What do we do with a free testosterone?

Put another way: what's the free testosterone cutoff we should use for initiating treatment in potentially hypogonadal men?

Spoiler alert: maybe 70 pg/mL?

Background: a new paper from Anna Goldman, Shalender Bhasin, Frederick Wu, Meenakshi Krishna, Alvin M Matsumoto, and Ravi Jasuja lays out their thoughts on the state of the science in free testosterone measurement. This is important because we currently operate under a theory of "bioavailable testosterone." That is, we think that only testosterone that is unbound by proteins, the most important one called "Sex Hormone Binding Globulin," or SHBG, has any effect on the testosterone receptor. All the testosterone that's floating around attached to SHBG or other proteins is inert.

But like any other hormone, testosterone's binding to SHBG or other proteins is affected by myriad causes, like obesity, other hormonal disorders, and other conditions or medications. Even the temperature at which it's measured. So guidelines from the Endocrine Society suggest measuring free testosterone levels in men whose total testosterone concentrations are low-ish and in men with conditions or medications that make total testosterone measurements less reliable (like obesity). But those same guidelines rely almost entirely on the total testosterone to determine who needs testosterone therapy. From their 2010 guideline:

The panelists disagreed on serum testosterone levels below which testosterone therapy should be offered to older men with symptoms. Depending on the severity of clinical manifestations, some panelists favored treating symptomatic older men with a testosterone level below the lower limit of normal for healthy young men [280–300 ng/dl (9.7–10.4 nmol/liter)]; others favored a level less than 200 ng/dl (6.9 nmol/liter). The panelists who favored treating men who had values less than 300 ng/dl were more influenced by the observation that men who have values below that level often have symptoms that might be attributable to low testosterone. The panelists who favored not treating unless the serum testosterone was as low as 200 ng/dl were more influenced by the lack of testosterone treatment effects in randomized clinical trials when subjects had pretreatment values of 300 ng/dl but suggestions of beneficial effects when the pretreatment values were closer to 200 ng/dl. The lack of definitive studies precludes an unequivocal recommendation and emphasizes the need for additional research. [emphasis mine]

No mention of the free testosterone in there. More research needed, they say. Well, Goldman et al have delivered it, in a way. They didn't do any new investigation, so far as I can tell, but they did review the existing literature pretty thoroughly and come up with a series of conjectures. The most important of these clinically is this (my words, not theirs):

 

Without a harmonized, replicable normal range between laboratories and methods, we cannot set a clinical threshold for free testosterone levels at which we should initiate treatment.

 

The authors point out that in a study by Le et al, only about a quarter of labs performing free testosterone assays would even confirm that they had performed validation studies on their assay. But seeking a clinically relevant answer, they go on to point out that In the Framingham Heart Study, the lower limit of the normal range for the calculated free testosterone for men between 19 and 40 (defined as the 2.5th %ile) was 70 pg/mL (242.7 pmol/L). They do not endorse this as a threshold. But given the lack of other published thresholds, I think it is at least a start. 

One more point before I wrap up: whatever value you or your doctor use, whether it's free testosterone, bioavailable, or total, the number is only one piece of data. A free testosterone of 70 pg/mL in a young man with normal body hair, normal muscles, and a normal libido would not cause me to treat him. That same level in a man with a known pituitary issue, enlarging breasts, and fatigue would definitely cause me to treat him. And I tend not to recommend checks of testosterone in elderly men, even those with fatigue, unless they have other compelling evidence of hypogonadism. And my opinion is generally in line with that of the Endocrine Society:

We recommend against a general policy of offering testosterone therapy to all older men with low testosterone levels. (1|⊕○○○)

We suggest that clinicians consider offering testosterone therapy on an individualized basis to older men with low testosterone levels on more than one occasion and clinically significant symptoms of androgen deficiency, after explicit discussion of the uncertainty about the risks and benefits of testosterone therapy. (2|⊕○○○)

Why else do I hesitate to give testosterone? In a series of trials in JAMA and JAMA internal Medicine earlier this year, men aged 65 and older with a total testosterone level <275 ng/dL plus either sexual or physical dysfunction or reduced "vitality" were randomized to get either testosterone gel (lotion that absorbs through the skin) or placebo for 1 year. The men who got testosterone developed more coronary plaque than the men on placebo. (This may or may not mean anything; in other observational studies, the rate of heart problems was lower in men prescribed testosterone than in untreated men). 

