Editing Sexual differentiation

{{Short description|Embryonic development of sex differences}}
{{Infobox anatomy
|Name=Sexual differentiation
|Image= 2915_Sexual_Differentation-02.jpg
|Caption= Differentiation of the male and female reproductive systems does not occur until the fetal period of development.
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'''Sexual differentiation''' is the process of development of the [[sex]] differences between [[male]]s and [[female]]s from an undifferentiated [[zygote]].<ref name="Beukeboom">{{Cite book|last1=Beukeboom|first1=Leo W.|last2=Perrin|first2=Nicolas|title=The Evolution of Sex Determination|date=2014|publisher=Oxford University Press|isbn=978-0199657148|page=158|url=https://books.google.com/books?id=7yrnAwAAQBAJ&pg=PA158}}</ref><ref name="Koob">{{Cite book|last1=Koob|first1=George F.|title=Encyclopedia of Behavioral Neuroscience|date=2010|publisher=Elsevier|isbn=978-0080914558|page=21|url=https://books.google.com/books?id=DfV-BwAAQBAJ&pg=RA1-PA21}}</ref> Sex differentiation is usually distinct from [[Sex-determination system|sex determination]]; sex determination is the designation of the development stage towards either male or female, while sex differentiation is the pathway towards the development of the [[phenotype]].<ref>{{Cite book|url=https://books.google.com/books?id=7yrnAwAAQBAJ&q=the+evolution+of+sex+determination|title=The Evolution of Sex Determination|vauthors=Beukeboom LW, Perrin N|date=2014|publisher=Oxford University Press|isbn=978-0-19-965714-8|pages=16|language=en}}</ref>

In many species, testicular or ovarian differentiation begins with the appearance of [[Sertoli cell]]s in males and [[granulosa cell]]s in females.<ref name=":62">{{Cite book|last=Pandian|first=T. J.|title=Endocrine Sex Differentiation in Fish|date=2013-05-07|publisher=CRC Press|doi=10.1201/b14771|isbn=978-0-429-10222-6}}</ref><ref>{{Cite journal |last=Bouma |first=Gerrit J. |last2=Hudson |first2=Quanah J. |last3=Washburn |first3=Linda L. |last4=Eicher |first4=Eva M. |date=February 2010 |title=New candidate genes identified for controlling mouse gonadal sex determination and the early stages of granulosa and Sertoli cell differentiation |url=https://pubmed.ncbi.nlm.nih.gov/19864314 |journal=Biology of Reproduction |volume=82 |issue=2 |pages=380–389 |doi=10.1095/biolreprod.109.079822 |issn=1529-7268 |pmc=2809227 |pmid=19864314}}</ref>

As [[Embryo|embryos]] develop into mature adults, sex differences develop at many levels, including [[chromosome]]s, [[gonad]]s, [[hormone]]s, and [[anatomy]]. Beginning with determining sex by genetic and/or environmental factors, humans and other organisms proceed towards different differentiation pathways as they grow and develop.

==Sex determination systems==
{{Main|Sex determination system}}Humans, many [[Mammal|mammals]], and some [[Insect|insects]] and other animals have an [[XY sex-determination system]]. Humans have 46 [[Chromosome|chromosomes]], including two [[Sex chromosome|sex chromosomes]], XX in females and XY in males. The [[Y chromosome]] must carry at least one [[essential gene]] which determines [[testis|testicular]] formation (originally termed ''TDF'').<ref name=":1">{{Cite journal|last1=Wilhelm|first1=Dagmar|last2=Palmer|first2=Stephen|last3=Koopman|first3=Peter|date=2007-01-01|title=Sex Determination and Gonadal Development in Mammals|journal=Physiological Reviews|volume=87|issue=1|pages=1–28|doi=10.1152/physrev.00009.2006|pmid=17237341|issn=0031-9333}}</ref> In [[Transgene|transgenic]] XX mice (and some human [[XX male syndrome|XX male]]s), the [[sex-determining region Y protein]] alone is sufficient to induce male differentiation.<ref>{{Cite journal|last=Gilbert|first=Scott F.|date=2000|title=Chromosomal Sex Determination in Mammals|url=https://www.ncbi.nlm.nih.gov/books/NBK9967/|journal=Developmental Biology. 6th Edition|language=en}}</ref>

