School Dropout, Absenteeism and Coverage of Sexual and Reproductive Health Services in South Africa: Are Those Most at Risk Reached?

School attendance or completion is important for adolescents' development. Adolescents who drop out or are regularly absent from school are at higher risk of adverse sexual and reproductive health (SRH) outcomes. However, there is little evidence evaluating SRH service coverage among adolescents in and out of school. In the context of a large-scale combination HIV and pregnancy prevention intervention funded by the Global Fund, we compared the SRH intervention coverage and SRH risks among adolescent girls who dropped out of school with those who were still in school or who had completed grade 12 in South Africa. Among those still in school, we compared the SRH intervention coverage and SRH risk profiles of those with high versus low or no absenteeism. In 2017 to 2018, we conducted a household survey of adolescent girls aged 15 to 19 years in six of the ten combination intervention districts. Of 2515 participants, 7.6% had dropped out of school. Among the 1864 participants still in school, 10.8% had high absenteeism. Ever having had sex, and condomless sex were more prevalent among dropouts compared with non-dropouts. Dropouts were more likely to access SRH services such as condoms and contraceptives, except the combination prevention intervention services which were more likely to reach those who had not dropped out and were equally likely to reach those in school with high versus low/no absenteeism. Combination SRH prevention programmes can improve the accessibility of SRH services for adolescents in school/who complete school.

Applying the HIV Prevention Cascade to an Evaluation of a Large-Scale Combination HIV Prevention Programme for Adolescent Girls and Young Women in South Africa.

Adolescent girls and young women (AGYW) in South Africa are at a three times higher risk of acquiring HIV than their male counterparts. The HIV prevention cascade is a tool which can be used to measure coverage of HIV prevention services, although there is limited empirical evidence to demonstrate its application in low-resourced settings. The unifying framework is a conceptualisation of the HIV prevention cascade which theorises that both motivation and access are required for an individual to effectively use an HIV prevention method. We applied this framework to data from a random sample of 127,951 beneficiaries of a combination HIV prevention programme for AGYW aged 15-24 in South Africa to measure the steps to, and identify key barriers to, effective use of male condoms and oral pre-exposure prophylaxis (PrEP) among this vulnerable population. Barriers to each step were analysed using univariate and multivariable logistic regression. Among self-reported HIV-negative AGYW who had sex in the past 6 months, effective use of condoms (15.2%), access to PrEP (39.1%) and use of PrEP (3.8%) were low. AGYW were: less likely to be motivated to use condoms if they believed that they had a faithful partner (aOR 0.44, 95% CI 0.22-0.90) or disliked condoms (aOR 0.26, 95% CI 0.11-0.57), less likely to access condoms if the place where AGYW accessed them was far away (aOR 0.25, 95% CI 0.10-0.64), more likely to effectively use condoms if they received counselling on how to use them (aOR 2.24, 95% CI 1.05-4.76), less likely to be motivated to use PrEP if they did not believe PrEP was efficacious (aOR 0.35, 95% CI 0.17-0.72), more likely to be motivated if they felt confident that they could use PrEP, and more likely to have access to PrEP if they had ever been offered PrEP (aOR 2.94, 95% CI 1.19-7.22). This combination HIV prevention programme and similar programmes should focus on risk-reduction counselling interventions for AGYW and their male partners to improve effective use of condoms and ensure easy access to condoms and PrEP by making them available in youth-friendly spaces. Our findings demonstrate that the application of HIV prevention cascades can inform AGYW HIV prevention programming in low-resourced settings.

Adolescent girls and young women's (AGYW) access to and use of contraception services in Cape Town: perspectives from AGYW and health care providers.

