Peter N. Schlegel

Best practice policies for male infertility

University of California, San Francisco, San Francisco, California; Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Louisville School of Medicine, Louisville, Kentucky; Baylor College of Medicine, Houston, Texas; Brown University, Providence, Rhode Island; Cleveland Clinic Foundation, Cleveland, Ohio; New York Presbyterian Hospital-Cornell, New York, New York; University of Virginia School of Medicine, Charlottesville, Virginia; Mayo Medical School, Rochester, Minnesota; University of Pennsylvania School of Medicine, York, Pennsylvania; University of California, Davis, Davis, California; and SUNY Health Science Center at Brooklyn, Brooklyn, New York

AROMATASE INHIBITORS FOR MALE INFERTILITY

PURPOSE Testosterone-to-estradiol ratio levels in infertile men improve during treatment with the aromatase inhibitor, testolactone, and resulting changes in semen parameters. We evaluated the effect of anastrozole, a more selective aromatase inhibitor, on the hormonal and semen profiles of infertile men with abnormal baseline testosterone-to-estradiol ratios. MATERIALS AND METHODS A total of 140 subfertile men with abnormal testosterone-to-estradiol ratios were treated with 100 to 200 mg. testolactone daily or 1 mg. anastrozole daily. Changes in testosterone, estradiol, testosterone-to-estradiol ratios and semen parameters were evaluated during therapy. The effect of obesity, diagnosis of the Klinefelter syndrome, and presence of varicocele and/or history of varicocele repair on treatment results was studied. RESULTS Men treated with testolactone had an increase in testosterone-to-estradiol ratios during therapy (mean plus or minus standard error of the mean 5.3 +/- 0.2 versus 12.4 +/- 1.1, p <0.001). This change was confirmed in subgroups of men with the Klinefelter syndrome, a history of varicocele repair and those with varicocele. A total of 12 oligospermic men had semen analysis before and during testolactone treatment with an increase in sperm concentration (5.5 versus 11.2 million sperm per ml., p <0.01), motility (14.7% versus 21.0%, p <0.05), morphology (6.5% versus 12.8%, p = 0.05), and motility index (606.3 versus 1685.2 million motile sperm per ejaculate, respectively, p <0.05) appreciated. During anastrozole treatment, similar changes in the testosterone-to-estradiol ratios were seen (7.2 +/- 0.3 versus 18.1 +/- 1.0, respectively, p <0.001). This improvement of hormonal parameters was noted for all subgroups except those patients with the Klinefelter syndrome. A total of 25 oligospermic men with semen analysis before and during anastrozole treatment had an increase in semen volume (2.9 versus 3.5 ml., p <0.05), sperm concentration (5.5 versus 15.6 million sperm per ml., p <0.001) and motility index (832.8 versus 2930.8 million motile sperm per ejaculate, respectively, p <0.005). These changes were similar to those observed in men treated with testolactone. No significant difference in serum testosterone levels during treatment with testolactone and anastrozole was observed. However, the anastrozole treatment group did have a statistically better improvement of serum estradiol concentration and testosterone-to-estradiol ratios (p <0.001). CONCLUSIONS Men who are infertile with a low serum testosterone-to-estradiol ratio can be treated with an aromatase inhibitor. With treatment, an increase in testosterone-to-estradiol ratio occurred in association with increased semen parameters. Anastrozole and testolactone have similar effects on hormonal profiles and semen analysis. Anastrazole appears to be at least as effective as testolactone for treating men with abnormal testosterone-to-estradiol ratios, except for the subset with the Klinefelter syndrome, who appeared to be more effectively treated with testolactone.

Neuroanatomical Approach to Radical Cystoprostatectomy with Preservation of Sexual Function

The technique for radical cystoprostatectomy has been modified to avoid injury to the branches of the pelvic plexus that innervate the corpora cavernosa. Although the course of the neurovascular bundles in the region of the prostate and urethra has been well charted, the exact relationship of the cavernous nerves to the seminal vesicles and bladder has remained unclear. In an effort to delineate this anatomy more clearly, detailed anatomical dissections were performed on 9 male human cadavers. This study demonstrated that the pelvic plexus is located retroperitoneally on the lateral wall of the rectum 5 to 11 cm. from the anal verge with its midpoint related to the tip of the seminal vesicle. The cavernous branches travel in a direct route from the pelvic plexus toward the posterolateral base of the prostate, gradually coalescing from a group of fibers approximately 12 mm. wide to a more organized bundle approximately 6 mm. wide at the level of the prostate. Because the bulk of the pelvic plexus and its important branches are located lateral and posterior to the seminal vesicles, the seminal vesicles can be used as a landmark intraoperatively to avoid injury to the pelvic plexus when ligating the posterior pedicle. During the last 5 years 25 men have undergone radical cystoprostatectomy. Pathological evaluation of all specimens demonstrated negative surgical margins and no patient has had locally recurrent tumor. Of the patients undergoing cystectomy alone 83 per cent are potent. Although all patients undergoing urethrectomy were able to have erections postoperatively, only 40 per cent have erections that are sufficient for intercourse. These data indicate that to date it is possible to perform radical cystoprostatectomy with preservation of sexual function in the majority of patients without compromise to the curative aspects of the radical operation.

Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia

OBJECTIVES To provide fertility for men with nonobstructive azoospermia. METHODS A retrospective review of treatment results at a university infertility center was undertaken. Sixteen couples entered an attempted in vitro fertilization (IVF)-intracytoplasmic sperm injection (ICSI) cycle for treatment of nonobstructive azoospermia. Each man was azoospermic, and the male factor diagnosis of nonobstructive azoospermia was made on testis biopsy for 14 men and on clinical grounds for 2 men. Sperm were retrieved by testicular biopsy on the day of oocyte retrieval. Results of testicular examinations, serum follicle-stimulating hormone levels, and testicular histology as well as evaluation of the success rates of sperm retrieval, fertilizations, and pregnancies were made. RESULTS Sperm were extracted from testis biopsies in 10 of 16 (62%) testicular sperm extraction (TESE) attempts. For cycles in which sperm were retrieved, normal fertilizations were achieved for 51 of 98 (52%) mature oocytes injected with testicular sperm in 10 couples. Biochemical pregnancies were achieved for 6 of 16 (38%) couples, with clinical pregnancies during 5 of 16 (31%) attempts at sperm retrieval, and ongoing pregnancy and subsequent live delivery for 4 of 16 (25%) attempts. CONCLUSIONS; Pretreatment clinical parameters are unable to predict which men with nonobstructive azoospermia will have spermatozoa retrieved by TESE. When sperm are found, clinical pregnancies can occur for half (5/10) of these couples using TESE with ICSI, with ongoing pregnancy and delivery for 4 of 10 (40%). Many men with nonobstructive azoospermia will have retrievable sperm with testis biopsy that are suitable for ICSI; however, 6 of 16 (38%) couples will not have sperm retrieved with TESE and may undergo an unnecessary IVF procedure.

Successful Fertility Treatment for Klinefelter's Syndrome

PURPOSE We examined preoperative factors that could predict successful microdissection testicular sperm extraction in men with azoospermia and nonmosaic Klinefelters syndrome. We also analyzed the influence of preoperative hormonal therapy on the sperm retrieval rate. MATERIALS AND METHODS A total of 91 microdissection testicular sperm extraction attempts were done in 68 men with nonmosaic Klinefelters syndrome. Men with serum testosterone less than 300 ng/dl received medical therapy with aromatase inhibitors, clomiphene or human chorionic gonadotropin before microdissection testicular sperm extraction. Preoperative factors of patient age and endocrinological data were compared in those in whom the procedure was and was not successful. The sperm retrieval rate was the main outcome. Clinical pregnancy (pregnancy with heartbeat) and the live birth rate were also calculated. RESULTS Testicular spermatozoa were successfully retrieved in 45 men (66%), representing 62 (68%) attempts. Increasing male age was associated with a trend toward a lower sperm retrieval rate (p = 0.05). The various types of preoperative hormonal therapies did not have different sperm retrieval rates but men with normal baseline testosterone had the best sperm retrieval rate of 86%. Patients who required medical therapy and responded to that treatment with a resultant testosterone of 250 ng/dl or higher had a higher sperm retrieval rate than men in whom posttreatment testosterone was less than 250 ng/dl (77% vs 55%). For in vitro fertilization attempts in which sperm were retrieved the clinical pregnancy and live birth rates were 57% and 45%, respectively. CONCLUSIONS Microdissection testicular sperm extraction is an effective sperm retrieval technique in men with Klinefelters syndrome. Men with hypogonadism who respond to medical therapy may have a better chance of sperm retrieval.

Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval.

