Color Doppler ultrasound imaging in varicoceles: Is the difference in venous diameter encountered during Valsalva predictive of palpable varicocele grade?

Objective: The clinical grading system for varicoceles is subjective and dependent on clinician experience. Color Doppler ultrasound (US) has not been standardized in the diagnosis of varicoceles. We aimed to determine if US measurement of varicocele could be predictive of World Health Organization (WHO) varicocele grade. Methods: Men who presented for either scrotal pain or infertility to a tertiary men's health clinic underwent physical examination, and varicoceles were graded following WHO criteria (0=subclinical, 1, 2, 3). US was used to measure largest venous diameter in the pampiniform plexus bilaterally at rest and during Valsalva maneuver. Receiver operator characteristic curve analysis was used to determine if resting diameter, diameter during Valsalva, or change in diameter between at rest and during Valsalva provided the highest sensitivity and specificity for determining clinical grade. Threshold values for diameter were determined from these receiver operator characteristic curves. Results: A total of 102 men (50 with clinical varicocele and 52 with subclinical varicocele) were included. Diameter at rest was the best ultrasonographic discriminator between subclinical and clinical varicoceles (area under the curve [AUC]=0.67) with a diameter threshold of 3.0 mm (sensitivity 79%, specificity 42%). Diameter during Valsalva had the greatest AUC for determining clinical Grades 1 versus 2 (AUC=0.57) with diameter threshold of 5.7 mm (sensitivity 71%, specificity 33%). For differentiating between Grades 2 and 3, diameter at rest had the greatest AUC of 0.65 with a threshold of 3.6 mm (sensitivity 71%, specificity 58%). Conclusion: Our results corroborate other studies that have shown a weak correlation between US and clinical grading. The use of diameter during Valsalva was less predictive than diameter at rest and was only clinically significant in differentiating between Grade 1 and 2 varicocele. A standardized method for determining clinically relevant varicoceles on US would allow for improved patient counseling and clinical decision-making.

Global Trends in Prevalence, Treatments, and Costs of Penile Prosthesis for Erectile Dysfunction in Men.

CONTEXT: Penile prosthesis is a durable and effective treatment for erectile dysfunction (ED). Even as other treatment options for ED have been brought to market, penile prosthetic surgery remains a mainstay for urologists treating ED. No systematic study has yet summarized the global trends in penile prosthetic surgery. OBJECTIVE: To systematically review studies of trends in penile prosthetic surgery to determine global movements in implantation rates, malleable versus inflatable prosthetic surgery, inpatient versus outpatient implantation surgery, proportion of men with ED undergoing penile prosthetic surgery, and prosthetic cost. EVIDENCE ACQUISITION: A systematic review of MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov was performed for studies assessing trends in penile prosthetic surgeries and costs associated with penile prosthetic device and inclusive surgical costs. EVIDENCE SYNTHESIS: Twenty-seven studies were identified during the systematic review, comprising 447,204 penile prosthetic surgeries reported from 1988 to 2019. A trend analysis demonstrates that rates of penile prosthetic surgery declined dramatically in the late 1980s and early 1990s, but have demonstrated modest growth since the mid-2000s. Outpatient inflatable penile prosthetic surgery has strongly trended upward. Costs of penile prosthetic device have matched the rate of inflation, but inclusive surgical cost has radically outpaced inflation. Growth has mainly been seen in the USA, with a more modest global growth. CONCLUSIONS: Penile prosthesis remains a viable option for the treatment of ED. Trends such as outpatient surgery and inflatable penile prosthesis placement may be driving the recent steady growth of penile prosthetic surgeries, but surging inclusive surgical cost may present a barrier for some patients without insurance coverage. PATIENT SUMMARY: Penile prostheses continue to be an important treatment for erectile dysfunction. While the volume of penile prosthetic surgeries dropped when phosphidiesterase-5 inhibitors became available, prosthetic surgery is becoming more patient centric, as seen by increases in inflatable prosthetic placement and outpatient surgery.

Evaluation of the impact of marijuana use on semen quality: a prospective analysis.

