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Gene variants provide insight into brain, body incongruence in trans people

About 0.5 to 1.4% of individuals born male and 0.2 to 0.3 % of individuals born female meet criteria for gender dysphoria. Identical twins are more likely than fraternal twins to both report gender dysphoria.

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Some of the first biological evidence of the incongruence transgender individuals experience, because their brain indicates they are one sex and their body another, may have been found in estrogen receptor pathways in the brain of 30 transgender individuals.

“Twenty-one variants in 19 genes have been found in estrogen signaling pathways of the brain critical to establishing whether the brain is masculine or feminine,” says Dr. J. Graham Theisen, obstetrician/gynecologist and National Institutes of Health Women’s Reproductive Health Research Scholar at the Medical College of Georgia at Augusta University.

Basically — and perhaps counterintuitively — these genes are primarily involved in estrogen’s critical sprinkling of the brain right before or after birth, which is essential to masculinization of the brain.

Variants investigators identified may mean that in natal males (people whose birth sex is male) this critical estrogen exposure doesn’t happen or the pathway is altered so the brain does not get masculinized. In natal females, it may mean that estrogen exposure happens when it normally wouldn’t, leading to masculinization.

Both could result in an incongruence between a person’s internal gender and their external sex. The negative emotional experience associated with this incongruence is called gender dysphoria.

“They are experiencing dysphoria because the gender they feel on the inside does not match their external sex,” Theisen says. “Once someone has a male or female brain, they have it and you are not going to change it. The goal of treatments like hormone therapy and surgery is to help their body more closely match where their brain already is.”

“It doesn’t matter which sex organs you have, it’s whether estrogen, or androgen, which is converted to estrogen in the brain, masculinizes the brain during this critical period,” says Dr. Lawrence C. Layman, chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics in the Department of Obstetrics and Gynecology. “We have found variants in genes that are important in some of these different areas of the brain.”

These brain pathways are involved in regions of the brain where the number of neurons and how connected the neurons are typically differ between males and females.

They note that while this “critical period” for masculinizing the brain may seem late, brain development actually continues well after birth and these key pathways and receptors already need to be established when estrogen arrives.

While it’s too early to definitively say the gene variants in these pathways result in the brain-body incongruence called gender dysphoria, it is “interesting” that they are in pathways of hormone involvement in the brain and whether it gets exposed to estrogen or not, says Layman.

He and Theisen are co-corresponding authors of the study in the journal Scientific Reports.

“This is the first study to lay out this framework of sex-specific development as a means to better understand gender identity,” Theisen says. “We are saying that looking into these pathways is the approach we are going to be taking in the years ahead to explore the genetic contribution to gender dysphoria in humans.”

In fact, they already are exploring the pathways further and in a larger number of transgender individuals.

For this study, they looked at the DNA of 13 transgender males, individuals born female and transitioning to male, and 17 transgender females, born male and transitioning to female. The extensive whole exome analysis, which sequences all the protein-coding regions of a gene (protein expression determines gene and cell function) was performed at the Yale Center for Genome Analysis. The analysis was confirmed by Sanger sequencing, another method used for detecting gene variants.

The variants they found were not present in a group of 88 control exome studies in nontransgender individuals also done at Yale. They also were rare or absent in large control DNA databases.

Reproductive endocrinologist/geneticist Layman says his experience with taking care of transgender patients for about 20 years, made him think there was a biological basis. “We certainly think that for the majority of people who are experiencing gender dysphoria there is a biologic component,” says Theisen. “We want to understand what the genetic component of gender identity is.”

While genetics have been suggested as a factor in gender dysphoria, proposed candidate genes to date have not been verified, the investigators say. Most gene or gene variants previously explored have been associated with receptors for androgens, hormones more traditionally thought to play a role in male traits but, like estrogen in males, also are present in females.

MCG investigators and their colleagues decided instead to take what little is known about sex-specific brain development — that estrogen bath needed in early life to ensure masculinization of the brain– to hone in on potential sites for relevant genetic variances. Extensive DNA testing initially revealed more than 120,000 variants, 21 of which were associated with these estrogen-associated pathways in the brain.

Animal studies have helped identify four areas of the brain with pathways leading to development of a male or female brain, and the investigators focused on those likely also present in humans. Laboratory studies have indicated that disrupting these brain pathways in males and females during this critical period results in cross sex behavior, like female rodents mounting and thrusting and males taking on a more traditional female posture when mating. These cross sex behaviors, which also have been documented in non-human primates, emerge during the natural sex hormone surge of puberty.

