Impact of cannabinoids on pregnancy, reproductive health, and offspring outcomes.

Cannabis is the most commonly used federally illegal drug in the United States and the world, especially among people of reproductive age. In addition, the potency of cannabis products has increased significantly in the past decade. This is concerning because the available evidence suggests an adverse effect of cannabis exposure on male and female reproductive health. Exposure to cannabinoids may have differential impacts on female reproductive health across a woman's lifespan, from preconception to pregnancy, throughout lactation, and during menopause. Moreover, cannabis use has been associated with adverse effects on fetal outcomes and longer-term offspring health and developmental trajectories. Despite the prevalence of cannabis use, there is limited available evidence regarding its safety, especially in regard to reproductive health, pregnancy, and lactation. The biological effects of cannabis are mediated by the endocannabinoid system, and studies have reported the presence of cannabinoid receptors in the male and female reproductive tract, on sperm and the placenta, suggesting that the endocannabinoid system plays a role in regulating reproduction. Cannabis use can affect male and female fertility and has been associated with altered reproductive hormones, menstrual cyclicity, and semen parameters. Use of cannabis in male patients has also been associated with erectile dysfunction, abnormal spermatogenesis, and testicular atrophy. In female patients, cannabis use has been associated with infertility and abnormal embryo implantation and development. The main psychoactive component of cannabis, the delta-9-tetrahydrocannabinol, can also cross the placenta and has been detected in breast milk. Maternal cannabis use during pregnancy and lactation has been associated with adverse effects, including small-for-gestational-age infants, preterm birth, fetal neurodevelopmental consequences, and impaired offspring sociobehavioral and cognitive development. The prevalence of cannabis use for alleviating menopausal symptoms has also increased despite the limited information on its benefits and safety. Given that cannabis use is on the rise, it is critical to understand its impact on reproductive health and offspring developmental outcomes. This is an understudied but timely subject requiring much further information to guide healthcare providers and those interested in conceiving or who are pregnant and lactating, and those at the end of their reproductive time span.

Perioperative stroke and myocardial infarction in urologic surgery.

INTRODUCTION Perioperative stroke and myocardial infarction are uncommon but devastating thromboembolic complications. There is no comprehensive study detailing these complications for urologic procedures. The primary aim of this study is to determine which urologic procedures and patients carry the highest risk of perioperative stroke and myocardial infarction. MATERIALS AND METHODS: The National Surgical Quality Improvement Program data set was reviewed from 2008-2017. Procedures coded under the urology specialty were included and patients who had a perioperative stroke or myocardial infarction were identified. CPTs were stratified into clinically relevant procedure groups. Two multivariable logistic regression analyses were performed to determine preoperative and procedural risk factors for developing perioperative stroke or myocardial infarction. A multivariable logistic regression analysis was performed to determine the association between these complications and 30-day mortality. RESULTS: A total of 281,744 cases were included, identifying 392 strokes (0.14%) and 1,016 myocardial infarctions (0.36%). Age ≥ 70, hypertension, and disseminated cancer were the strongest preoperative risk factors for perioperative stroke or myocardial infarction. Cystectomy was the highest risk urologic procedure (stroke: OR 3.3, 95%CI 2.3-4.8; MI: OR 7.2, 95%CI 5.6-9.1). Thirty-day mortality was dramatically worse for patients who had a perioperative stroke or myocardial infarction. CONCLUSIONS: Perioperative stroke and myocardial infarction were confirmed to be uncommon but devastating complications of urologic surgery, with incidence of 0.14% and 0.36%, respectively. Cystectomy was the highest risk urologic procedure. Perioperative stroke and myocardial infarction were strongly associated with age ≥ 70, hypertension, and disseminated cancer.

Educational value of the transplant experience in urology residency.

