Testosterone

Endogenous androgens, principally testosterone, secreted by the testes and its major metabolite DHT, are responsible for the development of the external and internal genital organs and for maintaining the secondary sexual characteristics (stimulating hair growth, deepening of the voice, development of the libido); for a general effect on protein anabolism; for development of skeletal muscle and body fat distribution; for a reduction in urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.

Androgens are also responsible for the growth spurt of adolescence and for the eventual termination of linear growth and stimulate the production of red blood cells by enhancing erythropoietin production.

The effects of testosterone in some target organs arise after peripheral conversion of testosterone to oestradiol, which then binds to oestrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone and testicular Leydig cells.

Exogenous administration of androgens inhibits endogenous testosterone release. With large doses of exogenous androgens, spermatogenesis may be suppressed.

Testosterone is the most important androgen of the male, mainly synthesised in the testicles, and to a small extent in the adrenal cortex.

Insufficient secretion of testosterone due to testicular failure, pituitary pathology or gonadotropin or luteinising hormone-releasing hormone deficiency results in male hypogonadism and low serum testosterone concentration. Symptoms associated with low testosterone include decreased sexual desire with or without impotence, fatigue, loss of muscle mass, mood depression and regression of secondary sexual characteristics. Restoring testosterone levels to within the normal range can result in improvements over time in muscle mass, mood, sexual desire, libido and sexual function including sexual performance and number of spontaneous erections.

Testosterone, after oral administration, delivers physiological amount of testosterone in the circulation. Treatment of hypogonadal men also results in a clinically significant rise of plasma concentrations of dihydrotestosterone and oestradiol, as well as a decrease of SHBG (sex hormone binding globulin). Treatment of males with primary (hypergonadotropic) hypogonadism results in a normalization of gonadotropin levels.

During exogenous administration of testosterone to normal males, endogenous testosterone release may be decreased through feedback inhibition of pituitary luteinising hormone (LH). With large doses of exogenous androgens, spermatogenesis may also be suppressed through inhibition of pituitary follicle stimulating hormone (FSH).

Androgen administration causes retention of sodium, nitrogen, potassium, phosphorus and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens have been reported to stimulate production of red blood cells by enhancing the production of erythropoietin.

Absorption

Testosterone caps must be taken with a normal meal or breakfast to ensure absorption. Food enhances the absorption of Restandol Testocaps: In healthy volunteers the AUC of testosterone was increased more than 12 –fold compared with fasted conditions when Restandol Testocaps was taken with a normal meal. No differences were found in the AUC of testosterone when Restandol Testocaps was taken with a normal meal (containing 18.8 grams of fat) as compared to a high fat meal (containing 44.1 grams of fat). The absorption is about 7%. Following oral administration of Restandol Testocaps, an important part of the active substance testosterone undecanoate is co-absorbed with the lipophilic solvent from the intestine into the lymphatic system, thus circumventing the first pass inactivation by the liver.

Testosterone depot intramuscularly administered circumvents the first-pass effect. Following intramuscular injection of testosterone undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into testosterone and undecanoic acid. An increase in serum levels of testosterone above basal values may be seen one day after administration.

The percutaneous absorption of testosterone ranges from approximately 9% to 14% of the applied dose. Following percutaneous absorption, testosterone diffuses into the systemic circulation at relatively constant concentrations during the 24 hour cycle.

Steady-state conditions

After the 1^st intramuscular injection of 1000 mg testosterone undecanoate to hypogonadal men, mean C_max values of 38 nmol/L (11 ng/mL) were obtained after 7 days. The second dose was administered 6 weeks after the 1s^t ^injection and maximum testosterone concentrations of about 50 nmol/L (15 ng/mL) were reached. A constant dosing interval of 10 weeks was maintained during the following 3 administrations and steady-state conditions were achieved between the 3^rd and the 5^th administration. Mean C_max and C_min values of testosterone at steady-state were about 37 (11 ng/mL) and 16 nmol/L (5 ng/mL), respectively. The median intra- and inter-individual variability (coefficient of variation, %) of C_min values was 22 % (range: 9-28%) and 34% (range: 25-48%), respectively.

Distribution

From the lymphatic system testosterone undecanoate is released into the plasma. Single administration of 20-80 mg testosterone caps to postmenopausal women leads to peak-levels of total plasma testosterone of approximately 1.5-2.0, 2.5-5.5 and 5.2-10.3ng/ml after a dose of 20, 40 and 80 mg testosterone, respectively. These levels are reached approximately 5-6h (t_max) after administration. Plasma testosterone levels remain elevated for at least 8 hours. In Japanese women the testosterone levels are about two fold higher.

