Sexual function remains persistently low in women after treatment for colorectal cancer and anal squamous cell carcinoma.

BACKGROUND: Women diagnosed with colorectal cancer (CRC) or anal squamous cell carcinoma (ASCC) are at high risk of sexual dysfunction after treatment, yet little is known about recovery and risk factors for chronic dysfunction. AIM: We aimed to describe sexual function and sexual activity among women who underwent definitive treatment for CRC or ASCC, examine relationships between time since treatment completion and sexual function, and explore factors associated with desire and changes in sexual desire over time. METHODS: As part of a prospective cohort study of patients with gastrointestinal cancer at the University of California San Francisco, female-identifying participants who finished definitive treatment for CRC or ASCC completed the Female Sexual Function Index (FSFI) at 6- to 12-month intervals. We used multivariable linear mixed models to explore factors associated with the FSFI desire subscale. OUTCOMES: Outcomes were rates of sexual activity, proportion at risk for sexual dysfunction (FSFI score <26.55), total FSFI score, and FSFI desire subscale. RESULTS: Among the 97 cancer survivors who completed at least 1 FSFI, the median age was 59 years, the median time since treatment end was 14 months, and 87% were menopausal. Fifty-five women (57%) had a history of colon cancer; 21 (22%), rectal cancer; and 21 (22%), ASCC. An additional 13 (13%) had a current ostomy. Approximately half the women were sexually active (n = 48, 49%). Among these 48 sexually active women, 34 (71%) had FSFI scores indicating risk for sexual dysfunction. Among the 10 sexually active women who completed a FSFI ≥2 years since end of treatment, the median total score was 22.6 (IQR, 15.6-27.3). None of the evaluated characteristics were associated with desire (age, tumor site, treatment, menopause status, or ostomy status). CLINICAL IMPLICATIONS: Consistent with prior studies, we found low desire scores after treatment for CRC or ASCC, with little recovery over time, suggesting that patients should not expect an eventual rebound of sexual function. STRENGTHS AND LIMITATIONS: Strengths of our study include longitudinal data and use of the validated FSFI. Women with ASCC composed 22% of our cohort, allowing for insight into this rare disease group. Limitations of this study include the small sample size, particularly for longitudinal analyses, and the enrollment of patients at variable times since treatment end. CONCLUSION: We observed a high prevalence of sexual health concerns, including low desire, after the treatment of CRC and ASCC that persisted for years after treatment was completed.

Hematospermia is rarely associated with urologic malignancy: Analysis of United States claims data.

BACKGROUND: Hematospermia is an alarming symptom and can cause significant patient distress, but work-up is often negative. OBJECTIVE: To characterize the clinical evaluation of hematospermia and its association with the diagnosis of urologic malignancy. MATERIALS AND METHODS: Using MarketScan insurance claims database, we identified adult males 18-64 years old diagnosed with hematospermia from 2010 to 2018. Benign hematospermia was defined as the absence of hematuria and elevated prostate-specific antigen. Patients with urologic cancer prior to diagnosis of hematospermia were excluded. We identified those who were diagnosed with a urologic malignancy. RESULTS: The annual average incidence rate of hematospermia was 56.6 per 100,000 (95% confidence interval 55.4-57.8 per 100,000) in 2010 and increased to 73.6 per 100,000 (95% confidence interval 71.7-75.4 per 100,000) in 2018. A total of 56,157 patients presented with benign hematospermia. Most (57.5%) underwent at least one test, with the most common being urinalysis (51.7%), followed by prostate-specific antigen testing (11.9%). All other tests were performed in less than 3% of patients. Forty-seven patients were diagnosed with a urologic cancer, including 28 with prostate cancer (0.05%), nine with testicular cancer (0.016%), six with prostate carcinoma in situ (0.01%), and four with bladder cancer (0.007%). Stratified by age, there was only one cancer diagnosis (testicular) in 15,106 patients under 40 years (0.01%) and 46 cancer diagnoses in 40,611 patients 40 years old or above (0.11%). The median age of patients diagnosed with cancer was 56 years (interquartile range 52-61). DISCUSSION AND CONCLUSION: A small minority of patients with benign hematospermia were later diagnosed with urologic cancer in a large nationally representative sample. After excluding hematuria with urinalysis, physicians should conservatively manage and reassure patients with hematospermia, especially those under 40 years of age.

