Testosterone Deficiency — Understanding a Complex Condition
Testosterone replacement therapy (TRT) for adult men has increased dramatically in recent years.1, 2 Reflecting an increased awareness among physicians and patients about testosterone deficiency, as well as the impact of an ageing population, this trend has given rise to discussion about the appropriateness and potential risk of TRT.2, 3, 4
Dr. Steven Lamm, Professor of Medicine, New York University and Medical Director, Preston Robert Tisch Center for Men’s Health, New York University Langone Medical Center, discusses the importance of hypogonadism as an issue beyond sexual health, and reviews approaches to enable the accurate diagnosis and optimum management of men with this condition.
A Prevalent Condition – With Significant Health Implications
“Hypogonadism is a significant health issue for men, beyond the area of sexual health, and is seen in many patients who present to an internal medicine or family practice setting,” says Dr. Lamm. “Obesity and diabetes are the two most significant disorders that appear to be comorbid with hypogonadism. So when managing those patients, or those with metabolic syndrome, a doctor needs to be aware of the possibility of hypogonadism.”
A consistent definition of a condition is needed to enable an accurate diagnosis, but until recently that has not been the case with hypogonadism.3 “There is a developing consensus that the definition of hypogonadism is that it is a clinical and biochemical syndrome characterized by a deficiency of testosterone or testosterone action and relevant symptoms and signs,” notes Dr. Lamm. “So, it’s not only based on a measurement of low testosterone, but a combination of measurement and clinical symptoms that accompany low testosterone. The implications are that testosterone deficiency may affect the function of multiple organ systems and results in significant detriment in the quality of life, including alterations in sexual functions.”
“While testosterone is most notably associated with sexual function,” continues Dr. Lamm, “it is also very important for bone health, muscle development, energy, and mood stabilization. This impact on organs outside of the sexual arena makes it particularly significant. Just as the diagnosis of an erectile dysfunction became important because of the implications for the cardiovascular system, so diagnosing hypogonadism is important not only for its impact on sexual function, but on the overall health of the patient. I see the low testosterone state as a harbinger of other health issues, which needs to be taken seriously. An understanding of the physiology of testosterone is therefore important in relation to the ultimate diagnosis of a patient’s condition.”
Physiology of Testosterone
“Testosterone is finely tuned and balanced by both the hypothalamic pituitary system and the testicular system, which work to produce a level of testosterone within the ‘normal range’. The testes are under the influence of hypothalamic pituitary hormones that stimulate both testosterone production as well as maturation of sperm. Any disruption in either the hypothalamic pituitary arena or in the testicular arena will create a testosterone deficiency state. The disorder could primarily be in the testicles as a result of injury, mumps, some infection, or it could be the result of a pituitary hypothalamic problem. It's important to differentiate the primary causes for low testosterone, because there are implications for treatment.”
“There are circadian changes in testosterone levels and a pulsatile nature to the release of different hypothalamic pituitary hormones, so that during any given day there are variations in the amount of testosterone in one’s blood,” explains Dr. Lamm. “There may be a 30% difference in testosterone levels between the morning and the evening. For this reason it’s established that testosterone should be tested in the morning, when it’s going to be at its highest level. Due to these fluctuations it is also recommended that as least two morning levels are obtained when testing for Testosterone deficiency.”
“It’s also important to appreciate that testosterone is bound to proteins in the blood, which either bind the testosterone tightly or loosely. This is important because only 2% of the circulating testosterone is in a free form, which is the active form that attaches to androgen receptors and performs its function. Based on this it is sometimes necessary to measure free testosterone levels in order to confirm a diagnosis of hypogonadism.”
Toward a Diagnosis – Clinical Signs
There is no one single complaint that is diagnostic of hypogonadism. “It's really a constellation of complaints that lead one to suspect the diagnosis,” notes Dr. Lamm, “but many of these symptoms could be ascribed to another disorder such as sleep apnea syndrome, or depression. Having a low libido, erectile dysfunction, low energy, fatigue, diminution in muscle tone or excess body fat is not in itself diagnostic of hypogonadism, but these symptoms taken together are very consistent with low testosterone. Because many of these complaints are so common, I believe it has resulted in many patients being labeled as having hypogonadism who really do not, and who are being inappropriately treated. On the other hand, there are probably many more men with these complaints who have not been diagnosed as they’ve never discussed their problem with a doctor.” Measurement of testosterone levels, combined with a patient’s clinical symptoms, can enable a diagnosis.
