Good morning, everyone. Thank you, everyone, for joining. Today, I will be talking about testosterone use and abuse in men. It's a big topic, it's hard to cover everything. My plan is to focus on two clinical scenarios. Let me get this ready. Good, perfect. I have no financial disclosures to make. Over the past two decades, there has been a marked surge in testosterone prescriptions in the US and other countries. While I don't have data from our region, I will show you today how even increased prescriptions in other countries affect our practice here. Structural hypogonadism, organic hypogonadism, remains uncommon. This increase in prescription raises concerns about inappropriate use of testosterone. The two main learning objectives for today's talk is to understand the challenges associated with establishing the diagnosis of functional hypogonadism and to recognize the negative impact of inappropriate use of testosterone as a performance-enhancing drug. Let's begin with a case. We have a 55-year-old man with class II obesity, BMI 36, type II diabetes with a hemoglobin A1C of 7.8%, who was referred to my clinic for obesity management. When I was taking the history, he mentioned he was in Thailand six months ago and underwent a wellness check. He was found to have low total testosterone. His testosterone was 230 nanogram per deciliter. The reference range for the assay was 264 to 916. He reported fatigue and erectile dysfunction, but no libido. His symptoms were attributed to the low testosterone level and was started on testosterone placement therapy, which he ran out of it three months ago. He came to clinic for weight management, but reports feeling worse. Increased fatigue, his erectile dysfunction is worse, and his energy is worse. So there are many questions that we need to answer. What population is the testosterone reference range based on? What are the factors that impact testosterone levels? What is the relationship between levels and symptoms? Will treatment improve symptoms? Functional hypogonadism refers to low testosterone levels without a recognizable structural or organic pathology in the hypothalamic pituitary gonadal axis. Unlike organic hypogonadism, functional hypogonadism is relatively common with an estimated prevalence of 2.1 to 12.3%. There are many etiologies, including obesity, metabolic syndrome, opioid use, inadequate sleep, and excessive exercise. While our goal in endocrinology is to optimize hormones, I'm using this term, hormonal optimization, which is commonly used by wellness programs to convince people to optimize their hormones to the optimal level, which is not well-defined. This has led to an increase in prescribing testosterone to men who do not have conclusive or definitive evidence of hypogonadism. What are the drivers that is making prescribers prescribe more testosterone? One important driver to keep in mind is a lack of proper understanding of the testosterone reference range, what population this range is based on, and what factors influence testosterone levels. Another driver is erroneously attributing nonspecific symptoms to hypogonadism. Hypogonadism has many symptoms. Many of these symptoms are not specific and can be explained by a myriad of medical conditions and psychiatric conditions. And the third driver is failure to recognize the benefits and risk of inappropriately used testosterone. You will be surprised to learn how easy it is to access testosterone prescription. This study was done in the US in 2022. A shopper contacted seven direct-to-consumer companies that offer testosterone. The shopper complained of low energy, low libido, and shared his testosterone level, which was 675 nanogram per deciliter, which is equivalent to 23.4 nanomole per liter. And you can see the reference range. How many of the seven companies prescribed him testosterone? Six out of the seven companies prescribed this individual testosterone. The only company that did not prescribe testosterone had a threshold of 450 nanogram per deciliter. So this is clearly inconsistent with the guidelines. Let's move on to discuss the likelihood of hypogonadism based on symptoms. As I mentioned earlier, there are a lot of symptoms that are associated with hypogonadism, many of which are nonspecific at all, such as decreased energy, feeling sad, poor concentration, sleep disturbance. Other symptoms are more suggestive, such as decreased libido, erectile dysfunction, and other symptoms are more specific, like loss of body hair, very small testes. Accurate assessment of testosterone levels is crucial. Serum testosterone follows a diurnal pattern with a peak early in the morning. It's recommended that testosterone should be measured early in the morning in a fasting state. If the result is low, the level should be repeated. Ideally, testosterone should be checked using liquid chromatography and tandem mass spectroscopy. Let's now move on to understand the testosterone reference range. The reference range for testosterone is based on healthy men between the age of 19 to 39 years. And these individuals do not have obesity. It's important to realize that testosterone