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Overweight men with nonobstructive azoospermia have worse pregnancy outcomes after microdissection testicular sperm extraction

      Objective

      To evaluate the effect of obesity on the outcome of testicular sperm extraction (TESE) and assisted reproductive technology.

      Design

      Clinical retrospective study.

      Setting

      Center for reproductive medicine at a tertiary-care university hospital.

      Patient(s)

      Nine hundred seventy patients with nonobstructive azoospermia.

      Intervention(s)

      Microdissection TESE followed by intracytoplasmic sperm injection (ICSI).

      Main Outcome Measure(s)

      Sperm retrieval rate and clinical pregnancy rate.

      Result(s)

      Testicular sperm were successfully retrieved in 55% of men overall. Of those with sperm found, clinical pregnancy rate was 51% and live birth rate 40%. Sperm retrieval rates were similar in men with body mass index (BMI) <25 kg/m2, 25–30 kg/m2, and >30 kg/m2 (59%, 57%, and 54%, respectively). Mean BMI of men who contributed to pregnancy (27.3 ± 4.9 kg/m2) was lower than for men whose sperm did not contribute to a pregnancy (28.2 ± 5.4 kg/m2). No man with BMI >43 kg/m2 (n = 11) contributed to a successful pregnancy, even though sperm were found in men with BMI up to 57 kg/m2. On multivariable logistic regression analysis, male BMI was the only predictor of successful pregnancy among the variables analyzed, including male age, female age, and female BMI.

      Conclusion(s)

      Overweight men have lower clinical pregnancy rate after microdissection TESE and ICSI compared with men with normal BMI. Men with BMI >43 kg/m2 did not contribute to any pregnancies, despite successful sperm retrieval.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/ramasamyr-obesity-azoospermia-microdissection/
      Obesity is increasing in prevalence in the United States. Currently, one-third of all American adults are obese, and this proportion is expected to continue to increase (
      • Arterburn D.E.
      • Alexander G.L.
      • Calvi J.
      • Coleman L.A.
      • Gillman M.W.
      • Novotny R.
      • et al.
      Body mass index measurement and obesity prevalence in ten U.S. health plans.
      ). Parallel to the global increase in obesity is the reported decrease in male fertility (
      • Swan S.H.
      • Elkin E.P.
      • Fenster L.
      Have sperm densities declined? A reanalysis of global trend data.
      ,
      • Merzenich H.
      • Zeeb H.
      • Blettner M.
      Decreasing sperm quality: a global problem?.
      ). Men with increased body mass index (BMI) were significantly more likely to be infertile than normal-weight men, according to research conducted at the National Institute of Environmental Health Sciences (
      • Sallmen M.
      • Sandler D.P.
      • Hoppin J.A.
      • Blair A.
      • Baird D.D.
      Reduced fertility among overweight and obese men.
      ). There is also a significant increase in the prevalence of obesity in patients with male-factor infertility and a greater likelihood of subfecundity in couples with obese male partners (
      • Magnusdottir E.V.
      • Thorsteinsson T.
      • Thorsteinsdottir S.
      • Heimisdottir M.
      • Olafsdottir K.
      Persistent organochlorines, sedentary occupation, obesity and human male subfertility.
      ). A Danish cross-sectional study found that obese men had a lower sperm concentration and lower absolute sperm count compared with normal-weight men (
      • Jensen T.K.
      • Andersson A.M.
      • Jorgensen N.
      • Andersen A.G.
      • Carlsen E.
      • Petersen J.H.
      • et al.
      Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men.
      ). Similarly, weight loss has been suggested to improve semen quality in obese men (
      • Hakonsen L.B.
      • Thulstrup A.M.
      • Skaerbech Aggerholm A.
      • Olsen J.
      • Bonde J.P.
      • Yding Andersen C.
      • et al.
      Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men.
      ). A recent study demonstrated that paternal BMI was associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ). Murine models of paternal diet-induced obesity have demonstrated impaired embryo development (
      • Mitchell M.
      • Bakos H.W.
      • Lane M.
      Paternal diet-induced obesity impairs embryo development and implantation in the mouse.
      ,
      • Bakos H.W.
      • Mitchell M.
      • Setchell B.P.
      • Lane M.
      The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model.
      ).
      Men with nonobstructive azoospermia (NOA) who wish to father children may undergo microdissection testicular sperm extraction (micro-TESE) to isolate sperm for use with intracytoplasmic sperm injection (ICSI). Although numerous studies have analyzed several clinical variables that may predict TESE and ICSI outcomes (
      • Mostafa T.
      • Amer M.K.
      • Abdel-Malak G.
      • Nsser T.A.
      • Zohdy W.
      • Ashour S.
      • et al.
      Seminal plasma anti-mullerian hormone level correlates with semen parameters but does not predict success of testicular sperm extraction (TESE).
      ,
      • Bohring C.
      • Schroeder-Printzen I.
      • Weidner W.
      • Krause W.
      Serum levels of inhibin B and follicle-stimulating hormone may predict successful sperm retrieval in men with azoospermia who are undergoing testicular sperm extraction.
      ,
      • Tsujimura A.
      • Matsumiya K.
      • Miyagawa Y.
      • Takao T.
      • Fujita K.
      • Koga M.
      • et al.
      Prediction of successful outcome of microdissection testicular sperm extraction in men with idiopathic nonobstructive azoospermia.
      ,
      • Tsujimura A.
      Microdissection testicular sperm extraction: prediction, outcome, and complications.
      ), to our knowledge there have been no studies analyzing obesity and related comorbidities on micro-TESE outcomes. In the present study, we evaluated the effect of BMI, hypertension, diabetes, and tobacco use on sperm retrieval rate and pregnancy outcomes in men undergoing micro-TESE.

