Diagnosis and Treatment of Azoospermia Resulting From Testicular Sarcoidosis

Transcription

1 Journal of Andrology, Vol. 33, No. 2, March/April 2012 Copyright E American Society of Andrology Diagnosis and Treatment of Azoospermia Resulting From Testicular Sarcoidosis Case Report JASON R. KOVAC,* DIANE FLOOD,* J. BRENDAN MULLEN,{ AND MARC ANTHONY FISCHER* From the *McMaster Institute of Urology, St Joseph s Hospital, Hamilton, Ontario; and the ÀAndrology Laboratory, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. ABSTRACT: Genitourinary sarcoidosis is uncommon, with only rare documented cases of testicular involvement reported. We detail the case of a 37-year-old male who initially presented for azoospermia and secondary infertility. A testicular biopsy revealed nonnecrotizing granulomas and a chest x-ray identified perihilar lymphadenopathy and granulomatous lung nodules. A corticosteroid regimen was administered, and routine semen analyses were conducted. Significant improvements were noted after prednisone treatments. A successful in vivo fertilization was obtained. This is the first known case of testicular sarcoidosis diagnosed during investigations into azoospermia and secondary infertility which, after treatment with corticosteroids, resulted in natural fertilization. J Androl 2012;33: Correspondence to: Dr Jason R. Kovac, McMaster Institute of Urology, St Joseph s Hospital, 50 Charlton Ave E, Hamilton, Ontario L8N 4A6, Canada ( kovacj4@mcmaster.ca). Received for publication November 23, 2010; accepted for publication April 28, DOI: /jandrol Sarcoidosis, a systemic disease of unknown etiology, can be either self-limiting or chronic (Baughman et al, 2001). Characterized pathologically by the presence of small inflammatory nodules known as nonnecrotizing granulomas, it affects many organs (Newman et al, 1997). Prevalence varies among families, races, and geographic regions, with common rates of per 100,000 that are often exceeded in those of Scandinavian heritage (Newman et al, 1997; Rybicki et al, 1997). People of European descent typically present with asymptomatic, chronic disease, whereas those of African descent tend to have a more acute course (Newman et al, 1997). The etiology of sarcoidosis is unknown with, among other possibilities, environmental agents, genetic factors, and mycobacteria theorized to contribute (Newman et al, 1997). Although virtually any organ may be affected, lung involvement occurs in more than 90% of cases (Baughman et al, 2001). Clinical diagnosis might suggest sarcoidosis, however confirmatory biopsy from an accessible organ is strongly recommended (Newman et al, 1997). In general, patients typically present with a wide variety of complaints, including fatigue, anorexia, and weight loss. Previous case reports on patients with genitourinary sarcoidosis have identified initial presenting complaints of uveitis (Rees et al, 2004; Takiguchi et al, 2008), joint pain, and lymphadenopathy (Svetec et al, 1998). However, infertility has previously only been identified after a diagnosis of sarcoidosis has already been made. With respect to treatment, patients with minimal symptoms are typically observed for several months because they have the potential for spontaneous resolution (Gibson et al, 1996). However, in patients with severe symptoms, treatment should be instituted immediately (Gibson et al, 1996; Newman et al, 1997). In general, suppression of the immune system with oral corticosteroids is the medication of choice. The optimal frequencies and dosages are unknown (Newman et al, 1997). In nonresponders, other medications like methotrexate may be considered (Newman et al, 1997). No previous report has ever identified successful fertilization as a result of corticosteroid treatment. In this report, we highlight the first known case of testicular sarcoidosis diagnosed after initial presentation for azoospermia. We also describe how corticosteroid treatment results in recovery of spermatogenesis, natural fertilization, and resolution of lung nodules. Case Reports A 37-year-old male of Scandinavian background presented with secondary infertility. The patient had successfully achieved 2 prior pregnancies with the same partner, and all female factors were fully investigated and pathology ruled out. This case was reported in accordance with accepted humane practices, as ex- 162

