Steroidogenesis of the testis - new genes and pathways

Defects of androgen biosynthesis cause 46,XY disorder of sexual development (DSD). All steroids are produced from cholesterol and the early steps of steroidogenesis are common to mineralocorticoid, glucocorticoid and sex steroid production. Genetic mutations in enzymes and proteins supporting the early biosynthesis pathways cause adrenal insufficiency (AI), DSD and gonadal insufficiency. The classic androgen biosynthesis defects with AI are lipoid CAH, CYP11A1 and HSD3B2 deficiencies. Deficiency of CYP17A1 rarely causes AI, and HSD17B3 or SRD5A2 deficiencies only cause 46,XY DSD and gonadal insufficiency. All androgen biosynthesis depends on 17,20 lyase activity of CYP17A1 which is supported by P450 oxidoreductase (POR) and cytochrome b5 (CYB5). Therefore 46,XY DSD with apparent 17,20 lyase deficiency may be due to mutations in CYP17A1, POR or CYB5. Illustrated by patients harboring mutations in SRD5A2, normal development of the male external genitalia depends largely on dihydrotestosterone (DHT) which is converted from circulating testicular testosterone (T) through SRD5A2 in the genital skin. In the classic androgen biosynthetic pathway, T is produced from DHEA and androstenedione/-diol in the testis. However, recently found mutations in AKR1C2/4 genes in undervirilized 46,XY individuals have established a role for a novel, alternative, backdoor pathway for fetal testicular DHT synthesis. In this pathway, which has been first elucidated for the tammar wallaby pouch young, 17-hydroxyprogesterone is converted directly to DHT by 5α-3α reductive steps without going through the androgens of the classic pathway. Enzymes AKR1C2/4 catalyse the critical 3αHSD reductive reaction which feeds 17OH-DHP into the backdoor pathway. In conclusion, androgen production in the fetal testis seems to utilize two pathways but their exact interplay remains to be elucidated.

Urinary diversion in elderly patients

BACKGROUND Bladder cancer represents one of the ten most prevalent cancers worldwide. More than 400,000 people worldwide are newly diagnosed every year. Within 2 years after diagnosis, 80 % of patients with muscle invasive bladder cancer without treatment die. METHODS The aggressive local surgical approach with a cystectomy is the therapy of choice. The median age of patients with de novo bladder cancer is 70 years. Thus bladder cancer is a cancer of the elderly. For demographical reasons, the number of eldery patients undergoing radical cystectomy will rise in the next few years. The type of urinary diversion is a major factor influencing perioperative morbidity and quality of life in these patients. Incontinent urinary diversions are preferentially used in daily practice. CONCLUSIONS There are only a few contraindications for orthotopic neobladder; however, age alone is not a contraindication. Patient selection and a nerve sparing approach are crucial in men and women to achieve excellent functional results with orthotopic neobladder in elderly patients.