Androgen metabolism Kieran Jefferson

Testosterone SMOOTH ENDOPLASMIC RETICULUM Cholesterol Pregnenolone Testosterone Progesterone 17  -OH- Progesterone Androstenedione cAMP ATP Cholesterylesters LH Cholesterol P450scc Pregnenolone MITOCHONDRIA Testosterone synthesis 17  -OH- Pregnenolone DHEA Androst -enediol 3β-HSD 17α-OH-lase 17,20 lyase 17β-HSD

Testosterone O OH Each day, 5-7mg testosterone are produced by the Leydig cells of an adult man 1

Hypothalamus (Activin) GnRH FSH Oestradiol Testosterone Inhibin B LH Leydig cells Sertoli cells Interstitial cells ENDOCRINE Seminiferous tubules EXOCRINE

T firmly bound to SHBG 60% BIOAVAILABLE TESTOSTERONE = Albumin-bound T + Free T Free T T loosely bound to albumin 2%38% Testosterone binding (T)

Sexual differentiation Musculature Bone mass Erythropoiesis Psychotropic action Potency/libido Lipid metabolism Bone mass Epiphyseal closure Psychotropic action Lipid metabolism Feedback action Prostate Sexual differentiation Secondary hair Sebum production Prostate Testosterone DihydrotestosteroneOestradiol Aromatase 5Ω - Reductase

LHFSH GnRH Hypothalamus Pituitary Testis SECONDARY HYPOGONADISM Secondary testicular failure Hypogonadotrophic hypogonadism PRIMARY HYPOGONADISM Primary testicular failure Hypergonadotrophic hypogonadism Hypogonadism

Circadian Rhythm

1940 Testosterone implant 1954 Short-acting injectable 1977 Oral testosterone 1992 Testosterone patch Testosterone gel 2004 Buccal testosterone tablet 2004 Long-acting injectable

Oral testosterone (Restandol;Andriol/Testocaps) Tablets containing 40mg testosterone undecanoate taken 2-3 times a day Route of absorption via lymphatic system –Needs to taken with a meal containing fat –Without dietary fat, absorption is minimal and pharmacokinetics unreliable

Buccal testosterone (Striant) 30mg tablet placed above incisor tooth bd Avoids first pass hepatic inactivation –Absorbed across oral mucosa Good pharmacokinetics, achieving normal testosterone levels May be difficulties with site reactions, etc.

Subdermal (Testosterone implants) Pellets ( mg) implanted subdermally –3 to 6 pellets (600mg to 1.2g) maintain plasma testosterone concentrations for 4-6 months 1 Risk of supraphysiological levels Minor surgical procedure –Pain/infection/extrusion (10%)/scarring –A new insertion site is used each time

Transdermal patches (e.g. Andropatch) mg testosterone starting dose Daily circadian profile of testosterone delivery Alcohol base to enhance permeation Skin reactions common (>50% patients) Size of patch and noise can be obtrusive

Transdermal gels (Testogel; Testim) mg gel applied each morning to shoulders, back, or abdomen Daily circadian profile of testosterone delivery Skin reactions in 4-10% patients Avoid washing for 6 hours Risk of transfer to another person via skin contact

Intramuscular injections - short acting (Sustanon 100; Sustanon 250; Testoviron) Most widely used form of testosterone Two short-acting preparations available –Sustanon 100 (fortnightly) & Sustanon 250 (3-weekly) Injection site reactions/patient discomfort Reaction to excipients (nut allergy )

Intramuscular injections - long acting (Nebido) 1000 mg testosterone undecanoate in 4 ml castor oil Loading dose (6 weeks) then every weeks Testosterone levels maintained in physiological range –Avoids frequent peaks and troughs from short-acting injections Increased patient convenience (quarterly injections) Injection site reactions/patient discomfort

Summary Several testosterone preparations available Differ by route of application Patient choice and satisfaction important Patients should be sufficiently informed to enable them to make a decision