AIMS: To assess if marijuana consumption - prevalent among men of reproductive age and becoming widespread due to decriminalization - is associated with changes in semen parameters. Marijuana's active metabolite, tetrahydrocannabinol, can alter signaling pathways within spermatozoa, affecting spermatogenesis and fertility. METHODS: We prospectively evaluated semen analyses (SA) from men presenting for infertility evaluation at one institution from July 2017 to April 2018. Participants completed a reproductive health questionnaire including items regarding marijuana consumption. SA was performed in accordance with World Health Organization (WHO) 5th Edition criteria. SA parameters included volume (ml), concentration (million/ml), motility (%), progressive motility (%), and Tygerberg strict morphology (%). RESULTS: A total of 409 patients completed the questionnaire; 174 (43%) men reported marijuana use (ever-users). Current and past users comprised 71 (17%) and 103 (25%), respectively. Compared with never-users, current and past users had a significantly higher likelihood of abnormal sperm strict morphology (33.1% versus 50.7% and 53.4%, respectively; p < 0.001). However, sperm motility was more likely to be less than WHO reference values in never-users than current and past-users (38.3% versus 21.1% and 27.2%, respectively; p = 0.01). In multivariate logistic regression analyses, current use was associated with increased odds of abnormal strict morphology [odds ratio (OR) 2.15, 95% confidence interval (CI): 1.21-3.79] and semen volume less than WHO reference value (OR 2.76, 95%CI: 1.19-6.42), while odds of less than WHO reference value sperm motility were reduced (OR 0.47, 95%CI: 0.25-0.91). CONCLUSION: Marijuana use is common among men presenting for fertility evaluation, and may have a detrimental effect on semen quality, particularly morphology and volume, but may be protective against abnormal sperm motility. Large, prospective studies of both semen quality and fertility in this growing, at-risk population are warranted.

Treatment Trends and Cost Associated With Peyronie's Disease.

INTRODUCTION: Providers may use several treatment options for patients with Peyronie's disease; however, it is unclear whether practice patterns have evolved over recent years and if this has impacted cost. AIMS: To investigate trends in the treatment of Peyronie's disease over time and the associated costs using a national, commercial insurance claims database. METHODS: A retrospective cohort study was conducted using claims from the Truven MarketScan database from 2007 to 2018 for men with Peyronie's disease. Cost was estimated as either the sum of prescription oral or injectable treatment costs or as the single net cost associated with the operative procedure. MAIN OUTCOME MEASURES: Frequency of use of various treatments for Peyronie's disease and associated costs were assessed as trends over the timeline by year. RESULTS: The estimated annual incidence of Peyronie's disease in this population rose from 61 to 77 per 100,000 patients over the included years, and the percent annual treatment rate rose from 17.8% to 26.2%. Colchicine was the most commonly prescribed oral agent in 2007 used in 22% of treated individuals; by 2018, pentoxifylline was the most common prescribed oral agent used in 33%. In 2007, 11% of treated patients received intralesional verapamil; however, by 2018, 24% received injectable collagenase, whereas <1% received intralesional verapamil. The mean annual, per-individual cost of Peyronie's disease treatment increased from $1,531 in 2007 to $10,339 in 2018. The cost increase was greatest for injectable therapies, which rose from $811 per individual in 2007 to $16,184 in 2018, a 19-fold increase. CONCLUSIONS: Diagnosis and treatment of Peyronie's disease is increasing over time. Pentoxifylline has become the most common oral prescription, whereas injectable collagenase has become most common injection. The mean cost associated with Peyronie's disease treatment increased more than 5 times from 2007 to 2018 corresponding with Federal Drug Administration's approval of injectable collagenase. Loftus CJ, Rajanahally S, Holt SK, et al. Treatment Trends and Cost Associated With Peyronie's Disease. Sex Med 2020;8:673-678.

Comparison of clinician and patient users of a mobile phone application to assess penile curvature in Peyronie's disease.

