Recognition of Genital Differences Among Some 47XXY Infants

Klinefelter syndrome (KS) is a sex chromosome variation caused by the presence of one or more supernumerary X chromosomes. Common clinical phenotypes of KS are comprised of tall stature with a feminine body type, gynecomastia, small testes and infertility. Cases of KS with genital differences as the main evaluation in childhood are rarely disclosed. We report four children presented to our clinic for assessment of ambiguous genitalia who were ultimately diagnosed with KS. The first patient was a 4 months male baby who presented with phenoscrotal hypospadias, bifid scrotal and small testes.

Endocrine studies suggested a normal hypothalamic-pituitary-gonadal axis. The second patient was a 3 weeks baby born with the concern for ambiguous genitalia. He was evaluated at birth for bifid scrotum, small testes and glanular hypospadias. The third and fourth patients were three and seven years old boys with severe hypospadias, bifid scrotal and small testes. Hormonal analysis showed a low level of testosterone with normal level of FSH and LH. The chromosome analysis was 47, XXY for all of the patients confirming the diagnosis of KS. Individuals with KS have a highly varied phenotype comprising a range of physical features, however, genital differences are rarely reported as characteristics feature of the syndrome in childhood. Clinicians need to be aware of the phenotypic variability of KS and recognize KS as one of the causes of abnormal genitalia at birth. This finding, along with appropriate genetic counselling, suggest that early detection of KS is important in monitoring potential development problems; such as hypogonadism, gynecomastia and gender dysphoria in the future.


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Evidence For Long Noncoding RNA Up-regulation in Klinefelter Syndrome

Klinefelter syndrome (KS) is the most common sex-chromosome variation among males, with an estimated prevalence of 1:660 newborns. The most common karyotype is the classic 47,XXY, which accounts for the 80–90% of all cases. It is a consequence of a non-disjunction of paired X-chromosomes during the first or second meiotic division, equally due to a paternal or maternal meiotic mal segregation event. The remaining 10% of KS are due to chromosome mosaicisms (e.g. 46,XY/47,XXY) or to more complex karyotypes (X chromosome structural abnormalities such as 47,XX, der(Y), 47,X, der(X),Y, or other numeric sex chromosome abnormalities such as 48, XXXY, 48, XXYY and 49, XXXXY).

The chromosomal abnormality leads to a progressive germ cell degeneration starting from mid-puberty, impaired Sertoli cell function. total tubular atrophy or hyalinizing fibrosis and Leydig cell hyperplasia, clinically causing hypergonadotropic hypogonadism, small testis with increased consistency and infertility. Occasionally, foci of spermatogenesis have been observed in testis of KS patients. Clinically, azoospermia is present in the 90% of non-mosaic KS, whereas severe oligozoospermia in the remaining 10%.

Several clinical manifestations are associated with KS. These include learning and language disability, reduction in intelligence quotient (IQ) scores of 10 to 15 points, but not into the intellectual disability range, increased risk for mitral valve prolapse, lower-extremity varicose veins, venous stasis ulcers, deep vein thrombosis and pulmonary embolism, autoimmune diseases, 20-fold-higher risk of developing breast cancer, type II diabetes mellitus (T2 DM) and metabolic syndrome , osteoporosis, extragonadal germ cell tumors and non-Hodgkin lymphoma.

Molecular mechanisms underlying the variability in KS phenotype have not been clearly understood yet. Epigenetic mechanisms have been suggested to play a role. Growth arrest-specific 5 (GAS5) gene, mapping on the 1q25.1 chromosome, encodes for a long non-coding RNA (lncRNA) which is involved in the modulation of gene expression, targeting many different downstream miRNAs.

LncRNA GAS5 was initially identified as a tumor suppressor gene. However, it has also been shown to support female germline stem cell (FGSC) survival and adipocyte differentiation. In addition, recent evidence pointed to lncRNA GAS5 a role in atherosclerosis and autoimmune diseases, which are widely recognized as KS comorbidities.

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Shifting Syndromes: Sex Chromosome Variations and Intersex Classifications

In 1942, Harry Klinefelter, along with the endocrinologists Fuller Albright and Edward Reifenstein, described what would become known as Klinefelter’s syndrome. Klinefelter was a rheumatologist and endocrinologist at the Massachusetts General Hospital in Boston working under the supervision of Albright considered by many the ‘most outstanding clinical endocrinologist in the world’. Like Turner syndrome, Klinefelter’s syndrome was an association of symptoms: gynecomastia (male breast enlargement), smaller than average testes with aspermatogenesis but without a-leydigism (non-production of sperm but with secretion of Leydig cells, the cells in testes that produce testosterone), and increased excretion of follicle-stimulating hormone (a hormone that plays a role in the regulation of growth, puberty and reproduction).

Klinefelter later stated that while he worked with Albright on the series of nine individuals with these symptoms, it was ‘really just another of Dr. Albright’s diseases’, but that Albright had been charitable in letting him be named first on the 1942 paper. Indeed, in the early 1950s there are references to the syndrome as ‘the K.R.A. Syndrome , after the three authors of the paper. After the initial description, the classification of Klinefelter’s syndrome loosened to include individuals without gynecomastia, but with low testosterone and small testes. Here, then, it is adult bodies that can be diagnosed with Turner or Klinefelter’s syndrome, through the association or co-existence of several specific bodily symptoms.