Resolving species boundaries in a recent radiation with the Angiosperms353 probe set: the Lomatium packardiae/L. anomalum clade of the L. triternatum (Apiaceae) complex.

PREMISE: Speciation not associated with morphological shifts is challenging to detect unless molecular data are employed. Using Sanger-sequencing approaches, the Lomatium packardiae/L. anomalum subcomplex within the larger Lomatium triternatum complex could not be resolved. Therefore, we attempt to resolve these boundaries here. METHODS: The Angiosperms353 probe set was employed to resolve the ambiguity within Lomatium triternatum species complex using 48 accessions assigned to L. packardiae, L. anomalum, or L. triternatum. In addition to exon data, 54 nuclear introns were extracted and were complete for all samples. Three approaches were used to estimate evolutionary relationships and define species boundaries: STACEY, a Bayesian coalescent-based species tree analysis that takes incomplete lineage sorting into account; ASTRAL-III, another coalescent-based species tree analysis; and a concatenated approach using MrBayes. Climatic factors, morphological characters, and soil variables were measured and analyzed to provide additional support for recovered groups. RESULTS: The STACEY analysis recovered three major clades and seven subclades, all of which are geographically structured, and some correspond to previously named taxa. No other analysis had full agreement between recovered clades and other parameters. Climatic niche and leaflet width and length provide some predictive ability for the major clades. CONCLUSIONS: The results suggest that these groups are in the process of incipient speciation and incomplete lineage sorting has been a major barrier to resolving boundaries within this lineage previously. These results are hypothesized through sequencing of multiple loci and analyzing data using coalescent-based processes.

Ex vivo human testes as a practical model to simulate ultrasound-guided testicular cell transplantation for human fertility restoration.

OBJECTIVE: To develop an ex vivo model to practice ultrasound-guided injection of cellular material into human seminiferous tubules to simulate testicular cell transplantation (TCT). DESIGN: Simulated TCT injections were performed in human testes removed during orchiectomy. The rete testis was the target site of injection. Successful retrograde infiltration of injected material into the lumen of the seminiferous tubules was detected using ultrasound and confirmed with histology. SETTING: Single academic surgical center. PATIENT(S): Adult patients undergoing orchiectomy for nononcologic indications. INTERVENTION(S): The testes were injected with sonographic contrast (Optison), methylene blue, and fluorescent-labeled cells. MAIN OUTCOME MEASURE(S): A characteristic streaming pattern of sonographic contrast in the testis was used to define sonographic success, and the presence of methylene blue and fluorescent-labeled cells within the seminiferous tubules confirmed histologic success. RESULT(S): We performed simulated TCT injections in 30 testes obtained from 16 patients undergoing orchiectomy. We were able to achieve sonographic success in 57% of injections and confirmed that sonographic success is correlated with histologic success. CONCLUSION(S): Testicular cell transplantation injections can be practiced using human testes. As there appears to be a learning curve associated with this procedure, developing this infrastructure to practice these skills is critical before implementation in patients.

Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences.

Translation of modulation of drug target activity to therapeutic effect is a critical aspect for all drug discovery programs. In this work we describe the profiling of a non-receptor tyrosine-protein kinase (TYK2) inhibitor which shows a functionally relevant potency shift between human and preclinical species (e.g. murine, dog, macaque) in both biochemical and cellular assays. Comparison of the structure and sequence homology of TYK2 between human and preclinical species within the ATP binding site highlights a single amino acid (I960 → V) responsible for the potency shift. Through TYK2 kinase domain mutants and a TYK2 980I knock-in mouse model, we demonstrate that this single amino acid change drives a functionally relevant potency difference that exists between human and all evaluated preclinical species, for a series of TYK2 inhibitors which target the ATP binding site.

