See Fig. 53.1 for testosterone biosynthesis. Cholesterol StAR 17 HSD 17, 20 lyase Pregnenolone 17OH pregnenolone Dehydroepiandrosterone 17 HSD 3 HSD Aromatase Testosterone Estradiol Progesterone 17OH progesterone Androstenedione 21 OH 11 Deoxycortisol Deoxy- corticosterone 11 OH Corticosterone Cortisol 18-OH corticosterone Aldosterone Fig. 53.1 Testosterone biosynthesis pathway. 53-Draznin-Chap53.indd 280 3/31/2011 3:00:08 PM REGULATION OF TESTICULAR FUNCTION 281 Regulation of testicular function Regulation of androgen production Hypothalamic hormones G onadotropin-releasing hormone (GnRH) is secreted by thehypothalamus in a pulsatile manner i n response to sex hormones and gonadal peptides, neurotransmitters, and neuropeptides (kiss peptin, leptin, etc.). Episodic GnRH secretion is present at birth, is inhibited across midchild- hood, and then i s augmented initially during sleep in early puberty and then throughout the day in adulthoo d. It stimulates the secretion of lutein- izing hormone (LH) and follicle-stimulating hormo ne (FSH) by the pituitary gland. The pattern of GnRH secretion is crucial for normal gonadotropin secretion. Faster pulse fr equencies are essential for LH secretion, whereas slower frequencies favor FSH secretion. C ontinuous administration of GnRH abolishes both LH and FSH secretion. Pituitary hormones LH binds to Leydig cell receptors and stimulates the synthesis and secre - tion of testosterone. FSH binds to Sertoli cell receptors and stimulates the production of seminiferous tubule \202 uid as well as a number of substances thought to be important for spermatogenesis. Their secretion is regulated by GnRH pulses and through negative feed- back from testicular hormones and peptides. Testis Testosterone is the main androgen produced by the Leydig cells of the testis. Small amounts of androstenedione, DHEA, and dihydrotestoster- one (DHT) are also produced. Testos terone has a circadian rhythm with maximum secretion at around 8 A.M. and minimum at around 9 P.M. Small amounts of estradiol are also produced in the testis by the con- version from testost erone. Additionally, most of the circulating estradiol in men occurs as a result of aromati zation of androgens in adipose tissue. FSH, in the presence of adequate testosterone levels , stimulates the secretion of inhibin B by Sertoli cells. This in turn acts as a potent inh ibitor of FSH secretion. The secretion of pituitary gonadotropins is tightly regulated by testicu- lar function. LH secretion is inhibited by testosterone and its metabolites whereas, FSH secretion is contro lled by both inhibin B and testosterone. High concentrations of testosterone or of inhibin B results in a negative feedback inhibition of FSH secretion ( b see Fig. 53.2 ). Testicular function is also under paracrine control. Inhibin and insulin- like growth facto r-1 (IGF-1) act with LH to enhance testosterone produc- tion, whereas cytokines inhibit Ley dig cell function. 53-Draznin-Chap53.indd 281 3/31/2011 3:00:08 PM CHAPTER 53 Testicular physiology 282 Regulation of spermatogenesis b See Fig. 53.2. Both FSH and LH are required for the initiation of spermatogenesisat puberty. LH, by stimul ating Leydig cell activity, plays an important part in the early phases of sperm production , when high intratesticular concentra- tions of testosterone are essential. FSH, through it s action on the Sertoli cells, is vital for sperm maturation. The whole process of spermatogenesis takes approximately 74 days, fol- lowed by another 12 \200\22321 days for sperm transportation through theepididymis. This means that events that may affect spermatogenesis may not be appar- ent for up to 3 months. Hypothalamus GnRH +ve \210\222ve Pituitary gland +ve LH FSH Inhibin \210\222ve +ve Testosterone Sertoli cells Leydig cells +ve Spermatozoa Fig. 53.2 Regulation of spermatogenesis. 53-Draznin-Chap53.indd 282 3/31/2011 3:00:08 PM PHYSIOLOGY 283 Physiology Testosterone transportation From 2 to 4% of circulating testosterone is free and therefore biologically active. The rest is bound to proteins, particularly albumin and sex hor- mone binding globulin (SHBG). Testosterone metabolism Testosterone is converted in target tissues to the more potent andr ogen DHT in the presence of the enzyme 5A reductase. There are multiple 5A-reductase isoenz ymes; type 2 is the isoenzyme responsible for DHT synthesis in the genitalia, genital skin, and hair follicles. It is therefore essential for normal male virilization and sexual deve lopment. Both testosterone and DHT exert their activity by binding to androgen receptors, the latter more avidly than testosterone. The androgen receptor is encoded by a gene found on the lon g arm of the X chromosome (Xq). Testosterone may alternatively be converted into estradiol through the action of the aromat ase enzyme, found