Other chromosomal systems exist in different [[taxa]], such as the [[ZW sex-determination system]] in birds<ref name=":22">{{Cite journal|last1=Chue|first1=J|last2=Smith|first2=C|date=2011-01-31|title=Sex Determination and Sexual Differentiation in the Avian Model|journal=The FEBS Journal|volume=278|issue=7|pages=1027–34|doi=10.1111/j.1742-4658.2011.08032.x|language=en|pmid=21281451|s2cid=24751510}}</ref> and the [[X0 sex-determination system|XO system]] in insects.<ref>{{Cite journal|last1=Blackmon|first1=Heath|last2=Ross|first2=Laura|last3=Bachtrog|first3=Doris|date=January 2017|title=Sex Determination, Sex Chromosomes, and Karyotype Evolution in Insects|journal=Journal of Heredity|volume=108|issue=1|pages=78–93|doi=10.1093/jhered/esw047|issn=0022-1503|pmc=6281344|pmid=27543823}}</ref>

[[Environmental sex determination]] refers to the determination (and then differentiation) of sex via non-genetic cues like social factors, temperature, and available nutrients. In some species, such as [[clownfish]] (known to be universally [[Hermaphrodite|hermaphroditic]]), sex differentiation can occur more than once as a response to different environmental cues,<ref name=":13">{{Cite journal|last1=Casas|first1=Laura|last2=Saborido-Rey|first2=Fran|last3=Ryu|first3=Taewoo|last4=Michell|first4=Craig|last5=Ravasi|first5=Timothy|last6=Irigoien|first6=Xabier|date=2016-10-17|title=Sex Change in Clownfish: Molecular Insights from Transcriptome Analysis|journal=Scientific Reports|volume=6|pages=35461|doi=10.1038/srep35461|issn=2045-2322|pmc=5066260|pmid=27748421|bibcode=2016NatSR...635461C}}</ref> offering an example of how sex differentiation does not always follow a linear path.

There have been multiple transitions between environmental and genetic sex determination systems in reptiles over time,<ref name=":02">{{Cite journal|last1=Rhen|first1=T.|last2=Schroeder|first2=A.|date=March 2010|title=Molecular Mechanisms of Sex Determination in Reptiles|journal=Sexual Development|volume=4|issue=1–2|pages=16–28|doi=10.1159/000282495|issn=1661-5425|pmc=2918650|pmid=20145384}}</ref> and recent studies have shown that temperature can sometimes override sex determination via chromosomes.<ref>{{Cite journal|last1=Pokorná|first1=Martina|last2=Kratochvíl|first2=Lukáš|date=2009-05-01|title=Phylogeny of sex-determining mechanisms in squamate reptiles: are sex chromosomes an evolutionary trap?|journal=Zoological Journal of the Linnean Society|language=en|volume=156|issue=1|pages=168–183|doi=10.1111/j.1096-3642.2008.00481.x|issn=0024-4082|doi-access=free}}</ref>

== Humans==
{{Main|Sexual differentiation in humans}}
[[File:YChromShowingSRY2.png|thumb|200px|The Human Y Chromosome shows the SRY gene which codes for a protein regulating sexual differentiation.]]
The early stages of human differentiation appear to be quite similar to the same biological processes in other mammals—and the interaction of genes, hormones and body structures is fairly well understood. In the first weeks of [[gestation]], a [[fetus]] is anatomically indistinguishable as male or female and lacks the production of any particular [[sex]] hormones. Only a [[karyotype]] distinguishes males from females. Specific genes induce [[gonad]]al differences, which produce hormonal differences, which cause anatomic differences, leading to psychological and behavioral differences, some of which are innate and some induced by the [[society|social environment]].