Fertility Related Quality of Life, Gonadal Function and Erectile Dysfunction in Male Partners of Couples with Unexplained Infertility.

PURPOSE: We sought to determine whether lower fertility related quality of life or depression in men of couples with unexplained infertility is associated with low total testosterone levels, abnormal semen quality or erectile dysfunction. MATERIALS AND METHODS: This study is a secondary analysis of a large, multicenter, randomized controlled trial in couples with unexplained infertility. Male partners underwent baseline semen analysis with measurement of fasting total testosterone and gonadotropin. They also completed surveys, including the FertiQOL (Fertility Quality of Life), the PHQ-9 (Patient Health Questionnaire-9) and the IIEF (International Index of Erectile Function). The primary study outcomes were total testosterone with low total testosterone defined as less than 264 ng/dl, semen parameters and the IIEF score. We performed multivariable logistic regression analyses adjusted for patient age, race, body mass index, education, smoking, alcohol use, infertility duration and comorbidity. RESULTS: A total of 708 men with a mean ± SD age of 34.2 ± 5.6 were included in study. Of the men 59 (8.3%) had a PHQ-9 score of 5 or greater, which was consistent with depression, 99 (14.0%) had low total testosterone and 63 (9.0%) had mild or worse erectile dysfunction. Neither the FertiQOL score nor depression was associated with total testosterone or any semen parameter. The FertiQOL score was inversely associated with erectile dysfunction (for every 5-point score decline AOR 1.30, 95% CI 1.16-1.46). Depressed men were significantly more likely to have erectile dysfunction than nondepressed men (AOR 6.31, 95% CI 3.12-12.77). CONCLUSIONS: In men in couples with unexplained infertility lower fertility related quality of life and depression are strongly associated with erectile dysfunction. However, neither is associated with spermatogenesis or testosterone levels. Erectile dysfunction in infertile men merits longitudinal investigation in future studies.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Fertility preservation for men with testicular cancer: Is sperm cryopreservation cost effective in the era of assisted reproductive technology?

INTRODUCTION: Many patients do not cryopreserve sperm before undergoing cancer treatment because of high perceived costs of cryopreservation. We sought to investigate the cost-effectiveness of fertility preservation compared to posttherapeutic fertility treatment in testicular cancer patients. MATERIALS AND METHODS: We performed a systematic search of the PubMed database for the following: risk of azoospermia 12 months after surveillance, chemotherapy, retroperitoneal lymph node dissection, and radiation therapy (RT); rates of natural conception, and rates of conception with the use of intrauterine insemination or assisted reproductive technology, with or without microsurgical testicular sperm extraction (microTESE). A decision tree was constructed using the TreePlan add-in for Microsoft Excel (TreePlan Software, San Francisco, California). Cost-effectiveness was calculated as the overall cost of a given management branch, divided by likelihood of pregnancy. Calculations accounted for variable number of years of cryopreservation, and variable costs of microTESE. RESULTS: 1,113 articles were identified; 44 were included in the final analysis. Overall probability of pregnancy was higher among couples who cryopreserved sperm, versus those who did not. In patients undergoing active surveillance or retroperitoneal lymph node dissection, cryopreservation was more cost-effective if storage time was short (<6 years) or microTESE cost was high (>7,000). Cryopreservation prior to chemotherapy was more cost-effective unless microTESE cost was low (<7,000). Cryopreservation prior to RT was more cost-effective in almost all scenarios. CONCLUSIONS: Sperm cryopreservation prior to undergoing chemotherapy or RT remains the most cost-effective strategy for fertility preservation, across a range of possible costs associated with surgical sperm retrieval and in vitro fertilization/intracytoplasmic sperm injection.

The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.

Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.

Tyrosine Kinase Inhibitors and Male Reproductive Health.

Tyrosine kinase inhibitors (TKIs) are a targeted class of cancer therapies effective against a range of malignancies and their use is growing significantly each year. Many men taking TKIs desire children, yet very little is known about the potential for reproductive harm of these medications. The mechanism of action of TKIs suggest a possible route to impairment of sperm functional properties or spermatogenesis.