BACKGROUND: Access and use of contraception services by adolescent girls and young women (AGYW) remains suboptimal, exposing AGYW to early and often unexpected pregnancy. Unexpected pregnancies are a public health concern, associated with poor neonatal and maternal health outcomes, as well as school dropout, which may result in economic hardships. This study aimed to explore (a) AGYW perceptions and experiences of receiving contraception services from health care providers and (b) health care providers' perceptions and experiences of providing contraception services to AGYW. METHODS: Data were collected through semi-structured individual interviews with AGYW aged 15-24 years old and health care providers working in eight health care facilities around the Cape Town metropolitan area, in South Africa's Western Cape Province. Thematic analysis was used to analyse the data. RESULTS: AGYW and health care providers voiced varying, and often contrasting, perceptions of some of the barriers that hinder AGYW's access to contraception services. AGYW indicated that provider-imposed rules about when to access contraceptive services hindered access, while health care providers felt that these rules were necessary for coordinating their work. In addition, AGYW highlighted health care providers' hostile attitudes towards them as an important factor discouraging access. On the contrary, health care providers did not think that their attitudes hampered AGYW's access to and use of contraception services, instead they emphasised that challenges at the health system level were a major issue, which they feel they have little control over. Such challenges made health care providers' work unpleasant and frustrating, impacting on their work approach and how they receive and offer services to AGYW. CONCLUSION: The expectation of negative attitudes from health care providers continues to be at the centre of AGYW discouragement towards accessing contraception services. System challenges are among some of the key drivers of health care provider's hostile attitudes, posing challenges to the efficient provision of services. In order to improve AGYW's access to and use of contraception services, and subsequently achieve the country's SDGs, conscious efforts need to be directed towards improving the workload and working conditions of health care providers.

Analytical Investigation of the Profile of Human Chorionic Gonadotropin in Highly Purified Human Menopausal Gonadotrophin Preparations.

Highly purified human menopausal gonadotropin (HP-hMG [Menopur®, Ferring Pharmaceuticals, Saint-Prex, Switzerland]) contains a 1:1 ratio of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This analysis aimed to assess gonadotropin (FSH, LH and hCG) abundance in HP-hMG and clarify the source of hCG by assessing the presence of sulfated glycans, which are diagnostic for pituitary hCG forms due to their distinct glycosylation patterns. Additionally, the purity of each sample, their specific components, and their oxidation levels were assessed. HP-hMG samples (three of Menopur® and two of Menogon® Ferring Pharmaceuticals, Saint-Prex, Switzerland) were included in the current analyses. Brevactid® (urinary hCG; Ferring Pharmaceuticals, Saint-Prex, Switzerland) and Ovidrel® (recombinant hCG; Merck KGaA, Darmstadt, Germany) were used as control samples. Glycopeptide mapping and analysis of impurities were carried out by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Oxidation was assessed through reducing peptide mapping using LC-MS/MS. The FSH and LH in the HP-hMG samples showed sulfated glycans, while no signals of sulfated glycopeptides were detected on any site of the beta subunit of hCG. HP-hMG test samples presented the same hCG glycan distribution as the control sample (placental hCG, Brevactid®) extracted from the urine of pregnant women, suggesting a non-pituitary source of hCG. Protein impurities were estimated to constitute approximately 20-30% of the entire HP-hMG protein content in the test samples. More than 200 non-gonadotropin proteins were identified in the HP-hMG test samples, of which several were involved in embryonic development or pregnancy. The alpha subunit of the tested samples was strongly oxidized, with a relative abundance of 20% of the total gonadotropin content. Without taking into account all the protein impurities, the beta subunit of LH was detected only in traces (0.9-1.2%) in all tested HP-HMG samples, confirming the data obtained by intact molecule analysis, while high levels of beta hCG (18-47%) were observed. Advanced molecular analysis of HP-hMG indicates a primarily placental origin of hCG, as evidenced by the absence of hCG sulfated glycans and the predominance of placental non-sulfated hCG in LH activity. The analysis revealed 20-30% of protein impurities and a significant presence of oxidized forms in the HP-hMG samples. These findings are critical for understanding the quality, safety, and clinical profile of HP-hMG.

Who is Exposed to HIV Prevention Interventions? An Assessment of Associated Factors Among Adolescent Girls and Young Women in South Africa.

This study examined the prevalence of HIV risk factors and their association with intervention exposure among adolescent girls and young women (AGYW) living in six South African districts in which a combination HIV-prevention intervention was being implemented. A cross-sectional household survey was conducted from 2017 to 2018 among a representative sample of AGYW aged 15-24 years living in the six districts. We used an electronic questionnaire for self-reported demographic and behavioural questions and blood samples were taken to confirm HIV status in the laboratory. Chi-Squared tests and multivariate binary logistic regression were used to examine associations between demographic characteristics, HIV acquisition and transmission risk factors and the likelihood of participating in any of the key components of the combination HIV-prevention intervention. Among the 4399 participants, 45.3% reported inconsistent condom use with casual partner and 46.6% with a main partner. Almost half of participants (47.8%) had participated in one or more components of the HIV-prevention intervention, and in a multivariate logistic regression, those reporting a higher number of HIV risk behaviours were no more (or less) likely to participate. Participants who were not in high school were significantly less likely to have participated in the intervention compared to those still in high school, when adjusting for age and HIV risk factors. The barriers to access and uptake of combination HIV prevention interventions among AGYW who are out of the education system need to be explored and combination HIV prevention interventions and implementation strategies need to be tailored to reach this population.

