Laboratory Assessment in the Diagnosis of Male Hypogonadism

Laboratory assessment in the diagnosis of male hypogonadism  
[PODCAST TRANSCRIPT]

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Male hypogonadism is a common clinical syndrome impacting the quality of life for many patients in the US. In fact, it's estimated that approximately 35% of men older than 45 are impacted by hypogonadism. And that percentage may be even higher in certain populations like men with type 2 diabetes or obesity.

I'm Dr Maeson Lasko, a researcher by training with a passion for learning. And I'm excited to learn alongside you today I'm joined today by Dr Sanjay Dixit board certified endocrinologist and Quest Diagnostics, Medical Director. Today, we're going to dive deep into the clinical and biochemical features of hypogonadism. Join us as we walk through the clinical background. And review a guideline supported algorithm that provides a step-by-step method to diagnosing adult male hypogonadism. Welcome Dr Dixit. Thank you for joining me today. 

Thanks, Maeson. Good to be here.

So let's start today with the very basics. What is adult male hypogonadism?

Male hypogonadism is a syndrome which results from decreased testosterone and or decreased sperm production due to abnormalities of the testicles and or the hypothalamic pituitary unit. The clinical presentation depends on the degree and the duration of the testosterone deficiency. As you said earlier, Maeson, it's a very common diagnosis. It's estimated to affect 4 to 5 million men in the United States, and it increases with age. So with the increasing population, you'll see this more and more. And it's also associated with some of the most common conditions found in primary care clinics, such as diabetes and obesity.

Interesting. This is a syndrome that seen more and more particularly in primary care. So for our primary care audience listening in today, what clinical signs and symptoms should they really be associating with hypogonadism? 

Some of these are nonspecific symptoms, which can be attributed to other causes. But to answer your question, things like decreased energy, low libido, erectile dysfunction, depressed mood, and osteoporosis, and in certain circumstances, factors such as low testicle size and a slight regression in sexual characteristics. As I mentioned in our wildly popular thyroid dysfunction podcast keep in mind that clinical symptoms are only part of the diagnosis. The laboratory assessment is the objective piece or pieces of data that a provider needs to make a diagnosis of hypogonadism. When I talk about laboratory testing in terms of hypogonadism, I mean an unequivocal and a consistently low serum testosterone concentration.

I love the shout out to our podcasts for fans listening in be sure to check out those podcasts for more learnings as well. Okay. So primary care provider has a patient who comes in complaining of declined energy, low libido, and other manifestations that their provider suspects might be symptoms of hypogonadism. You mentioned that the other half of the diagnosis, in addition to clinical symptoms, is laboratory testing, specifically testing for low testosterone. Can you expand on this? Where should providers start when assessing for male hypogonadism?

Well, first look at the whole patient, you know, evaluate the patient for other illnesses. For example, medications, certainly opioids are very well known to decrease testosterone concentrations. But once that initial assessment, that patient specific assessment is completed by the provider, start with the total testosterone measurement. And as you can imagine, there's multiple ways to measure total testosterone. One is immunoassay, that's an older method. The more modern method is something called liquid chromatography tandem mass spectrometry. For purposes of this podcast and for my sanity, I will say LC MS MS for the duration of the podcast. LC MS MS is the preferred and guideline recommended methodology for assessment of total testosterone as per my professional organization, the Endocrine Society. So this patient's with signs and symptoms of hypogonadism, as I just discussed, should get a total testosterone by LC MS MS. Now, if the testosterone is normal, the provider should consider other causes for those nonspecific symptoms that I mentioned earlier. However, if the testosterone concentration is found to be low, a provider should confirm this finding using a repeated total testosterone test, as well as a test for free testosterone. This should be done by equilibrium dialysis. And to obtain a diagnosis of hypogonadism, one would expect a low testosterone concentration or near lower limit of normal testosterone concentration and a low free testosterone concentration for adults less than 69 years of age.

A couple other things a provider needs to know regarding checking testosterone. Food, especially glucose ingestion, is known to decrease the serum testosterone concentration. So the blood should be drawn fasting. And as per Endocrine Society guidelines, the blood draw should occur between 8 AM. and 10 AM. 

