#462 Male Hypogonadism Pearls with Dr. Bradley Anawalt: Insights on Testosterone Deficiency

November 18, 2024 | By Matthew Watto, MD

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Transcript available via YouTube

Risks/benefits in older males, when to test, fertility considerations, and more.

Master male hypogonadism diagnosis and management. Discover when and how to test, how to tackle confounding conditions, and why lifestyle changes may be more effective than testosterone therapy in certain patients. We are joined by Dr. Brad Anawalt, an expert in endocrine care, to guide us through the essentials.

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Show Segments

• Intro
• Case 1
• History and Physical 
• Laboratory Testing 
• Effect of Lifestyle on Testosterone
• Case 2
• Prostate and Cardiovascular risk
• Treatment Options and Considerations
• Secondary Causes of Hypogonadism
• Case 3
• Testicular Size and Klinefelter Syndrome
• hCG and Clomiphene
• Monitoring and Follow-Up
• Take-Home Points
• Outro

Hypogonadism Pearls

1. Clinical assessment is vital: patients with a convincing history can increase or decrease the pretest probability that a patient is hypogonadal, thus influencing your interpretation of borderline values. 
2. Patients with signs and symptoms of low testosterone should be diagnosed with testosterone deficiency only when AM fasting testosterone is low on two occasions, using CDC validated laboratory methods whenever possible. 
3. Using accurate assays are vital to the diagnosis of hypogonadism, especially if presenting symptoms are vague and initial values are borderline.  
4. Free testosterone is rarely discrepant from total testosterone, but may happen in cases where sex-hormone binding globulin (SHBG) is altered such as obesity (lowers the SHBG, thus potentially showing a normal free testosterone even when total appears low) or old age (elevates the SHBG, thus possibly causing a normal total testosterone with low free testosterone). 
5. Labs that directly measure free testosterone are erroneous and should not be used. Free testosterone should be calculated (most commonly done) or measured by equilibrium dialysis (expensive, rarely done). 
6. Decreased libido is the most specific symptom of hypogonadism, especially when it is acute onset. Make sure patients are being realistic and not simply comparing themselves to when they were younger. 
7. Many symptoms of hypogonadism are nonspecific, and it is important to consider other  etiologies such as depression.
8. A testicular exam to assess the size of the testes and exclude a mass is essential. Orchidometers are inexpensive tools that can aid in testicular size assessments.
9. There is evidence in the literature that lifestyle modification (i.e. weight loss via diet and exercise) improves many symptoms of testosterone deficiency in men who have a high BMI, low serum testosterone, and no identifiable disorder of the hypothalamus-pituitary- testicular axis.

Male Hypogonadism Pearls – Notes

History

Identify and Treat Confounding Conditions

Dr. Anawalt underscores the value of clinical history when considering testosterone testing, emphasizing that many cases of low testosterone can stem from underlying issues like obstructive sleep apnea (OSA), depression, obesity, or metabolic dysfunction. In these situations, addressing the root cause often enhances the patient’s overall well-being and resolves primary complaints without the need for testosterone therapy. If testosterone is measured and found to be slightly low or low-normal in patients with mild secondary hypogonadism caused by an underlying condition, supplemental testosterone alone is unlikely to resolve their symptoms. Dr. Anawalt suggests that unless specifically requested by the patient, clinicians should carefully consider the implications of testing in cases with low suspicion for hypogonadism, as the results may not significantly change the management approach. When nonspecific symptoms or patient requests for testosterone testing arise, it is reasonable to screen for other conditions such as major depressive disorder. For patients with metabolic syndrome who express interest in testosterone testing, Dr. Anawalt recommends a primary focus on lifestyle modifications rather than supplemental testosterone as the preferred management approach. However, if a patient comes to the office with the goal in mind to get their testosterone checked, it may be difficult to dissuade them from doing so, and checking is reasonable (expert opinion).