Semen amyloids participate in spermatozoa selection and clearance.

Unlike other human biological fluids, semen contains multiple types of amyloid fibrils in the absence of disease. These fibrils enhance HIV infection by promoting viral fusion to cellular targets, but their natural function remained unknown. The similarities shared between HIV fusion to host cell and sperm fusion to oocyte led us to examine whether these fibrils promote fertilization. Surprisingly, the fibrils inhibited fertilization by immobilizing sperm. Interestingly, however, this immobilization facilitated uptake and clearance of sperm by macrophages, which are known to infiltrate the female reproductive tract (FRT) following semen exposure. In the presence of semen fibrils, damaged and apoptotic sperm were more rapidly phagocytosed than healthy ones, suggesting that deposition of semen fibrils in the lower FRT facilitates clearance of poor-quality sperm. Our findings suggest that amyloid fibrils in semen may play a role in reproduction by participating in sperm selection and facilitating the rapid removal of sperm antigens.

Mucosal stromal fibroblasts markedly enhance HIV infection of CD4+ T cells.

Understanding early events of HIV transmission within mucosal tissues is vital for developing effective prevention strategies. Here, we report that primary stromal fibroblasts isolated from endometrium, cervix, foreskin, male urethra, and intestines significantly increase HIV infection of CD4+ T cells-by up to 37-fold for R5-tropic HIV and 100-fold for X4-tropic HIV-without themselves becoming infected. Fibroblasts were more efficient than dendritic cells at trans-infection and mediate this response in the absence of the DC-SIGN and Siglec-1 receptors. In comparison, mucosal epithelial cells secrete antivirals and inhibit HIV infection. These data suggest that breaches in the epithelium allow external or luminal HIV to escape an antiviral environment to access the infection-favorable environment of the stromal fibroblasts, and suggest that resident fibroblasts have a central, but previously unrecognized, role in HIV acquisition at mucosal sites. Inhibiting fibroblast-mediated enhancement of HIV infection should be considered as a novel prevention strategy.

Fertility preservation options for prepubertal boys facing gonadotoxic therapies.

Infertility is a common disease affecting 10-15% of reproductive couples with significant psychological and financial impacts to both patients and society. Approximately 80 million people worldwide are infertile, with an increasing incidence of male infertility. Semen cryopreservation in adults is a proven method of fertility preservation for male patients undergoing gonadal toxic therapies. Unlike adults who can cryopreserve sperm at any time prior to gonadal toxic treatments, there are no effective fertility preservation options for children undergoing cancer treatment, a time when semen cryopreservation is not feasible. Thus, most of the childhood cancer survivor will develop irreversible azoospermia due to the gonadal toxicity of the treatment on spermatogononial stem cells. This review will summarize the possible options and challenges of fertility preservation in this vulnerable population.

Limitations and barriers in access to care for male factor infertility.

The primary challenge to identifying and addressing barriers in access to care for male factor infertility is accurate measurement of the prevalence of male infertility. Current estimates are based on couples pursuing assisted reproduction, and likely underestimate the problem. These estimates also fail to account for the number of patients facing infertility due to cancer or cancer treatment. Lack of health insurance coverage for the diagnosis and treatment of infertility presents a major barrier for couples struggling with infertility. However, it is not the only barrier. Education level, household income, cultural norms, religious beliefs, geographic location, and the availability of specialty-trained reproductive urologists are all important factors in determining the ease with which patients access and obtain infertility care. Addressing each of these obstacles directly is imperative to improving reproductive care and outcomes for infertile couples in the United States.

Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone.

Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/ß hydrolase domain-containing protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization.

The continuing threat of syphilis in pregnancy.