"Men Rule this is the Normal Thing. We Normalise it and it's Wrong": Gendered Power in Decision-Making Around Sex and Condom Use in Heterosexual Relationships Amongst Adolescents and Young People in South Africa.

We examined power and decision-making in heterosexual relationships amongst South African adolescents and young people. A survey conducted with 515 adolescent girls and young women (AGYW) included items from the Sexual Relationship Power Scale (SRPS) adapted for South African women. Qualitative interviews with fifty AGYW aged between 15 and 24, and nine males aged 18 years and above, explored decision-making in heterosexual relationships, particularly relating to timing of sex and condom use. Theories of gendered power, sexual relationship power and sexual scripting were used in interpreting the data. Findings showed that the power AGYW have in sexual relationships determines their ability to use condoms, and that males generally control condom use and timing of sex. Both survey and interview data suggest that male control over female partners' behaviour also extends beyond the sexual domain. Although while male power is pervasive and enduring, it is simultaneously contested and negotiated. Despite some young people believing that gendered power in decision-making should be equal, it is not always possible for AGYW to enact agency in the dyadic context of heterosexual relationships. Whilst adolescents and young people in South Africa move away from traditional cultural gendered expectations, relationship power inequity and hegemonic masculinities continue to legitimise men's power over women, constraining the sexual agency of adolescent girls and young women and discouraging them from taking control of their own sexual interests and sexual health.

"These Girls Have a Chance to be the Future Generation of HIV Negative": Experiences of Implementing a PrEP Programme for Adolescent Girls and Young Women in South Africa.

Daily oral pre-exposure prophylaxis (PrEP) is highly efficacious for HIV prevention. Adolescent girls and young women (AGYW) have been prioritised for PrEP delivery in South Africa. A combination HIV prevention intervention providing integrated biomedical, behavioural and structural interventions for AGYW aged 15-24 in twelve districts in South Africa characterised by high HIV prevalence, was implemented 2019-2022. We conducted qualitative interviews to explore PrEP implementation experiences with 38 individuals involved in the implementation of the combination HIV prevention programme, including programme managers and project coordinators, health care providers / nurses, social workers, counsellors, peer group trainers and outreach workers. Narratives included various challenges associated with PrEP uptake, adherence and acceptability experienced by implementers. Barriers to PrEP acceptability included AGYW fears of side effects and preference for injectable versus daily oral PrEP; resistance towards PrEP from AGYW, communities and parents due to a lack of accurate information; PrEP stigma linked to associations with antiretrovirals and assumptions of promiscuity; and issues pertaining to parental consent. Additionally, implementers faced logistical challenges related to procurement, stockouts, and supply of PrEP. Findings highlighted the critical role of parental and community acceptability of PrEP for successful implementation. Overall, PrEP was perceived by implementers as a valuable HIV prevention tool. In order to ensure the accessibility of PrEP for AGYW in South Africa, efforts to reduce stigma and foster social support for PrEP use, campaigns to raise awareness, ensure positive framing of PrEP, and build community acceptability of PrEP, are needed.

Examining the Relationship Between Psychosocial Factors with Knowledge of HIV-Positive Status and Antiretroviral Therapy Exposure Among Adolescent Girls and Young Women Living with HIV in South Africa.

Adolescent girls and young women (AGYW) living with HIV have poor antiretroviral therapy (ART) outcomes. We examined the relationship between psychosocial factors with knowledge of HIV-positive status and antiretroviral therapy exposure among AGYW living with HIV in South Africa. Participants 15-24 years responded to a survey including socio-demographics, psychosocial factors, and HIV testing. Blood was collected to determine HIV status and ART exposure. Multivariable analyses were conducted using R. Of 568 participants with HIV, 356 had knowledge of their HIV-positive status. Social support from family [aOR 1.14 (95% CI 1.04-1.24)] or from a special person [aOR 1.12 (95% CI 1.02-1.23)] was associated with knowledge of HIV-positive status. Resilience [aOR 1.05 (95% CI 1.01-1.08)] was the only psychosocial factor associated with a higher odds of ART exposure. Social support and resilience may increase knowledge of HIV-positive status and ART exposure among South African AGYW.