The initial description of Turner and Klinefelter’s syndromes illustrate what Jutel has called the ‘classificatory project’ in medicine. Jutel identifies a shift in eighteenth-century medicine away from a focus on individual symptoms towards a focus on ‘groups and patterns of symptoms that doctors could reliably recognise’ . She draws on Foucault to suggest that between the late eighteenth and late nineteenth centuries, clinical practice ‘removed the symptom from its previously supreme position, seeing it instead as simply one element in a symptom cluster which would constitute the disease’. The classificatory project saw a shift from the idea of bodies exhibiting single symptoms to bodies ‘having’ syndromes, evidenced by the association or co-existence of a number of symptoms. This gave new meaning to syndromes as diagnostic categories and shifted the meanings of human bodies as described by diagnosis. The shifts in the classificatory project were also shifts in the different ways that bodies could be enacted by biomedical science.

While the definition of Turner’s and Klinefelter’s as syndromes made up new categories of people and gave classificatory meaning to particular symptom clusters, these categories bore no relationship yet to older categories of hermaphroditism or the emerging category of ‘intersex’. Despite the reproductive issues and effects on sex characteristics associated with these two syndromes, their original descriptions did not suggest that these bodies were in any way ‘in doubt’, with regards to gender and sexuality. Original work on Turner syndrome included only women, but a number of published articles identified similar symptom clusters in male individuals. Original work on Klinefelter’s syndrome included only men. Significantly, Klinefelter (1986) always maintained that individuals with this syndrome cluster were unproblematically phenotypic males ‘and should never be considered otherwise’ . However, genetic science in the 1950s would significantly change the classification of individuals with diagnoses of Turner or Klinefelter’s syndromes.

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Diagnosing Sex Chromatin: A Binary for Every Cell

In 1949, Canadian anatomist Murray Barr announced the discovery of a peculiar entity in the cell nucleus that was present in females and absent in males. The identity of this entity remained uncertain for a decade even though Barr hypothesised a relationship between it and the sex chromosomes and called it the ‘‘sex chromatin.’’ This hypothesis inspired the development of the chromatin into a technology that could indicate ‘‘chromosomal’’ or ‘‘genetic’’ sex, which supposedly established male and female sex difference as a binary and fundamental characteristic of humans and other animals at conception. Barr collaborated with other researchers and potential patients who applied the sex chromatin test, hoping that it could identify the ‘‘true’’ sex of intersexuals, homosexuals, and transsexuals. Ironically, the application of the test to intersexuals would lead to a revision of the identity of the sex chromatin itself. The history of the sex chromatin illuminates how the significance and essence of this laboratory object evolved with its use as a clinical and research tool. Researchers had hoped that the test would sort the intersex into just two categories, male and female. Instead, the sex chromatin helped to multiply categories of the intersex, distinguished them from inverts, underpinned psychosocial gender as a new dimension of sex difference, and in the process had its own identity refashioned. Today, we call it the Barr body and its story reminds us of the power and limit of biotechnologies to determine who we are.

The easiest way to distinguish male from female was to count the smallest chromosomes. If there were four, then they assumed that the sample came from a female; if five, then a male. After verifying this assumption with the recorded sex of the samples, they examined cells in a bone marrow sample taken from a Klinefelter’s syndrome patient. They concluded that these were of the ‘‘female type’’ and that ‘‘there is agreement between the diagnoses of genetic sex by the presence of ‘sex chromatin’ and by direct examination of the chromosomes.


This article is about the hopes and the uncertainties that people expressed for what the sex chromatin test could do and what it could tell them. It is also about the making of a new technology for diagnosing ‘‘true sex’’ from bodily tissues that were not obviously sexual, like skin or cheek swabs. Initially a serendipitous discovery, the sex chromatin was fashioned into an authoritative, medical tool that could purportedly separate male from female, homosexual from heterosexual, and normal from abnormal. In what follows, I will make three major arguments. First, I will demonstrate how the sex chromatin satisfied social expectations that only two sexes existed. Even if the exact relationship between the sex chromosomes and chromatin remained ambiguous, the presence or absence of the chromatin provided a binary answer to a question presumed to have only two possibilities. Thus, the sex chromatin re-presented the essence of genetic sex. Second, I will argue that the chromatin test helped to erase old sexual identities and create new ones. After the test, inverts became homosexuals and transsexuals, psychological gender emerged as a dimension of difference distinct from biological sex, and two new kinds of intersexuals were minted. Third, in the most ironic twist of all, I will show how these new classes of intersexuals provided evidence that would re-identify the sex chromatin itself. The result was a resolution of a long-standing uncertainty regarding the relationship between the sex chromatin and X chromosomes. Together, these recursive histories of the sex chromatin test demonstrate how social expectations help to constitute an emerging medico-scientific technology, and how that technology can in turn reformulate the cultural expectations that gave it meaning.

