Another cause of andropause in men: cancer-related TESTOSTERONE DEFICIENCY

One problem I encounter quite frequently in daily practice is our male patients reporting symptoms such as fatigue, feeling cold, sweating or feverishness. Women readily describe this hormone-deficiency-related condition as menopausal symptoms, whereas men find it difficult to explain this unfamiliar condition, which they encounter less often than women, to their physicians. Let us learn together about the deficiency of male hormones, known as androgens, and its symptoms, called andropause in men. I believe that discussing this issue, often overlooked in oncology clinics, will benefit many of our patients.

Testosterone levels can decrease because of cancer itself or its treatments, causing symptoms that reduce patients’ quality of life. Achieving the quality of life that every patient with cancer deserves, whether their chances of treatment success are high or low, has become the most important goal of modern cancer treatment. In this context, addressing low testosterone levels, known to affect quality of life, is very important.

First, let us look at sex hormones, their decline and the related definitions

• Androgen is the general term for male sex hormones.
• Testosterone is the most important androgen hormone and is secreted mainly by the testes. Although primarily responsible for reproductive functions, testosterone also has many other effects, including regulating the ratio of muscle to fat tissue, increasing bone density and producing red blood cells.
• Hypogonadism is defined as reduced production of sex hormones in men or women and the resulting symptoms. Thus, testosterone deficiency in men is a form of hypogonadism. In otherwise healthy people, hypogonadism beginning in their 50s is expected; this is called menopause in women and andropause in men. Menopause and andropause are expected age-related forms of hypogonadism, producing symptoms familiar to most of us. Common symptoms in both sexes include hot flushes, sleep disturbances, and reduced sexual desire and function. In addition to aging, hypogonadism caused by reduced sex hormones can occur with certain diseases, such as cancer, kidney failure and COPD, or as a result of their treatments.

What causes male hypogonadism—low testosterone—in cancer?

Low testosterone can have various causes, including chemotherapy, radiotherapy, narcotic painkillers used for pain treatment, cortisone-containing medications, megestrol acetate used for poor appetite, or a mass affecting the hypothalamic–pituitary region of the brain that regulates testosterone secretion.

What problems accompany hypogonadism—low testosterone—in a patient with cancer?

Symptoms caused by low testosterone in patients with cancer resemble those in healthy individuals but may be more severe. Symptoms seen in healthy people and patients with cancer include:

• Reduced sexual desire
• Erectile problems
• Low energy
• Hot flushes
• Fatigue and increased sleepiness
• Irritability
• Depressed mood
• Difficulty concentrating
• Sleep disturbances
• Reduced muscle strength
• Weight gain and increased fat mass
• Reduced bone density (fragile bones)

Many studies show that low testosterone levels reduce quality of life

Men receiving sex hormone (androgen) suppression treatments, most notably for prostate cancer, may experience hot flushes, fatigue, mood fluctuations, reduced sexual desire, anemia and impaired recent memory. Loss of muscle mass, reduced muscle strength, increased fat mass and osteoporosis are effects seen later.

In young patients with cancer, such as those with testicular cancer, low testosterone has been shown to accompany fatigue, reduced sexual function and impaired quality of life.

These studies have shown that reduced survival and increased severity of anorexia (pathological loss of appetite), dyspnea (breathing difficulty), sleep disturbances, sexual dysfunction and depression symptoms accompany hypogonadism .

Looking at the rates of low testosterone in cancer

• Approximately two-thirds of male patients with advanced (stage 4 / metastatic) cancer have low testosterone. 
• Low testosterone occurring together with cancer cachexia at a frequency above %70 is an important figure highlighting the association between testosterone deficiency and cancer cachexia. 
• Low testosterone has been demonstrated before chemotherapy in %50 of patients whose cancer has spread to other organs.
• In addition, low testosterone was found in %90 of patients who had completed treatment, resumed their normal lives and were taking narcotic painkillers above a certain dose.

How is hypogonadism demonstrated in a patient with cancer?