Importantly for the men who tend to come to me with suspected androgen deficiency, though, the men in these studies had no improvement in memory or other measures of brain function.

Testosterone did slightly improve bone density and bone strength compared with placebo. And testosterone seems to have improved the hemoglobin level (the weight of the oxygen-carrying protein in our blood) in anemic men by 1 g/dl more often than placebo did.

If all that sounds confusing, it's because it is. When I was an endocrine fellow, one of my faculty told me that in almost every case, if you don't know what to do, the correct path is to do nothing. So that's the direction I lean in borderline androgen deficiency cases, whether determined by total or free testosterone levels. I lean toward withholding therapy. 

Circling the parking lot = circling the drain

A couple weeks ago, I spent some time in a YMCA parking lot to do the Wichita Area Metropolitan Planning Organization's bike/pedestrian count. I was in a pretty rural area, and the bike/ped traffic was light. It gave me a chance to watch the steady stream of cars in and out of the lot, though. The Y was rocking, which made me happy, but I couldn't help but wonder about the goals of the people in the cars screeching in and out of the driveway.

A woman who worked in the office of a YMCA recently told me that one of the biggest safety issues the organization deals with is parking lot safety for pedestrians. So many people circle the parking lot in their fancy gas-powered wheelchairs during busy times that pedestrians crossing the lot were in danger of being run over.

This is not the kind of wheelchair I'm talking about. I might respect someone who circled the health club parking lot in this rig. By the way, there was a third dog riding on the scooter. Respect. This must have been a logistical nightmare to get ou…

This is not the kind of wheelchair I'm talking about. I might respect someone who circled the health club parking lot in this rig. By the way, there was a third dog riding on the scooter. Respect. This must have been a logistical nightmare to get out the door. 

She was talking about people circling the lot, mind you, so that they could walk the minimum distance to get into the building and walk...on a treadmill. Or ride a stationary bike or something. 

This problem is a bit of a throwback for me. I remember as a kid, when the remote controls for TVs were still mostly up-and-down affairs (hit the up arrow to scroll upward through channels, hit the down arrow to go the other way; ditto volume), I would, out of habit, walk all over the room looking for the remote so I could change the channel on the TV. I would walk multiples of the distance it would have taken me to simply get off the couch and walk to the TV and push a button. But like the Kodak people who couldn't imagine a world without film, I couldn't imagine a world without the satisfying weight of that remote, with its sleek aluminum Sony case, in my hand. 

Is there a name for this particular brand of self-defeating convenience? I've stretched Google's abilities to the limit and I can't identify one. But it clearly pre-dates modern technology. And don't get me wrong. I've ridden, and continue to ride, an absurd number of miles in cars. But I've felt like an asshole for almost all of those miles that didn't involve traveling outside of town. 

But back to parking. Scott Wadle of the City of WIchita likes to say that there's no such thing as free parking. While he means that we all subsidize the space that cars take up whether we mean to or not, I think of it in more cosmic terms. All that space could be used for something else. And the physical activity it would take us to park in vertical garages and walk to our destination, or the slightly greater physical activity it would take for us to bike to work would be a small price to pay to get green space and health back. An optimist's view of the coming autonomous fancy gas-powered wheelchairs is that we'll need far less parking, thus opening up more and more space for commerce and for public use. A pessimist's view is that we'll eventually transition to a WALL-E situation in which your autonomous gas-powered wheelchair picks you up at your door to deposit you in front of the door to your office, at which point a smaller, more Segway-inspired motorized device takes you to your desk. Where you sit. All day. 

I'm not going to talk about "productivity" or "optimization" here. There are plenty of places to get a dose of that perspective. But just consider this when it comes to the YMCA or your local health club: grinding away on a treadmill for 30 minutes a day after driving an oversize luxury wheelchair to the building is not my idea of freedom. It's a chore. But if I turn that chore into the choice to walk or ride by the health club while I watch all the wheelchair circle: that choice makes me unspeakably happy.

