Jay I. Sandlow

Varicocele: current concepts in pathophysiology, diagnosis, and treatment

Although significant advances have been made in the understanding of varicoceles, a clear pathophysiologic mechanism remains elusive. Most likely, a varicocele is the result of a multifactorial process. Appreciation of the complex venous drainage of the testis remains a key to maximizing the chances for treatment success. Likewise, the advent of microsurgical repair has minimized complications. Fortunately, times have improved since the early nineteenth century, when the French surgeon Delpech (1772-1832) was killed by a disgruntled patient on whom he had performed a varicocele repair.

Decreased expression of the c-kit receptor is associated with increased apoptosis in subfertile human testes

OBJECTIVE To examine the expression of the c-kit receptor and its ligand, stem cell factor, and their possible relation with apoptosis in infertile men. DESIGN Prospective laboratory study. SETTING Urology laboratory in a university hospital. PATIENT(S) Men undergoing testicular biopsy during an investigation of subfertility. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Expression of the c-kit receptor protein, stem cell factor, and apoptosis in the testes. RESULT(S) The c-kit receptor was strongly present in Leydig cells and type A spermatogonia of normal testes, with decreased staining in Leydig cells and type A spermatogonia of testes with maturational arrest, and staining in only Leydig cells of Sertoli cell-only specimens. Stem cell factor was demonstrated in Leydig cells and Sertoli cells in all specimens. Western blotting demonstrated the 150-kd c-kit protein in the normal testes and the testes with maturational arrest, but not in the testes with the Sertoli cell-only pattern. Stem cell factor was expressed in all specimens, with a protein size of 45 kd. Increased apoptosis was demonstrated in type A spermatogonia and spermatocytes of tissue with maturational arrest compared with normal testicular tissue. CONCLUSION(S) C-kit receptor expression is decreased in subfertile testicular tissue compared with normal testicular tissue. Stem cell factor expression is present in Leydig cells and Sertoli cells. Increased apoptosis is seen in tissue with maturational arrest compared with normal tissue.

Decreased expression of the heat shock protein hsp70-2 is associated with the pathogenesis of male infertility.

OBJECTIVE To examine the expression of the heat shock protein hsp70-2, and the possible relationship with the pathogenesis of male infertility. DESIGN Prospective study. SETTING Reproductive testing laboratory in a university hospital. PATIENT(S) Men undergoing testicular biopsy during an investigation of subfertility. INTERVENTION(S) Testicular tissues were obtained from biopsies of men undergoing infertility evaluation and subdivided into three groups: normal testes, maturational arrest and Sertoli cell-only syndrome. Immunostaining and Western blotting techniques determined expression of the heat shock protein hsp70-2 MAIN OUTCOME MEASURE(S) Expression of the heat shock protein hsp70-2 in the testes. RESULT(S) The experimental data demonstrated that the heat shock protein hsp70-2 was expressed in the normal and maturation arrest testicular specimens. The heat shock protein hsp70-2 was strongly present in the cytoplasm of spermatocytes and spermatides in the adluminal compartment of the seminiferous epithelium in normal testis. However, maturation arrest testis tissue demonstrated light staining in spermatocytes and spermatides, and Sertoli-only specimens demonstrated no staining for the heat shock protein hsp70-2. The Western blotting data showed a 70-kDa heat shock protein in the normal and maturation arrest testicular tissues, but not in the Sertoli-only tissues. CONCLUSIONS These results suggest that the heat shock protein hsp70-2 is expressed in spermatocytes and spermatides in normal and maturation arrest tissues. However, the expression of the heat shock protein hsp70-2 was low in maturation arrest, and no heat shock protein hsp70-2 was demonstrated in Sertoli-only specimens. Therefore the decreased expression of the heat shock protein hsp70-2 is associated with the pathogenesis of male infertility.