Various processes are involved in the development of [[sex differences in humans]]. Sexual differentiation in humans includes the development of different genitalia—and the internal genital tracts, breasts, and body hair—and plays a role in gender identification.<ref>{{Cite web | url=http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html |title = Human sexual differentiation}}</ref>{{Better source needed|date=June 2021}}

The development of sexual differences begins with the [[XY sex-determination system]] that is present in humans, and complex mechanisms are responsible for the development of the phenotypic differences between [[male]] and [[female]] [[human]]s from an undifferentiated [[zygote]].<ref>{{cite journal |doi=10.1007/BF01726695 |title=Determination of sex chromosomal constitution and chromosomal origin of drumsticks, drumstick-like structures, and other nuclear bodies in human blood cells at interphase by fluorescence in situ hybridization |year=1990 |last1=Mukherjee |first1=Asit B. |last2=Parsa |first2=Nasser Z. |journal=Chromosoma |volume=99 |issue=6 |pages=432–5 |pmid=2176962|s2cid=25732504 }}</ref> Atypical sexual development, and ambiguous genitalia, can be a result of genetic and hormonal factors.<ref>{{cite journal |pmid=16160410 |year=2005 |last1=Kučinskas |first1=Laimutis |last2=Just |first2=Walter |title=Human male sex determination and sexual differentiation: Pathways, molecular interactions and genetic disorders |volume=41 |issue=8 |pages=633–40 |journal=Medicina |url=http://medicina.kmu.lt/0508/0508-01e.htm |access-date=2014-05-22 |archive-date=2014-04-06 |archive-url=https://web.archive.org/web/20140406213835/http://medicina.kmu.lt/0508/0508-01e.htm |url-status=dead }}</ref>

The differentiation of other parts of the body than the [[sex organ]] creates [[secondary sex characteristic]]s. [[Sexual dimorphism]] of skeletal structure develops during childhood and becomes more pronounced in adolescence. 

==Other animals==
The first genes involved in the cascade of differentiation can differ between taxa and even between closely related species. For example: in [[zebrafish]], the first known gene to induce male differentiation is the ''amh'' gene. In tilapia, it is ''tDmrt1'', and in southern catfish, it is ''foxl2''.<ref name=":72">{{Cite book|last=Pandian|first=T. J.|title=Genetic Sex Differentiation in Fish|date=2012-06-05|publisher=CRC Press|doi=10.1201/b12296|isbn=978-0-429-08641-0}}</ref>

In fish, because modes of reproduction range from [[gonochorism]] (distinct sexes) to self-fertilizing [[Hermaphrodite|hermaphroditism]] (where one organism has functioning gonadal features of multiple sexes), sexual differentiation is complex. Two major pathways in gonochores exist: one with a nonfunctional, undifferentiated phase leading to delayed differentiation (secondary), and one without (primary), where differences between the sexes can be noted before hatching.<ref name=":62"/> Secondary gonochorists remain in the [[bipotential]] phase until a biotic or abiotic cue directs development down one pathway. Primary gonochorism, without an intersex phase, follows classical pathways of genetic sex determination but can still be later influenced by the environment.<ref name=":62"/> Differentiation pathways progress, and secondary sex characteristics such as anal fin bifurcation and ornamentation typically arise at [[puberty]].<ref name=":72" />

In birds, research on ''[[Gallus gallus domesticus]]'' has shown that determination of sex is likely cell-autonomous, i.e., that sex is determined in each [[somatic cell]] independently of, or in conjunction with, the [[Cell signaling|hormone signaling]] that occurs in other species.<ref name=":2">{{Cite journal|title=Sex Determination and Sexual Differentiation in the Avian Model|last1=Chue|first1=J|last2=Smith|first2=C|journal=The FEBS Journal|date=2011-01-31|volume=278|issue=7|pages=1027–34|doi=10.1111/j.1742-4658.2011.08032.x|language=en|pmid=21281451|s2cid=24751510}}</ref> Studies on [[Gynandromorphism|gynandromorph]] chickens showed that [[mosaicism]] could not be explained by hormones alone, pointing to direct genetic factors, possibly one or a few Z-specific genes such as [[Doublesex|double-sex]] or [[DMRT1]].<ref name=":2" />

== Flexibility ==
The most intensively studied species, such as [[Drosophila melanogaster|fruit flies]], [[nematode]]s, and mice, reveal that evolutionarily, sex determination/differentiation systems are not wholly conserved and have evolved over time.<ref name=":02"/> Beyond the presence or absence of chromosomes or social/environmental factors, sexual differentiation can be regulated in part by complex systems like the ratio of genes on X chromosomes and autosomes, protein production and transcription, and specific mRNA splicing.<ref name=":02" />