Are triathlons dangerous?

First things first: I've never done a triathlon. I swim like a St. Bernard. But I've done a lot of endurance bike racing, and I've been at more than one event with a death, the most recent the 2017 Dirty Kanza. So I was interested that in the latest Annals of Internal Medicine, investigators looked into a sudden death database to identify 135 race-related deaths and cardiac arrests in American triathlons between 1985 and 2016. Interestingly, right at two-thirds of deaths and arrests happened in the swim part of races, which usually comes first, before the bike and run. The editorialists spend a lot of energy trying to link swimming to some special form of stress from cold water or other factors that might be extra-dangerous. But to me, the swimming link seems consistent with the finding that in autopsies, about half of subjects had cardiovascular abnormalities, most often old-fashioned atherosclerotic disease. Swimming caught most of these people simply because it was the first event. Had running or cycling come first, I suspect one of them might have been the death leader. I'm not convinced by their observation that most marathoners die toward the end of races; anyone who's seen the scrum at the beginning of a triathlon knows that it's inherently different than the often walking pace seen at the start of a marathon: 

From http://www.zwemza.com/?p=5515, triathletes tempting fate.&nbsp;

From http://www.zwemza.com/?p=5515, triathletes tempting fate. 

85% of victims were male, but I'm not sure the significance of that number, since >60% of participants (at least in pro Ironman races) are male:

From https://www.outsideonline.com/1964906/fight-gender-equality-ironman

From https://www.outsideonline.com/1964906/fight-gender-equality-ironman

And if you look at total Ironman competitors, the distribution of sex comes much closer to the death/cardiac arrest statistics:

kona-gender-breakdown-chart.jpg

But sex aside, we're forced to see that cardiac arrest and death are not rare among triathletes. Between 2006 and 2016, their incidence was 1.74 per 100,000 participants in the study. The risk of death increased with increasing age, unsurprisingly. Don't let this dissuade you from being more active. The benefits of physical activity far, far outweigh the risks in almost everyone. If you're inactive now and thinking of becoming active, or if you're active now and thinking of doing really hard-core things like triathlon, consider taking the American College of Sports Medicine's new-ish algorithm to your doctor and talking it over before you hit it really hard:

Original.00005768-201511000-00028.FF2.jpeg

We don't know how really weird stuff like performance enhancing drugs effects this. My suspicion is that it's not good. 

Is it too early for a Halloween reading list?

I picked up a copy of We Have Always Lived in the Castle by Shirley Jackson last week at the library:

You'll be missed, Wichita Public Library. #brutalismforever

You'll be missed, Wichita Public Library. #brutalismforever

It is a Gothic masterwork, and the speculation it allows around the psychopathology of Merricat and the townsfolk who hate her and her sister and uncle is irresistible.

Even though I didn't choose it with the intention of kicking off any kind of Halloween-y creepy reading list, now that I've started The Handmaid's Tale by Margaret Atwood, it seems I've inadvertently waded into Gothic waters. Atwood is incredible, but I'm in the mood for something a little more straightforward. So I've made it official: my next book will be It by Stephen King. I was a voracious King reader as a high-schooler. And a copy of Salem's Lot I found in a call room nightstand once got me through a snowy, slow call night as a resident. I left the book there when I finished, and I have wondered many times since how many residents at Deaconess Medical Center have found that same book and killed a couple hours with it. I know, I know, that King is hardly literary. His is not necessarily the kind of reading that increases empathy, but since It is currently crushing it (see what I did there?) at the box office and in critical reviews, it's time.

Assuming I can get through It's 900+ pages in the next few weeks, what other creepy-crawly books should I attack before All Hallow's Eve?

"The greatest favor you can do is...put away your phone."

Sherry Turkle from the MIT Media Lab talks about the frequency she hears people say they'd "rather text than talk." People say they feel less vulnerable when they text than they feel in a face-to-face conversation. I agree. I feel less vulnerable texting, too. 