Okay. So you mentioned that providers should start by you measuring a total testosterone and then add a free testosterone. When the total testosterone is low. Are there other circumstances when a provider should consider adding a free testosterone initially.

Great question, Maeson, and the answer is yes. Testosterone is bound to a protein called sex hormone binding globulin, or SHBG. So testosterone bound to SHBG is not bioavailable to the tissues in the body. There are a whole list of conditions that can either decrease or increase SHBG. Some things that can decrease SHBG include obesity and diabetes. Some things that can increase SHBG are aging and hyperthyroidism. For example, providers should consider ordering a total testosterone and a free testosterone at the same time in patients with any of these chronic conditions.

Great only a few minutes in, and I've already learned so much there's a lot of really helpful information coming at us today. So let's summarize what we've been talking about so far. A patient comes in with suspected hypogonadism, the initial action of the provider is to get a total testosterone measurement. And there are certain conditions that you just listed where SHBG may be influenced. These are the patients where we'll want to add a free testosterone to that initial, total testosterone measurement. If the results come back low, then the patient should follow up with a repeated total testosterone and an additional free testosterone. If their results are then still low, the patient has confirmed hypogonadism. Does that sound right to you?

That's correct. 

Let’s circle back to methodology. You mentioned equilibrium dialysis for measuring free testosterone. Is that the gold standard for free testosterone assessment?

Yes, it is the gold standard. It's considered the most accurate way to assess free testosterone. If equilibrium dialysis is unavailable at certain laboratories, guidelines recommend estimating free testosterone levels. Using a formula based on the measurement of total testosterone by LC MS MS, sex hormone binding globulin, and albumin. But I should note immunoassay platforms are less accurate when compared to equilibrium dialysis. It should not be used to measure free testosterone for a hypogonadism workup. 

Okay. So we're starting with a total testosterone using LC MS MS technology. We obtain a free testosterone with equilibrium dialysis, or calculation as a follow up. When that initial total testosterone is low, are there other tests that a provider should consider ordering when hypogonadism is confirmed?

That's a great question, Maeson. And the answer is yes. After the hypogonadism is confirmed with a low total testosterone, as well as a low free testosterone. The provider could consider assessing two other hormones, follicle stimulating hormone, FSH, and luteinizing hormone, LH. The reason for doing this is to help delineate between primary and secondary hypogonadism. As you may know, hypogonadism is a result of an impairment along the hypothalamic pituitary gonadal axis. So dysfunction can occur at any stage along that axis to cause the low testosterone. First, when the low testosterone is due to dysfunction in the testicles themselves, this is considered primary hypogonadism because it's occurring at the level of the testicle. Dysfunction, though, can happen earlier in the axis at the level of the hypothalamus or the pituitary, and that's considered secondary hypogonadism. To distinguish between primary and secondary hypogonadism, we can look at these gonadotropins, the FSH and the LH. These are signals for the gonads to secrete testosterone. 

Thank you for those definitions. I think it's helpful to start thinking about what labs are necessary for distinguishing between primary and secondary hypogonadism. So primary hypogonadism, low testosterone due to dysfunction at the level of the testes secondary hypogonadism low testosterone due to dysfunction in the hypothalamic pituitary axis before the level of the testes. What are the anticipated results of LH and FSH for primary and secondary hypogonadism?

Yeah, when a person has primary hypogonadism and dysfunction is happening at the level of the testicles, the FSH and LH basically shout at the testicles to release more testosterone. So in primary hypogonadism, you'll see a high FSH and LH. Contrast that to secondary hypogonadism. In that situation, the testicles aren't receiving the signal to release more testosterone. So that's when you would see a low or inappropriately normal FSH and LH. I should mention, just to complicate things a little bit more, there can be combined hypogonadism, which is a combined presentation, as you would expect, of primary and secondary hypogonadism. In this situation, the FSH and LH levels are variable, depending on whether primary hypogonadism or secondary hypogonadism predominates in that particular patient.

I love the analogy that you're talking about with primary hypogonadism, where FSH and LH are basically shouting at the testes to release more testosterone. But because the issue has at the level of the testes, the testes basically aren't listening. So you expect high levels of FSH, LH screaming at the testes to release more testosterone that testes aren't listening; testosterone is still low resulting in hypogonadism. So that's something that will definitely stick in my memory and help me remember the differences between primary and secondary hypogonadism as well as the laboratory results we should expect. But one thing I was curious about, I've heard a lot about the treatment of hypogonadism using testosterone replacement therapy. What should providers be considering for laboratory assessment in these patients?

