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CHICAGO -- A single-agent oral male contraceptive pill lowered key male hormones without causing permanent infertility or other hormone-related adverse events, researchers reported here.
In the double-blind randomized, dose escalation, placebo-controlled study, testosterone levels among patients receiving the highest dose of dimethandrolone undecanoate dropped to levels seen in medical castration for prostate cancer, according to Stephanie Page, MD, of the University of Washington in Seattle, and colleagues.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Despite those dramatically low levels of testosterone achieved in the 28-day study, symptoms of low testosterone did not emerge, improving the agent's chances as an oral male contraceptive, Page said at ENDO 2018.
"These results are a big step forward in the development of a male pill," she told ľֱ. "We are very encouraged by the results of this safety trial."
The researchers, from the University of Washington and Los Angeles Biomedical Research Institute, tested doses of 100 mg, 200 mg, and 400 mg of dimethandrolone in two delivery formulations -- with castor oil or in a capsule. For each dose, there were 12-15 men and five placebo patients so that adverse effects could be compared, Page said. The pill was given with high-fat meals. Overall, 100 men were enrolled in the trial and 82 completed all parts of the study.
They reported that all active treatment groups achieved reductions of serum T into the hypogonadal range (day 28 median 13.4 ng/dL, IQR 7.6-72.1 ng/dL), without significant differences between doses or formulations.
"The men experienced no hot flashes and no mood changes, and no problems with sexual function compared with the placebo group," she said. "There was no evidence of liver toxicity. We did see mild weight gain and an increase in cholesterol levels and that may require us to fine tune the dosing, but overall we are very encouraged about the safety profile of dimethandrolone."
Page said her group will begin a 3-month study in April, and then will do a study in couples to determine if the agent does work as a contraceptive. She said the current trial was to determine if the pill could be given safely for more than one dose, but did not test for its success or failure as contraception. Participants were advised to use contraception if they had sex with partners while on the pill.
"Condoms are the only practical reversible form of male contraception -- and it is more than 300-years-old," she noted. She said that that men would prefer oral contraception versus or implant.
Page said that previous attempts to drive down testosterone levels to reduce sperm production led to side effects and liver toxicity.
"Dimethandrolone is a modified form of testosterone, which has been chemically modified to get rid of the problem of liver toxicity," she explained. "A long fatty acid chain has been added to another portion of the molecule to increase its absorption in the blood stream, so we can get around the twice-a-day dosing. Dimethandrolone is different than testosterone in that it binds to both the progesterone receptor and the androgen receptor so we don't need two different steroids in order to have an effective male contraceptive."
The authors reported a "marked reduction of luteinizing hormone as the dosing continued over the course of the 28-day study. That has an effect on testosterone production which, in all doses, fell to low levels by day 7, and at the higher doses of dimethandrolone the testosterone levels had fall to that seen in patients undergoing medical castration for prostate cancer. These levels were maintained for the rest of the study period," Page stated.
A month after treatment stopped, testosterone levels had recovered, she added. "This shows reversibility, the key feature of a hormonal contraceptive. This was much more potent than we had expected with just once-day dosing. Despite these incredibly low levels of testosterone, the men did not have symptoms of low testosterone."
"Because dimethandrolone is a modified form of testosterone, when we give the right dose of dimethandrolone, all those important secondary sexual characteristic in the man will be maintained in the body," she added.
Alberto Ferlin, MD, PhD, of the University of Brescia in Italy, told ľֱ. "We have been trying for about 30 years to come up with a male contraceptive pill. We want the testosterone to go low, but this exposes the man to possible complications of low testosterone. This is an interesting pill because it can reduce testosterone, but apparently it does it without symptoms. This is very promising.
However, Ferlin, who was not involved in the study, noted that "we also need sperm count to go down too. Sperm count has to go way down for there to be complete contraception. The longer-term study should provide us with the answer for this important question."
Disclosures
Page disclosed relevant relationships with Clarus.
Frelin disclosed no relevant relationships with industry.
Primary Source
The Endocrine Society
Thirumalai A, et al "Pharmacokinetic and pharmacodynamic effects of 28 days of oral dimethandrolone undecanoate in healthy men: A Prototype Male Pill" ENDO 2018; Abstract OR15-2.