CLINICAL PICTURE


What is hypogonadism (testosterone deficiency syndrome)?
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.

•In children and adolescents androgen deficiency is usually of genetic origin or has congenital causes. It is diagnosed when puberty is retarded or does not occur at all.
•Hypogonadism in the young adult appearing after puberty is usually acquired (testicular trauma, mumps, of teratogenic origin or caused by hypophyseal, hypothalamic or general diseases).3 As the symptoms appear insidiously, this form of hypogonadism is not diagnosed until late on in its development: sometimes it is not recognized until investigations are being undertaken because of infertility.
•In men over 40, testosterone deficiency is in most cases a consequence of impairment of testicular function and/or the hypothalamo-pituitary control. The process and the consequences of hormone deficiency in men occur gradually. Clinically the symptoms encompass heterogeneous and less specific signs and for this reason are often not immediately recognized as symptoms of testosterone deficiency.


Does late-onset hypogonadism (LOH) really exist? Is there scientific evidence of it?
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:

•The easily recognized features of diminished sexual desire (libido), erectile quality and frequency, and nocturnal erections,
•Changes in mood with concomitant decreases in intellectual activity, cognitive functions, spatial orientation ability, fatigue, depressed mood and irritability,
•Sleep disturbances,
•Decrease in lean body mass with associated diminution in muscle volume and strength,
•Increase in visceral fat,
•Decrease in body hair and skin alterations, Decreased bone mineral density resulting in osteopenia, osteoporosis and increased risk of bone fractures.
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


What are the age-related changes in hormone production?
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.



DIAGNOSIS


How is testosterone deficiency diagnosed? (what measurements; parameters?)
If symptoms of testosterone deficiency are present, the doctor will investigate them using various diagnostic procedures. These include:
•Medical history (personal and familial)
•A general physical examination
•Laboratory tests including determination of testosterone values
•Examination of the prostate. Every man over 45 years of age should be regularly screened for prostate disease.

ISSAM, EAU, ISA, EAA and ASA4 suggest that the most widely accepted parameters to establish the presence of hypogonadism are the measurement of total testosterone and free testosterone calculated from measured total testosterone and SHBG, or measurement of free testosterone by an equilibrium dialysis method.

Depending upon these test results, supplementary tests may be required. These include a bone density test for suspected osteoporosis. If the patient wants to have children but has so far been unsuccessful, his ejaculate will be examined.

A morning testosterone concentration in the blood of 12-35 nmol/l is considered normal. Testosterone treatment might be recommended if this value is found to be below 12 nmol/l.

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.


What is the reference range to define male hypogonadism? Is there an age-adjusted reference range?[/
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

Can hypogonadal symptoms be present even if the testosterone level is in the normal range or above?
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.


TREATMENT WITH TESTOSTERONE IN GENERAL


Is testosterone treatment for aging men comparable for hormone replacement therapy for menopausal women?
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


What happens if hypogonadism is left untreated?
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


Is there a connection between general health and testosterone levels?
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.


Does testosterone have an effect on the heart?
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


TESTOSTERONE TREATMENT AND THE PROSTATE


What is PSA?
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


What are the effects of testosterone treatment on the prostate?
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.9
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 health

•prior to therapy with testosterone
•at 3 -6 months and at 12 months
•at least yearly thereafter


Why is it important to monitor markers for prostate disease?
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


Do any long-term studies exist which show that prostatic carcinoma is not triggered by testosterone replacement therapy?
Following long-term treatment of hypogonadal men with testosterone products there is no evidence that they are at any greater risk due to testosterone replacement 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.11 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


If testosterone levels are low, can this cause prostatic carcinoma?
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


TESTOSTERONE TREATMENT AND SAFTEY FOLLOW-UP MONITORING

Which checks should be performed?
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:13

•after starting testosterone therapy monitoring for prostate disease should be done at 3 to 6 months, then 12 months and then at least annually.
•Polycythemia occasionally develops during testosterone treatment. Therefore, periodic hematological assessment is indicated, i.e. before treatment, then after 3-4 and 12 months in the first year and then annually. Dose adjustments may be necessary in case of elevated hematocrit and/or hemoglobin. The number of red blood cells also provides information about an anemia, which is a symptom of testosterone deficiency. Anemia may improve rapidly under testosterone treatment so that the red blood cell count is a good marker of the success of therapy. The contrary, a too high count of red blood cells, must be monitored as well.
•Improvement in signs and symptoms of testosterone deficiency should be sought and failure to benefit clinical manifestations should result in discontinuation of treatment. Further investigation for other causes is then mandatory.
•Bone density increases under testosterone substitution and fracture rates may be reduced. Therefore assessment of bone density at two-year intervals may be advisable (if available and affordable).


References


1 Jockenhövel Fand Schubert M: Male Hypogonadism, 2nd edition. UNI-MED Verlag Bremen 2007.

2 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, ,Thompson IM, Weidner W, Wu FCW: Investigation, Treatment and Monitor-ing of Late-Onset Hypogonadism in Males – ISA, ISSAM, EAU, EAA, and ASA Recommendations. Aging Male 2008; in print (published online Sept. 2, 2008). Eur Urol 2008, in print

3 Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. J Clin Endocrinol Metab 2006; 91: 1995-2010.

4 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, ,Thompson IM, Weidner W, Wu FCW: Investigation, Treatment and Monito-ring of Late-Onset Hypogonadism in Males – ISA, ISSAM, EAU, EAA, and ASA Recommendations. Aging Male 2008; in print (published online Sept. 2, 2008). Eur Urol 2008, in print

5 Wang C: Europ Urol 2007; Suppl. 6: 862–867

6 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, ,Thompson IM, Weidner W, Wu FCW: Investigation, Treatment and Monitor-ing of Late-Onset Hypogonadism in Males – ISA, ISSAM, EAU, EAA, and ASA Recommendations. Aging Male 2008; in print (published online Sept. 2, 2008). Eur Urol 2008, in print

7 Jockenhövel F and Schubert M: Male Hypogonadism, 2nd edition. UNI-MED Verlag Bremen 2007

8 Auvinen A., Määttänen L. et al, Test sensitivity of PSA in the Finnish randomised prostate cancer screening trial, Int. J. Cancer: 111, 940-943 (2004)

9 Gould DC, Kirby RS: Testosterone replacement therapy for late-onset hypogonadism: what is the risk of induc-ing prostate cancer?; Prostate 2005; 1: 1-5

10 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, ,Thompson IM, Weidner W, Wu FCW: Investigation, Treatment and Monitor-ing of Late-Onset Hypogonadism in Males – ISA, ISSAM, EAU, EAA, and ASA Recommendations. Aging Male 2008; in print (published online Sept. 2, 2008). Eur Urol 2008, in print

11 Gould DC, Kirby RS: Testosterone replacement therapy for late-onset hypogonadism: what is the risk of induc-ing prostate cancer?; Prostate 2005; 1: 1-5

12 Calof OM et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol Med Sci 2005; 60A(11): 1451-1457

13 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, ,Thompson IM, Weidner W, Wu FCW: Investigation, Treatment and Monitor-ing of Late-Onset Hypogonadism in Males – ISA, ISSAM, EAU, EAA, and ASA Recommendations. Aging Male 2008; in print (published online Sept. 2, 2008). Eur Urol 2008, in print