The Montréal Classification of urethral lengthening for phalloplasty in transmasculine patients-surgical techniques and urethral complications.

Introduction: Phalloplasties are one of the most performed genital surgeries in the treatment of gender dysphoria for transmasculine patients. Urethral lengthening is an essential component of phalloplasties. Few techniques have been described for the creation of this pars fixa urethra. The purpose of this article is to present the Montréal Classification for pars fixa urethral lengthening, to detail the surgical techniques and to report on clinical outcomes. Materials and methods: All patients undergoing phalloplasty from November 2016 to February 2019 were included in this study. Patient demographics, type of surgery and urological complications were recorded. Statistics were performed using student's T-test, Chi-squared test, Fisher's exact test and One-way ANOVA. Patients underwent either type 1, type 2, or type 3 urethral reconstruction. Results: Of the 84 total patients, 45 underwent type 1 lengthening, 28 type 2, and 11 type 3. Eighteen and 33 patients underwent single-stage and two stage anastomosis of the pars fixa to the pars pendulans neourethra, respectively. Thirty-three patients have not had any additional surgeries to date. Post-operative urological complications for immediate anastomosis and two-stage anastomosis were reported in 77.7% and 18.2% of patients, respectively. Conclusions: We propose a classification as well as a description of three types of urethral lengthening techniques. Over the last few years, we have shifted away from single-stage anastomosis and have adopted a two-stage anastomosis technique. Our experience allows us to classify urethral lengthening and to standardize care depending on patient characteristics, leading to excellent results.

Gender-Affirming Vaginoplasty: A Comparison of Algorithms, Surgical Techniques and Management Practices across 17 High-volume Centers in North America and Europe.

Penile inversion vaginoplasty is the most common gender-affirming genital surgery performed around the world. Although individual centers have published their experiences, expert consensus is generally lacking. Methods: Semistructured interviews were performed with 17 experienced gender surgeons representing a diverse mix of specialties, experience, and countries regarding their patient selection, preoperative management, vaginoplasty techniques, complication management, and postoperative protocols. Results: There is significant consistency in practices across some aspects of vaginoplasty. However, key areas of clinical heterogeneity are also present and include use of extragenital tissue for vaginal canal/apex creation, creation of the clitoral hood and inner labia minora, elevation of the neoclitoral neurovascular bundle, and perioperative hormone management. Pathway length of stay is highly variable (1-9 days). Lastly, some surgeons are moving toward continuation or partial reduction of estrogen in the perioperative period instead of cessation. Conclusions: With a broad study of surgeon practices, and encompassing most of the high-volume vaginoplasty centers in Europe and North America, we found key areas of practice variation that represent areas of priority for future research to address. Further multi-institutional and prospective studies that incorporate patient-reported outcomes are necessary to further our understanding of these procedures.

Gender-Affirming Surgery in Adolescents and Young Adults: A Review of Ethical and Surgical Considerations.

BACKGROUND: The number of transgender adolescents seeking gender-affirming surgery (GAS) in increasing. Surgical care of the adolescent transgender patient is associated with several unique technical, legal, and ethical factors. The authors present a review of the current literature on gender-affirming surgery for individuals under the age of legal majority and propose directions for future research. METHODS: A scoping review of recent literature was performed to assess evidence on gender-affirming surgery in individuals under the age of legal majority. Articles were included that examined either ethical or technical factors unique to pediatric GAS. Study characteristics and conclusions were analyzed in conjunction with expert opinion. RESULTS: Twelve articles were identified that met inclusion criteria. Ten of these articles discussed ethical challenges in adolescent GAS, seven discussed legal challenges, and five discussed technical challenges. Ethical discussions focused on the principles of beneficence, nonmaleficence, and autonomy. Legal discussions centered on informed consent and insurance coverage. Technical discussions focused on the effects of puberty blockade on natal tissue. CONCLUSIONS: Surgical care of the adolescent transgender patient involves important ethical, legal, and technical considerations that must be addressed by the clinical team. As the population of individuals seeking GAS after puberty blockade increases, future research is needed describing functional and psychosocial outcomes in these individuals.

Incidence of Testicular Cancer in Transfeminine Patients following Vaginoplasty with Orchidectomy.

