View source for Sex differences in medicine

{{Short description|Medical differences in humans by sex}}
{{Sex differences|File=Brain stem normal human.svg}}
'''Sex differences in medicine''' include sex-specific [[diseases]] or conditions which occur only in people of one sex due to underlying biological factors (for example, [[prostate cancer]] in males or [[uterine cancer]] in females); sex-related diseases, which are diseases that are more common to one sex (for example, breast cancer and [[systemic lupus erythematosus]] which occur predominantly in females);<ref name="Ngo">{{cite journal | vauthors = Ngo ST, Steyn FJ, McCombe PA | title = Gender differences in autoimmune disease | journal = Frontiers in Neuroendocrinology | volume = 35 | issue = 3 | pages = 347–369 | date = August 2014 | pmid = 24793874 | doi = 10.1016/j.yfrne.2014.04.004 | doi-access = free }}</ref> and diseases which occur at similar rates in males and females but manifest differently according to sex (for example, [[peripheral artery disease]]).<ref>{{cite journal | vauthors = Barochiner J, Aparicio LS, Waisman GD | title = Challenges associated with peripheral arterial disease in women | journal = Vascular Health and Risk Management | volume = 10 | pages = 115–128 | date = 2014 | pmid = 24648743 | pmc = 3956880 | doi = 10.2147/vhrm.s45181 | doi-access = free }}</ref>
Sex differences should not be confused with [[gender]] differences. The US [[National Academy of Medicine]] recognizes sex differences as biological at the chromosomal and anatomical levels, whereas gender differences are based on self-representation and other factors including biology, environment and experience.<ref name="Oertelt-Prigione">{{cite book | veditors = Oertelt-Prigione S, Regitz-Zagrosek V |title=Sex and Gender Aspects in Clinical Medicine |date=2012 |publisher=Springer |isbn=978-1-4471-6002-1}}</ref><ref name="DoesSexMatter">{{cite book | author = Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Differences. | title = Exploring the Biological Contributions to Human Health: Does Sex Matter? | veditors = Wizemann TM, Pardue ML | location = Washington (DC) | publisher = National Academies Press | date = 2001 | pmid = 25057540 |url=https://www.nap.edu/read/10028/chapter/1 | isbn = 978-0-309-07281-6 }}</ref>
That said, both biological and behavioural differences influence human health, and may do so differentially. Such factors can be inter-related and difficult to separate. Evidence-based approaches to sex and gender medicine try to examine the effects of both sex and gender as factors when dealing with medical conditions that may affect populations differently.<ref name="Mauvais-Jarvis"/><ref name="Regitz‐Zagrosek">{{cite journal | vauthors = Regitz-Zagrosek V | title = Sex and gender differences in health. Science & Society Series on Sex and Science | journal = EMBO Reports | volume = 13 | issue = 7 | pages = 596–603 | date = June 2012 | pmid = 22699937 | pmc = 3388783 | doi = 10.1038/embor.2012.87 }}</ref><ref name="Oertelt-Prigione"/>
{{As of|2021}}, over 10,000 articles had been published addressing sex and gender differences in clinical medicine and related literature.{{citation needed|date=December 2021}} Sex and gender affect [[cardiovascular]],<ref name="Miller">{{cite journal | vauthors = Miller VM | author-link = Virginia M. Miller | title = Universality of sex differences in cardiovascular outcomes: where do we go from here? | journal = European Heart Journal | volume = 41 | issue = 17 | pages = 1697–9 | date = May 2020 | pmid = 32357237 | pmc = 7194182 | doi = 10.1093/eurheartj/ehaa310 }}</ref>
[[pulmonary]]<ref name="Weatherald">{{cite journal | vauthors = Weatherald J, Riha RL, Humbert M | title = Sex and gender in lung health and disease: more than just Xs and Ys | journal = European Respiratory Review | volume = 30 | issue = 162 | pages = 210217 | date = December 2021 | pmid = 34750117 | doi = 10.1183/16000617.0217-2021 | pmc = 9488524 | s2cid = 243861859 | doi-access = free }}</ref>
and [[autoimmune system]]s,<ref name="Rose"/><ref name="HayterCook2012"/>
[[gastroenterology]],<ref name="Greuter">{{cite journal | vauthors = Greuter T, Manser C, Pittet V, Vavricka SR, Biedermann L | title = Gender Differences in Inflammatory Bowel Disease | language = english | journal = Digestion | volume = 101 | issue = 1 | pages = 98–104 | date = 2020 | pmid = 31995797 | doi = 10.1159/000504701 | s2cid = 210946741 | author6 = Official working group of the Swiss Society of Gastroenterology | doi-access = free }}</ref><ref name="van Kessel">{{cite journal | vauthors = van Kessel L, Teunissen D, Lagro-Janssen T | title = Sex-Gender Differences in the Effectiveness of Treatment of Irritable Bowel Syndrome: A Systematic Review | journal = International Journal of General Medicine | volume = 14 | pages = 867–884 | date = March 2021 | pmid = 33758534 | pmc = 7979326 | doi = 10.2147/IJGM.S291964 | doi-access = free }}</ref><ref name=Fracas23/>