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Human Sex Chromosome Swapping Occurs More Often Than Previously Thought

It turns out that the rigid “line in the sand” over which the human sex chromosomes — the Y and X — go to avoid crossing over is a bit blurrier than previously thought. Contrary to the current scientific consensus, Arizona State University assistant professor Melissa Wilson Sayres has led a research team that has shown that X and Y DNA swapping may occur much more often. And this promiscuous swapping, may in turn, aid in our understanding of human history and diversity, health and disease, as well as blur rigid chromosomal interpretations of sexual identity.

Studying our sex chromosomes has consequences for human health and for trying to understand our history, where understanding the evolution of the X and Y is so important because we need to understand that there are all of these variations in the genetics of sex determination.

All of human diversity is spooled within our DNA across 23 pairs of chromosomes, containing an estimated 25,000 genes. For every generation, this DNA information — often including a baby’s sex — is shuffled like a deck of cards between a mother and father through a process called recombination.

Recombination makes every individual unique, down to the last pair of sex chromosomes. Recombination occurs routinely everywhere except on the sex chromosomes, where the genetic deck of cards remains stacked, unable to shuffle information — with the exception of two small regions located at the tips of the X and Y chromosome, called pseudoautosomal regions (PAR1 and PAR2). “The pseudoautosomal region, this tiny region that still recombines, is extremely understudied, typically filtered out of all analyses. In addition, there is a rogue island of the X chromosome, called the X-transposed region, or XTR, which was duplicated from the X to the Y around the last common ancestor of all humans

The study, published in the early online edition of the journal Genetics, includes ASU School of Life Sciences researchers Daniel J. Cotter and Sarah M. Brotman. Together, they challenged the widely held assumption that genetically there is a strict recombination boundary that suppresses swapping between the X and Y. Using the complete DNA sequence information from the X chromosomes of 26 unrelated females, the ASU team has shown that the genetic diversity in the region, called PAR1, is far greater than the other regions of the X, and that the diversity is elevated across the PAR1 region, rather than an abrupt cut-off as previously expected. After the PAR1, the diversity should drop off like a cliff, but instead, looks instead like a slow rolling hill, which could result in an increase in the number of X-linked disorders.

To understand the modern X and Y, evolutionary biologists have traced their history back to the dawn of mammals. About 200 million years ago, the X and Y were indistinguishable, but then had a long, drawn out breakup. It’s thought that little pieces of the future Y started doing genetic back flips, called inversions, that made it harder to recombine, and the genetic gulf between the sexes first began to widen. In addition to the PAR regions, XTR (X-transposed region) duplicated from the X to the Y in human after the human-chimp split about 6 million years ago, with two genes floating off on this genetic island.

The evolutionary outcome is striking; after 200 million years, the male Y is pruned up, having lost nearly 90 percent of the genes on the ancestral sex chromosomes and the ability to exchange information with the X.

Typically PAR1 and PAR2 are filtered out during sex demographic history studies, while XTR is not. To avoid bias in reporting and interpreting diversity, the new results need to be carefully factored in for future studies. And understanding the differences between the sex chromosomes is essential for understating traits involved in some sex-biased diseases (most famously in color-blindness and hemophilia). For example, a deficiency in PAR1 recombination has been linked to Klinefelter’s syndrome (XXY individuals), and an “unlucky” break involved in a key male reproductive switch, a testis determination region located nearby.

This sex-determining region of the Y in the testis determining pathway, is now in humans, right next to the boundary. “The big implication is that because of the way our Y chromosome is structured, SRY is immediately next to the boundary, and because the boundary is fuzzy, we can get SRY hopping over to an X chromosome.” SRY can be shuffled to the X, resulting in an increase in sex-linked disorders, such as a SRY positive XX males, known as de la Chappelle syndrome.

We know that large aspects of gender are really built on societal expectations, but it turns out that also our ideas of what sex is, genetically, may also be a little bit determined by public consensus.

Sex has to do with if you are making eggs or sperm in humans. Sex, in fact, can be decoupled from your sex chromosomes. This fuzzy boundary makes it even more messy. Other fuzzy sex-linked boundaries include Turner syndrome (females with only one X), affecting one in 2,500 individuals, and Klinefelter’s syndrome, found in one in a 1,000 individuals where despite what on the surface seem like rare conditions are not so rare if we changed our mindset.

Many people may not know their chromosome complement and as such we should be really careful when we are trying to define someone by their sex chromosomes. There are so many things that can affect sex determination. But (SRY) is the first switch in the testis determining pathway and behaves like a dimmer. There is another syndrome called Swyer Syndrome. An individual will inherit a Y chromosome, from their genetic father, and their SRY gene is turned on, but not on enough to turn on testis determination; they are XY, but develop ovaries.” Recombination suppression between X and Y is still an actively evolving process in humans. In an intriguing area ripe for future exploration, there are 24 additional genes located within PAR1 and countless others near the PAR1 boundary, which have been shown to be important for bone growth, melatonin production, and links to psychiatric disorders, including bipolar affective disorder.