While sex specific brain development has not been thoroughly evaluated in humans, as with animals, the effects typically play out most at the time of puberty, a time when sex hormones naturally surge, when the general awareness of our sexuality really begins to awaken and when the complex state of gender dysphoria may become easier for adolescents to articulate, the investigators say. Layman notes that many individuals will report experiencing gender incongruent feelings as early as age 5.

Theisen notes that we all are full of genetic variants, including ones that give us blue eyes versus brown or green, and the majority do not cause disease rather help make us individuals. “I think gender is as unique and as varied as every other trait that we have,” Theisen says.

The investigators suggest modification of the current system for classifying variants that would not imply that a variant means pathogenic, or disease causing.

Last year, the World Health Organization said that gender incongruence is not a mental health disorder and six years before that The Diagnostic and Statistical Manual of Mental Disorders, replaced gender identity disorder with general dysphoria.

About 0.5 to 1.4% of individuals born male and 0.2 to 0.3 % of individuals born female meet criteria for gender dysphoria. Identical twins are more likely than fraternal twins to both report gender dysphoria.

Gender affirming therapies, like hormone therapies and surgeries along with mental health evaluation and support, help these individuals better align their bodies and brains, the physician-scientists say.

Transgender individuals experience increased rates of discrimination, sexual violence and are at increased risk of depression, substance abuse and attempted suicide. About 26% report use of alcohol or other drugs to help cope; 19% have been denied medical care by a physician or other provider, some report verbal harassment in a medical environment and insurance companies do not consistently cover the cost of gender affirming hormone or surgical therapies.

A problem, the investigators say, is an overall lack of understanding of the biologic basis of gender dysphoria.

While their study of 30 individuals — they now have data on more than 30 others — appears to be the largest to date, the sample size prompted them to classify the published findings as preliminary.

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Efforts to increase sexual orientation acceptance can address LGBTQ youth suicide

Interventions aimed at increasing sexual orientation acceptance from supportive adults and peers have strong potential to address the public health burden of LGBTQ youth suicide.

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Interventions aimed at increasing sexual orientation acceptance from supportive adults and peers have strong potential to address the public health burden of LGBTQ youth suicide.

This is according to a study – titled: “Association of Sexual Orientation Acceptance with Reduced Suicide Attempts Among Lesbian, Gay, Bisexual, Transgender, Queer, and Questioning Youth” – by Amy E. Green, Myeshia Price-Feeney and Samuel H. Dorison and published in LGBT Health.

The researchers noted the relationship between sexual orientation acceptance from others and suicide attempts among LGBTQ youth. So to look into this closely, they analyzed data from a 2018 cross-sectional survey of LGBTQ youth between the ages of 13 and 24 years across the US. Youth reported sexual orientation acceptance levels from parents, other relatives, school professionals, health care professionals, friends, and classmates to whom who they were “out.” Adjusted logistic regression analyses were used to examine the association between sexual orientation acceptance and a past-year suicide attempt.

They found that all forms of peer and adult acceptance were associated with reduced reports of a past-year suicide attempt, with the strongest associations found for acceptance from parents (adjusted odds ratio [aOR] = 0.52) and straight/heterosexual friends (aOR = 0.54).

Youth who reported high levels of acceptance from any adult had nearly 40% (aOR = 0.61) lower odds of a past-year suicide attempt compared with LGBTQ peers with little to no acceptance. Youth with high levels of acceptance from any peer also had significantly lower odds of reporting a past-year suicide attempt (aOR = 0.55). These relationships remained significant even after controlling for the impact of each form of acceptance, suggesting unique associations with suicide risk for both peer and adult acceptance.

For the researchers, therefore, interventions aimed at increasing sexual orientation acceptance from supportive adults and peers should be considered as these have strong potential to address the public health burden of LGBTQ youth suicide.

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Effects of head trauma from intimate partner violence largely unrecognized

One in three women will experience intimate partner violence (IPV) in her lifetime, and studies suggest that anywhere between 30% to 90% of women who experience physical abuse at the hands of an intimate partner experience head trauma.

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Fact: The World Health Organization (WHO) estimates that one in three women will experience intimate partner violence (IPV) in her lifetime, and studies suggest that anywhere between 30% to 90% of women who experience physical abuse at the hands of an intimate partner experience head trauma. Yet not enough data is being collected to understand how this head trauma affects cognitive and psychological functioning as well as the underlying neural effects.