[[hepatology]],<ref name="Mauvais-Jarvis">{{cite journal | vauthors = Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, De Vries GJ, Epperson CN, Govindan R, Klein SL, Lonardo A, Maki PM, McCullough LD, Regitz-Zagrosek V, Regensteiner JG, Rubin JB, Sandberg K, Suzuki A | display-authors = 6 | title = Sex and gender: modifiers of health, disease, and medicine | language = English | journal = Lancet | volume = 396 | issue = 10250 | pages = 565–582 | date = August 2020 | pmid = 32828189 | pmc = 7440877 | doi = 10.1016/S0140-6736(20)31561-0 }}</ref>
[[nephrology]],<ref name="Bairey Merz">{{cite journal | vauthors = Bairey Merz CN, Dember LM, Ingelfinger JR, Vinson A, Neugarten J, Sandberg KL, Sullivan JC, Maric-Bilkan C, Rankin TL, Kimmel PL, Star RA | display-authors = 6 | title = Sex and the kidneys: current understanding and research opportunities | journal = Nature Reviews. Nephrology | volume = 15 | issue = 12 | pages = 776–783 | date = December 2019 | pmid = 31586165 | pmc = 7745509 | doi = 10.1038/s41581-019-0208-6 }}</ref>
[[endocrinology]],<ref name="Bhargava">{{cite journal | vauthors = Bhargava A, Arnold AP, Bangasser DA, Denton KM, Gupta A, Hilliard Krause LM, Mayer EA, McCarthy M, Miller WL, Raznahan A, Verma R | display-authors = 6 | title = Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement | journal = Endocrine Reviews | volume = 42 | issue = 3 | pages = 219–258 | date = May 2021 | pmid = 33704446 | pmc = 8348944 | doi = 10.1210/endrev/bnaa034 }}</ref><ref name="Lauretta">{{cite journal | vauthors = Lauretta R, Sansone M, Sansone A, Romanelli F, Appetecchia M | title = Gender in Endocrine Diseases: Role of Sex Gonadal Hormones | journal = International Journal of Endocrinology | volume = 2018 | pages = 4847376 | date = 21 October 2018 | pmid = 30420884 | pmc = 6215564 | doi = 10.1155/2018/4847376 | doi-access = free }}</ref>
[[haematology]],<ref name="Murphy">{{cite journal | vauthors = Murphy WG | title = The sex difference in haemoglobin levels in adults - mechanisms, causes, and consequences | journal = Blood Reviews | volume = 28 | issue = 2 | pages = 41–47 | date = March 2014 | pmid = 24491804 | doi = 10.1016/j.blre.2013.12.003 }}</ref>
[[neurology]],<ref name="Clayton">{{cite journal | vauthors = Clayton JA | title = Sex influences in neurological disorders: case studies and perspectives | journal = Dialogues in Clinical Neuroscience | volume = 18 | issue = 4 | pages = 357–360 | date = December 2016 | pmid = 28179807 | pmc = 5286721 | doi = 10.31887/DCNS.2016.18.4/jclayton }}</ref><ref>{{cite book |author=Institute of Medicine |title=Sex Differences and Implications for Translational Neuroscience Research : Workshop Summary |date=2011 |publisher=National Academies Press |location=Washington, DC |isbn=978-0-309-16124-4|url=https://www.ncbi.nlm.nih.gov/books/NBK53393/ |id=NBK53393}}</ref><ref name="Rippon">{{cite journal | vauthors = Rippon G, Eliot L, Genon S, Joel D | title = How hype and hyperbole distort the neuroscience of sex differences | journal = PLOS Biology | volume = 19 | issue = 5 | pages = e3001253 | date = May 2021 | pmid = 33970901 | pmc = 8136838 | doi = 10.1371/journal.pbio.3001253 | doi-access = free }}</ref><ref name="Shansky">{{cite journal | vauthors = Shansky RM, Murphy AZ | title = Considering sex as a biological variable will require a global shift in science culture | journal = Nature Neuroscience | volume = 24 | issue = 4 | pages = 457–464 | date = April 2021 | pmid = 33649507 | doi = 10.1038/s41593-021-00806-8 | s2cid = 232091204 }}</ref>
[[pharmacokinetics]], and [[pharmacodynamics]].<ref name="Zucker">{{cite journal | vauthors = Zucker I, Prendergast BJ | title = Sex differences in pharmacokinetics predict adverse drug reactions in women | journal = Biology of Sex Differences | volume = 11 | issue = 1 | pages = 32 | date = June 2020 | pmid = 32503637 | pmc = 7275616 | doi = 10.1186/s13293-020-00308-5 | doi-access = free }}</ref><ref name="Soldin">{{cite journal | vauthors = Soldin OP, Mattison DR | title = Sex differences in pharmacokinetics and pharmacodynamics | journal = Clinical Pharmacokinetics | volume = 48 | issue = 3 | pages = 143–157 | date = 2009 | pmid = 19385708 | pmc = 3644551 | doi = 10.2165/00003088-200948030-00001 }}</ref><ref name="Regitz‐Zagrosek"/><ref name="Oertelt-Prigione"/>
[[Sexually transmitted infection]]s, which have a significant probability of transmission through sexual contact, can be contracted by either sex. Their occurrence may reflect economic and social as well as biological factors, leading to sex differences  in the transmission, prevalence, and disease burden of STIs.<ref name="Madkan">{{cite journal | vauthors = Madkan VK, Giancola AA, Sra KK, Tyring SK | title = Sex differences in the transmission, prevention, and disease manifestations of sexually transmitted diseases | journal = Archives of Dermatology | volume = 142 | issue = 3 | pages = 365–370 | date = March 2006 | pmid = 16549716 | doi = 10.1001/archderm.142.3.365 }}</ref>