Assessment of Peyronie's disease with penile injection is invasive and uncomfortable. We developed a smartphone application (UWPEN) to assess penile angulation in the home environment. The purpose of this study was to compare clinician and patient measurements and assess the patient experience with UWPEN in a clinical setting. We prospectively enrolled patients with Peyronie's disease undergoing intracavernosal injection of alprostadil. Penile angulation and narrowing were then assessed by patients and clinicians using UWPEN and compared to values obtained via a goniometer and a ruler (gold standard). Measurements were compared using the Pearson correlation test. Upon completion of measurements, patients were surveyed regarding the ease of use, confidence with use, and measurement preferences. Twenty patients were enrolled in the study; two patients were excluded for poor penile turgidity after a maximum dosage of intracavernosal alprostadil. Correlation between UWPEN and gold standard measurements by patients and clinicians was R = 0.55 (p = 0.01) and R = 0.87 (p < 0.01) for dorsal measurements, R = 0.62 (p = 0.01) and R = 0.77 (p < 0.01) for lateral measurements, and R = 0.73 (p < 0.01) and R = 0.64 (p < 0.01) for girth measurements, respectively. Prior evaluation of correlation suggests a strong correlation at R = 0.8, and good correlation at R = 0.5. Overall, patients preferred using UWPEN to traditional measurements, and 75% reported UWPEN as their first preference for measurements. UWPEN enables patients to assess their disease severity with good correlation to gold standard measurements. Patients prefer mobile platforms for disease monitoring, and development of technology for disease monitoring should be a priority within the Peyronie's disease research community.

Undergoing varicocele repair before assisted reproduction improves pregnancy rate and live birth rate in azoospermic and oligospermic men with a varicocele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate how varicocele repair (VR) impacts pregnancy (PRs) and live birth rates in infertile couples undergoing assisted reproduction wherein the male partner has oligospermia or azoospermia and a history of varicocele. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Azoospermic and oligospermic males with varicoceles and in couples undergoing assisted reproductive technology (ART) with IUI, IVF, or testicular sperm extraction (TESE) with IVF and intracytoplasmic sperm injection (ICSI). INTERVENTION(S): Measurement of PRs, live birth, and sperm extraction rates. MAIN OUTCOME MEASURE(S): Odds ratios for the impact of VR on PRs, live birth, and sperm extraction rates for couples undergoing ART. RESULT(S): Seven articles involving a total of 1,241 patients were included. Meta-analysis showed that VR improved live birth rates for the oligospermic (odds ratio [OR] = 1.699) and combined oligospermic/azoospermic groups (OR = 1.761). Pregnancy rates were higher in the azoospermic group (OR = 2.336) and combined oligospermic/azoospermic groups (OR = 1.760). Live birth rates were higher for patients undergoing IUI after VR (OR = 8.360). Sperm retrieval rates were higher in persistently azoospermic men after VR (OR = 2.509). CONCLUSION(S): Oligospermic and azoospermic patients with clinical varicocele who undergo VR experience improved live birth rates and PRs with IVF or IVF/ICSI. For persistently azoospermic men after VR requiring TESE for IVF/ICSI, VR improves sperm retrieval rates. Therefore, VR should be considered to have substantial benefits for couples with a clinical varicocele even if oligospermia or azoospermia persists after repair and ART is required.

Characterizing the Morbidity of Postchemotherapy Retroperitoneal Lymph Node Dissection for Testis Cancer in a National Cohort of Privately Insured Patients.

OBJECTIVE: To characterize morbidity of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testis cancer, we analyze a contemporary national database. PC-RPLND is the standard for residual radiographic masses ≥1 cm (nonseminoma) and positron emission tomography-avid masses ≥3 cm (seminoma). Morbidity for PC-RPLND is greater than primary RPLND, which may be mitigated by performing surgery at a high-volume cancer center. METHODS: Current Procedural Terminology and International Classification of Diseases, Ninth Edition codes identified men with testis cancer undergoing PC- or primary RPLND in MarketScan (2007-2012). Multivariable logistic regression assessed factors associated with receiving adjunctive procedures (ie, nephrectomy, vascular reconstruction), prolonged hospitalization, and 90-day readmission. Geographic variables assessed regionalization of PC-RPLND. RESULTS: Of 559 men with claims for PC- or primary RPLND (206, 37% PC-RPLND), 19% of PC-RPLND underwent adjunctive procedures (vs 1% among RPLND, P < .01). For PC-RPLND, the nephrectomy rate was 10% and the vascular reconstruction rate was 8%. On multivariable analysis, PC-RPLND was associated with undergoing adjunctive procedures (odds ratio 41.9; 95% confidence interval 11.7, 150) and prolonged hospitalization (odds ratio 3.75; 95% confidence interval 1.68, 8.42) compared to primary RPLND. PC-RPLND was not associated with 90-day readmission. Up to 29% of PC-RPLNDs are performed in centers, billing just a single case through MarketScan in the 6 years studied. CONCLUSION: PC-RPLND is associated with adjunctive procedures and longer hospitalizations. Given the morbidity of PC-RPLND in this young patient population, efforts are needed to establish quality benchmarks for, reduce the morbidity of, and to accurately discriminate risk during patient discussions prior to this complex, specialized surgery.

