The true natural cycle frozen embryo transfer - impact of patient and follicular phase characteristics on serum progesterone levels one day prior to warmed blastocyst transfer.

BACKGROUND: In a true-natural cycle (t-NC), optimal progesterone (P4) output from the corpus luteum is crucial for establishing and maintaining an intrauterine pregnancy. In a previous retrospective study, low P4 levels (< 10 ng/mL) measured one day before warmed blastocyst transfer in t-NC were associated with significantly lower live-birth rates. In the current study, we aim to examine the relationship between patient, follicular-phase endocrine and ultrasonographic characteristics, and serum P4 levels one day prior to warmed blastocyst transfer in t-NC. METHOD: 178 consecutive women undergoing their first t-NC frozen embryo transfer (FET) between July 2017-August 2022 were included. Following serial ultrasonographic and endocrine monitoring, ovulation was documented by follicular collapse. Luteinized unruptured follicle (LUF) was diagnosed when there was no follicular collapse despite luteinizing-hormone surge (> 17 IU/L) and increased serum P4 (> 1.5 ng/mL). FET was scheduled on follicular collapse + 5 or LH surge + 6 in LUF cycles. Primary outcome was serum P4 on FET - 1. RESULTS: Among the 178 patients, 86% (n = 153) experienced follicular collapse, while 14% (n = 25) had LUF. On FET-1, the median serum luteal P4 level was 12.9 ng/mL (IQR: 9.3-17.2), ranging from 1.8 to 34.4 ng/mL. Linear stepwise regression revealed a negative correlation between body mass index (BMI) and LUF, and a positive correlation between follicular phase peak-E2 and peak-P4 levels with P4 levels on FET-1. The ROC curve analyses to predict < 9.3 ng/mL (< 25th percentile) P4 levels on FET-1 day showed AUC of 0.70 (95%CI 0.61-0.79) for BMI (cut-off: 23.85 kg/m2), 0.71 (95%CI 0.61-0.80) for follicular phase peak-P4 levels (cut-off: 0.87 ng/mL), and 0.68 (95%CI 0.59-0.77) for follicular phase peak-E2 levels (cut-off: 290.5 pg/mL). Combining all four independent parameters yielded an AUC of 0.80 (95%CI 0.72-0.88). The adjusted-odds ratio for having < 9.3 ng/mL P4 levels on FET-1 day for patients with LUF compared to those with follicle collapse was 4.97 (95%CI 1.66-14.94). CONCLUSION: The BMI, LUF, peak-E2, and peak-P4 levels are independent predictors of low serum P4 levels on FET-1 (< 25th percentile; <9.3 ng/ml) in t-NC FET cycles. Recognition of risk factors for low serum P4 on FET-1 may permit a personalized approach for LPS in t-NC FET to maximize reproductive outcomes.

Male infertility.

Clinical infertility is the inability of a couple to conceive after 12 months of trying. Male factors are estimated to contribute to 30-50% of cases of infertility. Infertility or reduced fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors (such as tobacco and obesity), congenital anatomical factors, gonadotoxic exposures and ageing, among others. The evaluation of male infertility includes detailed history taking, focused physical examination and selective laboratory testing, including semen analysis. Treatments include lifestyle optimization, empirical or targeted medical therapy as well as surgical therapies that lead to measurable improvement in fertility. Although male infertility is recognized as a disease with effects on quality of life for both members of the infertile couple, fewer data exist on specific quantification and impact compared with other health-related conditions.

Comparison of the efficacy of subcutaneous versus vaginal progesterone using a rescue protocol in vitrified blastocyst transfer cycles.