INTRODUCTION To evaluate the educational value of transplant rotation in urology residency. In the United States, exposure to kidney transplantation during urology residency has declined significantly over the past few decades. At our institution, transplantation has been a core component of urology residency since its inception in 1959. MATERIALS AND METHODS: A 15-question anonymous survey was developed. The first 8 questions queried demographics and the last 7 were a set of questions with a Likert Scale response. The survey was electronic- mailed to past and current urology residents who had completed the transplant rotation, dating back to 1972. RESULTS: A total of 61 out of 98 (62%) individuals responded. The majority (59%) were general urologists, and one (2%) had completed a transplant fellowship. In their practices, 17% performed kidney transplants and 28% performed donor nephrectomies. Overall, 100% responded that the skills learned on the transplant rotation were beneficial for urology training, 100% had learned valuable vascular surgical techniques, and 93% felt that urology residents should have clinical transplant experience during their training. There was no statistical difference between the younger and older graduates in Likert scale responses. CONCLUSION: The majority of graduates did not perform transplants in their practice, yet, all of responders agreed that the skills learned on the transplant rotation were beneficial and 93% expressed that urology residents should have clinical transplant experience during residency. Kidney transplantation should be an integral part of urology residency training.

Retroperitoneal Leydig cell tumor recurrence presenting 14 years after orchiectomy.

Malignant Leydig cell tumor is a rare entity that has been previously described as rapidly progressive and uniformly fatal. We present the case of a malignant Leydig cell tumor that presented 14 years after orchiectomy with an isolated retroperitoneal metastasis. Our patient underwent a retroperitoneal lymph node dissection and has been free of recurrence or progression at 12 months of follow up. Additionally, we describe the symptomatic hormone dysfunction experienced by our patient as a result of his tumor.

Cannabis Use and Perinatal Health Research.

This Viewpoint examines the significant gap in knowledge regarding the effects of cannabis use on perinatal health outcomes.

Factors and practice patterns that affect the decision for vasoepididymostomy.

INTRODUCTION: To determine the factors used to make the decision between vasovasostomy (VV) and vasoepididymostomy (VE) by leaders performing microsurgical vasectomy reversal using a questionnaire. MATERIALS AND METHODS: An online questionnaire was sent to all members of the Society for the Study of Male Reproduction (SSMR), a male reproduction subspecialty society of the AUA, using the SurveyMonkey platform. RESULTS: Sixty-seven surgeons responded to the questionnaire (27% of SSMR members). Of which 72% of members performed less than 50 vasectomy reversals per year. Also, 71% of members stated that less than 20% of their vasectomy reversals are vasoepididymostomies. When evaluating epididymal fluid at the time of reversal, 87% would perform a VE for pasty fluid, 66% with creamy fluid without sperm heads and 55% with no or scant fluid. With respect to banking sperm, 36% take sperm or testicular tissue at the time of VE while 37% sometimes take sperm mostly depending on the couple's preference. The Berger end-to-side with intussusception VE technique is used by the majority of members (78%). The presence of intact sperm or sperm parts determined the location in the epididymis for anastomosis for 55% and 19% of members respectively. Postoperative semen testing after a VE is evaluated first between 6 weeks to 3 months for 64%. The procedure is considered a failure between 6 to 12 months for 34% and 12 to 18 months for another 48% if no sperm is seen on semen analysis. CONCLUSIONS: Most members perform a VE with pasty fluid or creamy fluid without sperm heads. Three out of four members are using the Berger end-to-side intussusception technique to perform their VE. More studies are needed to determine the optimal circumstances to perform a VE as there is significant variation in responses even among members of the SSMR.

Higher outcomes of vasectomy reversal in men with the same female partner as before vasectomy.

PURPOSE: We reviewed fertility outcomes of vasectomy reversal at a high surgical volume center in men with the same female partner as before vasectomy. MATERIALS AND METHODS: We retrospectively studied a prospective database. All vasectomy reversals were performed by a single surgeon (EFF). Patients who underwent microsurgical vasectomy reversal and had the same female partner as before vasectomy were identified from 1978 to 2011. Pregnancy and live birth rates, procedure type (bilateral vasovasostomy, bilateral vasoepididymostomy, unilateral vasovasostomy or unilateral vasoepididymostomy), patency rate, time from reversal and spouse age were evaluated. RESULTS: We reviewed the records of 3,135 consecutive microsurgical vasectomy reversals. Of these patients 524 (17%) who underwent vasectomy reversal had the same female partner as before vasectomy. Complete information was available on 258 patients (49%), who had a 94% vas patency rate. The clinical pregnancy rate was 83% by natural means compared to 60% in our general vasectomy reversal population (p <0.0001). On logistic regression analysis controlling for female partner and patient ages, years from vasectomy and vasectomy reversal with the same female partner the OR was 2 (p <0.007). Average time from vasectomy was 5.7 years. Average patient and female partner age at reversal was 38.9 and 33.2 years, respectively. CONCLUSIONS: Outcomes of clinical pregnancy and live birth rates are higher in men who undergo microsurgical vasectomy reversal with the same female partner. These outcomes may be related to a shorter interval from vasectomy, previous fertility and couple motivation.