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History of The Research on Sex Determination

Since the beginning of humanity, people were fascinated by sex and intrigued by how the differences between sexes are determined. Ancient philosophers and middle age scholars proposed numerous fantastic explanations for the origin of sex differences in people and animals. However, only the development of the modern scientific methods allowed us to find, on the scientific ground, the right answers to these questions. In this review article, we describe the history of these discoveries, and which major discoveries allowed the understanding of the origin of sex and molecular and cellular basis of the differentiation of male and female sex characteristics during embryo development and in the adult

Jacek Z Kubiak, Malgorzata Kloc, Rafal P Piprek.
History of The Research on Sex Determination.
The First Concepts of Sex Determination

In the multicellular organisms, sex is a set of features of the structure, function, and behaviour of the body that allows it to be classified as a male or female individual. Sex determination is directly linked to the determination of the direction of the development of yet undifferentiated gonads into the testes or ovaries. The sexual characteristics of the individual are formed during the process of sexual differentiation. For sexually reproducing multicellular organisms, the correct structure and function of the reproductive system is a prerequisite for having a healthy and fertile offspring, which is the basis of maintaining the continuity of the species. The emergence of sex turned out to be a significant advancement in evolution, as the merger of the male and female gametes, resulting from the existence of sex, provided a high degree of genetic variability of the offspring.

For centuries, humanity has been intrigued by the nature of sex, the sense of its existence and origin.

Thus, in contrast to the asexually reproducing organisms, the population of sexually reproducing organisms became more diverse, and as a result, more easily adaptable to the changing environment. For centuries, humanity has been intrigued by the nature of sex, the sense of its existence and origin. The issue of sex already appeared in the book of Genesis (2: 21-24), which tells about the creation by God of the man (Adam) and the women from Adam’s rib. Plato, in his work entitled “Symposium”, written around 385-370 BC, presented his vision of the origin of human sex. In this work, Aristophanes talks about primitive people with round shapes, two pairs of arms and legs, and two faces. These people had exerted an extraordinary fear even among the gods. The god Zeus, to guard against these strong creatures, decided to cut them in half. This is how men and women were created. Both halves began to miss each other, showing the need for unity expressed in the form of love. In this way, Plato explained the essence of sex inseparable from the feeling of love.

One of the most mysterious issues remaining for centuries was what determines the sex of the individual, and thus how the sex is determined. The Greek philosopher Parmenides (540-470 BC) claimed that the sex of a child is determined by the position of the fetus in the womb. Male development would be determined by the position of the fetus on the right side of the womb and the female on the left. Around 500-428 BC, another Greek philosopher – Anaxagoras recognised that it is the paternal factor that determines the sex of the child; namely, the boys develop from the sperm from the right testicle and the girls from the left testicle. Then, Empedocles (494-434 BC) claimed that organisms consist of four elements: fire (heat), water (cold), air (moisture) and earth (dryness), and that the men have a more warm ingredient.

The most outstanding biologist of the antiquity – Aristotle (384-322 BC) did not agree with the statements of the above-mentioned thinkers. He believed that he had evidence that the female and male offspring could develop on both sides of the womb (uterus) and noted that the men with only one testicle could conceive both male and female offspring . Similar to Empedocles, Aristotle saw the mechanisms of sex determination as the predominance of hot or cold ingredients in the body.In his work, “Historia Animalium”, he pointed out that males are stronger, which is due to their higher heat, enabling the transformation of food into the concentrated seed. Females, on the other hand, in Aristotle’s opinion, were weaker and cooler, which meant that they could not convert food into sperm, and instead produced more blood that is excreted during menstruation.

Empedocles (494-434 BC) claimed that organisms consist of four elements: fire (heat), water (cold), air (moisture) and earth (dryness), and that the men have a more warm ingredient.

According to Aristotle, the development of fetus sex was dependent on the connection of sperm with menstrual blood during conception. Sperm thickening due to the heat was to lead to the development of the male individual, while liquefaction of the sperm at a lower temperature, leading to its mixing with the mother’s blood, resulted in the development of the female individual. He also stated that both man and woman (through semen and blood) contribute to the offspring, and thought, which turned out to be true, that male and female organs develop during development from undifferentiated buds. Importantly, he stated that the testes are responsible for the development of male traits, i.e. masculinization since the testisdeprived eunuchs show feminization features. Thus, among the ancient thinkers, it was Aristotle who was closest to the truth, and his observations did indeed contribute to the broadening of knowledge about gender determination.

Among the ancient thinkers, it was Aristotle who was closest to the truth, and his observations did indeed contribute to the broadening of knowledge about gender determination.