RESEARCH QUESTION: Does administration of subcutaneous (s.c.) progesterone support ongoing pregnancy rates (OPR) similar to vaginal progesterone using a rescue protocol in hormone replacement therapy frozen embryo transfer cycles? DESIGN: Retrospective cohort study. Two sequential cohorts - vaginal progesterone gel (December 2019-October 2021; n=474) and s.c. progesterone (November 2021-November 2022; n=249) -were compared. Following oestrogen priming, s.c. progesterone 25 mg twice daily (b.d.) or vaginal progesterone gel 90 mg b.d. was administered. Serum progesterone was measured 1 day prior to warmed blastocyst transfer (i.e. day 5 of progesterone administration). In patients with serum progesterone concentrations <8.75 ng/ml, additional s.c. progesterone (rescue protocol; 25 mg) was provided. RESULTS: In the vaginal progesterone gel group, 15.8% of patients had serum progesterone <8.75 ng/ml and received the rescue protocol, whereas no patients in the s.c. progesterone group received the rescue protocol. OPR, along with positive pregnancy and clinical pregnancy rates, were comparable between the s.c. progesterone group without the rescue protocol and the vaginal progesterone gel group with the rescue protocol. After the rescue protocol, the route of progesterone administration was not a significant predictor of ongoing pregnancy. The impact of different serum progesterone concentrations on reproductive outcomes was evaluated by percentile (<10th, 10-49th, 50-90th and >90th percentiles), taking the >90th percentile as the reference subgroup. In both the vaginal progesterone gel group and the s.c. progesterone group, all serum progesterone percentile subgroups had similar OPR. CONCLUSIONS: Subcutaneous progesterone 25 mg b.d. secures serum progesterone >8.75 ng/ml, whereas additional exogenous progesterone (rescue protocol) was needed in 15.8% of patients who received vaginal progesterone. The s.c. and vaginal progesterone routes, with the rescue protocol if needed, yield comparable OPR.

Towards infertility care on equal terms: a prime time for male infertility.

Male infertility is a disease that deserves greater clinical attention and research. A universally accepted definition that emphasizes the modulatory impact of age, lifestyle and environmental factors and includes comprehensive diagnostic and treatment guidelines is needed to ensure accurate evaluation and effective care. Accordingly, male infertility should be defined as a disease of the male reproductive system, caused primarily by congenital and genetic conditions, anatomical, endocrine, functional or immunological abnormalities of the reproductive system, genital tract infections, cancer and its related treatments, and sexual disorders incompatible with intercourse. Inadequate lifestyle, exposure to toxicants and advanced paternal age are critical factors acting alone or exacerbating the impact of known causative factors. The focus on male infertility must be balanced with that on female infertility to ensure the best possible outcome for the couple. Fertility clinics are encouraged to prioritize collaboration with reproductive urologists and andrologists to provide the best possible care for male infertility patients.

Exploring the potential impact of human papillomavirus on infertility and assisted reproductive technology outcomes.

Human papillomavirus (HPV) is a common sexually transmitted disease that has been linked to both cancer and reproductive health issues. While its impact on fertility and pregnancy success has been studied, there is still too little evidence about the influence of HPV on assisted reproductive technology (ART). Therefore, there exists a need for HPV testing in couples undergoing infertility treatments. Infertile men have been found to have a higher prevalence of seminal HPV infection, which can compromise sperm quality and reproductive function. As such, it could be important to investigate the correlation between HPV and ART outcomes in order to improve the quality of evidence. Understanding the potentially detrimental effects of HPV on ART outcomes may have promising important implications for the management of infertility. This minireview summarizes the so far limited developments in this area and highlights the major need for further well-designed studies to address this issue.

A drop in serum progesterone from oocyte pick-up +3 days to +5 days in fresh blastocyst transfer, using hCG-trigger and standard luteal support, is associated with lower ongoing pregnancy rates.

