Genetic Testing of Infertile Patients

CASE SCENARIO Genetic Testing of Infertile Patients Scott I. Zeitlin, MD,*† Jacob Rajfer, MD* *Department of Urology, UCLA School of Medicine, Los Angeles, CA; †Department of Surgery, Division of Urology, VA Greater Los Angeles Healthcare System, Los Angeles, CA [Rev Urol. 2004;6(4):211-213] © 2004 MedReviews, LLC CASE REPORT he urologist needs to be aware of what tests to perform in the workup of the infertile patient. In the last few years, as molecular biology has moved from the laboratory to the bedside, it is becoming apparent that many men with a zero sperm count (azoospermia) or a low sperm count (oligospermia) may have genetic abnormalities causing their infertility, and, more importantly, these abnormalities could be passed on to their offspring. Because the Y chromosome is inherited from the father, it stands to reason that genetic defects located on the Y chromosome could be transmitted during fertilization from father to son. Many of these genetic defects are naturally self-limiting, that is, only the affected man is unable to achieve fertilization normally and cannot pass on the genetic defects. The advent of intracytoplasmic sperm injection (ICSI) with in vitro fertilization (IVF) bypasses this natural selection process and allows these genetic defects to be transmitted. Because many of these genetic abnormalities affecting spermatogenesis have both diagnostic and prognostic significance and are increasingly being recognized at the molecular level, it is imperative that urologists become familiar with the tests used to identify such patients. A 31-year-old Israeli man presented with azoospermia T on 2 separate semen analyses showing normal semen volumes of 5 to 6 cc. His endocrine and sexual histories were normal, although he had not tried to achieve a pregnancy. He had no history of undescended testes, genitourinary surgery, or cancer, and no known prior exposure to radiation, chemotherapy, or environmental toxins. Of note, he was born without a lower left leg, ankle, and foot. The patient had a cousin who required a testicular sperm extraction in conjunction with ICSI in order to achieve a pregnancy via IVF. On examination, except for the prosthesis on his left lower extremity, he appeared normal with normal male hair distribution and no gynecomastia. His testes were descended bilaterally and firm to palpation. The right and left testes were 10 and 8 cc in volume, respectively, and both epididymides and vasa deferentia were palpably normal. The serum luteinizing hormone was 12.3
IU/mL, follicle stimulating hormone (FSH) was 12.3
IU/mL, and testosterone was 400 ng/dL. A third semen analysis using a spun pellet confirmed the azoospermia. What is the next test that should be performed to determine whether the patient has sperm in his testes? Should it be a testis biopsy? Is there another less invasive test that may be diagnostic? MANAGEMENT OPTIONS Which test should be performed next for this patient (once you know what his FSH and sperm count are)?



1. 2. 3. 4. Diagnostic testis biopsy Karyotype and Y chromosome microdeletion test TRUS and possible SV aspiration Treatment with hCG and FSH Vote online at www.medreviews.com; fax your response to MedReviews (212) 971-4047; or e-mail your selection to dgern@medreviews.com. VOL. 6 NO. 4 2004 REVIEWS IN UROLOGY 211 Case Scenario continued Discussion of Last Issue’s Case Scenario IN THE LAST ISSUE, DR ASSIMOS AND COLLEAGUES PRESENTED THIS CASE REPORT: A 54-year-old African American woman is referred for evaluation of clitoromegaly. Review of systems is normal. The patient is taking no medications, including exogenous steroids. She does not use alcohol, tobacco, or illicit drugs. Two of her sisters had thyroid goiters; family history otherwise is unremarkable. Physical examination demonstrates a body weight of 198 lb (90 kg), normal vital signs, and no abnormalities except an enlarged clitoris. Complete blood count; blood urea nitrogen, serum creatinine, glucose, and electrolyte levels; and urinalysis are normal. Serum testosterone level is 152 ng/dL (normal, 8–61 ng/dL in postmenopausal women). Serum calcium level is 10.8 mg/dL (normal, 8.5–10.5 ng/dL). Serum intact parathyroid hormone level is 135 pg/mL (normal, 12–72 pg/mL). Serum follicle-stimulating hormone, luteinizing hormone, and prolactin; plasma catecholamine; and adrenocorticotropic hormone levels are normal. Twenty-four-hour urinary excretion of free cortisol and ketosteroids is normal. Chest radiograph, pelvic and thyroid ultrasound studies, and magnetic resonance image (MRI) of the brain are normal. An uninfused computed tomography scan of the abdomen and pelvis demonstrates a 2 cm right adrenal mass with an attenuation coefficient of 5 Hounsfield units. Pertinent MRI images of the adrenal glands are shown in Figures 1 and 2. THE 1. 