may decline with age, and the reference range does not adjust for this. The Massachusetts Male Aging Study aimed to assess the relationship between testosterone level and aging. What they found is that the lower limit of the reference range drops significantly with aging. The lower limit of the reference range for men who are in their 40s is 251, 8.7 nanomole, and it drops to 156, 5.4 nanomole per liter. It's important to keep in mind that there was no major changes in the 50th percentile or the 97.5 percentile values. For example, the 50th percentile for men in their 40s was 507, and for men who are in their 70s was 446 nanogram per deciliter. Let's now move on to discuss the relationship between levels and symptoms. Erectile dysfunction is something that we see in patients with hypogonadism, but it's a symptom that can be seen in other conditions, such as diabetes, atherosclerosis, depression. The European Male Aging Study is a prospective cohort study that aimed to assess the relationship between sexual symptoms and testosterone levels. And what they found is that the probability of erectile dysfunction increased when total testosterone dropped below 245 nanogram per deciliter. When they looked at sexual thoughts, they found that the frequency of sexual thoughts decreased when total testosterone dropped below 230 nanogram per deciliter. Now that we have discussed the testosterone reference range, what population it's based on, and what happens with aging, let's move on to discuss the impact of obesity on testosterone levels. As we discussed earlier in this conference, obesity is highly prevalent worldwide, and our region is not an exception. Men with overweight and obesity have lower testosterone than men who do not have overweight or obesity. In the European Male Aging Study, men with overweight had a testosterone level that was lower by 66 nanogram per deciliter. Men with obesity had a testosterone level that was lower by 147 nanogram per deciliter compared to men who do not have overweight or obesity. This is largely explained by the low sex hormone binding globulin that we see in patients with obesity. When you have low sex hormone binding globulin, your total testosterone will be low. It's important to keep in mind that patients with obesity have aromatization of testosterone by adipose tissue into estrogen. Estrogen may exert negative feedback on the hypothalamus. The guidelines recommend checking free testosterone, either measured or calculated, in patients with conditions that alter sex hormone binding globulin. It's a good screening test that will rule out hypogonadism in many of these patients. Let's now move on to discuss the management of functional hypogonadism. An important question to ask, does this patient have symptoms suggestive of hypogonadism with unequivocally low total testosterone? If this is the case, then work up and manage as hypogonadism. But many of the patients who are referred to us have symptoms that are not specific for hypogonadism with borderline low total testosterone, which is similar to the patient that I saw in clinic. It's important to look for causes of functional hypogonadism. Many of these causes are reversible. There is a linear relationship between weight loss and increase in testosterone. We've known for many years that bariatric surgery is associated with an increase in testosterone level. The relationship is linear. The more the weight loss, the higher the testosterone. And an important question to ask, are the symptoms in patients with borderline low total testosterone going to improve with testosterone treatment? I found this study to be interesting. It questioned the benefits of testosterone treatment in patients with low testosterone. This was a randomized controlled trial that included older individuals who had induced hypogonadism by GnRH agonist. And they randomized them to get testosterone versus placebo. They found that testosterone treatment significantly improved sexual desire and erectile dysfunction only in individuals who had a total testosterone less than 100 nanogram per deciliter. The guidelines also recommend against the use of testosterone for weight reduction, for improvement in body composition. And they recommend against using it to improve glycemia and menopause. To improve glycemia in men with diabetes. I know there's some literature on the bi-directional association between low testosterone and diabetes, but it's a lecture on its own. So I don't have time to go over it in this talk. Let's go back to our patient. This patient had low total testosterone with conditions that are associated with low testosterone. He has a symptom of erectile dysfunction that can be explained by low testosterone and other conditions. Since this patient has a condition that if addressed can lead to an increase in testosterone, I think assessment for secondary causes of hypogonadism should be assessed. Assessment for other medical and psychiatric conditions that could explain his symptoms should be done before initiating testosterone in this patient. All right, so that was case one. Let's move on to talk about case two. This