STUDY QUESTION: Do early- and mid-luteal serum progesterone (P4) levels impact ongoing pregnancy rates (OPRs) in fresh blastocyst transfer cycles using standard luteal phase support (LPS)? SUMMARY ANSWER: A drop in serum P4 level from oocyte pick-up (OPU) + 3 days to OPU + 5 days (negative ΔP4) is associated with a ∼2-fold decrease in OPRs. WHAT IS KNOWN ALREADY: In fresh embryo transfer cycles, significant inter-individual variation occurs in serum P4 levels during the luteal phase, possibly due to differences in endogenous P4 production after hCG trigger and/or differences in bioavailability of exogenously administered progesterone (P) via different routes. Although exogenous P may alleviate this drop in serum P4 in fresh transfer cycles, there is a paucity of data exploring the possible impact on reproductive outcomes of a reduction in serum P4 levels. STUDY DESIGN, SIZE, DURATION: Using a prospective cohort study design, following the initial enrollment of 558 consecutive patients, 340 fulfilled the inclusion and exclusion criteria and were included in the final analysis. The inclusion criteria were: (i) female age ≤40 years, (ii) BMI ≤35 kg/m2, (iii) retrieval of ≥3 oocytes irrespective of ovarian reserve, (iv) the use of a GnRH-agonist or GnRH-antagonist protocol with recombinant hCG triggering (6500 IU), (v) standard LPS and (vi) fresh blastocyst transfer. The exclusion criteria were: (i) triggering with GnRH-agonist or GnRH-agonist plus recombinant hCG (dual trigger), (ii) circulating P4 >1.5 ng/ml on the day of trigger and (iii) cleavage stage embryo transfer. Each patient was included only once. The primary outcome was ongoing pregnancy (OP), as defined by pregnancy ≥12 weeks of gestational age. PARTICIPANTS/MATERIALS, SETTING, METHODS: A GnRH-agonist (n = 53) or GnRH-antagonist (n = 287) protocol was used for ovarian stimulation. Vaginal progesterone gel (Crinone, 90 mg, 8%, Merck) once daily was used for LPS. Serum P4 levels were measured in all patients on five occasions: on the day of ovulation trigger, the day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days; timing of blood sampling was standardized to be 3-5 h after the morning administration of vaginal progesterone gel. The delta P4 (ΔP4) level was calculated by subtracting the P4 level on the OPU + 3 days from the P4 level on the OPU + 5 days, resulting in either a positive or negative ΔP4. MAIN RESULTS AND THE ROLE OF CHANCE: The median P4 (min-max) on the day of triggering, day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days were 0.83 ng/ml (0.18-1.42), 5.81 ng/ml (0.80-22.72), 80.00 ng/ml (22.91-161.05), 85.91 ng/ml (15.66-171.78) and 13.46 ng/ml (0.18-185.00), respectively. Serum P4 levels uniformly increased from the day of OPU to OPU + 3 days in all patients; however, from OPU + 3 days to OPU + 5 days, some patients had a decrease (negative ΔP4; n = 116; 34.1%), whereas others had an increase (positive ΔP4; n = 220; 64.7%), in circulating P4 levels. Although the median (min-max) P4 levels on the day of triggering, the day of OPU, and OPU + 3 days were comparable between the negative ΔP4 and positive ΔP4 groups, patients in the former group had significantly lower P4 levels on OPU + 5 days [69.67 ng/ml (15.66-150.02) versus 100.51 ng/ml (26.41-171.78); P < 0.001] and OPU + 14 days [8.28 ng/ml (0.28-157.00) versus 19.01 ng/ml (0.18-185.00), respectively; P < 0.001]. A drop in P4 level from OPU + 3 days to OPU + 5 days (negative ΔP4) was seen in approximately one-third of patients and was associated with a significantly lower OPR when compared with positive ΔP4 counterparts [33.6% versus 49.1%, odds ratio (OR); 0.53, 95% CI; 0.33-0.84; P = 0.008]; this decrease in OPR was due to lower initial pregnancy rates rather than increased overall pregnancy loss rates. For negative ΔP4 patients, the magnitude of ΔP4 was a significant predictor of OP (adjusted AUC = 0.65; 95% CI; 0.59-0.71), with an optimum threshold of -8.73 ng/ml, sensitivity and specificity were 48.7% and 79.2%, respectively. BMI (OR; 1.128, 95% CI; 1.064-1.197) was the only significant predictor of having a negative ΔP4; the higher the BMI, the higher the risk of having a negative ΔP4. Among positive ΔP4 patients, the magnitude of ΔP4 was a weak predictor of OP (AUC = 0.56, 95% CI; 0.48-0.64). Logistic regression analysis showed that blastocyst morphology (OR; 5.686, 95% CI; 1.433-22.565; P = 0.013) and ΔP4 (OR; 1.013, 95% CI; 0.1001-1.024; P = 0.031), but not the serum P4 level on OPU + 5 days, were the independent predictors of OP. LIMITATIONS, REASONS FOR CAUTION: The physiological circadian pulsatile secretion of P4 during the mid-luteal phase is a limitation; however, blood sampling was standardized to reduce the impact of timing. WIDER IMPLICATIONS OF THE FINDINGS: Two measurements (OPU + 3 days and OPU + 5 days) of serum P4 may identify those patients with a drop in P4 (approximately one-third of patients) associated with ∼2-fold lower OPRs. Rescuing these IVF cycles with additional P supplementation or adopting a blastocyst freeze-all policy should be tested in future randomized controlled trials. STUDY FUNDING/COMPETING INTEREST(S): None. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. P.H. has received unrestricted research grants from MSD and Merck, as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, Theramex, and IBSA. H.Y. declares receipt of honorarium for lectures from Merck, IBSA and research grants from Merck and Ferring. The remaining authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: The study was registered at clinical trials.gov (NCT04128436).

