New research published in the journal Diabetes Therapy suggests that the diagnosis threshold for type 2 diabetes (T2D) should be lowered in women aged under 50 years, since natural blood loss through menstruation could be affecting their blood sugar management.
Analysis of the national diabetes audit results has shown that women of younger age with type 2 diabetes mellitus (T2D) seem to have a higher mortality rate than men. The underlying mechanisms remain unclear. However, it is known that women are on average diagnosed with T2D at a later age than men. In this new study, the authors investigated whether a contributing factor to this late diagnosis may be a sex difference in the levels of glycated haemoglobin (HbA1c) due to haemoglobin replacement linked to menstrual blood loss.
This mechanism behind this could be shorter erythrocyte (red blood cell) survival which results in shorter exposure of haemoglobin to glucose compared with individuals who do not menstruate. Given that the diagnosis of T2D is also based on HbA1c, the use of the same reference range irrespective of age and sex, when a slightly lower point for T2D for premenopausal women may be appropriate, could potentially lead to under diagnosis of T2D in women and missed opportunities for intervention.
The study, by Dr Adrian Heald, Salford Royal Hospital, UK, and colleagues, examined HbA1c testing across seven UK laboratory sites (representing 5% of UK population). They conducted an exploratory analysis in two cohorts: cohort 1 was from one laboratory tested between 2012 and 2019 (146 907 participants). They assessed the sex and age differences of HbA1c in individuals who underwent single testing only, that had not been diagnosed with diabetes and had an HbA1c result of equal to or less than 48mmol/mol (the cutoff for diagnosing diabetes). The process was replicated in cohort 2 results from six laboratories with individuals tested between 2019 and 2021 (total people included 938 678). The possible national impact was estimated by extrapolating findings based on the Office of National Statistics (ONS) England population data and National Diabetes Audit published T2D prevalence and related excess mortality.
At age 50 years, average HbA1c levels in women lag by approximately five years compared to men. The data also show women aged under 50 years old had an HbA1c distribution that was lower than that of men by an average of 1.6mmol/mol (4.7% of the overall mean) while the difference in the distribution of HbA1c for individuals aged 50 years and over was less pronounced. Further analysis showed that, at HbA1c of 48mmol/mol, 50% fewer women could be diagnosed with T2D than men under the age of 50, whilst only 20% fewer women could be diagnosed with T2D than men over or equal to the age of 50. These findings were consistent with those in cohort 2.
Based on these observations, the authors estimated the effects of lowering the threshold for diagnosis of diabetes from HbA1c (48mmol/mol) by 4.2% to 46mmol/mol for women under the age of 50. This analysis showed that an additional 35 345 currently undiagnosed women in England would be reclassified as being diagnosed with T2D (17% more than the current 208 000 recorded women with T2D aged under 50 years). Lifestyle changes and treatment for diabetes would then be initiated for these women enabling improvement in health outcomes over both the short and longer term.
The authors also highlight that sex and gender difference in adverse cardiovascular risk factors are known to be present prior to the development of T2D. Once diagnosed, the prevalence of atherosclerotic cardiovascular disease is twice as high in patients with diabetes mellitus compared to those without diabetes mellitus. For women, diabetes mellitus is a stronger risk factor for cardiovascular disease than for men: women with diabetes aged 35–59 years have the highest relative cardiovascular death risk across all age and sex groups.
Furthermore, there is disparity in cardiovascular risk factor management between men and women, including in high-risk groups such as women with T2D. Women are less likely than men to receive treatment and cardiovascular risk reduction interventions that are recommended by international guidelines on diabetes. In addition, concordance with medication or prescription treating cardiovascular risk factors is lower in women than men with T2D, with less use of statins, aspirin and beta blockers. The authors say taken together, these factors mean “timely diagnosis of type 2 diabetes and initiation of preventative treatment has the potential to improve cardiovascular risk profile over lifetime and facilitate longer life quality and expectancy in women. Our findings provide evidence that the HbA1c threshold for this group should be re-evaluated.”
Improved modelling of male and female livers can help lead to safer drugs
Photo by Danilo Alvesd on Unsplash
Researchers report in PLOS Computational Biology that they developed a powerful new tool to understand how medications affect men and women differently, and that will help lead to safer, more effective drugs in the future.