is also a true story. I was meeting friends. I met this new guy. When he knew that I'm an endocrinologist, he came to ask me some questions. So he was 28-year-old, healthy. He has been trying to bulk for years, but is not happy with the results. He was thinking about using anabolic agents. He contacted one of the direct-to-consumer companies in the US and was recommended the following. The individual was in the Middle East. And this is the recommendation. This is a screenshot from his phone. The cycle for your case would be 10 weeks according to your body area. I don't know what that means. Testosterone, enanthate, 250 milligram weekly. We're all familiar with what testosterone is. Winstrol and boldenone, which are non-testosterone anabolic steroids. And then after the cycle is completed, you must do a post-cycle 10 days after finishing the cycle to regulate and detoxify the body, to avoid side effects and maintain the results of treatment. And what they use in the PCT is tamoxifen and beta HCG, and the course costs $350. There are many drugs that are used to enhance performance. Androgens are the most commonly used performance-enhancing drugs. Ugonadal individuals who use androgens are abusing them. Androgens are banned by the World Anti-Doping Agency. Selling them or having them for personal use may be considered a criminal offense in some countries. I know the regulations are very strict on Qatar. In other countries, selling them is illegal, but having them for personal use may be allowed. So it's very important to know where you stand based on your country. The estimated lifetime prevalence in men is one to 5%. What's interesting is that the rate is higher among recreational athletes compared to professional and elite athletes. And what was even more interesting is that the reported use is higher in the Middle East compared to other regions in the world. So what are the questions that we need to answer? What drives men to use performance-enhancing drugs? What are the androgenic performance-enhancing drugs? What are the consequences of using them? And how to manage people who are considering using them or who have used them? There are many factors that could drive the use of androgen performance-enhancing drugs. Many of these individuals have underlying psychiatric conditions, muscle dysmorphia, obsession that they have low muscle mass, they really wanna build muscles, anxiety, depression, which lead to low self-esteem, distorted body image. Many use them because they want immediate results. They prioritize the immediate gain over the long-term complication. And many downplay the risk. They truly believe that the post-cycle therapy will detoxify the body and reduce the risk. And they trust the role models, their gym trainers. What are the androgen performance-enhancing drugs? Testosterone is a common one. They prefer injectables because it's known in the gym, no pain, no gain. We're all familiar with testosterone. It leads to high testosterone level with a suppression of FSH and LH. Other agents that could be used is testosterone precursors, DHEA, not very common in men because testosterone precursors in men do not increase testosterone significantly. Other agents that can be used commonly is non-testosterone androgenic steroids, and I shared with you two examples. There are many drugs under this list. It's hard to remember all of them. You'll need to look it up. So they don't increase serum testosterone, but they do suppress the hypothalamic-pituitary-gonadal axis. How do these patients come to clinical attention? Unfortunately, many of them present late after they've used it for years, and now they're presenting to urology with infertility. Or they may present to endocrinology with hypogonadotropic hypogonadism from the suppression of the HPG axis. Many of these patients are in the community. They're probably not gonna seek medical attention when they're actively abusing them, so it's something that may come up in the community more than in clinical practice. In my practice, I do obesity management, so usually patients who have used it for some time when they were athletes and then something happened in their life, they stopped exercising, they gained weight, and now they're presenting to me for weight management. If you don't ask about it, you will never identify it. Other consequences of androgens is that they can lead to gynecomastia. As I mentioned earlier, testosterone is aromatized to estrogen. Estrogen increases the risk of gynecomastia. The relationship between high androgens levels and cardiovascular disease is not well-established, but there are several case reports of sudden cardiac death in athletes who do not have cardiac conditions but have used androgens. And there's risk of liver injury with oral androgens. Let's go back to our patient. So for the cycle, the individual was planning to take testosterone with non-testosterone androgens. The combination of testosterone and other agents is called stacking in the doping world. I'm not sure if there is any benefit of adding things to testosterone. I doubt there's efficacy by doing that, but probably added