Problems accompanying low testosterone, such as hot flushes, fatigue, loss of appetite, depressed mood, insomnia and reduced sexual desire, warrant laboratory confirmation of testosterone deficiency. Testosterone should be measured early in the morning, when its blood level is highest, and the measurement should again be repeated in the morning. Factors such as age, diurnal rhythm (biological clock), genetics and inflammation in the body affect blood testosterone levels. These should be considered when diagnosing hypogonadism through laboratory testing.

Deciding on testosterone replacement therapy

The endocrine diseases society has recommendations for testosterone replacement therapy in chronic diseases. These recommendations mainly concern chronic conditions such as HIV, type 2 diabetes, kidney failure and chronic lung disease; no cancer-specific recommendation has been made.

Among male patients with different cancer diagnoses (%28 of whom had stage 1 or stage 2 disease), hypogonadism was found to correlate directly with impaired quality of life and sexual function. Another study in patients with advanced cancer found low testosterone levels associated with increased fatigue, weight loss, reduced sexual desire, depression and insomnia. Studies also show testosterone deficiency occurring together with cancer cachexia.

A comprehensive randomized controlled study of cancer-related low testosterone showed improvements in reduced sexual desire and fatigue among patients given testosterone.

In light of these findings supporting the association between testosterone deficiency and problems affecting quality of life, many oncology and palliative care physicians recommend testosterone treatment to their patients.

When deciding on testosterone replacement therapy for patients with advanced cancer, an individualized approach should be preferred, assessing symptoms, the course of the disease and the patient’s personal goals.

Male patients may not adequately report hot flushes, reduced sexual desire and other symptoms of testosterone deficiency. Viewed another way, hot flushes in women immediately suggest female hypogonadism, whereas the possibility of male hypogonadism may initially be overlooked when this symptom occurs in healthy men or men with cancer. Physicians’ awareness of this issue is therefore important in following patients receiving cancer treatment.

When should testosterone replacement therapy not be given?

According to the endocrine diseases society’s recommendations, testosterone replacement therapy should not be given to patients with blood hematocrit levels (a measure reflecting red blood cells) above %50, severe sleep apnea syndrome, heart failure, acute cardiovascular disease within the last 6 months, or severe lower urinary tract problems. It was also previously not recommended for patients with breast or prostate cancer, because testosterone produced in the body or obtained externally was considered a risk factor for developing prostate and breast cancer. However, recent studies of prostate cancer and testosterone treatments have shown that giving testosterone to healthy individuals does not increase prostate cancer risk or PSA levels and does not increase urinary tract problems caused by prostate enlargement. Recent studies of testosterone administration in patients previously treated for prostate cancer are also moving away from the position that it must never be given. The aim here should be noted: restoring testosterone to normal values, not raising it above normal. In patients with advanced cancer and a short life expectancy, choices aimed at improving quality of life may take priority .

How can testosterone replacement therapy be administered?

Testosterone can be administered through skin patches or gels, intramuscular injections, oral tablets or tablets that dissolve in the mouth, or medications implanted under the skin. Although the patient’s views are important in choosing the route, the availability and suitability of the formulation should also be considered. Different administration routes also have advantages and disadvantages in effectiveness. For example, blood testosterone levels fluctuate with intramuscular injections, whereas skin patches or gels may provide steadier levels. With patches, the application site must be clean and dry, and the patch must not peel off during the required application period to ensure adequate effectiveness. Gels are applied to the underarm area. Oral tablets can have liver-related side effects and are not a particularly preferred route. Tablets dissolving in the mouth leave an unpleasant taste.

In conclusion, we would like to emphasize that physician-recommended testosterone replacement therapies have an important place in improving quality of life for patients with cancer: both in addressing reduced sexual desire, hot flushes, fatigue and insomnia, and in preventing later consequences of testosterone deficiency such as reduced muscle mass, muscle weakness, increased fat mass, osteoporosis and the resulting increase in bone fragility.