig cells, in he testicles, to produce testosterone. Testosterone is then aromatized into estrogen which which plays a part in the regulation of test production, through binding to the hypothalamus and pituitary. Testosterone is converted into dihydrotestosterone as well. Follicle stimulating acts upon Sertoli cells, which play a role in sperm production. LH, FSH, estrogen, DHT and testosterone all generally appear on bloodwork, which we’ll come back to later.
Interpreting Blood Work
The amount of testosterone, measured in nanograms per deciliter of blood (ng/dL), will be labeled as total testosterone on your blood work results. There’s a few types of tests that measure total testosterone. The first two are radio immunoassaying and enzyme immunoassaying (EIA or ELISA), which use antibodies to detect testosterone. The most accurate, though, is gas chromatography-tandem mass spectrometry.
A large amount of total testosterone is carried through the body by albumin as well as a protein called sex hormone binding globulin (SHBG). SHBG is also tested for on most hormone panels and is measured in nanonmols per liter or nmol/L. SHBG’s primary function is to regulate the amount of unbound and useable steroid hormones in the blood, which also includes DHT and estrogen [1]. There is research showing SHBG has other functions as well, although outside the scope of this article [2]. Testosterone that’s not bound to SHBG is labeled as free testosterone, and is able to exert it’s effect on the androgen receptor. Low free testosterone can be a marker for and cause symptoms of low testosterone [3] in those with regular total testosterone levels. Free testosterone is measured a couple of different ways as well. One is ultrafiltration, the use of a centrifuge to separate free testosterone from the blood. The most accurate, though, is equilibrium dialysis, where free testosterone is separated using a semipermeable membrane and then directly measured through assaying [4][5].
Circling back to LH and FSH, normal or elevated levels with exceedingly low total testosterone and sperm production is representative of primary hypogonadism, or the lack of testicular function. It is generally caused by genetic disorders where the testicles don’t properly form or as the result of physical damage which can range from things such a dog bites to radiation exposure. Lack of hypothalamus and/or pituitary function, or low LH and FSH levels, leading to low test and sperm production, is called secondary or central hypogonadism. Secondary hypogonadism can be caused by a variety of things such nutrient deficiency, obesity, medications such as opiates, head trauma to include things such as radiation and surgery, as well as genetic conditions again [6]. While some men with secondary hypogonadism can see improvements with lifestyle changes, primary hypogonadism’s treatment seems limited to hormone replacement therapy.
Best Practices
Hormone panels should be taken at a consistent time. Optimally in the morning, as this is when production is at its highest. It’s also worth knowing that testosterone production can vary widely day to day depending on lifestyle factors. If you’ve been sleeping for four hours a night and eating more microwavable meals than normal due to it being finals week, then wake up hung over on Saturday morning to go get blood drawn, the results could convince you that TRT is medically necessary. It is completely normal for alcohol, poor diet and lack of sleep to crush hormone production by a significant amount. Sleep deprivation for a week, more than halved the testosterone production in mice [7]. This is why getting a running average of hormone levels paints a better picture. This is also why testosterone replacement has “benefits”, even if you only replace testosterone to natural levels. Keeping testosterone at a static point, achieved through frequent administration, will remove dips due to poor lifestyle choices or periods of overwork and low sleep. Overall good health and and sufficient data points will lead to the best outcomes.
Sources:
[1] Geoffrey L. Hammond, Diverse Roles for Sex Hormone-Binding Globulin in Reproduction, Biology of Reproduction, Volume 85, Issue 3, 1 September 2011, Pages 431–441, https://doi.org/10.1095/biolreprod.111.092593Url:https://academic.oup.com/biolreprod/article/85/3/431/2530485
[2] Wallace, I.R., McKinley, M.C., Bell, P.M. and Hunter, S.J. (2013), Sex hormone binding globulin and insulin resistance. Clin Endocrinol, 78: 321-329. https://doi.org/10.1111/cen.12086Url:https://onlinelibrary.wiley.com/doi/10.1111/cen.12086
[3] Urlhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164116
[5] Jennifer L. Shea, Pui-Yuen Wong, Yu Chen, Chapter Two – Free Testosterone: Clinical Utility and Important Analytical Aspects of Measurement, Editor(s): Gregory S. Makowski, Advances in Clinical Chemistry, Elsevier, Volume 63,2014, Pages 59-84, Url:https://www.sciencedirect.com/science/article/abs/pii/B9780128000946000029
[6] Url: https://www.mayoclinic.org/diseases-conditions/male-hypogonadism/symptoms-causes/syc-20354881#causes
[7] Choi JH, Lee SH, Bae JH, Shim JS, Park HS, Kim YS, Shin C. Effect of Sleep Deprivation on the Male Reproductive System in Rats. J Korean Med Sci. 2016 Oct;31(10):1624-1630. https://doi.org/10.3346/jkms.2016.31.10.1624Url:https://jkms.org/DOIx.php?id=10.3346/jkms.2016.31.10.1624
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