First Scientific Evidence of Sex Determination

The belief that the heat, positioning of the fetus in the womb and food determine sex, nestled in peoples’ minds for a long time, and survived for nearly two thousand years. In the second half of the nineteenth century, it was believed that heat and nutrition affect a child’s sex. This faith resounds even today in folk beliefs. The milestone in the biological research was the discovery of chromosomes in 1888 by the German anatomist, physiologist and pathologist Heinrich Waldeyer. Already three years later, in 1891, the German cytologist Hermann Henking, studying the meiotic division in the nuclei of a wingless blacksmith (Hemiptera), noticed that some sperm cells of this species have 12 chromosomes, and some 11. He noticed that, during meiosis, one of the 12 chromosomes behaves differently than others. By naming this strange chromosome the X chromosome, he wanted to emphasise its mysterious nature. He then searched for the X chromosome in the grasshopper cells, but to no avail. It wasn’t until 1901 that American zoologist Clarence Erwin McClung pointed out that the X chromosome, as an “additional chromosome,” could be associated with sex determination.

Stevens stated that the larger chromosome is the X chromosome, while the smaller chromosome, which she called Y, must be responsible for male determination

In 1905, American geneticist Edmund Beecher Wilson, studying spermatogenesis of several insect species, showed that there are two types of sperm, which differ in the presence or absence of one of the chromosomes. In the same year, the American geneticist Nettie Maria Stevens, studying the gametogenesis of the mealworm beetle, found that in males, but not females, one chromosome was significantly different in size. Therefore, Stevens stated that the larger chromosome is the X chromosome, while the smaller chromosome, which she called Y, must be responsible for male determination. She also suggested that there must be some unknown factor in the Y chromosome that determines male development. Wilson, on the other hand, believed that both chromosomes, X and Y, determine sex equally [11]. Stevens died in 1912 without confirming her hypothesis, and Wilson has been described in scientific literature as a discoverer of sex-determining X and Y chromosomes.

Description of sex chromosomes contributed to the statement that sex is determined by genes. Around the same period (early 20th century), chromosomes were found to carry genetic information. Walter Sutton and Theodor Boveri discovered this, independently, in 1903. The term “gene” was introduced in 1909 by the Danish botanist Wilhelm Johannsen. However, in 1910, the American geneticist Thomas Hunt Morgan, studying the inheritance of features in the fruit fly, showed that the genes are located in the chromosomes where they are linearly arranged, and occupy strictly defined places, the so-called loci. In addition, he showed that some features (e.g. eye color) are sex-linked because their genes are located in the sex chromosomes. Interestingly, the understanding of the basics of inheritance mechanisms was possible at the beginning of the 20th century, again, thanks to the research on insects. Nevertheless, the mechanism by which sex chromosomes determine sex was to remain unexplained for a long time.

The discovery of the function of the Y chromosome in the determination of the male sex in humans initiated the search for a hypothetical factor determining this particular sex.

Only a few decades later, in 1956, in Great Britain, Charles Ford and John Hamerton, using cytogenetic methods, determined the number of chromosomes in humans and found that men have X and Y chromosomes (karyotype 46, XY), and women two chromosomes X (karyotype 46, XX) [15]. Three years after this discovery, the first chromosomal aberrations in humans were described. It was noticed that people with Klinefelter syndrome are men with 47, XXY karyotype, while people with Turner syndrome are women with 45, X0 karyotype. This was the first scientific evidence confirming that the Y chromosome in humans determines the male sex.

Searching for the Factor Determining Male Sex

The discovery of the function of the Y chromosome in the determination of the male sex in humans initiated the search for a hypothetical factor determining this particular sex. This hypothetical factor was named TDF (Testis-Determining Factor) in humans, and Tdy (testis-determining factor on the Y chromosome) in mice. At that time, the most informative objects of research on sex determination were patients with sex reversal symptoms, i.e. incompatibilities between the presence of sex chromosomes and phenotypic features. The analyses of chromosomal aberrations, such as translocations and fusions, indicated that it is the short arm of the Y chromosome that is responsible for male determination. Also, the search area for the TDF factor has been gradually narrowing. Among the genes of the smaller arm of the Y chromosome, the first candidates were the H-Y antigen and BKM genes (Banded Krait Minor Gene), but their involvement in sex determination has not been demonstrated. The next gene tested was ZFY (Zinc-Finger Protein Y-Linked). It turned out that this gene also does not determine sex because it is not expressed in the mouse gonads. In addition, it was observed that the male patients with karyotype 46, XX developed male traits despite the absence of the ZFY gene.

Patients described by Palmer and colleagues (four men with karyotype 46, XX) had in their genome a small, 35,000 base pair, Y chromosome-specific region. This Y chromosome region was isolated, divided into fragments and compared with Y chromosome fragments of other mammals in Southern blotting analysis. It turned out that there is only one conserved fragment of the Y chromosome in mammals, which also does not show much variation between species. Thus, it was assumed that this fragment of the Y chromosome must contain the sex-determining gene. Sequencing of this fragment indicated only one Open Reading Frame (ORF) coding for the gene consisting of a single exon. This gene was called “sex determining region on the Y chromosome” (SRY in humans and Sry in mice). RT-PCR gene expression analysis showed that the Sry gene is expressed in developing gonads of XY mice at embryonic day 11.5, just before the first signs of testicular sexual differentiation.

