Respiratory Outcomes in Hypogonadal Men with COPD May Improve with TRT

Testosterone replacement therapy may be warranted to reduce hospitalizations for chronic obstructive pulmonary disease.

With Randall J. Urban, MD, Jacques Baillargeon, PhD, and  Martin M. Miner, MD

The World Health Organization (WHO) predicts that chronic obstructive pulmonary disease (COPD) will become the third-leading cause of morbidity and mortality worldwide by 2030. Between 22% and 69% of men with COPD have delayed hypogonadism, owing in part to the prolonged use of glucocorticoids, numerous comorbidities, and hypoxemia.1-4

While it is not yet known exactly how testosterone deficiency influences COPD, observational studies introduced the prospect that testosterone replacement therapy (TRT) may have a protective effect for several respiratory functions.5-7

Older men with COPD may benefit from testosterone replacement therapy.

To explore the potential for TRT to reduce the risk of hospitalization due to respiratory distress in men with COPD, a team of investigators from the University of Texas undertook a retrospective cohort study that utilized two databases to identify about 700 men with COPD who used TRT. This study represents the first large-scale, nationally representative study on the effect of TRT on respiratory outcomes (specifically, hospitalizations) in middle-aged and older men with COPD.8

Fewer Pulmonary Hospitalizations May Occur with Testosterone Therapy  

According to Randall J. Urban, MD, professor of internal medicine and Vice Dean for Clinical Research at the University of Texas School of Medicine in Galveston, “testosterone replacement therapy was initially administered to men with end-stage COPD with the aim of improving muscle mass; however, there did not appear to be much benefit, possibly because these men were too far along in the disease process.”

A number of earlier studies explored the relationship between testosterone supplementation and respiratory factors in healthy men, including body composition, skeletal muscle strength, and exercise capacity.9-10 Consequently, these effects prompted queries, regarding the prospect that testosterone supplementation may impart a beneficial effect, either directly or indirectly, on respiratory outcomes.5,7,11

To support this premise further, combining TRT with standardized pulmonary rehabilitation, nutritional support, and resistance training has been shown to confer favorable effects, including peak oxygen uptake;9,13 but findings were also introduced that countered any positive outcomes.8

Examining Hypogonadal Older Men with COPD 

In this study,8 the primary study outcome was the rate of hospitalizations for respiratory conditions in the 12 months prior to and 12 months after initiation of > 60 days of TRT, as compared to hospitalization rates for all non-respiratory conditions during this same time period.

In the first database, the investigators identified 450 men, ages 40-63 years, who were part of a large US commercially-insured population (CDM); and, for the second cohort, men (n=253) who were > 66 years and were included in the national 5% Medicare database were evaluated.8

For both studies, the men had to have initiated TRT within the 12 months following the date of their COPD diagnosis; men who had fewer than 60 days of testosterone treatment in the year following their first TRT prescription were excluded from the study cohorts.8

Patients were identified as having chronic obstructive pulmonary disease if they had:

  • At least 2 outpatient/consultation visits with COPD-related diagnostic codes
  • An acute care hospitalization with a primary discharge diagnosis of COPD

Codes referencing a prescription of TRT (in any formulation) were used to identify men with hypogonadism.8

The mean age at TRT initiation in the CDM cohort was 55.8 years. Nearly two-thirds of the men had at least one comorbidity, and less than 7% of them had “high complexity” COPD. The older Medicare cohort initiated TRT at a mean of 74.5 years, with 91% of them having at least one comorbidity–and 72% having 2 or more comorbidities.About 11% of the older patients had COPD that was defined as “high” complexity. 

Fewer Respiratory Hospitalizations in Men on TRT

A significant decrease in the rate of respiratory-related hospitalizations was noted among the younger cohort in the 12 months after initiating TRT (P = 0.04), but not in the older cohort,8 according to the researchers. However, when compared with the control, non-TRT users, both age groups who were taking TRT demonstrated a greater relative decrease in respiratory hospitalizations (P = 0.03). 

Notably, in assessing for respiratory hospitalizations, the middle-aged men revealed a 4.2% greater decrease and the older cohort had a 9.1% greater decrease compared with the non-TRT cohorts.8 However, these findings held up only during the first 60 days of the analyses–subsequent analyses failed to reach statistical significance. Further, there were no statistically significant differences in hospitalizations for non-respiratory conditions in either group after initiation of TRT compared to prior to TRT treatment.

COPD severity increased faster over the 24-month follow-up period in the older versus middle-aged cohort. Further, the investigators noted that in the older cohort, an increase in hospitalizations among non-TRT men was likely the reason for the findings as versus a decrease in the hospitalization rate in the TRT group.8 The findings suggest that in some men with COPD, TRT may slow the progression of the disease.

Comparing Results to Clinical Guidelines for Testosterone Supplementation

In an interview with EndocrineWeb, Jacques Baillargeon, PhD, associate professor of preventive medicine and community health at the University of Texas Medical Branch in Galveston, said, “one of the limitations of the study was that we relied on administrative claims data, and therefore did not have access to baseline or follow up lab findings for testosterone levels.

We also were unable to determine an indication for testosterone therapy in the complete cohort. So, it is likely that the majority of men may have had a diagnosis of hypogonadism (defined as total testosterone < 300 ng/dL) and some symptoms of hypogonadism, such as decreased muscle mass, increased adiposity, low libido, and osteoporosis, to name a few.”

Martin M. Miner, MD, clinical associate professor of family medicine and urology at the Warren Alpert School of Medicine at Brown University, and director of the Men’s Health Center at Miriam Hospital in Providence, Rhode Island, commented on the limitations of retrospective investigations, but noted that this was a cross-sectional study involving two different age groups of men with COPD using testosterone replacement therapy, in an interview with  EndocrineWeb.

Dr. Miner said, “during the time covered by this study (from 2005-2014), clinicians were less cautious regarding age or the level of testosterone before initiating TRT for their patients, making it difficult to translate the study results into current clinical practice.”

“The most recent update of the Endocrine Society guidelines regarding testosterone therapy for men indicates that men over age 65 years should not be prescribed testosterone therapy routinely,"14 he said. "However, testosterone replacement therapy may be appropriate for middle-aged men with a diagnosis of low testosterone (and no contraindications), and can be prescribed to others on an individualized basis after discussing the potential risks and benefits."

Therapeutic Benefits Look Promising But Not Yet Confirmed

Ultimately, this current retrospective study highlights the need for additional studies into how and why TRT reduced respiratory-associated hospitalizations in middle-aged men with COPD.”

“We don’t know if the improvement [seen in these men] was related to increased skeletal muscle, reduced hypoxemia, increased mobility, decreased inflammation, or some other reasons,” said Dr. Baillargeon. Yet, “it is possible that TRT slows progression,” said Dr. Miner, “Future studies, and particularly clinical trials, are needed to explore these findings to confirm a clinical benefit” from testosterone replacement therapy in men with hypogonadism and COPD. 

Continue Reading:
Benefits of Testosterone Supplementation Elusive in TTrials
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