in greatest quantities in the testes and adipose tissue. Testosterone and its metabolites are inactivated in the liver and excreted in the urine. Androgen action \200 Male sexual differentiation during embryogenesis \200 Development and maintenance of male secondary sex characteristics after puberty Normal male sexual function and behavior \200 Spermatogenesis \200 Regulation of gonado tropin secretion Estrogen metabolism in males \200 Estradiol daily production rate in men: 35 \200\22345 m cg \200 Source of circulating estradiol: \200 Peripheral aromatization of testosterone (60%) \200 Testes (20%) \200 Peripheral conversion from estrone (20%) \200 2 \200\223 3% free estradiol that is biologically active; the rest is bound to SHBG Estrogen action in males \200 Pubertal growth and fusion of the epiphyses \200 Maintena nce of bone density \200 Regulation of gonadotropin secretion . Further reading De Ronde W, Pols HAP, Van Leeuwen JPTM, et al. (2003). The importance of oe strogens in males. Clin Endocrinol 58(5):529 \200\223542. 53-Draznin-Chap53.indd 283 3/31/2011 3:00:08 PM CHAPTER 54 Male hypogonadism 284 Male hypogonadism De \201 nition Male hypogonadism is the failure of testes to produce adequate amounts of t estosterone, spermatozoa, or both. Epidemiology Klinefelter \200\231s syndrome (XXY) ( b see p. 289 \200\223290) is the most c ommon congenital cause and is thought to occur with an incidence of 1:500 live births. Acquired hypogonadism is even more common, affecting 1:200 men. Evaluation of male hypogonadism Presentation \200 Failure to progress through puberty \200 Sexual dysfunction \200 In fertility \200 Nonspeci \201 c symptoms, e.g., lethargy, reduced libido, mood changes, weight gain The clinical presentation depends on the following: \200 Age of onset (congenital vs. acq uired) \200 Severity (complete vs. partial) \200 Duration (functional vs. permanent) 54-Draznin-Chap54.indd 284 4/1/2011 6:11:20 PM SECONDARY HYPOGONADISM 285 Secondary hypogonadism (hypogonadotropic hypogonadism) De \201 nition This is hypogonadism as a result of hypothalamic or pituitary dysfunction. Diagnosis \200 Low serum testosterone \200 Low \200\223normal or low LH and FSH (normal inhibin B and anti-M llerian hormone) Causes b See Box 54.1. Idiopathic hypogonadotropic hypogonadism (IHH) \200 The congenital form is indistinguishable from Kallmann syndrome apart from the absence of anosmia. >90% o f patients are men. \200 GnRH receptor gene mutation is an uncommon cause of IHH. Box 54.1 Causes of secondary hypogonadism Idiopathic \200 Kallmann syndrome. \200 Other genetic causes, e.g., mutations of GnRH-R or GPR54 genes \200 Idiopathic hypogonadotropic hypogonadism (IHH) \200 Fertile eunuch syndrome \200 Congenital adrenal hypoplasia (DAX-1 gene mutation) Functional \200 Exercise \200 Weight changes \200 Anabolic steroids \200 Stress \200\224physical or psychological \200 Systemic illness \200 Medication and recreationa l drugs Structural \200 Tumors, e.g., pituitary adenoma, craniopharyngioma, germinoma \200 In \201 ltrative disorders, e.g., sarcoidosis, hemochromatosis \200 Head trauma \200 Radio therapy \200 Surgery to the pituitary gland or hypothalamus Miscellaneous \200 Hemochromatosis \200 Prader \200\223Willi syndrome \200 Laurence \200\223Moon \200\223Biedl syndrome 54-Draznin-Chap54.indd 285 4/1/2011 6:11:20 PM CHAPTER 54 Male hypogonadism 286 Men with acquired IHH may go through normal puberty and have normal testicular size, but present with infertility or poor libido and potency. It may be temporary, with normalization of gonadal function after stopping GnRH or testosterone thera py. Fertile eunuch syndrome \200 Incomplete GnRH de \201 ciency. Enough to maintain normal s permatogenesis and testicular growth but insuf \201 cient for adequate virilization May require testosterone/hCG for fertility Congenital adrenal hypoplasia (CAH) \200 Rare X-linked or autosomal recessive disease cau sed by mutation of the DAX gene, located on the X chromosome \200 Presents with primary adrenal failure in i nfancy \200 Hypothalamic hypogonadism is also present. Structural \200 Usually associated with other pituitary hormonal de \201 ciencies \200 In children, craniopharyngiomas are the most common cause. Cranial irradiation for leukemi a or brain tumors may also result in secondary hypogonadism. The most common lesions in adulthood are prolactinomas. Kallmann syndrome This genetic disorder is characterized by failure of episodic GnRH secre- tion anosmia. It results from failure of the proper migration of GnRH- producing neuron s into the hypothalamus. Epidemiology \200 Incidence of 1 in 10,000 men \200 4:5 ratio = 4:1. Diagnosis \200 Anosmia in 75% \200 i Risk of cleft lip and palate, sensorineural deafne ss, cerebellar ataxia, and renal agenesis Low testosterone, LH, and FSH levels \200 Rest of pituitary function is normal \200 Nor mal MRI pituitary gland and hypothalamus; absent olfactory bulbs may be seen on MRI Normalization of pituitary and gonadal function in response to physiological GnRH replacement Genetics \200 Most commonly a result of an isolated gene mutation \200 May be inherited in an X-linked (KAL1) , autosomal dominant FGFR1 mutation/ KAL2 , or recessive trait KAL1 gene mutation responsible for some cases of X-linked Kallmann syndrome is located on X p22.3. It has a more severe reproductive phenotype. 