2 Kovac et al N Testicular Sarcoidosis and Azoospermia 163 pressed in the Declaration of Helsinki. All appropriate consents were obtained and documented. Exposure to environmental toxins had occurred in the past, with prior employment in a copper refinery. Seven years before presentation, the patient developed a persistent cough with hemoptysis. At that time, a computed tomography (CT) scan did not identify any pathology. The only other significant factor in his history was an open, left-sided hernia repair with placement of a mesh in the distant past. A child was conceived naturally after this surgical intervention, arguing against iatrogenic vasal obstruction as a cause for this patient s azoospermia. On initial assessment, physical examination was unremarkable. A semen analysis noted an ejaculate volume of 3.2 ml with azoospermia. Blood work revealed normal levels of luteinizing hormones (5.5 IU/ L, reference range IU/L), follicle-stimulating hormone (FSH; 5.6 IU/L, reference range IU/L), testosterone (17.4 nmol/l, reference range nmol/l), estradiol (76 pmol/l, reference range pmol/l), and prolactin (8.9 mg/l, reference range mg/l). Urinalysis was negative, as were HIV and VDRL screens. Given the presence of normal FSH levels and azoospermia, a right-sided testicular biopsy was conducted. The fixative used was 10% neutral buffered formalin. Although not optimal for exquisite nuclear detail, the fixative is more than sufficient to identify spermatocytes, spermatids, and spermatozoa. Pathology revealed hypospermatogenesis with 2 interstitial granulomas suggestive of sarcoidosis (Figure 1). The observed granulomas were not typical of idiopathic granulomatous orchitis (Figure 1). After the pathological diagnosis, a chest x-ray and CT scan identified mild lymphadenopathy in the perihilar region and small granulomatous nodules in the right lung (Figure 2). The patient subsequently developed a mild, but persistent rash on the lower legs (Figure 2) and isolated episodes of blurry vision. Pulmonary function studies were normal. Taken together, a diagnosis of sarcoidosis was made. Given the patient s desire for fertility, a corticosteroid treatment was instituted. Oral dosages were commenced at 40 mg once per day (Figure 3). After 1 month, the dosages were titrated (Figure 3). Residronate (35 mg weekly) was given to combat bone loss secondary to the high-dose corticosteroids. Sperm concentrations and morphology improved rapidly after the institution of prednisone. Long-term changes in sperm concentrations were documented (Figure 3). Morphology improved from 2% normal forms to 5% normal forms (optimal, 4% or more) during the initial treatment period (May June, obtained Figure 1. Testicular biopsy specimen with nonnecrotizing granulomas characteristic of testicular sarcoidosis. There is a well-formed granuloma composed of epithelioid histiocytes, multinucleated giant cells, and lymphocytes present in the interstitium. The majority of the tubules are lined by Sertoli cells only, with the remaining tubules lined by a multilayered germinal epithelium. Spermatozoa are present, although reduced in number. Hematoxylin-eosin; original magnifications 6250 (A) and 6400 (B). Color figure available online at at same times as in Figure 3). Motility remained constant at 40% (reference, more than 50%) during this same time frame. With tapering dosage of the steroids, sperm concentrations decreased concurrently (Figure 3). Corticosteroids were again reintroduced, resulting in parallel improvements in sperm concentrations (Figure 3). These findings argue against the spontaneous resolution of disease because the pattern directly corresponded with the corticosteroid dosages. After treatment, semen photomicrographs identified isolated spermatozoa, and a chest x-ray confirmed the absence of pulmonary nodules (Figure 4). Just before the initial decrease in prednisone, the couple was able to achieve a spontaneous, natural fertilization. Beta HCG levels were elevated, indicating conception; however, further testing revealed a blighted ovum. The previously observed rash and lung lesions (Figure 2) resolved after treatment with steroids (Figure 4B).

3 164 Journal of Andrology N March ÙApril 2012 Figure 2. Chest x-ray (A, B) reveals multiple pulmonary nodules (arrowhead) and photomicrographs of lower limbs (C, D) displaying atypical, erythematous skin nodules. Images were obtained before commencement of prednisone treatment. Color figure available online at www. andrologyjournal.org. Discussion An uncommon, multisystemic disorder, sarcoidosis is characterized by nonnecrotizing granulomas. Although typically involving the lungs, any organ may be affected. The genitourinary system is implicated in less than 0.2% of clinically diagnosed cases (Turk et al, 1986; Newman et al, 1997; Rees et al, 2004), with the epididymis being the most commonly involved component (Rees et al, 2004). Sarcoidosis is a diagnosis of exclusion, which makes it important to properly identify cases, especially in the rare cases that demonstrate testicular involvement. Indeed, many other diseases can result in granulomatous changes within the testicles, including tuberculosis, syphilis, lymphogranuloma venereum, and granuolma ingunale (Svetec et al, 1998; Reineks and MacLennan, 2008). In all of these, physical examination might reveal firm nodules, inciting cancer concerns (Reineks and

