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 Intermittent claudication suggests a vascular cause. \200 A history of genitourinary trau ma or surgery is also important. \200 Recent change in bladder or bowel function may indi cate neurological cause. Psychological history Drug history \200 Onset of impotence in relation to commencing a new medication Social hi story \200 Stress \200 Relationship history \200 Smoking history \200 Recreational drugs, including alcohol Physical examination \200 Evidence of primary or secondary hypogonadism \200 Evidence o f endocrine disorders: Hyperprolactinemia, thyroid dysfunction, hypopituitarism. \200 Other complications of dia betes mellitus, if present Evidence of neurological disease Autonomic or peripheral neuropathy \200 Spinal cord lesions Evidence of systemic disease, e.g.: Chronic liver disease \200 Chronic cardiac disease \200 Peripheral vascular disease Genital examination \200 Assess testicular size \200\224?atrophy \200 Penile abnormalit ies, e.g., Peyronie \200\231s disease b See Box 57.1 for causes of erectile dysfunction. 57-Draznin-Chap57.indd 308 3/31/2011 3:17:26 PM EVALUATION 309 Box 57.1 Causes of erectile dysfunction Psychological (20%) \200 Stress, anxiety \200 Psychiatric illness Drugs (25%) \200 Al cohol \200 Antihypertensives, e.g., diuretics, B-blockers, methyldopa \200 Cimetidine \200 Marijuana, heroin, methadone \200 Major tranquilizers \200 Tricyclic antidepressa nts, benzodiazepines \200 Digoxin \200 Glucocorticoids, anabolic steroids \200 Estrog ens, antiandrogens Endocrine (20%) \200 Hypogonadism (primary or secondary) \200 Hyperprolactinemia \200 Diabetes mellitus (30 \200\22350% of men with DM >6 years) \200 Thyroid dysfunction \200 Obstructive sleep apnea Neurological \200 Spinal cord disorders \200 Peripheral and autonomic neuropathies \200 Multiple sclerosis Vascular \200 Peripheral vascular disease \200 Trauma \200 Diabetes mellitus \200 V enous incompetence Other \200 Hemochromatosis \200 Debilitating diseases \200 Penile abnormalities, e.g. , priapism, Peyronie \200\231s disease \200 Prostatectomy Investigation of erectile dysfunction Baseline investigations \200 Serum testosterone \200 Prolactin, LH, and FSH if serum te stosterone is low \200 Fasting blood glucose \200 Thyroid function tests 57-Draznin-Chap57.indd 309 3/31/2011 3:17:26 PM CHAPTER 57 Erectile dysfunction 310 Liver function tests \200 Renal function \200 Serum lipids \200 Serum ferritin (hemac hromatosis) Additional investigations Evaluate for obstructive sleep apnea This is rarely required. To assess vascular causes of impotence if correc- tive surgery is contemplated: \200 Intraca vernosal injection of a vasodilator, e.g., alprostadil E1 or papaverine. A sustained erecti on excludes signi \201 cant vascular insuf \201 ciency. Penile Doppler ultrasonography: Cavernous arterial \202 ow and venous insuf \201 ciency are assessed. 57-Draznin-Chap57.indd 310 3/31/2011 3:17:26 PM MANAGEMENT 311 Management Treat underlying disorder or withdraw offending drugs where possible. Androgens This should be \201 rst-line therapy in males with hypogonadism ( b see p. 296) . Hyperprolactinemia, when present, should be treated with dopamine ago- nists and the unde rlying cause of hypogonadism treated. Phosphodiesterase (PDE) inhibitors b See Table 57.1 and Box 57.2. These act by enhancing cGMP activity in erectile tissue by blocking the enzyme PDE-5, there by amplifying the vasodilatory action of nitric oxide and thus the normal erectile response to sexual stimulation. Trials indicate a 50 \200\22380% success rate. Alprostadil Alprostadil results in smooth muscle relaxation and vasodilatation. It is admin istered intraurethrally and is then absorbed into the erectile bodies. \200 60 \200\22366 % success rate \200 Side effects: local pain Intracavernous injection This has a 70 \200\223100% success rate and is highest in men with