2. 3. 4. 5. 212 Figure 2. Left, T1-weighted, in-phase, axial image showing a right adrenal mass. Right, T1-weighted, out-of-phase, axial image showing the same adrenal mass. FOLLOWING MANAGEMENT OPTIONS WERE OFFERED: Repeat imaging studies in 3 months Dexamethasone suppression test Percutaneous biopsy of the right adrenal gland Right adrenalectomy Bilateral adrenalectomy VOL. 6 NO. 4 2004 Figure 1. T2-weighted, single-shot, coronal image showing a right adrenal mass. REVIEWS IN UROLOGY Case Scenario AUTHORS’ DISCUSSION This patient has a right adrenal mass and physical and laboratory evidence of virilization. The imaging features of this lesion are consistent with an adrenal adenoma. These tumors are usually homogeneous, are 2 to 5 cm in diameter, and range in attenuation from 0 to 20 Hounsfield units on uninfused computed tomography. Adrenal adenomas typically have relatively low signal intensity on all magnetic resonance image spin-echo sequences. The finding of a large signal drop from in-phase to out-ofphase imaging indicates that this is a lipid-containing mass and is most likely an adenoma.1 The increased serum calcium and intact parathyroid hormone levels indicate that this patient also has primary hyperparathyroidism. Therefore, a diagnosis of multiple endocrine neoplasia type 1 (MEN-1), also known as Wermer’s syndrome, is a consideration (Table 1). The patient initially underwent laparoscopic right adrenalectomy because it was thought that she had a functioning adrenal adenoma. Her recovery was uneventful. Pathologic analysis demonstrated multinodular adrenal hyperplasia. She subsequently underwent neck exploration. All four parathyroid glands were enlarged, and subtotal parathyroidectomy was undertaken. Pathology revealed parathyroid hyperplasia. Serum calcium normalized postoperatively, whereas serum testosterone remained elevated at 146 ng/dL (normal, 8–61 ng/dL). The patient’s persistent virilization is most likely caused by hyperplasia in the remaining adrenal gland, despite its normal radiographic appearance. The above findings are consistent with a diagnosis of atypical MEN-1. Multiple endocrine neoplasia type 1 is a heritable autosomal dominant disorder with a prevalence of about 1:50,000.2 It is most commonly associated with primary hyperparathyroidism (90%-100%), pancreatic islet cell tumors (50%-70%), and anterior pituitary tumors (10%60%). The presence of 2 of these 3 features is sufficient for diagnosis.3 MEN-1 may also rarely be associated with a variety of other tumors, including adrenal adenomas4,5 and, more rarely, adrenal nodular hyperplasia.4 There is evidence suggesting that atypical presentations reflect different pathways of tumorigenesis compared with Table 1 Classification of Multiple Endocrine Neoplasia (MEN) MEN-1: Parathyroid tumors, anterior pituitary tumors, and pancreatic islet cell tumors MEN-2: MEN-2A: Medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia, and cutaneous lichen amyloidosis MEN-2B: Medullary thyroid cancer, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, and, in some instances, marfanoid habitus Familial medullary thyroid cancer: medullary thyroid cancer classical MEN-1–associated tumors.6 The most common manifestation of MEN-1 is primary hyperparathyroidism, which has a nearly 100% penetrance by age 50. The etiology of hyperparathyroidism is typically parathyroid hyperplasia in younger patients and parathyroid adenoma in older patients.7 The classical sequelae of the resultant hypercalcemia include kidney stones, osteopenia, and gastrointestinal and musculoskeletal complaints. References 1. 2. 3. 4. 5. 6. 7. Fujiyoshi F, Nakajo M, Fukukura Y, Tsuchimochi S. Characterization of adrenal tumors by chemical shift fast low-angle shot MR imaging: comparison of four methods of quantitative evaluation. Am J Roentgenol. 2003;180:1649-1657. Teh BT, McArdle J, Parameswaran V, et al. Sporadic primary hyperparathyroidism in the setting of multiple endocrine neoplasia type 1. Arch Surg. 1996;131:1230-1232. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrin Metab. 2001;86:5658-5671. Skogseid B, Larsson C, Lindgren P, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrin Metab. 1992;75:76-81. Frilling A, Becker H, Rocher HD. Unusual features of multiple endocrine neoplasia. Henry Ford Hosp Med J. 1992;40:253-255. Vortmeyer AO, Lubensky IA, Skarulis M, et al. Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors. Med Pathol. 1999;12:919-924. Sherman SI, Gagel RF. Disorders affecting multiple endocrine systems. In: Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill Professional; 2001:2184-2191. VOL. 6 NO. 4 2004 REVIEWS IN UROLOGY 213