54-Draznin-Chap54.indd 286 4/1/2011 6:11:20 PM SECONDARY HYPOGONADISM 287 Mutations of FGFR1 ( \201 broblast growth factor receptor 1) gene, located on chromosome 8 p11, is associated with the autosomal dominant form of Kallmann syndrome. Affected men have an i likelihood of undescended testes at birth. 12 \200\22315% incidence of delayed puberty in families of subjects with Kallmann syndrome compared with 1% general population \200 Men with autosomal dominant fo rm ( FGFR1 mutation): 50% transmitted to offspring. Management \200 Androgen replacement therapy \200 When fertility is desired, testostero ne is stopped and exogenous gonadotropins are administered ( b see p. 294). Systemic illness Severe illness of any kind may cause hypogonadotropic hypogonadism ( b see Box 54.2 ). Obstructive sleep apnea may present with low normal testosterone lev- els and erectile dysfunction together with metabolic syndrome. Drugs Anabolic steroids, cocaine, and narcotic drugs may all result in secondary hypogonadi sm. All drugs causing hyperprolactinemia ( b see Box 16.1, p. 105) will also cause hypogonadism. Prader \200\223Willi syndrome This is a congenital syndrome affecting 1:25000 births caused by loss of an imprinted gene on paternally derived chromosome 15q11 \200\22313. It should be suspected in infancy in the presence of characteristic facial features (almond eyes, down-turned mouth, strabismus, thin upper lip), severe hypotonia, poor feeding, and developmental delay. The child then develops hyperphagia due to hypothalamic dysfunction, r esulting Box 54.2 Systemic illness resulting in hypogonadism \200 Any acute illness (e.g., myocard ial infarction, sepsis, head injury) \200 Severe stress \200 Hemochromatosis \200 End ocrine disease (Cushing \200\231s syndrome, hyperprolactinemia) \200 Liver cirrhosis \200 Chronic renal failure \200 Chronic anemia (thalassemia major, sickle cell disease) \200 GI disease (celiac disease, Crohn \200\231s disease) \200 AIDS \200 Rheumatologi cal disease (rheumatoid arthritis) \200 Respiratory disease (e.g., chronic obstructive ai rways disease, cystic \201 brosis) Cardiac disease (e.g., congestive cardiac failure) 54-Draznin-Chap54.indd 287 4/1/2011 6:11:20 PM CHAPTER 54 Male hypogonadism 288 in severe obesity. Other characteristic features include short stature, hypogonadotropic hy pogonadism, and learning disability. Diabetes mellitus type II occurs in 15 \200\22340% of adults. Laurence \200\223Moon \200\223Biedl syndrome This congenital syndrome is characterized by s evere obesity, gonadotropin de \201 ciency, retinal dystrophy, polydactyly, and learning d isability. 54-Draznin-Chap54.indd 288 4/1/2011 6:11:20 PM PRIMARY HYPOGONADISM 289 Primary hypogonadism (hypergonadotropic hypogonadism) This condition is due to testicular f ailure with normal hypothalamus and pituitary function. Diagnosis \200 Low serum testosterone \200 Elevated LH and FSH (low inhibin B and anti- M llerian hormone) Causes Genetic: Klinefelter \200\231s syndrome This is the most common congenital form of primary hypogonadism. It is thought that a signi \201 cant number of men with Klinefelter \200\231 s syn- drome are not diagnosed. Clinical manifestations will depend on the age of diagnosis . Patients with mosaicism tend to have less severe clinical features. Adolescence \200 Small \201 rm testes (mean 5 mL) \200 Gynecomastia \200 Tall statu re (i leg length) \200 Other features of hypogonadism \200 Cognitive dysfunction Adulthood \200 Reduced libido and erectile dysfunction \200 Gynecomastia \200 Reduced facial hair \200 Obesity \200 Infertility Risks \200 Type 2 diabetes mellitus \200 Osteoporosis \200 Thromboembolism \200 Mal ignancies e.g., extragonadal germ cell tumors Diagnosis \200 Karyotyping: 47,XXY in 80%; higher-grade chromosomal aneuploidies (e.g., 48,XXXY) or 46,XY/47,XXY mosaicism in the remainder Low testosterone, elevated FSH and LH \200 Elevated SHBG and estradiol \200 Azoospermia Management \200 Lifelong androgen replacement \200 May need surgical reduction of gynec omastia 54-Draznin-Chap54.indd 289 4/1/2011 6:11:20 PM CHAPTER 54 Male hypogonadism 290 Fertility: Intracytoplasmic sperm injection (ICSI, b see Chapter 59, Infertility, pp. 316 \200\223331) using testicular spermatozoa from men with