Historically, medical research has primarily been conducted using the male body as the basis for clinical studies. The findings of these studies have often been applied across the sexes, and healthcare providers have traditionally assumed a uniform approach in treating both male and female patients. More recently, medical research has started to understand the importance of taking sex into account as evidence increases that the symptoms and responses to medical treatment may be very different between sexes.<ref name="MauvaisLancet2020">{{cite journal  | vauthors = Mauvais-Jarvis F, Merz BN, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, Vries GJ, Epperson CN, Govindan R, Klein SL, Lonardo A, Maki PM, McCullough LD, Regitz-Zagrosek V, Regensteiner SG, Rubin JB, Sandberg K, Suzuki A | display-authors = 6 |title=Sex and gender: modifiers of health, disease, and medicine |journal=The Lancet |date=22 August 2020 |volume=396 |issue=10250 |pages=565–582 |doi=10.1016/S0140-6736(20)31561-0 | pmid = 32828189 | pmc = 7440877 }}</ref>
==Background==
Females and males exhibit many differences in terms of risk of developing disease, receiving an accurate diagnosis, and responding to treatments. A patient's sex has been increasingly recognized as one of the most important modulators of clinical decision making.<ref>{{cite journal |last1=Legato |first1=Marianne J. |last2=Johnson |first2=Paula A. |last3=Manson |first3=JoAnn E. |title=Consideration of Sex Differences in Medicine to Improve Health Care and Patient Outcomes |journal=JAMA |date=8 November 2016 |volume=316 |issue=18 |pages=1865–6 |doi=10.1001/jama.2016.13995|pmid=27802499 }}</ref> Sex differences have been found across a broad range of disease areas, including many diseases which are sex-specific. The sex chromosome complement and sex hormone environment are known to be the primary constitutive difference between females and males.<ref>{{cite journal |last1=Miller |first1=Leah R. |last2=Marks |first2=Cheryl |last3=Becker |first3=Jill B. |last4=Hurn |first4=Patricia D. |last5=Chen |first5=Wei-Jung |last6=Woodruff |first6=Teresa |last7=McCarthy |first7=Margaret M. |last8=Sohrabji |first8=Farida |last9=Schiebinger |first9=Londa |last10=Wetherington |first10=Cora Lee |last11=Makris |first11=Susan |last12=Arnold |first12=Arthur P. |last13=Einstein |first13=Gillian |last14=Miller |first14=Virginia M. |last15=Sandberg |first15=Kathryn |last16=Maier |first16=Susan |last17=Cornelison |first17=Terri L. |last18=Clayton |first18=Janine A. |title=Considering sex as a biological variable in preclinical research |journal=The FASEB Journal |date=January 2017 |volume=31 |issue=1 |pages=29–34 |doi=10.1096/fj.201600781r|doi-access=free |pmid=27682203 |pmc=6191005 }}</ref> The imbalance of gene expression between the X and Y chromosomes is present within virtually all cells in the human body. Sex hormones are crucial in body development and function and also thought to contribute to sex differences in some diseases.<ref>{{cite journal |last1=Maeng |first1=Lisa Y. |last2=Milad |first2=Mohammed R. |title=Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones |journal=Hormones and Behavior |date=1 November 2015 |volume=76 |pages=106–117 |doi=10.1016/j.yhbeh.2015.04.002 |pmid=25888456 |pmc=4823998 |language=en |issn=0018-506X}}</ref> It is suspected that many differences between the sexes are also influenced by social, environmental, and psychological factors which are difficult to tease apart from biological ones.<ref name="DoesSexMatter"/>
==Causes==
Sex-related illnesses have various causes:<ref name="Mauvais-Jarvis"/>
* Genetic sex differences start at [[Human fertilization|conception]] depending on whether an ovum fuses with a sperm cell carrying an X or a Y chromosome. This leads to sex-based differences at the molecular level for all male and female cells.<ref name="Mauvais-Jarvis"/>
*  In males, the X chromosome carries only maternal imprints, while in females  X chromosomes are present with both maternal and paternal imprints. In female cells, random processes of [[X-inactivation]] "turn off" the extra X chromosome. As a result, females, but not males, are [[Mosaic (genetics)|mosaics]]. Female cells may express higher levels of some genes.<ref name="Migeon"/><ref name="Barbara"/><ref name="Brown"/>
* Sex differences at the chromosome and molecular level exist in all human cells, and persist life-long, independent of sex hormones in the body.<ref name="Mauvais-Jarvis"/>
*  [[Sex-linked]] genetic conditions that differ in males and females may reflect the effects of genetic damage on an X chromosome. In some cases, the presence of an "extra" X chromosome in female cells may lessen the impact of such damage. In severe cases, males may die during development and females may survive but display a sex-linked illness.<ref name="Migeon"/>