Ask About Libido

A key component of the assessment, Dr. Anawalt highlights, is asking about libido. A decline in libido is  relatively specific compared to other symptoms of hypogonadism, but low or decreased libido is common in men with depression or who are having relationship problems with their intimate partner(s). He advises framing the question to help patients compare their current libido with the past few years rather than their younger years. Dr. Anawalt often uses the term “sex drive” for clarity, tailoring the language based on the patient’s individual context and sexual practices. He also reminds clinicians that those with lifelong primary hypogonadism may lack a baseline of “normal” testosterone, so typical changes in libido may not be reported in the history. Using questions such as “Do you think about sex as much as you used to?” or “Are you as interested in sex as you used to be?” can help elicit the response in a patient-centered way.

Physical Exam

Look for exam signs such as obesity and a thick neck that can point to a potentially reversible etiology. A thick neck (> 17 inches) might be a clue to obstructive sleep apnea (expert opinion).

Waist Circumference

Dr. Anawalt explains that measuring waist circumference is better than using BMI; he recommends measuring from the posterior iliac crest to just below the umbilicus, acknowledging that this may be difficult in patients with severe obesity and that staying consistent may be challenging.

Testicular Exam

The most helpful physical exam sign is the testicular exam, which can be performed with the help of an orchidometer (expert opinion). A small testicular size in a hypogonadal patient points to either androgen use (prolonged recovery phase) or Klinefelter syndrome; the former will also have suppressed gonadotropins but Klinefelter syndrome will not. According to Dr. Anawalt, testicles can be expected to shrink as much as 5-35% during testosterone therapy, but this is reversible. Most men do not even notice it; hence counseling may not be 100% necessary since such a small number of men actually check (expert opinion).

Laboratory Evaluation

Timing

Dr. Anawalt reminds us to check an early morning testosterone measurement between 7-10 AM if concerned for hypogonadism (Mulhall, 2018). Patients should also fast for at least six hours prior to obtaining measurements. Per Dr. Anawalt, checking fasting levels is not correlated to outcomes but has the potential to raise testosterone by up to 50 ng/dL (Jucá 2019). When there is a low baseline suspicion for hypogonadism, this effect may elevate testosterone levels from subnormal to normal, potentially deferring a diagnosis of hypogonadism. According to Dr. Anawalt, the normal range of testosterone can vary but is often 300-900 ng/dL; in a CDC-validated lab the range should be 264-916 ng/dL (Travison, 2017). Using your own laboratory is acceptable, but CDC-validated labs are preferred if possible to ensure standardization and accurate measurements (expert opinion). 

Other Labs

It is reasonable to check TSH/FT4 in secondary hypogonadism  (low T, non-elevated FSH and LH) to exclude secondary hypothyroidism (low free T4 and low or normal TSH) that would suggest a pituitary problem such as a macroadenoma (expert opinion). According to Dr. Anawalt, ordering follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gives you the opportunity to explain physiology to patients at the follow-up visit, however doing this with the initial round of testing is not required and may not always be the highest-value care (although the cost of this is likely low) depending on the circumstances. Additionally, if FSH/LH are normal, this provides an opportunity to tell men that have a BMI > 30 or waist > 40 inches that they can improve their testosterone with lifestyle modification (Grosmann, 2024, Anawalt expert opinion). Low/very low FSH/LH suggests secondary hypogonadism such as an infiltrating or structural process, hyperprolactinemia, or anatomic malfunction such as a pituitary tumor (Mulhall, 2018). Borderline low testosterone with normal/slightly low FSH/LH can be due to obesity, diabetes, OSA, etc. (Bhasin, 2018). 

Leptin is a key modulator here; leptin signals to the body that energy stores are bountiful and that it can procreate. The body becomes resistant to leptin in obesity, and weight loss helps reverse this phenomenon (Zhai, 2016). 

High FSH and LH indicate  primary hypogonadism which  is a problem with the testicles. Karyotype should be ordered in this scenario to evaluate for Klinefelter’s syndrome (Mulhall, 2018). 

When secondary hypogonadism is suspected, it is important to understand the underlying cause prior to initiating therapy. Conditions such as hyperprolactinemia or a pituitary tumor should be considered, and a prolactin level should be measured early in the evaluation process (Bhasin, 2018).