Background: Little is known about the prevalence of testicular cancer in the transfeminine population. Only six cases have been reported in the literature. This case series reports six additional cases of various testicular cancers found in transfeminine patients who underwent vaginoplasty with orchidectomy in our institution. Methods: In our institution, all specimens are routinely sent to pathology following vaginoplasty with orchidectomy. This permitted the identification of all positive cases of testicular cancer. A chart review was conducted to retrieve patient demographics, duration of hormonotherapy, type of neoplasm, the context of its discovery, and cancer follow-up. Results: A total of 2555 patients underwent vaginoplasty with orchidectomy between January 2016 and January 2021. All specimens were sent to pathology for analysis. A total of six (0.23% of patients) specimens revealed malignant lesions. Conclusions: Increased societal awareness toward the transgender population encourages recourse to gender-affirming procedures. Little is known about the incidence of testicular cancer in the transfeminine population. In total, 0.23% of patients in our cohort presented with positive pathology findings indicative of testicular cancer. All cancers were found to be only locally invasive, and all patients were successfully treated. We therefore encourage routine pathology examination for all specimens following vaginoplasty with orchidectomy.

HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy.

HIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune-privileged tissues, such as the testes, may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed the proviral burden and genetics in the blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by quantitative PCR, and subgenomic proviral sequences (nef region) were characterized from single templates. HIV diversity, compartmentalization, and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from the blood (396 sequences; 354 nef-intact sequences) and testes (326 sequences; 309 nef-intact sequences) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and the immune escape burden correlated positively between blood and testes. When all intact nef sequences were evaluated, 60% of participants exhibited significant blood-testis genetic compartmentalization, but none did so when the evaluation was restricted to unique sequences per site, suggesting that compartmentalization, when present, is attributable to the clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testis reservoirs. Furthermore, while the testis microenvironment may not be sufficiently unique to facilitate the seeding of unique viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication.IMPORTANCE Two key questions in HIV reservoir biology are whether immune-privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy and, if so, by what mechanism. While our results indicated that blood-testis HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood-tissue data set retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testis reservoirs differ is not via seeding of divergent HIV sequences therein but, rather, via differential clonal expansion of latently infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of a broadly similar magnitude across the blood and testes, clonal expansion represents a challenge. The results support individualized analysis of within-host reservoir diversity to inform curative approaches.

Assessment of Pelvic Floor Anatomy for Male-to-Female Vaginoplasty and the Role of Physical Therapy on Functional and Patient-Reported Outcomes.

BACKGROUND: Rapid increase in number of male-to-female vaginoplasties emphasizes the need for preoperative measures to optimize final surgical and patient-reported outcomes. Hormonal therapy and socioeconomic factors may contribute to a higher incidence of pelvic floor dysfunction in patients undergoing male-to-female vaginoplasty. The purpose of this study was to evaluate the incidence of pelvic floor dysfunction in this population and the role of physical therapy in its treatment. METHODS: From July 2016 to July 2018, patients scheduled to undergo male-to-female vaginoplasty were evaluated by a physical therapist for pelvic floor dysfunction. Patient charts were reviewed for demographics, comorbidities, and length of hormonal therapy. Those with and without symptoms were compared. Symptomatic patients underwent therapy. Assessment of symptom severity and its impact on daily living were completed at 2- to 3-month intervals with physical therapy using the 6-item Urinary Distress Index 6 and 8-item Colorectal Anal Distress Index components of the 20-item Pelvic Floor Distress Inventory (PFDI-20) before and after surgery. A third component of the PFDI-20, the 6-item Pelvic Organ Prolapse Distress Inventory, was also included in the postoperative assessment. RESULTS: Over a 24-month period, a total of 40 patients with a mean age of 40.7 (19-72) years and body mass index of 27.1 kg/m (22-39 kg/m) were enrolled. Comorbidities included 4 patients (10%) with diabetes and 6 patients (15%) with hypertension. Patients with symptoms had a significantly higher mean age (P < 0.01). Only 1 patient (2.5%) had new-onset pelvic floor dysfunction after surgery, and there was no significant increase in severity of symptoms in those with a previous pelvic floor dysfunction postoperatively. Physical therapy significantly (P < 0.01) reduced severity of symptoms and its impact on daily living as assessed by the Urinary Distress Index and Colorectal Anal Distress Index before and after surgery and by the PFDI-20 and 7-item Pelvic Floor Dysfunction Index postoperatively. CONCLUSIONS: A high incidence of pelvic floor dysfunction may exist in patients undergoing male-to-female vaginoplasty preoperatively. Screening at this early stage with both preoperative and postoperative therapy can significantly reduce pelvic floor dysfunction and improve symptoms and quality of life for this population.