      Materials and methods

       Patient Selection

      The medical records of 1,054 consecutive patients with NOA who underwent micro-TESE from March 1999 to June 2010 were retrospectively analyzed. Of these patient records, 84 were incomplete and therefore excluded, leaving 970 for analysis. The study protocol was approved by the Institutional Review Board of Weill Cornell Medical College. Azoospermia in all patients was confirmed by analysis of at least two different centrifuged ejaculated semen specimens analyzed according to World Health Organization guidelines. An additional ejaculate sample was obtained and confirmed to be azoospermic using an extended sperm preparation on the day of the planned micro-TESE. Karyotype analysis along with Y chromosome microdeletions were performed on all patients. Patients with AZFa and AZFb microdeletions did not undergo micro-TESE.
      Testicular volume was measured by physical examination using an orchidometer, and the average volume of both testes was used for analysis. Additionally, physical examination was used to detect the presence of a varicocele. Testicular histology determination was based on either the results of previous biopsy or intraoperative random sampling during testis exploration via microdissection. Hormonal evaluation included FSH obtained within 2 months before the micro-TESE attempt. Clinical pregnancy in female partners was defined by the identification of at least one gestational sac with at least one fetal heartbeat on transvaginal ultrasound examination at 6–7 weeks after embryo transfer. Confirmation of live birth was obtained by telephone interviews of couples who achieved clinical pregnancy. Height and weight evaluations were obtained from anesthesia reports on the day of the planned micro-TESE. BMI <25 kg/m2 was classified as normal, BMI 26–30 kg/m2 as overweight, and BMI >30 kg/m2 as obese. Hypertension, diabetes mellitus, and tobacco use were self-reported on the day of operation using a standard form. Patients who had previously smoked but had been tobacco free for >3 months before the operation were considered to be historical smokers only.

       Micro-TESE

      The micro-TESE procedure has been described previously (
      • Ramasamy R.
      • Yagan N.
      • Schlegel P.N.
      Structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction.
      ). Sperm retrieval surgery was typically attempted the day before the female partner's oocyte retrieval. Briefly, a midline incision was made in the scrotum, and the testis with spermatic cord was preferentially delivered from the hemiscrotum with the larger testis. The tunica vaginalis was opened, and the tunica albuginea was visualized. Under an operative microscope, the tunica albuginea was widely opened in an equatorial plane, around ∼270 degrees of the circumference of the testis, with preservation of subtunical vessels. After the tunica albuginea was opened, direct examination of the testicular parenchyma was performed at a magnification of ×12 to ×18 under an operating microscope. The examination included as much of the testicular parenchyma as was necessary until spermatozoa were identified. Small samples (1–15 mg) were excised by teasing out larger more opaque tubules from surrounding Leydig cell nodules or hyperplasia in the testicular parenchyma.