This is why Carrie Esopenko, assistant professor in the Department of Rehabilitation and Movement Sciences in the Rutgers School of Health Professions, looked into this as part of an Intimate Partner Violence Working Group studying intimate partner violence-related head trauma as part of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, an international, multidisciplinary group that seeks to provide a collaborative framework for large-scale analysis and neuroimaging and genetic studies in patient groups. The data was published in the journal Brain Imaging and Behavior.

What is the risk for traumatic brain injury in those who suffer abuse?

Although IPV occurs at any age, it is most prevalent in the 18- to 24-year-old age group, and older adults are also vulnerable. Males and females experience IPV, but violence against women tends to result in more severe and chronic injuries. Due to the high degree of physical aggression associated with this type of abuse, there is a significant risk for traumatic brain injury caused by blunt force trauma, being violently shaken or pushed.

Another significant concern is anoxic brain injury, which can occur due strangulation or attempts to impede normal breathing. The prevalence of head injuries in women who have sustained IPV is estimated to be between 30% and 92%, with a high proportion of these women reporting injuries as a result of strangulation. It is estimated that more than 50% of women exposed to IPV suffer multiple brain injuries due to abuse-related head trauma.

What are the consequences of such injuries?

Past research suggests that IPV can impact cognitive and psychological functioning as well as have neurological effects. These seem to be compounded in those who suffer a brain injury as a result of trauma to the head, face, neck or body due to physical and/or sexual violence. However, the understanding of the neurobehavioral and neurobiological effects of head trauma is limited.

Studies suggest that women who experience IPV report cognitive dysfunction, including impaired reaction time, response inhibition, working memory, attention and a range of other cognitive, behavioral and emotional difficulties. They often report a high degree of mental health disorders, such as depression, anxiety, substance use disorders, suicidal ideation and PTSD. There is evidence that IPV-related brain injury also alters brain function and structure.

What is unknown about traumatic brain injury in victims of domestic violence?

While research on traumatic brain injury in other populations, like athletes and the military, has dramatically increased over the past two decades, research on intimate partner-related brain injury is vastly understudied.

“We need to know more about the effect of sex, socioeconomic status, race and/or ethnicity, age at first exposure – including childhood trauma, duration and severity of IPV exposure, and psychiatric disorders on the neural, cognitive and psychological outcomes associated with IPV-related brain injuries. Knowing this can help us to predict outcomes and help personalize treatment and intervention strategies,” Esopenko said.

IPV is an issue that also affects members of the LGBTQIA community.

In the Philippines in December 2020, Atty. Clara Rita Padilla, who helms EnGendeRights, Inc., recalled helping remove LGBTQIA people from the abusive situations. And so for her, LGBTQIA people in GBV/IPV/FV ought to know that their situation can be managed; they just need to – first – not fear seeking for help.

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Community-based programs reduce sexual violence – study

We know that young men often need job skills and opportunities to discuss healthy relationships and healthier manhood. Combining these two proven approaches seems particularly promising and necessary.

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Through small, neighborhood classes, sexual violence can be reduced among teenage boys living in areas of concentrated disadvantage.

This is according to a study published in JAMA; a culmination of a Centers for Disease Control and Prevention clinical trial spanning 20 racially segregated neighborhoods in the Pittsburgh area to evaluate two violence prevention programs. The proportion of youth reporting the use of sexual or partner violence in their relationships decreased in both groups by about 12%.

“To accomplish something like this requires nurturing community partnerships,” said study senior author Elizabeth Miller, M.D., Ph.D., chief of adolescent and young adult medicine at UPMC Children’s Hospital of Pittsburgh. “In each of these neighborhoods, we worked with community members to facilitate the programs with an eye toward sustainability.”

Between 2015-2017, nearly 900 boys between the ages of 13-19 enrolled in these small group programs, which were run by community leaders from each neighborhood.

Half of the sites were randomized to receive job readiness training and the other half were assigned a curriculum called “Manhood 2.0,” which is based on Promundo’s “Program H” in Brazil. The “H” stands for hombres.

“Manhood 2.0 engages young men in questioning harmful ideas about manhood,” said Promundo-US Chief Executive Officer Gary Barker. “It calls men into being part of the solution to ending violence in intimate partner relationships and helps them see the benefits to healthier manhood in their own lives.”