The final evidence confirming the determination of male sex by the Sry gene was provided through the study of XX transgenic mice into which the Sry transgene was introduced. These individuals, despite having the female karyotype XX, developed into typical males with normally developed testes (sex reversal), but they were sterile due to the lack of Y chromosome, which, as it turned out, also contains genes responsible for the proper course of spermatogenesis. These studies proved that the Sry gene is both necessary and sufficient to determine male sex. In addition, it was shown that the Sry gene is present only in marsupials and placental mammals, all mammals except monotremes.


Sex differences have puzzled humanity for a very long time in both scientific and social contexts. A thorough understanding of the mechanisms determining sexual development has been achieved through the use of advanced scientific techniques developed in the 20th century. However, surprisingly, the network of genes that control sex determination is still incomplete, and relatively poorly understood. Further research is likely to find novel genes involved in gonadal development and to show the complexity of the mechanisms controlling sexual development. It appears that the cascade of events leading to the sex determination is much more complicated than originally imagined. In addition, in many cases of human sex disorders, their source remains unknown, indicating that the research on the genes involved in gonadal development has a long way to go.

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Fertility Rates Among Non-Mosaic XXY; At Odds With Real Life Experience

Klinefelter syndrome (KS) is the one of the most frequent chromosomal disorder affecting 1/500–600 male newborns in the general population. The vast majority of the cases shows the 47,XXY karyotype, although mosaicism (46,XY/47,XXY) or higher-grade X aneuploidies can be rarely detected. Despite its high incidence, KS frequently remains undiagnosed and it is suspected later in adulthood after a diagnostic workup for hypogonadism, couple’s infertility, and/or sexual dysfunction.

Approximately 90% of adult men with homogeneous KS suffer from non-obstructive azoospermia (NOA), while fertility in mosaic KS seems to be less severely affected. Fathering is an important aspect for Klinefelter patients. Maiburg et al. performed a survey on 260 adults with KS and showed that most couples would like to have children and show a positive attitude toward assisted-reproductive techniques (ART). Infertility has been considered an untreatable disease in Klinefelter patients for many years. However, testicular sperm extraction (TESE), associated with ART, were found to be a valuable option for azoospermic men with KS to father a child, due to the presence of residual foci with preserved spermatogenesis

A recent systematic review and meta-analysis evaluated the outcomes of sperm retrieval by conventional TESE (cTESE) and by micro-surgical TESE (mTESE)in 1248 individuals with KS (Corona et al., 2017). Authors reported an average sperm retrieval rate (SRR) of 44% (43% and 45% after cTESE and mTESE, respectively), which is similar to that reported for men without KS. However, these meta-analytic data do not necessarily reflect the rates of SR that physician observe in clinical practice, which is typically lower than 50%. Moreover, results of meta-analysis should be interpreted according to the limitation of the study itself (inclusion of small, single centre studies, effect of un-adjusted confounders).

These meta-analytic data do not necessarily reflect the rates of SR that physician observe in clinical practice, which is typically lower than 50%. Moreover, results of meta-analysis should be interpreted according to the limitation of the study itself (inclusion of small, single centre studies, effect of un-adjusted confounders).

These observations prompted us to conduct a multicenter collaborative study to investigate the rate of and potential predictors of sperm retrieval by TESE in a cohort of azoospermic patients with KS presenting for primary couple’s infertility in the real-life setting.

With the recent improvements of TESE and ICSI procedures infertility has been no longer considered an untreatable disease in Klinefelter patients. In this context, most studies investigating TESE outcomes in patients with KS depicted conflicting results, in spite of having been generally rated of limited quality. A recent review showed that SRR in Klinefelter patients was approximately 50% world wide, thus similar to that of men without genetic abnormalities. However, these results appear to be unrealistic and even far from what physicians typically observe in the clinical practice.

The aim of this cross-sectional, real-life study was to investigate the prevalence of and possible factors associated with a positive SR in a cohort of white-European azoospermic patients with KS undergoing TESE at seven academic Andrology centres.

  • Department of Urology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
  • Division of Experimental Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy
  • Division of Urology; A.O.U. Città della Salute e della Scienza di Torino – Presidio Molinette; Turin, Italy
  • Andrology Unit, University Hospital S. Orsola, Bologna, Italy
  • Fundació Puigvert, Department of Andrology, Universitat Autonoma de Barcelona, Barcelona, Spain
  • Department of Urology and Andrology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
  • Department of Urology, AO Papa Giovanni XXIII, Bergamo, Italy

Of clinical relevance, we found that only one out of five KS men had positive SR in the real-life setting. Moreover, we failed to find any clinical, hormonal or procedural factors associated with SRR. These findings confirmed previous studies, where in contrast meta analytic data reported a significant higher SRR.

So far, there is a lack of reliable clinical and biological predictors for sperm retrieval success in NOA patients with KS. Advanced paternal age has been considered a negative predictive factor for SR in Klinefelter men undergoing TESE. Ozer et al, showed that TESE had better outcome before the critical age of 30.5 years, while other Authors suggested that TESE should be performed before 35 years. Recent evidence, however, support the lack of association between age and SR outcome. It has been shown that performing TESE between 15 and 23 years did not increase the SR rate compared to adult KS patients (25–29 years). We also confirm that SRR was not influenced by patient’s age in a real-life study with a large cohort of Klinefelter men.