PURPOSE We present treatment results of testicular sperm extraction with intracytoplasmic sperm injection for men with nonobstructive azoospermia and reevaluate the role of testicular histology on open diagnostic testicular biopsy as a predictor of sperm retrieval success. MATERIALS AND METHODS We evaluated 75 men diagnosed with nonobstructive azoospermia. Cases were categorized into 3 groups of hypospermatogenesis, maturation arrest or Sertoli-cell-only based on the most advanced pattern of spermatogenesis seen on histology. A total of 81 testicular sperm extractions with intracytoplasmic sperm injection were performed for these 75 men. The main outcome measures reviewed included sperm retrieval, fertilization and pregnancy rates with intracytoplasmic sperm injection. Sperm retrieval success rates for men in the 3 histological categories were compared. RESULTS Spermatozoa were successfully retrieved during 47 of 81 (58%) testicular sperm extraction attempts, with subsequent fertilization of 268 of 439 (61%) injected metaphase II oocytes using intracytoplasmic sperm injection. Clinical pregnancies were obtained in 26 of 47 (55%) cycles when sperm were retrieved, with ongoing pregnancies or live deliveries for 20 of 47 (43%). Of 39 men with hypospermatogenesis on diagnostic biopsy 31 (79%) had successful sperm retrieval, compared to 9 of 19 (47%) with maturation arrest and 5 of 21 (24%) with a pure Sertolicell-only pattern. CONCLUSIONS Critical examination of the most advanced pattern of spermatogenesis from open diagnostic testis biopsy allows prediction of sperm retrieval success with testicular sperm extraction. In this study population spermatozoa were retrieved in 58% of attempts. When this testicular sperm was used with intracytoplasmic sperm injection, clinical pregnancy rate was 55% for men with nonobstructive azoospermia.

The effect of varicocelectomy on serum testosterone levels in infertile men with varicoceles

PURPOSE We evaluated the effect of varicocelectomy on serum testosterone. MATERIALS AND METHODS We retrospectively reviewed the effect of varicocelectomy on serum testosterone levels in 53 infertile men with varicoceles. RESULTS Mean serum testosterone increased from a preoperative level of 319 +/- 12 to 409 +/- 23 ng./dl. postoperatively (p < 0.0004). Men with at least 1 firm testis preoperatively had a greater increase in serum testosterone (p < 0.005). An inverse correlation was noted between preoperative testosterone levels and change in testosterone after varicocelectomy (r = -0.34, p < 0.013). CONCLUSIONS Varicocelectomy can increase serum testosterone for infertile men with varicoceles. Although improvement in serum testosterone does not necessarily cause a direct improvement in semen quality, varicocelectomy may improve hormonal and spermatogenic function.

EVIDENCE OF A TREATABLE ENDOCRINOPATHY IN INFERTILE MEN

PURPOSE We establish whether a subset of infertile men have decreased serum testosterone-to-estradiol ratios and whether this condition can be corrected with an oral aromatase inhibitor. MATERIALS AND METHODS The serum testosterone-to-estradiol ratios of 63 men with severe male factor infertility or hypergonadotropic hypogonadism (mean follicle-stimulating hormone 21.2 +/- 1.8) were compared with those of an age matched, fertile, control reference group. Of the 63 men 43 were azoospermic with biopsy proved severe male infertility and 20 were oligospermic. The men with the lowest ratios (less than 20th percentile) were treated with 50 to 100 mg of the aromatase inhibitor testolactone orally twice daily. Testosterone-to-estradiol ratios and semen analyses were evaluated during testolactone therapy. RESULTS Men with severe male infertility had significantly lower testosterone (328 versus 543 ng/dl, p <0.01) and higher estradiol (58.4 versus 43.5 ng/l, p = 0.01) than fertile control reference subjects, resulting in a decreased testosterone-to-estradiol ratio (x10(-1) = 6.9 +/- 0.6 versus 14.5 +/- 1.2, respectively, p <0.01). Of the 45 men treated with testolactone a correction of these abnormalities was seen and ratios (x10(-1)) increased into the normal range (5.0 +/- 0.3 to 12.7 +/- 1.2, p <0.01). Semen analyses were considered evaluable only in men with sperm in the ejaculate before aromatase inhibitor treatment. Semen analyses before and during testolactone treatment revealed significant increases in sperm concentration (16.1 to 28.9 million sperm per ml, p = 0.03) and motility (27.1% to 45.3%, p <0.01) in 12 oligospermic men. CONCLUSIONS We identified an endocrinopathy in men with severe male factor infertility that is characterized by a decreased serum testosterone-to-estradiol ratio. This ratio can be corrected by aromatase inhibition, resulting in a significant improvement in semen parameters in oligospermic patients.

Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A cost-effectiveness analysis.

OBJECTIVES To evaluate the cost-effectiveness of assisted reproduction using in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) as a primary treatment for varicocele-associated infertility. METHODS Analysis of cost per delivery using published and contemporary results for treatment with ICSI in the United States for male factor infertility was compared with cost per delivery after surgical varicocelectomy. Only results from controlled trials of varicocelectomy were used for evaluation of pregnancy and delivery rates. Cost estimates were based on prevailing nationwide charges for services in 1994. RESULTS The cost per delivery with ICSI was found to be

Urogenital Anomalies in Men with Congenital Absence of the Vas Deferens

89,091 (95% confidence interval