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Male Contraceptive Pill Appears Feasible in Very Early Trials

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Male Contraceptive Pill Appears Feasible in Very Early Trials

ATLANTA — Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at ENDO 2022.

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, BS, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Jacobsohn in an interview.

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However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Jacobsohn.

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Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 Results With DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are be presented in a poster on Monday, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to <100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose.

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From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero Sperm Production Is Not the Goal. Lowering It Sufficiently Is

Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

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Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

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In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Jacobsohn and Thirumalai report no relevant financial relationships.

Annual Meeting of the Endocrine Society #ENDO2022: Poster PMON261. To be presented June 13, 2022.

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A Relationship Therapist Ranked the Most Problematic Disney Romances

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A Relationship Therapist Ranked the Most Problematic Disney Romances

Disney romances have long been critiqued for being, well, entirely unrealistic. Not only have animated cartoons set some seriously unobtainable romantic standards for us all, but there are some pretty concerning themes presented in classic children’s movies. Falling in love with a literal vendetta-driven Beast aside—ehm, Belle—consent and logic are often missing from the fictional relationships, not to mention a fairly standard period of getting to know each other before going all in.

So what does a relationship therapist have to say about all this?

In a recent YouTube video, relationship therapist Jonathan Decker analyzed a random assortment of Disney romantic relationships to see which are most problematic and which actually have a solid basis. Testing their partnerships in the battle-royal are animated couples Alladin and Jasmine, Cinderella and Prince Charming, Fix-It Felix and Calhoun from Wreck-It Ralph, Rapunzel and Eugene from Tangled, Simba and Nala from The Lion King, and Snow White and Prince Florian.

Out of the selected couples, Decker ranks Snow White and Prince Florian (yes, the prince as a name — and it apparently is that) as the most problematic pairing. After all, the two meet only once (without talking!) before betrothing themselves to one another with Snow White becoming so scared during that meeting that she literally runs away.

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So this is love? Well, maybe not.

“Snow White, you are experiencing a chemical rush that is probably a combination of responding to his pheromones and being physically attracted to him, and the adrenaline of absolute terror,” Decker says. “So those things combined can be kind of potent. Doesn’t mean it’s love.”

That’s all not to mention the little (or, rather, absolutely blatantly massive) issue of consent in their relationship — or lack thereof.

Decker says, “[Snow White] eats the poison apple, she gets knocked out, and then he sees her and is like, ‘I should totally kiss that.’”

Now, remember, Prince Florian has absolutely no idea a kiss will save Snow White from the poison. As Decker says, he just stumbles upon her unconscious and thinks “now’s my window.”

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Obviously, the vintage Disney couple is outdated and problematic by any standards — but what about the least problematic couple of the bunch? Decker says Fix-It Felix and Calhoun from Wreck-It Ralph actually have a relationship to envy, creating a dynamite team and embracing each other’s personalities.

“They accept influence from each other,” Decker says. “On the surface, [Calhoun] is tough, no-nonsense, leads troops into battle — and Felix seems like this really sweet, kind of derpy, doesn’t-really know what he’s doing guy. But she accepts influence from him, he definitely accepts it from her all throughout, and they complement each other. It’s like salty and sweet.”

Though the two may win all-or-nothing video games with their complemenary personalities and differing approaches, they also make each other grow and flourish in their relationship.

“She softens because of his influence, and he toughens up because of her influence,” Decker says. “And there’s kind of a meeting in the middle.”

Curious to find out where the other couples land? Watch the full video above to see get the entire definitive ranking.

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Former MLB Pitcher Kyle Farnsworth Is an Absolutely Shredded Bodybuilder Now

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Former MLB Pitcher Kyle Farnsworth Is an Absolutely Shredded Bodybuilder Now

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Brace HemmelgarnGetty Images

You may know Kyle Farnsworth for his 17-year Major League Baseball career spanning from 1999 to 2014. Though the 46-year-old former pitcher left the major leagues in 2014, he hasn’t let his love of fitness falter. In fact, Farnsworth is now an absolutely jacked bodybuilder in his “retirement.”

Once sporting a relatively-slim baseball player physique, Farnsworth recently captured headlines for his status as a bludging competitive bodybuilder. In a recent YouTube video, Athlean-X trainer Jeff Cavaliere broke down Farnsworth’s incredible physical transformation—and why it may not be as surprising as it seems.