* The [[Human reproductive system|reproductive system]] develops differently for each sex.  Sex-specific parts of the male and female reproductive systems affect the rest of the body and also can be affected differently by diseases.<ref name="Zimmermann">{{cite news | vauthors = Zimmermann KA |title=Reproductive System: Facts, Functions & Diseases |url=https://www.livescience.com/26741-reproductive-system.html |access-date=11 November 2021 |work=Live Science |date=22 March 2018|language=en}}</ref>
* Socially constructed norms relate to [[gender role]]s, relationships, positional power, and a wide variety of behaviours.  Norms affect people differentially depending on their sex and gender.<ref name="Mauvais-Jarvis"/>
* Different levels of prevention, reporting, diagnosis, and treatment have been observed based on sex and gender.<ref name="Mauvais-Jarvis"/>
==Examples of sex-related illnesses and disorders in humans==
===Females===
Examples of sex-related illnesses and disorders in [[Female#Mammalian female|human females]]:<ref name="Regitz‐Zagrosek"/>
* 99% of breast cancer occurs in women.<ref>{{cite web|url=http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional|title=Male Breast Cancer Treatment|year=2014|publisher=[[National Cancer Institute]]|archive-url=https://web.archive.org/web/20140704182515/http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional|archive-date=4 July 2014|url-status=live|access-date=29 June 2014|df=dmy-all}}</ref>
* [[Ovarian cancer]], [[endometriosis]],{{efn|Endometriosis very rarely affects men.<ref>{{cite journal |last1=Rei |first1=Christina |last2=Williams |first2=Thomas |last3=Feloney |first3=Michael |title=Endometriosis in a Man as a Rare Source of Abdominal Pain: A Case Report and Review of the Literature |journal=Case Reports in Obstetrics and Gynecology |date=2018 |volume=2018 |pages=1–6 |doi=10.1155/2018/2083121 |doi-access=free}}</ref>}} and other diseases affect the [[female reproductive system]].<ref>{{cite journal | vauthors = Reid BM, Permuth JB, Sellers TA | title = Epidemiology of ovarian cancer: a review | journal = Cancer Biology & Medicine | volume = 14 | issue = 1 | pages = 9–32 | date = February 2017 | pmid = 28443200 | doi = 10.20892/j.issn.2095-3941.2016.0084 | pmc = 5365187 }}</ref>
* Females are more likely to experience severe outcomes from [[Virus|viral]] [[respiratory tract infections]] during their reproductive years, compared to males of the same age. In response to treatment, females may develop greater immune responses but may also experience more adverse reactions than males.<ref name="Ursin"/><ref name="Klein">{{cite journal | vauthors = Klein SL, Flanagan KL | title = Sex differences in immune responses | journal = Nature Reviews. Immunology | volume = 16 | issue = 10 | pages = 626–638 | date = October 2016 | pmid = 27546235 | doi = 10.1038/nri.2016.90 | s2cid = 2258164 | doi-access = free }}</ref>
* Approximately four times more women have [[osteoporosis]] than men.<ref>{{cite journal | vauthors = Alswat KA | title = Gender Disparities in Osteoporosis | journal = Journal of Clinical Medicine Research | volume = 9 | issue = 5 | pages = 382–7 | date = May 2017 | pmid = 28392857 | pmc = 5380170 | doi = 10.14740/jocmr2970w }}</ref>
* [[Autoimmune diseases]], such as [[Sjögren's syndrome]] and [[scleroderma]], are more prevalent in women. Roughly 70% of those living with autoimmune diseases are female.<ref name="Rose">{{cite journal | vauthors = Rose NR, Bona C | title = Defining criteria for autoimmune diseases (Witebsky's postulates revisited) | journal = Immunology Today | volume = 14 | issue = 9 | pages = 426–430 | date = September 1993 | pmid = 8216719 | doi = 10.1016/0167-5699(93)90244-F }}</ref><ref name="HayterCook2012">{{cite journal | vauthors = Hayter SM, Cook MC | title = Updated assessment of the prevalence, spectrum and case definition of autoimmune disease | journal = Autoimmunity Reviews | volume = 11 | issue = 10 | pages = 754–765 | date = August 2012 | pmid = 22387972 | doi = 10.1016/j.autrev.2012.02.001 }}</ref> See [[Autoimmunity#Sex|Sex differences in autoimmunity]].