PURPOSE OF REVIEW: Syphilis in pregnancy continues to be a worldwide threat to mothers and their fetuses, and in recent years has been increasing in prevalence. The purpose of this short review is to address current issues in the diagnosis and management of syphilis complicating pregnancies. RECENT FINDINGS: Maternal syphilis infections and congenital syphilis appear to be increasing in both high and low resource settings. Treponema pallidum ssp. pallidum, the causative spirochete of syphilis, remains one of the few human infectious pathogens that has not been successfully cultured, making identification difficult and research in targeted antimicrobial therapies challenging. Fortunately, syphilis remains sensitive to penicillin, which remains the foundational therapy for this infection. Patients with syphilis and significant penicillin allergies remain a specific challenge in treatment. Of concern is the emergence of T. pallidum resistant to macrolides such as azithromycin. This will limit options in patients with penicillin allergies, and potentially contribute to suboptimal treatment. During pregnancy, penicillin is the only known effective treatment for congenital syphilis, and pregnant patients with penicillin allergy should be desensitized and treated with penicillin. Research focusing on protein expression of the genome of T. pallidum may lead to more accurate screening and diagnosis and development of novel antibiotic therapies. SUMMARY: Obstetric and pediatric providers, public health organizations, and governments should recognize the re-emergence of syphilis globally and in their local healthcare environments. Screening of all pregnant patients with robust treatment and follow-up represents the most effective method to reduce congenital syphilis currently available.

Testicular niche required for human spermatogonial stem cell expansion.

Prepubertal boys treated with high-dose chemotherapy do not have an established means of fertility preservation because no established in vitro technique exists to expand and mature purified spermatogonial stem cells (SSCs) to functional sperm in humans. In this study, we define and characterize the unique testicular cellular niche required for SSC expansion using testicular tissues from men with normal spermatogenesis. Highly purified SSCs and testicular somatic cells were isolated by fluorescence-activated cell sorting using SSEA-4 and THY1 as markers of SSCs and somatic cells. Cells were cultured on various established niches to assess their role in SSC expansion in a defined somatic cellular niche. Of all the niches examined, cells in the SSEA-4 population exclusively bound to adult testicular stromal cells, established colonies, and expanded. Further characterization of these testicular stromal cells revealed distinct mesenchymal markers and the ability to undergo differentiation along the mesenchymal lineage, supporting a testicular multipotent stromal cell origin. In vitro human SSC expansion requires a unique niche provided exclusively by testicular multipotent stromal cells with mesenchymal properties. These findings provide an important foundation for developing methods of inducing SSC growth and maturation in prepubertal testicular tissue, essential to enabling fertility preservation for these boys.

Characterization of human spermatogonial stem cell markers in fetal, pediatric, and adult testicular tissues.

Autologous spermatogonial stem cell (SSC) transplantation is a potential therapeutic modality for patients with azoospermia following cancer treatment. For this promise to be realized, definitive membrane markers of prepubertal and adult human SSCs must be characterized in order to permit SSC isolation and subsequent expansion. This study further characterizes the markers of male gonocytes, prespermatogonia, and SSCs in humans. Human fetal, prepubertal, and adult testicular tissues were analyzed by confocal microscopy, fluorescence-activated cell sorting, and qRT-PCR for the expression of unique germ cell membrane markers. During male fetal development, THY1 and KIT (C-Kit) are transient markers of gonocytes but not in prespermatogonia and post-natal SSCs. Although KIT expression is detected in gonocytes, THY1 expression is also detected in the somatic component of the fetal testes in addition to gonocytes. In the third trimester of gestation, THY1 expression shifts exclusively to the somatic cells of the testes where it continues to be detected only in the somatic cells postnatally. In contrast, SSEA4 expression was only detected in the gonocytes, prespermatogonia, SSCs, and Sertoli cells of the fetal and prepubertal testes. After puberty, SSEA4 expression can only be detected in primitive spermatogonia. Thus, although THY1 and KIT are transient markers of gonocytes, SSEA4 is the only common membrane marker of gonocytes, prespermatogonia, and SSCs from fetal through adult human development. This finding is essential for the isolation of prepubertal and adult SSCs, which may someday permit fertility preservation and reversal of azoospermia following cancer treatment.