Impact on Pregnancy of Gross and Microscopic Vasal Fluid during Vasectomy Reversal.

PURPOSE: We compared fertility outcomes with gross and microscopic fluid findings at vasectomy reversal at a high volume vasectomy reversal center. MATERIALS AND METHODS: A retrospective study of a prospective database was performed. All vasectomy reversals were performed by a single surgeon (EFF) between 1978 and 2011. The clinical pregnancy rate was self-reported or determined via patient mailers. Patient and operative findings were determined through database review. We classified vasal fluid as opalescent, creamy, pasty or clear. Intraoperative light microscopy was used to determine if sperm or sperm parts were present and if they were motile. Multivariate analysis was performed evaluating patient age, partner age, years after vasectomy, type of surgery, and gross and microscopic fluid analysis. RESULTS: A total of 2,947 microsurgical vasectomy reversals were reviewed after we excluded reversals performed for post-vasectomy pain. We determined the pregnancy status of 902 (31%) cases. On univariate analysis with respect to pregnancy the presence of motile sperm at vasovasostomy neared statistical significance (p=0.075) and there was no difference between bilateral vs unilateral motile sperm. Gross fluid appearance was not statistically significant but we found the order of pregnancy success to be opalescent, creamy, clear then pasty fluid. On multivariate analysis only female partner age and sperm heads only or no sperm seen on light microscopy had statistical significance (p <0.05). CONCLUSIONS: The presence of motile sperm at vasectomy reversal approaches statistical significance on univariate analysis as a factor that affects clinical pregnancy rates. On multivariate analysis female partner age and microscopic findings of sperm heads only or no sperm are inversely related to pregnancy rates. These data will help counsel couples after vasectomy reversal and reinforce the importance of female partner age.

Renal Autotransplantation: 27-Year Experience at 2 Institutions.

PURPOSE: Renal autotransplantation is an infrequently performed procedure. It has been used to manage complex ureteral disease, vascular anomalies and chronic kidney pain. We reviewed our 27-year experience with this procedure. MATERIALS AND METHODS: This is a retrospective, observational study of 51 consecutive patients who underwent renal autotransplantation, including 29 at Oregon Health and Science University between 1986 and 2013, and 22 at Virginia Mason Medical Center between 2007 and 2012. Demographics, indications, operative details and followup data were collected. Early (30 days or less) and late (greater than 30 days) complications were graded according to the Clavien-Dindo system. Factors associated with complications and pain recurrence were evaluated using a logistic regression model. RESULTS: The 51 patients underwent a total of 54 renal autotransplants. Median followup was 21.5 months. The most common indications were loin pain hematuria syndrome/chronic kidney pain in 31.5% of cases, ureteral stricture in 20.4% and vascular anomalies in 18.5%. Autotransplantation of a solitary kidney was performed in 5 patients. Laparoscopic nephrectomy was performed in 23.5% of cases. Median operative time was 402 minutes and median length of stay was 6 days. No significant difference was found between preoperative and postoperative plasma creatinine (p = 0.74). Early, high grade complications (grade IIIa or greater) developed in 14.8% of patients and 12.9% experienced late complications of any grade. Two graft losses occurred. Longer cold ischemia time was associated with complications (p = 0.049). Of patients who underwent autotransplantation for chronic kidney pain 35% experienced recurrence and 2 underwent transplant nephrectomy. No predictors of pain recurrence were identified. CONCLUSIONS: The most common indications for renal autotransplantation were loin pain hematuria syndrome/chronic kidney pain, ureteral stricture and vascular anomalies in descending order. Kidney function was preserved postoperatively and 2 graft losses occurred. At a median followup of 13 months pain resolved in 65% of patients who underwent the procedure. Complication rates compared favorably with those of other major urological operations and cold ischemia time was the only predictor of postoperative complications.

