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How to take testosterone? Risks and benefits analysis.

Oliver Zolman MD

· Fitness

Section 1: Benefits of Testosterone

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systematic[sb] AND testosterone muscle

A meta analysis (MA) (Skinner et al., 2018) of double blind RCTs of men aged 45 to 75 who were taking transdermal or intramuscular (IM) testosterone for a minimum of 8 weeks was found. The study reported that all its results had high heterogeneity, however they did not report heterogeneity values. They also did not adjust for majorly flawed studies, however inclusion criteria of “double blind” could be argued to fractionally offset bias from other sources that were not adjusted for. Additionally, DEXA was used which is prone to measuring water content alongside muscle in a “fat free mass (FFM)” measure; with the authors stating MRI is a better measure of muscle gain. One study appeared to leverage results in the IM subgroup, however removing this study would not change statistical significance of results given all other IM studies were above -0.01. 20one retrieved the leveraging study and identified incomplete follow up of 50/70; despite using intention to treat analysis it was not stated which time points patients dropped out at; the study can be argued to be invalid (https://doi.org/10.1210/jc.2004-1933). The authors did not provide weights of each study or raw data, so assuming this leveraged study is removed it could be estimated that the effect sizes of IM are only half, as a conservative estimate.

The (Skinner et al., 2018) study showed transdermal patches had an estimated 1.5 – 5.5% increase in total body strength, whilst IM testosterone had an 8 to 15% increase – but halving this due to the removal of the leveraging study results in a 4 – 7% increase in total body strength for IM testosterone. Regards fat free mass, understanding that estimates may be confounded by DEXA scan measuring water as well as muscle, as MRI was not used; IM route provided a 4 – 7% increase in fat free mass (bone, water, organ tissue, cardiac muscle, skeletal muscle), which can be understood to be only 2 – 3.5% increase after removing the leveraging study; and transdermal a 1 – 2 % increase.

Notably those included in this MA did not have hypogonadism as an inclusion criteria.

Do these findings extend to people outside the over age 45 and male population?

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(Therapy/Broad[filter]) AND (testosterone athletes)

Changed filter to narrow after low specificity

Similar to my estimated results of effect of T on performance, a literature review (Bermon, 2017) of T in female athletes estimated a 2-5% performance versus those with lower free testosterone, even when this was from exogenous testosterone.

An ultra high dose of IM T study (Bhasin et al., 1996) in men around age 20 – 30, BMI 20 – 30, found a 2.5-3.5kg greater increase in fat free mass versus placebo after 10 weeks; and increase in total T from 500 to 3000, and free T from 80 to 500, 40cm^2 increase in mean cross sectional area on MRI versus placebo, and likewise a 80 cm^2 increase in quadriceps; as well as a 10 kg and 20 kg increase over placebo in bench press and squat respectively; all assuming strength training is ongoing whilst using IM T. The study concluded that (quoted): “Our results in no way justify the use of anabolic–androgenic steroids in sports, because, with extended use, such drugs have potentially serious adverse effects on the cardiovascular system, prostate, lipid metabolism, and insulin sensitivity. Moreover, the use of any performance-enhancing agent in sports raises serious ethical issues. Our findings do, however, raise the possibility that the short-term administration of androgens may have beneficial effects in immobilized patients, during space travel, and in patients with cancer-related cachexia, disease caused by the human immunodeficiency virus, or other chronic wasting disorders.” This study was not majorly flawed.

Fat loss effects

T therapy likely preferences towards fat loss over muscle loss in obese(https://www.ncbi.nlm.nih.gov/pubmed/27716209) and elderly (https://www.ncbi.nlm.nih.gov/pubmed/22190001) men; however it is not clear if this is so in people at lower body fat or normal bioactive testosterone levels.

Notably no change in body fat % was found in (Bhasin et al., 1996) in young male athletes with lower end body fat %, even at the very high 600 mg/week dose of IM T; body fat % did not change, suggesting T only serves to increase FFM (muscle, bone and non-fat organs).

There was a borderline significant decrease in total body fat mass with 200 mg/week IM T in non-athletic young men taking T for contraceptive purposes.

