Performance-boosting steroids are even worse than scientists realized

In one of the great ironies of using a chemical shortcut typically associated with macho displays of strength, illicit steroid use by males could do long-term damage to testicles and their function.

A new study published Tuesday in the Journal of Clinical Endocrinology & Metabolism found that anabolic androgenic steroids (AAS) were linked to lowered capacity for testosterone production, also known as hypogonadism, even years after stopping the steroid use.

“Our results suggest that the capacity of testosterone production in Leydig cells of the testicles could be persistently impaired,” lead author Jon Rasmussen, a researcher at the University Hospital of Copenhagen's Department of Endocrinology, tells Inverse.

But, in the future, it’s possible experts will be able to remedy what’s impaired. Rasmussen suggests that a newly identified chemical marker used to estimate testosterone production may point a way toward novel treatments.

Though the study was funded by a group called Anti Doping Denmark, Rasmussen said the grant was “unrestricted” and the funding source had no role in preparation, conduction, or analysis of the study.

What are the worst side effects of steroids?

According to the study, anabolic steroid use is on the rise, and not just for muscle men. “Illicit AAS use has been widespread among bodybuilders and elite athletes for decades but is now frequently observed among men in the broader population,” the researchers write.

One estimate from 2014 found that as many as 4 million American men had used anabolic steroids.

Some take anabolic steroids like testosterone cypionate, nandrolone decanoate, or methenolone by pill or injection to enhance performance or endurance in sports. Others use them to increase their lean muscle mass, whether it’s for sports, work performance in physical jobs, or appearance.

Anabolic steroids have legitimate medical uses and are used for anemia, muscle loss from some diseases, or in hormone therapy for transgender men. But because the abuse of these steroids outside of authorized treatments has known risks — cardiovascular risk, dependence, sharing or reusing of needles, and yes, reduced reproductive function — it’s a public health concern.

Digging into the details — To assess the capacity for testosterone production after stopping steroid use, researchers looked at:

• 44 men who had never used AAS
• 46 who were currently using them
• 42 former users who had not used for an average of 32 months (almost three years)

To measure the capacity of special testosterone producing cells called Leydig cells in the testicles, researchers used a new marker called serum insulin-like factor 3, or INSL3. It’s a peptide hormone (insulin is another) that’s only made by Leydig cells.

Testosterone itself can be an unreliable measure of testosterone production because its levels can fluctuate throughout the day or even within the hour. Body composition, or even smoking a cigarette, can impact testosterone. INSL3, according to Rasmussen, is much more reliable.

The team discovered INSL3 levels from blood taken from the men were lower in both current and former users than in controls. In current and former users, levels were between 0.4 and 0.39 micrograms per liter. Among controls, it was closer to 0.59 micrograms per liter. Higher levels suggest more testosterone production.

What we didn’t know — Anabolic steroids already had a bad rap for reducing testosterone after stopping use and even in the long-term, but this research uses a more accurate measurement to suggest effects of steroids on the male reproductive system could be lasting.

Rasmussen explains that, although it was known that testosterone in AAS users was deficient even after quitting, “it has been unclear whether this testosterone deficiency persists or would fully recover.”

Now, those considering “juicing” have yet another reason not to: they may not completely recover.

Why it matters — It might be enough to know that using steroids could lead to long-term testicle problems, but Rasmussen said he was curious about the potential to develop a treatment that reverses the damage. Specifically, he’s interested in a study to test “stimulation therapy” for recovering Leydig cell capacity in AAS users who had stopped.

Stem cell therapy has been suggested as one route that may hold potential in regenerating mature Leydig cells for hypogonadism, a condition where not enough testosterone is produced (but not necessarily because of AAS use).

What’s next — Apart from cementing the dangers of illicit steroid use and pointing toward new avenues for treatment, Rasmussen tells Inverse he is working on a new study related to AAS use in females and its effects on fertility.

Though male AAS users far outnumber female users (one estimate held male AAS users outnumbered female users anywhere from 8 to one to 50 to one) women do use anabolic steroids for many of the same reasons and in the same settings as men. Though changes in the menstrual cycle are a known side effect of AAS use in women, more research is needed to know the full extent of the situation.

The study also suggests that, although the creation of sperm in the testes (spermatogenesis) was not investigated, previous studies showed sperm count and movement may not be affected by AAS. In the future, further investigation is needed to examine whether the actual “fertility potential” of semen would deteriorate.

Abstract:

Background: Illicit use of anabolic androgenic steroids (AAS) is frequently observed in men and is associated with subsequent testosterone deficiency although the long-term effect on gonadal function is still unclear. Serum insulin-like factor 3 (INSL3) has been suggested to be a superior biomarker of Leydig cell secretory capacity compared to testosterone. The objective of this study was to investigate serum INSL3 concentrations in AAS users.

Methods: This community-based cross-sectional study included men aged 18 – 50 years, involved in recreational strength training and allocated to one of three groups: never-AAS users as controls (n=44), current (n=46) or former AAS users (n=42) with an average duration since AAS cessation of 32 (23;45) months.

Results: Serum INSL3 was lower in current AAS users and former AAS users than in controls, median (IQR), 0.04 (ND – 0.07) and 0.39 (0.24 – 0.62) versus 0.59 (0.45 – 0.72) µg/L, P<0.001. Former AAS users exhibited lower serum INSL3 levels than controls in a multivariate linear regression even after adjusting for serum total testosterone and other relevant confounders, (B) (95%CI), -0.16 (-0.29;-0.04) µg/L, P=0.011. INSL3 and total testosterone were not associated in the model, P=0.821. Longer accumulated AAS duration (log2) was associated with lower serum INSL3 in former AAS users, (B) (95%CI), -0.08 (-0.14;-0.01), P=0.022. Serum INSL3, but not inhibin B or testosterone, was associated with testicular size in a multivariate linear regression, (B) (95%CI); 4.7 (0.5 ; 8.9), P=0.030.

Conclusions: Serum INSL3 is reduced years following AAS cessation in men, independently of testosterone, suggesting persistently impaired Leydig cell capacity.