Ordering an up-front hematocrit is helpful (Mulhall, 2018). Most men with true hypogonadism are anemic or have normal hematocrit (Dhindsa, 2016). If it is high prior to starting treatment, for example > 48-52% range, it should be questioned whether or not they are truly hypogonadal or have concomitant OSA. Similarly, if their hematocrit rises significantly after initiating testosterone therapy, you should consider OSA (expert opinion).

When Do You Order a Free Testosterone Level?

Free testosterone should be ordered whenever you suspect an alteration in SHBG measurements which include (Guzelce, 2018):

• Aging – serum total testosterone decreases and SHBG increases in aging men; serum free testosterone decreases even more than total testosterone (Antonio, 2016).
• Longstanding primary hypogonadism – causes increases in serum LH that increases aromatization of testosterone to estrogen, leading to higher SHBG and side effects such as gynecomastia in these patients (Liang, 2021).
• Metabolic syndrome causes decreases in SHBG, which can lead to a discrepancy between total and free testosterone levels. Dr. Anawalt advises to consider ordering free testosterone up-front whenever features of metabolic syndrome such as obesity, diabetes, or insulin resistance are present. These conditions all cause decreased synthesis of SHBG, which in turn leads to pseudo-hypogonadism, as characterized by a low serum testosterone but a normal free testosterone (Gyawali, 2018). 

Dr. Anawalt states that it is not wrong to wait until an initial abnormal value to order free levels, but ordering them up front can often save the patient time and give the clinician an opportunity to explain everything up front at the next follow up visit.

How Do You Order a Free Testosterone Level?

The modality you use has to be accurate, and there are generally two ways to do this:

• You can use a calculated value (Wang, 2009) which should be done by the lab itself (expert opinion). This is the easiest and most common way to do it.
• Equilibrium dialysis is also validated (Jasuja, 2022), but is expensive and can take time to come back. This method is much less commonly used (expert opinion). 

The calculated lab value should report an SHBG level that was used for this calculation, but Dr. Anawalt states that clinicians should not be using this to calculate the values themselves, the lab should do it for you. If no SHBG is reported, be wary that the lab may be using a direct measurement. Dr. Anawalt reminds the audience that direct measurements of free testosterone are not useful, and should not be used (Wang, 2009). Direct measurements are often labeled, but you can also glean that most numbers that are reported in single digits are likely to be done by this method and should be questioned (expert opinion).

Discrepant Total and Free Testosterone

We are reminded by Dr. Anawalt that discrepancies between total and free testosterone are less likely in cases of true hypogonadism, particularly when measurements are conducted using accurate laboratory methods. Treatment is most effective in patients with concordant values (expert opinion). Thus, these labs should be interpreted within the context of whether or not you believe the patient to be truly hypogonadal by clinical history. For instance, it would be reasonable to treat an elderly male with new onset low libido and low free testosterone levels, even if his total testosterone levels are normal. Alternatively, if an underlying cause such as obesity or OSA is present, then addressing that condition rather than initiating testosterone therapy would be advisable (expert opinion).

Karyotype and Klinefelter Syndrome

In patients in which primary hypogonadism is suspected, ordering a karyotype assessment is helpful in establishing a diagnosis of Klinefelter syndrome (Bhasin, 2018). Per Dr. Anawalt, the diagnosis can likely be made presumptively in patients with low testosterone, high gonadotropins, and small testes on exam (usually 2-3cc), but a karyotype can give a clear diagnosis, which has fertility implications (Boehm, 2015). Patients with Klinefelter syndrome can undergo sperm harvesting procedures, as up to 40-45% of patients may have viable sperm. Sperm harvesting and injection of the sperm into the egg (called ICSI) does not appear to increase the risk of having a son with Klinefelter syndrome (Rosália, 2023). Eunuchoid body habitus can be a helpful exam finding if you compare the lengths of the legs to the wingspan, but in general is not exceedingly useful (Chang 2014, Anawalt expert opinion).

