This is something I originally wrote up as a collection of research for someone who was considering writing a piece on TRT in MMA, but since it's come up again and i've noticed some misconceptions starting to fly I figured i'd put it up here.



It's not a particularly easy read, and I think at some point it mentions Doc Benjamin by name - as i say it's an old piece, i'm not harking back to take a shot at him or anything, at the time this was written it was timely and relevant.



Hopefully you guys find it informative or useful, and i apologize for the dryness.



Research including sources after the jump.



Testosterone Replacement Therapy is the term used to refer to treatment of two specific diagnoses – Primary hypogonadism and Secondary hypogonadism.



Primary hypogonadism refers to any issue which causes the testicles (gonads) to no longer produce the required amount of testosterone for a person to function normally. In women it refers to the ovaries rather than the testicles. Primary Hypogonadism is also known as Hypergonadotropic Hypogonadism.



A non-exhaustive list of causes of primary hypogonadism[1][2]:



Certain autoimmune disorders

Genetic & Developmental disorders: e.g., Klinefelter's syndrome, Anorchia

Toxins: Alcohol, heavy metals

Orchitis (inflammation of the testicles, caused by infections or STDs. Most common post puberty)

Infection

Liver & Kidney Disease

Radiation

Surgery

Trauma (Trauma in this incidence refers to direct testicular trauma, as opposed to in Secondary Hypogonadism which refers most often to head trauma.)

Steroid abuse[3]

Ageing [4]



In total the American Association of Clinical Endocrinologists lists 18 direct biological causes of primary hypogonadism. This list does not speculate as to the reason or causes for any of these biological methods of action (e.g. it does not list steroid abuse as a cause, simply the biological result of steroid abuse).[4]



It should be noted that while some sources consider ageing to be a cause of primary hypogonadism, others (such as the AACE) feel it is more likely to be a secondary cause of hypogonadism. This is because the exact mechanism of reduced testosterone in older men is varied and is often not the result of a single cause, but of reduced testicular action combined with other hormonal issues. Because it is not solely a testicular issue, the AACE does not consider it a cause of primary hypogonadism.



The AACE do however concede that “more recent evidence

supports the view that an age-related decline in testicular

function may occur with associated symptoms and often

responds to testosterone replacement therapy”



As we can see, there are reversible causes on this list (such as infections, inflammation of the testicles & heal-able trauma). This is in direct opposition to what some people have claimed (including Dr Johnny Benjamin, a respected orthopaedic surgeon & MMA pundit: https://twitter.com/DrJCBenjamin/status/209971489888415744 ) and is a common misunderstanding of hypogonadism.



In an ideal world, treatment for hypogonadism would not be prescribed or used until the exact cause of hypogonadism had been diagnosed. In practice many doctors will treat the condition first in order to improve a patients quality of life before the cause of low testosterone is diagnosed.



[5]Of all causes of primary hypogonadism in men Klinefelter's syndrome is the most common, occurring in 1 in every 500-1000 live births in males (an incidence rate of approx 0.1-0.2% of all males).



Secondary Hypogonadism refers to any problems in producing testosterone or related substances where problems with the testicles are not a primary factor. Most often this involves issues with the Hypothalamus & hormones, or the Pituitary Gland. Secondary Hypogonadism is also known as Central Hypogonadism.



A non-exhaustive list of causes of Secondary Hypogonadism[1][2]:



Bleeding

Certain medications including steroids and opiates*

Genetic problems

Infections

Nutritional deficiencies

Hemochromatosis (excess iron)

Radiation

Rapid, significant weight loss

Surgery

Trauma (especially to the back of the head)*[6]

Tumors

Lesions occupying space at or near the pituitary or hypothalamus

Pituitary disease





In relation to MMA we see several causes which will by definition put mixed martial artists at a higher risk of hypogonadism compared to the general population:



Rapid significant weight loss – extreme dieting and weight cutting is something that athletes competing in MMA must do regularly and often without medical supervision.



Medications such as opiates – MMA Athletes are often injured and in pain, the de-facto out of competition treatment for these injuries is usually a non-steroidal anti inflammatory coupled with an opiate-based painkiller. MMA Athletes will use opiate based painkillers more often than the general population due to the prevalence of injury in their lifestyle.



Trauma (especially to the back of the head) – Studies have shown that minor whiplash is enough to cause secondary hypogonadism, or at least reduced testosterone production. MMA Athletes will often be struck accidentally to the back of the head both during sparring and during competition. In addition the wrestling aspect of MMA means that the forces subjected to the back of the head upon a completed takedown could also be sufficient to cause damage to the pituitary gland, not to mention after a knockdown or knockout during competition or sparring.



Interestingly studies indicate that most (but not all) trauma related changes in testosterone recover in a 6-12 month period [7]



As we can see, many causes of Secondary Hypogonadism are reversible, and there is reason to believe that MMA Athletes may be specifically vulnerable to several of them.



