We are doctors developing hormonal male contraception - 1 year follow up, AMA!
We recently made headlines again for our work on hormonal male contraception. We were here about a year ago to talk about our work then; this new work is a continuation of our series of studies. Our team is here to answer any questions you may have!
DMAU and 11B-MNTDC:
Earlier studies by our group on DMAU, 11B-MNTDC, and Nes/T gel:
Proof: https://imgur.com/a/7nkV6zR https://imgur.com/a/dklo7n0
Edit: Thank you guys for all the interest and questions! As always, it has been a pleasure. We will be stepping offline, but will be checking this thread intermittently throughout the afternoon and in the next few days, so feel free to keep the questions coming!
Good question. First off, side effects encountered in our trials are uncommon and none have ever been serious. To be more specific, some of the side effects we've noticed in the Phase 1 studies we've conducted include: mild/moderate acne, weight gain (muscle or fat), fatigue, and changes in libido/sexual desire (up or down), as well as changes in cholesterol levels. Not all participants respond the same way, and these side effects were classified as mild subjectively (no one discontinued because of side effects) but these are things we are working on minimizing in future studies, by choosing the appropriate dose. Many of these side effects (changes in mood, libido, weight, and acne) have been encountered by women on the female oral contraceptive pill, and over the years formulations have improved to minimize those adverse effects. The majority of men who've been part of our trials have found the drugs acceptable and have even gone on to be part of other male contraceptive trials. We're optimistic.
For full disclosure, regarding the gentleman who reported increased libido - I've been working on the manuscript for the past month and so have stared at the results for hours on end. It turns out that the subject who reported increased libido was in the placebo group - so it was a placebo effect.
So, by the data, it mostly lowers libedo then?
It increases placebo, however.
I'm not going to lie, when I saw the data I may have snorted a little. But it was in the safety of my own office and no one saw/heard me!
Was he assuming that he was in the active group and so he started having more sex? Were participants limited to certain activities or same activity levels with restrictions (using condoms, giving their partners oral contraceptives)? It seems like a bit of a fluke for someone to randomly have a higher libido, but also I'm interested to know if there were any unwanted pregnancies because someone in a control group was having unprotected sex.
Interesting question. First things first: all participants agreed to use an approved form of contraception during the study (condoms, or their partner was on the pill/IUD/etc). We did not physically monitor participants to make sure they actually did that... but we told them to use it. This drug wouldn't work so rapidly to decrease sperm count, we don't know if it's effective, etc. This phase I trial is for safety of the drug in healthy men.
The increased libido was most likely due to the placebo effect. Sexual libido and sexual desire were both assessed via subject report (ie this participant specifically said he had increased libido) and via questionnaires. It's pretty interesting, actually, because in the placebo group the median score did seem to go up slightly (median 0.3, 95% CI -0.7 to 2.4) but on eyeballing at least, I doubt that is a significant change in the group overall.
Lastly, spermatogenesis take about 74 days, so even if you turned off sperm production, you aren't sperm free for a couple of months.
This was my immediate thought as well. I want to hypothesize further but the more I started typing the more I realized that I was making a whole lot of assumptions based on zero information other than the subject was given the placebo. I am also very interested in whether or not unwanted pregnancies occured, within either of the test groups, but mostly the placebo group as I hope the treatment was extrenely effective.
Right. I'm even curious about the test group. The OP(s) keep spouting off about dropping sperm counts below so many millions/mL, and it seems like even those few 100 thousand could do the job. It just takes a few lucky swimmers to fertilize an egg. That's why even anal sex and the pull-out method aren't 100% safe.
I just keep finding more and more questions, not very many answers, but maybe all in good time.