Good question, Maeson. As you can imagine, this is a provider patient discussion about risks and benefits of testosterone replacement therapy. I think it's beyond the scope of this talk. However, if the provider and the patient have decided that testosterone replacement therapy is in the best interest of the patient. Monitoring of testosterone, hematocrit, and prostate specific antigen, also abbreviated as PSA, is recommended, as well as a measurement of bone mineral density. And the Endocrine Society guidelines recommend measuring total testosterone as well as hematocrit three to six months after initiation of testosterone replacement therapy. Now this is an important point to make that total testosterone levels should be measured midway between injections when using intramuscular testosterone esters or 2 to 8 hours after application of a transdermal gel. 

So testosterone isn't just utilized to diagnose hypogonadism, but should also be utilized in patients who are administered testosterone replacement therapy per the guidelines. Really great to know. Thank you. So here it goes. Another shameless plug to our podcasts. I know in a previous podcast that you recorded with my colleague, Sarah Walsh, you discussed the cardiometabolic connection with common endocrine conditions and in those podcasts you were talking about PCOS and thyroid disease So, is there a similar impact here? Does hypogonadism impact cardio-metabolic health or risk in male patients?

Hypogonadism and cardiometabolic health are linked, as you would suspect. So just a few statistics. Men who have a low testosterone level have four times greater risk of diabetes, and they also have an increased likelihood of having metabolic dysfunction associated liver disease, formerly known as nonalcoholic fatty liver disease. Testosterone deficiency is also associated with hypertension and atherosclerotic cardiovascular disease and reduced testosterone is associated with increased mortality.

Wow. Those stats really underscore how interconnected these disease states are. Thanks for sharing those with us. Today we've covered a lot, the clinical signs and symptoms of hypogonadism that laboratory testing associated with primary and secondary hypogonadism, and even the follow up testing a provider should consider ordering when starting a patient on testosterone replacement therapy. Where can our audience go to gain a better understanding of all the things that you helped us learn today?

Our team of medical experts have developed a diagnostic algorithm for hypogonadism that can simplify the path to diagnosis, aligning the medical society guidelines with our comprehensive endocrine test menu. And we've included the link to this algorithm in the podcast description. 

Thanks Dr. Dixit. In addition to that algorithm, we've also included a Clinical Focus on hypogonadism that takes a deeper dive than what time allotted for today. Also look at the Quest Diagnostics clinical education center for additional recorded podcasts and webinars related to cardiovascular, metabolic, endocrine, and wellness medicine. So one last question, as we round out today's podcast. The diagnosis of these endocrine conditions feels complex and you've helped break that down for us today regarding hypogonadism. Can you give our listeners some final takeaways?

Yes, you mentioned that endocrine diagnoses are complex. But I'll go back to what we talked about at the beginning of the podcast. These symptoms are nonspecific, somewhat vague. The laboratory assessment is really the objective evidence you need to make diagnoses of any endocrine disorder, hypogonadism included. So in terms of hypogonadism, all providers can start with a total testosterone measurement. And if the results are low, they can confirm with repeat testing. As well as adding additional tests, as we've discussed, including free testosterone, FSH, and LH. If patients are on testosterone placement therapy, there are guidelines on what labs need to be monitored, as we discussed just a few minutes ago testosterone, hematocrit and PSA.

Also remember that LC MS MS is preferred per guidelines for total testosterone measurement. Although the immunoassay total testosterone may be acceptable, guidelines encourage the use of LC MS MS when testosterone levels are suspected to be low.

And if a provider has a clinical suspicion from the beginning that a male has low testosterone, and or the male is obese, is older, has diabetes, etc., they should start with LC MS MS. And we talked a lot about free testosterone in this podcast. Free testosterone by equilibrium dialysis is the gold standard and guideline supported 

Thank you so much for your time and expertise today, Dr Dixit, it was wonderful to have you on the podcast and learn from you today.

Great to be here. Thank you. 

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