       Statistical Analysis

      Microsoft Excel 2008, Graphpad Prism 5, and Stata version 11.0 software were used to perform all statistical calculations with P<.05 considered to be statistically significant. Student t test (unpaired) and χ2 analysis were used to compare factors between men with successful and failed sperm discovery in the laboratory. Fisher exact test, rather than χ2 analysis, was used when n < 10 in one of the cells of the 2 × 2 contingency table (n = number of patients). Univariate and multiple logistic regression analyses were performed to identify variables predictive of sperm retrieval. Variables analyzed included age, serum FSH level, average testicular volume, diagnosis of Klinefelter syndrome, varicocele, history of cryptorchidism, BMI, diagnosis of diabetes mellitus, diagnosis of hypercholesterolemia, history of tobacco use, and tobacco use at time of micro-TESE. Age and mean testicular volume were evaluated as continuous variables. Variables that were significant (P<.05) or near significant (P<.10) in the univariate analysis were included in the multivariable analysis. Data are presented as mean ± SD. Pregnancy outcomes are defined as clinical pregnancy and live birth.

      Results

      Of the 970 patients who underwent micro-TESE, sperm were successfully retrieved in 554 men (57.1%). A total of 272 men (28%) were obese (BMI >30 kg/m2), 400 men (41.2%) were overweight (BMI 25–30 kg/m2), and 298 men (30.7%) were a normal weight (BMI <25 kg/m2). Sperm retrieval rates, pregnancy rates, and live birth rates were similar in normal weight and obese men (Table 1). Diabetes mellitus, hypercholesterolemia, hypertension, and prevalence of smoking were found more frequently in obese men compared with men with normal weight. Age, mean FSH level, mean testicular volume, frequency of diagnosis of Klinefelter syndrome, varicocele, and cryptochoridism were not different between the obese men (BMI >30 kg/m2) and men with normal weight (BMI <25 kg/m2). The frequencies of Sertoli cell–only syndrome, maturation arrest, and hypospermatogenesis on histopathology also were similar between the men.
      Table 1Baseline characteristics of men undergoing microdissection testicular sperm extraction.
      BMI <25 kg/m2BMI 25–30 kg/m2BMI >30 kg/m2P value
      n298400272
      Male age (y), mean ± SD34.1 ± 236.6 ± 1.434.9 ± 1.6.20
      Female age (y), mean ± SD31.5 ± 432.5 ± 5.334.1 ± 6.4.78
      Female BMI (kg/m2), mean ± SD24.2 ± 6.524.6 ± 4.327.8 ± 7.2.32
      Testis vol. (cc), mean ± SD8.9 ± 1.49.2 ± 1.19.2 ± 1.6.26
      FSH (IU/L), mean ± SD25.1 ± 225.6 ± 1.122.6 ± 1.8.05
      Klinefelter syndrome (%)12.19.511.4.90
      Varicocele (%)22.120.019.5.50
      Cryptorchidism (%)17.111.817.6.96
      Sertoli cell only (%)59.354.658.7.96
      Maturation arrest (%)17.820.618.9.85
      Hypospermatogenesis (%)19.319.318.1.74