Indeed, we hope to achieve sperm concentrations of 0. With any non zero number, there is a risk of pregnancy, even if it's lower than normal. To match female typical use efficacy rates, we want to be under 8 pregnancies per 100 person-years, but the best is to have 0 of course. It's about what is considered to be an acceptable chance of pregnancy. Nothing is 100% safe (though the closest is vasectomy/tubal ligation/IUD/implant). But I'm sure the statistics are cold comfort if you're one of the unlucky 1%. We continue to try to improve though!
Snorted a little... cocaine?
This is completely off topic from the AMA, but as a doctor - my opinion is, there are tiers of danger when it comes to drugs. Alcohol will kill you rapidly if you overdo it; if you drink more than you should it will kill you in the long run via your liver or stomach. Cigarettes will kill you from giving you cancer (or burning down your couch if you're careless). Meth, heroin, cocaine... All those will kill you or seriously mess up your life in a very short period of time if you use it. There was a famous Reddit user a while back; some young kid completely screwed up his life because he thought he could dabble in heroin without suffering its consequences. It's not worth it.
Yes. Specifically, what we saw in the oral 11B-MNTDC 28 day study we just conducted was that participants in the 200 mg group had more of a decrease in libido subjectively than the 400 mg group. One possibility is that the androgenic activity of 11B-MNTDC is not sufficient in the 200 mg group, and that the 400 mg group may be better in terms of maintaining libido.
With regards to the 30-odd individuals who stopped taking the medication post-trial period, was there any common explanation given as to the side-effect that caused most (or a majority of that "leaving" group) to stop?
In the 28 day 11B-MNTDC study, we had 42 participants total. One participant did drop out mid-study (on day 24) due to scheduling issues if I remember correctly (I think he was unable to do the overnight stay on day 28; he finished all the visits up to the visit before the overnight stay. If I remember correctly, he told our coordinators it was a scheduling issue, but I don't have that data with me). The other 41 finished the active treatment phase. During the follow-up phase, we lost another 5 participants (at which point they were no longer taking the drug). None discontinued because of an adverse event. In total, 6 participants out of 42 discontinued early from the study; only 1 out of 42 discontinued during the active treatment portion of the study.
Discontinuation from a study is always something we are very mindful of - for example, if a ton of people discontinue from the higher dose groups, we worry that it's a side effect that they're not reporting to us that is causing them to discontinue. In this case though, almost everyone made it through the active phase. This was just a 28 day study, so in the longer studies we will continue to monitor for uneven dropout as you mentioned. Great question!
Just curious, how exactly is a placebo supposed to work in birth control? You tell them they may possibly be in the placebo group so they don't go around go around firing a loaded gun?
The study isn’t being done to determine if it works - it’s being done to determine if there are side effects. For example if this was medication for a disease - it would not be done on people with the disease, it would be done on healthy people so we could see what the medicine does on it’s own. The people in the study were likely told to act as if they weren’t on a new/experimental birth control.
That is exactly right! Phase I: placebo vs active drug: check for safety. Phase II: check for efficacy: everyone gets the active drug. We're still working on the safety/dosing.
Dermatologist here, what treatments either self or recommended worked for the acne? We have the opportunity to address hormone related acne with spironolactone in women but this option is generally not recommended in men due to the undesired SE, like gynecomastia.
For the acne, in the DMAU and 11B-MNTDC 28 day studies, in general just soap and water/general hygiene worked. We didn't have anyone need to use anything for their acne as it was not too bothersome and disappeared, but I imagine benzoyl peroxide might work? If it is anything significant we would likely refer them to a dermatologist, so I'm afraid I'm not of much help unfortunately. I imagine the topical cleansers could work as they work in teenagers with acne.
wait wait wait, so if the placebo group goes out and gets some people pregnant... i'm sure your lawyers thought of this.