Relating economic conditions to vasectomy and vasectomy reversal frequencies: a multi-institutional study.

PURPOSE: It was theorized that the use of permanent contraceptive methods may vary with economic conditions. We evaluated the relationship between vasectomy/vasectomy reversal frequencies at several large referral centers and national economic indicators during 2 recessions spanning 2001 to 2011. MATERIALS AND METHODS: We performed an institutional review board approved, retrospective chart review to identify the number of vasectomies/vasectomy reversals per month at several large referral centers from January 2001 to July 2011. The rates of these procedures were pooled, correlated with national economic data and analyzed in a multivariate linear regression model. RESULTS: A total of 4,599 vasectomies and 1,549 vasectomy reversals were performed at our institutions during the study period. The number of vasectomies per month positively correlated with the unemployment rate (r=0.556, p<0.001) and personal income per capita (r=0.276, p=0.002). The number of reversals per month negatively correlated with the unemployment rate (r=-0.399, p<0.001) and personal income per capita (r=-0.305, p<0.001). Neither vasectomy nor vasectomy reversal frequency significantly correlated with the inflation rate or the S&P 500®. Regression models confirmed that the unemployment rate explained more of the variance in vasectomy/vasectomy reversal frequencies than other indicators. CONCLUSIONS: We noted a correlation between the number of vasectomies/vasectomy reversals performed at our institutions and national economic indicators. The strongest association was with the unemployment rate. This points to the importance of financial pressure on family planning decisions.

Influence of substance use on male reproductive health and offspring outcomes.

The prevalence of substance use globally is rising and is highest among men of reproductive age. In Africa, and South and Central America, cannabis use disorder is most prevalent and in Eastern and South-Eastern Europe, Central America, Canada and the USA, opioid use disorder predominates. Substance use might be contributing to the ongoing global decline in male fertility, and emerging evidence has linked paternal substance use with short-term and long-term adverse effects on offspring development and outcomes. This trend is concerning given that substance use is increasing, including during the COVID-19 pandemic. Preclinical studies have shown that male preconception substance use can influence offspring brain development and neurobehaviour through epigenetic mechanisms. Additionally, human studies investigating paternal health behaviours during the prenatal period suggest that paternal tobacco, opioid, cannabis and alcohol use is associated with reduced offspring mental health, in particular hyperactivity and attention-deficit hyperactivity disorder. The potential effects of paternal substance use are areas in which to focus public health efforts and health-care provider counselling of couples or individuals interested in conceiving.

Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes.

BACKGROUND: With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly increasing. However, the potential effects of prenatal cannabis use on fetal developmental programming remain unknown. RESULTS: We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta-9-tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Foundation Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrichment, including genes differentially methylated in placentas from a prospective ASD study. CONCLUSIONS: Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at genes involved in neurobehavioral development that may influence longer-term offspring outcomes. The data from this study add to the limited existing literature to help guide patient counseling and public health polices focused on prenatal cannabis use in the future.

Cessation of chronic delta-9-tetrahydrocannabinol use partially reverses impacts on male fertility and the sperm epigenome in rhesus macaques.