Klinefelte r \200\231s syndrome has resulted in successful pregnancies. However, couples should be cou nseled about the i risk of chromosomal abnormalities in offspring. Genetic: Other chromosomal disorders XX males \200 Due to an X to Y translocation with only a part of the Y present in one of the X chromosomes \200 Incidence is 1:10,000 births \200 Similar clinical and bi ochemical features to Klinefelter \200\231s syndrome. In addition, short stature and hypospadias may be present. XX/X0 (mixed gonadal dysgenesis) \200 Occasionally, phenotypically men with hypospadias a nd intra- abdominal dysgenetic gonads Bilateral gonadectomy is essential because of the risk of neoplasia, followed by androgen replacement therapy. XYY syndrome \200 Taller than average, but often have primary gonadal failure with impaired spermatogenesis Y chromosome microdeletions: \200 Causes oligo- and azoospermia. Testosterone levels are not usually affected. Noonan \200\231s syndrome \200 Autosomal dominant disorder with an incidence of 1:1000 to 1:2500 live births 46,XY karyotype and secondary external genitalia. However, several stigmata of Turner \200 \231s syndrome (short stature, webbed neck, ptosis, low-set ears, lymphedema) and i risk ca rdiac anomalies (valvular pulmonary stenosis and hypertrophic cardiomyopathy). Most have cr yptorchidism and primary testicular failure. Cryptorchidism \200 10% of secondary neonates have undescended testes, but most of these will descend into the scrotum eventually, so that the incidence of postpubertal crypt orchidism is < 0.5%. \200 15% of cases have bilateral cryptorchidism. Consequences \200 75% of males with bilateral cryptorchidism are infertile. \200 10% ri sk of testicular malignancy, highest risk in those with intra- abdominal testes Low testosterone and raised gonadotropins in bilateral cryptorchidism 54-Draznin-Chap54.indd 290 4/1/2011 6:11:20 PM PRIMARY HYPOGONADISM 291 Treatment \200 Orchidopexy : best performed before 18 months, certainly before age 5 years, to reduce risk of later infertility Gonadectomy : in patients with intra-abdominal testes, followed by androgen replacement. Orchitis \200 25% of males who develop mumps after puberty have associated orchitis and 25 \200\22350% of these will develop primary testicular failure. HIV infection may also be associated with orchitis. \200 Primary testicular failure may o ccur as part of an autoimmune disease. Chemotherapy and radiotherapy Cytotoxic drugs, particularly alkylating agents, are gonadoto xic. Infertility occurs in 50% of patients following chemotherapy for most malignancies, an d a signi \201 cant number of males require androgen replacement therapy because of low te stosterone levels. The testes are radiosensitive, so hypogonadism can occur from scattered radiation during th e treatment of Hodgkin \200\231s disease, for example. If fertility is desired, sperm should be cryopreserved prior to cancer therapy. Other drugs Sulfasalazine, colchicine, and high-dose glucocorticoids may reversibly affect testicular function. Alcohol excess will also cause primary testicular failure. Chronic illness Any chronic illness may affect testicular function, in particular chronic r enal failure, liver cirrhosis, and hemochromatosis. Testicular trauma Testicular torsion is another common cause of loss of a testis, and it ma y also affect the function of the remaining testis. 54-Draznin-Chap54.indd 291 4/1/2011 6:11:20 PM CHAPTER 54 Male hypogonadism 292 Box 54.3 Testicular dysfunction \200\224clinical characteristics of male hypogonadism Testicular failure occurring before onset of puberty \200 Testicular volume <5 mL \200 Penis <5 cm long \200 Lack of scrotal pigmentation and rugae \200 Gynecomastia \200 H igh-pitched voice \200 Central fat distribution \200 Eunuchoidism \200 Arm span 1 cm greater than height \200 Lower segment > upper segment \200 Delayed bone age \200 No male escutcheon \200 d Body and facial hair Testicular failure occurring after puberty \200 Testes soft, volume <15 mL. \200 Normal penile length \200 Normal skeletal proportions \200 Gynecomastia \200 Normal male ha ir distribution but reduced amount \200 Pale skin, \201 ne wrinkles \200 Central fat distribution \200 Osteoporosis \200 Anemia (mild) 54-Draznin-Chap54.indd 292 4/1/2011 6:11:20 PM CLINICAL ASSESSMENT 293 Clinical assessment History \200 Developmental history: congenital urinary tract abnormalities, e.g., hypospa dias, late testicular descent, or cryptorchidism Delayed or incomplete puberty \200 Infections, e.g., mumps, orchitis \200 Abdominal or genital trauma \200 Testicular torsion \200 Anosmia \200 Drug history : e.g., sulfasa lazine, antihypertensives, chemotherapy, cimetidine, radiotherapy; alcohol and recreational drugs also important General medical history: chronic illness, particularly