Women are known to suffer a disproportionate number of liver problems from medications but also usually underrepresented in drug testing. To address this, University of Virginia scientists have developed sophisticated computer simulations of male and female livers and used them to reveal sex-specific differences in how the tissues are affected by drugs.
The new model has already provided unprecedented insights into the biological processes that take place in the liver, the organ responsible for detoxifying the body, in both men and women. But the model also represents a powerful new tool for drug development, helping ensure that new medications will not cause harmful side effects.
“There are incredibly complex networks of genes and proteins that control how cells respond to drugs,” said UVA researcher Jason Papin, PhD, one of the model’s creators. “We knew that a computer model would be required to try to answer these important clinical questions, and we’re hopeful these models will continue to provide insights that can improve healthcare.”
Harmful side effects
Papin, of UVA’s Department of Biomedical Engineering, developed the model in collaboration with Connor Moore, a PhD student, and Christopher Holstege, MD, a UVA emergency medicine physician and director of UVA Health’s Blue Ridge Poison Center. “It is exceedingly important that both men and women receive the appropriate dose of recommended medications,” Holstege noted. “Drug therapy is complex and toxicity can occur with subtle changes in dose for specific individuals.”
Before developing their model, the researchers first looked at the federal Food and Drug Administration’s Adverse Event Reporting System to evaluate the frequency of reported liver problems in men and women. The scientists found that women consistently reported liver-related adverse events more often than did men.
The researchers then sought to explain why this might be the case. To do that, they developed computer models of the male and female livers that integrated vast amounts of data on gene activity and metabolic processes within cells. These cutting-edge liver simulations provided important insights into how drugs (xenobiotics) affect the tissue differently in men and women and allowed the researchers to understand why.
They found that xenobiotic metabolism was more active in untreated males, while pentose and glucoronate interconversions were female-biased, suggesting a difference in pretreatment gene expression, which may result in different initial responses of phase I and phase II metabolism to hepatotoxic drugs. They also observed sex-bias in bile acid biosynthesis, which in combination with xenobiotic metabolism, this result may suggest differences in bacterial deconjugation driven by sex differences in the gut microbiome. Differences were also found in several essential metabolic pathways, such as glycolysis/gluconeogenesis, nucleotide metabolism, and lipid metabolism with supporting evidence in human or rat hepatocytes.
“We were surprised how many differences we found, especially in very diverse biochemical pathways,” said Moore, a biomedical engineering student in Papin’s lab. “We hope our results emphasise how important it is for future scientists to consider how both men and women are affected by their research.”
The work has already identified a key series of cellular processes that explain sex differences in liver damage, and the scientists are calling for more investigation of it to better understand “hepatotoxicity” — liver toxicity. Ultimately, they hope their model will prove widely useful in developing safer drugs.
“We’re hopeful these approaches will be help address many other questions where men and women have differences in drug responses or disease processes,” Papin said. “Our ability to build predictive computer models of complex systems in biology, like those in this study, is truly opening all kinds of new avenues for tackling some of the most challenging biomedical problems.”
New research led by King’s College London researchers has found that depression and the risk of depression are linked to different inflammatory cytokines in boys and girls. Previous research has shown that higher levels of inflammatory cytokines are associated with depression in adults, but little is known about this relationship in adolescence.
This study, published in the Journal of Affective Disorders, found that different cytokines were implicated in depression risk and severity in boys compared to girls. The research was part of the IDEA (Identifying Depression Early in Adolescence) project funded by MQ Mental Health Research.
To assess inflammation, researchers measured the blood cytokine levels in 75 adolescent boys and 75 adolescent girls (aged 14–16 years) from Brazil. The 150 participants had been recruited into three groups with equal numbers (50 participants in each group: 25 girls and 25 boys). The groups were those at low-risk for depression and not depressed, those at high risk of depression and not depressed, and those currently experiencing major depressive disorder (MDD).