If you're in a test group for birth control, I would imagine they tell you no matter what to use other means of birth control
That is exactly correct. During these Phase 1 studies when there are placebo groups, everyone is on a form of birth control. During the Phase II trials for efficacy, which has recently started for the Nestorone/testosterone gel, everyone receives active drug, and in the consent process we discuss the risk that they may become pregnant.
as someone who has participated in many paid healthy volunteer medical trials its important to remind you, as a researcher, that we , as lab rats, are financially incentivized to under report negative side effects because reporting side effects can result in being removed from the trial and denied our completion bonus( often 50% of payment)
if that's true (removing you early) that's terrible. how can they expect results if the participants have an incentive to lie?
yerp a derp. i did a 2 week generic seroquil study in canada and described being tired around day 11 to the dr instead of just saying i was tired (45 guys in the room morning high dose, literally everyone but me was asleep all day)and she said she was going to have to pull me from the study because i said a key word. I broke down because of this and she asked my why i was so upset and i mentioned not being paid for the study and she said something like "you will still be paid for your time here". I had to explain to her that (for maths sake) if my payment was $4000, $2000 of that was a completion bonus so "paid for my time" while being removed from the study for medical reasons 3 days before the end of the study meant i would get like $1600 instead of $4000 because i would forfeit my "bonus". the general culture of a labrat is head down, "no sir, yes sir, im not bleeding out of my ass and having a seizure so im fine". i always look at the post market reports of side effects because the data that they collected in many of the studies i did was complete bullshit because no one reported stuff like headaches and whatnot unless it was very very bad. also tons of the time they collected bullshit floating data points like marking how many times you went to the washroom for a urinary incontinence drug but not monitoring your water intake( wat?!?). just because you are a drug researcher doesnt mean you have your shit together.
to her credit though she did keep me on for "medical observation" so i did get the full payment. especially for the longer term studies where you stay in the facility you definatly DO NOT tell the researchers about problems unless its really bad.
This sounds like a clear case of something introducing bias and I literally cannot imagine anyone with a shred of scientific integrity agreeing to that kind of setup.
To u/tsundokulove - I read your comment. I cannot imagine the pain of having to decide between telling the truth and knowing that you may be terminated from the study.
Even when doing the preliminary assessments, I get the sense sometimes that people are purposefully not telling me a full medical history because they want to be included in the trial. When I get that sense, I tell them, this questionnaire is to know what you have at baseline, so if you develop anything we know if it's something that's new or something that was ongoing. Even so, sometimes someone complains about something and upon further questioning you learn that, yes, they actually did have a history of xyz that they forgot to mention on the initial history. We try to make it clear that we don't terminate you from the study unless we think your health is in danger - it is unethical to give someone something that is making them unwell. Money isn't worth your life or health.
There are guidelines on how much money can be offered to participants - it's only supposed to cover the lost time/travel/etc. https://www.irb.vt.edu/pages/compensation.htm It's meant as compensation for the time. Giving too much money is considered undue influence. The trouble is, if someone is unemployed, maybe that money is a lot of money for them. The whole topic of compensation for research participants is tricky.
One of the side effects noted in their most recent (iirc) study was that 17% of participants experienced a decreased sex drive. Granted that’s only about 5 people in a study of 30.
It's amazing to me that a study is composed of 30 people. I realize it is difficult to fund these studies and get participants, but damn, that gives you very little data as to side effects.
That is exactly correct. Phase I studies are a small number of people (42 in ours) to make sure the drug is safe. But those numbers aren't enough to really talk about efficacy. Phase II studies occur once the drug has been shown to be safe in healthy people, and efficacy is examined at that point. https://www.cancer.net/research-and-advocacy/clinical-trials/phases-clinical-trials
Many men might consider taking male hormonal contraception because their partners have negative mental effects from the pill/implant etc.. Eg moodyness, reduced sex drive etc..
Are you expecting similar effects?
Yes. Hormones such as estrogen, testosterone, progesterone, etc have been shown to have effects on libido and mood. (For example, premenstrual dysphoric disorder, PMDD, in women is clearly tied to changes in hormone levels) The hope is to find a dose/formulation that minimizes these effects.