non-vasculo- genic impotence. Alprostadil is a potent vasodilator. The dose should be titrated in 1 mcg increments until the desired effect is achieved to minimize side effects. Papaverine, a PDE inhibitor, induces cavernosal vasodilatation and pen- ile rigidity but causes more side effects. Side effects \200 Priapism in 1 \200\2235%. Patients must seek urgent medical advice if a n erection lasts >4 hours. Table 57.1 PDE-5 inhibitors Sildena \201 l Vardena \201 l Tadala \201 l Dose (mg/day) 50 \200\223100 10 \200\22320 10 \200\22320 Recommended interval between drug administration and sexual activity 60min >30min 30 \200\22360min Half life (hours) 3 \200\2234 4 \200\2235 17 Adverse effects (%) Headaches Facial \202 ushing Dyspepsia Nasal congestion Visual distur bance 15 \200\22330 10 \200\22325 2 \200\22315 1 \200\22310 1 \200\22310 7 \200\22315 10 0.5 \200\2236 3 \200\2237 0 \200\2232 7 \200\22320 1 \200\2235 1 \200\22315 4 \200\2236 0.1 57-Draznin-Chap57.indd 311 3/31/2011 3:17:26 PM CHAPTER 57 Erectile dysfunction 312 Box 57.2 PDE-5 inhibitors \200\224contraindications and cautions Contraindications \200 Recent myocardial infarction or stroke \200 Unstable angina \200 Current nitrate use, including isosorbide mononitrate/GTN \200 Hypotension (<90/50 mmHg) \200 Severe heart failure \200 Severe hepatic impairment \200 Retinitis pigment osa \200 Ketoconazole or HIV protease inhibitors Cautions (reduce dose) \200 Hypertension \200 Heart disease \200 Peyronies disease \200 Sickle cell anemia \200 Renal or hepatic impairment \200 Elderly \200 Leukemia \200 Multiple myeloma \200 Bleeding disorders e.g., active peptic ulcer disease Avoid c oncomitant opiates as they may result in prolonged erections. Fibrosis in the injection site in up to 5% of patients. Minimize risk by alternating sides of the penis for injection and injecting a maximum of twice a week. Infection at injection site is rare. Contraindication \200 Sickle cell disease Injection technique Avoid the midline so as to avoid urethral and neurovascular damage. Clean the injection site, hold the penis under sli ght tension, and intro- duce the needle at 90 . Inject after the characteristic \200\234g ive \200\235 of piercing the \201 brous capsule. Apply pressure to injection site after r emoving the needle to prevent bruising. Vacuum device Results are good, with 90% of men achieving a satisfactory erection. The \202 accid penis is put into the device and air is withdrawn, creating a vacuum that then a llows blood to \202 ow into the penis. A constriction band is then placed on to the base of the penis so that the erection is maintained. This should be removed within 30 minutes. \200 Side effects: pain, hematoma 57-Draznin-Chap57.indd 312 3/31/2011 3:17:26 PM MANAGEMENT 313 Penile prosthesis This is usually tried in men either reluctant to try other forms of thera py or when other treatments have failed. The prosthesis may be semi-rigid or in \202 atabl e. \200 Complications: infection, mechanical failure Psychosexual counseling Consider counseling particularly for men with psychogenic impotence and in men who fail to improve with the above therapies. Surgical Surgery is rarely indicated, as results are generally disappointing. Revasculariza tion techniques may be available in some centers. Ligation of dorsal veins may restore erectile function temporarily in men with venous insuf \201 ciency, although rarely permanently. Further reading Beckman TJ, Abu-Lebdeh HS, Mynderse LA (2006). Evaluation and medical manag ement of erectile dysfunction. Mayo Clin Proc 81:385 \200\223390. Cohan P, Korenman SG (2001). Erectile dysfunction. J Clin Endocrinol Metab 86:2391 \200\223 2394. Fazio L, Brick G (2004). Erectile dysfunction: management update. CMAJ 170(9):1429 \200\223 1437. 