March/April 2023

The Condition No One Wants to Talk About
By Mark Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 16 No. 2 P. 18

Diagnosis and Treatment of Andropause Is Hindered by Stigma

Andropause refers to symptoms men may experience as testosterone levels decrease during the normal aging process. Andropause is also sometimes referred to as testosterone deficiency (Low-T), androgen deficiency, and late-onset hypogonadism (LOH). Not all men experience low testosterone symptoms; however, for those who do, the symptoms can have serious consequences related to how they feel and their quality of life. Unwarranted stigmas associated with the disorder can discourage men from seeking treatment and may make it difficult for some to discuss their symptoms with health care providers. This can result in underdiagnoses and undertreatment, leading to potentially significant risks such as cardiovascular disease, osteoporosis, and diabetes. Despite the significant benefits for some men, testosterone replacement therapy (TRT) carries its own risk, which makes it essential for health care professionals to feel comfortable openly discussing the condition and potential treatment options with patients.

Andropause vs Female Menopause
“The Male Climacteric,” a 1944 landmark article published in JAMA, first used the term “male menopause” to compare various complaints of aging men, including nervousness, reduced potency, decreased libido, irritability, fatigue, depression, memory problems, sleep disturbances, and hot flushes to symptoms partially similar to female menopause symptoms.1 Nearly 80 years later, the term and its comparison to female menopause continues to be used by some in the media but is inaccurate and may discourage some from seeking treatment. Whereas menopause in women tends to be a more rapid and dramatic hormonal change, andropause is a slow and lengthy decline that’s harder to identify. In males, testosterone levels increase until about the age of 17, and then, starting at approximately 40 years of age, testosterone levels begin to decline at a rate of about 1.2% per year.2

Late-Onset Hypogonadism
The term “andropause” is also not completely accurate as it implies total cessation of testosterone production. Androgen deficiency of the aging male and LOH are terms that more accurately describe the gradual decline in testosterone levels seen in aging adults.3 Low-T symptoms associated with hypogonadism are highly variable and it’s not clear why some men present with symptoms even when they have normal testosterone levels while other men with low testosterone levels have no symptoms.

Hypogonadism symptoms may include the following:

• Mood and mental function changes: anxiety, depression, mood swings, irritability, poor sleep, difficulty concentrating, poor short-term memory, decreased motivation, and low self-esteem.

• Virility changes: decreased physical energy, decreased muscle strength, constant tiredness, and joint pain.

• Alterations in circulatory and nervous systems: sweating, hot flashes, and insomnia or other sleep disorders.

• Sexual function changes: infertility, reduced libido, erectile dysfunction (ED), and impaired ejaculation.

• Changes in physical appearance: abnormal weight gain, gynecomastia, decreased testicle size, loss of body hair, loss of muscle mass, and height loss.

• Changes in body metabolism and chemistry: increased body fat and cholesterol, decreased bone density (osteoporosis), and reduced red blood cells.

Underdiagnoses and Undertreatment
As noted previously, stigmas associated with hypogonadism may contribute to the condition going undiagnosed and untreated.4 Some men may be embarrassed about discussing intimate symptoms such as sexual dysfunction and fertility concerns. In addition, hypogonadism can have a significant effect on mood, and the reality is that stigma still exists as well around mood disorders. Regardless of the reason, the consequences of failing to address low testosterone levels can negatively affect quality of life and pose serious health risks, including increased obesity, cardiovascular disease, anemia, diabetes, and osteoporosis.

Diagnosis
Diagnosing hypogonadism involves assessing for consistent physical signs and symptoms and unequivocally low testosterone levels.5 Physicians should consider checking testosterone levels in men with symptoms specific for hypogonadism, such as delayed sexual development, decreased spontaneous erections, gynecomastia, loss of axillary or pubic hair or reduced shaving, hot flushes or sweats, reduced height, or increased low-trauma fractures.5

The Endocrine Society defines hypogonadism as a combination of low testosterone levels and the presence of any of these symptoms: drop in sex drive (libido), ED and loss of spontaneous erections, lowered sperm count and infertility, breast enlargement or tenderness, reduced energy, hot flashes (when testosterone levels are very low), increased irritability, inability to concentrate, and depressed mood.6 There should be at least two early morning (7–10 am) blood tests that reveal low testosterone, with low testosterone levels typically noted as being less than 300 ng/dL or free testosterone less than 5 ng/dL should be used.