Safe spaces for beneficiaries of a combination HIV prevention intervention for adolescent girls and young women in South Africa: access, feasibility, and acceptability.

BACKGROUND: Safe Spaces are a feature of combination HIV prevention interventions for adolescent girls and young women (AGYW) in South Africa. We investigated whether AGYW at risk for adverse sexual and reproductive health (SRH) outcomes accessed Safe Spaces that were part of an intervention, as well as their feasibility and acceptability. METHODS: In December 2020 to February 2021, as part of a process evaluation of a combination HIV prevention intervention, we randomly sampled 2160 AGYW intervention beneficiaries aged 15-24 years from 6 of the 12 intervention districts. We invited them to participate in a phone survey, with questions about their vulnerability to adverse SRH outcomes, and participation in intervention components including Safe Spaces. We examined factors associated with use of Safe Spaces using bivariate analyses and Pearson's chi squared tests. We also conducted in-depth interviews with 50 AGYW beneficiaries, 27 intervention implementers, 4 health workers, 7 social workers, and 12 community stakeholders, to explore perceptions and experiences of the intervention. Thematic analysis of the qualitative data was performed. RESULTS: At least 30 Safe Spaces were established across 6 districts. Five hundred fifteen of two thousand one hundred sixty sampled AGYW participated in the survey of whom 22.6% visited a Safe Space, accessing HIV testing (52.2%), mobile health services (21.2%) and counselling for distress (24.8%) while there. Beneficiaries of lower socioeconomic status (SES) were less likely to have visited a Safe Space, compared with those of higher SES (13.6% versus 25.3%; p < 0.01). Implementers described political, structural and financial challenges in identifying and setting up Safe Spaces that were safe, accessible and adequately-resourced, and challenges with AGYW not utilising them as expected. AGYW shared positive views of Safe Spaces, describing benefits such as access to computers and the internet, support with homework and job and education applications, and a space in which to connect with peers. CONCLUSION: AGYW are attracted to Safe Spaces by educational and employment promoting interventions and recreational activities, and many will take up the offer of SRH services while there. The poorest AGYW are more likely to be excluded, therefore, an understanding of the obstacles to, and enablers of their inclusion should inform Safe Space intervention design.

Hypo-glycosylated hFSH drives ovarian follicular development more efficiently than fully-glycosylated hFSH: enhanced transcription and PI3K and MAPK signaling.