Testosterone measurement is not indicated as a routine test, so there has to be a certain level of suspicion of hypogonadism on the doctor’s part. This will be determined by whether the patient is actually complaining of symptoms that are consistent with hypogonadism or if the doctor knows that the patient has osteoporosis or has suffered bone fractures. It may also be suspected in obese or diabetic patients. With these populations a physician should discuss the possibility of hypogonadism with the patient, and then pursue an evaluation.
Testing and Evaluation
“The evaluation first requires the measurement of the morning testosterone level - a total testosterone level. If this is abnormally low, below 300 ng/dl, a repeat morning level should be obtained within a few days to a week. At that time it's important to determine whether you are dealing with a primary testicular problem or hypothalamic pituitary problem, or whether it is clearly a temporary situation due to acute illness or another condition. With the second blood test to confirm the low testosterone level, I will perform the hypothalamic pituitary assessment, by obtaining a luteinizing hormone (LH) level and a follicle-stimulating hormone (FSH) level. If low testosterone is confirmed an evaluation should then be pursued.”
“If not performed with the second test, LH and FSH levels should be measured, together with a general metabolic profile, as it’s important to know if the patient has diabetes. I also want to measure their PSA, not because testosterone treatment causes prostate cancer, but because it may fuel it in men who have prostate cancer.3, 4 Taking baseline measures of the parameters that you're going to be monitoring in the future - blood count, PSA, lipids and the gonadotropin levels - will determine whether other pituitary testing may be necessary. For example, if one had a very low testosterone level, and the LH and/or FSH level were very low as well, concern for a hypothalamic pituitary disorder would be justified, and a prolactin level could be obtained, as well as a ferritin level, and an MRI of the pituitary gland, due to concern about hemochromatosis. A referral to a specialist may be warranted at this point.”
“If the testosterone levels are equivocal, that is they're low but not significantly low – in the range of 290 mg/dLto 315 mg/dL- and the physician is convinced, that the patient truly has hypogonadism, a free testosterone measurement should be performed.”
“The mere fact that you diagnose a patient with hypogonadism does not necessarily mean that you need to initiate pharmaceutical treatment,” concludes Dr. Lamm. “The treatment may be weight loss, improved sleep, improved diet, or an exercise program. Actually diagnosing hypogonadism is important because it is linked with increased morbidity and mortality. It doesn't necessarily follow that treatment prevents those outcomes but hopefully preventive strategies can be applied to improve morbidity and mortality and quality of life.”
The Endocrine Society recommends against testosterone therapy in patients with breast or prostate cancer and recommends that clinicians assess prostate cancer risk in men being considered for testosterone therapy. It is recommended that testosterone therapy is not initiated without further urological evaluation in patients with palpable prostate nodule or induration or prostate-specific antigen (PSA) >4 ng/mL or PSA >3 ng/mL in men at high risk of prostate cancer, such as African Americans or men with first-degree relatives with prostate cancer.3
“There is lot of concern about the risk of potential treatment, both for prostate disease as well as cardiovascular disease, so all of us in the medical profession are looking for greater specificity and sensitivity in the approach to these patients,” concludes Dr. Lamm. “Hypogonadism is an important condition, but we know many physicians are not following recommendations in relation to testosterone testing, both for diagnosis and treatment monitoring. It is clear there needs to be a greater understanding and awareness of its complexities.”\
- Baillargeon J, Urban RJ, Ottenbacher KJ et al. Trends in androgen prescribing in the United States, 2001 to 2011.JAMA Intern Med. 2013 Aug 12; 173:1465-6.
- Grech A, Breck J, Heidelbaugh J. Adverse effects of testosterone replacement therapy: an update on the evidence and controversy. Therapeutic Advances in Drug Safety. 2014;5:190-200.
- Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. June 2010, 95:2536–2559
- John D. Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The Journal of Sexual Medicine. 2015 Aug, 12:1660-1686
- Muram D, Zhang X, Cui Z, Matsumoto AM. Use of Hormone Testing for the Diagnosis and Evaluation of Male Hypogonadism and Monitoring of Testosterone Therapy: Application of Hormone Testing Guideline Recommendations in Clinical Practice. The Journal of Sexual Medicine. 2015. 12:1886-1894