Snapshot A 31-year-old man presents to his primary care physician for the evaluation of infertility. He and his wife have been trying to become pregnant for over a year. His wife was extensively evaluated, which showed no reason on her end for their inability to conceive. Upon further questioning, the patient reports decreased spontaneous erections, breast discomfort, and a reduced need to shave. On physical examination, the patient has a eunuchoid body habitus, gynecomastia, and small testes. On laboratory testing, there is a elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with a low testosterone level. The patient is prescribed testosterone replacement therapy after testing his hematocrit and prostate-specific antigen (PSA) level. (Klinefelter syndrome) Introduction Mechanism of action testosterone has 3 modes of action (based on its structure or its derivatives) directly on androgen receptors as testosterone as dihydrotestosterone (DHT) after being converted by 5-α-reductase DHT has a higher avidity for androgen receptors than testosterone leads to development of external genitalia (e.g., hair and prostate) as estrogen after being converted by aromatase, acting on estrogen receptors Clinical use testosterone should only be administered in a man who is hypogonadal primary hypogonadism can be congenital (e.g., Klinefelter syndrome) can be acquired (e.g., orchitis caused by mumps and radiation) secondary hypogonadism can be congenital (e.g., congenital GnRH deficiency) can be acquired (e.g., hyperprolactinemia) low testosterone, low GnRH, low FSH/LH ratio initial diagnostic testing should also include TSH and prolactin levels further testing may include brain imaging and karotyping anabolic steroid abuse anabolic steroids are structural analogs of testosterone and have anabolic and androgenic effects anabolic effects increased protein synthesis increased muscle mass increased RBC production (i.e., elevated hematocrit) androgenic effects increased libido acne male pattern hair loss gynecomastia dyslipidemia irritability aggressive behavior chronic use leads to suppression of the hypothalamic-pituitary-gonadal axis, causing hypogonadotropic hypogonadism treatment involves cessation of the anabolic steroid may take several months for the hypothalamic-pituitary-gonadal axis to recover Adverse effects masculinization in females prostate disorders (e.g., benign prostatic hyperplasia) worsening of sleep apnea erythrocytosis testicular atrophy in males premature closure of epiphyseal plates in adolescents worsening of lipid profile ↑ LDL and ↓ HDL hepatic adenoma benign mass that can rupture cause of sudden hypotension in a weightlifter (presumably abusing steroids)