57-Draznin-Chap57.indd 313 3/31/2011 3:17:26 PM CHAPTER 58 Testicular tumors 314 Testicular tumors Epidemiology \200 6/100 000 men per year \200 Incidence is rising, particularly in nort hwest Europe. b See Table 58.1 for classi \201 cation. Risk factors \200 Cryptorchidism. \200 Gonadal dysgenesis. \200 Infertility or reduce d spermatogenesis Table 58.1 Classi \201 cation of testicular tumors Tumors Tumor markers Germ cell tumors (95%) Seminoma Non-seminoma Mixed None hCG, -fetoprotein, CEA Stromal tumors (2%) Leydig cell Sertoli cell Gonadoblastoma (2%) Other (1%) Lymphoma Carcinoid 58-Draznin-Chap58.indd 314 3/31/2011 3:17:54 PM PROGNOSIS 315 Prognosis Seminomas \200 95% cure for early disease. 80% cure for stages II/IV \200 i I ncidence of second tumors and leukemias 20 years after therapy Non-seminoma germ cell tumors \200 90% cure in early disease, falling to 60% in metastati c disease \200 i Incidence of second tumors and leukemias 20 years after therapy Stromal tumors \200 Excellent prognosis for benign tumors \200 Malignant tumors are agg ressive and are poorly responsive to treatment. Further reading Grif \201 n JE, Wilson JD (1998). Disorders of the testes and male reprodu ctive tract. In Wilson JD, Foster DW, Kronenberg HM, Larson PR (eds.), William \200\231s Te xtbook of Endocrinology , 9th ed, Philadelphia: WB Saunders, pp. 819 \200\223876. 58-Draznin-Chap58.indd 315 3/31/2011 3:17:55 PM CHAPTER 59 Infertility 316 Infertility De \201 nition Infertility , de \201 ned as failure of pregnancy after 2 years of unprote cted regular (2 x week) sexual intercourse, affects approximately 10% of all couples. Couples who fail to conceive after 1 year of regular unprotected sexual intercourse should be investigated. If there is a known predisposing factor or the female partner is over 35 years of age, then investigation should be offered earlier. 59-Draznin-Chap59.indd 316 3/31/2011 3:21:25 PM CAUSES 317 Causes b See Boxes 59.1 and 59.2. \200 Female factors (e.g., PCOS, tubal damage) (35%) \200 Male factors (idiopathic gonadal failure in 60%) (25%) \200 Combined factors (25%) \200 Unexplained infertility (15%) Box 59.1 Causes of female infertility Anovulation \200 PCOS (80% of anovulatory disorders) \200 Secondary hypogonadism \200 Hyperprolactinemia \200 Thyroid dysfunction \200 Hypothalamic disease \200 Pituitary disease \200 Systemic illness \200 Drugs, e.g., anabolic steroids \200 POF (5% of an ovulatory disorders) Tubal disorders \200 Infective, e.g., Chlamydia \200 Endometriosis \200 Surgery Cervical mucus defects Uterine abnormalities \200 Congenital \200 Intrauterine adhesions \200 Uterine \201 broids 59-Draznin-Chap59.indd 317 3/31/2011 3:21:25 PM CHAPTER 59 Infertility 318 Box 59.2 Causes of male infertility Primary gonadal failure \200 Genetic, e.g., Klinefelter \200\231s syndrome, Y-chromosome microdeletions, immotile cilia/Kartagener syndrome, cystic \201 brosis Congenital cryptorchidism \200 Orchitis \200 Torsion or trauma \200 Chemotherapy and radiotherapy \200 Other toxins, e.g., alcohol, anabolic steroids \200 Varicocele \200 Idiopathic Secondary gonadal failure \200 Kallman \200\231s syndrome (b see Secondary hy pogonadism, p. 285) \200 IHH \200 Structural hypothalamic or pituitary disease Genital tract abnormalities \200 Obstructive congenital, infective, postsurgical \200 S perm autoimmunity Other \200 Erectile dysfunction \200 Drugs, e.g., spironolactone, corticosteroids, sulf asalazine \200 Systemic disease, e.g., cystic \201 brosis, Crohn \200\231s disease, and other chronic debilitating diseases 59-Draznin-Chap59.indd 318 3/31/2011 3:21:25 PM EVALUATION 319 Evaluation Sexual history \200 Frequency of intercourse: sexual intercourse every 2 \200\2233 days s hould be encouraged. Use of lubricants should be avoided because of the detrimental effect on semen quality. Female factors History \200 Age: Fertility declines rapidly after the age of 36 years. Menstrual history \200 Age at menarche \200 Length of menstrual cycle and its regularity (e.g., oligo- o r amenorrhea) \200 Presence or absence of