The findings indicated that there are sex differences between the individual cytokines that are associated with depression in adolescents. Higher levels of the cytokine interleukin-2 (IL-2) were associated with both increased risk for depression and the severity of depressive symptoms in boys, but not in girls. However, higher levels of IL-6 were associated with severity of depression in girls, but not boys. In boys the levels of IL-2 were higher in the high-risk than the low-risk group and even higher in the group diagnosed with depression, indicating that in boys IL-2 levels in the blood could help indicate the onset of future depression.
Dr Zuzanna Zajkowska, Postdoctoral Researcher at King’s IoPPN and first author of the study, said: “This is the first study to show differences between boys and girls in the patterns of inflammation that are linked to the risk and development of adolescent depression.
“We found that the severity of depressive symptoms was associated with increased levels of the cytokine interleukin-2 in boys, but interleukin-6 in girls. We know more adolescent girls develop depression than boys and that the disorder takes a different course depending on sex so we hope that our findings will enable us to better understand why there are these differences and ultimately help develop more targeted treatments for different biological sexes.”
Researchers recruited adolescents from public schools in Brazil. Risk of depression was assessed by a composite risk score for depression based on 11 sociodemographic variables that had been developed as part of the IDEA project. Adolescents completed several questionnaires, self-reporting their emotional difficulties, relationships, experiences, and mood. They also completed a clinical assessment with a child and adolescent psychiatrist.
Senior author on the study Professor Valeria Mondelli, Clinical Professor of Psychoneuroimmunology at King’s IoPPN and theme-lead for Psychosis and Mood Disorders at the NIHR Maudsley BRC, said:
“Our findings suggest that inflammation and biological sex may have combined contribution to the risk for depression. We know that adolescence is a key time when many mental disorders first develop and by identifying which inflammatory proteins are linked to depression and how this is different between boys and girls we hope that our findings can pave the way to understanding what happens at this critical time in life. Our research highlights the importance of considering the combined impact of biology, psychology, and social factors to understand the mechanisms underlying depression.”
Females’ kidneys are known to be more resilient to disease and injury, so what about them can be applied to treat males’ kidneys? A new USC Stem Cell-led study published in Developmental Cell describes not only how sex hormones drive differences in male and female mouse kidneys, but also how lowering testosterone can “feminise” this organ and improve its resilience.
“By exploring how differences emerge in male and female kidneys during development, we can better understand how to address sex-related health disparities for patients with kidney diseases,” said Professor Andy McMahon, the study’s corresponding author, and the director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine of USC.
First authors Lingyun “Ivy” Xiong and Jing Liu from the McMahon Lab and their collaborators identified more than 1000 genes with different levels of activity in male and female mouse kidneys, in a study supported by the National Institutes of Health. The differences were most evident in the section of the kidney’s filtering unit known as the proximal tubule, responsible for reabsorbing most of the nutrients such as glucose and amino acids back into the blood stream. Most of these sex differences in gene activity emerged as the mice entered puberty and became even more pronounced as they reached sexual maturity.
Because female kidneys tend to fare better in the face of disease or injury, the researchers were interested how the gene activity of kidneys becomes “feminised” or “masculinised” – and testosterone appeared to be the biggest culprit.
To feminize the kidneys of male mice, two strategies worked equally well: castrating males before puberty and thus lowering their natural testosterone levels, or removing the cellular sensors known as androgen receptors that respond to male sex hormones.
Intriguingly, three months of calorie restriction – which is an indirect way to lower testosterone – produced a similar effect. Accordingly, calorie restriction has already been shown to mitigate certain types of kidney injuries in mice.
To re-masculinize the kidneys of the castrated males, the researchers only needed to inject testosterone. Similarly, testosterone injection masculinised the kidneys of females who had their ovaries removed before puberty.
The scientists performed some similar experiments with mouse livers. Although this organ also displays sex-related differences, the hormones and underlying factors driving these differences are very different than those at play in the kidney. This suggests that these sex-related organ differences emerged independently during evolution.
To test whether the same genes are involved in sex-related kidney differences in humans, the scientists analysed a limited number of male and female donor kidneys and biopsies. When it came to genes that differed in their activity between the sexes, there was a modest overlap of the human genes with the mouse genes.