Cadaver Study of Combined Neurovascular Sensate Flaps to Create Vaginal Erogenous Sensation During Male-to-Female Genital Confirmation Surgery: The Pedicle "O" Flap.

PURPOSE: The lack of erogenous sensitivity in the neovagina is one of the major shortcomings for patients undergoing male-to-female genital confirmation surgery. Remnant fibers of the dorsal nerve of the penis (DNP) after clitroplasty can potentially be used for a second neurovascular pedicle flap for intravaginal erogenous sensation. METHODS: An anatomic dissection of the DNP was performed in 10 male frozen pelvises to identify major trunks and their branches. Lateral branches of DNP were preserved for a sensate "O" pedicle flap for the vagina. The number of main branches in the lateral dorsal aspect of the penis was calculated to ensure sufficient erogenous innervation to the vagina. Cross sections of the penis were used for histological analysis. Optimal width and length of the new sensate flap were described. RESULTS: There were 1, 2, and 3 main branches in the lateral compartment in 2 (20%), 6 (30.7%), and 2 (42.8%) cadavers, respectively. A sensate pedicle flap from the lateral aspect of the glans penis with a mean width of 1.14 cm (range, 0.9-1.28 cm) ensured at least one main branch of the DNP for erogenous sensitivity of the vagina. This sensate vaginal flap and its neurovascular pedicle had a mean length of 9.8 cm (range, 8.7-10.3 cm) allowing its inset into the anterior vaginal canal. CONCLUSION: Lateral branches of the DNP can be preserved for a pedicle sensate flap to the vagina, which can provide patients with an erogenous vaginal "spot" during male-to-female confirmation surgery.

Characterization of myeloid cell populations in human testes collected after sex reassignment surgery.

The testis has been described in animal models as a site of immune privilege, which protects spermatids against tissue damage during inflammation. Myeloid cells, including macrophages and dendritic cells (DC), are defined as key players in the testicular immune privilege in animal models. However, their distribution and frequency in human testis remain poorly described. To overcome the challenges related to tissue sampling, we obtained testicular tissue from men under hormonal therapy who elected to have sex reassignment surgery (SRS). We examined the distribution of myeloid cell populations in tissue sections using immunohistofluorescence and evaluated their relative frequencies in fresh testicular cell suspensions compared with matched blood using multi-parametric flow cytometry. We identified 4.9% of CD45+ leucocytes in testicular cell suspensions, of which 0.4% were B cells, demonstrating a low level of blood contamination. Myeloid cells (Lin-HLA-DR+) were located in the testicular interstitium and represented a median of 23.4% of testicular leucocytes, displaying higher HLA-DR expression compared to their counterparts in blood (p=0.001). The frequency of testicular myeloid cells was not linked with the duration of hormonal therapy. Resident macrophages (CD14+CD163+) constituted the most frequent myeloid cell subset and expressed high levels of CD163. Elevated proportion of myeloid DC (CD14-CD11c+) contrasted with the paucity of plasmacytoïd DC (CD14-CD123+) in testis. Myeloid-derived suppressor cells (Lin-HLA-DR-CD33hiCD11bhi) were not detected in the testis while constituting 0.5% of blood leucocytes. For the first time, we characterized myeloid cell subsets in human testes collected after SRS, providing a basis to assess their contribution to immune privilege.

Immune tolerance properties of the testicular tissue as a viral sanctuary site in ART-treated HIV-infected adults.