      Atrophy/sclerosis (%)3.75.54.3.82
      Diabetes mellitus (%)1.31.85.5.01
      Current smoker (%)11.713.819.1.02
      Hypertension (%)4.77.514.0.0002
      Sperm retrieval rate (%)59.757.554.4.23
      Pregnancy rate (%)52.049.044.3.06
      Live birth rate (%)45.039.034.8.09
      The mean BMI of men who had successful sperm retrieval (27.7 ± 5.2 kg/m2) was similar to men who did not have sperm found (28.2 ± 5.5 kg/m2) with micro-TESE (P=.22). However, for men who had a successful sperm retrieval, BMI of those that contributed to a pregnancy (27.3 ± 4.9 kg/m2) was lower (P=.04) than men who did not (28.2 ± 5.4 kg/m2; Fig. 1). Using univariate and multivariable binary logistic regression analysis, we found that a lower male BMI predicted a higher chance of clinical pregnancy (Table 2). Female age or female BMI in this study cohort did not predict pregnancy following micro-TESE. Of the 358 female partners whose data were available, mean female BMI was 25.3 ± 5.5 kg/m2.
      Figure thumbnail gr1
      Figure 1Sperm retrieval (P=.22) and pregnancy (P=.04) outcomes in couples undergoing microdissection testicular sperm extraction.
      Table 2Predictors of clinical pregnancy following intracytoplasmic sperm injection in men undergoing successful microdissection testicular sperm extraction: univariate and multivariable analysis.
      Odds ratio (95% CI)P value
      Univariate analysis
       Male age0.98 (0.96–1.00).06
       Female age0.97 (0.94–1.00).12
       Female BMI0.99 (0.93–1.05).15
       FSH0.99 (0.98–1.00).36
       Testis volume0.98 (0.96–1.01).48
       Male BMI0.93 (0.87–0.99).04
       Klinefelter syndrome (yes vs. no)1.07 (0.67–1.73).75
       Varicocele (yes vs. no)0.93 (0.70–1.39).93
       Cryptorchidism (yes vs. no)1.31 (0.85–2.00).21
       Diabetes (yes vs. no)0.93 (0.33–2.09).77
       History of smoking (yes vs. no)0.99 (0.71–1.36).96
       Current smoking (yes vs. no)1.15 (0.73–1.82).52
       Hypercholesterolemia (yes vs. no)0.23 (0.22–1.58).31
      Multivariable analysis
       Male BMI0.93 (0.86–0.99).03
       Male age0.96 (0.89–1.03).29
       Female age1.01 (0.92–1.10).82
       Female BMI0.86 (0.93–1.07).86
      Note: Variables that were significant (P<.05) or near significant (P<.15) were included in the multivariable analysis. BMI = body mass index; CI = confidence interval.
      Of the 15 men with BMI >40 kg/m2 who had sperm retrieved, five men (33%) went on to contribute to a successful pregnancy. A subgroup analysis of partners of these 15 men with BMI >40 kg/m2 demonstrated no difference in median female age (32 y vs. 30 y), female BMI (33 kg/m2 vs. 32 kg/m2), or number of oocytes injected (11 vs. 8) between those who achieved a successful pregnancy and those who did not. Specifically, no man with BMI >43 kg/m2 who had sperm retrieved contributed to a successful pregnancy in this study.