intermenstrual spotting Other \200 Hot \202 ashes may be indicative of estrogen de \201 ciency. \200 Spontan eous galactorrhea may be caused by hyperprolactinemia. \200 Hypothalamic hypogonadism is suggested by excessive physical exercise (e.g., running >4 miles/day) or weight loss in exc ess of 10% in 1 year. Drug history \200 Drugs that may cause hyperprolactinemia ( b see Box 16.1, p. 106), including cocaine and marijuana Smoking is thought have an adverse effect on fertility. \200 The use of anabolic steroids may cause secondary hypogonadism. \200 Cytotoxic chemotherapy or radiotherapy may cause ovarian failure. Medical history \200 Diabetes mellitus, thyroid or pituitary dysfunction, and other syste mic illnesses Exclude tubal disease \200 Recurrent vaginal or urinary tract infections may predispose t o pelvic in \202 ammatory disease (PID). Dyspareunia and dysmenorrhea are often present. \200 Sexually transmitted disease and pre vious abdominal or gynecological surgery all predispose to fallopian tube obstruction. Secondary infertility \200 Details of previous pregnancies, including abortions (spontane ous and therapeutic) and ectopic pregnancies, should be ascertained. Family history \200 Suggestive of risk of POI, PCOS, endometriosis Physical examination \200 BMI: The ideal BMI for fertility is 20 \200\22329. 59-Draznin-Chap59.indd 319 3/31/2011 3:21:25 PM CHAPTER 59 Infertility 320 Secondary sexual characteristics: If absent, look for evidence of Turner \200\231s syndrome. Hyperandrogenism: PCOS \200 Galactorrhea: hyperprolactinemia \200 External genitalia an d pelvic examination Investigations b See Fig. 59.1. Assess ovulatory function \200 In women with regular mens trual cycles, measure midluteal progesterone (day 21 or approximately 7 days before expected onset of menses). Check serum FSH and LH. In women who are not amenorrheic this should be measured on days 2 \200\2236 of the menstrual cycle (day 1 = \201 rst day of menses). Follicular phase FSH > 10 is indicative of reduced ovarian reserve. Ovarian failure is diagnosed if FSH is >30. Measure TSH, free T 4 , and serum prolactin in women with irregular menstrual cycles or who are not ovulating. Other investigations \200 Karyotype: if primary ovarian failure is present (raised FSH, L H) \200 Serum testosterone, androstenedione, DHEA, sex hormone binding globulin, and 17OH progesterone: if there is clinical evidence of hyperandrogenism, in the presence of irregu lar menstrual cycles, or if anovulation is con \201 rmed Assess ovulation in 2 \210\2223 cycles Not ovulating midluteal progesterone <30pmol/L Ovulating (d21) midluteal progesterone >30pmol/L If normal semen analysis FSH, LH, E2 Laparoscopy FSH FSH (>30) Normal FSH Hypogonadotropic hypogonadism POF PCOS Normal Tubal factor Karyotype autoantibodies Androgens SHBG PRL MRI pituitary Cervical factors (PCT, bacteriology, sperm antibody) Fig. 59.1 Investigation of female infertility. 59-Draznin-Chap59.indd 320 3/31/2011 3:21:25 PM EVALUATION 321 MRI of the pituitary fossa: in hyperprolactinemia and hypogonadotropic hypogonadism Exclude cervical infection: Send vaginal discharge for bacteriology and do Chlamydia trachomatis serology Pelvic US: Assess uterine and ovarian anatomy. Assess tubal patency (refer to specialist multidisciplinary fertility clinic) \200 Hyster osalpingography (HSG) or laparoscopy and dye test (do in the early follicular phase of cycle to avoid doing during pregnancy) Give prophylactic antibiotics if Chlamydia status is unknown, to avoid postoperative infection. Postcoital test \200 To assess cervical mucus receptivity to sperm penetration and measurement of antisperm antibodies. These tests are rarely performed, as they are unreliab le and the results do not alter management. Male factors History and physical examination Symptoms of androgen de \201 ciency \200 Reduced libido and potency \200 Reduced frequency of shaving \200 May