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“No doubt, he looks like an absolute beast,” Cavaliere says of Farnsworth’s current physique. “The vascularity is sort of crazy, the size is ridiculous, the legs are absolutely shredded and humongous…Basically, Kyle Farnsworth is a big, jacked dude.”

At 6’4″ and currently 240 pounds, Cavaliere says Farnsworth has always had bodybuilding potential from a genetic standpoint, adding that he was also “one of the hardest workers in the room,” giving him the ability to capitalize on the hereditary leg-up.

“He was an anomaly when it came to baseball players, especially as a pitcher,” Cavaliere says in the video. “His size and his overall appearance were not what you would typically see. So he was always big.”

Cavaliere, who worked for the Mets from 2006 to 2008, was with the New York-based team at the same time that Farnsworth played for the Yankees. The trainer said he personally would see the pitcher “cranking out” countless leg extensions before any other players showed up on game day, showing his bodybuilding potential several years ago.

“I didn’t really see that as being the best, most functional way to train for his sport. Step-ups, lunges — there are better things that he could do,” Cavaliere said. “But he did a lot of leg extensions, so the fact that he’s now become a bodybuilder certainly doesn’t surprise me at all because I always wondered if he was more interested in bodybuilding versus pitching.”

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Cavaliere also mentions the possibility of performance-enhancing drugs playing a role in the transformation, though the speculation is just that — entirely speculation. Yet, the trainer says performance-enhancers were a reality of the baseball era Farnsworth played in, citing that the former pitcher was on the receiving end of some PED rumors during his major league tenure.

During his time in the major leagues, the pitcher played for several teams from 1999 to 2014. He signed with the Chicago Cubs in 1999, playing with the team until 2004. He was then traded to the Detroit Tigers in 2005, then traded again to the Atlanta Braves later that same year. Farnsworth signed with the New York Yankees in 2006, playing with the team until 2008. In 2008, he was traded back to the Tigers, but swiftly signed to the Kansas City Royals from 2009-2010. In 2010, Farnsworth was traded back to the Braves, then signed with the Tampa Bay Rays from 2011 to 2013. In 2013, he traded to the Pittsburgh Pirates, then to the New York Mets in 2014. He wrapped up his MLB career with the Houston Astros in 2014.

You can watch the entire video below:

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‘Pam and Tommy’ Originally Wanted Chris Evans to Voice Tommy Lee’s Penis

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‘Pam and Tommy’ Originally Wanted Chris Evans to Voice Tommy Lee’s Penis

If a penis could talk, what would it sound like? That’s the burning question creators of Hulu’s Pam & Tommy had to grapple with when creating the now-infamous talking penis scene in the biopic series.

Well, according to Sebastian Stan, who stars as Tommy Lee in the series, the show’s creative team originally thought Lee’s penis would sound something like Chris Evans.

In a recent interview with Awards Daily, Stan revealed that he shot the comedic yet vulnerable scene not knowing who would voice the prosthetic appendage.

“He actually wasn’t there on the day,” Stan told the outlet. “We didn’t know who we were going to get at that point. The guys, I think, called me at one point and were like, ‘What do you think? Do you think Chris Evans would do this with you?’ And I was like, ‘I’m not calling him, OK?’”

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Just consider it: Captain America voicing Bucky Barnes’ penis? What in the MCU multiverse…

Eventually, the role ended up going to Big Mouth and Brooklyn Nine-Nine actor Jason Mantzoukas, whose delightfully brash voice is inarguably perfect for Tommy Lee’s sentient penis.

In a February interview with Entertainment Weekly, showrunner Rob Siegel revealed some of the inner workings of creating the oddly captivating scene with a puppet-like animatronic penis, which was created from a lifecast of Stan’s actual appendage.

“I can’t think of a more fun and cuddly way to get away with extended full-frontal male nudity,” Siegel said. “It’s a puppet, it’s like Yoda.”

To get a seamless look that makes it appear like Stan is standing nude and not with a puppet hanging from his member, the SFX team used a lot of glue (ouch) and paint to secure and blend the appendage.

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“There were wires running between his legs from behind, and a guy crouched on the floor with joysticks, mechanically controlling what’s going on,” showrunner D.V. DeVincentis told Entertainment Weekly. “That animatronic guy had to look in a mirror and sort of really act with Sebastian physically, like all the gestures and the nods and looks up, and we had to actually direct that. I’ve never done anything quite like that.”

Truly, that’s not surprising.

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