Manhood 2.0 was adapted for young men in US urban communities, but the core message remains the same: challenging gender norms that foster violence against women and unhealthy sexual relationships.

For young men enrolled in Manhood 2.0, the use of partner violence–including physical or verbal abuse, sexual harassment, sexual coercion and cyber abuse–dropped from 64% at baseline to 52% in the months following the program. For those who received job training, self-reported sexual violence dropped from 53% to 41%.

That was a surprise. Miller said she expected job training to have a positive impact in other areas of life, but not violence towards women.

“Job skills training is a structural intervention, grounded in economic justice,” Miller said. “Perhaps this resonated and resulted in young men using less violence because they felt more hopeful about their future.”

Next, the researchers hope to study whether combining Manhood 2.0 with job readiness training might have an even greater impact on intimate partner and sexual violence than either curriculum alone.

“We know that young men often need job skills and opportunities to discuss healthy relationships and healthier manhood,” Barker said. “Combining these two proven approaches seems particularly promising and necessary.”

Additional authors on the study include Kelley Jones, Ph.D., Alison Culyba, M.D., Ph.D., Taylor Paglisotti, M.P.H., Namita Dwarakanath, Michael Massof, M.P.A., and Zoe Feinstein of UPMC Children’s Hospital; Katie Ports, Ph.D., at the Centers for Disease Control and Prevention; Dorothy Espelage, Ph.D., of the University of North Carolina at Chapel Hill; Julie Pulerwitz, Sc.D., of the Population Council; Aapta Garg, M.A., and Jane Kato-Wallace, M.P.H., of Promundo-US; and Kaleab Z. Abebe, Ph.D., of the University of Pittsburgh School of Medicine.

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Almost half of young gay sportsmen experience homophobia

Nearly half of young gay men who play sports have been the target of bullying, assaults and slurs.

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Discrimination in sports.

Nearly half of young gay men who play sports have been the target of bullying, assaults and slurs, according to research coming out from New Zealand.

Authored by Erik Denison, Ruth Jeanes, Nick Faulkner and Kerry S. O’Brien, “The Relationship Between ‘Coming Out’ as Lesbian, Gay, or Bisexual and Experiences of Homophobic Behaviour in Youth Team Sports” appeared in Sexuality Research and Social Policy.

Involving 1,173 participants aged from 15 to 21 years old (collected in 2014–2015) from six countries (US, UK, Canada, Australia, New Zealand, Ireland), the study eyed to examine whether LGB youth who come out to teammates experience homophobic behavior.

It found that close to half of the sample (41.6%) reported having been the target of homophobic behavior. This included verbal slurs, bullying and assaults.

Multivariate logistic regression models adjusting for age, gender, country and contact sport participation found that participants who came out as being LGB to sports teammates were significantly more likely to report being a target of homophobic behavior. There appeared to be a dose response with coming out to more people associated with a greater likelihood of experiencing homophobic behavior.

“The study results suggest a relationship between coming out as LGB and encountering homophobic behavior in team sports. LGB experiences of homophobic behavior appear common overall in this sample, but are greater in those who have come out to teammates,” the researchers noted.

They recommended the development of strategies aimed at reducing homophobic behavior in sport.

“Although there is some evidence that education may be effective in reducing homophobia… stronger regulatory principals and actions are needed to address prejudices around sexuality. In so doing, better regulations and policies can enhance the health and well-being of LGB youth through their increased and/or ongoing participation in team sport.”

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Bullied lesbian, gay and bisexual students more likely to carry weapons

14% of heterosexual, 21.8% of gay/lesbian,18.5% of bisexual and 17.4% of “not sure” students reported carrying a weapon in the past 30 days.

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In the 1990s, Pablo – a high school student in a Roman Catholic school in Cotabato City in Mindanao – used to carry a bottle of muriatic acid when he went to school. The trigger for him was an earlier bullying that, even when allegedly reported to school authorities, left unresolved.

“I felt I had to have a way to protect myself,” he said years later, when he was already working as a nurse overseas. And though he knew “throwing muriatic acid on people seemed extreme”, but for a young gay boy at that time, he said he didn’t really know what steps he could take. “No one seemed (eager to protect me); I had to take matters in my own hands.”

Pablo never had to use the muriatic acid; in fact, that need to have a bottle in his bag eventually waned. But what he did (i.e. carrying a tool for self-protection) was – for a while – never really closely considered in studies; at least until a new study that appears in the Journal of Interpersonal Violence.