respiratory, neurological, and cardiac Gynecomastia : common ( b see Chapter 56, Gynecomastia, pp. 301) during adolescence. If rec ent-onset gynecomastia in adulthood, must rule out estrogen-producing tumor Family history : Young syndrome ( b p. 321), cystic \201 brosis, Kallmann \200\231s syndrome Sexual history : erectile function, frequency of intercourse, sexual techniques. Absence of morning erections suggests an organic cause of erectile dysfunction. Physical examination \200 Body hair distribution \200 Muscle mass and fat distribution \200 Eunuchoidism \200 Gynecomastia Genital examination \200 Pubic hair normal male escutcheon \200 Phallus normal >5 cm le ngth and >3 cm width \200 Testes size (using Prader orchiometer) and consistency (normal >15 m and \201 rm) Look for nodules or areas of tenderness. \200 Look for evidence of systemic disease. \200 Assess sense of smell and visual \201 elds Re \202 exes \200 Peripheral pulses \200 Rectal examination Hormonal evaluation of testicular function Serum testosterone There is diurnal variation in circulating testosterone, with peak levels occurring in the early morning. A 30% variation occurs between the high- est and lowest testosterone levels, so morning plasma testosteron e is use- ful. If the level is low, this should be repeated. 54-Draznin-Chap54.indd 293 4/1/2011 6:11:20 PM CHAPTER 54 Male hypogonadism 294 Sex hormone binding globulin (SHBG) Only 2 \200\2234% of circulating testosterone is unboun d; 50% is bound to SHBG and the rest to albumin. Concentrations of SHBG should be taken into account when interpret- ing a serum testosteron e result. SHBG levels may be affected by a variety of conditions ( b see Table 54.1). Gonad otropins Raised FSH and LH levels occur in primary testicular failure and are inappropriate ly low in pituitary or hypothalamic hypogonadism. One should always exclude hyperprolactine mia in secondary hypogonadism. Estradiol Estradiol results from the conversion of testosterone and androstenedione by arom atase. b See Table 54.2 for causes of elevated estradiol. Request serum estradiol level if gynecomastia is present or a testicular tumor is suspected. Table 54.1 Factors affecting SHBG concentrations Raised SHBG Low SHBG Androgen de \201 ciency GH de \201 ciency Hyperinsulinemia Obesity Aging Acromegaly Thyrotoxicosis Androgen treatment Estrogens HypothyroidismLiver Liver cirrhosis Cushing \200\231s syndrome/glucocorticoid therapy Nephrotic syndrome Table 54.2 Causes of raised estogens in men Neoplasia \200 Testicular \200 Adrenal \200 Hepatoma Primary testicular failure Liver disease Thyrotoxicosis Obesity Androgen resistance syndromes Antiandrogen therapy 54-Draznin-Chap54.indd 294 4/1/2011 6:11:21 PM CLINICAL ASSESSMENT 295 Inhibin B and AMH Gonadal glycoproteins secrete into the circulation. These are useful mark - ers of normal testicular functions. They are low if there is primary testicu- lar failure and normal with pituitary or hypothalamic dysfunction. Other investigations \200 Scrotal US (testicular volume/blood \202 ow with Doppler/pres ence of hydrocele, etc.) Semen analysis (A normal semen analysis is indicative of gonadal health. Men with low sperm count should consider sperm cryopreservation to preserve fertili ty.) Dynamic tests These are of limited clinical value and are rarely performed routinely. hCG stimulation test \200 Diagnostic test for examining Leydig cell function \200 hCG 2 000 IU IM given on days 0 and 2; testosterone measured on days 0, 2, and 4 In prepubertal boys with absent scrotal testes, a response to hCG indicates intra-abdominal testes. Failure of testosterone to rise after hCG suggests absenc e of functioning testicular tissue. An exaggerated response to hCG is seen in secondary hyp ogonadism. Clomifene stimulation test \200 Used to assess integrity of the hypothalamic \200\223pitu itary testicular axis \200 Normal response to 3 mg/kg (max 200mg) clomifene daily for 7 d ays is a 2-fold increase in LH and FSH measured on days 0, 4, 7, and 10. A subnormal response indicates hypothalamic or pituitary hypogonadism but does not differen tiate between the two. Further reading AACE Hypogonadism Task Force. (2002). American Association of Clinical Endo crinologists Medical Guidelines for clinical practice for the evaluation and treatment of h ypogonadism in adult male patients \200\2232002 update. Endocr Pract 8(6):439 \200\223456. Lanfranco F, Kamischke A, Zitzmann M, et al. (2004). Klinefelter \200\231s syndrome. Lancet 364:273 \200\223283. AQ: We couldn \200\231t locate this content in the text. Please advise. 