Hypospadias, a developmental defect of the penis, is one of the most common congenital malformations in humans. Its incidence has rapidly increased over recent decades, and this has been largely attributed to our increased exposure to endocrine‐disrupting chemicals. Penis development is primarily an androgen‐driven process; however, estrogen and xenoestrogens are known to affect penis development in both humans and mice. Here, we investigated the role of estrogen in the developing penis. Using a novel penis culture system, we showed that exogenous estrogen directly targets the developing penis in utero to cause hypospadias. In addition, we also uncovered an unexpected endogenous role for estrogen in normal postnatal penis development and showed that a loss of estrogen signaling results in a mild hypospadias phenotype, the most common manifestation of this disease in humans. Our findings demonstrated that both androgen and estrogen signaling are intrinsically required for normal urethral closure. These findings confirmed that penis development is not an entirely androgen‐driven process but one in which endogenous estrogen signaling also plays a critical role.—Govers, L. C., Phillips, T. R., Mattiske, D. M., Rashoo, N., Black, J. R., Sinclair, A., Baskin, L. S., Risbridger, G. P., Pask, A. J. A critical role for estrogen signaling in penis development. FASEB J. 33, 10383†10392 (2019). www.fasebj.org

Mice are routinely used to study the development of the external genitalia and, in particular, the process of male urethral closure. This is because misplacement of the male penile urethra, or hypospadias, is amongst the most common birth defects reported in humans. While mice present a tractable model to study penile development, several structures differ between mice and humans, and there is a lack of consensus in the literature on their annotation and developmental origins. Defining the ontology of the mouse prepuce is especially important for the relevance and interpretation of mouse models of hypospadias to human conditions. We have developed a detailed annotation of the adult mouse penis that addresses these differences and enables an accurate comparison of murine and human hypospadias phenotypes. Through MRI data, gross morphology and section histology, we define the origin of the mouse external and internal prepuces, their relationship to the single human foreskin as well as provide a comprehensive view of the various structures of the mouse penis and their associated muscle attachments within the body. These data are combined to annotate structures in a novel 3D adult penis atlas that can be downloaded, viewed at any angle, and manipulated to examine the relationship of various structures.

IntroductionOur aim was to describe trends in the number of bacterial sexually transmitted infections (STIs) diagnosed at Melbourne’s sexual health clinic over a century.MethodsA retrospective analysis of STI diagnoses (gonorrhoea, infectious syphilis and chancroid) among individuals attending Melbourne’s sexual health service over 99 years between 1918 and 2016.ResultsSubstantial increases in STI rates coincided with World War II, the ‘Sexual Revolution of the 1960s and 1970s’, and the last 10 years. Substantial declines coincided with the advent of antibiotics and the HIV/AIDS pandemic. There were also key differences between STIs. Chancroid virtually disappeared after 1950. Syphilis fell to very low levels in women after about 1950 and has only rebounded in men. The declines in gonorrhoea were less marked. A substantial peak in gonorrhoea occurred in women in the early 1970s and rates are currently rising in women, albeit much less than in men.ConclusionsBoth antibiotics and changing sexual behaviour have had a powerful effect on STI rates. These data suggest gonorrhoea is more difficult to control than syphilis or chancroid. Indeed, the past rates suggest substantial endemic gonorrhoea transmission in heterosexuals occurred in the third quarter of last century before the appearance of the HIV pandemic. Worryingly, there is a suggestion that endemic heterosexual gonorrhoea may be returning. The data also suggest that future control of gonorrhoea and syphilis in men who have sex with men is going to be challenging.

Objectives Oropharyngeal gonorrhoea is common among men who have sex with men (MSM). We aimed to clarify which oral sex practices were independent risk factors for oropharyngeal gonorrhoea: tongue kissing, receptive oro-penile sex (fellatio) or insertive oro-anal sex (rimming), and whether daily use of mouthwash and recent antibiotic use was protective. Methods In 2015, we conducted an age-matched case–control study of MSM who attended the Melbourne Sexual Health Centre. Cases had tested positive for oropharyngeal gonorrhoea by nucleic acid amplification testing, and controls had tested negative. Questionnaire items included tongue kissing, oral sex practices, condom use, recent antibiotic use, mouthwash use and alcohol consumption. Results We identified 177 cases, age matched to 354 controls. In univariable analyses, cases were 1.90 times (95% CI 1.13 to 3.20) more likely than controls to have had casual sexual partners (CSP) in the preceding 3 months, were 2.17 times (95% CI 1.31 to 3.59) more likely to have kissed CSP and were 2.04 times (95% CI 1.26 to 3.30) more likely to have had receptive oro-penile sex with CSP. Oropharyngeal gonorrhoea was not associated with insertive oro-anal sex or mouthwash use. The number of CSP for tongue kissing and receptive oral sex and total CSP were highly correlated, and in multivariable analysis neither kissing nor receptive oro-penile sex was significantly associated with having oropharyngeal gonorrhoea, after adjusting for total number of CSP. Conclusions The finding that oropharyngeal gonorrhoea was associated with a higher number of sexual partners but not specific sexual practices highlights the need for further research in the area of gonorrhoea transmission to define the probability of transmission from specific sex acts.

Introduction: Effective linkage to prevention and care is a crucial step following HIV testing services. This systematic review aimed to determine the proportion of individuals linked to prevention and care after HIV self‐testing (HIVST) and describe factors associated with linkage.Methods: Following PRISMA guidelines, a comprehensive search across eight databases (2010–October 2023) identified studies on linkage to care after HIVST, defined as receiving a confirmatory test or initiating antiretroviral therapy (ART) if the self‐test was reactive, and/or pre‐exposure prophylaxis (PrEP) if the self‐test was non‐reactive. A random‐effects meta‐analysis summarized the findings and meta‐regression explored study‐level covariates, such as world region, population type and service delivery model, that might explain the between‐study heterogeneity.Results: From 10,071 screened studies, 173 were included in the meta‐analysis. The majority of studies focused on key populations in Africa using unassisted, oral fluid‐based HIVST kits. Among those with reactive HIVST results, 92% (95% confidence interval [CI]: 88–95) were linked to confirmatory testing (n = 124 studies), and 89% (95% CI: 84–93) of newly diagnosed individuals initiated ART (n = 88 studies). Overall, 84% (95% CI: 74–93) of self‐testers were linked to care (n = 69 studies). However, only 9% (95% CI: 2–19) of individuals with non‐reactive HIVST results were linked to PrEP services (n = 9 studies). Assisted HIVST was associated with higher linkage rates to confirmatory testing and ART initiation compared to unassisted testing. Meta‐regression revealed that the type of delivery model for the HIVST kits influenced linkage and that individuals who obtained their HIVST kits through a social network‐based approach (SNA) were more likely to be linked to confirmatory testing (adjusted odds ratio = 1.28 [95% CI: 1.10–1.50], p = 0.001) compared to non‐SNA service delivery model.Discussion: In the context of expanding HIVST services globally, we found that linkage to confirmatory testing and ART initiation after HIVST is generally high, particularly when assisted HIVST or SNA‐based distribution is used.Conclusions: Strengthening timely linkage is vital for improving health outcomes, reducing HIV transmission and achieving the UNAIDS 95‐95‐95 goal. Ongoing research and collaboration with community‐based organizations are needed to overcoming barriers and ensuring positive outcomes for those using HIVST.PROSPERO Number: CRD42022357570.