Studies that were invalid

Another MA on T effects on FFM could not be considered on (https://doi.org/10.1530/EJE-15-0262) due to lack of subgroups based on testosterone delivery method or dose and over 50% heterogeneity in all results.

A 1998 study of IM T in young healthy athlete males could not be considered as 95% confidence intervals and p values were not shown in the results section https://doi.org/10.1016/S1440-2440(99)80007-3.

Dosing

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systematic[sb] AND testosterone muscle

The average dose of IM testosterone was not reported in (Skinner et al., 2018) but was estimated by me to be 100 mg/week, with likely no difference if taken as 200mg/2 weeks, 400mg/4 weeks or 1000mg/10 weeks, for a total dosage of around 5g per year.

Section 2: Risks of Testosterone

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systematic[sb] AND testosterone muscle; searching of resultant systematic review studies

A systematic review of RCTs

Cardiovascular risks

IM T may have no significant cardiovascular risks, however patches and oral types likely do: In a MA of 45 trials with people age 45 to 80 “Intramuscular testosterone appeared neutral for CVE (rr = 0·96 (0·462;1·98, P = 0·91)) compared with oral testosterone (rr = 2·28 (95% CI 2·28;8·59, P = 0·22)) and transdermal testosterone (rr = 2·80 (1·38;5·68, P = 0·004)). Intramuscular testosterone had the least effect of lowering HDL and non-HDL cholesterol (both P < 0·001).”: https://www.ncbi.nlm.nih.gov/pubmed/27124404

Note that this MA only had 10 months average follow up; 10 years follow up is the preferred time to assess such outcomes.

Anabolic androgenic steroid (AAS) dependencehttps://www.ncbi.nlm.nih.gov/pubmed/19922565/

Quoted from (Piacentino et al., 2015): “AAS use becomes abuse when an uncontrolled urge to take AASs arises, even if it proves to be detrimental for health; it becomes dependence when withdrawal symptoms appear upon abrupt discontinuation. Dependence is usually accompanied by tolerance, which fosters the need for dose increase to obtain the same effect. This ensues in habitual, chronic use that renders AASs even more harmful. In AAS dependence, athletes begin to take doses from 10 to 100 times higher than those used in legitimate medical practice (hence the term “supraphysiological”) and often employ a pyramid administration schedule (a practice known as “pyramiding”), progressively increasing doses in a stepwise manner through the first half of a cycle before reducing them symmetrically in the second half, disregarding all safety issues [117]; they take a combination of two or more different AASs (a practice known as “stacking”), sometimes through different routes of administration, although the combination has not been demonstrated to possess any added desirable effect [130]; they consume very frequent or lengthy cycles, often despite adverse effects [117,131-132]; they use AASs almost continuously for years, reaching an excessive cumulative duration of use [130].”

Long-term suppression of natural testosterone and androgen production after cessation of exogenous AASs; which can cause depression

Unclear absolute risk of long term suppression of

Overall mental health risks of AASs, particularly in very high dose or dependent users

Observational studies have found a relationship between AAS use and mental health disorders, such as depression and bipolar disorder, however no interventional trials were reported in (Piacentino et al., 2015) so causation cannot be proven. However, it appears that the potential relationship is dose dependent.

(Piacentino et al., 2015): “Addicted AAS users may possibly benefit from a dose reduction through a tapering course of medically prescribed steroids, as abrupt AAS discontinuation may precipitate severe depression and suicide [66, 73]. However, the detoxification of AAS abusers is a poorly studied area, and the prescription of an abused substance to a substance user can be problematic, unless close supervision is provided. Caution in using clonidine for AAS detoxification is recommended, as clonidine itself has been associated with depression. Antidepressants, which have shown promising results during cocaine withdrawal, deserve to receive trials in the treatment of AAS withdrawal.”

Anger or "roid rage"

(Tricker et al., 1996) found no increase in anger inventory scores at 600 mg IM T per week for 10 weeks in young athletic men. However, of 50 participants on the same dose in another RCT (https://www.ncbi.nlm.nih.gov/pubmed/10665615) found that for ~15% of people became mildly or markedly hypomanic; it is plausible the sample size in the first RCT was too small to detect this.