Vasectomy: AUA Guideline

PURPOSE The purpose of this guideline is to provide guidance to clinicians who offer vasectomy services. MATERIALS AND METHODS A systematic review of the literature using the search dates January 1949-August 2011 was conducted to identify peer-reviewed publications relevant to vasectomy. The search identified almost 2,000 titles and abstracts. Application of inclusion/exclusion criteria yielded an evidence base of 275 articles. Evidence-based practices for vasectomy were defined when evidence was available. When evidence was insufficient or absent, expert opinion-based practices were defined by Panel consensus. The Panel sought to define the minimum and necessary concepts for pre-vasectomy counseling; optimum methods for anesthesia, vas isolation, vas occlusion and post-vasectomy follow up; and rates of complications of vasectomy. This guideline was peer reviewed by 55 independent experts during the guideline development process. RESULTS Vas isolation should be performed using a minimally-invasive vasectomy technique such as the no-scalpel vasectomy technique. Vas occlusion should be performed by any one of four techniques that are associated with occlusive failure rates consistently below 1%. These are mucosal cautery of both ends of the divided vas without ligation or clips (1) with or (2) without fascial interposition; (3) open testicular end of the divided vas with MC of abdominal end with FI and without ligation or clips; and (4) non-divisional extended electrocautery. Patients may stop using other methods of contraception when one uncentrifuged fresh semen specimen shows azoospermia or ≤ 100,000 non-motile sperm/mL. CONCLUSIONS Vasectomy should be considered for permanent contraception much more frequently than is the current practice in the U.S. and many other nations. The full text of this guideline is available to the public at http://www.auanet.org/content/media/vasectomy.pdf.

Localization and expression of the c-kit receptor protein in human and rodent testis and sperm.

OBJECTIVES To examine the localization and expression of the c-kit receptor protein in the testes of the mouse, rat, and human, and then compare these among the three species. METHODS Testis tissue from all three species was obtained through biopsy or orchiectomy. Immunohistochemistry was used for the localization, using a monoclonal antibody to the c-kit receptor. The expression of the c-kit receptor protein was examined in the testes and sperm with Western blot analysis. RESULTS Localization was noted in the early spermatogenic cells, most likely type A spermatogonia, as well as in the acrosomal region of more mature germ cells, such as the round spermatids. The c-kit receptor was localized in analogous sites in all three species. The Western blot data revealed testicular expression of the c-kit receptor protein in all three species as well. Similar bands were recognized on the Western blots of all three species in testes at approximately 75 kDa and approximately 90 kDa, and sperm at approximately 90 kDa only. CONCLUSIONS The c-kit receptor protein is expressed in the early spermatogenic cells, as well as the later stages of spermatogenesis, specifically, the acrosomal granules of the round spermatids, and the acrosomal region of testicular spermatozoa, in the mouse, rat, and human. All three species exhibit similar expression of the c-kit receptor protein in both testis and sperm, although to a varying degree. We believe that these observations allow direct valid comparisons concerning the expression of the c-kit receptor to be made cautiously to the human condition from experimental data obtained from rodents.

The C‐kit receptor and its possible signaling transduction pathway in mouse spermatozoa

The presence and role of the c‐kit protein was investigated in the mature sperm of the mouse. The c‐kit monoclonal antibody (mAb) ACK2 reacted specifically with the acrosomal region and the principal piece of fixed noncapacitated sperm but did not react with the acrosome region in acrosome‐reacted sperm. ACK2 significantly inhibited the acrosome reaction; this inhibition was relieved by the calcium ionophore A23187. The kit ligand stem cell factor (SCF) significantly increased the percentage of sperm undergoing acrosome reaction. This increase was partially inhibited by the calcium channel inhibitor (verapamil), the PI3k inhibitor (wortmannin), and the PLC inhibitor (U‐73122). ACK2 predominantly recognized c‐kit proteins of 33, 48, and 150 kDa by Western blotting of mouse sperm extracts. The 48‐ and 150‐kDa protein bands were released into the media and tyrosine autophosphorylated at low basal levels during acrosome reaction. On stimulation with SCF, the level of c‐kit phosphorylation increased significantly. These findings suggest that c‐kit is present in mature sperm, and its binding to SCF may result in the activation of PLCγ1 and PI3K, leading to receptor autophosphorylation, and ultimately may play a role in capacitation and/or the acrosome reaction. Mol. Reprod. Dev. 49:317–326, 1998.