STUDY QUESTION: Does hypo-glycosylated human recombinant FSH (hFSH18/21) have greater in vivo bioactivity that drives follicle development in vivo compared to fully-glycosylated human recombinant FSH (hFSH24)? SUMMARY ANSWER: Compared with fully-glycosylated hFSH, hypo-glycosylated hFSH has greater bioactivity, enabling greater follicular health and growth in vivo, with enhanced transcriptional activity, greater activation of receptor tyrosine kinases (RTKs) and elevated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling. WHAT IS KNOWN ALREADY: Glycosylation of FSH is necessary for FSH to effectively activate the FSH receptor (FSHR) and promote preantral follicular growth and formation of antral follicles. In vitro studies demonstrate that compared to fully-glycosylated recombinant human FSH, hypo-glycosylated FSH has greater activity in receptor binding studies, and more effectively stimulates the PKA pathway and steroidogenesis in human granulosa cells. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional study evaluating the actions of purified recombinant human FSH glycoforms on parameters of follicular development, gene expression and cell signaling in immature postnatal day (PND) 17 female CD-1 mice. To stimulate follicle development in vivo, PND 17 female CD-1 mice (n = 8-10/group) were treated with PBS (150 µl), hFSH18/21 (1 µg/150 µl PBS) or hFSH24 (1 µg/150 µl PBS) by intraperitoneal injection (i.p.) twice daily (8:00 a.m. and 6:00 p.m.) for 2 days. Follicle numbers, serum anti-Müllerian hormone (AMH) and estradiol levels, and follicle health were quantified. PND 17 female CD-1 mice were also treated acutely (2 h) in vivo with PBS, hFSH18/21 (1 µg) or hFSH24 (1 µg) (n = 3-4/group). One ovary from each mouse was processed for RNA sequencing analysis and the other ovary processed for signal transduction analysis. An in vitro ovary culture system was used to confirm the relative signaling pathways. PARTICIPANTS/MATERIALS, SETTING, METHODS: The purity of different recombinant hFSH glycoforms was analyzed using an automated western blot system. Follicle numbers were determined by counting serial sections of the mouse ovary. Real-time quantitative RT-PCR, western blot and immunofluorescence staining were used to determine growth and apoptosis markers related with follicle health. RNA sequencing and bioinformatics were used to identify pathways and processes associated with gene expression profiles induced by acute FSH glycoform treatment. Analysis of RTKs was used to determine potential FSH downstream signaling pathways in vivo. Western blot and in vitro ovarian culture system were used to validate the relative signaling pathways. MAIN RESULTS AND THE ROLE OF CHANCE: Our present study shows that both hypo- and fully-glycosylated recombinant human FSH can drive follicular growth in vivo. However, hFSH18/21 promoted development of significantly more large antral follicles compared to hFSH24 (P < 0.01). In addition, compared with hFSH24, hFSH18/21 also promoted greater indices of follicular health, as defined by lower BAX/BCL2 ratios and reduced cleaved Caspase 3. Following acute in vivo treatment with FSH glycoforms RNA-sequencing data revealed that both FSH glycoforms rapidly induced ovarian transcription in vivo, but hypo-glycosylated FSH more robustly stimulated Gαs and cAMP-mediated signaling and members of the AP-1 transcription factor complex. Moreover, hFSH18/21 treatment induced significantly greater activation of RTKs, PI3K/AKT and MAPK/ERK signaling compared to hFSH24. FSH-induced indices of follicle growth in vitro were blocked by inhibition of PI3K and MAPK. LARGE SCALE DATA: RNA sequencing of mouse ovaries. Data will be shared upon reasonable request to the corresponding author. LIMITATIONS, REASONS FOR CAUTION: The observations that hFSH glycoforms have different bioactivities in the present study employing a mouse model of follicle development should be verified in nonhuman primates. The gene expression studies reflect transcriptomes of whole ovaries. WIDER IMPLICATIONS OF THE FINDINGS: Commercially prepared recombinant human FSH used for ovarian stimulation in human ART is fully-glycosylated FSH. Our findings that hypo-glycosylated hFSH has greater bioactivity enabling greater follicular health and growth without exaggerated estradiol production in vivo, demonstrate the potential for its development for application in human ART. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by NIH 1P01 AG029531, NIH 1R01 HD 092263, VA I01 BX004272, and the Olson Center for Women's Health. JSD is the recipient of a VA Senior Research Career Scientist Award (1IK6 BX005797). This work was also partially supported by National Natural Science Foundation of China (No. 31872352). The authors declared there are no conflicts of interest.

From Survival to Glamour: Motivations for Engaging in Transactional Sex and Relationships Among Adolescent Girls and Young Women in South Africa.

We explored transactional sex and relationships (TSR) among South African adolescent girls and young women (AGYW) using (1) survey data from 4,399 AGYW aged 15-24 years, and (2) qualitative data from 237 AGYW and 38 male peers. Ten percent of sexually active AGYW reported having ever had transactional sex; 14% reported having stayed in a relationship for money or material items. Factors associated with higher reporting of TSR included HIV positivity, higher food insecurity, and alcohol use. Those AGYW who were between the ages of 20-24 years (OR: 1.0; 95% CI: 0.81-1.24), had a sexual partner older than her by 5 years or more (OR: 1.89; 95% CI: 1.58-2.26), and had a transactional relationship in the past (OR: 61.1; 95% CI: 47.37-78.76) were more likely to report having transactional sex. AGYW qualitative narratives included both assertions of agency in choosing to engage in TSR, and power inequities resulting in condomless sex. Our findings can inform interventions to addressing transactional sex and relationships, critical to South Africa's HIV response.

"As a Young Pregnant Girl The Challenges You Face": Exploring the Intersection Between Mental Health and Sexual and Reproductive Health Amongst Adolescent Girls and Young Women in South Africa.