Urethral diverticulum after midurethral sling erosion, excision, and subsequent management.

BACKGROUND: Urethral diverticulum formation after midurethral sling placement is a very rare complication. Only 3 previous cases have been reported in the English literature. This is the first reported case of urethral diverticulum formation after midurethral sling excision for urethral erosion. CASE: A 43-year-old female patient presented with recurrent stress incontinence after midurethral tension-free vaginal tape sling removal for urethral erosion. Retrograde urethrogram demonstrated a urethral diverticulum. Video urodynamics showed a Valsalva leak point pressure of 50 cm H2O at 250 mL. She subsequently underwent urethral diverticulectomy with pubovaginal sling placement. CONCLUSIONS: We present the first reported case of urethral diverticulum formation after midurethral sling excision for urethral erosion. Future consideration must be given to full excision of the sling tract during the sling removal operation in cases of urethral erosion to prevent this rare complication.

The fate of transitional urology patients referred to a tertiary transitional care center.

OBJECTIVE: To determine the changes in management of children with neurogenic bladder (NGB) or genitourinary congenital anomalies as they moved to our transitional care clinic at the Center for Restorative Pelvic Medicine, a multidisciplinary center led by an adult urologic team dedicated to the long-term care of these patients. MATERIALS AND METHODS: We retrospectively reviewed charts of patients with NGB or genitourinary congenital abnormalities referred between 2010 and 2013. Analysis included patient characteristics, causes of NGB, bladder management, recurrent urinary tract infection, stones, renal function, upper tract studies, video urodynamics, and change in management. RESULTS: Twenty-four patients with an average age of 22.0 ± 2.7 years were included in analysis. Management was altered in 70.8% of patients (n = 17). Surgical management was instituted in 58.3% (n = 14 of 24) of patients and included bladder augmentation or urinary diversion (n = 7), intravesical botulinum toxin A injections (n = 5), cystolitholapaxy, or cystolithotomy (n = 2). Conservative management was changed in 12.5% (n = 3) of patients and included initiating anticholinergic medication (n = 2) or self-catheterization (n = 1). Follow-up was 8.9 ± 12.1 months. CONCLUSION: There is an immense need for transitional care of patients with NGB or genitourinary congenital abnormalities as they grow into adulthood. Nearly 71% of our patients had a change in their bladder management with 38% undergoing a major surgery. This study emphasizes the necessity for a dedicated adult urologic team in conjunction with a comprehensive team to care for these complex patients because their urologic care and needs may vary significantly from their childhood.

Patient satisfaction with testosterone replacement therapies: the reasons behind the choices.

INTRODUCTION: Testosterone replacement therapy (TRT) for male hypogonadism is rapidly gaining popularity and acceptance. Options include gels, injections, and implantable subcutaneous pellets. AIMS: The aim of this study was to determine rates of patient satisfaction and reasons for patient preferences in hypogonadal men on TRT. METHODS: An anonymous, prospective survey was distributed to men presenting for TRT at an academic urology clinic. The survey was organized into multiple domains including patient satisfaction and treatment motivation. MAIN OUTCOME MEASURES: Patient satisfaction responses obtained via anonymous survey. RESULTS: Average patient age was 49 ± 0.7 years (n = 382). Injectable testosterone was chosen by 53%, gel-based regimens by 31%, and pellets by 17%. Overall, 70% of patients were satisfied with their TRT and 14% reported dissatisfaction. Satisfaction rates were similar between gels (68%), injections (73%), and implantable pellets (70%). Doctor recommendation was the sole significant reason for patients preferring gel-based TRT (66% vs. 37% injection users vs. 31% pellet users). Injectable TRT was favored because of lower cost (35% vs. 21% gel users vs. 19% pellet users). Pellets were favored for ease of use (64% vs. 44% injection users vs. 43% gel users) and convenience (58% vs. 26% injection users vs. 19% gel users). Pellets had increased rates of satisfaction within the first 12 months. Improvements in concentration and mood occurred at higher percentages in satisfied patients. CONCLUSIONS: Patients are satisfied with TRT. Lower costs are important to patients on injections. Convenience and ease of use are central in choosing pellet therapy. Men on TRT should be questioned about mood and concentration because these factors exhibited the greatest improvements in satisfied patients.