54-Draznin-Chap54.indd 295 4/1/2011 6:11:21 PM CHAPTER 55 Androgen therapy 296 Androgen therapy Treatment goals \200 I mprove libido and sexual function Testosterone therapy will induce virilization in the hypogonadal males and restores libido and erectile function. \200 Im prove mood and well-being Most studies show an improvement in mood, well-being, and QoL fol low- ing physiologic testosterone therapy. \200 Improve muscle mass and strength Testoste rone has direct anabolic effects on skeletal muscle and has been shown to increase muscle m ass and strength when given to hypogonadal men. Lean body mass is also i with a reduction i n fat mass. \200 Prevent osteoporosis Hypogonadism is a risk factor for osteoporosis. Tes tosterone inhibits bone resorption, thereby reducing bone turnover. Its administration to h ypogonadal men has been shown to improve bone mineral density and reduce risk of developing osteoporosis. Few fracture data are available. \200 Fertility Fertility is inhibited by testosterone therapy. Men with secondary hypo- gonadism who desire fertility may be treated with gonadotropins to ini- tiate and maintain spermatogenesis (b see p. 296). Prior testos terone therapy will not affect fertility prospects but should be stopped before initiating gonadotropin treatment. Men with primary hypogonadism will not respond to gonadotropin or GnRH therapy. 55-Draznin-Chap55.indd 296 3/31/2011 3:15:29 PM INDICATIONS FOR TREATMENT 297 Indications for treatment \200 Men with established primary or secondary hypogonadism of any cause \200 b See Box 55.1 for contraindications. Pretreatment evaluation Clinical evaluation History or symptoms of the following: \200 Prostatic hypertrophy \200 Breast or prostate cancer \200 Cardiovascular disease \200 Sleep apnea Examination \200 Rectal examination of prostate \200 Breasts Laboratory evaluation \200 Prostatic speci \201 c antigen (PSA) (PSA is often low in hyp ogonadal men, rising to normal age-matched levels with androgen replacement) Hemoglobin and hematocrit \200 Serum lipids Box 55.1 Contraindications to androgen replacement therapy Absolute \200 Prostate cancer \200 Breast cancer Relative \200 Benign prostate hyperplasia \200 Polycythemia \200 Sleep apnea Box 55.2 Monitoring of therapy Monitor 3 months after initiating therapy and then every 6 \200\22312 months: \200 Clinic al evaluation \200\224relief of symptoms of androgen de \201 ciency and exclude side effects \200 Serum testosterone \200 Rectal examination of the prostate (i f >45 years) \200 PSA (if >45 years) \200 Hemoglobin and hematocrit \200 Serum lipids 55-Draznin-Chap55.indd 297 3/31/2011 3:15:30 PM CHAPTER 55 Androgen therapy 298 Risks and side effects Prostatic disease Androgens stimulate prostatic growth, and testosterone replacement therap y may therefore induce symptoms of bladder out \202 ow obstruction in men with prostatic h ypertrophy. It is unlikely that testosterone increases the risk of developing prostate cancer, but it may promote the growth of an existing cancer. Polycythemia Testosterone stimulates erythropoiesis. Androgen replacement therapy may incre ase hemoglobin levels, particularly in older men. It may be neces- sary to reduce the dose of testosterone in men with clinically signi \201 cant polycythemia. Cardiovascular disease Testosterone replacement therapy may cause a fall in both LDL and HD L cholesterol levels, the signi \201 cance of which remains unclear. The effect of androge n replacement therapy on the risk of developing coronary heart disease is unknown. Other (see Table 55.1) \200 Acne \200 Gynecomastia is occasionally enhanced by testoste rone therapy, particularly in peripubertal boys. This is the result of the conversion of testosterone to estrogens. Fluid retention may result in worsening symptoms in those with underlying congestive cardiac failure or hepatic cirrhosis. Obstructive sleep apnea may be exacerbated by testosterone therapy. \200 Hepatotoxicity m ay be induced by oral androgens, particularly the 17A alkylated testosterones. Mood swings 55-Draznin-Chap55.indd 298 3/31/2011 3:15:30 PM 5 5 D r a z n i n C h a p 5 5 . i n d d 2 Table 55.1 Testosterone preparations 9 9 Preparation Dose Advantage Problems 2- to 3-week dosage Effective and cheap Painful IM injection Contraindicated in bleeding disorders Wide variations in serum testost erone levels between injections that may be associated with symptoms. IM testosterone esters 250 mg every 2 \200\2233 weeks Monitor predose serum testosterone (should be above the lowe r limit of normal) \200\230Nebido \200\231 1 g q3 months (after loading dose) Convenience of infrequent injection Testosterone implants 100 \200\223600 mg every 3 \200\2236 months Monitor predose serum testosterone Physiological testosterone levels achieved. 