Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania
Disclosure: Matthew F. Watto, MD, has disclosed no relevant financial relationships.
Paul N Williams, MD
Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, Pennsylvania
Disclosure: Paul N. Williams, MD, has disclosed no relevant financial relationships.
Matthew F. Watto, MD: Welcome back to The Curbsiders. I'm Dr Matthew Frank Watto, here with my great friend and America's primary care physician, Dr Paul Nelson Williams. Paul, if I have very low energy, is that the main symptom of low testosterone?
Watto: Dr Bradley Anawalt was a fantastic guest and is an international expert who gave us some amazing pearls on this topic. So, what is the main symptom of low testosterone?
Williams: It's a great question. Typically, a patient will come in and ask about testosterone testing. They might report vague symptoms. That sounds kind of judgy, but they may say they have low energy or are just not feeling well. Maybe they have seen commercials about low testosterone and have become worried about their levels.
Libido is typically the best indicator of whether a patient has hypogonadism. To avoid the use of jargon, Dr Anawalt talks about it in terms of sex drive. Ask the patient whether their desire to have sex has decreased significantly, and make sure they recognize that it's normal to have a decrease in sex drive as you age. However, if they have had a huge decrement in sex drive, it might be time to have that conversation about testosterone.
As a provider, that significant decrease in sex drive, more than anything, is probably the best indicator that you should move forward and conduct hypogonadism testing. Other patient-reported issues like depression, fatigue, and general malaise are not, in and of themselves, great indicators of testosterone level. And these other issues may not even resolve if you opt to treat.
Now, let's say we do have a suspicion of hypogonadism and we actually want to do a laboratory workup to confirm. What sort of laboratory work or clinical evaluation should we conduct?
Watto: I think most clinicians are aware that you should check an early-morning testosterone because that's when levels tend to be high, and all of our normal ranges are calibrated to an early-morning testosterone level.
However, Dr Anawalt suggested that you should get a fasting testosterone, as a fasting testosterone level may be 50-60 points higher than a nonfasting reading. That 50- to 60-point difference could be enough to elevate testosterone levels from subnormal to normal, potentially deferring a diagnosis of hypogonadism. That's why it's key. If we test a patient without fasting and they're in the 270 ng/dL range, their fasting value would potentially be around 320 ng/dL. That's a much better, healthier value.
Dr Anawalt said the lab range for the CDC-validated laboratories is 264-916 ng/dL. If you see that on your lab value, you know it's a CDC-validated lab.
Let's say we ordered the total testosterone fasting and it comes back low. What other steps could we take to help us further determine whether this is primary vs secondary hypogonadism or any other condition we should be worried about?
Williams: We asked Dr Anawalt if we should consider checking luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels during our confirmatory testing in patients we're evaluating for hypogonadism. The answer is , it depends. It's probably not unreasonable to order that as part of your secondary evaluation when the patient comes back for repeat testing. However, it's more appropriate to order that test if you have clinical suspicion of Klinefelter syndrome.
Many cases of Klinefelter syndrome are missed or go undiagnosed in this country. We should have a lower threshold to consider Klinefelter syndrome as a potential diagnosis, and we should order the FSH/LH to evaluate. If those values come back screamingly high, then you might have a diagnosis on your hands and you could conduct karyotyping to confirm.
But if the FSH/LH levels come back low, you should probably consider checking prolactin. If the prolactin comes back abnormal, then you're in the realm of doing pituitary testing — specifically a pituitary MRI.
There are specific indications to order a pituitary MRI, but generally if a patient has high prolactin, undetectable FSH/LH, and low testosterone, then perhaps there's a pituitary issue that requires a bit more evaluation.
Watto: And if you think about the HPA axis, FSH and LH signal the testes to make testosterone. If FSH/LH levels are really high but testosterone remains low, that's a signal that the testosterone is not being made in the testicles. That's primary hypogonadism. On the other hand, if FSH/LH levels are extremely low, there may be something compressing the pituitary that's leading to those undetectable levels of FSH/LH. But for our typical metabolic syndrome middle-aged man, they typically present with FSH/LH values in the normal range and have low to low-normal levels of testosterone.
When discussing treatment options, Dr Anawalt prefers lifestyle modifications over testosterone therapy among patients with a reversible cause (like underlying metabolic dysfunction), because you don't want to put a patient on a lifelong therapy they don't need. Eugonadal men don't experience a huge improvement in symptoms when you put them on testosterone. For me, that was one of the big takeaways of our conversation. Patients are hoping testosterone therapy will be like the Fountain of Youth , but most of them don't feel that much better. Dr Anawalt says that, statistically, most men will stop taking testosterone within a year if they're eugonadal.