“There is much more work to be done in studying sex-related differences in normal human kidneys,” said McMahon. “Given the divergent outcomes for male and female patients with kidney disease and injury, this line of inquiry is important for making progress toward eventually closing the gap on these sex-related health disparities.”
Scanning electron micrograph of a B cell. Credit: NIH
When the immune system is compromised due to various conditions and medicines, patients can experience opportunistic infection. Now, researchers reporting in Cell Reports have uncovered a sex-based variance in the trained immune memory response to infection in mice that might translate to humans.
The researchers, from the University of Missouri School of Medicine, found that female mice were more vulnerable to opportunistic infection from a bacterial pathogen to which they had previously been exposed when progesterone levels were naturally elevated as part of their reproductive cycle.
“Differences in immune response in males and females have been observed before. For instance, males had increased morbidity and severity of COVID-19 from SARS-CoV-2 infections,” said Dr Adam Schrum, associate professor in the Department of Molecular Microbiology and Immunology. “But females are known to suffer other infections worse than males. Our research found that female mice were far more vulnerable to opportunistic bacterial infection than male mice because of a sex-based difference in their trained immunity.”
To understand why the immune systems of female and male mice responded differently to a bacterial pathogen, the researchers examined whether the reproductive cycle affected immune training. They found that elevated progesterone levels correlated with lower trained immune responses. To test this more fully, the researchers gave the female mice progesterone blockers and found that their trained immune response was subsequently enhanced.
“The female mice had significantly restored trained immune response when progesterone was blocked, reaching comparable levels to those of male mice,” said Schrum. “Sex hormone-based modulation of immune function needs more study to be fully understood, but as a first step we can conclude that immune training is influenced by a progesterone-dependent mechanism that results in a sex bias in mice.”
In addition to further study to understand how and why progesterone specifically influences trained immune responses in mice, the researchers pointed out that because mice have shorter estrous cycles than the human menstrual cycle, further research is needed to understand how sex hormones might affect human immune training.
Reaching the age of 90, 95 or 100, known as exceptional longevity, was more likely for women who maintained their body weight after age 60, according to a multi-institutional study led by University of California San Diego. Older women who sustained a stable weight were 1.2 to 2 times more likely to achieve longevity compared to those who lost 5% of their weight or more.
In this study published in the Journal of Gerontology: Medical Sciences, researchers investigated the link between weight changes later in life with exceptional longevity among 54 437 women who enrolled in the Women’s Health Initiative, a prospective study investigating causes of chronic diseases among postmenopausal women. Throughout the follow up period, 30 647 (56%) of the participants survived to the age of 90 or beyond.
Women who lost at least 5% weight were less likely to achieve longevity compared to those who achieved stable weight. For example, women who unintentionally lost weight were 51% less likely to survive to the age of 90. However, gaining 5% or more weight, compared to stable weight, was not associated with exceptional longevity.
“It is very common for older women in the United States to experience overweight or obesity with a body mass index range of 25 to 35. Our findings support stable weight as a goal for longevity in older women,” said first author Aladdin H. Shadyab, PhD, MPH, associate professor at UC San Diego.
“If aging women find themselves losing weight when they are not trying to lose weight, this could be a warning sign of ill health and a predictor of decreased longevity.”
The findings suggest that general recommendations for weight loss in older women may not help them live longer. Nevertheless, the authors caution that women should heed medical advice if moderate weight loss is recommended to improve their health or quality of life.
The data adds to research connecting weight change and mortality and is notably the first large study to examine weight change later in life and its relation to exceptional longevity.
Thanks to a study recently published in The Lancet Digital Health, clinicians are one step closer to helping people catch a sudden cardiac arrest before it happens. The study, found that 50% of individuals who experienced a sudden cardiac arrest also experienced a telling symptom 24 hours before their loss of heart function.
The investigators from the Smidt Heart Institute at Mount Sinai also learned that this warning symptom was different for women than it was for men. For women, the most prominent symptom of an impending sudden cardiac arrest was shortness of breath, whereas men experienced chest pain. Smaller subgroups of both genders experienced abnormal sweating and seizure-like activity.
Out-of-hospital sudden cardiac arrest is fatal 90% of the time, so there is an urgent need to better predict and prevent the condition.