4 Kovac et al N Testicular Sarcoidosis and Azoospermia 165 Figure 3. Schematic representation correlating sperm concentrations obtained on semen analysis with prednisone dosage and time. Initially, prednisone (arrowhead bars) was given at 40 mg/d and tapered slowly. Azoospermia (open diamond) improved to a value of 22 million sperm/ml on day 41 of prednisone treatment (closed diamonds). Sperm concentrations improved consistently with time; however, with tapering, they returned to lower levels. Rebound improvements were noted after reinstitution of 40 mg of prednisone, suggesting a correlation to prednisone treatment and arguing against spontaneous resolution. MacLennan, 2008). Serum tumor markers and ultrasound are helpful to elucidate etiology, with orchiectomy frequently performed (Reineks and MacLennan, 2008), partially because of previous findings that suggest an increased presence of testicular cancer in patients with sarcoidosis (Rayson et al, 1998). Some authors have even advocated for scrotal exploration or orchiectomy on the basis of this relationship (Geller et al, 1977; Droz et al, 1990). However, it is unknown whether the association is due to a common etiology or surveillance bias (Rees et al, 2004). Several cases dealing with genitourinary sarcoidosis and fertility have been described in the literature. Svetec et al (1998) reported on a 36-year-old male who had 3 previous children. He initially presented with joint pain and diffuse lymphadenopathy but ultimately developed epididymal enlargement with painful nodules (Svetec et al, 1998). He underwent a partial epididymectomy, and pathology revealed sarcoidosis. Treatment with corticosteroids was instituted for control of his pulmonary disease. He was followed over a 10-year period with semen analyses. He fluctuated between azoospermia and oligospermia (Svetec et al, 1998), eventually being treated with sperm aspiration and intracytoplasmic sperm injection. Unfortunately, the results of the infertility treatment were not reported. The case of a 23-year-old male presenting with ophthalmic sarcoidosis and bilateral uveitis was reported by Takiguchi et al (2008). In this case, the testes were normal in size, but ultrasound identified hypoechoic lesions. Although serological investigations for testicular cancer were normal, semen analyses yielded decreased sperm counts and motility (Takiguchi et al, 2008). Treatment was instituted with 60 mg of oral prednisone. Repeat semen analyses showed gradual improvements in sperm count (Takiguchi et al, 2008), similar to the results reported by Svetec et al (1998). The case of a 27-year-old man who had bilateral testicular masses and normal testicular tumor markers Figure 4. Treatment of testicular sarcoidosis with prednisone results in resolution of azoospermia and disappearance of lung nodules. (A) Photomicrograph depicting the presence of sperm after the initial trial of 40 mg of prednisone daily (6200). (B) Chest x-ray noting absence of lung nodules after long-term treatment with prednisone.

5 166 Journal of Andrology N March ÙApril 2012 was highlighted by Rees et al (2004). An open testicular biopsy was performed to rule out a cancerous cause. Pathology identified that 90% of the testicular tissue was replaced with granulomas, and no spermatogenesis was observed (Rees et al, 2004). Corticosteroid treatment resulted in improved sperm count, and, although the patient had no immediate plans for fertility, sperm banking was performed. The authors also identified, on initial presentation, primary hypogonadism with low serum testosterone and elevated gonadotropins (Rees et al, 2004). These values subsequently normalized in parallel to systemic disease activity (Rees et al, 2004). In our case, we did not observe any initial alterations in serum blood values and, as such, did not measure them throughout the prednisone treatments. Similar to our findings, 2 other case reports (Opal et al, 1979; Takiguchi et al, 2008) also noted no hormonal abnormalities on initial presentation. In summary, we present a rare case of testicular sarcoidosis diagnosed during investigations performed for azoospermia. Excellent recovery of sperm count was obtained with prednisone treatment, and a natural in vivo fertilization was achieved. The exact association between infertility and sarcoidosis is unknown (Takiguchi et al, 2008). Given the variable and unpredictable effects of sarcoidosis on the genitourinary tract in general and the testes in particular, affected men should consider semen analysis at the time of diagnosis (Svetec et al, 1998). In cases of altered spermatogenesis, dramatic improvements in sperm count could be achieved with prednisone treatment. In these cases, while natural fertilization might be possible, sperm banking should still be offered given the relapsing nature of the disease. References Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H Jr, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164: Droz JP, Ruffie P, Piot G, Ghosn M, Gaillaud JM. Sarcoidosis and testicular germ cell tumor. Case report. Scand J Urol Nephrol. 1990;24: Geller RA, Kuremsky DA, Copeland JS, Stept R. Sarcoidosis and testicular neoplasm: an unusual association. J Urol. 1977;118: Gibson GJ, Prescott RJ, Muers MF, Middleton WG, Mitchell DN, Connolly CK, Harrison BD. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51: Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997;336: Opal SM, Pittman DL, Hofeldt FE. Testicular sarcoidosis. Am J Med. 1979;67: Rayson D, Burch PA, Richarson RL. Sarcoidosis and testicular carcinoma. Cancer. 1998;83: Rees DA, Dodds AL, Rathbone N, Davies JS, Scanlon MF. Azoospermia in testicular sarcoidosis is an indication for corticosteroid therapy. Fertil Steril. 2004;82: Reineks EZ, MacLennan GT. Sarcoidosis of the testis and epididymis. J Urol. 2008;179:1147. Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997;145: Svetec DA, Waguespack RL, Sabanegh ES Jr. Intermittent azoospermia associated with epididymal sarcoidosis. Fertil Steril. 1998;70: Takiguchi Y, Matsuno D, Kurosu K, Okada O, Tatsumi K, Ohta S, Ichikawa T, Kuriyama T. Impaired spermatogenesis by testicular sarcoidosis. Respirology. 2008;13: Turk CO, Schacht M, Ross L. Diagnosis and management of testicular sarcoidosis. J Urol. 1986;135: