We are doctors developing hormonal male contraceptives, AMA!

Do you think this drug could exacerbate prostate cancer risk due to it's androgen activity? Or actually may be useful for treating it due to the testosterone decrease?

In all of our trials, we are very cautious about changes in the prostate. In the hormonal contraceptive gel, previous studies (2012, Ilani) showed that there were no changes in serum PSA and a survey of prostate symptoms (IPSS) did not change, which is reassuring.

Regarding a decrease in testosterone, we are actually trying to maintain normal levels - these men are receiving either testosterone or another androgen, in order to maintain all functions including libido.

Are there other tests to assess the prostate other than PSA levels, since a normal PSA does not exclude cancer?

In human clinical trials, participants also receive a digital rectal exam to assess the size and contour of the prostate to detect other changes to the prostate that may be indicative of cancer. These exams have not shown any changes and some men find them somewhat uncomfortable.

Only some?

Well, to put this into perspective, men over the age of 50 do require screening for prostate cancer after all :P

Edit: sadman81 is correct, this is hour 4 and I am tired :)

Monitoring vs. Screening

https://legacyscreening.phe.org.uk/prostatecancer

(I trust NHS and British guidelines)

Indeed, this is a very controversial topic. The article published in https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2018.3710 notes that:

For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. (C recommendation) The USPSTF recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation).

The American Cancer Society (https://www.cancer.org/cancer/prostate-cancer/early-detection/acs-recommendations.html) recommends that men have careful discussions with their doctors at:

Age 50 for men who are at average risk of prostate cancer and are expected to live at least 10 more years.

Age 45 for men at high risk of developing prostate cancer. This includes African Americans and men who have a first-degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65).

Age 40 for men at even higher risk (those with more than one first-degree relative who had prostate cancer at an early age).

The important take-away point from this is that if you are African-American or if you have a first-degree relative with prostate cancer, you are at higher risk of developing prostate cancer.

Honestly you might as well just say that you have no idea if it increases the risk.

PSA is a horrible way of saying if it increases the risk for cancer. There is no way of determining if it increases the risk on that single test over such a short period.

Digital rectal exam is almost entirely useless unless you have a clearly pathological prostate. Small changes are hard/impossible to detect and it's extremely user dependent.

I am all for a male contraceptive pill but are you trying to mislead people intentionally or are you just dumb?

To be clear: there is no guarantee that there is no increased risk of prostate cancer. This is a controversial topic with testosterone replacement therapy, however the published studies are reassuring that there is no increased incidence of prostate cancer with testosterone replacement therapy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709428/);

"As large, randomized placebo-controlled trials are lacking, the uncertainty surrounding the safety of TT and prostate cancer will remain. Nevertheless, most published studies are reassuring, with most of the discrepancy likely due to methodologic and patient heterogeneity."

This is a slightly different scenario, in which androgens other than testosterone are used. Because no one can guarantee that there is not an increased risk of prostate cancer, the DRE and PSA levels are things we do to try to assess for any changes in the prostate. The fact that we don't see changes is reassuring.

Does this mean that when developed all male contraceptives will have an effect of decreased testosterone?

No; with male hormonal contraceptives, the goal is to supply men with sufficient testosterone (or another androgen) to maintain normal levels. For example, with the Nestorone-testosterone gel, we are giving men testosterone back while decreasing their own production of testosterone, to decrease intratesticular testosterone levels and spermatogenesis. Some contraceptives being studied use another androgen such as dimethandrolone (DMA) and 11β-Methyl-19-nortestosterone (11b-MNT).

after receiving testosterone supplements it's typically found that males lose capacity for the level of testosterone production they had before starting if they ever go off medication. Wouldnt this have a similar effect?

This is a very complicated question that is relevant for anyone on any drug for a long period of time. There is a normal decrease in testosterone with age. We know that for the short-term trials that have been conducted (including Gu 2009 https://academic.oup.com/jcem/article/94/6/1910/2596558), testosterone levels return to baseline.

Is there pressure to make the “perfect” male birth-control free of side-effects before it is approved or widely accepted?

I ask because there is very little discussion about making current birth controls easier on our bodies and females are encouraged to just deal with side effects of their birth control.

I was wondering the same thing. So many men seem to be incredibly concerned with the side effects of male birth control and they are the exact same side effects that women are expected to deal with without complaint.

It’s a bit unfair to say that women are just “expected to deal with without complaint”. I most certainly care about the side-effects the pill has on my partner. I don’t like that it depresses her, and even convinced her to take a break from the pill for a while, knowing that it was likely we wouldn’t have any sexual contact during that time.

In my opinion there should be just as much research going on into reducing the side effects to women as there should be to create a male contraceptive pill/gel. Both sexes should be able to choose any method they wish for contraception without having to worry about the side effects.

This is slightly off topic but I wanted to make sure you two are aware of the non hormonal methods of contraception including the copper IUD (or even the Mirena since changes in systemic levels are low) and the cervical cap? I am assuming this has already been discussed

This is a great question. Dr. Nguyen may add more later, but while we would love for the male contraceptive to be free from side effects, we are all aware that different people will respond differently. Potential side effects have been seen in the study, including mood changes, mild acne, and weight changes; hopefully with some adjustment of the formulation or dose those effects can be minimized in the majority of populations. The goal is to find a method that is safe (no serious adverse side effects) and that is acceptable to the participants. That is why it is so important to have multiple potential methods of birth control. For example, women with migraines with auras should not take the pill, but they can use the copper IUD.

Does it work?

Does it make you fat/sad/kill your sex drive? Edit: If not, why not (since the female pill does, presumably messing with hormones is going to disturb the body somehow)?

Put simply, it works. Preparations that have been studied have been shown to suppress spermatogenesis to levels that make men infertile (< 1 million/mL).

Side effects including changes in libido, changes in mood, and changes in body composition have been reported, but 1) they are uncommon, and 2) a dose finding trial of the male contraceptive gel has been conducted and with the current dose that is to undergo Phase II testing, we are not expecting significant side effects. That being said, every person is different, and their body may react differently, which is the exact same situation for women on hormonal contraception. This is why we are advocating studies on multiple different methods, to fit the needs of different populations.

suppress spermatogenesis to levels that make men infertile (< 1 million/mL)

I'm assuming that number is some sort of a standard for infertility. I'm really not familiar with the field. Still, it seems like a high number (to a layman). is there some corresponding "risk of pregnancy" associated with that number or is it functionally zero?

The concentration < 1 million/mL comes from World Health Organization sponsored studies that showed that it was sufficient for contraception purposes, and even reduced from standards previously set at <3 million/mL in order to ensure a high standard of pregnancy prevention (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393365/).

For reference, the lower limit reference range of sperm concentration in men trying to achieve pregnancy with a partner within a year is at least 15 million/mL (https://academic.oup.com/humupd/article/16/3/231/639175), so the threshold that we've set at 1 million/mL is well below this lower limit.

When you say “changes in body composition” do you mean increased muscle? I am on TRT and my production was super low and for a while was not detectable. I am curious how this differs from straight testosterone replacement

Testosterone replacement therapy is used in hypogonadal men - men who otherwise would have low testosterone levels. In men with hypogonadism, they may have reduced muscle mass, hyperlipidemia, insulin resistance, gynecomastia, and decreased bone mineral density. The goal of testosterone replacement therapy in hypogonadal men is to restore testosterone concentrations to physiological ranges to avoid these symptoms.

In male contraception, we are also trying to maintain androgen levels at physiological ranges, in men who would otherwise have normal testosterone levels.

Do you forsee any application to male-to-female transgender hormone replacement therapy? It seems like a targeted antiandrogen, but could addition of another chemical give it a more generalized uptake and overall bioavailability?

The goal is to maintain androgen levels; this is not an antiandrogen. There are other compounds that can be used for the hormonal transition from male to female, but this would not be one of them.

However, we recognize that anyone of any gender or sexual orientation deserves effective contraception.

Side effects including changes in libido, changes in mood, and changes in body composition have been reported

Welp that's it, pack it up, folks.

We do note as well though, that side effects of an unintended pregnancy among men could also include changes in libido, changes in mood, and changes in body composition. ;)

Well, is it possible that it could be increased libido, better moods and more healthy body composition are side effects? Or is it always negative consequences?

Both increased libido and increased lean body mass are possible. It is dependent upon each individual's response to the medication.

Realistically- when is this likely to become FDA approved / available to get a prescription for?

The most promising study of a hormonal male contraceptive at this point is a male contraceptive gel that contains an androgen plus a progestin (testosterone + Nestorone), which is undergoing a Phase IIb efficacy trial to be started in a couple of months.

Even if the trial succeeds, there are still several hurdles from a production standpoint that might delay FDA approval. Realistically, our best estimate would be not until 2030. Nonhormonal methods face similar barriers. What will speed this up is industry partnership and funding.

male contraceptive gel

Name?

I feel there is a better male contraceptive that is non hormonal and is a gel injected in to the vas defrens called Vasal Gel.

Is that out? I read something in wired about it then heard nothing more.

They studied it in animals so far; it hasn't been tested in humans yet. It's pretty exciting! It seems like it would be analogous to a reversible vasectomy if it works. If it makes it, it would require a specialist to perform the procedure, analogous to the female IUD.

"RISUG is not yet on the market in India, [but] clinical trials of RISUG are currently restricted to Indian men who live near the study sites. Recent media reports indicate that it might be on the market in the near future." You should clarify that it has/ is being studied in humans. Just not in the U.S. and not for nearly as long as male hormonal contraception.

https://www.parsemus.org/projects/vasalgel/vasalgel-faqs/

Hmm, that's pretty cool, I didn't know RISUG got all the way to Phase III. Unfortunately the study wasn't published anywhere apparently, so we can't tell what happened with the men who received the injection; we don't know how safe it was, and there is no way to replicate their data. Vasalgel has not made it into human trials yet.

Would the gel be applied daily or only before intercourse?

The gel would have to be taken regularly to suppress spermatogenesis, just as women have to take the oral contraceptive pill regularly.

Why would a gel be ideal instead of a pill?

Multiple formulations are being studied, but the gel formulation is a little ahead of the other formulations. Oral androgens with progestational activity have been studied as well, but they are a little behind the Nestorone + testosterone combination gel. As for testosterone itself, oral testosterone has to be taken multiple times a day, unfortunately, and no oral forms of testosterone are currently FDA approved for use in the US.

1.According to your research how wide spread so you expect the adoption rate to be of male birth control vs female birth control? 2. Have there been any any studies done on the quality of the sperm? Meaning any known defects in the sperm?

Thank you very much!

Great question! In answer to your first question, the adoption of male birth control is really dependent upon the culture of men's engagement in reproductive health, which seems to be changing. A decade ago, men wouldn't even talk about male birth control, let alone what they think about preventing an unplanned pregnancy. Now, you'll hear all sorts of stories about men trying to take control of their fertility and "close calls" they've had in the past. With more young people seeking higher education and careers, we're going to see more men wanting ways to maintain their life plans/goals via the use of contraception. Plus, we've had countless men talk to us about how they'd love to STOP using condoms. So, we actually think that the uptake of male birth control could be quite high, but perhaps limited by some of the access issues that women currently face, such as having insurance coverage to pay for their birth control and finding a place to obtain it.

In answer to your second question, when we manage male fertility, we primarily rely on the man's sperm count more than its other parameters, which haven't been proven to have significant impact on fertility rates. The average man can have numerous abnormalities in his semen analysis and still be considered normal. If you'd like proof, the WHO notes that men are able to achieve pregnancy within 12 months even if their semen analysis only shows 32% motility, 58% live sperm, and 4% normal-appearing sperm morphology. Therefore, sperm concentration matters most.

What are the hypothesized long-term side-affects? My concern over such contraceptions is male sterility or long-term male infertility. We seem to have already been having issues in that area.