In South Africa, adolescent girls and young women (AGYW) are at risk of poor mental health, HIV infection and early pregnancy. Poor mental health in AGYW is associated with increased sexual risk behaviours, and impeded HIV testing and care. Using in-depth interviews and focus group discussions, we explored subjective experiences of mental health and sexual and reproductive health (SRH) amongst 237 AGYW aged 15-24 years in five South African districts. Respondents shared narratives of stress, emotional isolation, feelings of depression, and suicidal ideation, interconnected with HIV, pregnancy and violence in relationships. Findings show that AGYW in South Africa face a range of mental health stressors and lack sufficient support, which intersect with SRH challenges to heighten their vulnerability. Framed within the syndemic theory, our findings suggest that South African AGYW's vulnerability towards early pregnancy, HIV infection and poor mental health are bidirectional and interconnected. Considering the overlaps and interactions between mental health and SRH amongst AGYW, it is critical that mental health components are integrated into SRH interventions.

Factors influencing adolescent girls and young women's participation in a combination HIV prevention intervention in South Africa.

BACKGROUND: For interventions to reach those they are intended for, an understanding of the factors that influence their participation, as well as the facilitators and barriers of participation are needed. This study explores factors associated with participation in a combination HIV prevention intervention targeting adolescent girls and young women (AGYW) aged 15-24-years-old, as well as the perspectives of AGYW, intervention implementers, and facilitators who participated in this intervention. METHODS: This study used mixed-methods approach with quantitative household survey data from 4399 AGYW aged 15-24-years-old in six of the ten districts in which the intervention was implemented. In addition, qualitative methods included a total of 100 semi-structured in-depth interviews and 21 focus group discussions in five of the ten intervention districts with 185 AGYW who participated in one or more of the key components of the intervention, and 13 intervention implementers and 13 facilitators. Thematic analysis was used to explore the perspectives of participating and implementing the intervention. RESULTS: Findings reveal that almost half of AGYW (48.4%) living in the districts where the intervention took place, participated in at least one of the components of the intervention. For both 15-19-year-olds and 20-24-year-olds, factors associated with increased participation in the intervention included being HIV negative, in school, never been pregnant, and having had a boyfriend. Experiencing intimate partner violence (IPV) and/or sexual violence in the past 12 months was associated with increased levels of participation in the intervention for 20-24-year-olds only. In our analysis of the qualitative data, facilitators to participation included motivating participants to join the interventions through explaining the benefits of the programme. Barriers included misguided expectations about financial rewards or job opportunities; competing responsibilities, interests or activities; family responsibilities including childcare; inappropriate incentives; inability to disrupt the school curriculum and difficulties with conducting interventions after school hours due to safety concerns; miscommunication about meetings; as well as struggles to reach out-of-school AGYW. CONCLUSION: Designers of combination HIV prevention interventions need to address the barriers to participation so that AGYW can attend without risking their safety and compromising their family, childcare and schooling responsibilities. Strategies to create demand need to include clear communication about the nature and potential benefits of such interventions, and the inclusion of valued incentives.

Mechanistic insight into how gonadotropin hormone receptor complexes direct signaling†.

Gonadotropin hormones and their receptors play a central role in the control of male and female reproduction. In recent years, there has been growing evidence surrounding the complexity of gonadotropin hormone/receptor signaling, with it increasingly apparent that the Gαs/cAMP/PKA pathway is not the sole signaling pathway that confers their biological actions. Here we review recent literature on the different receptor-receptor, receptor-scaffold, and receptor-signaling molecule complexes formed and how these modulate and direct gonadotropin hormone-dependent intracellular signal activation. We will touch upon the more controversial issue of extragonadal expression of FSHR and the differential signal pathways activated in these tissues, and lastly, highlight the open questions surrounding the role these gonadotropin hormone receptor complexes and how this will shape future research directions.

Two human menopausal gonadotrophin (hMG) preparations display different early signaling in vitro.

Commercial hMG drugs are marketed for the treatment of infertility and consist of highly purified hormones acting on receptors expressed in target gonadal cells. Menopur® and Meriofert® are combined preparation of FSH and hCG and are compared in vitro herein. To this purpose, the molecular composition of the two drugs was analyzed by immunoassay. The formation of FSH receptor and LH/hCG receptor (FSHR; LHCGR) heteromer, intracellular Ca2+ and cAMP activation, ß-arrestin 2 recruitment and the synthesis of progesterone and estradiol were evaluated in transfected HEK293 and human primary granulosa lutein cells treated by drugs administered within the pg-mg/ml concentration range. Molecular characterization revealed that Meriofert® has a higher FSH:hCG ratio than Menopur® which, in turn, displays the presence of LH molecules. While both drugs induced similar FSHR-LHCGR heteromeric formations and intracellular Ca2+ increase, Meriofert® had a higher potency than Menopur® in inducing a cAMP increase. Moreover, Meriofert® revealed a higher potency than Menopur® in recruiting ß-arrestin 2, likely due to different FSH content modulating the tridimensional structure of FSHR-LHCGR-ß-arrestin 2 complexes, as evidenced by a decrease in bioluminescence resonance energy transfer signal. This drug-specific activation of intracellular signaling pathways is consistent with the molecular composition of these preparations and impacts downstream progesterone and estradiol production, with Menopur® more potent than Meriofert® in inducing the synthesis of both the steroids. These findings are suggestive of distinct in-vivo activities of these preparations, but require cautious interpretation and further validation from clinical studies.

