Modern androgen therapy was initiated in the last century by the French physiologist and neurologist Charles Edouard Brown-Sequard (1817 -1894). After noticing clear signs of aging in himself at the age of 72, he first performed a subcutaneous injection of animal testicular extract in a self-experiment in 1889. Although he thus circumvented the problem of insufficient hormone absorption and the first-pass effect with oral application, the amount of testosterone he administered was nevertheless far below the necessary therapeutic dose, so that the improvement in his bodily functions described by him can only be attributed to a placebo effect [5]. The Viennese physiologist Eugen Steinach (1861-1944) also worked on the hormonal function of the gonads since 1894 and, among other things, performed numerous testicular transplants in animal experiments. He became world-famous, however, for his theory of “autoplastic age control”. He assumed that by surgically cutting off the spermatic ducts after the secretory output of the gonads had dried up, increased incretoric hormone production would take place. His theories gained him great popularity and triggered a veritable vasectomy wave in the 1920s [18]. At that time, Serge Voronoff (1866 -1951), a Russian physician living in Paris, performed transplantations of tissue from monkey testicles into human gonads. After only 5 years, he had performed this procedure on 300 patients for rejuvenation reasons [20]. With the introduction of artificial synthesis of testosterone in 1935, these questionable surgical treatments to rejuvenate the body and increase vita sexualis finally became obsolete.
More than 95% of androgen production and release takes place in the Leydig cells of the testicular parenchyma in the form of testosterone and is controlled by the pulsatile luteinizing hormone (LH) released in the pituitary gland. This circadian rhythm peaks in the morning hours, which is why androgen determination in serum should always be carried out at this time. In the bloodstream, only 2% of testosterone is present in free form; 44% is bound to sex hormone-binding globulin (SHBG) and 54% to albumin [4]. The decisive factor for the peripheral effect at the receptor of the organ of success is mostly the conversion of testosterone into the active form as dihydrotestosterone (DHT).
The action spectrum of androgens shows a wide range of psychological factors (well-being, performance, and mood) and somatic effects (e.g., on body muscles, fat distribution, bone density or body hair). With regard to sexual functions, libido, erectile function, spermiogenesis and function of the accessory sex glands, prostate and seminal vesicles, are influenced. For the proper development of the male sex organs and their function, the presence of androgens is obligatory already intrauterine and until the end of puberty. A hormone deficiency or defect during this phase leads to malformation or irreversible loss of function in this area. For the sexually mature male, androgens are then necessary to maintain these functions. Erectile function is affected by both central and peripheral effects. In the hypothalamus and the limbic system, testosterone has been shown to have an activating effect on the sexually stimulating dopaminergic system and an inhibitory effect on the inhibitory serotonergic system [8]. These mechanisms are of particular importance for an unbroken libido. Peripherally, sites of action exist at proerectile postganglionic parasympathetic neurons [9] and at androgen receptors in the corpus cavernosum penis itself [16,19]. The exact significance of these different sites of action has not yet been clearly elucidated and, in part, has only been demonstrated in animal models. However, of particular importance for erectivity seems to be the testosterone-dependent modulation of arousal propagation via the autonomic nervous system and the neurotransmitter systems involved in it [1,9,12]. For androgen receptors in the erectile tissue itself, it is clear that they are present in greater density before puberty and thus are likely to be essential for regular tissue development. However, at sexually mature age, this receptor density is significantly reduced [16], making their importance unclear. However, studies in the rat have demonstrated that androgen deprivation leads to programmed cell death (apoptosis) of erectile tissue [17]. If these experimental results are transferable to humans, which can be assumed, neurogenic and cavernous myopathic etiology could be detected in patients with manifest testosterone deficit in special diagnostics. Clinical experience shows that surgical or chemical castration does not obligatorily lead to total loss of erectile function [1, 6]. Besides, androgen substitution in hypogonadism leads to an increase in libido and a more frequent frequency of nocturnal erections, but the occurrence of visually induced erections is not increased [1,6,14]. These facts make it clear that not all mechanisms important for erectivity are subject to hormone dependence.
