The pleasure of going deep

I took the ABIM endocrine maintenance exam a couple months ago.

I love the ABIM logo. It reminds me of the logo for the Southeastern Conference.

Spoiler alert: I passed. But this isn’t about my ability to pass a standardized test designed to fail only the small number of docs who can’t achieve a minimum level of competence. This post is about how good it feels to set aside the distractions of the world for a fraction of the day and really concentrate on learning something.

Ironically, the format of the exam was new. The test now includes sections in which UpToDate is available for reference. These were tricky because the availability of a reference was so seductive, much like the availability of the internet in your pocket at all times is so seductive. Lucky for me, my preparation had somewhat steeled me against this. I forced myself to use the physical version of the Endocrine Self-Assessment Program (ESAP), and I forced myself not to look up answers on the computer or my phone willy-nilly. I read through the questions, answered, read the responses, and took old-fashioned analog notes that I reviewed later. I studied around 30 minutes a day, five days/week for September and October. I kept a “30 min board review” item on my daily to-do list. I attended the Cleveland Clinic review course, which was helpful. I was amazed at the new diagnoses that have come about since I last did full-time endocrine practice. Pigmented macronodular hyperplasia? Okay then.

Analog study materials.

Ironically, I’ve somehow activated notifications on my computer so that Apple News headlines keep popping up in the corner of my screen as I’m typing this, which only serves to show how much attention residue I avoided by doing it the old-fashioned way. But even still, the first section that allowed access to UpToDate almost tripped me up. I found myself second-guessing even simple answers and clicking on the UpToDate icon to double-check myself. Even though I’m a pretty fast test-taker, and even though every UpToDate check took only a minute or so, they really added up, and I had to really hustle toward the end of that section to get done on time. For the next two sections I forced myself to finish the questions to the best of my ability and then go through any that I’d marked as potentially wrong to check them. This method left me much, much more time.

When I finished the test, mostly sure that I’d passed, I felt a sense of satisfaction that only intensified when I got my test results back. I had prepared for the test, performed well enough to pass, and legitimately increased my knowledge of endocrine diseases and their treatments. As big a pain as the board certification process is, it ultimately made me a better doctor and reinforced some of my technological minimalist views of the world.

Many of us do the same job tasks day after day. I’ve warned med students and residents about the “Groundhog Day” phenomenon. If you go into general surgery, you better like gallbladder disease, because you’re going to see it all day, every day, forever. If you become an endocrinologist you better like hyperthyroidism, because again, it’s gonna take up a lot of your day. (I would have said diabetes there, but it’s so rapidly automating that I’m not sure it will be part of the day-to-day of endocrine practice for much longer.) I’m sure the same thing is true of banking, law, manufacturing, farming, or a thousand other professions. But by going deep, you can find new sources of pleasure and satisfaction even in work that has a tendency to become rote.

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.