However, testosterone therapy is highly effective for men with truly low testosterone, well below normal levels. For those men, they do tend to feel much better, especially if you can identify a cause like Klinefelter syndrome or acquired primary hypogonadism.
Williams: For those borderline cases, Dr Anawalt again talked about those lifestyle modifications. It's the thing no one wants to hear about, but therapeutic lifestyle changes (ie, improving diet, exercising, and weight loss) can actually raise testosterone levels and make people feel better. So, this might be a chance to do good primary care counseling and encourage patients to make these changes, because they'll feel better without necessarily having to go down the medication route. You can make some meaningful changes in ways that are not just testosterone therapy.
Watto: But if you do offer testosterone therapy, you can tell your male patients that there have been four large trials, recently, looking at the cardiovascular prostate safety of testosterone therapy. These results indicate that even for men with benign prostatic hyperplasia or cardiovascular risk factors, testosterone does not significantly increase the risk for cardiovascular events or prostate cancer. For most men, it's going to be safe to take testosterone.
Dr Anawalt also said he usually doesn't start patients on the lowest dose when initiating testosterone therapy. Instead, he starts with a "medium" dose. He explained that if patients are feeling bad, you want them to feel better right away, and you can always adjust the dose down the line. When we previously talked about menopausal hormone replacement therapy with our guest, Dr Monica Christmas, she gave similar guidance.
In terms of treatment options, injections are cheaper than gels. In the United States, testosterone cypionate is a weekly injection that can be given to patients. Dr Anawalt also mentioned another point that I think will be practice-changing: He checks testosterone levels between individual doses when someone's on treatment. So, if it's a weekly injection, he checks midway (approximately 3-4 days) between injections to check their levels in response to acute treatment. If patients are using a topical testosterone gel, he would check 4-6 hours after application.
So, instead of getting a trough value, you get a better sense of how high their levels are going. That's not something I have been doing, and that will definitely be practice-changing for me. With these continuous checks, you can kind of prove to patients that the treatment is working and their testosterone levels are improving with use of medication. It also helps providers ensure they're not overdosing, because if you're just checking troughs and you keep going up on the dose, those peak levels may be incredibly high. This method allows you to check those peak levels.
Click here if you'd like to hear the full conversation with Dr Anawalt.
COMMENTARY
Low T, Big Impact: Diagnostic and Treatment Tips for Hypogonadism
DISCLOSURES
| April 10, 2025This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. I'm Dr Matthew Frank Watto, here with my great friend and America's primary care physician, Dr Paul Nelson Williams. Paul, if I have very low energy, is that the main symptom of low testosterone?
Paul N. Williams, MD: Masterful transition, Matt. Yes, it's a great question because today we are talking about male hypogonadism, a topic we recently discussed in our episode about hypogonadism with Dr Anawalt.
Watto: Dr Bradley Anawalt was a fantastic guest and is an international expert who gave us some amazing pearls on this topic. So, what is the main symptom of low testosterone?
Williams: It's a great question. Typically, a patient will come in and ask about testosterone testing. They might report vague symptoms. That sounds kind of judgy, but they may say they have low energy or are just not feeling well. Maybe they have seen commercials about low testosterone and have become worried about their levels.
Libido is typically the best indicator of whether a patient has hypogonadism. To avoid the use of jargon, Dr Anawalt talks about it in terms of sex drive. Ask the patient whether their desire to have sex has decreased significantly, and make sure they recognize that it's normal to have a decrease in sex drive as you age. However, if they have had a huge decrement in sex drive, it might be time to have that conversation about testosterone.
As a provider, that significant decrease in sex drive, more than anything, is probably the best indicator that you should move forward and conduct hypogonadism testing. Other patient-reported issues like depression, fatigue, and general malaise are not, in and of themselves, great indicators of testosterone level. And these other issues may not even resolve if you opt to treat.
Now, let's say we do have a suspicion of hypogonadism and we actually want to do a laboratory workup to confirm. What sort of laboratory work or clinical evaluation should we conduct?
Watto: I think most clinicians are aware that you should check an early-morning testosterone because that's when levels tend to be high, and all of our normal ranges are calibrated to an early-morning testosterone level.
However, Dr Anawalt suggested that you should get a fasting testosterone, as a fasting testosterone level may be 50-60 points higher than a nonfasting reading. That 50- to 60-point difference could be enough to elevate testosterone levels from subnormal to normal, potentially deferring a diagnosis of hypogonadism. That's why it's key. If we test a patient without fasting and they're in the 270 ng/dL range, their fasting value would potentially be around 320 ng/dL. That's a much better, healthier value.