So there are no long term studies on hormonal male contraception in humans yet, so there are no definitive answers. However, we know that with the use of testosterone and norethisterone to suppress spermatogenesis in the most recent efficacy trial (https://academic.oup.com/jcem/article/101/12/4779/2765061), out of the 266 participants, 94.8% recovered to sperm count of > 15 million/mL by 52 weeks of the recovery phase.

I was part of a Pfizer study for injectible male hormonal birth control. Other than having to inject weekly it was fantastic and the side effects were very manageable. As far as I understand the chief reason injectible hormonal birth control never made it to production is because pharmaceutical companies didn't think men would have it in them to stab a 1 inch needle into themselves every week. What is the current state of injectible male BC?

It is being studied as well. The WHO sponsored a trial on testosterone + norethisterone injections; that study was halted prematurely due to side effects unfortunately. Our lab group is studying various formulations of male contraception, including gel preparations, pills, and injections. Partially because of the other study, we are being cautious with adverse effects, and have placed safeguards in the protocol to attempt to detect changes early.

What benefits are there to choosing a hormonal contraceptive over something like Vasalgel?

So people may have different needs and preferences when it comes to contraception and so even non-hormonal methods like Vasalgel are necessary. However, one of the benefits to hormonal contraception is not having to undergo a procedure to attain contraception. Hormonal contraception can be administered at home, by you, either orally or topically, whereas Vasalgel would need to be injected by a doctor into the vas deferens. Since an injection into the vas deferens isn't a procedure that can be done by just any doctor, it might be a little bit harder to find such a specialist. We are excited about Vasalgel though, because it would be a long-acting, reversible method that could possibly have benefits similar to women's contraceptive implants and intrauterine devices.

From your other responses, I understand that you end up giving men testosterone to maintain "normal" levels.

Are these "normal" as defined by their individual baseline, or by population norms?

Additionally, you mention that sperm production recovers above some threshold, but does it recover fully (again referencing the individual's baseline)?

I partially ask because I understand that testosterone supplementation in those with normal levels can permanently suppress endogenous testosterone production; this is typically from recreational steroid use in unusual doses, but I wonder what lower levels might do.

When administering androgens, we aim to maintain levels seen with population norms--an androgen level equivalent to the mean for men who are of age 18-50 years.

In a prior contraceptive efficacy study (Gu et al 2009), the recovery of spermatogenesis was defined as sperm concentration reaching the mean of the participant’s baseline values or the normal reference value (sperm concentrations above 20 million/ml). The median time to recovery was 196 days. Out of 729 participants who completed the efficacy phase and recovery period, and out of 97 participants who discontinued early but completed the follow-up visits during the recovery period, spermatogenesis recovered in all but 17 participants, and 15 of those 17 returned to normal reference levels at an extra 3-month follow up visit. 2 men did not recover at the end of 18 months, and in one participant he was found to have developed epididymitis that was not present at his prior physical exams--it's possible that his epididymitis may have impacted his return to baseline.

In our current studies, we have not continued follow-up once men reach population-normal levels (beyond 15 million/mL) because it is possible to achieve pregnancy with those sperm concentrations and because previous trials generally show that recovery continues.

Aren't there significant differences in testosterone levels between an 18 yr old and 50 yr old males? If so, would an average drawn from that large of a demographic be a safe basis for 'normal'?

In the recent study by Keevil (2017, https://academic.oup.com/jes/article/1/1/14/2890811), median salivary testosterone levels were about 20% lower from age 45-54 compared to age 25-34. However, it would be prohibitively expensive and difficult to study the safety and efficacy of a different dose of androgen for men of different ages - we would need to find enough men in those age groups to conduct the study and would need to produce the compounds in different dosages. Thus, this is what we have given the limitations of the study/funding/available volunteers/etc.

There is some work being done by Dr. Chen's lab at Stanford to develop a small molecule HIPK4 inhibitor, which has been demonstrated to be nessecary for later stages of spermatogenesis, and has expression primarily in testes and the brain (mouse and rat models). Bayer has a patent on nucleotide/biological inhibitors for the same function. Do you see this method of birth control being successfully developed, and do you think the presence of expression in the brain will be an issue?