be asymptomatic Drug history \200 Drug or alcohol abuse and the use of anabolic steroids may all contribute to hypogonadism. Other drugs that may affect spermatogenesis, e.g., sulfasalazine, methotrexate Cytotoxic chemotherapy may cause primary testicular failure. Other factors \200 History of infection, e.g., mumps, orchitis, sexually transmitted dise ase, or epididymitis. Bronchiectasis may be associated with epididymal obstruction (Young syndrome) or severe asthenospermia (immotile cilia syndrome). \200 Testicular injury or s urgery may cause disordered spermatogenesis. \200 Secondary sex characteristics may be ab sent in congenital hypogonadism. Anosmia: Kallmann \200\231s syndrome \200 Eunuchoid habitus (b see Box 54.3, p. 293) sugg estive of prepubertal hypogonadism Gynecomastia may suggest hypogonadism. Testicular size (using orchidometer) \200 Normal: 15 \200\22325 mL \200 Reduced to <15 mL in hypogonadism \200 In Klinefelter \200\231s syndrome, they are often <5 mL. \200 I n patients with normal testicular size, suspect genital tract obstruction, e.g., congenital absence of vas deferens. 59-Draznin-Chap59.indd 321 3/31/2011 3:21:25 PM CHAPTER 59 Infertility 322 Examine the rest of external genitalia, looking for penile and urethral abnormalities and e pididymal thickening. Investigations b See Fig. 59.2. Semen analysis This is essential in the diagnostic workup o f any infertile couple. \200 If normal ( b see Table 59.1 ), then a male cause is exclude d. \200 If abnormal, then repeat semen analysis approximately 6 \200\22312 weeks later. \200 Semen collection should be performed after 3 days of sexual abstinence. b See Table 5 9.1 for interpretation of results . \200 If azoospermia is present, rule out obstruction if FSH and testosterone concentrations are normal. Asthenospermia, or immotile sperm, is usually due to immunological infertility or infection , e.g., of the prostate (high semen viscosity and pH, and leukocytospermia). FSH, LH, and testosterone levels FSH may be elevated in the presence of normal LH and testo sterone lev- els and oligospermia. This may be seen in men who are normally virilized but i nfertile as a result of disordered spermatogenesis. Low FSH, LH, and testosterone concentrations suggest secondary hypo- gonadism. An MRI of th e pituitary gland and hypothalamus is necessary to exclude organic disease. Semen analysis lamroN lamronbA Investigate partner FSH, testosterone FSH Normal FSH FSH Hypogonadotropic hypogonadism Primary gonadal failure Exclude obstructive lesions, immunological causes and infection Prolactin pituitary MRI Karyotype Fig. 59.2 Investigation of male infertility. 59-Draznin-Chap59.indd 322 3/31/2011 3:21:26 PM EVALUATION 323 Table 59.1 WHO criteria for normal semen analysis* Normal values (fertile) Nomenclature for abnormal values Test Volume >2 mL Aspermia (no ejaculate) pH >7.2 >40 x 106/ejaculate Total sperm number Azoospermia (no sperm in ejaculate) >48 x 106/mL Sperm concentration Oligozoospermia Motility >63% progressive motilty Asthenospermia Morphology >12% normal forms Teratospermia Live sperm >75% Necrospermia <1 \227 106/mL Leucocytes Leucocytospermia Reprinted with permission from Guzick DS, Overstreet JW, Factor-Litvak P, et al. (2001). Sp erm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 345: 1388 \200\2231393. Copyright 2001 Massachusetts Medical Society. All rights reserved. Further investigations \200 Urinary bacteriology should be performed in men with leukocytospermia. Scrotal US may help in the diagnosis of chronic epididymitis. Men being investigated for infertility are at i risk of testicular tumors. Karyotyping may be helpful in men with primary testicular failure. Klinefelter \200\231s syndrome (47,XXY) is a cause of infertility, and deletions on the lon g arm of the Y chromosome have been found in a signi \201 cant proportion of azoospermic m en. Sperm antibodies in semen should not be measured routinely, as speci \201 c treatment is rarely effective. Testicular biopsy is rarely diagnostic but may be used to retrieve sperm for assisted reproduction techniques in specialist fertility centers. Sperm function tests are not performed routinely. 