“Harnessing warning symptoms to perform effective triage for those who need to make a 911 call could lead to early intervention and prevention of imminent death,” said sudden cardiac arrest expert Sumeet Chugh, MD, senior author of the study. “Our findings could lead to a new paradigm for prevention of sudden cardiac death.”
For this study, investigators used two established and ongoing community-based studies, each developed by Chugh: the ongoing Prediction of Sudden Death in Multi-Ethnic Communities (PRESTO) Study in Ventura County, California, and the Oregon Sudden Unexpected Death Study (SUDS), based in Portland, Oregon.
Both studies provide Cedars-Sinai investigators with unique, community-based data to establish how to best predict sudden cardiac arrest.
“It takes a village to do this work,” said Chugh. “We initiated the SUDS study 22 years ago and the PRESTO study eight years ago. These cohorts have provided invaluable lessons along the way. Importantly, none of this work would have been possible without the partnership and support of first responders, medical examiners and the hospital systems that deliver care within these communities.”
In both the Ventura and Oregon studies, Smidt Heart Institute investigators evaluated the prevalence of individual symptoms and sets of symptoms prior to sudden cardiac arrest, then compared these findings to control groups that also sought emergency medical care.
The Ventura-based study showed that 50% of the 823 people who had a sudden cardiac arrest witnessed by a bystander or emergency medicine professional, such as an emergency medicine service (EMS) responder, experienced at least one telltale symptom before their deadly event. The Oregon-based study showed similar results.
“This is the first community-based study to evaluate the association of warning symptoms – or sets of symptoms – with imminent sudden cardiac arrest using a comparison group with EMS-documented symptoms recorded as part of routine emergency care,” said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute.
Such a study, Marbán says, paves the way for additional prospective studies that will combine all symptoms with other features to enhance prediction of imminent sudden cardiac arrest.
“Next we will supplement these key sex-specific warning symptoms with additional features – such as clinical profiles and biometric measures– for improved prediction of sudden cardiac arrest,” said Chugh.
Long overlooked by genetics, the Y chromosome is surprisingly quite challenging to sequence, and so its contributions to health and disease remain largely unknown. For the first time, the complete sequences of 43 human Y chromosomes from lineages from around the globe provides an essential step forward in understanding the roles of the Y chromosome in human evolution and biology. The researchers behind the effort published their findings in two papers in Nature.
Even as the field of human genomics forged ahead at an astonishing pace, the Y chromosome has long remained overlooked. It has been postulated that the human sex chromosomes once originated from a pair of structurally similar chromosomes, but subsequently one of the sex chromosomes, the ancestral Y chromosome, underwent significant degradation, losing 97%of its former complement of genes over many millions of years. This peculiar evolutionary trajectory has given rise to speculation that the human Y chromosomes might eventually disappear completely, albeit millions of years from now, and we already observe that some biological males do lose them in dividing cells as they age, with unclear health consequences.
In practical terms, the Y chromosome contains a large proportion of repetitive and heterochromatic (highly condensed, gene-poor and not transcribed to messenger RNA) sequences, making it exceptionally difficult to fully sequence. Using sequencing methods that can cover long, continuous sequences, the Telomere-to-Telomere (T2T) consortium has now published the first complete Y chromosome assembly from a single individual of European descent in Nature. At the same time, a team led by Jackson Laboratory (JAX) Professor and The Robert Alvine Family Endowed Chair Charles Lee, PhD, FACMG, has published, also in Nature, the assembled Y chromosomes from 43 unrelated males, with nearly half coming from African lineages. These two papers provide intriguing insights into human Y chromosomes, reveal the highly variable nature of Y chromosomes across individuals, and provide an important foundation for future studies on how they may be contributing to certain disorders and diseases.
The need for long reads
Standard short-read genomic sequencing technologies require breaking genomic DNA into short (~250-base-long) fragments. These fragments are then reassembled into the full genome of more than 3 billion base pairs across 46 chromosomes in humans. The method is very accurate and works well for most, but not all, of the genome. Almost all “complete” human genome sequences, including the current reference genome sequence (known as GRCh38), are actually only about 90% complete, because it is difficult to assemble the highly repetitive and other complex sections accurately. GRCh38 falls particularly short for the Y chromosome, as it barely assembles half of that chromosome.