3- to 6-month dosing Minor surgical procedure. Risk of infection and pellet extrusion (3 \200\22310%). Must remo ve pellet surgically if complications of androgen replacement therapy develop. Transdermal gel (1%) 5 \200\22310 g gel daily Physiological testosterone levels achieved. Convenience Skin reactions (rare). Possible person-to- person transfer through direct skin contact R Transdermal patch 2.5 \200\2237.5 mg daily Physiological testosterone levels acheived. Skin reactions are common. I S K S A N D Oral, e.g., testosterone undecanoate and mesterolone 40 mg tid 25 mg tid Oral preparations Highly variable ef \201 cacy and bioavailability. Rarely achieves therapeutic ef \201 cac y. Multiple daily dosing. 17A alkylated testosterones are not used because of risk of hepat otoxicity. S I D E E F F E C T S Physiological testosterone levels achieved Local discomfort. Gingivitis. Bitter taste Twice- daily dosing Buccal testosterone 30 mg bid 3 / 3 1 2 9 9 / 2 0 1 1 3 : 1 5 : 3 0 P M CHAPTER 55 Androgen therapy 300 Further reading Handelsman DJ, Zajac JD (2004). Androgen de \201 ciency and replacement th erapy in men. Med J Aust 180:529 \200\223535. Nieschlag E, Behre HM, Bouchard P, et al. (2004). Testosterone replacement therapy: current trends and future directions. Hum Reprod Update 10(5):409 \200\223419. Rhoden EL, Morgentaler A (2004). Risks of testosterone replacement therapy and recommenda- tions for monitoring. N Engl J Med 350:482 \200\223492. 55-Draznin-Chap55.indd 300 3/31/2011 3:15:30 PM DEFINITION 301 Gynecomastia De \201 nition Gynecomastia is enlargement of the male breast as a result of hyperplasia o f the glandular tissue to a diameter of >2 cm. b See Fig 56.1. This condition is common, present in up to 1/3 of males <30 years and in up to 50% of men >45 years. b See Box 56.1 for causes. Aromatase activity (converts testosterone to estrogen) LH/hCG Increased estrogen action on breast tissue and resultant gynecomastia Testosterone replacement SHBG (binds testosterone more than estrogen) Testosterone Estrogen Fig. 56.1 Hormonal in \202 uences on gynecomastia 56-Draznin-Chap56.indd 301 3/31/2011 3:16:12 PM CHAPTER 56 Gynecomastia 302 Box 56.1 Causes of gynecomastia Physiological \200 Neonatal \200 Puberty: 50% of boys develop transient gynecomastia \200 Idiopathic: 25% of all cases Drugs Possible mechanisms include estrogen-containing a gents, androgen receptor blockers, and inhibition of androgen production: \200 Estrogens, antiandrogens, testosterone \200 Spironolactone, ACE inhibitors, calcium antagonists, di goxin \200 Alkylating agents \200 Alcohol, marijuana, heroin, methadone \200 Cimetidi ne \200 Ketoconazole, metronidazole, antituberculous agents, tricyclic antidepressants, d opamine antagonists, opiates, benzodiazepines Antiretroviral drugs \200 Imatinib (chronic myeloid leukemia) Hypogonadism \200 Primary \200 Secondary Tumors \200 Estrogen or androgen-producing testicular or adrenal tumors \200 Human chorionic gonadotropin-producing tumors, usually testicular, e.g., germinoma; occasionally ectopic, e.g., lung \200 Aromatase-producing testicular or hepatic tumors Endocrine \200 Thyrotoxicosis \200 Cushing \200\231s syndrome \200 Acr omegaly \200 Androgen-insensitivity syndromes Systemic illness \200 Liver cirrhosis \200 Chronic renal failure \200 HIV infection \200 Malnutrition 56-Draznin-Chap56.indd 302 3/31/2011 3:16:13 PM EVALUATION 303 Evaluation History \200 Duration and progression of gynecomastia \200 Further investiga tion is warranted if there is the following: Rapidly enlarging gynecomastia \200 Recent-onset gynecomastia in a lean postpubertal male . \200 Painful gynecomastia Exclude underlying tumor, e.g., testicular cancer \200 Symptoms of hypogonadism: reduced libido, erectile dysfunction \200 Symptoms of systemic disease, e.g., hepatic, renal, end ocrine disease \200 Drug history, including recreational drugs, e.g., alcohol Physical examination Breasts \200 Pinch breast tissue between the thumb and fore \201 ng er \200\224distinguish it from fat. Measure glandular tissue diameter; gynecomastia if >2 cm \200 If diameter is >5 cm, hard, or irregular, investigate further to exclude breast cancer. Look for galactorrhea. Testicular palpation \200 Exclude tumor \200 Assess testicular size \200\224?atrophy Other \200 Secondary sex characteristics \200 Look for evidence of systemic disease, e. g., chronic liver or renal disease, thyrotoxicosis, Cushing \200\231s syndrome, or chronic cardiac or pulmonary disease. Investigations (see Fig. 56.2 ) Baseline investigations \200 Serum testosterone \200 Se rum estradiol \200 LH and FSH \200 Prolactin \200 SHBG \200 hCG \200 Liver functi on tests 56-Draznin-Chap56.indd 303 3/31/2011 3:16:13 PM CHAPTER 56 Gynecomastia 304 hCG, LH, testosterone, E2, TSH LH and testosterone LH , testosterone LH , testosterone hCG or E2 TSH Normal Testicular US Androgen resistance Prolactin Thyrotoxicosis Primary hypogonadism If normal Testicular tumor Secondary hypogonadism Prolactinoma Abdominal/ chest imaging Extragonadal E2 or hCG secreting tumor Fig. 56.2 Investigation of gynecomastia . Additional