OBJECTIVE: HIV persistence in long-lived infected cells and in anatomical sanctuary sites are major hurdles to HIV eradication. Testicular tissue may represent a significant viral sanctuary site as it constitutes an immunologically privileged compartment. We assessed immunotolerance properties of the testicular tissue in individuals receiving suppressive antiretroviral therapy (ART). DESIGN AND METHODS: Testicular tissue and matched blood samples were collected from six virally suppressed adults and 10 HIV-uninfected controls prior to sex reassignment surgery. T cells were purified from freshly isolated testicular interstitial cell suspensions. T-cell subsets, expression of immune activation markers and HIV DNA were assessed in matched testicular cells and peripheral blood mononuclear cells (PBMCs). RESULTS: When compared with PBMCs, testes were characterized by a lower CD4 T-cell proportion among total T cells, a decrease in the frequency of naive cells, an increase in the frequency of effector-memory T cells and an increase in CCR5 expression in both the HIV+ and HIV- groups. In HIV-infected individuals on ART, testes displayed higher T-cell immune activation (Coexpression of CD38 and Human Leukocyte Antigen - antigen D Related) than PBMCs. In both groups, testes were characterized by higher frequencies of immunosuppressive CD39 regulatory T cells and a massive increase in CD73 expression on CD8 T cells. In addition, a remarkable increase in indoleamine-pyrrole 2,3-dioxygenase immunosuppressive enzyme involved in tryptophan/kynurenine catabolism was observed in testes versus blood. Rare cells harboring HIV DNA were detected in testes from five out six participants. CONCLUSION: These findings suggest that the adenosine and tryptophan/kynurenine immune-metabolic pathways contribute to immune tolerance in testicular tissue. Our results suggest that testes may represent a distinctive HIV sanctuary site during ART.

Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site.

OBJECTIVES: The testes are a potential viral sanctuary site for HIV-1 infection. Our study aims to provide insight into the expression and localization of key drug transporters and metabolic enzymes relevant to ART in this tissue compartment. METHODS: We characterized gene and protein expression of 12 representative drug transporters and two metabolic enzymes in testicular tissue samples obtained from uninfected (n = 8) and virally suppressed HIV-1-infected subjects on ART (n = 5) and quantified antiretroviral drug concentrations in plasma and testicular tissues using LC/MS/MS from HIV-1-infected subjects. RESULTS: Our data demonstrate that key ABC drug transporters (permeability glycoprotein, multidrug-resistance protein 1, 2 and 4, and breast cancer resistance protein), solute carrier transporters (organic anion transporting polypeptides 1B1 and 2B1, organic anion transporter 1, concentrative nucleoside transporter 1, equilibrative nucleoside transporter 2) and cytochrome P450 metabolic enzymes (CYP3A4 and CYP2D6) previously shown to interact with many commonly used antiretroviral drugs are expressed at the mRNA and protein level in the testes of both subject groups and localize primarily at the blood-testis barrier, with no significant differences between the two groups. Furthermore, we observed that PIs known to be substrates for ATP-binding cassette membrane transporters, displayed variable testicular tissue penetration, with darunavir concentrations falling below therapeutic values. In contrast, the NRTIs emtricitabine, lamivudine and tenofovir displayed favourable tissue penetration, reaching concentrations comparable to plasma levels. We also demonstrated that nuclear receptors, peroxisome proliferator-activated receptors α and γ exhibited higher gene expression in the testicular tissue compared with pregnane X receptor and constitutive androstane receptor, suggesting a potential regulatory pathway governing drug transporter and metabolic enzyme expression in this tissue compartment. CONCLUSIONS: Our data suggest the testes are a complex pharmacological compartment that can restrict the distribution of certain antiretroviral drugs and potentially contribute to HIV-1 persistence.

Pilot study on the use of psychotropic medication in persons with mental retardation.

OBJECTIVE: To explore the status of the psychotropic medication in persons with mental retardation 6 years after their deinstitutionalization. METHOD: The authors compared the profiles of psychotropic medication of 60 persons with mental retardation deinstitutionalized (D-sample) from our local mental hospital 6 years ago, to their actual pharmacological profile. Later, we compared our results to the ones of persons with mental retardation on an in-patient (In-sample) unit where existed a concerted team effort to lower the medication when deemed appropriate. RESULTS: Six years post-deinstitutionalization, the authors observed that the same percentage of patients remained on antipsychotic and benzodiazepine medication in our D-sample, and a threefold increase of those using antidepressive medication. However, we observe a general decrease of all types of psychotropic medication in the In-sample with complete withdrawal in a substantial number of patients. CONCLUSIONS: The authors take these pilot data to mean that a concerted team effort at lowering medication in persons with mental retardation makes a significant difference. The possibility of other factors (age, sex, severity of mental retardation, psychiatric diagnosis) explaining the difference in the results is discussed.