Recombinant gonadotropin therapy to improve spermatogenesis in nonobstructive azoospermic patients - A proof of concept study

ABSTRACT Purpose: Nonobstructive azoospermia (NOA) associated with primary spermatogenic failure is a common cause of male infertility usually considered untreatable; however, some reports have suggested that hormonal stimulation to boost the intra-testicular testosterone level and spermatogenesis might increase the chance of achieving pregnancy using homologous sperm. Materials and Methods: We report a series of eight NOA males who received long-term treatment with recombinant human chorionic gonadotropin twice a week for spermatogenesis stimulation. Six males received additional recombinant follicle-stimulating hormone (FSH) supplementation 150-225 IU twice weekly. Results: After recombinant gonadotropin therapy, viable spermatozoa were retrieved from the ejaculate in two patients and by testicular sperm aspiration (TESA) in another two subjects. Singleton spermatozoon retrieved from testes were frozen by vitrification on Cell-Sleeper devices. Two live births were obtained after intracytoplasmic sperm injection with ejaculated spermatozoa and one live birth and an ongoing pregnancy using thawed spermatozoa from TESA. Conclusion: Our proof-of-concept study indicates that hormonal therapy with recombinant gonadotropins could be considered in infertile men with NOA as an alternative to sperm donation. Large-scale studies are needed to substantiate hormone stimulation therapy with recombinant gonadotropins in routine clinical practice for this severe form of male infertility.

Who cares about oligozoospermia when we have ICSI.

The value of assessing subfertile males with oligozoospermia is controversial due to prevailing notions that therapies are limited and ICSI may provide the couple with a baby without the need to explain the nature or cause of underlying male infertility. This article highlights that indiscriminately offering ICSI to oligozoospermic men is not free of potential adverse effects and does not grant subfertile men the best fertility pathway. Recent data support associations between oligozoospermia and poor male reproductive health, DNA and epigenetic damage in spermatozoa, and possible adverse health consequences to offspring. Many conditions affecting the testicles are capable of causing oligozoospermia (varicocele, genital infections, congenital and genetic defects testicular torsion/trauma, chronic diseases, inadequate lifestyle, occupational/environmental exposure to toxicants, drugs, cancer and related treatments, acute febrile illness, endocrine disorders, and iatrogenic damage to the genitourinary system). If oligozoospermia is detected, therapeutic interventions can improve sperm quantity/quality and the overall male health, ultimately resulting in better pregnancy outcomes even when ICSI is used. Fertility clinics are urged to engage male infertility specialists in diagnosing and treating oligozoospermia as a matter of best clinical practice. A well-conducted male infertility evaluation represents a unique opportunity to identify relevant medical and infertility conditions, many of which may be treated or alleviated. The andrological assessment may also help guide the optimal application of ICSI. The final goals are to positively impact the overall patient health, the couple's pregnancy prospects, and the offspring's well-being.

The combined effect of lifestyle intervention and antioxidant therapy on sperm DNA fragmentation and seminal oxidative stress in IVF patients: a pilot study