Depression, hypothyroidism, chronic alcoholism, and use of medications such as corticosteroids, cimetidine, spironolactone, digoxin, opioid analgesics, antidepressants, and antifungal agents should be excluded before making a diagnosis of LOH. Similarly, diagnosis of LOH should not be made during acute illness, which decreases testosterone levels temporarily.7

Testosterone Replacement Therapy
Patients should be cautioned about exaggerated marketing that hypes the benefits of TRT. While testosterone replacement can be safe and effective when used in men who are diagnosed with hypogonadism and have consistent symptoms and low testosterone levels, it is not the fountain of youth or antiaging miracle drug that it is often marketed to be. Remind patients that testosterone replacement is not approved by the FDA to help improve strength, athletic performance, or physical appearance or to treat or prevent problems associated with aging alone and that the inappropriate use of testosterone for these purposes could be harmful.

Benefits of Testosterone Replacement
Used appropriately, TRT can provide a number of benefits for those men with symptomatic hypogonadism, including improvements in muscle mass and strength, sexual function, anemia, and mood, a decrease in body fat, preservation of bone mass, reduced fall and fracture risk, possible reduced cardiovascular risk.

Obesity
Males with hypogonadism are at greater risk of increased fat mass and reduced muscle mass, which contribute to obesity and health risks, such as cardiovascular disease. Obesity is also known to be associated with low testosterone levels, and there’s an inverse relationship between abdominal circumference and serum testosterone concentrations.8 Furthermore, obesity is the most important risk factor for low testosterone levels, even more than age and other chronic diseases.9 This bidirectional relationship between low testosterone and obesity is supported by clinical studies showing that weight loss increases testosterone levels.10 For some obese men with low testosterone, intervention measures such as diet and exercise or surgical treatment of obesity may be appropriate to increase testosterone levels.11

Testosterone replacement in men with testosterone deficiency has been shown to have profound effects on body composition, including reduced body fat and increased lean body mass, along with significant reduction in weight, waist circumference, and BMI.12 Long-term testosterone treatment of hypogonadal men—up to five years in duration—has been shown to produce marked and significant decrease in body weight, waist circumference, and body mass index.13

Metabolic Syndrome, Diabetes, and Cardiovascular Disease
Metabolic syndrome, sometimes referred to as insulin resistance syndrome, is a cluster of conditions that raise the risk of coronary heart disease, diabetes, stroke, and other serious health concerns. The clinical manifestations of metabolic syndrome may include hypertension, hyperglycemia, hypertriglyceridemia, low HDL (good cholesterol) levels, and abdominal obesity (apple shape).

Low testosterone is an independent risk factor for development of metabolic syndrome and type 2 diabetes in men. Conversely, men with metabolic syndrome are at increased risk of developing hypogonadism.14 Testosterone may also protect against type 2 diabetes, as men with higher testosterone levels had a 42% lower risk of type 2 diabetes.14 Several studies suggest that low testosterone may, in fact, be a precursor to the development of diabetes or insulin resistance.14 In hypogonadal men, long-term TRT has been shown to ameliorate the components of the metabolic syndrome, with reductions in waist circumference, total and LDL cholesterol, blood pressure, blood glucose, HbA1c, and C-reactive protein, and increases in HDL cholesterol.15

Osteoporosis
Testosterone plays an important role in the maintenance of bone mineral density (BMD) in men and there is a strong association between low testosterone and a significant decrease in BMD, including osteopenia and osteoporosis. This relationship appears to be stronger in young adult men with moderate to severe hypogonadism.16

Fall risk is also associated with lower testosterone levels.17 Furthermore, in hypogonadal men, reduced BMD is associated with a significant increase in bone fractures, including hip and spine fractures.18,19 Despite osteoporosis prevalence among males older than the age of 50 being significantly lower than in females, male osteoporosis and osteopenia have significant consequences. Although men tend to sustain fractures up to 10 years later in life than women do, the mortality and morbidity associated with male hip fractures are higher than those experienced by women, and men with known fragility fractures are less likely than women to receive treatment.20

A number of studies have demonstrated that TRT increases BMD in hypogonadal men with osteopenia and osteoporosis.21 Testosterone appears to produce this effect by increasing osteoblastic activity and, through aromatization into estrogen, reduces osteoclastic activity, with pooled data from a meta-analysis suggesting a beneficial effect on lumber spine density but less certain findings on the femoral neck.22

TRT has been shown to increase BMD in hypogonadal men of all ages.23 Due to potential risks associated with it, the use of testosterone to improve BMD is not recommended unless the patient is experiencing symptomatic hypogonadism.5 Testosterone replacement may be recommended in hypogonadal men with symptomatic low testosterone who are at high risk of fracture, though this should be done in combination with a medication with a proven antifracture effect such as a bisphosphonate.24

Anemia
Testosterone deficiency causes a 10% to 20% decrease in hemoglobin concentration.25 The common symptoms of anemia, which can reduce patients’ quality of life, include frequent fatigue and muscle weakness, lower cognitive function, dementia, depression, increased odds of developing cardiovascular disease, higher risk of heart attack and heart failure, and worsening of other diseases such as cancer and renal failure. Anemia can also lead to increased hospitalization. Moreover, mortality risk increases even with mild anemia.