The Laboratory Diagnosis of Testosterone Deficiency

The evaluation and treatment of hypogonadal men has become an important part of urologic practice. Fatigue, loss of libido, and erectile dysfunction are commonly reported, but nonspecific symptoms and laboratory verification of low testosterone (T) are an important part of evaluation in addition to a detailed history and physical examination. Significant intraindividual fluctuations in serum T levels, biologic variation of T action on end organs, the wide range of T levels in human serum samples, and technical limitations of currently available assays have led to poor reliability of T measurements in the clinical laboratory setting. There is no universally accepted threshold of T concentration that distinguishes eugonadal from hypogonadal men; thus, laboratory results have to be interpreted in the appropriate clinical setting. This review focuses on clinical, biological, and technological challenges that affect serum T measurements to educate clinicians regarding technological advances and limitations of the currently available laboratory methods to diagnose hypogonadism. A collaborative effort led by the American Urological Association between practicing clinicians, patient advocacy groups, government regulatory agencies, industry, and professional societies is underway to provide optimized assay platforms and evidence-based normal assay ranges to guide clinical decision making. Until such standardization is commonplace in clinical laboratories, the decision to treat should be based on the presence of signs and symptoms in addition to serum T measurements. Rigid interpretation of T ranges should not dictate clinical decision making or define coverage of treatment by third party payers.

Preoperative semen analysis as a predictor of seminal improvement following varicocelectomy

OBJECTIVE To determine the predictive role of preoperative semen analysis on both seminal improvement and pregnancy rates following varicocelectomy. DESIGN Retrospective data analysis. SETTING Two academic medical center infertility clinics. PATIENT(S) One hundred ten consecutive patients who underwent varicocelectomies. Seminal improvement data were available for 84 patients, and pregnancy data were available for 58 patients. INTERVENTION(S) Stratification of patients based on preoperative total motile sperm count (TM). Varicocelectomy was performed on all patients. MAIN OUTCOME MEASURE(S) TMs, pregnancy rates, and conception techniques following varicocelectomy of each preoperative group. RESULT(S) Men with mild to moderate oligoasthenospermia (TM >5 million) had significantly better seminal improvement following varicocelectomy. While preoperative stratification showed no difference in pregnancy rates (when assisted reproductive techniques were included), men who achieved a postoperative TM >20 million were more likely to achieve conception by less invasive techniques (natural and intrauterine insemination vs. in vitro fertilization [IVF]). CONCLUSION(S) Varicocelectomy may be the most cost-effective initial intervention in males with TM >5 million. Patients with TM <5 million and concomitant female factor infertility may be better initial candidates for IVF.

Clinical and genetic features of patients with congenital unilateral absence of the vas deferens

OBJECTIVES To review the clinical and genetic findings in men with congenital unilateral absence of the vas deferens (CUAVD). CUAVD is important because of its association with renal anomalies and cystic fibrosis transmembrane conductance regulator gene mutations. METHODS A retrospective review of two urologic practices, both with subspecialty interest in male infertility, was performed. Renal imaging and cystic fibrosis (CF) testing were recommended to all men found to have CUAVD. RESULTS Fifteen men with CUAVD were identified. Only the 12 men with sufficient clinical data were selected for this study. Three patients had CF mutations, and all had obstruction of the contralateral vas deferens in either the pelvis or retroperitoneum. One patient had obstruction of the contralateral pelvic vas deferens and was negative for all CF mutations tested. Four patients (33%) had renal agenesis. Three patients had ipsilateral renal agenesis, and one had contralateral renal agenesis. No patient with CF mutations had renal agenesis. One had polycystic kidney disease, which was considered an incidental finding. CONCLUSIONS Patients with CUAVD may have CF mutations and renal agenesis. Renal ultrasonography and CF testing are therefore recommended for these patients. Patients of reproductive age found to have CUAVD should be counseled about the potential risk of transmission of renal anomalies and CF mutations.

Psychological correlates of vasectomy

OBJECTIVE To examine the thoughts and concerns of men contemplating vasectomy before speaking to a physician as well as their partners role in reaching this decision. DESIGN A questionnaire analysis using response rates, ANOVA, and regression analyses. SETTING A large Midwestern teaching hospital. PATIENT(S) Visitors to the urology clinic of the hospital. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) [1] Questionnaire designed by authors. [2] Measures of self-concept, relationship satisfaction, and problem-solving abilities. RESULT(S) [1] Subjects had been considering vasectomy for an average of 1 year and were fairly certain of their decision. [2] Anxiety about vasectomy surgery was mostly driven by fear about pain and fear of the unknown. [3] Concerns about the finality of the procedure did not emerge as a big concern. [4] There is confusion about the reversibility of the procedure. [5] Subjects are better problem solvers and have a higher self-concept than people in general. CONCLUSION(S) Our findings demonstrate the need for adequate prevasectomy counseling, particularly in the area of postoperative expectations, as well as reversibility of the procedure.