59-Draznin-Chap59.indd 323 3/31/2011 3:21:26 PM CHAPTER 59 Infertility 324 Management Female partner Anovulation Hypogonadotropic (WHO class 1) \200 If hyperprolactinemic, then dopamine agonists are usu ally effective \200 Lifestyle changes if underweight or excessive exercise \200 Otherwi se, ovulation induction ( b see Ovulation induction, p. 328) Normogonadotropic (WHO class 2) \200 Usually PCOS: weight reduction if obese \200 Ovula tion induction ( b see Ovulation induction p. 328) Hypergonadotropic (WHO class 3) \200 P OF ovum donation followed by IVF is the only option. \200 Spontaneous transient remission is possible in early POF. \200 If still cycling and FSH is 15 \200\22325 IU/L, ovarian h yperstimulation and IVF may be attempted, but with poor results. Tubal infertility Surgical tubal reconstruction may be attempted in specialist centers. There is a 50 \200\22360% 2-year cumulative pregnancy rate in patients with mild disease, b ut only 10% in more severe disease and a high risk of ectopic pregnancy, so IVF may be more appropriate in women with severe disease. Cumulative pregnancy rate is at least 50% following IVF (20 \200\22325% per cycle) unless h ydrosalpinx is present. Women with hydrosalpinx should be offered salpingectomy prior to IV F to improve success rates. Endometriosis Minimal/mild \200 GnRH agonists, danazol, and progestins do not improve fertility. \200 Laparoscopic destruction of super \201 cial disease improves pregnancy chances. Resection of ovarian endometriomas may improve ovarian folliculogenesis and thus fertility. Assisted reproductive techniques (ART) (Table 59.2) have a pregnancy rate of 25 \200\22335% per cycle. Moderate/severe \200 Surgery may improve fertility. However, ART is often necessary. Vagi nal and cervical factors Each episode of acute PID causes infertility in 10 \200\22315% of cases. Chlamydia trachomatis is responsible for half the cases of PID in the developed countries. Treat both partners with antibiotics. Uterine factors Intracavity \201 broids, polyps, and uterine septum can be resected hyste ro- scopically with a high chance of restoring fertility. 59-Draznin-Chap59.indd 324 3/31/2011 3:21:26 PM MANAGEMENT 325 Intramural \201 broids may also reduce fertility and require myomectomy. Fibroid embolization is not recommended for women wishing fertility, as safety in pregnancy is not established. Male partner Hypogonadotropic hypogonadism \200 Gonadotropins: chorionic gonadotropin 1500 \200\223200 0 IU IM 3 \227 week. Most also require FSH/hMG 75 \200\223150 IU IM 3 x week. Monitor seru m testosterone and testicular size. The main side effect is gynecomastia. or \200 Pulsatile GnRH using an SC infusion pump (b see p. 331). Dose varies from 25 to 5 00 ng/kg every 90 \200\223120 minutes. Titrate to normalize LH, FSH, and testosterone. This will not work in pituitary disease. \200 Once testes are >8 mL, get semen analysis every 3 \200\2236 months. It takes at least 2 years to maximize spermatogenesis. Normalization of spermatogenesis occurs in 80 \200\22390% of men. Once spermatogenesis is induced it may be maintained by hCG alone. Idiopathic semen abnormalities There is no evidence to suggest that the use of androgens, g onadotropins, or antiestrogens help improve fertility in men with idiopathic disorders of s permatogenesis. Obstructive azoospermia Reversal of vasectomy will result in successful pregnancy in up to 50% of cases within 2 years. Microsurgery is possible for most other causes, with successful pregnan- cies in 25 \200 \22335% of couples within 18 months of treatment. During surgery, sperm is often retrieved and stored for possible future intracytoplasmic sperm injection (ICSI). Varicocele There is a controversial association with male subfertility. Surgical correc- ti on is currently not recommended for fertility treatment as there is little evidence that su rgery improves pregnancy rates. Unexplained infertility De \201 nition This is infertility despite normal sexual intercourse occurring at least tw ice weekly, normal semen analysis, documentation of ovulation in several cycles, and normal patent tubes (by laparoscopy). Management From 30 to 50% will become pregnant within 3 years of expectant man- agement. If not pregnant by then, chances that spontaneous pregnancy will occur are greatly reduced an d ART should be considered. In women >34 years of age, expectant management is not an option and up to 6 cycles of intr auterine insemination (IUI), or IVF should be considered. 59-Draznin-Chap59.indd 325 3/31/2011 3:21:26 PM 5 9 D r a z n i n C h a p 5 3 2 6 9 . i n d d 3 Table 59.2 Assisted reproduction techniques (ART) 2 C H A P T E R 6 Technique Indications Pregnancy rates Notes <15% per cycle 15%. Washed and prepared motile spermatozoa are injected into the uterine cavity through a cathe ter just before ovulation Superovulation may improve success rates but is asso- ciated with an increased risk of multiple pregnancy Unexplained infertility mild oligozoospermia (>2 x 10 6 motile sperm) Intrauterine insemination (IUI) (usually offered up to 6 cycles 5 9 I n f e r t i l i t y In vitro fertilization (IVF) Most forms of infertility unless severe male factor 20 \200\22330% pregnancy rate per cycle. After superovulation, ovarian follicles are aspirated under ultrasonic guidance and are fer tilized with prepared sperm in vitro. The embryos are then transferred back into the uterin e cavity, usually 48 hours after insemination. Luteal support using progesterone supplement ation (pessaries or PO) is then provided until pregnancy is con \201 rmed. May adopt a sim ilar technique in women with premature ovarian failure using donated ova which are then fer tilized in vitro with the partner \200\231s sperm. Hormonal support will be required follow ing embryo transfer 80 \200\22390% delivery rate after 6 cycles in women under the age of 35 years. Success rat es markedly reduced after 40 years of age. Babies conceived by IVF have a 2 \227 increased risk of low birth weight and preterm delivery. Gamete intrafallopian transfer (GIFT) Most forms of infertility unless severe male factor. Do not use in women with tubal disease Similar to IVF. Similar to IVF except that retrieved follicles and sperm are injected laparoscopically into a fallopian tube to fertilize naturally. over IVF Intracytoplasmic sperm injection (ICSI) Male infertility. 20 \200\22330% per cycle if female partner is under 40 years of age.There is a small risk o f sex chromosome abnormalities in males (1%) conceived following ICSI Viable spermatozoa are injected directly into oocytes retrieved following superovulation. E mbryos are then implanted into the uterus. Spermatozoa may be concentrated from an ejaculat e or be aspirated from the epididymis or testis in men with obstructive azoospermia. 3 / 3 1 / 2 0 1 1 3 : 2 1 : 2 7 P M MANAGEMENT 327 Results IUI can achieve a pregnancy rate of 15% per cycle, and cumulative delivery rate aft er several cycles is 50%. IVF offers a live birth rate per cycle of >25% in younger women and a cumulative delivery r ate approaching 80%. ICSI allows IVF to be offered in severe oligospermia, with pregnancy r ates equivalent to standard IVF. There is a slight increase in congenital malformations aft er ICSI. A signi \201 cant risk of multiple pregnancy occurs with any form of ART. 59-Draznin-Chap59.indd 327 3/31/2011 3:21:27 PM CHAPTER 59 Infertility 328 Ovulation induction Indications \200 Anovulation due to the following: PCOS \200 Hypopituitarism \200 Hypogonadotropic hypogonadism Controlled ovarian hyperstimulation for ART Pretreatment assessment \200 Exclude thyroid dysfunction and hyperprolactinemia. \200 C heck rubella serology. \200 Con \201 rm normal semen analysis. \200 Con \201 rm tubal patency (laparoscopy, hysterosalpingogram [HSG], or hysterosalping-contrast sonography [Hy CoSy]) prior to gonadotropin use and/or after failed clomifene use. Optimize lifestyle: maintain satisfactory BMI, exercise in moderation, reduce alcohol intake, and stop smoking. Baseline pelvic US is essential to exclude ovarian masses and uterine abnormalities prior to treatment. Clomifene citrate Mode of action \200 Binds to estrogen receptors in hypothalamus, blocking normal negative feedback, thereby i pulse frequency of GnRH. This stimulates FSH and LH release, thereby s timulating the production of one or more dominant ovarian follicles. Antiestrogen effect on endometrium, cervix, and vagina Indications \200 Eugonadotropic anovulation, e.g., PCOS. May also be used in unexplained infertility. It requires normal hypothalamic \200\223pituitary \200\223 ovarian axis to work, thus is ineffective in hypogonadotropic hypogonadism. Contraindications \200 Hepatic dysfunction Administration \200 Start on days 5 of menst rual cycle (may have to induce bleed by giving a progestin for 10 days) and take for a total of 5 days. Dose \200 Start on 50 mg/day and increase by 50 mg every month until midluteal progesterone is >30 nmol/L. Spontaneous ovulation should occur 5 \200\22310 days after the last day of medication. Remain on optimum dose for 6 \200\22312 months. \200 Most patients require 50 \200\223100 mg/day. 59-Draznin-Chap59.indd 328 3/31/2011 3:21:27 PM OVULATION INDUCTION 329 Ideally, follicle growth should be monitored by regular vaginal US to minimize the risk of multiple pregnancies and ovarian hyperstimulation. Ef \201 cacy \200 80 \200\22390% ovulate, with conception rates of 50 \200\22360% in \201 rst 6 ovulatory cycles. Chances of ovulation can be enhanced in nonresponders by admin istration of 10,000 IU of hCG mid-cycle (use US guidance; administer hCG when leading folli cle is at least 20 mm). In overweight women with PCOS who remain anovulatory, the addition of metformin (500 mg tid ) to clomifene may improve ovulation rates. Side effects \200 Hot \202 ashes in 10%, mood swings, depression and headaches in 1%, p elvic pain in 5%, nausea in 2%, breast tenderness in 5%, hair loss in 0.3%, visual disturba nces in 1.5% Ovarian hyperstimulation syndrome (OHSS) in 1% \200 Multiple pregnancies in 7 \200\22310% Risk of ovarian cancer This risk is unknown. Infertility is associated with an i risk of o varian can- cer. Additionally, one study suggests a 2-fold i risk of low-grade ovarian canc er following long-term clomifene use. Further studies are neces- sary, but currently recomm ended maximum treatment duration is 6 \200\22312 months. Tamoxifen Tamoxifen is also an antiestrogen that has similar properties to clomifene. It ca n be used to induce ovulation with results comparable to clomifene. The dose used is 20 \200\22340 mg od for 5 \200\2237 days starting on days 2 \200\2235 of men- strual cycle. Ovarian drilling Laparoscopic ovarian drilling by laser or diathermy in 4 \200\22310 points on the surface of the ovaries may be used in women with PCOS who have failed to conceive o n clomifene. Its ovulation rate of >80% and pregnancy rate of >60% are comparable to gonadotropin therap y, without the risk of multiple pregnancy or ovar- ian hyperstimulation syndrome. It is mos t effective in slim women with PCOS with a high LH. There are few controlled studies, howev er. There is a low risk of pelvic adhesions following ovarian diathermy and a theoretical risk of premature ovarian failure. Gonadotropins Indications \200 Hypogonadotropic hypogonadism \200 Women with PCOS who are clomifene r esistant \200 For superovulation as part of ART 59-Draznin-Chap59.indd 329 3/31/2011 3:21:27 PM CHAPTER 59 Infertility 330