My colleague also responded to a similar comment at https://old.reddit.com/r/IAmA/comments/b7cqwe/we_are_doctors_developing_hormonal_male/ejqpp29/.
Can candidates sign up for trials? Is there a chance it may be available in less than a decade to the public?
We're ALWAYS accepting participants for clinical trials and right now are in the greatest need of couples who want to join our male contraceptive topical gel trials, being conducted at 9 sites worldwide. You can get on our mailing list for trials at our site: https://malecontraception.center and you can get more info about trial here: https://clinicaltrials.gov/ct2/show/NCT03452111
Clinical trials for contraceptives always seemed strange to me. On the link you provided for the study, I found this quote interesting:
Willingness to accept a low but unknown risk of pregnancy and able to understand the need for follow-up in case of pregnancy
Is there any help provided for women who do get pregnant? Do you provide access to abortions or other monetary compensation? As someone who meets all the criteria and would be interested in participating, this would potentially make me lose all interest.
(I am not even close to an expert) Couldn’t you continue to use other methods of contraception and then just test the patient’s ejaculate for effectiveness? No need to risk pregnancy unless you can’t use other methods for some reason.
The page requires the female participants to go off of their contraception prior to the study. Another thing is that female participants who want to get pregnant are excluded from participating. They must be pretty darn confident in their information on sperm count and pregnancy. Unless I read something wrong and the participants will all be using a secondary form of BC.
To clarify, the participants use birth control until the man's sperm concentration is below the threshold twice. The sperm concentration is monitored throughout the study, when it gets below the threshold twice, they discontinue the other form of contraception. There is a risk that two sperm concentrations are below the threshold, then for some reason the sperm concentration rebounds/rises and we wouldn't find out until the next check. There is a low but non zero chance that the partner becomes pregnant. This study is looking for couples who plan to be together long term (for the next few years at a minimum).
We are confident in the prior studies' results on rates of pregnancy at various sperm concentration thresholds - the World Health Organization did two studies in 1990 and 1996, and there hasn't been any conflicting data since then. For example, the testosterone + norethisterone study also showed no pregnancy occurring during the 1486 person-years; all participants were under 1 million/mL.
So my understanding is that you're giving a progesterone analog to down regulate release of FSH and LH and then supplementing an androgen to prevent sexual/testosterone side effects. My question is won't your HPG axis be suppressed if you decide to come off of this combination of drugs? And if so, how will you counteract this situation? Would doctors have to prescribe something like tamoxifen to up regulate LH production and try to recover the axis if someone came off of your drug after a year or two? What about side effects of testicular atrophy?
Great question! Scientists have already examined the recovery of the HPG axis, using testosterone and various progestins (https://www.ncbi.nlm.nih.gov/pubmed/16172147 and https://www.ncbi.nlm.nih.gov/pubmed/15671109). The FSH and LH recovered rapidly, and testosterone levels dipped slightly at first but then recovered to normal. Once the exogenous testosterone is gone, the pituitary gland wakes up and wakes up the testes; there was no need for any treatment other than the tincture of time. Testes volume decreased during treatment, but returned to normal after coming off the treatment in both studies.
First of all, thank you for all the work you're putting in, my balls appreciate it. Is there any way a simpleton like me could help out further your research?
Thank you for your interest! We have a website https://malecontraception.center, for ways you can get involved. We are currently conducting studies in Los Angeles and our colleagues at the University of Washington are conducting studies in Seattle, if you happen to live near those areas. If not, our goal is to generate interest and knowledge about the topic of male contraception :)
So the effectiveness of the female contraceptive pill is 99.9%
What is the current effectiveness of the male contraceptive pill? Or is that data not currently known?
Does it sterilise or kill sperm cells somehow like preventing the production of sperm cells when the chemicals in the pill are metabolised?