During steady state after 28 days of administration plasma levels of total testosterone in hypogonadal men were increased after administration of 40 mg t.i.d, 40 b.i.d+80 mg, 80 mg b.i.d and 80 mg t.i.d. The dose of 80 mg b.i.d or 80 mg t.i.d. resulted in levels in the male physiological range for a considerable proportion of the time during the day. Testosterone and testosterone undecanoate display a high (over 97%) non-specific binding to plasma proteins and sex hormone binding globulin in in vitro tests.

In serum of men, about 98% of the circulating testosterone is bound to sex hormone binding globulin (SHBG) and albumin. Only the free fraction of testosterone is considered as biologically active. Following intravenous infusion of testosterone to elderly men, the elimination half-life of testosterone was approximately one hour and an apparent volume of distribution of about 1.0 l/kg was determined.

Serum testosterone concentrations increase from the first hour after a cutaneous application, reaching steady state from day two. Daily changes in testosterone concentrations are then of similar amplitude to those observed during the circadian rhythm of endogenous testosterone. The percutaneous route therefore avoids the blood distribution peaks produced by injections. It does not produce supra-physiological hepatic concentrations of the steroid in contrast to oral androgen therapy. Administration of 5 g of testosterone gel produces an average testosterone concentration increase of approximately 2.5 ng/ml (8,7 nmol/l) in plasma. When treatment is stopped, testosterone concentrations start decreasing approximately 24 hours after the last dose. Concentrations return to baseline approximately 72 to 96 hours after the final dose.

Biotransformation

Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolised and excreted the same way as endogenous testosterone. The undecanoic acid is metabolised by ß-oxidation in the same way as other aliphatic carboxylic acids. The major active metabolites of testosterone are oestradiol and dihydrotestosterone.

Elimination

Excretion mainly takes place via the urine as conjugates of etiocholanolone and androsterone.

Testosterone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radio-labelled testosterone, about 90% of the radioactivity appears in the urine as glucuronic and sulphuric acid conjugates and 6% appears in the faeces after undergoing enterohepatic circulation. Urinary medicinal products include androsterone and etiocholanolone. Following intramuscular administration of this depot formulation the release rate is characterised by a half life of 90±40 days.

Linearity

Dose-linearity has been demonstrated for 20-240 mg/day.

Transdermal use

Testosterone transdermal gel dries very quickly when applied to the skin surface. The skin acts as a reservoir for the sustained release of testosterone into the systemic circulation.

With once daily application of 50mg or 100mg to adult males with early morning serum testosterone levels ≤300 ng/dL, follow up measurements at 30, 60 and 90 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the normal range.

Following 50 mg daily in hypogonadal men, the C_avg was shown to be 365±187 ng/dL (12.7±6.5 nmol/L), C_max was 538±371 ng/dL (18.7±12.9 nmol/L) and C_min was 223±126 ng/dl (7.7±4.4 nmol/L), measured at steady-state. The corresponding concentrations following 100 mg daily were C_avg = 612±286 ng/dL (21.3±9.9 nmol/L), C_max = 897±566 ng/dL (31.1±19.6 nmol/L) and C_min = 394±189 ng/dL (13.7±6.6 nmol/L). Steady state is reached by day 7. Steady state may be reached at an earlier time-point although the timing for this was not determined from the clinical studies.

In the young eugonadal man, normal levels of serum testosterone are in the range of 300-1000 ng/dL (10.4–34.6 nmol/L).

The measurement of serum testosterone levels can be variable depending on the laboratory and method of assay used.

Special Patient groups

In patients treated with testosterone transdermal gel no differences in the average daily serum testosterone concentration at steady state were observed based on age or cause of hypogonadism.

Preclinical data with androgens in general reveal no special hazards for humans. Experimental data in rodents have shown testosterone can promote the development of certain tumours in hormone responsive tissues. In reproductive studies the use of androgens in different species has been demonstrated to result in virilisation of the external genitals of female fetuses.

Testosterone has been found to be non-mutagenic in vitro using the reverse mutation model (Ames test) or hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on laboratory animals. Experimental data in rats have shown increased incidences of prostate cancer after treatment with testosterone.

Sex hormones are known to facilitate the development of certain tumours induced by known carcinogenic agents. The clinical relevance of the latter observation is not known.