According to this view it has been postulated that the progressive hyalinization and fibrosis of seminiferous tubules that is accelerated with the onset of puberty in KS is not ubiquitous and it is possible to observe tubules with normal residual activity. The impaired spermatogenesis could also be caused by an intrinsic problem of the germ cells, possibly linked to (epi)- genetics of the X surplus chromosome.

Testicular volume has been considered a possible factor associated with TESE success in Klinefelter patients, for example, showed that testicular volume was significantly higher in men with positive SRR. However, there are several studies reporting that testicular atrophy does not affect the success of SR (Corona et al., 2017; Franik et al., 2016; Garolla et al., 2018; Majzoub et al., 2016; Ozer et al., 2018; Vicdan et al., 2016). Garolla et al. (Garolla et al., 2018), indeed, observed a 23% SRR even in KS patients with testicles <1 mL. Our results support these findings since we failed to find any relationship between testicular volume and SRR in NOA patients with KS.

The clinical strength of our study is several-fold. First, we showed a low rate of positive sperm retrieval (up to 21%) in azoospermic men with KS in the real-life setting, thus suggesting that the crude data coming from meta-analytic studies cannot be routinely used in the everyday clinical practice.

There are conflicting results showing the association between serum hormones levels and TESE outcome in Klinefelter patients. Higher serum testosterone levels were found in Klinefelter men with positive SR as compared to those with negative SR . Similarly, the combination of high testosterone levels and low levels of LH was considered as positive predictive marker for SR in in both adolescents and adults with KS. Conversely, recent meta analytic data showed that serum hormones levels did not influence SRR in Klinefelter patients. We also showed that testosterone, FSH and LH levels were not different according to TESE outcome in our cohort of Klinefelter patients; however, additional studies are needed to explore the predictive value of serum hormones levels in KS

Testosterone treatment in KS has been previously considered as a negative factor for sperm recovery. In our population TRT was not associated with worse SRR as compared to that of men who did not received any supplementation. Our findings are in line with previous studies that
did not show any impact of testosterone treatment on spermatogenesis in adolescents and adults Klinefelter men. Therefore, some authors did not recommend postponing androgen treatment in adolescent boys with KS for fear of impairing their TESE results .

Lastly, the superiority of mTESE as compared to cTESE in NOA men has been extensively investigated in the previous literature but with conflicting results. This is particularly true also in the Klinefelter population. Only few reports have shown that mTESE could be associated with better SRR than cTESE. Conversely, our results, in agreement with recent studies showed that TESE technique is not associated with SRR.

Further strength of present study is that we have comprehensively investigated a large homogenous group of patients with a detailed hormonal evaluation, and an accurate assessment of possible confounders for impaired semen parameters, such as recreational habits and health comorbidities. However, none of these parameters were found to be associated with SRR.

The clinical strength of our study is several-fold. First, we showed a low rate of positive sperm retrieval (up to 21%) in azoospermic men with KS in the real-life setting, thus suggesting that the crude data coming from meta-analytic studies cannot be routinely used in the everyday clinical practice. Second, we cross-sectionally showed that clinical, hormonal and procedural factors are unable to predict the SRR in patients with KS. In this context, we believe that Klinefelter patients should be carefully counselled regarding their chance of retrieving spermatozoa after TESE. Further strength of present study is that we have comprehensively investigated a large homogenous group of patients with a detailed hormonal evaluation, and an accurate assessment of possible confounders for impaired semen parameters, such as recreational habits and health comorbidities. However, none of these parameters were found to be associated with Sperm Retrieval Rates.

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Cognitive and Neurological Aspects of Sex Chromosome Variations

Sex chromosome variations (SCV) are characterised by an atypical variation in the number or function of sex chromosomes. They are some of the most common genetic differences in human beings, and include 47 XXY; one in six hundred live births, 45X ; one in two thousand and 47 XYY; one in one thousand. However, by comparison with other chromosomal variations, such as Trisomy 21 (one in six hundred), clinicians have relatively little awareness about diagnosis or management of associated cognitive, psychiatric, and neurological symptoms.

These circumstances create a potential gap in clinical practice, with risk of missed diagnoses and high disease burden for patients who might otherwise receive treatments that would improve outcomes. As an example, about 50–85% of individuals who are XXY or XYY are not identified. Taken together with evidence that earlier detection could positively affect psychosocial, cognitive, physiological, and reproductive outcomes, it is imperative for health professionals to increase their familiarity with this group of SCV’s.

In addition to improvements in clinical practice, increased understanding of SCV’S provide an important opportunity to advance knowledge of sex-related differences in clinical disease in general. Advances in genomics and neuro-imaging research have made it increasingly possible that genotype–phenotype links will be established in the foreseeable future. Sex chromosome variations are ideal models for investigation of genotype–phenotype correlations because of their well defined genetic basis and relatively well described phenotypic characteristics.