Perceptions of contraception services among recipients of a combination HIV-prevention interventions for adolescent girls and young women in South Africa: a qualitative study.

BACKGROUND: Adolescent girls and young women (AGYW) in low- and middle- income countries (LMICs) have high rates of unintended pregnancies and are at higher risk for HIV infection compared to older women of reproductive age. Using a socio-ecological model approach, this research investigated perceptions of contraception services among AGYW who had been recipients of a combination HIV-prevention intervention, to better understand factors affecting their access to and use of contraception services. METHOD: Qualitative methods used in this study included focus group discussions (FGDs) and in-depth interviews (IDIs) with 185 AGYW aged 15-24 years living in five of the ten intervention districts. All interviews and FGDs were audio-recorded and data were analyzed thematically using Nvivo 12 software with manual identification of themes and labelling of raw data. RESULTS: The findings reveal that many AGYW, especially those in the younger age group 15-19 years, experience difficulties in accessing contraception services, mainly at the interpersonal and health service levels. Lack of support for the use of contraceptives from parents/caregivers as well as from sexual partners were key barriers at the interpersonal level; while providers' negative attitude was the main barrier at the health service level. The majority of school-going AGYW felt that bringing contraception services and other sexual and reproductive health (SRH) services on to the school premises would legitimize their use in the eyes of parents and help to overcome barriers related to parental support and acceptance, as well as overcome some of the health service and structural level barriers. However, views among school-going AGYW about school-based provision of contraception services were mixed, clouded with concerns relating to confidentiality. CONCLUSION: Interventions to improve parental/caregiver and sexual partner support for the use of contraception services by AGYW, as well as efforts to expand the provision of contraception services on the school premises are urgently needed. Future interventions should incorporate multi-level approaches to address structural and contextual barriers to access and use of contraception services to gain maximum effect.

"There is no fear in me well, that little fear is there": dualistic views towards HIV testing among South African adolescent girls and young women.

In spite of the high HIV burden and high prevalence and incidence of HIV infection among adolescent girls and young women (AGYW) in South Africa, uptake of HIV testing in this population falls short of the UNIADS 90-90-90 targets, leading to late diagnosis, late entry into HIV care and treatment, and poor uptake of prevention services. There is a critical need to update and deepen our understanding of attitudes towards testing in this population, in order to appropriately respond to their specific needs. This article reports on findings from an exploration of perceptions of HIV testing and testing behaviour amongst AGYW in South Africa using a combination of quantitative and qualitative data. Analysis included data on testing behaviour and reasons for never testing from a survey conducted with 4 399 AGYW aged 15-24 years in six provinces. Combined with survey data is qualitative analysis from 63 in-depth interviews and 24 focus group discussions with 237 AGYW from five provinces. Findings revealed complex, dualistic and often contradictory views towards HIV testing in this population, with fear of HIV and the consequences of testing positive existing alongside a lack of concern towards HIV infection because of the availability and accessibility of antiretrovirals. These findings can help to address barriers to HIV testing in this population and ensure appropriateness of future interventions and HIV messaging.

Healthcare workers' beliefs, motivations and behaviours affecting adequate provision of sexual and reproductive healthcare services to adolescents in Cape Town, South Africa: a qualitative study.