Imaging

MRI – When to Order:

Dr. Anawalt emphasizes that there are four main indications for ordering an MRI of the pituitary in the setting of hypogonadism evaluation, aside from when it is more clearly indicated such as headache, visual disturbances etc. (Bhasin, 2018):

• Patients with markedly low testosterone (Rhoden, 2003).
• Consider an MRI in all patients younger than age 50 with non-elevated FSH/LH  given that many of the reversible causes of secondary hypogonadism are uncommon in this age group (expert opinion).
• Any man with a low serum T, non-elevated serum FSH and LH, and elevated prolactin (Bhasin, 2018), even if only slightly.
• If FSH/LH are undetectable (Rhoden, 2003), then it’s probably not just due to aging (expert opinion).

Lifestyle Modification

Prioritizing Lifestyle Changes in Metabolic-Related Hypogonadism

Dr. Anawalt stresses that lifestyle modifications should be prioritized over testosterone therapy in patients with obesity who have  low to low-normal testosterone, particularly when metabolic syndrome is likely the underlying cause. This suspicion is supported by FSH and LH levels that are normal—rather than markedly low or undetectable—suggesting secondary hypogonadism due to metabolic dysfunction (Yeap, 2016).

These cases are defined by all of the following:

• Slightly low / low-normal total serum total testosterone and/or free testosterone
• Normal or low-normal FSH/LH. If undetectable, other etiologies of secondary hypopituitarism should be suspected (Bhasin, 2018).
• No identifiable cause of low testosterone such as obstructive sleep apnea, hyperprolactinemia, pituitary adenoma, or Cushing syndrome

Literature Insights: Lifestyle vs. Testosterone Therapy

Dr. Anawalt cites an Australian study called T4DM and specifically its secondary analysis: lifestyle modification had a more significant impact on quality of life across various domains than testosterone therapy in men over age 50 at high risk for type 2 diabetes. While testosterone improved aspects like social status and coherence, weight loss through lifestyle changes led to greater gains in health-related quality of life and psychosocial function, including mental clarity and sexual function. Notably, the benefits of weight loss on mental and psychosocial outcomes were independent of testosterone use (Grosmann, 2024).

Monitoring Response

In clinical practice, Dr. Anawalt recommends 6-12 months of lifestyle modification prior to considering testosterone replacement for patients who have reversible hypogonadism due to obesity. This includes 30-40 minutes of exercise five times per week, increasing to more if they are currently exercising.

When monitoring for response to lifestyle intervention, Dr. Anawalt emphasizes that serially measuring waist circumference may be a better marker of weight loss than weight, as it is a truer reflection of visceral adiposity.

GLP-1 Analogs

He also makes a point about using GLP-1 analogs for weight loss: these medications, although effective at treating obesity, do have side effects of reduced muscle mass and bone density (Jensen, 2024), which may be in opposition to what many hypogonadal patients are seeking to achieve. Additionally, they work by reducing the brain’s pleasure signal which can be undesirable for some patients (Badulescu, 2024).

Age-Related Testosterone Decline

Normal Physiology

Testosterone levels typically begin to decline around the ages of 30-35 at a rate of about 0.5% per year, with a significant decrease occurring between ages 65-70. This gradual decline can lead to clinical hypogonadism, which may involve a combination of primary and secondary factors that vary from one individual to another. As men age, there is a reduction in both the function and number of GnRH-secreting neurons, contributing to secondary hypogonadism. Concurrently, Leydig cells may become less responsive to LH, a condition that may be exacerbated by Leydig cell ischemia, leading to primary hypogonadism. The presence of metabolic syndrome can intensify these effects. While secondary hypogonadism might improve with lifestyle modifications, particularly if obesity, diabetes, and insulin resistance are present, primary hypogonadism could benefit from testosterone therapy (Anawalt, 2017).

Primary vs Secondary Hypogonadism in Older Men

In older men, low testosterone levels alongside elevated FSH and LH may suggest either previously undiagnosed Klinefelter syndrome—which affects approximately 0.2% of the population—or age-related testicular dysfunction (Anawalt, 2017). For these men, lifestyle changes alone are unlikely to sufficiently improve testosterone levels, and testosterone replacement therapy can be beneficial and safe when they present with clinical symptoms of hypogonadism, but requires an individualized approach (expert opinion).

Prostate and Cardiovascular Considerations

The TTrials, T4DM, TRAVERSE, and TEAAM are useful trials to answer the question regarding the cardiovascular and prostatic risks of testosterone. All analyzed patients with mild to moderate lower urinary tract symptoms (LUTS) and found that there was no increase in these symptoms. Of note, the trials excluded patients with severe LUTS.