Testosterone replacement increases hemoglobin, hematocrit, and red blood cells by stimulating iron-dependent erythropoiesis and has been shown to correct unexplained anemia in the elderly, anemia of inflammation, and anemia of chronic kidney disease.26

Erectile Dysfunction and Libido
Men with low testosterone frequently experience decreased libido, ED, decreased energy, depressive symptoms, and fatigue.27 Testosterone therapy has been shown to at least partially reverse these symptoms. It’s also been demonstrated that testosterone therapy improves libido in men with low testosterone levels at baseline and improves mild ED, though it’s less useful in men with more severe ED.28 In men unresponsive to phosphodiesterase type 5 inhibitors and with mild ED, the addition of testosterone can further improve erectile function.28

Cognition
Lower free testosterone levels are associated with poorer outcomes on measures of cognitive function, particularly in older men.25 Low testosterone levels have also been associated with higher risk of Alzheimer’s disease and mild cognitive impairment in men.29 Studies looking at the effects of testosterone replacement on cognition have been mixed, however, several observational studies have shown testosterone replacement to have positive effects on certain cognitive domains in normal and hypogonadal older men and suggest that testosterone replacement in men with cognitive impairment and testosterone deficiency may be appropriate.29 Larger clinical placebo-controlled trials are needed to determine whether testosterone supplementation in older adults with low testosterone levels may reduce the risk of cognitive decline.30

Mood
Men with low testosterone levels have been found to be more likely to have symptoms such as dysphoria, low vigor and vitality, irritability, lack of assertiveness, anxiety, and depression. Men with hypogonadism and mood disorders, including depression, may benefit from testosterone replacement.31

Testosterone Risks
The Endocrine Society provides the following information about the associated risks of testosterone.6

Although testosterone is generally considered safe it is not without some risks, including elevated red blood cell count, acne, sleep apnea, and possible prostate and/or breast enlargement.

The FDA requires that patients are made aware that the possibility of cardiovascular events may exist during treatment. Despite this warning, there’s no firm scientific evidence that long-term testosterone replacement is associated with cardiovascular events, and the evidence supporting the drug safety warning remains controversial.

Patients should not receive testosterone therapy if they have the following:

• prostate or breast cancer (or suspected);
• enlarged prostate causing difficulty with urination;
• elevated prostate specific antigen levels;
• high number of red blood cells;
• untreated sleep apnea (obstructed breathing during sleep);
• planning to have children;
• had a heart attack or stroke within the last six months; and
• blood clots.

There’s no evidence that testosterone causes prostate cancer; however, testosterone can fuel prostate cells and cancer that has already started. For this reason, extra vigilance is required concerning prostate cancer screenings, especially for those patients at increased risk of prostate cancer, including those with a family history of cancer and Black men older than age 45.

Final Thoughts
The identification of hypogonadism and its appropriate treatment is important in helping to improve symptoms in men with hypogonadism. Health care professionals should be prepared to inquire about the symptoms associated with low testosterone and counsel patients on the appropriate and safe use of testosterone replacement therapies.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
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2. Heller CG, Myers GB. The male climacteric, its symptomatology, diagnosis and treatment. JAMA. 1944;126(8):472-477.

3. Morales A. Andropause (or symptomatic late-onset hypogonadism): facts, fiction and controversies. Aging Male. 2004;7(4):297-303.

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6. The Endocrine Society. The truth about testosterone treatments. https://www.endocrine.org/-/media/endocrine/files/patient-engagement/patient-guides/patient_guide_the_truth_about_testosterone_treatments.pdf

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26. Guo W, Abou Ghayda R, Schmidt PJ, Fleming MD, Bhasin S. The role of iron in mediating testosterone's effects on erythropoiesis in mice. FASEB J. 2020;34(9):11672-11684.

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28. Rizk PJ, Kohn TP, Pastuszak AW, Khera M. Testosterone therapy improves erectile function and libido in hypogonadal men. Curr Opin Urol. 2017;27(6):511-515.

29. Mohamad NV, Ima-Nirwana S, Chin KY. A review on the effects of testosterone supplementation in hypogonadal men with cognitive impairment. Curr Drug Targets. 2018;19(8):898-906.

30. Dong X, Jiang H, Li S, Zhang D. Low serum testosterone concentrations are associated with poor cognitive performance in older men but not women. Front Aging Neurosci. 2021;13:712237.

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