* While estimates vary widely,<ref>{{cite journal |last1=Franceschini |first1=Anna |last2=Fattore |first2=Liana |title=Gender-specific approach in psychiatric diseases: Because sex matters |journal=European Journal of Pharmacology |date=5 April 2021 |volume=896 |pages=173895 |doi=10.1016/j.ejphar.2021.173895 |pmid=33508283 |s2cid=231753879 |url=https://www.sciencedirect.com/science/article/pii/S0014299921000480 |access-date=23 December 2021 |language=en |issn=0014-2999}}</ref><ref name="Sweeting">{{cite journal | vauthors = Sweeting H, Walker L, MacLean A, Patterson C, Räisänen U, Hunt K | title = Prevalence of eating disorders in males: a review of rates reported in academic research and UK mass media | journal = International Journal of Men's Health | volume = 14 | issue = 2 | date = 2015 | pmid = 26290657 | pmc = 4538851 <!-- | doi = 10.3149/jmh.1402.86 | doi-broken-date = 31 January 2024 --> }}</ref> [[eating disorder]]s are estimated to affect as high as 13% of women in some age groups<ref name="Stice">{{cite journal | vauthors = Stice E, Marti CN, Rohde P | title = Prevalence, incidence, impairment, and course of the proposed DSM-5 eating disorder diagnoses in an 8-year prospective community study of young women | journal = Journal of Abnormal Psychology | volume = 122 | issue = 2 | pages = 445–457 | date = May 2013 | pmid = 23148784 | doi = 10.1037/a0030679 | pmc = 3980846 }}</ref><ref name="Gagne">{{cite journal | vauthors = Gagne DA, Von Holle A, Brownley KA, Runfola CD, Hofmeier S, Branch KE, Bulik CM | title = Eating disorder symptoms and weight and shape concerns in a large web-based convenience sample of women ages 50 and above: results of the Gender and Body Image (GABI) study | journal = The International Journal of Eating Disorders | volume = 45 | issue = 7 | pages = 832–844 | date = November 2012 | pmid = 22729743 | doi = 10.1002/eat.22030 | pmc = 3459309 }}</ref><ref name="Schaumberg">{{cite journal | vauthors = Schaumberg K, Welch E, Breithaupt L, Hübel C, Baker JH, Munn-Chernoff MA, Yilmaz Z, Ehrlich S, Mustelin L, Ghaderi A, Hardaway AJ, Bulik-Sullivan EC, Hedman AM, Jangmo A, Nilsson IA, Wiklund C, Yao S, Seidel M, Bulik CM | display-authors = 6 | title = The Science Behind the Academy for Eating Disorders' Nine Truths About Eating Disorders | journal = European Eating Disorders Review | volume = 25 | issue = 6 | pages = 432–450 | date = November 2017 | pmid = 28967161 | pmc = 5711426 | doi = 10.1002/erv.2553 }}</ref>  and 3% of men in Western cultures, with  [[anorexia nervosa]] affecting 10 women for each man and [[bulimia nervosa]] affecting 8 women for each man.<ref name="DSM5">{{Cite book|title=Diagnostic and Statistical Manual of Mental Disorders|last=American Psychiatric Association|publisher=American Psychiatric Publishing|year=2013|isbn=978-0-89042-555-8|edition=5th|location=Arlington, VA|pages=[https://archive.org/details/diagnosticstatis0005unse/page/345 338–349]|url=https://archive.org/details/diagnosticstatis0005unse/page/345}}</ref>
* [[Alzheimer's disease]] has a higher incidence in females compared to males.<ref>{{cite journal |last1=Hanamsagar |first1=Richa |last2=Bilbo |first2=Staci D. |title=Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development |journal=The Journal of Steroid Biochemistry and Molecular Biology |date=June 2016 |volume=160 |pages=127–133 |doi=10.1016/j.jsbmb.2015.09.039 |pmid=26435451 |pmc=4829467 |language=en}}</ref> There are also phenotypic differences, with females displaying more cognitive deficits. Females are also more likely to have [[neurofibrillary tangle]]s present on autopsy.<ref name="Ullah2019NeuroBioRev"/>
* [[Huntington's disease]] affects females and males differently. Females have faster disease progression, and display symptoms with fewer [[Trinucleotide repeat disorder|trinucleotide repeat]]s.<ref name="Ullah2019NeuroBioRev"/><ref name="Zielonka">{{cite journal | vauthors = Zielonka D, Stawinska-Witoszynska B | title = Gender Differences in Non-sex Linked Disorders: Insights From Huntington's Disease | journal = Frontiers in Neurology | volume = 11 | pages = 571 | date = 2020 | pmid = 32733356 | pmc = 7358529 | doi = 10.3389/fneur.2020.00571 | doi-access = free }}</ref>
* About two times more women than men have unipolar clinical depression<ref name=Fracas23>{{cite journal |vauthors=Fracas E, Costantino A, Vecchi M, Buoli M |title=Depressive and Anxiety Disorders in Patients with Inflammatory Bowel Diseases: Are There Any Gender Differences? |journal=Int J Environ Res Public Health |volume=20 |issue=13 |pages=6255 |date=June 2023 |pmid=37444101 |pmc=10340762 |doi=10.3390/ijerph20136255 |doi-access=free}}</ref> (although [[bipolar disorder]] appears to affect both sexes equally).<ref name="DSM53">{{citation|author=American Psychiatric Association|title=Diagnostic and Statistical Manual of Mental Disorders|url=https://archive.org/details/diagnosticstatis0005unse/page/160|pages=[https://archive.org/details/diagnosticstatis0005unse/page/160 160–68]|year=2013|edition=5th|location=Arlington|publisher=American Psychiatric Publishing|isbn=978-0-89042-555-8|access-date=22 July 2016}}</ref><ref name="Schmitt2014">{{cite journal | vauthors = Schmitt A, Malchow B, Hasan A, Falkai P | title = The impact of environmental factors in severe psychiatric disorders | journal = Frontiers in Neuroscience | volume = 8 | issue = 19 | pages = 19 | date = February 2014 | pmid = 24574956 | pmc = 3920481 | doi = 10.3389/fnins.2014.00019 | doi-access = free }}</ref>
