According to the definition, hypogonadism is the inadequate secretion of testosterone by the testes linked with corresponding symptoms. It has different causes: hypogonadism may be congenital or acquired. Hypogonadism is called primary if the cause is in the testes and secondary if the cause is in the hypothalamus or pituitary. Furthermore, hypogonadism may be related to age. This is usually a mixed form of primary and secondary hypogonadism. It is known that serum testosterone decreases with advancing age, especially in the presence of underlying conditions such as the components of the metabolic syndrome and chronic diseases.
One differentiates between “classical” forms of hypogonadism (e.g. Klinefelter syndrome, testicular damage) and late-onset hypogonadism.
The international medical societies European Association of Urology (EAU), International Society for the Study of the Aging Male (ISSAM), International Society of Andrology (ISA), European Academy of Andrology (EAA), and American Society of Andrology (ASA) issued recommendations on the definition, investigation, treatment and follow-up of men with late-onset hypogonadism. They have recognized and defined late-onset hypogonadism as a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels. They have described that late-onset hypogonadism may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems.2
EAU, ISSAM and ISA have listed the following symptoms as typical complaints that can be associated with low levels of testosterone:
Diagnosis and treatment of Late-Onset Hypogonadism has also been addressed by the Clinical Practice Guidelines of Endocrine Society. These guidelines explicitly acknowledge the association of LOH with chronic diseases, e.g. type 2 diabetes.3
Patients with Late-Onset Hypogonadism (LOH) show symptoms comparable with those of the classical male hypogonadism. These often include loss of libido, erectile dysfunction, loss of vigor and energy, physical weakness, depression, and increased visceral fat (measured by waist circumference).
Several studies (Massachusetts Male Aging Study in 1991, Vermeulen Study in 1972) have confirmed that the levels of testosterone decrease with age, i.e., from 40 years of age by approximately 1.2 % annually. Between 40 and 70 years of age, therefore, a man loses approximately 35 % of his normal daily testosterone production.
If symptoms of testosterone deficiency are present, the doctor will investigate them using various diagnostic procedures. These include:
In addition, concentrations of the pituitary hormones LH and FSH (gonadotropins) can be measured. They provide information as to whether the testosterone deficiency is due to disorders of testicular function (primary hypogonadism, elevated gonadotropins) or of the hypothalamic-pituitary system (secondary hypogonadism, low to normal gonadotropins). It may also be advisable to measure prolactin.
There is a general agreement that total testosterone level above 12 nmol/L (350 ng/dL) does not require testosterone treatment.
ISSAM, EAU, ISA, EAA and ASA suggest that serum total testosterone levels below 8 nmol/L (230 ng/dL) require substitution. Since symptoms of testosterone deficiency become manifest between 8 and 12 nmol/L, trials of treatment can be considered in those in whom alternative causes of these symptoms have been excluded.
There is no generally accepted age-adjusted reference range. However, laboratories may have specific reference ranges for different age groups for the laboratory method they are using to measure testosterone. In general, lower normal serum levels should be expected for an elderly population as the decline in testosterone secretion is a general phenomenon of aging in men. An increase in LH may indicate that the organism tries to counterregulate the impaired testicular function and that the measured low testosterone serum levels may be of clinical relevance.
Yes, this is possible, for instance, if there is a testosterone receptor defect. This means that there is enough testosterone in the blood but it does not reach its proper site of action. In such cases, administering exogenous testosterone may be ineffective. A complete receptor defect is however a very rare finding. A normal total testosterone level with low levels of the biologically active hormone (free testosterone), is in contrast a very common finding in elderly men. In particular, SHBG levels tend to increase with age so that quite a portion of the testosterone is bound to this protein which prevents the hormone from reaching the receptor.
If these or other causes are present, the patient with borderline testosterone levels may benefit from treatment. The doctor may decide together with the patient to prescribe individualized treatment to investigate whether short-term use of testosterone treatment can alleviate the symptoms. Such a therapeutic trial can be justified where there are no contraindications to androgen therapy and proper monitoring is performed according to the guidelines.5,6
No, there are fundamental differences between menopause which is a physiologic process affecting all women and Late-Onset Hypogonadism (LOH) affecting only a small proportion of aging men, especially those with comorbid conditions. Neither the medication type nor the treatment populations are comparable.