So don't be a phone worm. When I was in medical school in the late '90s, I remember classmates making fun of a woman in our class who was pathologically attached to her cell phone. We'd all just learned the word "pathologic," and our family members were already asking us for medical advice, so we all felt comfortable making the diagnosis. Anyway, hers was the phone that would ring its Nokia ringtone multiple times a day to interrupt class back when this was still a novel occurrence:

In the year 2017, I'm not sure she'd even hit the average cell phone use. Recently, at my kids' gymnastics lesson, I was flanked by two women on cell phones. The first one sat to my right, bouncing off my shoulder as she sat. I forgave her for this, because she couldn't see me past the smartphone glued to her left ear. Then she proceeded to scream intermittently at two kids who were not in the gymnastics class, all while never removing the phone from her ear. I didn't blame the kids for being wound up; it was after school, and they were stuck in a building watching a sister when they would've undoubtedly preferred to be outside on the playground. But she couldn't be bothered to interrupt what seemed like a very non-urgent conversation.

I moved to a quieter place, sacrificing my chair for the floor. Then, three feet away, a second person started talking at full voice on her cell phone, telling the unfortunate listener on the other end repeatedly how pissed she'd been earlier in the day. Keep in mind, it was sunny and 66 degrees outside. Either person stepping outside to take her call would have been healthful and humane. But both women, insofar as my amateur observational skills could tell, sat in the middle of a crowded room and talked on their phones for the duration of the one-hour practice, save for the intermittent screaming at their kids. One child actually begged lady number two not to talk on the phone anymore, and was told to "zip it." A third man, who I assume was also a parent, broke his phone conversation only to tell a toddler to "stop fucking around." The toddler did not heed his instruction, and the man was soon sufficiently lost in his talking and texting to allow, shall we say, ample f'ing around, toddler-style. 

Sherry Turkle doesn't get into this directly in the brief video above, but this is all consistent with her observations that technology is killing social skills. We collectively show decreased empathy and a decreased ability for self-reflection. A big part of my job is handling sometimes delicate negotiations within clinics or within medical systems or between payers and doctors. In those situations, vulnerability is key. If the interested parties can't look one another in the eye and feel insecure and feel like their decisions impact the other people around the table, we get nowhere. 

Don't get me wrong. I've taken my share of calls and texts in crowds. But I've felt like an asshole almost every time. So to keep from being a hypocrite, I've set my phone to no alerts for messages or emails, and I frequently put it on sleep mode, meaning it won't ring unless an immediate family member or neighbor calls (I figure the neighbors have the best view of my house burning down). And though I've occasionally feared that this would kill my productivity, I'm fairly certain now that it does the opposite. I'm more productive the more time I spend apart from my device. People think email is urgent, for example. According to psychologist Dan Ariely, it's not. Yuval Noah Harari, author of some incredible work including Sapiens, meditates for two hours a day. And the astonishingly productive computer scientist and self-help writer Cal Newport is "indifferent" to his smartphone, still subscribes to paper newspapers, and only upgraded from a flip phone because his wife guilted him into it when they had their first baby. 

So here's a challenge for this week: Go outside your phone (comfort) zone. The next time you're standing in line waiting for something to happen, or watching your kids jump on the trampoline, or between innings at a softball game, or waiting for a movie to start, leave your phone in your pocket. Better yet, take it to whatever vehicle brought you to the game (except your skateboard; skateboards are a bad place to store a phone). It'll be hard to do, but you have the strength. Concentrate on your breathing. Once you've safely stowed the phone away, look at the others around you. You might have to work for some eye contact, because they probably aren't following the same rules you are. While you're gyrating around trying to get them to look at you, think about their stories. It'll give you something to ask them about. If they won't talk to you, make like Yuval Harari and make this time your meditation. If you're not the meditative sort, think about what you want to accomplish with the rest of the day. Make a mental plan. For a few minutes, don't be a phone drone.

See also: CRANK UP THE BASS, HOW ELSE CAN YOU CRANK UP THE BASS?, SOCIAL MEDIA IS A SET OF COMMON PLATFORMS TO DRAW OUT OUR WORST TENDENCIES, HAVE SMARTPHONES DESTROYED A GENERATION?