* About three times more women than men are diagnosed with [[borderline personality disorder|borderline]] or [[histrionic personality disorder]].<ref name="DSM52">{{cite book|title=Diagnostic and statistical manual of mental disorders: DSM-5|date=2013|publisher=American Psychiatric Publishing|isbn=978-0-89042-555-8|edition=5th |pages=[https://archive.org/details/diagnosticstatis0005unse/page/645 645, 663–6]|url=https://archive.org/details/diagnosticstatis0005unse/page/645}}</ref>
*Conditions such as [[chronic fatigue syndrome]] (CFS)/myalgic encephalomyelitis (ME), [[postural orthostatic tachycardia syndrome]] (POTS), [[fibromyalgia]], [[irritable bowel syndrome]] (IBS) and [[idiopathic hypersomnia]], which have unclear causes, are more common in women, with sex ratios ranging from 2:1 in IBS,<ref>{{Cite web|url=https://www.niddk.nih.gov/health-information/digestive-diseases/irritable-bowel-syndrome/definition-facts|title=Definition & Facts for Irritable Bowel Syndrome {{!}} NIDDK|website=National Institute of Diabetes and Digestive and Kidney Diseases|access-date=2019-07-04}}</ref> fibromyalgia,<ref name="JAMA2014">{{cite journal | vauthors = Clauw DJ | title = Fibromyalgia: a clinical review | journal = JAMA | volume = 311 | issue = 15 | pages = 1547–55 | date = April 2014 | pmid = 24737367 | doi = 10.1001/jama.2014.3266 }}</ref> and idiopathic hypersomnia<ref name="MallampalliCarter2014">{{cite journal | vauthors = Mallampalli MP, Carter CL | title = Exploring sex and gender differences in sleep health: a Society for Women's Health Research Report | journal = Journal of Women's Health | volume = 23 | issue = 7 | pages = 553–562 | date = July 2014 | pmid = 24956068 | pmc = 4089020 | doi = 10.1089/jwh.2014.4816 }}</ref> to 4:1 in CFS,<ref>{{cite web|url=https://www.womenshealth.gov/a-z-topics/chronic-fatigue-syndrome|title=Chronic fatigue syndrome|date=21 February 2017|website=womenshealth.gov|access-date=13 May 2019}}</ref> and 5:1 in POTS.<ref name="Ben2012">{{cite journal | vauthors = Benarroch EE | title = Postural tachycardia syndrome: a heterogeneous and multifactorial disorder | journal = Mayo Clinic Proceedings | volume = 87 | issue = 12 | pages = 1214–25 | date = December 2012 | pmid = 23122672 | pmc = 3547546 | doi = 10.1016/j.mayocp.2012.08.013 }}</ref>
*Most people with [[psychogenic non-epileptic seizures]] (PNES) (75%) are female.<ref>{{cite journal |last1=Dworetzky |first1=Barbara A. |last2=Baslet |first2=Gaston |title=Psychogenic Nonepileptic Seizures in Women |journal=Seminars in Neurology |date=December 2017 |volume=37 |issue=6 |pages=624–631 |doi=10.1055/s-0037-1607971 |pmid=29270935 |s2cid=11959147 |url=https://pubmed.ncbi.nlm.nih.gov/29270935/ |issn=1098-9021}}</ref><ref>{{cite journal |last1=Türe |first1=H. Sabiha |last2=Tatlidil |first2=Işıl |last3=Kiliçarslan |first3=Esin |last4=Akhan |first4=Galip |title=Gender-Related Differences in Semiology of Psychogenic Non-Epileptic Seizures |journal=Archives of Neuropsychiatry |date=September 2019 |volume=56 |issue=3 |pages=178–181 |doi=10.29399/npa.23420 |pmid=31523142 |pmc=6732800 |language=en}}</ref><ref>{{cite journal |last1=Asadi-Pooya |first1=Ali A. |last2=Homayoun |first2=Maryam |title=Psychogenic nonepileptic seizures: The sex ratio trajectory across the lifespan |journal=Seizure |date=1 February 2020 |volume=75 |pages=63–65 |doi=10.1016/j.seizure.2019.12.017 |pmid=31874361 |s2cid=209413248 |language=en |issn=1059-1311|doi-access=free }}</ref>
*[[Ataxic cerebral palsy]] is more common in women and girls.<ref name="sdpalsy"/>
*[[Turner Syndrome]] only occurs in females.<ref>{{cite journal |last1=Kruszka |first1=Paul |last2=Silberbach |first2=Michael |title=The state of Turner syndrome science: Are we on the threshold of discovery? |journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics |date=March 2019 |volume=181 |issue=1 |pages=4–6 |doi=10.1002/ajmg.c.31688 |pmid=30790455 |s2cid=73499005 |quote=[Turner Syndrome] is one of the most common genetic syndromes that occurs only in females...}}</ref>
===Males===
Examples of sex-related illnesses and disorders in [[Male#Genetic determination|male humans]]:<ref name="Regitz‐Zagrosek"/>
* [[Prostate cancer]], [[testicular cancer]] and other diseases of the male reproductive system occur in males.<ref name="MNT">{{cite web |title=Prostate vs. testicular cancer: Similarities and differences |url=https://www.medicalnewstoday.com/articles/testicular-cancer-vs-prostate-cancer |website=Medical News Today |access-date=10 November 2021 |language=en |date=25 October 2021}}</ref>
* Diseases of [[X-linked recessive inheritance]], such as [[color blindness|colour blindness]], occur more frequently in males, and [[haemophilia]] A and B occur almost exclusively in males.<ref>{{cite web|url=https://www.nlm.nih.gov/medlineplus/hemophilia.html|title=U.S. National Library of Medicine|archive-url=https://web.archive.org/web/20071012095806/http://www.nlm.nih.gov/medlineplus/hemophilia.html|archive-date=12 October 2007|url-status=live|access-date=2 December 2007}}</ref>