Neurotoxicity

There is cellular evidence that 50 times the normal T concentration can cause neuronal cell death (and potentially cardiomyocytes). The upper normal total T range in men is around 1000 ng/dL, or 1 microgram /dL, or 10 micrograms per L, or 50 micrograms in the total blood assuming 5L blood volume. 50 micrograms x 50 = 2500 micrograms or 2.5 mg. A normal IM T dose is 100 mg/week or 14 mg/day, suggesting even this dose could theoretically cause such damage if applied to users who have normal testosterone.

Reverse body dysmorphic syndrome that can lead to AAS dependence

“Specifically, men with body-image concerns may be motivated to use AAS initially, and then paradoxically become increasingly concerned about their muscularity even as they are growing bigger on AAS. Muscularity becomes central to their self-esteem, and loss of muscularity triggers anxiety. This phenomenon frequently contributes to the syndrome of AAS dependence (Brower, 2002; Brower et al., 1990).” Quoted from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646607/.

Long-term psychiatric problems that persist indefinitely after cessation of use

Observational studies found a 160% increased risk of seeking treatment for psychiatric symptoms in former elite male athlete AAS users https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646607/ (secondary reference available only – search “Lindqvist et al., 2007” within this article)

All-cause-mortality

A small observational study of 62 powerlifters found a 300% increase in death from all causes, mostly suicide, in power lifters suspected to use AAS (10.1055/s-2000-304)

Gynaecomastia

Increased incidence in observational study: https://www.ncbi.nlm.nih.gov/pubmed/8179461

Fertility

A meta analysis (doi: 10.1007/s40279-017-0709-z.) of fertility side effects of T use could not be commented on due to it combining poor observational studies with randomized trials and having high heterogeneity.

https://www.ncbi.nlm.nih.gov/pubmed/15906618 found that the average time to restore fertility after AAS use was 6 months, with some people requiring tamoxifen therapy to restore fertility.

Long term impacts on sperm or egg quality are not known, e.g. risks to offspring as AAS can cause genetic damage to sperm: “ FISH sperm analysis revealed XY and chromosomes 1 and 9 disomies, suggesting anomalies in the meiotic process and genetic damage among AAS users”, quoted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744441/.

(Matsumoto, 1988) Found that sperm counts and function were dramatically reduced on “High dose IM T”, however the study could not be retrieved in full. They quote: “In male contraceptive trials, approximately half of normal men become azoospermic on high dosages of testosterone enanthate (TE), whereas the other half of men become severely oligozoospermic.”

(Bhasin et al., 1996) found that a supraphysiologic dose of T in young men, 600 mg per week IM, massively reduced the sex hormones LH and FSH from around 3 to around 0.4 and 0.1 respectively after 10 weeks, below the normal range of 2 – 6 for males for LH and 1.7 – 4.1 for FSH (http://accessmedicine.mhmedical.com/content.aspx?bookid=1069&sectionid=60775149)

Acne

3/21 men in the T group had acne, when taking very high dose 600 mg/week IM T (Bhasin et al., 1996).

Loss of benefits after cessation

All gains in performance were lost likely within 6 weeks of cessation in https://doi.org/10.1016/S1440-2440(99)80007-3.

Assessing testosterone status and body composition effects

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testosterone concentration age

Total and free testosterone (T) does not clearly decline with age (doi: 10.2337/dc09-1649), however a small study looking at serum-non-SHBG-testosterone found a significant drop 10.1210/jcem-63-6-1418, with these results repeated for bioavailable testosterone by another small study https://doi.org/10.1016/0022-4731(90)90287-3.

Hence if one may better assess testosterone function by measuring bioavailable T, as opposed to free T or total T.

MRI should be used over DEXA due to higher accuracy of muscle and organ volumes; however, DEXA likely outperforms MRI at bone mineral density measurements.

In those that it is of high importance to assess muscle quality (elderly, otherwise at high risk of low muscle quality and need to verify interventions to improve muscle quality above DEXA or functional strength measurements), an MRI of appropriate muscle groups such as thighs, calves and biceps, or thighs only given this is the largest muscle group and would save costs of MRI to a single scan region, could be done every ~2 years.

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