investigations \200 If testicular tumor is suspected, e.g., elevated estradiol /hCG: testicular US \200 If adrenal tumor is suspected, e.g., markedly raised estradiol: dehydroepiandrosterone sulfate (DHEAS); abdominal CT or MRI scan \200 If breast malignanc y is suspected: mammography; FNAC/tissue biopsy \200 If lung cancer is suspected, e.g., r aised hCG: chest radiograph \200 Other investigations depending on clinical suspicion, e. g., renal or thyroid function 56-Draznin-Chap56.indd 304 3/31/2011 3:16:13 PM MANAGEMENT 305 Management Treat underlying disorder when present. Withdraw offending drugs where possible. Reassurance is adequate treatment in the majority of idiopathic cases. The condition often resolves spontaneously. Treatment may be required for cosmetic reasons or to alleviate pain and tenderness. Drug treatment is only partially effective. It may be of bene \201 t in treating gynecomastia of recent onset. Medical b See Table 56.1. Surgical Reduction mammoplasty may be required in males with severe and per- sistent gyneco mastia. Table 56.1 Medical treatment of gynecomastia Tamoxifen (10 \200\22330 mg/day) Antiestrogenic effects. Particularly effective in reducing pain and swelling if used in gyn ecomastia of recent onset. A 3-month trial before referral for surgery may be of bene \201 t. Clomifene (50 \200\223100 mg/day) Antiestrogenic. May be effective in reducing breast size in pubertal gynecomastia Danazol (300 \200\223600 mg/day) Nonaromatizable androgen. May also reduce breast size in adults. Its use is limited by side effects, particularly weight gain and acne. Testolactone (450 mg/day) Aromatase inhibitor. May be effective in reducing pubertal gynecomastia. However, tamoxifen appears to be more effective and better tolerated. Anastrozole (1 mg/day) Another aromatase inhibitor. Clinical trials have failed to show a bene \201 cial effect o n gynecomastia compared with placebo. Further reading Khan HN, Blarney RW (2003). Endocrine treatment of physiological gynaecomas tia. BMJ 327:301 \200\223302. 56-Draznin-Chap56.indd 305 3/31/2011 3:16:13 PM CHAPTER 57 Erectile dysfunction 306 Erectile dysfunction De \201 nition Erectile dysfunction (ED) is the consistent inability to achieve or maintai n an erect penis suf \201 cient for satisfactory sexual intercourse. ED affects approximat ely 10% of men and >50% of men >70 years. Physiology of male sexual function The erectile response is the result of the coordinated i nteraction of nerves, smooth muscle of the corpora cavernosa, pelvic muscles, and blood ves sels. It is initiated by psychogenic stimuli from the brain or physi- cal stimulation of th e genitalia, which are modulated in the limbic system, transmitted down the spinal cord to the sympathetic and parasympathetic out \202 ows of the penile tissue. Penile erectile tissue consists of paired corpora cavernosa on the dor- sum of the penis an d the corpus spongiosum. These are surrounded by \201 brous tissue known as the tunica al buginea. In the \202 accid state, the corporeal smooth muscle is contracted, minimiz- ing corporeal blood \202 ow and enhancing venous drainage. Activation of the erectile pathway results in penile smooth muscle relaxation and cavernosa l arterial vasodilatation. As the corporeal sinuses \201 ll with blood, the draining venu les are compressed against the tunica albuginea so venous out \202 ow is impaired. This re sults in penile rigidity and an erection. Corporeal vasodilatation is mediated by parasympathetic neuronal acti- vation, which induce s nitric oxide release by the cavernosal nerves. This activates guanyl cyclase, thereby i c GMP, and causing smooth muscle relaxation. Detumescence occurs after the inactivation of cGMP by the enzyme in smooth muscle contracti on and phosphodiesterase, resulting vasoconstriction. Ejaculation is mediated by the sympathetic nervous system. 57-Draznin-Chap57.indd 306 3/31/2011 3:17:26 PM PATHOPHYSIOLOGY 307 Pathophysiology Erectile dysfunction may occur as a result of several mechanisms: \200 Ne urological damage \200 Arterial insuf \201 ciency \200 Venous incompetence \200 Andr ogen de \201 ciency \200 Penile abnormalities \200 Iatrogenic: medications or suppleme nts \200 Psychogenic 57-Draznin-Chap57.indd 307 3/31/2011 3:17:26 PM CHAPTER 57 Erectile dysfunction 308 Evaluation History Sexual history \200 Extent of the dysfunction, its duration, and progression \200 Prese nce of nocturnal or morning erections \200 Abrupt onset of erectile dysfunction that is i ntermittent is often psychogenic in origin. Progressive and persistent dysfunction indicates an organic cause. Symptoms of hypogonadism \200 Reduced libido, muscle strength, and sense of well-being. F ull medical history \200 E.g., diabetes mellitus, liver cirrhosis, or neurological, cardi ovascular, or endocrine disease