Cognitive and Neurological Aspects of Sex Chromosome
David S Hong, Allan L Reiss

Targeted research can elucidate how disrupted expression of sex chromosome genes and aberrant sex hormone production specifically affects cognitive and neurological function, and how this disruption can affect sex differences in clinical patho-physiology in general. Many immunological, cognitive, and motor features associated with sex chromosome differences are also commonly associated with disease states that have highly skewed sex differences in prevalence and symptom-atology. As such, improved knowledge of the inter-relation between genetics and nervous system function in sex chromosome differences can provide clinicians with an expanded understanding of mechanisms underlying sex differences in the nervous system.

In this Review, we summarise the major clinical features of sex chromosome variations, focusing mainly on XO (Turner’s), XXY (Klinefelter’s), and XYY (Jacobs), although we also briefly review other supernumerary sex chromosome variations. We present cognitive, motor, and other neurological outcomes associated with these variations, and mechanistic models and treatment frameworks that are used. Additionally, we delineate clinical features for each of these variations and discuss how continuing research in this area has broad implications for future understanding of sex differences in cognitive and neurological functioning in human beings.

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NHS in Disarray with Dispensing Hormones

Given the treatment of XXY individuals is (questionably) a sub speciality of Endocrinology it is envisaged that XXY’s regardless of how they identify their gender would be exposed to the same difficulties experienced by GD and Trans Individuals.

If you are an XXY individual we would love to hear of any difficulties you are experiencing with getting the care you believe you deserve, please comment below. Thanks.

Gender dysphoria can be difficult terrain for primary care doctors. Gender identity and gender dysphoria are not part of the GP curriculum. Patients face an average 18 month wait for specialist referral. And the NHS’s frontline doctors may bear the brunt of some patients’ distrust of a system that can’t cope with the current demand for services.

Specialist gender identity clinics (GICs) have seen referrals at least double over the five years to 2018, said James Palmer, medical director for specialised services at NHS England. As of 2019, about 7839 adults were waiting for a first appointment. Some 4000 young people are waiting for a specialist appointment.

Chris Preece, a GP in North Yorkshire, told The BMJ that the two year wait for patients to be seen by his local gender identity clinic puts pressure on GPs to provide bridging prescriptions for hormone treatment, even though they lack formal training in treating gender dysphoria.

General Medical Council guidance recommends that GPs consider prescribing hormone treatment to adult transgender patients who try to medicate themselves while awaiting specialist care. Preece says that waits can create “perverse incentives” for patients to buy hormones on the internet or elsewhere. Without training, and given the media controversies about trans care, Preece adds, many GPs “actively choose not to prescribe
[hormone treatments]—which protects us, but is unhelpful to the patient.”

Last year the Royal College of General Practitioners published a statement on caring for gender questioning and transgender patients. This says that long waits for patients to see a specialist are putting pressure on GPs to provide services beyond their remit and with limited access to specialist support if they do so. The college adds, “GPs should not be expected to fill the gaps in commissioned gender identity specialists and clinics.”

This month the Royal College of General Practitioners launched an e-learning course on gender variance this year.

A recent study by Anna Carlile, a sociologist at Goldsmiths University of London, investigated the experience of trans children and their parents in English healthcare. She told The BMJ that participants reported experiencing direct discrimination and being referred to by a previous name in GP surgeries and other clinical settings and believed that GPs “lack clinical and therapeutic knowledge,” particularly concerning the prescribing of drugs to delay puberty.

GPs are wary of prescribing without robust research into the outcomes and side effects of puberty blockers and cross sex hormones, and the co-occurrence of gender dysphoria and autism can complicate diagnosis and treatment. The UK has no nationally recognised training programme for gender identity healthcare, although there are apprenticeship training models in specialist clinics and guidelines from international professional bodies

Nearly two in five adult trans respondents to a large government survey reported dissatisfaction with NHS services related to their gender identity. Jane Fae of the charity Trans Media Watch, which campaigns for better media coverage of trans issues, says that many trans people now view GPs as “an obstruction to overcome.” Some trans groups, including Non
Binary London and Trans Forum UK, circulate lists of GPs they deem to be sympathetic or unsympathetic to requests for referrals to gender identity clinics or to prescribe treatments that patients have asked for.

Some areas in in the UK are showing signs of service reconfiguration. Cardiff’s new gender identity clinic has GPs on site. A model is being trialled in Manchester in which GPs work with gender identity clinics to improve their diagnostic skills. And the Royal College of Physicians intends to introduce a professional development programme for GPs about gender
identity this year.

NHS England, meanwhile, is considering a decentralised service for adults in which GPs can prescribe cross sex hormones without specialist involvement if they have sufficient expertise.

The royal college recommends that the GP curriculum should cover gender dysphoria and trans issues, that expanding specialist gender services be a priority, and that NHS IT systems be updated to record patients’ gender identity and trans status.

Preece would welcome such changes. “The hardest thing about being a GP is when you know that the service being offered to patients falls short of what you believe they need and deserve,” he says. “That chasm is at its greatest when dealing with patients with gender dysphoria.”

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