Methadone Treatment Reduces Sex Hormone in Men Only

Deborah Brauser

September 04, 2014

(Updated Sept. 8, 2014) Treating opioid dependence with methadone can dramatically lower testosterone levels, but only in men, new research suggests.

Dr. Zena Samaan

A cross-sectional study of more than 1000 adults showed that the men who were treated with methadone for opioid addiction had roughly one quarter of the testosterone found in the men who did not use opioids.

However, there were no significant associations found in the female participants.

"We expected that men would have lower testosterone. That was not something new," principal investigator Zainab (Zena) Samaan, MD, PhD, associate professor in the Department of Psychiatry and Behavioral Neurosciences in the School of Medicine at McMaster University in Hamilton, Ontario, Canada, told Medscape Medical News.

"What was surprising was the magnitude of the reduction," added Dr. Samaan.

She noted that clinicians should be aware of these findings and should manage symptoms of testosterone deficiency. This includes routinely checking levels before starting any opioid therapy and continuing to do so at regular intervals.

"Doctors should also ensure the patients are being prescribed the lowest dose of opioids, including methadone, for effective treatment to minimize testosterone suppression," she added in a release.

The study was published online August 26 in Scientific Reports.

Sex-Specific Effect

Previous research has shown that long-term opioid use can decrease androgen function.

"Opioids exert inhibitory effects on the hypothalamus, the area responsible for production of gonadotropin-releasing-hormone (GnRH). GnRH normally acts on the pituitary gland to stimulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); when GnRH is inhibited, this leads to low LH and FSH causing suppression of sex hormone secretion from the gonads," they write.

However, the association between opioid use and levels of sex hormones, including testosterone, has not been widely examined in women.

For the study, investigators assessed the effect of opioids, including methadone, on testosterone levels in a cohort of men and women.

A total of 231 adults older than 18 years (56.7% men) with opioid dependence who were receiving methadone treatment in 4 outpatient clinics between June and December 2011 were recruited. The mean age for the men was 38.3 years; for the women, the mean age was 35.2 years.

In addition, the study included 783 age- and sex-matched control individuals who did not take opioids. The mean age of the 287 men in the control group was 46.2 years, and the mean age of the 496 women was 44.6 years.

Information on demographics, history of current and past substance use, and medical conditions was collected from all participants, in addition to urine and blood samples.

Results showed significantly lower testosterone levels in the subgroup of men undergoing methadone treatment vs the men in the control group (mean, 100.10 ng/dL vs 414.74 ng/dL, respectively; P < .0001). In addition, there was an inverse association between methadone dose and testosterone level (P = .02).

In women, testosterone levels did not differ significantly between those taking methadone and their counterparts in the control group (mean, 36.61 ng/dL vs 25.93 ng/dL, respectively).

In addition, the investigators assessed the possible impact of menstrual cycle phase on testosterone levels. They found no significant difference between any of 3 phases (follicular, luteal, and menopause) and testosterone when controlling for age and smoking status.

Guide for Decision-Making

"Our results have confirmed the suppressive effect of methadone on testosterone in men undergoing methadone treatment," write the researchers.

"This sex-specific indicative of a distinct biological mechanism between men and women," they add.

Whereas opioids, including methadone, affect the gonads in men, which causes the suppression of sex hormones, these drugs may suppress B-estradiol as a primary target in women and testosterone as a secondary androgen.

However, the investigators note that the number of women treated with methadone in their study sample was very low, and therefore the study lacked the power to support the detection of any significant associations for the women.

Still, "it may provide some information regarding the magnitude and direction of effect," they add. Overall, the researchers note, the study results can be used to guide the decision-making process in the treatment of men with opioid addiction.

"We hope this kind of work will have an effect in the clinical arena as well as in the public arena. It is important to screen for testosterone deficiency through a simple blood test and then to provide careful monitoring and follow-up," said Dr. Samaan.

The researchers speculate that treating testosterone deficiency may improve patients' quality of life and may potentially improve treatment outcomes.

On the Other Hand...

Commenting on the study for Medscape Medical News, Roger Chou, MD, professor of medicine at the Oregon Health and Science University in Portland, noted that these findings are not entirely novel.

"There have been prior studies that have shown an association between opioid use and possible effects on sex hormones, including testosterone," said Dr. Chou, who was not involved with the research.

"This isn't the first study to look at this, but I believe this may be the first to focus on methadone," he added.

However, Dr. Chou, who is also head of the American Pain Society Clinical Practice Guideline Program, noted that the study has several limitations, including its cross-sectional design. This means that because the patients were examined at just 1 point in time, it is not known whether they had low testosterone for a variety of other reasons.

"For example, addiction may be associated with effects on sex hormones in this patient group," he said.

In fact, that ties into another problem he had with the study: that the control group did not include individuals with addiction.

"So, although this study found a potential association, I think all of these factors show that we really need better evidence to know what's going on for sure."

Dr. Chou added that although the findings are consistent with previous research, stronger evidence is needed before its clinical importance can be determined. Also, he does not agree with the investigators that clinicians should routinely monitor testosterone levels in these patients, especially women.

"I think it's more important to assess the patient clinically. This means if somebody isn't having any sexual dysfunction or other things that might signal testosterone deficiency, I personally don't think there's any reason to check their testosterone level," he said.

"As a clinician, I think it's much more important to focus on what's happening with the patient rather than jumping to a lot of additional testing."

The study authors and Dr. Chou have reported no relevant financial relationships.

Sci Rep. Published online August 24, 2014. Full article


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