OBJECTIVE: To determine whether discontinuation of delta-9-tetrahydrocannabinol (THC) use mitigates THC-associated changes in male reproductive health using a rhesus macaque model of daily THC edible consumption. DESIGN: Research animal study. SETTING: Research institute environment. PATIENT(S): Adult male rhesus macaques (age, 8-10 years; n = 6). INTERVENTION(S): Chronic daily THC edible administration at medically and recreationally relevant contemporary doses followed by cessation of THC use. MAIN OUTCOME MEASURE(S): Testicular volume, serum male hormones, semen parameters, sperm deoxyribonucleic acid (DNA) fragmentation, seminal fluid proteomics, and whole genome bisulfite sequencing of sperm DNA. RESULT(S): Chronic THC use resulted in significant testicular atrophy, increased gonadotropin levels, decreased serum sex steroid levels, changes in seminal fluid proteome, and increased DNA fragmentation with partial recovery after discontinuation of THC use. For every increase of 1 mg/7 kg/day in THC dosing, there was a significant decrease in the total testicular volume bilaterally by 12.6 cm3 (95% confidence interval [CI], 10.6-14.5), resulting in a 59% decrease in volume. With THC abstinence, the total testicular volume increased to 73% of its original volume. Similarly, with THC exposure, there were significant decreases in the mean total testosterone and estradiol levels and a significant increase in the follicle-stimulating hormone level. With increasing THC dose, there was a significant decrease in the liquid semen ejaculate volume and weight of coagulum; however, no other significant changes in the other semen parameters were noted. After discontinuing THC use, there was a significant increase in the total serum testosterone level by 1.3 ng/mL (95% CI, 0.1-2.4) and estradiol level by 2.9 pg/mL (95% CI, 0.4-5.4), and the follicle-stimulating hormone level significantly decreased by 0.06 ng/mL (95% CI, 0.01-0.11). Seminal fluid proteome analysis revealed differential expression of proteins enriched for processes related to cellular secretion, immune response, and fibrinolysis. Whole genome bisulfite sequencing identified 23,558 CpGs differentially methylated in heavy-THC vs. pre-THC sperm, with partial restoration of methylation after discontinuation of THC use. Genes associated with altered differentially methylated regions were enriched for those involved in the development and function of the nervous system. CONCLUSION(S): This is the first study demonstrating that discontinuation of chronic THC use in rhesus macaques partially restores adverse impacts to male reproductive health, THC-associated sperm differentially methylated regions in genes important for development, and expression of proteins important for male fertility.

Improved fertility preservation care for male patients with cancer after establishment of formalized oncofertility program.

PURPOSE: Survival to reproductive age among men with cancer has steadily increased and yet cancer therapy and cancer itself may carry the risk of infertility. Since 2006, we have used a formalized fertility preservation program with expedited fertility care at our institution. We assessed the impact of this program by comparing the frequency of sperm cryopreservation and patient characteristics before and after its implementation. MATERIALS AND METHODS: Men 18 to 55 years old diagnosed with cancer at our institution from 2002 to 2010 were included in our study. We retrospectively reviewed patient charts to identify those who were offered and subsequently used fertility preservation services before and after program formalization. RESULTS: From 2002 to 2010 at our institution 4,818 men 18 to 55 years old were diagnosed with cancer, of whom 411 were offered fertility preservation consultation and 249 underwent sperm cryopreservation. Since program implementation, the annual number of men receiving fertility preservation consultation and undergoing sperm cryopreservation increased by 2.4 and 2.7-fold, respectively, while the total number diagnosed with cancer remained fairly constant. Upon substratifying patients into the more conventional reproductive age range of 18 to 40 years 23.4% of all men with cancer in this group were offered consultation before formalization vs 43.3% after formalization (p <0.05). The overall sperm use and discard rates were 8.4% and 14.8%, respectively. CONCLUSIONS: A formalized institutional fertility preservation program significantly increased the overall number and percent of male patients with cancer who received fertility preservation consultation and pursued sperm cryopreservation. These increases were seen in men with all types of cancer and across all demographics assessed at our institution.

Testosterone replacement therapy and prostate health.

There is an emerging evolution in the understanding of the relationship between the prostate and testosterone. It has long been generally believed that with testosterone replacement therapy (TRT), increasing serum testosterone levels led to prostatic growth and worsening of voiding dysfunction and associated complications. A new theory, the Saturation Model of Testosterone and its effect on the Prostate has gained attention. This theory suggests that the prostate's response to increasing levels of serum testosterone reaches a limit beyond which there is minimal effect. This model predicts that testosterone replacement therapy occurs above this saturation point, and replacing testosterone to eugonadal levels should not worsen prostate related benign disease. We evaluated the recent published data, with an emphasis on clinical studies done within the last 3 years, for the effects of testosterone supplementation on benign prostatic disease.

Vasectomy reversal outcomes in men after testosterone therapy.