harm. Let's now move on to talk about the post-cycle therapy and whether it really makes any difference or not. So is post-cycle therapy effective? Very frequently, HCG is used. We have good clinical experience with HCG. We use it in patients with hypogonadism who are desiring fertility. And the reason we do so is to stimulate spermatogenesis. But one thing that HCG will do is that it will increase testosterone production, which will lead to negative feedback and prolong the hypothalamic-pituitary-gonadal axis suppression, prolong their abuse of testosterone. And many of them are not aware of this point. Other agents that are commonly used in post-cycle therapy is tamoxifen and clomiphene. The anti-estrogen effect of this medication on the hypothalamic-pituitary-gonadal axis is the reason why people use it, but there's no evidence to support their safety and efficacy in this population. Another agent that's used in this population is letrozole, which is an aromatase inhibitor to inhibit the aromatization and decrease the risk of gynecomastia. Long-term use is concerning for low bone density. Let's move on to talk about the management. How would you approach someone who is considering performance-enhancing drugs? It's very important to establish a relationship of trust based on respect and nonjudgmental behavior. I'm not a big fan of fear-based intervention to change behavior. It works for a few people, but for the majority of people, it does not. It's very important to investigate what are the drivers behind performance-enhancing drugs. If their preference is for rapid gain, it's important to highlight that this gain is not sustainable once they stop the cycle, and they will not be able to achieve their goal. And long-term treatment is something that many of them are not interested in, and long-term treatment is associated with several complications. Some of them are misinformed about the strategies to avoid consequences, the post-cycle therapy. So just educating them about the post-cycle therapy and how using beta-HCG is actually not helping by prolonging the abuse and the hypothalamic pituitary-gonadal axis suppression may help. And it's important to assess for underlying anxiety disorder, depression disorder. You'll probably need help from psychotherapy to help manage this. And try to counsel some patients, some individuals are gonna use it regardless. Try to counsel them about ways to minimize the risk. I try to empower them to make the decision their own. Have them question the sources. So if they're using testosterone, we have an extensive experience with testosterone in clinical practice. The testosterone that we use is regulated. The testosterone that we use is well-stored. I would encourage them to ask, where is the testosterone coming from? Is it from compounded pharmacies? Do you know if it's regulated? Are you confident that it's appropriately stored? The big issue is with non-testosterone androgenic steroids. These are not things that we're familiar with in practice. Their production is not regulated. There is a black market and I'm not sure there's benefit from using them. So I would be very careful with all of them, but specifically non-testosterone androgenic steroids. Let's now move on to talk about people who have abused androgens. There are no guidelines to guide us on how to manage these patients. I don't think there's anyone who is an expert in this, primarily because patients do not present to us while they're taking it, they present very late. Management depends on the duration of abuse. If they've used it for one year or less, then the best thing that you could do is probably do nothing. Their gonadotropins and testosterone will likely normalize in three to six months. Spermatogenesis will likely return to normal in three to six months. So the best thing that you can do is just do nothing. Educate the individual about what's expected and just wait and observe. If they've used it for years, then they're at higher risk of withdrawal due to the hypothalamic-pituitary-gonadal axis suppression. It may take years for the axis to recover. So in these individuals, some studies recommend considering medical treatment to address the withdrawal symptoms and gradually decrease the dose with time. So to conclude, functional hypogonadism, the diagnosis is challenging, requiring proper understanding of the testosterone reference range and factors that influence its level. In those without definitive diagnosis of hypogonadism, testosterone treatment should not be initiated as the first line. In patients who have reversible cases, it's ideal to assess for reversible cases and treat reversible cases. Doping with androgens, it's not uncommon. Counsel patients about the risks. Counsel the patients about the lack of production regulation and safety data. You may need to manage withdrawal symptoms in those who have used it for several years. Thank you everyone for listening and I'll be happy to take questions later on. Thank you.

testosterone prescriptions

performance-enhancing drugs

functional hypogonadism

androgen misuse

testosterone misuse risks

psychological factors