ABSTRACT Purpose: Sperm DNA fragmentation (SDF) and seminal oxidative stress are emerging measurable factors in male factor infertility, which interventions could potentially reduce. We evaluated (i) the impact of lifestyle changes combined with oral antioxidant intake on sperm DNA fragmentation index (DFI) and static oxidation-reduction potential (sORP), and (ii) the correlation between DFI and sORP. Materials and Methods: We conducted a prospective study involving 93 infertile males with a history of failed IVF/ICSI. Ten healthy male volunteers served as controls. Semen analysis was carried out according to 2010 WHO manual, whereas seminal sORP was measured using the MiOXSYS platform. SDF was assessed by sperm chromatin structure assay. Participants with DFI >15% underwent a three-month lifestyle intervention program, primarily based on diet and exercise, combined with oral antioxidant therapy using multivitamins, coenzyme Q10, omega-3, and oligo-elements. We assessed changes in semen parameters, DFI, and sORP, and compared DFI results to those of volunteers obtained two weeks apart. Spearman rank correlation tests were computed for sORP and DFI results. Results: Thirty-eight (40.8%) patients had DFI >15%, of whom 31 participated in the intervention program. A significant decrease in median DFI from 25.8% to 18.0% was seen after the intervention (P <0.0001). The mean DFI decrease was 7.2% (95% CI: 4.8-9.5%; P <0.0001), whereas it was 0.42% (95%CI; -4.8 to 5.6%) in volunteers (P <0.00001). No differences were observed in sperm parameters and sORP. Based on paired sORP and DFI data from 86 patients, no correlation was observed between sORP and DFI values (rho=0.03). Conclusion: A 3-month lifestyle intervention program combined with antioxidant therapy reduced DFI in infertile men with elevated SDF and a history of failed IVF/ICSI. A personalized lifestyle and antioxidant intervention could improve fertility of subfertile couples through a reduction in DFI, albeit controlled trials evaluating reproductive outcomes are needed before firm conclusions can be made. Trial registration number and date: clinicaltrials.gov NCT03898752, April 2, 2019.

Effects of mobile phone radiofrequency radiation on sperm quality.

In the last decades, the universal use of mobile phones has contributed to radiofrequency electromagnetic radiation environmental pollution. The steady growth in mobile phone usage has raised concerns about the effects of phone radiation on male reproductive health. Epidemiological studies report a sharp decline in sperm counts in developing countries, and worldwide with c. 14% of couples having difficulties to conceive, many of which are attributed to a male infertility factor. Environment and lifestyle factors are known to contribute to male infertility. Exposure to heat, radiation, or radioactivity might induce damage to biological tissue organs, including the testis. Given the ubiquitous use of mobile phones, the potential adverse effects of the resulting environmental radiation needs to be elucidated further. It seems to be an apparent relationship between the increased exposure to mobile phone radiofrequency and sperm quality decline, but the evidence is not conclusive. Our review summarizes the evidence concerning the possible adverse effects of cell phone radiation on the male reproductive system, with a focus on sperm quality. Also, we critically analyze the effects of elevated testicular temperature and oxidative stress on male fertility and how these factors could interfere with the physiological activities of the testis.

The negative impact of most relevant infections on fertility and assisted reproduction technology.

Infections may act with variable impact on the physiopathology of the reproductive organs, determining infertility or reducing the outcomes of assisted reproduction technology. The aim of this narrative review is to describe the existing evidence regarding the pathogens with a supposed or recognized role in reproductive medicine. Viral hepatitis, as well as HIV, can reduce sperm quality. Syphilis carries a risk of erectile dysfunction and increased endometrial thickness. Chlamydia is the main cause of pelvic inflammatory disease. In relation to Mycoplasma and Ureaplasma spp., only few species seem to show a correlation with infertility and poor in-vitro fertilization outcomes. There is evidence of a role for bacterial vaginosis in early pregnancy loss. HPV infection in males seems to determine infertility. Herpesviruses are more a risk for fetuses than for fertility itself. Zika virus is responsible for altered early embryo development and waiting to conceive is recommended in suspected or confirmed cases. The impact of SARS-CoV-2 is yet to be elucidated. Rubella and toxoplasmosis can provoke important congenital defects and therefore screening is mandatory before conception; a vaccine for Rubella is recommended. Further and well-designed studies are still needed to better elucidate the role of some infectious agents, to improve fertility and its treatments.

Microdissection testicular sperm extraction (micro-TESE) in men with infertility due to nonobstructive azoospermia: summary of current literature.