Thanks for your question! In general, sperm concentrations under 15 million/mL are considered to be low. The WHO 1996 study https://www.ncbi.nlm.nih.gov/pubmed/8654646 showed that if sperm concentrations are 1.0 million/mL or less, the pregnancy rate was 0.7 per 100 person-years; if the concentrations were 3.0 million/mL or less, the pregnancy rate was 1.4 per 100 person-years. However, this data lumps together several different "tiers" of sperm concentrations: if you look solely at people with sperm concentrations of under 0.1 million/mL, their pregnancy rate was 0; for sperm concentrations of 0.1-1.0 million/mL, 2 pregnancies occurred out of 39 person-years of exposure for a pregnancy rate of 5.1 per 100 person-years. For reference, the CDC has a list of contraceptive methods and efficacy in the typical-use setting: https://www.cdc.gov/reproductivehealth/contraception/unintendedpregnancy/pdf/Contraceptive_methods_508.pdf.
Thanks for replying, that’s all very interesting to know.
Based on that I guess your goal would be to match the efficacy of the female contraceptive pill by reducing concentrations of sperm in users to sub 3 million/mL?
I’m still curious how does this new male contraceptive reduce sperm concentrations, especially as each individual has a different baseline with some people having much much higher concentrations. I presume such people would need to take a stronger dose of the medicine to reduce their sperm levels compared to people with lower baseline concentrations?
And how does the medicine reduce sperm rates? Does it kill sperm cells or reduce production?
Thanks for sharing your findings and thanks for your research, this could be a major breakthrough in equality between the sexes!
Independent of how much each person starts off with, the goal is always to drop countdown to zero or azoospermia. for most men, this is a matter of time moreso than a matter of dose and even then, we believe that getting men down to a threshold of less than 3 million or 1 million would still provide contraceptive efficacy. Practically, that couples would be able to know when the male contraceptive is working, is a helpful improvement over female methods whereby women have no way of being sure.
How would couples know if the male contraceptive was working? Are there any physical indicators? Is there a visible reduction in ejaculate volume?
The only way to know would be by performing a semen analysis. Currently for people who have had vasectomies, doctors check a semen analysis after approximately 3 months to make sure it is negative for sperm. This pill would work similarly.
Are there ever any trials on unhealthy males eg blood pressure or age issues? Or do you eventually expect doctors simply not to prescribe these to anyone other than fit, healthy and under 40?
New drugs go through a fairly standard series of trials that the FDA requires for drug approval. Before it ever reaches a human, it undergoes studies on animals and in the laboratory. In Phase I clinical trials, the most important question (the primary outcome) is safety: is this drug safe in healthy people with the condition of interest (ie if you are studying a medication for diabetes, your subjects have diabetes, but not the complications of diabetes). In Phase II clinical trials, you have shown that the drug is safe in a small number of healthy people, and now you want to show that the drug is safe in a larger number of fairly healthy people, and that it is effective in treating your condition of interest. Phase III studies are the studies with large numbers of people. In general, the Phase I trials have the most rigorous exclusion criteria, so that only healthy people are enrolled. By Phase III, the exclusion criteria are generally relaxed so that people with some comorbidities, ie hypertension, fatty liver, etc may be included, as long as their disease is not uncontrolled.
How soon will we see it on the market. What are potential side effects and complications?
Thanks for the interest! My colleague replied at https://old.reddit.com/r/IAmA/comments/b7cqwe/we_are_doctors_developing_hormonal_male/ejqpp29/.
We also don't know the long-term effects on bone, though results of animal studies are comforting (the rodents maintained their bone mineral density). Animals aren't the same as humans, but it is something to continue to study for now.
Regarding the time frame, it would probably be at least a decade out. After Phase 1 studies are done, Phase 2 and 3 studies will need to be completed before it can be approved by the FDA.
Attardi et al: https://www.ncbi.nlm.nih.gov/pubmed/20798389
"What has been the reception you've seen? Do you think there is an audience for this drug?
Is their difficulty getting American pharmacies to back the medicine?
What has been the hardest part of the trial?"