As a result, while the much larger and gene-rich X chromosome has been extensively studied, the Y chromosome has been often overlooked outside of male-based fertility studies. In a significant step forward for the genomics field, scientists from JAX, including first author and JAX Associate Research Scientist, Pille Hallast, PhD, with collaborators from Clemson University, Heinrich Heine University (Germany) and more, have now revealed a full picture of the Y chromosome’s key characteristics and differences between individuals for the first time. Of note is the striking variation in size and structure across the 43 Y chromosomes sequenced that covered 180 000 years of human evolution and range from 45.2 million to 84.9 million base pairs in length.
The inclusion of 43 different individuals representing diverse Y lineages allowed the researchers to redefine inter-chromosomal region boundaries and identify large-scale variations at an unprecedented resolution and clarity. The study also revealed an unexpected degree of structural variation across the Y chromosomes. For example, half of the euchromatin (gene-rich region) of the sequenced chromosomes carries large recurrent inversions (segments that contain the same nucleotide sequences but oriented in the opposite direction) at a rate much higher than anywhere else in the genome. The study further identified regions of the Y chromosome that demonstrate little single nucleotide variation but show high gene copy number variation for specific gene families. Other gene families tended to maintain their copy numbers, however, consistent with their roles in fertility and normal development.
Role in overall health
“Having fully resolved Y chromosome sequences from multiple individuals is essential in order for us to begin to understand how this variation can affect function” says Hallast. “The degree of structural variation between individuals came as a big surprise to me, even though the nucleotide sequences within the Y chromosome genes are comparatively conserved. The variable gene copy numbers in certain gene families and extremely high inversion rates are almost certain to hold significant biological and evolutionary roles.”
The Y chromosome’s contributions to male health are poorly understood. Some unexpected indications of its importance to human health have recently come into focus in two new research studies that collectively implicate the Y chromosome in aggressive features of colorectal and bladder cancers in men. Indeed, one of the studies showed that tumors that had lost the Y chromosomes can more effectively evade T cell immunity, are infiltrated with higher numbers of dysfunctional CD8+ T cells, and are more responsive to anti-PD1 treatments compared to similar tumors retaining the Y chromosome.
“Research is emerging that shows proper Y chromosome gene function is incredibly important for the overall health of men,” says Lee, senior author on the paper. “Our study enables the inclusion of the full Y chromosome in all future studies when sequencing male genomes to understand health and disease.”
Researchers have added several genes, which appear to affect obesity risk in certain sexes and ages, to the list of genes which influence weight gain. The study, published in the journalCell Genomics, may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease.
“There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone,” says senior author John Perry, a geneticist and professor at the University of Cambridge. “We’re not expecting people to have completely different biology, but you can imagine things like hormones and physiology can contribute to specific risks.”
To untangle sex’s role in obesity risk, the research team sequenced the exome (the protein-coding part of the genome) of 414 032 adults from the UK Biobank study. They looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. Five genes influencing BMI in women and two in men were identified.
Among them, faulty variants of three genes – DIDO1, PTPRG, and SLC12A5 – are linked to higher BMI in women, up to nearly 8 kg/m² more, while having no effect on men. Over 80% of the women with DIDO1 and SLC12A5 variants had BMI-indicated obesity. Those carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both risk indicators for obesity-related complications like diabetes and heart disease. Others with SLC12A5 variants had higher odds of having type 2 diabetes compared with non-carriers. These findings highlight previously unexplored genes that are implicated in the development of obesity in women but not men.
Perry and his colleague then repeated their method to look for age-specific factors by searching for gene variants associated with childhood body size based on participants’ recollections. They identified two genes, OBSCN and MADD, that were not previously linked to childhood body size and fat. While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes. In addition, the genetic variants acting on MADD had no association with adult obesity risk, highlighting age-specific effects on body size.
“What’s quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death,” says Perry. Obesity is a brain-related disorder, whereas biological and environmental factors act to influence appetite. “There’s currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the aetiology of obesity.”
