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The large doses needed due to extensive first-pass metabolism through the liver to achieve therapeutic levels would make oral administration of unmodified T unsuitable for therapeutic use long-term.
Pharmacology of testosterone preparations
H.M. Behre, C. Wang, D.J. Handelsman and E. Nieschlag
To make testosterone therapeutically effective three approaches have been used:
1) different routes of administration,
2) esterification in positions 17, and
3) chemical modification of the molecule. In addition, these approaches have been combined. Since of practical clinical relevance, the route of administration is used here for categorizing the various testosterone preparations (overview in Table 14.1).
14.3.1 Oral administration
14.3.1.1 Unmodified testosterone
Unmodified testosterone is physiologically secreted by the testes would appear to be the first choice when considering substitution therapy. When ingested orally in its unmodified form testosterone is absorbed well from the gut but is effectively metabolized and inactivated in the liver before it reaches the target organs (“first-pass-effect”). Only when a dose of 200 mg is ingested which exceeds 30fold the amount of testosterone produced daily by a normal man, is the metabolizing capacity of the liver overcome. With such doses, an increase in peripheral testosterone blood levels becomes measurable and clinical effects can be observed (Daggett et al. 1978; Johnsen et al. 1974; Nieschlag et al. 1975; 1977). The testosterone-metabolizing capacity of the liver, however, is age- and sex-dependent. An oral dose of 60 mg unmodified testosterone does not affect peripheral testosterone levels in normal adult men but produces a significant rise in prepubertal boys and women (Nieschlag et al. 1977). This demonstrates that testosterone induces liver enzymes responsible for its own metabolism (Johnsen et al. 1976). When the liver is severely damaged its metabolizing capacity decreases. Thus, in patients with liver cirrhosis, a dose of 60 mg of testosterone (ineffective in normal men) produces high serum levels (Nieschlag et al. 1977).
In hypogonadal men with normal liver function, 400–600 mg testosterone must be administered daily if the patient is to be substituted by oral testosterone (Johnsen 1978; Johnsen et al. 1974), a dose exceeding the testosterone production of a normal man almost 100fold. Aside from being uneconomical, the possibility of adverse effects of such huge testosterone doses cannot be excluded, especially when given over long periods of time as required for substitution therapy. However, in a small group of patients treated for as long as seven years with oral testosterone, no serious side effects were observed (Johnson 1978). Nevertheless, oral administration of unmodified testosterone has not become a generally accepted method for therapeutic purposes.
Pharmacology of testosterone replacement therapy preparations (2016)
Jennifer J. Shoske, Meghan K. Wilson, Michael L. Spinner
Oral administration
Historically, oral administration of physiological testosterone (Figure 1A) has been proven unsuccessful due to extensive first-pass metabolism through the liver despite having good gastrointestinal absorption. Ingestion of supra-physiological doses was required to overcome this and allow for measurable amounts in the serum (10). Alkylation of testosterone at carbon 17α resulted in 17α-methyltestosterone (Figure 1B) with the ability to bypass first-pass metabolism. However, this modification caused significant liver toxicity and lowering of HDL cholesterol (11). Esterification at carbon 17β yielded testosterone undecanoate (TU) (Figure 2A) which is absorbed via the lymphatic system and also bypasses liver degradation. This formulation required a high capsule burden due to low bioavailability along with gastrointestinal and liver adverse effects (12,13). Currently, oral testosterone preparations are not options for TRT in the USA due to these adverse effects.
JATENZO®: Challenges in the development of oral testosterone
Testosterone therapy (TT) for the treatment of testosterone deficiency (TD) can be administered via several routes of administration. Due to a variety of concerns such as hepatotoxicity, an oral formulation has long been absent in the United States. Recently, JATENZO® (testosterone undecanoate)...
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*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPY
Oral administration of exogenous TT historically has proven to be unsuccessful. Despite adequate absorption in the gastrointestinal system, this form of testosterone undergoes extensive first-pass metabolism through the liver, and thus requires ingestion of supraphysiological doses to attain therapeutic serum levels [14]. As a way to circumvent the liver metabolism pathway, research efforts to administer oral testosterone have taken two primary paths: alkylation of testosterone at the carbon-17 position and fatty-acid esterification of testosterone to create a testosterone ester (Fig. 1).
Alkylation of testosterone at carbon 17α results in 17αmethyltestosterone which allows for the ability to bypass the first metabolism in the liver. However, this modification has been linked to significant liver toxicity including cholestasis, hepatitis, and hepatic adenocarcinoma [15–17] and lowering of HDL cholesterol [18, 19]. The effects of methyltestosterone on liver function were first described in the 1940s, with studies of liver function demonstrating elevations in both serum direct and indirect bilirubin levels [19]. Foss and Simpson also described a case series of 42 patients who developed jaundice during methyltestosterone therapy [20]. They noted that the duration of therapy to the onset of jaundice ranged from 8 days to 10 months and withdrawal of methyltestosterone therapy resulted in remission of hepatocellular dysfunction within a few days to weeks. Recent work has focused on testing the effects of synthetic androgens on liver function utilizing animal models [21] and has corroborated prior work demonstrating direct increases in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and sorbitol dehydrogenase. Therefore, methyltestosterone is largely not recommended for the management of male hypogonadism [6, 22].
Esterification of testosterone at carbon 17β yields testosterone esters such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU). Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation. An early oral TU formulation (ANDRIOL®) was approved for use in many countries but never in the United States. This formulation is heavily reliant on dietary fat intake as a means of increasing absorption and therefore leads to significant intra- and inter-patient variability in testosterone response [23, 24]. This results in the need to dose hypogonadal men with several capsules three or more times daily affecting compliance. Several studies have also demonstrated both gastrointestinal and liver adverse effects including severe cholestasis and jaundice [25, 26]. Consequently, these oral TU formulations have never been widely utilized to treat TD in the United States although they remain available in many countries
*SELF-EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS)
TU has been formulated in a unique self-emulsifying drug delivery system (SEDDS) that was initially evaluated in multi-institutional placebo-controlled studies in Europe [27]. SEDDS formulations combine hydrophilic and lipophilic components that enable the solubilization of lipophilic molecules such as TU in the gut (Fig. 2). This promotes intestinal lymphatic absorption of lipophilic testosterone esters, thereby reducing first-pass hepatic metabolism. Furthermore, this formulation allows absorption after oral ingestion with a typical meal as opposed to high-fat content meals required for prior formulations. Yin et al. showed that this TU with SEDDS resulted in adequate serum testosterone levels within the physiologic range after dosing with just TU 200 mg twice per day in most hypogonadal men [28].