* The presence of a single X chromosome in males (rather than two in females) may explain why males are more susceptible to genetic diseases linked to the X chromosome,<ref name="Barbara">{{cite journal | vauthors = Migeon BR | title = Why females are mosaics, X-chromosome inactivation, and sex differences in disease | journal = Gender Medicine | volume = 4 | issue = 2 | pages = 97–105 | date = June 2007 | pmid = 17707844 | doi = 10.1016/S1550-8579(07)80024-6 }}</ref><ref name="Brown">{{cite journal | vauthors = Brown C |title=Patchwork women |journal=Nature Genetics |date=September 2007 |volume=39 |issue=9 |pages=1043 |doi=10.1038/ng0907-1043 |s2cid=32145544 |doi-access=free }}</ref><ref name="Migeon">{{cite book | vauthors = Migeon BR |title=Females are mosaics : X inactivation and sex differences in disease |date=2014 |publisher=Oxford University Press |location=Oxford |isbn=978-0-19-992753-1 |edition=2nd}}</ref> including [[hemophilia]], [[Duchenne muscular dystrophy]], and [[Hunter syndrome]].<ref name="Doblhammer">{{cite book | veditors = Doblhammer D, Gumà J |title=A Demographic Perspective on Gender, Family and Health in Europe |date=February 12, 2018 |publisher=Springer |isbn=978-1-01-326907-3 |page=78 |vauthors=Oksuzyan A, Gumà J, Doblhammer D |chapter=Sex Differences in Health and Survival §Effects of Sex Hormones on the Immune System |chapter-url=https://books.google.com/books?id=MuBLDwAAQBAJ&pg=PA78 |access-date=11 November 2021}}</ref>
* Certain [[neurodegenerative diseases]] ([[Parkinson's disease]] (2:1 ratio) and [[Lewy body dementia]] (4:1 ratio)) are more prevalent in males.<ref name="Ullah2019NeuroBioRev"/><ref>{{cite journal |last1=Latimer |first1=Caitlin S. |last2=Keene |first2=C. Dirk |last3=Flanagan |first3=Margaret E. |last4=Hemmy |first4=Laura S. |last5=Lim |first5=Kelvin O. |last6=White |first6=Lon R. |last7=Montine |first7=Kathleen S. |last8=Montine |first8=Thomas J. |title=Resistance to Alzheimer Disease Neuropathologic Changes and Apparent Cognitive Resilience in the Nun and Honolulu-Asia Aging Studies |journal=Journal of Neuropathology and Experimental Neurology |date=1 June 2017 |volume=76 |issue=6 |pages=458–466 |doi=10.1093/jnen/nlx030 |pmid=28499012 |pmc=6334750 |issn=1554-6578}}</ref> Parkinson's also displays phenotypic differences: males are more likely to present with sleep disturbances and deficits in verbal fluency and facial expression.<ref name="Ullah2019NeuroBioRev">{{cite journal |last1=Ullah |first1=Mohammad Fahad |last2=Ahmad |first2=Aamir |last3=Bhat |first3=Showket Hussain |last4=Abu-Duhier |first4=Faisel M. |last5=Barreto |first5=George E. |last6=Ashraf |first6=Ghulam Md |title=Impact of sex differences and gender specificity on behavioral characteristics and pathophysiology of neurodegenerative disorders |journal=Neuroscience & Biobehavioral Reviews |date=1 July 2019 |volume=102 |pages=95–105 |doi=10.1016/j.neubiorev.2019.04.003 |pmid=30959072 |s2cid=102487049 |url=https://www.sciencedirect.com/science/article/pii/S014976341830811X |access-date=28 December 2021 |language=en |issn=0149-7634}}</ref>
* [[Abdominal aortic aneurysm]]s are six times more common in males, and thus some countries have introduced screening for males at risk of developing the condition.<ref name="aneurysm">{{cite news|title=Men to get aneurysm screening|url=http://news.bbc.co.uk/2/hi/health/7172094.stm|access-date=6 June 2016|work=BBC|date=5 January 2008}}</ref>
* [[Sex differences in autism|Autism]] is approximately four times more prevalent in males than females.<ref name=Newschaffer>{{cite journal | vauthors = Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J, Reaven J, Reynolds AM, Rice CE, Schendel D, Windham GC | display-authors = 6 | title = The epidemiology of autism spectrum disorders | journal = Annual Review of Public Health | volume = 28 | pages = 235–258 | year = 2007 | pmid = 17367287 | doi = 10.1146/annurev.publhealth.28.021406.144007 | doi-access = free }}</ref> Males also have distinct autism phenotypes compared to females, including a higher prevalence of restrictive and repetitive behaviors.<ref>{{cite journal |last1=Werling |first1=Donna M. |last2=Geschwind |first2=Daniel H. |title=Sex differences in autism spectrum disorders |journal=Current Opinion in Neurology |date=April 2013 |volume=26 |issue=2 |pages=146–153 |doi=10.1097/WCO.0b013e32835ee548 |pmid=23406909 |pmc=4164392 }}</ref>
*Males have increased risk of [[athetoid cerebral palsy|dyskinetic cerebral palsy]] and [[spastic diplegia]], as well as lower limb deformities.<ref name="sdpalsy">{{cite journal | vauthors = Romeo DM, Sini F, Brogna C, Albamonte E, Ricci D, Mercuri E | title = Sex differences in cerebral palsy on neuromotor outcome: a critical review | journal = Developmental Medicine and Child Neurology | volume = 58 | issue = 8 | pages = 809–813 | date = August 2016 | pmid = 27098195 | doi = 10.1111/dmcn.13137 | doi-access = free }}</ref>