If testosterone deficiency continues for a long period, osteoporosis and anemia may develop, furthermore reduced muscle mass and strength may lead to severe physical weakness and a significantly impaired general well-being. Negative changes in body composition and metabolism may continue with, so far, unknown consequences for long-term cardiovascular health. Patients will continue to suffer from a loss of libido, erectile dysfunction and severe depression may develop.7
Many systemic diseases (e.g. diabetes mellitus, generalized infections, metabolic syndrome) correlate with low testosterone levels. Therefore, hypogonadism as an early sign can contribute to an early diagnosis of the underlying condition.
Testosterone values in the normal range do not have a negative effect on a healthy heart. Long-term investigations to date actually show positive effects of testosterone on cardiovascular risk factors. In several studies, testosterone has been used successfully in patients with coronary artery disease.
Recent clinical results show favorable effects of testosterone on endothelial function such as reduction of inflammatory cytokines and increase of endothelial progenitor cells.
The abuse of androgenic anabolic steroids by competitive athletes and bodybuilders has given androgens a bad reputation. In rare isolated cases, heart diseases in these men were reported. However, it should not be forgotten that these men take largely supraphysiologic doses, frequently 100 times the recommended dose.
A common question among HCPs and patients is how long testosterone therapy should be provided. Several studies have demonstrated that the beneficial effects of testosterone therapy are not maintained after cessation of treatment.8-14 This applies to improvements in body composition, erectile function, HbA1c, total cholesterol, LDL, HDL, triglycerides, AMS, IPSS, IIEF-EF, residual voiding volume and bladder wall thickness, and quality of life, and likely most – if not all - other testosterone-related outcomes.8-11,13 If testosterone therapy is discontinued, beneficial effects are to appear again when testosterone therapy is resumed.8
As pointed out in the British Society for Sexual Medicine guidelines on Adult Testosterone Deficiency, cessation of testosterone therapy results in reappearance of symptoms and reversal of benefits within 6 months, so testosterone therapy is likely to be required lifelong for persistent symptom resolution and maintenance of health benefits.15
The Prostate Specific Antigen (PSA) is a specific marker that gives information about possible pathological processes in the prostate. PSA measurement is the most widespread screening method for prostate cancer The rate of PSA rise (the velocity) is probably the most important measure that needs monitoring.16
There is no direct correlation between serum testosterone levels in men and the risk of developing prostate cancer. There has been no conclusive evidence that levels of serum testosterone are higher in men developing prostate cancer than in controls. Whereas some studies even suggest that men with low testosterone levels are at greater risk of developing more aggressive disease.17
Testosterone administration does not cause prostatic carcinoma. However, prostatic carcinoma is a sexual hormone-dependent tumor and therefore a pre-existing tumor may be stimulated to further growth. Any testosterone product is thus strictly contraindicated in patients with diagnosed prostatic carcinoma.
Digital rectal examination and determination of PSA levels are mandatory according to ISSAM, EAU, ISA, EAA and ASA recommendations in men over the age of 45 years as baseline measurements of prostate health18
As prostatic carcinoma is curable if diagnosed at an early stage, it is advisable that every man above the age of 45 undergoes regular screening procedures. As testosterone can promote the growth of a pre-existing prostatic carcinoma, regular monitoring is necessary during testosterone treatment in order to diagnose all cases where this may occur. In the past decade, widespread PSA screening has increased the diagnosis incidence for prostatic carcinoma at a curable early stage of the disease.
Following long-term treatment of hypogonadal men with testosterone products there is no evidence that they are at any greater risk due to testosterone therapy than are healthy men. Testosterone has been widely available and prescribed to hypogonadal men for more than 60 years and no carcinogenic signal has emerged yet.19 A meta-analysis of placebo-controlled trials in more than 1,000 elderly men have revealed equally low incidences of prostate cancer in the testosterone-treated and the placebo group.20
It is certainly noticeable that testosterone levels are often low when prostatic carcinoma is diagnosed. Moreover high grade prostate cancer has been associated with low plasma levels of testosterone appears too early, however, to establish any causal association. The low testosterone levels can also be interpreted as a result of the underlying disease. It is known that testosterone levels decrease as a result of disease or stress.
The recommendations of ISSAM, EAU, ISA, EAA and ASA on investigation, treatment and monitoring of late-onset hypogonadism in Males recommend the following periodical check-ups during testosterone therapy:21