Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Endo Ventures Limited, First Floor, Minerva House, Simmonscourt Road, Ballsbridge, Dublin 4, IRELAND
Pharmacotherapeutic group: Androgens
ATC code: G03BA03
Testosterone and dihydrotestosterone (DHT), endogenous androgens, are responsible for the normal growth and development of the male sex organs and for the maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis and scrotum; the development of male hair distribution on the face, chest, axillae and pubis; laryngeal enlargement, vocal chord thickening, alterations in body musculature and fat distribution.
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.
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.
TESTIM 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 TESTIM 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 TESTIM daily in hypogonadal men, the Cavg was shown to be 365±187 ng/dL (12.7±6.5 nmol/L), Cmax was 538±371 ng/dL (18.7±12.9 nmol/L) and Cmin was 223±126 ng/dl (7.7± 4.4 nmol/L), measured at steady-state. The corresponding concentrations following 100 mg TESTIM daily were Cavg = 612±286 ng/dL (21.3±9.9 nmol/L), Cmax = 897±566 ng/dL (31.1±19.6 nmol/L) and Cmin = 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 (see section 4.2).
Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.
There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten to 100 minutes.
Testosterone is metabolised to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are oestradiol and dihydrotestosterone (DHT). Testosterone is metabolised to DHT by steroid 5α reductase located in the skin, liver and the urogenital tract of the male. DHT binds with greater affinity to SHBG than does testosterone. In many tissues, the activity of testosterone depends on its reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolised to 3-α and 3-β androstanediol.
Inactivation of testosterone occurs primarily in the liver.
DHT concentrations increased during TESTIM treatment. After 90 days of treatment, mean DHT concentrations remained within the normal range for TESTIM treated subjects.
About 90% of testosterone given intramuscularly is excreted in the urine as glucuronic and sulphuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the faeces, mostly in the unconjugated form.
In patients treated with TESTIM no differences in the average daily serum testosterone concentration at steady state were observed based on age or cause of hypogonadism.
Toxicological studies have not revealed effects other than those which can be explained based on the hormonal profile of TESTIM.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