Next, the research team hopes to replicate the study in a larger and more diverse population. They also plan to study the genes in animals to peer into their function and relationship with obesity.
“We’re at the very earliest stages of identifying interesting biology,” says Perry. “We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity.”
Circumcision rates in South Africa have increased dramatically over the last decade with 62.5% of males aged 15 to 49 who were circumcised as of 2022. PHOTO: Rodger Bosch
There is compelling scientific evidence that Voluntary Male Medical Circumcision (VMMC) is both safe and significantly reduces a man’s risk of becoming infected with HIV. While there can also be some protection from traditional circumcision, the protective effect of medical circumcision is thought to be much greater. The World Health Organization (WHO) has recommended medical circumcision for HIV prevention since 2007.
Circumcision rates in South Africa have increased dramatically over the last decade. According to estimates from Thembisa, the leading mathematical model of HIV in South Africa, 62.5% of males aged 15 to 49 were circumcised as of 2022. In 2012, this number stood at 38.8%. Experts ascribe some of the reduction in the country’s rate of new HIV infections to the massive circumcision drive over the last decade.
But the choice between medical, traditional, or no circumcision is often about much more than HIV risk. For one thing, traditional circumcision has great cultural meaning for some groups.
‘From boyhood to manhood’
Spotlight visited Lwazi Mfeka* at his ibhoma (traditional hut) during his last week at an initiate school in the Eastern Cape this winter. The first-year Walter Sisulu University student asked to remain anonymous for fear of victimisation, as talking openly about initiation is taboo in many rural communities.
He said leaving his ibhoma on the last day of his tenure as an initiate is a moment that will forever be etched in his mind. Not only did this signal the end of a “challenging” three-week period at the school, but it was also a symbolic moment where he says he has graduated from boyhood to manhood.
Mfeka said he was supposed to have undergone the ritual in December last year, but due to a bereavement in his family, he couldn’t. “At varsity, I was often mocked and isolated because I was still a ‘boy’. This bothered me a lot and I couldn’t wait to come here (to the mountain) and finally become a man,” he said.
He admits he was gripped by fear in the months leading up to his initiation.
“For starters, many young boys die while undergoing the custom and I didn’t want to add to the numbers. But, fortunately, my dad chose an ingcibi (traditional surgeon) with a good track record. I first had to go and get tested by a doctor for chronic illnesses such as HIV and TB as I had to present a medical certificate to the ingcibi before being circumcised. At the initiation school, everything was done according to the rules. After each cut, the spear gets sanitised to avoid any spread of infections,” Mfeka said.
Botched circumcisions
Mfeka’s fears are not without merit. In recent years, traditional male circumcision has often made headlines for all the wrong reasons, with the lives of young men lost due to botched or unhygienic circumcisions.
According to Mamnkeli Ngam, spokesperson for the Eastern Cape Department of Cooperative Governance and Traditional Affairs, in the 2022 winter initiation season, 11 of 10 794 boys who underwent traditional circumcision in the province died, while in the summer initiation season, 23 of 51 601 died. Ngam says around 20 000 boys went into the mountains to undergo traditional circumcision this winter (2023).
He told Spotlight that some fly-by-night ingcibis, desperate to make a quick buck, are the ones giving the custom a bad name. He says that assisted by the local chiefs and the police, they have been clamping down on illegal initiation schools and arresting bogus traditional surgeons.
“During the period between 1 June to 20 July, nine bogus traditional surgeons have been arrested in the Eastern Cape,” Ngam said.” We have been conducting safety campaigns ahead of the winter circumcision season to educate communities. Circumcising boys without parental consent [and] not having undergone medical examination to perform the procedure is against the law.”
Nkosi Mpumalanga Gwadiso, the Eastern Cape House of Traditional and Khoisan Leaders’ chair, told Spotlight that parents need to be involved throughout the process. “Often, parents leave everything to the amakhankatha (traditional nurses). That’s where things go wrong. As chiefs, we always emphasise the importance of parental involvement from day one until the initiates come back home safely. Some traditional nurses are the reason things go wrong because they neglect the initiates and go drinking. It is therefore the responsibility of the fathers to ensure that they visit the initiation schools regularly and monitor everything,” Gwadiso said.