Prior research has revealed sexual minority youth (lesbian, gay, bisexual) are more likely to carry weapons both outside of and within school, this study noted. However, no study has really examined the degree to which bullying and harassment is associated with weapon carrying among this group.

And – perhaps as expected – the study found youth who report carrying a weapon have higher odds of experiencing bullying and bullying-related victimization. Minoritized student populations, especially sexual minority youth disproportionately experience bullying and bullying victimization.

“Pediatricians should recognize that experiencing bullying and feeling unsafe are associated with weapon carrying, particularly among sexual minorities,” said corresponding author Carl Streed, Jr., MD, MPH, FACP, assistant professor of medicine at Boston University School of Medicine (BUSM).

The researchers used the Youth Risk Behavior Survey to examine the prevalence and likelihood of carrying weapons by sexual identity, examining self-report of adverse experiences (being bullied, skipping school due to fear for personal safety) and performing analysis to estimate the odds of carrying a weapon. When surveyed by sexual identity, 14% of heterosexual, 21.8% of gay/lesbian,18.5% of bisexual and 17.4% of “not sure” students reported carrying a weapon in the past 30 days.

The odds of carrying a weapon were significantly increased for youth who skipped school due to feeling unsafe at school, had ever been threatened with a weapon in the past year and had ever been in a physical fight.

Compared to heterosexual female peers, sexual minority women had increased odds of carrying a weapon.

“Pediatricians and professionals who work with youth should recognize that reported experiences of bullying may not be the most salient indicator of risk for weapon carrying among all youth, and that other fears of or experiences with bullying are crucial to screen for among sexual minorities in particular,” added Streed, who also is a primary care physician and research lead in the Center for Transgender Medicine & Surgery at Boston Medical Center.

According to the researchers, this work is critical in the current political climate that is witnessing an erosion of LGBTQIA acceptance and is leading to a potential increase in minority stress through the bullying of certain youth populations, particularly sexual minority youth.

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Sexual consent better taught in continuum style approach, rather than by legal definition of ‘consent’ alone

Findings suggest the need to encourage and embrace a wider variety of terminology regarding consent and sexual violence in order to invite more people into the consent conversation.

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By teaching consent using this continuum style approach, rather than by the legal definition of ‘consent’ alone, young people are able to talk more openly and honestly in a way that relates to their own sexual and relationship experiences.

These latest results are published in the peer-reviewed journal, Sex Education.

Carried out in partnership with UK-based sexual health and wellbeing charity Brook, the findings follow an innovative two-year project which tested the teaching method out during workshops across seven educational institutes including a university, two youth clubs and an all-girls comprehensive school.

According to Dr. Elsie Whittington, who led the research, while young people were able to explain the legal definition of consent, they found this awkward and restrictive when applied to real-world scenarios. Therefore, this sometimes led to contradictory views and double standards based on gender.

“So, framing consent simply in this ‘black and white’ way does not match up with young people’s sexual and relationship experiences,” she said. “While a legal framework may feel simpler to teach, it does not give young people techniques or ideas for encouraging good communication and feeling informed and empowered.”

To encourage the 103 young adults, aged between 13 and 25, who took part in the project, Whittington used various creative methods and activities, including cake decorating, interactive games and scenario-based discussions. These group activities generated various forms of data from which Whittington was able to draw out several common themes. The activities have since been used with hundreds of young people in university and school teaching.

She found that by using a continuum to explore consent, it offered young people a way of viewing sex and consent that is not rigid, and which mirrored their own experiences.

“We found that using continuums and diverse scenarios enabled the young people to think critically about different ways of doing and negotiating consent enabling wider conversations that promote positive sexual ethics,” she said.

Scenarios allowed people to explore gendered double standards, societal expectations and the ways in which age can impact people’s ability to negotiate consent.

“The device of the continuum offered a way of speaking about and viewing sex, consent and violation that is not absolute – which mirrored the ways young people spoke about the topic,” she said.

Based on a feminist concept to consider the educational possibilities of teaching and talking about sexual consent as a continuum rather than a simple binary between active consent and rape, the sexual consent continuum developed by Whittington, and colleagues at Brook, comprises four sections as defined by young people varying from rape to where consent is explicitly negotiated.

In the end, the findings suggest the need to encourage and embrace a wider variety of terminology regarding consent and sexual violence in order to invite more people into the consent conversation.

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