Differentiation pathways can be altered at many stages of the process. [[Sex reversal]], where the development of a sexual phenotype is redirected during embryonic development, happens in the initiation phase of gonadal sex differentiation. Even in species where there is a well-documented master regulator gene, its effects can be overridden by a downstream gene.<ref>{{Cite journal|last=Capel|first=Blanche|date=2017-08-14|title=Vertebrate sex determination: evolutionary plasticity of a fundamental switch|journal=Nature Reviews Genetics|volume=18|issue=11|pages=675–689|doi=10.1038/nrg.2017.60|pmid=28804140|s2cid=4313871|issn=1471-0056}}</ref>

Furthermore, hermaphrodites serve as examples of the flexibility of sexual differentiation systems. [[Sequential hermaphroditism|Sequential hermaphrodites]] are organisms that possess reproductive capabilities of one sex, and then that sex changes.<ref>{{Cite journal|last=Warner|first=Robert R.|date=1975|title=The Adaptive Significance of Sequential Hermaphroditism in Animals|journal=The American Naturalist|volume=109|issue=965|pages=61–82|doi=10.1086/282974|jstor=2459637|s2cid=84279130|issn=0003-0147}}</ref> Differentiated gonadal tissue of the organism's former sex degenerates, and new sex gonadal tissue grows and differentiates.<ref name=":13"/> Organisms that have the physiological capability to reproduce as a male and as a female at the same time are known as [[simultaneous hermaphrodite]]s. Some simultaneous hermaphroditic organisms, like certain species of [[Gobiidae|goby]], have distinctive male and female phases of reproduction and can flip back and forth, or "sex reverse", between the two.<ref>{{Cite journal|last=St. Mary|first=Colette M.|date=1996-02-01|title=Sex allocation in a simultaneous hermaphrodite, the zebra goby Lythrypnus zebra: insights gained through a comparison with its sympatric congener, Lythrypnus dalli|journal=Environmental Biology of Fishes|language=en|volume=45|issue=2|pages=177–190|doi=10.1007/BF00005232|bibcode=1996EnvBF..45..177S |s2cid=1769706|issn=1573-5133}}</ref>

=== Socially-determined ===
In some species, such as sequentially hermaphroditic [[Amphiprioninae|clownfish]], changes in social environment can lead to sexual differentiation or sex reversal, i.e. differentiation in the opposite direction.<ref name=":13"/> In clownfish, females are larger than males. In social groups, there is typically one large female, multiple smaller males, and undifferentiated juveniles. If the female is removed from the group, the largest male changes sex, i.e. the former gonad tissue degenerates and new gonad tissue grows. Furthermore, the pathway of differentiation is activated in the largest juvenile, which becomes male.<ref name=":13" />