Factors influencing patient decisions to initiate and discontinue subcutaneous testosterone pellets (Testopel) for treatment of hypogonadism.

INTRODUCTION: A variety of modalities for testosterone replacement therapy (TRT) are available, including topical gels, injections, and Testopel subcutaneous testosterone pellets (STP). STP are becoming more commonly utilized in the United States; however, patient preferences, expectations, and usage patterns regarding this therapy remain poorly characterized. AIM: To identify factors influencing patients' decisions to initiate or discontinue STP. METHODS: A total of 175 men from an academic urology clinic who were currently using or who had previously used STP for hypogonadism received a 32-item electronic survey. MAIN OUTCOME MEASURES: Assessment of the impact of convenience, efficacy, side effects, cost, and symptom relief on initiation and discontinuation of STP. RESULTS: One hundred and thirteen men (64.6% response rate) of mean age 51.4 years who previously underwent a mean of 2.8 STP implant procedures completed the survey. Fifty-nine (52.2%) and 40 (35.4%) men had switched to STP from topical gel and injection therapy, respectively, whereas 14 (12.4%) men initially started TRT with STP. Convenience (68.8%) was the most important factor in patients' decision to start STP, while cost of the previous form of TRT (14.7%) was least important. At the time of the survey, 32 men (28.3%) had discontinued STP therapy. Cost of therapy (50%) was the primary factor in discontinuing STP. There was no difference in serum testosterone levels between men who continued STP and those who discontinued therapy (642.8 vs. 629.0 ng/dL, P = 0.83). Overall, 68.1% of patients continued STP therapy at the time of survey completion. CONCLUSIONS: Convenience is the most important factor in a patient's decision to initiate STP; however, physician recommendation also plays a substantial role. Cost was the primary reason for discontinuation. Upon survey completion, greater than two-thirds of respondents elected to continue STP therapy. STP are a viable treatment option for hypogonadal men seeking a convenient and efficacious alternative modality of TRT.

Anabolic steroid induced hypogonadism in young men.

PURPOSE: The use of anabolic androgenic steroids has not been traditionally discussed in mainstream medicine. With the increased diagnosis of hypogonadism a heterogeneous population of men is now being evaluated. In this larger patient population the existence of anabolic steroid induced hypogonadism, whether transient or permanent, should now be considered. MATERIALS AND METHODS: We performed an initial retrospective database analysis of all 6,033 patients who sought treatment for hypogonadism from 2005 to 2010. An anonymous survey was subsequently distributed in 2012 to established patients undergoing testosterone replacement therapy. RESULTS: Profound hypogonadism, defined as testosterone 50 ng/dl or less, was identified in 97 men (1.6%) in the large retrospective cohort initially reviewed. The most common etiology was prior anabolic androgenic steroid exposure, which was identified in 42 men (43%). Because of this surprising data, we performed an anonymous followup survey of our current hypogonadal population of 382 men with a mean±SD age of 49.2±13.0 years. This identified 80 patients (20.9%) with a mean age of 40.4±8.4 years who had prior anabolic androgenic steroid exposure. Hypogonadal men younger than 50 years were greater than 10 times more likely to have prior anabolic androgenic steroid exposure than men older than 50 years (OR 10.16, 95% CI 4.90-21.08). Prior anabolic androgenic steroid use significantly correlated negatively with education level (ρ=-0.160, p=0.002) and number of children (ρ=-0.281, p<0.0001). CONCLUSIONS: Prior anabolic androgenic steroid use is common in young men who seek treatment for symptomatic hypogonadism and anabolic steroid induced hypogonadism is the most common etiology of profound hypogonadism. These findings suggest that it is necessary to refocus the approach to evaluation and treatment paradigms in young hypogonadal men.

