CHICAGO, Illinois — Anti-inflammatory therapy may be a novel approach to treating hypogonadism and possibly reducing cardiovascular risk in men with metabolic syndrome, new research suggests.
Findings from the randomized, double-blind, placebo-controlled TestIL trial were presented March 18 here at ENDO 2018: The Endocrine Society Annual Meeting by Fahim Ebrahimi, MD, of University Hospital Basel, Switzerland.
TestIL is the first study to investigate the use of an anti-inflammatory for the treatment of hypogonadism. The drug used in the study, anakinra (Kineret, Sobi), is a recombinant human interleukin-1 receptor antagonist used in the treatment of rheumatoid arthritis and other less-common inflammatory conditions.
"Men with metabolic syndrome often have low testosterone. Metabolic syndrome is a state of chronic, low-grade inflammation. We have shown in this trial for the first time that an anti-inflammatory treatment increases testosterone levels," Ebrahimi told Medscape Medical News.
He added, "We still don't know if testosterone replacement therapy is beneficial or potentially harmful on cardiovascular endpoints. We do know that inflammatory parameters influence testosterone levels, and that the higher the inflammation, the lower the testosterone levels."
In addition to a significant improvement in testosterone levels, the men in the study randomized to anakinra also had reductions in C-reactive protein (CRP) and blood pressure, along with improvements in sexual function and grip strength compared with placebo.
"We believe that's clinically relevant against the background of the large CANTOS trial published recently showing that antagonism of the inflammation of interleukin-1 reduces cardiovascular mortality," he noted.
But, he cautioned that the current study is just proof of concept. "The treatment duration was quite short, only 4 weeks. We need to conduct larger trials to show clinical effects."
Asked to comment, session moderator Monica M Laronda, PhD, director of basic and translational research for the Fertility & Hormone Preservation & Restoration Program at Northwestern University, Chicago, told Medscape Medical News, "We're continuing to find that reproductive hormones — both ovarian and testicular — have great systemic effects on our overall health."
Replacing the lost testosterone is likely to remain first-line hypogonadism treatment for the time being, she said, but "there has been an increase in the anti-inflammatory literature in other disorders. I would be really interested to see other types of metabolic markers or other markers besides blood pressure and hand strength. I'm anxious to see what else comes out of this research."
Raises Testosterone, Improves Metabolic Parameters
The study included 70 obese men aged 18 to 75 years with total morning testosterone levels less than 12 nmol/L and at least one manifestation of the metabolic syndrome, including prediabetes, diabetes, hypertension, and/or dyslipidemia. They were randomized 1:1 to self-injected anakinra or placebo twice daily for 4 weeks.
The men were a mean age of 54 years and had a mean body mass index of 36 kg/m2. About half had diabetes or prediabetes, three quarters had hypertension, and 83% had dyslipidemia. Baseline total testosterone was 9.3 nmol/L, and CRP was 4.5 mg/L.
By 4 weeks, total testosterone had risen by 11% in the anakinra group compared with no significant change in the placebo group (P = .044). CRP dropped by 51% with anakinra at 4 weeks (P = .002) vs no change with placebo.
Total testosterone response to anakinra was limited to the men with baseline CRP greater than 2.0 mg/L, in whom there was a 24% increase (P = .039) vs a nonsignificant drop in total testosterone with anakinra among those with baseline CRP of 2.0 mg/L or lower.
Similarly, anakinra had a much greater effect on total testosterone among the men with baseline BMI over 40 kg/m2, with a 29% increase from placebo at 4 weeks (P = .035).
And while there was no significant overall effect on free testosterone, those levels significantly increased with anakinra compared with placebo in both subgroups with baseline CRP over 2.0 mg/L and BMI over 40 kg/m2 (P = .013 and .020, respectively).
Secondary endpoints with significant results included a 2.94-mmHg drop in diastolic blood pressure from baseline to 4 weeks with anakinra vs a 0.80-mmHg fall with placebo (P = .058 for treatment difference) and a significant improvement in hand grip with the nondominant hand with anakinra compared with a decline in the placebo group (P = .036).
The anakinra group also had improved scores on the International Index of Erectile Function questionnaire (P = .057).
Adverse Events Mild, Tolerable
There were no serious adverse events. The most common adverse event was transient injection-site reactions in 21 patients with anakinra vs none in the placebo group. The reactions were deemed mild in 11 patients and moderate in 10 patients. Mild nausea was reported in 2 anakinra patients vs none with placebo, diarrhea in 5 vs 2, and upper respiratory tract infection in 3 vs 4.
In response to an audience member's concern that people who were immunosuppressed or had a recent infection were excluded from the study, Ebrahimi responded that anakinra has been prescribed to more than 150,000 patients worldwide for rheumatoid arthritis and hasn't shown a higher frequency of infections or immunosuppression.
And he pointed out that this contrasts with testosterone replacement therapy, which "we don't know if it's harmful."
Ebrahimi has reported no relevant financial relationships.
ENDO 2018. March 18, 2018; Chicago, Illinois. Abstract OR15-6
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Cite this: Anakinra Boosts Testosterone Levels in Obese Hypogonadal Men - Medscape - Mar 20, 2018.