While numbers vary widely and we haven’t been able to get a full picture, we understand that initiation schools can admit around 100 initiates during each of the winter and summer circumcision seasons. Our informal survey of several initiation camps in the former Transkei suggests the cost is typically around R300.
The medical alternative
While medical male circumcision is a generally available alternative to traditional circumcision, its provision in the Eastern Cape is influenced by cultural factors. For example, according to Eastern Cape Provincial Health Department spokesperson, Yonela Dekeda, the department does not conduct open marketing or demand creation in the communities/public “due to cultural dynamics within the province”.
“Medical Male Circumcision services are actually confined within the health facility level. Therefore, intake depends on the walk-ins, not on demand creation or promoting of the MMC services,” Dekeda said. “MMC is the choice of individual families. However, as the department, we are ensuring that all the designated MMC sites are well equipped with necessary MMC equipment, including training of clinicians such as medical doctors, clinical associates, and professional nurses to provide quality voluntary medical male circumcision services.”
Despite the lack of promotion, some young men, such as Bandile Macetywa*, have opted to go the medical route. He asked that we not use his real name for fear of victimisation from people who disapprove of his decision not to be circumcised in the traditional manner.
Speaking to Spotlight, the 20-year-old from Cofimvaba in the Eastern Cape said he pleaded with his parents, who are staunch traditionalists, to do the custom the medical way. “I know I disappointed my parents, especially my father, but at the end of the day, it was about my safety. I was happy when they respected my decision,” he said.
However, Mecatywa says he is all too aware of the discrimination that awaits him in society. “There are already naysayers. But I’m just glad the whole process went well. For Pete’s sake, we are in 2023. People are free to choose where they get circumcised. Some people had the guts to tell me to my face that I deserved to be abducted and circumcised again the traditional way?” he said.
Mecetywa believes many lives will be saved if rural communities can be educated to accept medical male circumcision. “It is much safer with [fewer] risks of getting infected while undergoing it. I am not saying traditional male circumcision is wrong. But why do initiates continue to die or have botched operations if things are done the right way,” he asked.
While the department does not actively promote medical circumcision, and while Mecetywa is clearly very aware of being in a minority, there are in fact significant numbers of medical circumcisions being conducted in the Eastern Cape. According to Dekeda, 14 637 were performed in the province in 2022, while 14 300 have been performed so far this year.
Medical male circumcision is an elective procedure that is widely available in the public sector, often provided via NGOs. The process typically involves counselling, a pre-assessment to check for anything that may hamper a client’s ability to be circumcised, post-operative care, and follow-up visits. Clients will typically also be offered an HIV test.
VMMC in the Western Cape
Meanwhile, in the Western Cape, the Department of Health and Wellness in collaboration with the City of Cape Town and the Department of Cultural Affairs and Sport has implemented an initiation consent form as a mechanism to uphold ethics. It includes medical screening that helps minimise and mitigate potential risks.
Western Cape Department of Health spokesman Mark Van der Heever told Spotlight, “The initiation consent form is further reviewed to enable alignment to developments as these emerge. Training and capacitation of traditional surgeons is a key element to strengthening partnership following a whole of government and whole of society approach.”
Van der Heever says since 2020, 274 circumcisions were performed by a Medical Officer invited by the traditional healers to perform the circumcisions. A total of 131 977 medical male circumcisions, according to Van der Heever, were performed at the Western Cape health facilities since 2013, with 13 105 performed just last year.
The rest of the stats are as follows:
2013 – 12 581
2014 – 15 990
2015 – 14 131
2016 – 11 982
2017 – 15 127
2018 – 14 557
2019 – 18 000
2020 – 5 750 (COVID)
2021 – 10 754 (COVID)
2022 – 13 105
Van der Heever adds that between April and March 2023, Medical Male Circumcision was reported at 130 public health sites and a total of 12 259 circumcisions were performed across the province.
“The province also has two Men’s Health Clinics (in Karl Bremer and Elsies River). With the intention of increasing access to services, we are in discussions to upskill clinicians to enable service provision at health facilities. Current service provision is based on roving teams in both the metro and rural districts, which limit access to availability of the team.”