Prostate

Recent studies show that there was no increase in LUTS (lower urinary tract symptoms) in patients on testosterone therapy, but those with severe symptoms were excluded from the trial (Bhasin, 2023). There were also no significant increases in prostate cancer. Similar to the normal population, in some patients it may be reasonable to establish a baseline prostate specific antigen (PSA), and monitor annually in patients who desire screening. This conversation is usually brought up in men aged 50-70 or starting at age 40 in patients with a family history or increased risk (Bhasin, 2018). Most patients who start androgen therapy can expect only a small increase in PSA of 0.2-0.5. However, some men will see larger increases of three or more. This does not mean they have a higher risk of prostate cancer, but does mean they may be hyper-responsive to androgens (Cunningham, 2019).

Cardiovascular Risk

The TRAVERSE trial evaluated the cardiovascular safety and efficacy of testosterone replacement therapy (TRT) in 5,246 hypogonadal men aged 45 to 80 with low testosterone levels and preexisting or high-risk cardiovascular disease. There was no increased incidence of major adverse cardiovascular events (MACE), such as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, though it was associated with higher rates of pulmonary embolism (Lincoff, 2023). Nearly twice as many men had pulmonary emboli in the testosterone arm than the placebo arm, but the total number of events was small at just under 40. Nonetheless, this is another reason to be hesitant about prescribing testosterone to people in whom the clinical suspicion for hypogonadism is low (expert opinion).

Testosterone Replacement Therapy

Formulations

Dr. Anawalt mentions that many formulations of TRT exist including oral, nasal gel, and long-acting depot. However, the two that he typically uses are intramuscular testosterone cypionate and transdermal gel. The choice between gel and intramuscular (IM) testosterone therapy often hinges on cost-effectiveness and side effect profiles. The risk of unintentionally transferring gel to others is a notable concern with the gel formulation (Bhasin, 2018). Many men report a perceptible increase in testosterone levels following an injection, leading them to favor this method (expert opinion). Additionally, Dr. Anawalt mentions that some men prefer the less frequent dosing schedule of IM injections. However, since the gel poses a lower risk of increasing hematocrit, it may be a preferable option for patients experiencing erythrocytosis with the IM option (Nackeeran, 2022).

Optimizing Dosage

Identify the appropriate dosage and initiate treatment at that level. While a cautious approach of starting low and escalating slowly may be suitable for patients at high risk of adverse effects, such as those with significant LUTS, for others, swiftly achieving the correct dose is key. This approach does not advocate beginning with the maximum dose; instead, it emphasizes that patients generally feel better faster when their optimal dosage is quickly established (expert opinion).

Treatment Response

Patients who show the most improvement are typically those with severe hypogonadism, characterized by very low levels of serum testosterone, and those with a well-defined underlying cause, such as Klinefelter syndrome (Ponce, 2018). In contrast, individuals with only mildly low testosterone often experience minimal benefit and may discontinue therapy on their own, as noted by Dr. Anawalt. This underscores the significance of addressing any reversible causes of hypogonadism. Additionally, Dr. Anawalt points out that patients with low hematocrit represent a distinct group who generally feel better once their hypogonadism is treated (Lincoff, 2023).

Fertility in Young Patients with Secondary Hypogonadism

Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) has long been established as an effective method to boost endogenous testosterone by stimulating the testes directly. Acting as a surrogate for gonadotropins, primarily LH, hCG stimulates the testes to produce testosterone (Pieters, 1979). This mechanism is similar to how hCG increases estradiol during pregnancy (Casarini, 2018). Human chorionic gonadotropin is generally well-tolerated, with minimal side effects (expert opinion), and is administered subcutaneously 2-3 times per week (Saal 1991, Mulhall 2018). If hCG treatment alone does not stimulate sufficient sperm production, FSH can be added (Practice Committee of the American Society for Reproductive Medicine, 2018).