I don't know enough about the HIPK4 inhibitor to comment, but it looks interesting. Not a very useful comment, I know, but we shall see what happens with it!

How similar is a potential male contraceptive to the already existing pill for women? Do both do similar things, or is one completely and radically different than the other?

Both act on the same axis in the pituitary gland. The hypothalamic-pituitary-gonadal axis is suppressed by the administered hormones (estrogen + progestin in women, androgen + progestin in men) and that suppresses folliculogenesis+ovulation in women and spermatogenesis in men.

What's the fail ratio? Is it as reliable as the female pill?

In Behre's 2016 study of a hormonal male contraceptive injection by the WHO (https://academic.oup.com/jcem/article/101/12/4779/2765061), 4 pregnancies occurred among the partners of the 266 male participants, (1.57 per 100 continuing users). We expect the failure rate of hormonal male contraceptive methods to be comparable to those of female hormonal contraceptive methods currently on the market. In measuring contraceptive efficacy, we sometimes use the Pearl Index as a measure, which gives the rate of pregnancy per 100 years of use, which in female OCPs, hovers somewhere around 2 per 100 person-years. In the Behre efficacy trial, the Pearl Index was 2.18 (95% CI: 0.82-5.80) -- so not too different, however all of this is dependent upon the user's willingness to use the method consistently.

I would absolutely use this if it was demonstrated to be safe and I was happy with the side effects.

Slightly left-field question: given this acts on testosterone are there any implications for male pattern baldness – accelerating or slowing?

Regarding the Nestorone-testosterone gel combination, the goal is to achieve physiological levels of male androgens while suppressing spermatogenesis and intratesticular testosterone, so there should be no effects on male pattern baldness.

Will the contraceptive be similar to the female equivalents at the moment? E.g Pill, implant etc. - and how will they affect men differently than their female counterparts in terms of symptoms and processes?

Sorry for the long winded questions!

Edit - spelling.

Injections, implants, oral pills, and topical gels have all been studied for use as male contraception. All formulations have different pharmacokinetic characteristics that can affect efficacy and side effects. The primary goal is to have a range of potential methods that men and couples can choose from. In general, possible side effects would be expected to be from changes in androgen levels (ie change in libido: either increased or decreased; acne/oily skin; increased/decreased muscle mass and body fat composition). These effects are expected to be reversible.

Have you experienced any negative reactions by one or more religious or political groups?

There is no method on the market yet, however our research has received nothing but positive feedback thus far.

How did you both get started in this field of study/career? Was this something you've always wanted to pursue?

For me (Dr Yuen), I got interested after learning about Dr. Swerdloff and Dr. Wang's research. I think it is important to give men options for contraception; most methods are currently geared towards women, and so men are left with vasectomies (surgical procedures, and reversal is a second procedure and not guaranteed) and condoms.

Regarding whether this was something I've always wanted to pursue... uh... definitely... blinks twice Definitely! Yes! Avoids looking over my shoulder

On a serious note, I came into this field as a happy accident and haven't regretted it so far :)

Does male hormonal contraception could produce the same side effect as the women contraceptive pills does to fish population in the ocean ?

For those of you who aren't informed on the issue, right now as millions of women ingest one pill of hormones everyday, we've seen an increase of hormones in the ocean, causing an increase of female fish in some species, because the sex of the babies are environmentally determined for a lot a fish species.

I'm definitely not an expert on the issue, feel free to correct me if I said something wrong.

Personally (as an endocrinologist) I feel that endocrine disrupting chemicals such as BPA and certain pesticides have a far larger effect on the environment than targeted compounds meant for human consumption/use which will be processed in the body, but that is a whole different field of conversation.

Hi! Thanks for doing this AMA.

What sets dimethandrolone apart from other 19-nortestosterone derivatives like trenbolone, trestolone and 19-nortestosterone itself? Has trestolone (MENT) been abandoned as a potential contraceptive preparation?

It seems that DMA does not undergo aromatization. How will a patient taking DMA get an appropriate amount of estrogen in his body?