BACKGROUND: Adolescents' sexual and reproductive healthcare (SRH) needs have been prioritized globally, and they have the rights to access and utilize SRH services for their needs. However, adolescents under-utilize SRH services, especially in sub-Saharan Africa. Many factors play a role in the under-utilization of SRH services by adolescents, such as the attitude and behaviour of healthcare workers. The aim of this study therefore, was to explore and gain an in-depth understanding of healthcare workers' beliefs, motivations and behaviours affecting adequate provision of these services to adolescents in South Africa. METHODS: Twenty-four healthcare workers in public SRH services in Cape Town, South Africa participated in this qualitative study through focus group discussions. To fulfill the aims of this study, nine focus group discussions were conducted among the SRH nurses. RESULTS: SRH nurses indicated that they are experiencing challenges with the concept and practice of termination of pregnancy. They explained that this practice contradicted their opposing beliefs and values. Some nurses felt that they had insufficient SRH skills, which hinder their provision of adequate SRH services to adolescents, while others described constraints within the health system such as not enough time to provide the necessary care. They also explained having limited access to schools where they can provide SRH education and pregnancy prevention services in the surrounding area. CONCLUSIONS: Nurses are faced with numerous challenges when providing SRH services to adolescents. Providing the nurses with training programmes that emphasize value clarification may help them to separate their personal beliefs and norms from the workplace practice. This may help them to focus on the needs of the adolescent in a way that is beneficial to them. At the health systems level, issues such as clinic operating hours need to be structured such that the time pressure and constraints upon the nurse is relieved.

Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes.

The natriuretic peptides, Atrial-, B-type and C-type natriuretric peptides (ANP, BNP, CNP), are regulators of many endocrine tissues and exert their effects predominantly through the activation of their specific guanylyl cyclase receptors (GC-A and GC-B) to generate cGMP. Whereas cGMP-independent signalling has been reported in response to natriuretic peptides, this is mediated via either the clearance receptor (Npr-C) or a renal-specific NPR-Bi isoform, which both lack intrinsic guanylyl cyclase activity. Here, we report evidence of GC-B-dependent cGMP-independent signalling in pituitary GH3 cells. Stimulation of GH3 cells with CNP resulted in a rapid and sustained enhancement of ERK1/2 phosphorylation (P-ERK1/2), an effect that was not mimicked by dibutryl-cGMP. Furthermore, CNP-stimulated P-ERK1/2 occurred at concentrations below that required for cGMP accumulation. The effect of CNP on P-ERK1/2 was sensitive to pharmacological blockade of MEK (U0126) and Src kinases (PP2). Silencing of the GC-B1 and GC-B2 splice variants of the GC-B receptor by using targeted short interfering RNAs completely blocked the CNP effects on P-ERK1/2. CNP failed to alter GH3 cell proliferation or cell cycle distribution but caused a concentration-dependent increase in the activity of the human glycoprotein α-subunit promoter (αGSU) in a MEK-dependent manner. Finally, CNP also activated the p38 and JNK MAPK pathways in GH3 cells. These findings reveal an additional mechanism of GC-B signalling and suggest additional biological roles for CNP in its target tissues.

Healthcare workers' behaviors and personal determinants associated with providing adequate sexual and reproductive healthcare services in sub-Saharan Africa: a systematic review.

BACKGROUND: Healthcare workers may affect the utilization of sexual and reproductive healthcare (SRH) services, and quality of care thereof, for example by their behaviours or attitudes they hold. This can become a hindrance to accessing and utilizing SRH services, particularly by young people, and thus a better understanding of these behaviours and associated factors is needed to improve access to and utilization of SRH services. METHODS: A systematic review of literature was conducted to identify studies focusing on healthcare workers' behaviors and personal determinants associated with providing adequate SRH services in sub-Saharan Africa (January 1990 - October 2015). Five databases were searched until 30th October 2015, using a search strategy that was adapted based on the technical requirements of each specific database. Articles were independently screened for eligibility by two researchers. Of the 125-screened full-text articles, 35 studies met all the inclusion criteria. RESULTS: Negative behaviours and attitudes of healthcare workers, as well as other personal determinants, such as poor knowledge and skills of SRH services, and related factors, like availability of essential drugs and equipment are associated with provision of inadequate SRH services. Some healthcare workers still have negative attitudes towards young people using contraceptives and are more likely to limit access to and utilization of SRH by adolescents especially. Knowledge of and implementation of specific SRH components are below optimum levels according to the WHO recommended guidelines. CONCLUSIONS: Healthcare workers' negative behaviours and attitudes are unlikely to encourage women in general to access and utilize SRH services, but more specifically young women. Knowledge of SRH services, including basic emergency obstetric care (EmOC) is insufficient among healthcare workers in SSA. TRIAL REGISTRATION: A protocol for this systematic review was registered with PROSPERO and the registration number is: CRD42015017509 .