The prevalence of males on testosterone therapy (TT) seeking vasectomy reversal (VR) is rising. As medical therapy (MT) to recover spermatogenesis after TT has been previously described, our study's objective is to present our institution's management and outcomes of VR in men previously on TT. We performed a retrospective case series of vasectomy patients on TT with subsequent VR by a single microsurgeon between March, 2010 and March, 2022. 14 men undergoing VR during the study period met inclusion criteria. The median age at VR was 43 years with a median obstructive interval of 11 years. Median time from MT to VR was 5 months. Post-operative semen analysis was performed in 10 men and all demonstrated patency. 2 patients had very low sperm counts secondary to continuing TT following VR contrary to medical advice and 5 men with patency achieved pregnancy. Our study noted a high rate of vasovasostomy (VV) (96%) and sustained patency despite a 12-year median obstructive interval. Our findings support favorable outcomes with less stringent VV indications after MT in patients previously on TT that desire VR. The use of MT reduces the recommended wait times for VR after TT discontinuation by more than half.

Development of a Hemostatic Urinary Catheter for Transurethral Prostatic Surgical Applications.

OBJECTIVE: To investigate a novel transurethral hemostatic catheter device with an integrated chitosan endoluminal hemostatic dressing (CEHD). Development and implementation of this technology may help address bleeding following surgery such as transurethral resection of prostate (TURP). Bleeding remains the most common complication following TURP, leading to increased morbidity and hospitalization. METHODS: Investigation of hemostasis, delivery, safety and efficacy of the CEHD device is conducted using Female Yorkshire swine (N = 23). Hemostatic efficacy of the CEHD (N = 12) is investigated against a control of gauze (N = 12) in a splenic injury model (3 swine). The delivery, safety, and efficacy of the CEHD device (N = 10) are investigated against Foley-catheter control (N = 10) for 7 days using a swine bladder-neck-injury model. RESULTS: In the splenic injury study, 9/12 CEHD dressings successfully achieved hemostasis within 150 seconds (mean 83 seconds) vs success of 6/12 (mean 150 seconds) for gauze (P = .04). In the 7-day study, the CEHD was successfully deployed in 10/10 animals and all dressings were tolerated without histologic or clinical adverse effect. Hemostasis of the CEHD device was found to be noninferior to control catheters. Noninferiority is attributed to low bleeding rates in the swine bladder neck injury model. CONCLUSION: This investigation successfully demonstrated the feasibility of transurethral deployment of the CEHD in vivo. Routine use of safe and slowly dissolvable CEHDs could reduce the rate of complications and hospitalizations associated with bleeding and blood loss in TURP procedures. Further investigation is warranted.

Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques.

OBJECTIVE: To determine the dose-dependent effect of delta-9-tetrahydrocannabinol (THC) exposure on male testes and reproductive health in a nonhuman primate model. DESIGN: Research animal study. SETTING: Research institute. ANIMAL(S): Adult male rhesus macaques 8-10 years of age (n = 6). INTERVENTION(S): Daily edible THC at medically and recreationally relevant doses. MAIN OUTCOME MEASURE(S): Testicular volume and epididymal head width, serum levels of inhibin B, albumin, total testosterone, prolactin, follicle-stimulating hormone, estradiol, and luteinizing hormone; semen volume; and sperm motility, morphology, and concentration. RESULT(S): For each 1 mg/7 kg/day increase in THC dosing, there was a marked loss in total bilateral testicular volume of 11.8 cm3 (95% confidence interval [CI]: 8.3-15.4). In total, average bilateral testicular volume decreased by 58%. Significant dose-response decreases in mean total testosterone level by 1.49 ng/mL (95% CI: 0.83-2.15) and in estradiol level by 3.8 pg/mL (95% CI: 2.2-5.4) were observed, but significant increases in the levels of follicle-stimulating hormone by 0.06 ng/mL (95% CI: 0.02-0.10), luteinizing hormone by 0.16 ng/mL (95% CI: 0.08-0.25), and prolactin by 7.4 ng/mL (95% CI: 3.4-11.3) were observed. There were no statistically significant changes in semen parameters. CONCLUSION(S): In rhesus macaques, chronic exposure to THC resulted in significant dose-response testicular atrophy, increased serum gonadotropin levels, and decreased serum sex steroids, suggestive of primary testicular failure. Further studies are needed to determine if reversal of these observed adverse effects would occur if THC was discontinued and for validation of thefindings in a human cohort.