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Current topics in testosterone replacement of hypogonadal men

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All forms of hypogonadism – primary, secondary and late-onset – require testosterone substitution. The indication is given when the patient presents with symptoms of androgen deficiency and the serum testosterone levels are below normal. Several testosterone preparations and modes of application are available of which those producing physiologic serum levels should be preferred e.g. preferentially transdermal gels and long-acting intramuscular testosterone undecanoate. Testosterone substitution must be monitored at regular intervals, best at 3, 6 and 12 months after initiation and then annually. Parameters for surveillance include well-being, libido and sexual activity, measurement of serum testosterone levels, haemoglobin and haematocrit, PSA and digital rectal examination, and, biannually, bone mineral density. Testosterone has positive effects on comorbidities such as obesity, metabolic syndrome, diabetes type II, cardiovascular diseases and osteoporosis.

Introduction

The testes have the dual function of producing hormones and sperm. Hypogonadism, defined as impaired function of the testes is expressed either as testosterone deficiency or as infertility or as a combination of both. Its causes are so manifold that the reader is referred to relevant textbooks for pathophysiological details *[1], *[2].

However, all forms of hypogonadism – primary, secondary and late-onset – are characterized by symptoms of testosterone deficiency. Hypogonadism with testosterone deficiency is the universally accepted indication for testosterone treatment. As practically all tissues and all organs have androgen receptors and/or may also show non-genomic response to testosterone, testosterone deficiency results in a broad spectrum of symptoms. Some of these symptoms such as fatigue, loss of libido, erectile dysfunction, depression and osteoporosis can also be caused by diseases other than hypogonadism and would not respond to testosterone treatment unless serum levels are below normal. Therefore, all current guidelines agree that the combination of symptoms of testosterone deficiency and subnormal testosterone levels are prerequisites for diagnosis and treatment (*[3], [4], [5], for review [6]).

Disregarding these clear precepts, testosterone preparations appear to be increasingly prescribed and consumed for symptoms without documented testosterone deficiency. This seems to be more prevalent in the USA than in Europe as US sales of testosterone preparations have quadrupled from 2000 to 2011 although the number of low testosterone levels revealed in laboratory testing has remained constant [7]. In comparison, in the UK testosterone prescriptions have doubled within a decade [8], almost in pace with low testosterone levels detected in laboratory testing [7]. Prescribing testosterone at random without documented low testosterone levels and symptoms of testosterone deficiency is not in accordance with current good medical practice and borders on testosterone abuse, culminating in doping with androgens to enhance physical performance in sports and bodybuilding. Currently discussed unwanted side-effects of testosterone may, at least in part, be caused by improper prescribing (see below).

Section snippets

Normal testosterone levels: thresholds for substitution

As stated above, good clinical practice requires that testosterone is only to be administered if symptoms of testosterone deficiency are encountered and levels are below normal. But what is the lower limit of normal?

First, due to the diurnal rhythm of testosterone in serum [9] blood samples of testosterone should always be taken in the morning hours from men with a regular day–night rhythm in order to obtain results comparable to reference values.

While there is not one fixed lower limit of

Testosterone preparations and modes of application

Testosterone was synthesized in 1935 and has now been in clinical use for almost 8 decades [24]. While today intramuscular, subdermal, transdermal, oral and buccal testosterone preparations are available (Table 1), until the 1990s only preparations resulting in unphysiologic serum levels existed. Aware of these shortcomings, WHO, NIH and FDA jointly formulated general principles of testosterone therapy as “Guidelines for the use of androgens in men” [25].

Only preparations of natural

Sexual function

Loss of libido and erectile dysfunction are early signs of hypogonadism and return to normal under testosterone substitution [54]. In fact, they are the first symptoms to respond to substitution, i.e. as early as 2–4 weeks [55]. For objective evaluation to psychosexual effects weekly questionnaires on sexual thoughts and function, sexual intent and desire, satisfaction with sexuality, frequency of erection and number of morning erections and ejaculations may be used (e.g. [56], [57]). While

Bone density and fracture rates

Testosterone replacement therapy closes the epiphyses in hypogonadal adolescents who have not gone through puberty, and will increase low bone mineralization in hypogonadal adults, preventing and reversing osteoporosis [62], [63]. The effects on bones take longest to become quantifiable [55]. As the testosterone effects on bones are mainly transmitted through estradiol [64], [65] it is important that natural testosterone that can be converted to estradiol be used for substitution. In addition

Obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases

Patients with hypogonadotropic hypogonadism show a fivefold higher incidence of the metabolic syndrome than eugonadal male controls [72]. Its incidence is even higher in men with Klinefelter syndrome [73]. Testosterone substitution leads to weight loss in hypogonadal men. Normalization of testosterone by substitution of testosterone undecanoate given i.m. over 5 years led to a mean weight loss of 15.3 kg in 255 hypogonadal patients, as well as to reduction in fasting glucose and HbA1c levels

Prostate cancer

The 2008 guidelines on late-onset hypogonadism (LOH) [3] state “There is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or BPH. There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer. However, there is unequivocal evidence that testosterone can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer”.

In the meantime no data have

Timing of testosterone treatment

As a general rule hormone substitution is initiated when levels fall below the lower limit of normal. In the case of all forms of hypogonadism this means when testosterone levels fall below 12 nmol/L. However, there are situations where this rule may require consideration and modification.

Monitoring of testosterone substitution

Some recent publications indicate that testosterone is frequently prescribed without proper patient follow-up [7], [8], [87], [88]. However, although careful monitoring at regular intervals is emphasized in most of the current guidelines [6], they are not consistent concerning follow-up intervals and the parameters to be evaluated. It is advisable to see the patient following initiation of treatment after 3, 6 and 12 months and then annually.

On these occasions the patient should be interviewed

Conclusion

As described above, testosterone substitution is a powerful tool for the treatment of hypogonadism, and different testosterone preparations are available to achieve effective substitution. In cases of congenital or acquired irreversible forms of hypogonadism such as isolated hypogonadotropic hypogonadism, post-hypophysectomy, Klinefelter syndrome and anorchia there are no alternatives to testosterone for long-term substitution. However, hypogonadism may not only favour coinciding diseases such

Acknowledgement

Language editing by Susan Nieschlag M.A. and secretarial help by Maria Schalkowski are gratefully acknowledged.

The author is a consultant to Clarus Therapeutics Ltd., Epinamics GmbH and Dr. August Wolff Arzneimittel GmbH.

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