      Discussion

      Micro-TESE is an increasingly attractive option for men with infertility secondary to NOA. Little is known about the success of this procedure in men with significant comorbidities, including obesity, diabetes, hypertension, and smoking. In the present cohort, we found no difference in the sperm retrieval rate between men with normal BMI and obese men, but we did observe a significant difference in pregnancy rates between the groups. In addition, there were more men with BMI >40 kg/m2 in the group that did not contribute to a successful clinical pregnancy in their female partners. These findings suggest that BMI, especially BMI >40 kg/m2, may have an effect on the quality of sperm found rather than on the chance of finding sperm at all. The possibility that paternal BMI may affect sperm quality in men undergoing infertility evaluation has been suggested by a recent study (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ). Semen from men with normal BMI exhibited a significantly lower sperm DNA fragmentation than that of overweight or obese men (BMI >25 kg/m2) (
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • et al.
      Impact of body mass index values on sperm quantity and quality.
      ,
      • Paasch U.
      • Grunewald S.
      • Kratzsch J.
      • Glander H.J.
      Obesity and age affect male fertility potential.
      ), suggesting that obesity might compromise the integrity of sperm chromatin. Men with a high DNA fragmentation tend to have reduced natural fertility and their partners may have an increased risk of miscarriage (
      • Gopalkrishnan K.
      • Padwal V.
      • Meherji P.K.
      • Gokral J.S.
      • Shah R.
      • Juneja H.S.
      Poor quality of sperm as it affects repeated early pregnancy loss.
      ). In addition, BMI was inversely correlated with hyaluronan-binding score (
      • Wegner C.C.
      • Clifford A.L.
      • Jilbert P.M.
      • Henry M.A.
      • Gentry W.L.
      Abnormally high body mass index and tobacco use are associated with poor sperm quality as revealed by reduced sperm binding to hyaluronan-coated slides.
      ). Hyaluronan-binding score has been associated with higher percentage motility, progressive motility, normal morphology, and fertilization rate (
      • Ye H.
      • Huang G.N.
      • Gao Y.
      • Liu de Y.
      Relationship between human sperm-hyaluronan binding assay and fertilization rate in conventional in vitro fertilization.
      ). One of the purported mechanisms of effect of obesity on sperm quality is that an elevated BMI can impair or adversely affect spermatogenesis by causing an increase in scrotal temperature (
      • Du Plessis S.S.
      • Cabler S.
      • McAlister D.A.
      • Sabanegh E.
      • Agarwal A.
      The effect of obesity on sperm disorders and male infertility.
      ). Increased fat distribution in the upper thighs, suprapubic area and scrotum in conjunction with the sedentary lifestyle often associated with obesity can result in increased testicular temperature (
      • Kasturi S.S.
      • Tannir J.
      • Brannigan R.E.
      The metabolic syndrome and male infertility.
      ,
      • Hammoud A.O.
      • Wilde N.
      • Gibson M.
      • Parks A.
      • Carrell D.T.
      • Meikle A.W.
      Male obesity and alteration in sperm parameters.
      ).
      Obesity in women is known to contribute to anovulation, a reduced conception rate, and an increased risk of miscarriage and prenatal complications (
      • Zain M.M.
      • Norman R.J.
      Impact of obesity on female fertility and fertility treatment.
      ), and BMI of the female partner has been found to be inversely correlated with pregnancy rate (
      • Singh N.
      • Gupta P.
      • Mittal S.
      • Malhotra N.
      Correlation of body mass index with outcome of in vitro fertilization in a developing country.
      ). Furthermore, obesity was associated with fewer normally fertilized oocytes, lower E2 levels, and lower pregnancy and live birth rates (
      • Shah D.K.
      • Missmer S.A.
      • Berry K.F.
      • Racowsky C.
      • Ginsburg E.S.
      Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization.
      ). We have data on female BMI for 358 women partners of the 554 men who had successful sperm retrieval. We demonstrated that female BMI, female age, and number of oocytes injected did not predict successful clinical pregnancy. Although female age and BMI were higher in the partners of men with BMI >30 kg/m2, the difference was not statistically significant on multivariable analysis. Despite the multivariable analysis demonstrating male BMI as the only factor predicting successful pregnancy, it is possible that pregnancy rates were influenced by female/assisted reproduction factors that we did not evaluate as part of our retrospective analysis. Comorbidities such as hypertension, diabetes, and smoking were all more prevalent in the obese group compared with the normal BMI group, and this could have led to increased DNA fragmentation, generating worse pregnancy outcomes. However, these comorbidities were not statistically significant on univariate analysis, and therefore we conclude that smoking and diabetes did not have an effect on pregnancy outcomes in our cohort.
      Men undergoing micro-TESE have demographics similar to the general population, with 28% of our patient population classified as obese (BMI >30 kg/m2). The increasing prevalence of obesity in the general population and apparent simultaneous decrease in male reproductive potential calls for greater clinician awareness of the possible adverse effects of obesity on male fertility, better understanding of underlying mechanisms, and implementation of effective avenues of treatment.
      For patients undergoing an emotional, involved, and expensive procedure such as TESE-ICSI, it is important to optimize the chances of success. Knowledge of factors influencing the chance of successful treatment may help physicians and their patients decide the best time to undergo micro-TESE. Higher BMI is correlated with a lower pregnancy rate after micro-TESE and ICSI in men with NOA, despite similar sperm retrieval rates for men with normal weight and obese men. This information is useful in counseling men presenting for micro-TESE and ICSI that weight may affect their ability to father children. Future studies need to focus on causes of poor sperm quality in obese men.

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