Defective gonadotropin-dependent ovarian folliculogenesis and granulosa cell gene expression in inhibin-deficient mice.

Inhibin-α knockout (Inha-/-) female mice develop sex cord-stromal ovarian cancer with complete penetrance and previous studies demonstrate that the pituitary gonadotropins (FSH and LH) are influential modifiers of granulosa cell tumor development and progression in inhibin-deficient females. Recent studies have demonstrated that Inha-/- ovarian follicles develop precociously to the early antral stage in prepubertal mice without any increase in serum FSH. These studies suggest that in the absence of inhibins, granulosa cells differentiate abnormally and thus at sexual maturity may undergo an abnormal response to gonadotropin signaling contributing to tumor development. To test this hypothesis, we stimulated immature wild-type and Inha-/- female mice with gonadotropin analogs prior to tumor formation and subsequently examined gonadotropin-induced ovarian follicle development as well as preovulatory and human chorionic gonadotropin-induced gene expression changes in granulosa cells. We find that at 3 wk of age, inhibin-deficient ovaries do not show further antral development or undergo cumulus expansion. In addition, there are widespread alterations in the transcriptome of gonadotropin-treated Inha-/- granulosa cells, with significant changes in genes involved in extracellular matrix and cell-cell communication. These data indicate the gonadotropins initiate an improper program of cell differentiation prior to tumor formation in the absence of inhibins.

Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice.

BACKGROUND: Inhibin is a tumor-suppressor and activin antagonist. Inhibin-deficient mice develop gonadal tumors and a cachexia wasting syndrome due to enhanced activin signaling. Because activins signal through SMAD2 and SMAD3 in vitro and loss of SMAD3 attenuates ovarian tumor development in inhibin-deficient females, we sought to determine the role of SMAD2 in the development of ovarian tumors originating from the granulosa cell lineage. METHODS: Using an inhibin alpha null mouse model and a conditional knockout strategy, double conditional knockout mice of Smad2 and inhibin alpha were generated in the current study. The survival rate and development of gonadal tumors and the accompanying cachexia wasting syndrome were monitored. RESULTS: Nearly identical to the controls, the Smad2 and inhibin alpha double knockout mice succumbed to weight loss, aggressive tumor progression, and death. Furthermore, elevated activin levels and activin-induced pathologies in the liver and stomach characteristic of inhibin deficiency were also observed in these mice. Our results indicate that SMAD2 ablation does not protect inhibin-deficient females from the development of ovarian tumors or the cachexia wasting syndrome. CONCLUSIONS: SMAD2 is not required for mediating tumorigenic signals of activin in ovarian tumor development caused by loss of inhibin.

Stable expression and characterization of N-terminal tagged recombinant human bone morphogenetic protein 15.

Oocyte-derived growth factors are critically involved in multiple ovarian processes via paracrine actions. Although recombinant proteins have been applied to dissect the physiological functions of these factors, variation of activities among different protein preparations remains an issue. To further elucidate the roles of one of these growth factors, bone morphogenetic protein 15 (BMP15), in mediating oocyte-regulated molecular and cellular events and to explore its potential clinical application, we engineered the human BMP15 sequence to efficiently produce bioactive recombinant human BMP15 (rhBMP15). The proteolytic cleavage site of the hBMP15 precursor was optimized to facilitate the production of the mature protein, and a FLAG-tag was placed at the N-terminus of the mature region to ease purification and avoid potential interference of the tag with the cystine knot structure. The rhBMP15 protein was purified using anti-FLAG M2 affinity gel. Our results demonstrated that the N-terminal tagged rhBMP15 was efficiently processed in HEK-293 cells. Furthermore, the purified rhBMP15 could activate SMAD1/5/8 and induce the transcription of genes encoding cumulus expansion-related transcripts (Ptx3, Has2, Tnfaip6 and Ptgs2), inhibitory SMADs (Smad6 and Smad7), BMP antagonists (Grem1 and Fst), activin/inhibin betaA (Inhba) and betaB (Inhbb) subunits, etc. Thus, our rhBMP15 containing a genetically modified cleavage sequence and an N-terminal FLAG-tag can be efficiently produced, processed and secreted in a mammalian expression system. The purified rhBMP15 is also biologically active and very stable, and can induce the expression of a variety of mouse granulosa cell genes.