WHEN will this be on the market???
Best time estimate is in a decade if all goes well. There are other trials of other formulations that are a little ahead, but full disclosure: it has been "in a decade" for several decades... We are hopeful though! The most important factor is to ensure its safety and tolerability (ie, will men actually want to take this). The efficacy and reversibility of hormonal male contraception has been well studied by now, in other formulations, and is also something we will follow in these compounds once they reach Phase II studies. There are also some issues such as funding - if there was unlimited money (or if a large company were to take this project under its wing) we could run multiple studies simultaneously; however, we are very grateful for the support we have from the NIH and are working as fast and as hard as we can!
Firstly, it's awesome to see this starting to come through. Really great to see male contraceptives being researched, good luck with the development!
What sperm counts do you need to reduce to in order to provide a comparable effect to currently used contraceptives? Are you currently just targeting production or are there other potential mechanisms, maybe inhibiting motility or ability to enter the egg?
The World Health Organization conducted a study of a weekly injectable male hormonal contraceptive composed of a synthetic testosterone (testosterone enanthate). They found that if sperm concentration was 3.0 million/mL or less, the pregnancy rate was 1.4 per 100 person-years. If the sperm concentration was 1.0 million/mL or less, the pregnancy rate was 0.7 per 100 person-years. If you look at each tier specifically (ie, 0-0.1, 0.1-1.0, 1.1-2.0, 2.1-3.0, etc) the data definitely look better the lower you go - ie the lower your sperm concentration, the lower the chance of pregnancy.
For reference, this is the CDC data on effectiveness of contraceptive methods in the typical use setting: https://www.cdc.gov/reproductivehealth/contraception/unintendedpregnancy/pdf/Contraceptive_methods_508.pdf
Regarding other methods, other groups have looked at ways to inhibit sperm motility (https://www.ncbi.nlm.nih.gov/pubmed/18945989), but we are not involved in that research.
Hi! I was wondering what's the use case of your drug. As a male I don't see an advantage over a condom as it doesn't protect from std. If I were a woman, the one that actually has an uterus and would suffer a pregnancy, would I trust a dude who says that he's been taking a pill?
The only reason I could see to take would be if I'm in a long term relationship with a woman and I'm the one not trusting her.
Thanks for your thoughts! Some women are unable to tolerate the pill due to specific side effects/experiences, and some men in committed relationships do not like the forms of contraception we currently have that are male-based (primarily the condom, withdrawal method, or vasectomy). We agree in that no pill, whether it is taken by the man or the woman, would protect against STDs. The purpose of our research is to develop an alternate method of birth control, so that couples can have that choice available to them.
Have there been any studies looking at the potential to increase/decrease the risk for certain types of cancer?
We can't really study things like risk of cancer in a clinical trial like this as prostate cancer or other cancers may take years to develop, but we have some animal data and data from observational studies on humans receiving testosterone replacement therapy that appear to indicate the safety of testosterone administration in men who have low testosterone. Men with higher levels of testosterone do not appear to be at increased risk, but men who are low in testosterone do appear to have less prostate cancer; however, the prostate cancers that develop are more aggressive. The theory is that the prostate normally receives a certain amount of stimulation from testosterone. If prostate cancer were stimulated by testosterone you also might expect younger men, with higher levels of testosterone, to develop more prostate cancer, but instead prostate cancer develops as you age. You can read a summary of a Harvard urologist here: https://www.health.harvard.edu/blog/a-harvard-expert-shares-his-thoughts-on-testosterone-replacement-therapy-2009031141. We are closely monitoring the prostate in these studies via PSA levels and digital rectal exams.
Medicine wise similar can still be significantly different based on the cause of things, as well as the frequency. Male BC messes with testosterone production which regulates a lot of important neurological functions. That concerns me a lot compared to bloodclot risks which are serious but more easy to monitor and treat with proper attention.
What are some of the current side effects?
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