The clinical appearance of androgen deficiency or hypogonadism depends strongly on the extent of the hormone deficit and the time of onset. Severe or congenital disorders can already be determined anamnestically, are accompanied by typical somatic changes and do not become clinically conspicuous primarily through erectile dysfunction. In these cases, special diagnostics and, if possible, causal treatment should be initiated, which will not be discussed in detail here.
In addition to taking a medical history and performing a physical examination, the question arises again and again as to which endocrine laboratory parameters are necessary in the routine clarification of erectile dysfunction [13]. In this regard, only the determination of total testosterone in the morning hours can be recommended as the first screening examination, taking into account cost-effectiveness [4]. Some authors see an advantage in the determination of free testosterone, since only this is biologically active and in the case of disturbances in protein binding (SHBG, albumin), total testosterone alone is not meaningful [4, 11]. Only if the repeated testosterone determination shows reduced values or the patient has already indicated a reduced libido in his medical history, should the complete endocrinological diagnostics with LH, FSH and prolactin be carried out. Only then can a distinction be made between hypergonadotropic hypogonadism, i.e., a defect in androgen production in the terminal organ testis (e.g., after orchitis, radiation or congenital disorder), or hypogonadotropic hypogonadism and thus a superordinate disorder. Hyperprolactinemia, whether triggered by a pituitary process or, much more commonly, induced by drugs or stress, is then also recognized. In the case of a prolactin disorder, patients also often report a libido disorder.
Secondary disturbances of the androgen metabolism and thus also a restriction of the sexual function can occur, however, especially in thyroid diseases (both hyper- and hypothyroidism) and general stress situations. In these cases, treatment of the triggering noxious agent is a priority and androgen substitution alone is unsuccessful.
Controversial is androgen substitution for the treatment of erectile dysfunction in older men with moderate to borderline testosterone depletion, possibly in combination with other andropausal symptoms [10]. This can be classified in the complex of male menopause, recently also called PADAM (“partial androgen deficiency of aging male”). It has not yet been clarified whether the cause lies in the pituitary gland, the gonads or, for example, an altered hormone sensitivity of the organs of success. The therapeutic benefit of testosterone treatment has yet to be proven in larger studies; in any case, the possible effects on the cardiovascular system and the prostate should be considered, especially in these patients. Since there is usually still an own androgen production, a high-dose substitution is not necessary, so that oral or transdermal application is to be regarded as suitable.
Mostly, treatment is performed in older men with andropausal symptoms and slightly decreased testosterone levels. Especially in this age group, the effect of androgens on the cardiovascular system as well as on the prostate must be taken into account.
Through changes in blood lipid metabolism, induction of insulin resistance and vasoconstrictor properties, androgens can increase the rate of cardiovascular adverse events [10]. Manifest heart failure or other relevant cardiac risk factors are therefore considered absolute or relative contraindications.
The presence of androgens is obligatory for the proper development of the prostate. Hormone administration in hypogonadism enlarges an underdeveloped gland to its normal volume and thus also raises the PSA value into the normal range [3]. The frequent development of benign prostatic hyperplasia was not observed even with long-term substitution. Even in patients without hypogonadism, there was only a minimal increase in prostate volume or PSA value [10].
Of great importance, however, is the problem of prostate carcinoma. If such a cancer is present in a clinical stage, it cannot be excluded at present that external testosterone administration can stimulate growth and thus metastasis. As a result, prostate carcinoma must be excluded by means of rectal examination and PSA before and during any androgen treatment. Whether a primary latent carcinoma can be transformed into a clinical stage by long-term androgen administration has not been proven to date [10]. The induction of malignant transformation in a benign gland appears to be extremely unlikely.
In hypogonadal patients, it has been shown that testosterone substitution leads to a significant increase in bone density and thus reduces the risk of fractures [7]. The extent to which this effect also plays a role in the rest of the patient population has not yet been clearly demonstrated [10].
The oral testosterone derivatives methyltestosterone and fluoxymesterone have been shown to cause hepatotoxicity, which is why these methylated substances are no longer on the German market. The androgens currently on the market, in particular the orally applied testosterone undecanoate and mesterolone, have not yet shown any liver-damaging potential.
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