I was unable to source an accurate breakdown of all causes of primary hypogonadism in men aged 20-40 or thereabouts. Overall (primary + Secondary) rates are estimated to be 2-5 million men in the US [8][9]



In men under the age of 40, according to the Baltimore Longitudinal Study of Ageing, the prevalence in men under 40 was approx 5%, though the sample size was very small. Overall incidence rates varied from 5.6% to 49% depending on age.[10]





TESTOSTERONE TESTING IN MMA



Testing for testosterone levels in MMA is conducted via urine testing. Levels of testosterone are not detectable in urine (this requires a blood test), however the ratio of testosterone to epitestosterone is.



The normal ratio in the average male is 1:1. The average for athletes is 2:1.[11] In approx 0.5% of the population the ratio will be 4:1 naturally[12]. As a result most athletic commissions and sporting leagues use 4:1 as their natural cut-off. Some, including Nevada, use 6:1.



When a person has hypogonadism both testosterone AND epitestosterone output is decreased, however TRT usually only returns testosterone itself to normal levels.



The cut-off AMOUNT of testosterone in the blood for consideration for TRT is generally between 200ng/dL and 319ng/dL according to the AACE guidelines[4]



Normal levels of testosterone for a male are 300ng/dL to 1000ng/dL[13] Average levels for healthy males are[12]:



Age : ng/dL

<25: 692

25-29: 669

30-34: 621

35-39: 597

40-44: 597



So how do some athletes hit ratios such as 17:1 after receiving TRT?



There are two causes of this. The first is simply that while TRT boosts testosterone, it does not boost epitestosterone. Thus if an athletes testosterone production is 20% of normal, so is their epitestosterone.



This means the person could only be producing 120 ng/dL of epitestosterone assuming a 1:1 ratio. If they had the 2:1 ratio most common in athletes, they would only produce 60ng/dL of epitestosterone. This means if they have their testosterone boosted back up to a “normal” level of 1000ng/dL, they would suddenly have a ratio of 1000:60, or approx 17:1.



The other factor is that most Testosterone Replacement Therapy is based around intramuscular injections of testosterone. An issue with these is that for a few days after receiving the injection, testosterone levels will be ABOVE normal levels, but for the majority of the 2-3 weeks between injections will be within normal limits (but slowly falling). This means the day after an injection an athletes testosterone levels could be 1500ng/dL, but 2/3 days later be back within normal limits and stay there for the next 2-3 weeks.



Conversely an athlete could have a ratio of 1:1 and be just below the low testosterone cut-off. Thus they could be producing 320ng/dL of epitestosterone and a high ratio could indicate extreme levels of testosterone. Urine testing is unable to make that distinction.



For this reason urine testing of T:E ratios is an unreliable method of determining whether or not an athlete is abusing testosterone. It is reasonably accurate for determining whether or not an athlete has injected testosterone into their body, but not how much. (in other words it can tell you if someone is on TRT, but not if they are abusing the TRT). For this blood testing would be required at regular intervals in order to measure the levels immediately post-injection, and then the levels several days later once they have normalised.









[1]Definitions of primary/secondary hypogonadism and list of causes: http://www.nlm.nih.gov/medlineplus/ency/article/001195.htm

[2]Further list of causes of primary/secondary hypogonadism: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/male-hypogonadism/

[3]Steroid abuse as cause of primary hypogonadism: http://www.ncbi.nlm.nih.gov/pubmed/21575947

[4] AACE diagnoses & treatment guidelines of Hypogonadism: https://www.aace.com/files/hypo-gonadism.pdf

[5]Incidence rate of Klinefelter's syndrome: http://emedicine.medscape.com/article/922038-overview#a0199

[6]Head Trauma & Hypogonadism: http://jcem.endojournals.org/content/85/4/1353.long

[7]Recovery following head trauma: http://www.springerlink.com/content/u77p2t822qw76760/

[8]Overall prevalence of hypogonadism 4-5 million (paragraph 2): http://www.bumc.bu.edu/sexualmedicine/publications/prevalence-diagnosis-and-treatment-of-hypogonadism-in-primary-care-practice/

[9]Overall prevalence of hypogonadism 2-4million (Abstract): http://www.utasip.com/files/articlefiles/pdf/ASP_3_4p136_141.pdf

[10]Graph of hypogonadism in men 29-29 and 30-39: http://www.ismh.org/en/sys/wp-content/uploads/2012/04/2_MERYN-epidemiology-SR-formatted-and-second-checked1.pdf

[11]T:E ratios for athletes: http://doping-info.de/proceedings/proceedings_10_pdf/10_261.pdf

[12]Average T:E levels: http://www.mens-hormonal-health.com/normal-testosterone-levels.html

[13]Normal levels of testosterone:http://www.nlm.nih.gov/medlineplus/ency/article/003707.htm