=== Alternative morphs ===
{{Further|Polymorphism (biology)}}Sexual differentiation in a species does not have to produce one recognizable female and one recognizable male type. In some species alternative morphs, or [[morphotype]]s, within one sex exist, such as flanged (larger than females, with large flap-like cheek-pads) and unflanged (about the same size as females, with no cheek-pads) male [[orangutan]]s,<ref>{{Cite journal|last1=Knott|first1=Cheryl Denise|last2=Emery Thompson|first2=Melissa|last3=Stumpf|first3=Rebecca M.|last4=McIntyre|first4=Matthew H.|date=2010-01-07|title=Female reproductive strategies in orangutans, evidence for female choice and counterstrategies to infanticide in a species with frequent sexual coercion|journal=Proceedings of the Royal Society B: Biological Sciences|volume=277|issue=1678|pages=105–113|doi=10.1098/rspb.2009.1552|issn=0962-8452|pmc=2842634|pmid=19812079}}</ref> and sometimes differences between male morphs can be more noticeable than differences between a male and a female within such species.<ref>{{Cite journal|last1=Taborsky|first1=Michael|last2=Schütz|first2=Dolores|last3=Goffinet|first3=Olivier|last4=Doorn|first4=G. Sander van|date=2018-05-01|title=Alternative male morphs solve sperm performance/longevity trade-off in opposite directions|journal=Science Advances|language=en|volume=4|issue=5|pages=eaap8563|doi=10.1126/sciadv.aap8563|pmid=29806019|pmc=5966226|bibcode=2018SciA....4.8563T|issn=2375-2548}}</ref> Furthermore, [[sexual selection]] can be involved in the development of different types of males with alternative reproductive strategies, such as sneaker and territorial males in [[dung beetle]]s<ref>{{Citation|last=Partridge|first=Charlyn|title=Sneak Copulation as an Alternative Mating Strategy |date=2017|encyclopedia=Encyclopedia of Evolutionary Psychological Science|pages=1–3|editor-last=Shackelford|editor-first=Todd K.|publisher=Springer International Publishing|language=en|doi=10.1007/978-3-319-16999-6_3610-1|isbn=978-3-319-16999-6|editor2-last=Weekes-Shackelford|editor2-first=Viviana A.}}</ref> or harem males and pair-bonding males in the Nigerian [[Cichlid|cichlid fish]] ''P. pulcher.''<ref name=":72"/><ref>{{Cite book|last=Oliveira, Rui F. (Rui Filipe Nunes Pais de)|title=Alternative reproductive tactics an integrative approach|date=2008|publisher=Cambridge University Press|isbn=978-0-521-83243-4|pages=1–21|oclc=850824972}}</ref> Sometimes alternative morphs are produced by genetic differences, and in other cases, the environment can be involved, demonstrating some degree of [[phenotypic plasticity]].<ref>{{Cite journal|last1=Gotthard|first1=Karl|last2=Berger|first2=David|last3=Bergman|first3=Martin|last4=Merilaita|first4=Sami|date=2009-10-01|title=The evolution of alternative morphs: density-dependent determination of larval colour dimorphism in a butterfly|journal=Biological Journal of the Linnean Society|language=en|volume=98|issue=2|pages=256–266|doi=10.1111/j.1095-8312.2009.01290.x|issn=0024-4066|doi-access=free}}</ref>

==Brain differentiation==
{{Main|Neuroscience of sex differences}}

In many animals, differences in the exposure of a fetal [[brain]] to sex hormones are correlated with significant differences in brain structure and function, which correlate with adult reproductive behavior.<ref name=":1"/> The causes of differences between the sexes are only understood in some species. Fetal sex differences in human brains coupled with early differences in experience may be responsible for sex differences observed in children between 4 years old and adolescence.<ref name=":5">{{Cite journal|last1=Fausto-Sterling|first1=Anne|last2=Coll|first2=Cynthia Garcia|last3=Lamarre|first3=Meghan|date=2012-06-01|title=Sexing the baby: Part 1 – What do we really know about sex differentiation in the first three years of life?|url=http://www.sciencedirect.com/science/article/pii/S0277953611003558|journal=Social Science & Medicine|series=Gender and health: Relational, intersectional, and biosocial approaches|language=en|volume=74|issue=11|pages=1684–1692|doi=10.1016/j.socscimed.2011.05.051|pmid=21802808|issn=0277-9536|url-access=subscription}}</ref>

Many individual studies in humans and other primates have found statistically significant sex differences in specific brain structures; however, some studies have found no sex differences, and some meta-analyses have called into question the over-generalization that women's and men's brains function differently.<ref>{{Cite journal|last1=Bishop|first1=KATHERINE M.|last2=Wahlsten|first2=DOUGLAS|date=1997-01-01|title=Sex Differences in the Human Corpus Callosum: Myth or Reality?|url=http://www.sciencedirect.com/science/article/pii/S0149763496000498|journal=Neuroscience & Biobehavioral Reviews|language=en|volume=21|issue=5|pages=581–601|doi=10.1016/S0149-7634(96)00049-8|pmid=9353793|s2cid=9909395|issn=0149-7634}}</ref> Males and females statistically differ in some aspects of their brains, still there are areas of the brain which appear not to be sexually differentiated at all. Some scholars describe human brain variation not as two distinct categories, and not even a maleness-femaleness continuum, but as mosaics.<ref>{{Cite journal|last1=Joel|first1=Daphna|last2=Berman|first2=Zohar|last3=Tavor|first3=Ido|last4=Wexler|first4=Nadav|last5=Gaber|first5=Olga|last6=Stein|first6=Yaniv|last7=Shefi|first7=Nisan|last8=Pool|first8=Jared|last9=Urchs|first9=Sebastian|last10=Margulies|first10=Daniel S.|last11=Liem|first11=Franziskus|date=2015-11-30|title=Sex beyond the genitalia: The human brain mosaic|journal=Proceedings of the National Academy of Sciences|language=en|volume=112|issue=50|pages=15468–15473|doi=10.1073/pnas.1509654112|pmid=26621705|pmc=4687544|bibcode=2015PNAS..11215468J|issn=0027-8424|doi-access=free}}</ref>