Why is stand alone dimethandrolone better than a combination of testosterone and a highly suppressive progestin?

There is work on developing MENT as a implant as well. DMAU has both androgenic and progestational activity which is why it is being studied - it can be taken orally in a once-daily formulation and can be given as an injection. 11β-methyl-19-nortestosterone is also being studied in various formulations (it has androgenic and progestational activity as well). Basically multiple compounds are being studied :)

Regarding the estrogen, this is a good question. In the study by Finkelstein https://www.ncbi.nlm.nih.gov/pubmed/26901812, only low doses of estrogen (10 pg/mL) were needed to maintain bone mineral density. This is something that will need close observation in future studies.

I see the ads for this, am I able to participate in clinicals if I take lexapro?

More details on our clinical trials can be found here https://www.malecontraception.center/clinical-trials-1. Because mood changes are one of the possible side effects (either improved or worsened), at this point in time we are not able to accept participants who are currently taking a psychiatric medication.

I have heard that you are targetting the enzyme that is critical for the sperm formation, what is the nature of the blocker and how it will work ?

Hi! So this exciting compound is being studied by another group at OHSU (Mary Zelinski); their work can be found at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195953. They are targeting the protein EPPIN, on the surface of human sperm, to rapidly inhibit sperm motility. They just recently published a trial done in non-human primates (Rhesus macaques; no human trials published yet). There is still a ways to go, but it is exciting as well and we look forward to seeing more of their work.

Sorry if it's been asked already I just didn't see it when I skimmed the thread. What's the mechanism of action? And What is the projected price per dose?

For the first part of the question, the mechanism of action is that the androgen plus progestin suppresses the hypothalamic-pituitary-gonadal axis (the signaling system for sperm production). Basically it works by negative feedback (like a thermostat) - it tells the testes to stop producing testosterone and suppresses spermatogenesis.

If you used an androgen alone (ie bodybuilders who are taking anabolic steroids), you would get suppression of spermatogenesis, but it would require supraphysiologic doses of testosterone (higher than is good for the body). The addition of a progestin lowers the dose of testosterone required to a safe level and improves spermatogenesis suppression. The goal is to provide the correct dose of testosterone that maintains all male function, including libido--all juice, no seeds.

So you stated elsewhere that

Side effects including changes in libido, changes in mood, and changes in body composition have been reported, but 1) they are uncommon, and 2) a dose finding trial of the male contraceptive gel has been conducted and with the current dose that is to undergo Phase II testing, we are not expecting significant side effects. That being said, every person is different, and their body may react differently, which is the exact same situation for women on hormonal contraception. This is why we are advocating studies on multiple different methods, to fit the needs of different populations.

Do you feel the chances of side effects on this medication will be lower than the next best thing which is probably the female combined pill? If so do you believe it could become a viable alternative to the combined pill?

I think it's far too early to say whether this will have fewer side effects than the female pill; our goal is to develop a "male pill" (or gel or injection, etc) that men can take, to give them the option of a male hormonal contraception that they can control. Other teams are working on non-hormonal methods as well. I believe the term is, "For science!"

Does it have an effect on acne?

Yes, it could increase acne. Our goal is to provide an androgen level that mimics normal physiological levels in these men, but everyone responds differently, and if the androgen level is elevated for them, they could develop acne. Of the studies that have been done, the acne tends to be mild and occur on the chest or back. In our experience, men have never discontinued for this reason. We are looking at acceptability in the participants, to ensure that the compound is acceptable to them.

Your opening post mentions its impact on society, but I'm having a hard time picturing what that'll be. All I can think of is less unwanted pregnancies, what other things do you expect it to influence?

More than just decreasing the incidence of unintended pregnancy, the existence of a reversible male contraceptive method allows men to enter the conversation of how to plan and prevent pregnancies. If acceptable methods are only available to women, some men may feel as if they can't or don't need to be involved in thinking about family planning and so they might not open up about their thoughts and have the necessary conversations with their female partner(s) about family planning. We see a future where contraception is an issue for men, women, and couples, rather than just a woman's responsibility alone.