Clomiphene Citrate

On the other hand, clomiphene, a selective estrogen receptor modulator (SERM), has a shorter track record than hCG for  treatment of male infertility due secondary hypogonadism. It works by blocking estrogen receptors in the brain, which disrupts the natural negative feedback mechanism and leads to increased production of gonadotropins (Mulhall, 2018). However, it tends to be less effective in older men (Guay, 2003) and there are some reports of central retinal vein thrombosis, raising concerns about thrombotic events, although more research is needed in this area (Viola, 2011). 

Monitoring on TRT

IM Injections

Monitor concentrations after a change in dose or once per year. Measure the level halfway between injections (Mulhall, 2018). Dr. Anawalt notes that for a weekly injection, this would be 3.5 days after injection. Do not try to target the middle of the normal range, Dr. Anawalt emphasizes that this is challenging to do. If the patient’s serum testosterone is low normal, it is reasonable to slightly increase the dose (Bhasin 2018, Anawalt expert opinion).

Transdermal Gel

Wait until 4-6 hours after application (Bhasin, 2018), as this allows for airing on the side of not overtreating, since the concentration will be higher after application (expert opinion). Target anywhere in the normal range (expert opinion).

Hematocrit and Obstructive Sleep Apnea

The intervals for checking hematocrit are: initially at diagnosis, 3-6 months later, and then annually (Bhasin, 2018). Monitor hematocrit levels closely; if they exceed 50%, decrease the testosterone dosage and consider evaluating for OSA. For men who have obesity and/or thick necks and secondary hypogonadism, it is reasonable to first address OSA before considering testosterone therapy, as treating OSA can sometimes resolve their complaints. If the hypogonadism is primary, treating OSA alone will not fully correct the condition, and both issues should be managed simultaneously. Additionally, treatment for hypogonadism can sometimes unmask OSA, necessitating treatment for both conditions concurrently (expert opinion).

Nadir Levels

For patients who are inclined to continuously increase their testosterone dosage, it is helpful to check nadir levels (expert opinion). This can demonstrate to patients that their testosterone levels are within normal ranges, even at their lowest point. To measure these nadir or “trough” levels, conduct the test just before their scheduled testosterone administration. For instance, if dealing with injectables, measure testosterone levels right before the next injection is due (Bhasin, 2018). Similarly, for those using gels, assess the levels just before the gel is applied (expert opinion). Evaluating trough levels is particularly useful for identifying how quickly or slowly a patient metabolizes testosterone, providing insights into the hormone’s stability between doses (expert opinion).

Stopping Testosterone

Irreversible Causes

Patients with causes of testosterone deficiency that are unlikely to resolve will need lifelong therapy. This includes individuals with genetic conditions such as Klinefelter syndrome (Wikström, 2011), as well as those with irreversible conditions, like opioid-induced hypogonadism in patients who require long-term buprenorphine treatment (Bhasin 2018, Anawalt expert opinion).

Reversible Causes

Patients may struggle to discontinue therapy due to suppression of their hypothalamic-pituitary axis (Bhasin, 2018). This is why Dr. Anawalt stresses the importance of addressing any reversible causes and treating underlying conditions before starting testosterone therapy. He also recommends discontinuing the therapy if there is no improvement in symptoms.

Links

1. Orchidometer 

Goal

Listeners will feel empowered to guide their patients through the jungle of misinformation surrounding testosterone testing and replacement.

Learning objectives

After listening to this episode listeners will…

1. Recognize signs and symptoms of testosterone deficiency from history and exam, and decide when to order testing 
2. Discuss the nuances behind laboratory methods for testing and when to order free testosterone, and how to interpret it to patients 
3. Identify who is at higher risk of adverse events from testosterone therapy, including older males, and be able to guide the patient through the risk/benefit conversation 
4. Discern between various forms of T replacement, including IM, transdermal, and oral options. Be able to discuss monitoring options for each. 
5. Learn how to counsel a male patient with testosterone deficiency who is interested in having children, including options such as hCG and clomiphene  

Disclosures

Dr. Anawalt reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Wurtz PJ, Anawalt BD, Williams PN, Watto MF. “#462 Male Hypogonadism Pearls with Dr. Bradley Anawalt: Insights on Testosterone Deficiency”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast November 18, 2024.