In birds, hypotheses of male-female brain sex differences have been challenged by recent findings that differences between groups can be at least partially explained by the individual's dominance rank.<ref>{{Cite journal|last1=Voigt|first1=Cornelia|last2=Gahr|first2=Manfred|date=2011-06-08|title=Social Status Affects the Degree of Sex Difference in the Songbird Brain|journal=PLOS ONE|language=en|volume=6|issue=6|pages=e20723|doi=10.1371/journal.pone.0020723|issn=1932-6203|pmc=3110770|pmid=21687671|bibcode=2011PLoSO...620723V|doi-access=free}}</ref> Furthermore, the behavioral causes of brain sex differences have been enumerated in studies of sex differences between different mating systems. For example, males of a polygynous [[vole]] species with intrasexual male competition have better spatial learning and memory than the females of their species, but also better spatial learning and memory than all sexes of other closely related species that are monogamous; thus the brain differences commonly seen as "sex differences" have been instead linked to competition.<ref name=":4">{{Cite journal|last=Geary|first=David C.|date=2017|title=Evolutionary framework for identifying sex- and species-specific vulnerabilities in brain development and functions|journal=Journal of Neuroscience Research|language=en|volume=95|issue=1–2|pages=355–361|doi=10.1002/jnr.23794|pmid=27870407|issn=1097-4547|doi-access=free}}</ref> [[Sexual selection]] does play a role in some species, though, as males who display more song behaviors are selected for by females⁠—so some sex differences in bird song brain regions seem to have been evolutionarily selected for over time.<ref name=":4" />

==References==
{{Reflist}}

===Bibliography===
*{{cite journal |doi=10.1016/j.yhbeh.2006.06.003 |title=Mammalian animal models of psychosexual differentiation: When is 'translation' to the human situation possible? |year=2006 |last1=Baum |first1=Michael J. |journal=Hormones and Behavior |volume=50 |issue=4 |pages=579–88 |pmid=16876166|s2cid=7465192 }}
*{{cite journal |pmid=10029838 |year=1998 |last1=Crouch |first1=RA | title=Betwixt and between: The past and future of intersexuality|volume=9 |issue=4 |pages=372–84 |journal=The Journal of Clinical Ethics |doi=10.1086/JCE199809406 |s2cid=43549952 }}
*{{cite journal |doi=10.1136/adc.2006.098319 |pmid=16624884|pmc=2082839|title=Consensus statement on management of intersex disorders|journal=Archives of Disease in Childhood|volume=91|issue=7|pages=554–63|year=2005|last1=Hughes|first1=I A|last2=Houk|first2=C|last3=Ahmed|first3=S. F.|last4=Lee|first4=P. A.}}
*{{cite journal |doi=10.1210/endo-65-3-369 |pmid=14432658 |title=Organizing Action of Prenatally Administered Testosterone Propionate on the Tissues Mediating Mating Behavior in the Female Guinea Pig |year=1959 |last1=Phoenix |first1=C. H. |last2=Goy |first2=R. W. |last3=Gerall |first3=A. A. |last4=Young |first4=W. C. |journal=Endocrinology |volume=65 |issue=3 |pages=369–382}}
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==External links==
* [http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html Human Sexual Differentiation] by P. C. Sizonenko
* [https://web.archive.org/web/20030810201305/http://www.the-clitoris.com:80/n_html/n_netter.htm The Ciba Collection of Medical Illustrations: Vol.2, Reproductive System] by Frank H. Netter, M.D. comparing female and male reproductive systems development and anatomy
* [https://web.archive.org/web/20030622164928/http://the-clitoris.com:80/n_html/n_develop.htm Development of the Female Sexual & Reproductive Organs] – illustrations comparing female and male genitalia during the early development

{{Sex determination and differentiation}}
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[[Category:Sex differences in humans]]