PURPOSE: Nonobstructive azoospermia (NOA) is associated with intrinsic testicular defects that severely impair sperm production. Although NOA invariably leads to infertility, focal sperm production may exist in the testicles of affected patients, which can be retrieved and used for intracytoplasmic sperm injection (ICSI) to generate healthy offspring. However, geographic locations of testicular sperm producing-areas are uncertain, making microsurgical-guided sperm retrieval (microdissection testicular sperm extraction; micro-TESE) an attractive method to identify and retrieve sperm in patients with NOA due to spermatogenic failure. Given the widespread use of micro-TESE, its effectiveness in harvesting sperm and related potential complications need to be clarified. METHODS: We queried PubMed/MEDLINE for studies published in English, from inception to May 2021, concerning the effect of micro-TESE on sperm retrieval rate (SRR), complication rate and ICSI pregnancy rate-using retrieved testicular sperm in subfertile couples where the male had NOA. RESULTS: We found 116 articles, including 70 original papers, 32 review articles, and 14 systematic reviews. The evidence accounted for 4895 patients. Micro-TESE retrieved sperm in 46.6% of men with NOA, but SRRs varied considerably (18.4-70.8%) and were mainly related to the treated population characteristics. Concerning the general population of NOA patients who have not undergone previous sperm retrieval (naïve population), the SRR by micro-TESE was 46.8% (1833 of 3914 patients; range 20-70.8%; 28 studies). In studies reporting SR by micro-TESE for men who had failed percutaneous testicular sperm aspiration or non-microsurgical testicular sperm extraction, the SRR was 39.1% (127 of 325 patients; range 18.4-57.1%; 4 studies). Data on adverse events indicated that micro-TESE was associated with low (~ 3%) short-term postoperative complication rates. The fertilizing ability of testicular sperm retrieved by micro-TESE and used for ICSI was adequate (~ 57%), whereas clinical pregnancy and live birth were obtained in 39% and 24% of couples who had an embryo transfer, respectively. The health of the resulting children seems reassuring, but the evidence is limited. The procedure increases sperm retrieval success compared to non-microsurgical retrieval methods, particularly in men with Sertoli cell-only testicular histopathology. CONCLUSION: We concluded that micro-TESE is an effective and safe method to retrieve sperm from men with NOA-related infertility, with potential advantages over non-microsurgical methods. Nevertheless, high-quality, head-to-head comparative randomized controlled trials by sperm retrieval method, focusing on SRR, live birth rate and assessing long-term adverse events and health of children conceived using testicular sperm from NOA patients are lacking. Therefore, further research is required to determine the full clinical implications of micro-TESE in male infertility treatment.

Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review.

Despite the worldwide increase in frozen embryo transfer, the search for the best protocol to prime endometrium continues. Well-designed trials comparing various frozen embryo transfer protocols in terms of live birth rates, maternal, obstetric and neonatal outcome are urgently required. Currently, low-quality evidence indicates that, natural cycle, either true natural cycle or modified natural cycle, is superior to hormone replacement treatment protocol. Regarding warmed blastocyst transfer and frozen embryo transfer timing, the evidence suggests the 6th day of progesterone start, LH surge+6 day and hCG+7 day in hormone replacement treatment, true natural cycle and modified natural cycle protocols, respectively. Time corrections, due to inter-personal differences in the window of implantation or day of vitrification (day 5 or 6), should be explored further. Recently available evidence clearly indicates that, in hormone replacement treatment and natural cycles, there might be marked inter-personal variation in serum progesterone levels with an impact on reproductive outcomes, despite the use of the same dose and route of progesterone administration. The place of progesterone rescue protocols in patients with low serum progesterone levels one day prior to warmed blastocyst transfer in hormone replacement treatment and natural cycles is likely to be intensively explored in near future.

Differential Diagnosis of Azoospermia in Men with Infertility.

The differential diagnosis between obstructive and nonobstructive azoospermia is the first step in the clinical management of azoospermic patients with infertility. It includes a detailed medical history and physical examination, semen analysis, hormonal assessment, genetic tests, and imaging studies. A testicular biopsy is reserved for the cases of doubt, mainly in patients whose history, physical examination, and endocrine analysis are inconclusive. The latter should be combined with sperm extraction for possible sperm cryopreservation. We present a detailed analysis on how to make the azoospermia differential diagnosis and discuss three clinical cases where the differential diagnosis was challenging. A coordinated effort involving reproductive urologists/andrologists, geneticists, pathologists, and embryologists will offer the best diagnostic path for men with azoospermia.