Dr Anawalt said the lab range for the CDC-validated laboratories is 264-916 ng/dL. If you see that on your lab value, you know it's a CDC-validated lab.
Let's say we ordered the total testosterone fasting and it comes back low. What other steps could we take to help us further determine whether this is primary vs secondary hypogonadism or any other condition we should be worried about?
Williams: We asked Dr Anawalt if we should consider checking luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels during our confirmatory testing in patients we're evaluating for hypogonadism. The answer is , it depends. It's probably not unreasonable to order that as part of your secondary evaluation when the patient comes back for repeat testing. However, it's more appropriate to order that test if you have clinical suspicion of Klinefelter syndrome.
Many cases of Klinefelter syndrome are missed or go undiagnosed in this country. We should have a lower threshold to consider Klinefelter syndrome as a potential diagnosis, and we should order the FSH/LH to evaluate. If those values come back screamingly high, then you might have a diagnosis on your hands and you could conduct karyotyping to confirm.
But if the FSH/LH levels come back low, you should probably consider checking prolactin. If the prolactin comes back abnormal, then you're in the realm of doing pituitary testing — specifically a pituitary MRI.
There are specific indications to order a pituitary MRI, but generally if a patient has high prolactin, undetectable FSH/LH, and low testosterone, then perhaps there's a pituitary issue that requires a bit more evaluation.
Watto: And if you think about the HPA axis, FSH and LH signal the testes to make testosterone. If FSH/LH levels are really high but testosterone remains low, that's a signal that the testosterone is not being made in the testicles. That's primary hypogonadism. On the other hand, if FSH/LH levels are extremely low, there may be something compressing the pituitary that's leading to those undetectable levels of FSH/LH. But for our typical metabolic syndrome middle-aged man, they typically present with FSH/LH values in the normal range and have low to low-normal levels of testosterone.
When discussing treatment options, Dr Anawalt prefers lifestyle modifications over testosterone therapy among patients with a reversible cause (like underlying metabolic dysfunction), because you don't want to put a patient on a lifelong therapy they don't need. Eugonadal men don't experience a huge improvement in symptoms when you put them on testosterone. For me, that was one of the big takeaways of our conversation. Patients are hoping testosterone therapy will be like the Fountain of Youth , but most of them don't feel that much better. Dr Anawalt says that, statistically, most men will stop taking testosterone within a year if they're eugonadal.
However, testosterone therapy is highly effective for men with truly low testosterone, well below normal levels. For those men, they do tend to feel much better, especially if you can identify a cause like Klinefelter syndrome or acquired primary hypogonadism.
Williams: For those borderline cases, Dr Anawalt again talked about those lifestyle modifications. It's the thing no one wants to hear about, but therapeutic lifestyle changes (ie, improving diet, exercising, and weight loss) can actually raise testosterone levels and make people feel better. So, this might be a chance to do good primary care counseling and encourage patients to make these changes, because they'll feel better without necessarily having to go down the medication route. You can make some meaningful changes in ways that are not just testosterone therapy.
Watto: But if you do offer testosterone therapy, you can tell your male patients that there have been four large trials, recently, looking at the cardiovascular prostate safety of testosterone therapy. These results indicate that even for men with benign prostatic hyperplasia or cardiovascular risk factors, testosterone does not significantly increase the risk for cardiovascular events or prostate cancer. For most men, it's going to be safe to take testosterone.
Dr Anawalt also said he usually doesn't start patients on the lowest dose when initiating testosterone therapy. Instead, he starts with a "medium" dose. He explained that if patients are feeling bad, you want them to feel better right away, and you can always adjust the dose down the line. When we previously talked about menopausal hormone replacement therapy with our guest, Dr Monica Christmas, she gave similar guidance.
In terms of treatment options, injections are cheaper than gels. In the United States, testosterone cypionate is a weekly injection that can be given to patients. Dr Anawalt also mentioned another point that I think will be practice-changing: He checks testosterone levels between individual doses when someone's on treatment. So, if it's a weekly injection, he checks midway (approximately 3-4 days) between injections to check their levels in response to acute treatment. If patients are using a topical testosterone gel, he would check 4-6 hours after application.
So, instead of getting a trough value, you get a better sense of how high their levels are going. That's not something I have been doing, and that will definitely be practice-changing for me. With these continuous checks, you can kind of prove to patients that the treatment is working and their testosterone levels are improving with use of medication. It also helps providers ensure they're not overdosing, because if you're just checking troughs and you keep going up on the dose, those peak levels may be incredibly high. This method allows you to check those peak levels.
Click here if you'd like to hear the full conversation with Dr Anawalt.
TOP PICKS FOR YOU