*[[Schizophrenia]] is about 1.4 times as common in males, and on average starts two years earlier and has more severe symptoms.<ref name="BMJ07">{{cite journal | vauthors = Picchioni MM, Murray RM | title = Schizophrenia | journal = BMJ | volume = 335 | issue = 7610 | pages = 91–95 | date = July 2007 | pmid = 17626963 | pmc = 1914490 | doi = 10.1136/bmj.39227.616447.BE }}</ref>
* More than two times more males than females are affected by [[antisocial personality disorder]] and [[substance use disorder]].<ref>{{cite journal|author4-link=Andrew E. Skodol | vauthors = Alegria AA, Blanco C, Petry NM, Skodol AE, Liu SM, Grant B, Hasin D | title = Sex differences in antisocial personality disorder: results from the National Epidemiological Survey on Alcohol and Related Conditions | journal = Personality Disorders | volume = 4 | issue = 3 | pages = 214–222 | date = July 2013 | pmid = 23544428 | pmc = 3767421 | doi = 10.1037/a0031681 }}</ref><ref name=":0">{{Cite book|title=The American Psychiatric Publishing Textbook of Substance Abuse Treatment| veditors = Galanter M, Kleber HD, Brady KT |date=17 December 2014|isbn=978-1-58562-472-0|doi=10.1176/appi.books.9781615370030| last1 = Galanter | first1 = Marc | last2 = Kleber | first2 = Herbert D. | last3 = Brady | first3 = Kathleen T. }}</ref>
*Several cancers, including [[stomach cancer]] (2:1),<ref name="WCR2014">{{cite book|title=World Cancer Report 2014|date=2014|publisher=World Health Organization|isbn=978-92-832-0429-9|chapter=5.4 Stomach Cancer |pages=383–391 |url=https://publications.iarc.who.int/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014 |ref={{harvid|World Cancer Report|2014}}}}</ref> [[oesophageal cancer]] (3:1),<ref name="WCR20142">{{cite book|title=5.3 Oesophageal Cancer | vauthors = Montgomery EA |date=2014 |pages=528–543}} In {{harvnb|World Cancer Report|2014}}</ref> [[liver cancer]] (2:1 to 4:1)<ref>{{cite journal | vauthors = Hefaiedh R, Ennaifer R, Romdhane H, Ben Nejma H, Arfa N, Belhadj N, Gharbi L, Khalfallah T | display-authors = 6 | title = Gender difference in patients with hepatocellular carcinoma | journal = La Tunisie Médicale | volume = 91 | issue = 8–9 | pages = 505–8 | date = Aug–Sep 2013 | pmid = 24227507 }}</ref> and [[oral cancer]] (2:1 to 3:1),<ref name=":11">{{cite journal | vauthors = Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, Franceschi S, Rosenberg PS, Bray F, Gillison ML | display-authors = 6 | title = Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers | journal = Journal of Clinical Oncology | volume = 31 | issue = 36 | pages = 4550–9 | date = December 2013 | pmid = 24248688 | pmc = 3865341 | doi = 10.1200/jco.2013.50.3870 }}</ref> which have mostly lifestyle-based risk factors, are more common in males.
* Males are more likely to experience severe outcomes from [[Virus|viral]] [[respiratory tract infections]] than females, at younger and older ages.<ref name="Ursin">{{cite journal | vauthors = Ursin RL, Klein SL | title = Sex Differences in Respiratory Viral Pathogenesis and Treatments | journal = Annual Review of Virology | volume = 8 | issue = 1 | pages = 393–414 | date = September 2021 | pmid = 34081540 | doi = 10.1146/annurev-virology-091919-092720 | s2cid = 235333732 | doi-access =free  }}</ref>
* [[Tuberculosis]] is more common in males.<ref>{{cite journal | vauthors = Hertz D, Schneider B | title = Sex differences in tuberculosis | journal = Seminars in Immunopathology | volume = 41 | issue = 2 | pages = 225–237 | date = March 2019 | pmid = 30361803 | doi = 10.1007/s00281-018-0725-6 | s2cid = 53030554 }}</ref>
* In cases of [[preterm birth]], being male is associated with higher mortality and morbidity in terms of respiratory distress, cardiovascular disorders (specifically hypotension), neurodevelopmental disorders, and immune disorders.<ref>{{cite journal | vauthors = O'Driscoll DN, McGovern M, Greene CM, Molloy EJ | title = Gender disparities in preterm neonatal outcomes | journal = Acta Paediatrica | volume = 107 | issue = 9 | pages = 1494–9 | date = May 2018 | pmid = 29750838 | doi = 10.1111/apa.14390 | s2cid = 21676905 | doi-access = free }}</ref>
* Although both males and females can have [[eating disorder]]s, males are less likely to be diagnosed and receive treatment.<ref>{{cite journal |last1=Gorrell |first1=Sasha |last2=Murray |first2=Stuart B. |title=Eating Disorders in Males |journal=Child and Adolescent Psychiatric Clinics of North America |date=October 2019 |volume=28 |issue=4 |pages=641–651 |doi=10.1016/j.chc.2019.05.012 |pmid=31443881 |pmc=6785984 |issn=1558-0490}}</ref><ref>{{cite journal |last1=Strother |first1=Eric |last2=Lemberg |first2=Raymond |last3=Stanford |first3=Stevie Chariese |last4=Turberville |first4=Dayton |title=Eating Disorders in Men: Underdiagnosed, Undertreated, and Misunderstood |journal=Eating Disorders |date=October 2012 |volume=20 |issue=5 |pages=346–355 |doi=10.1080/10640266.2012.715512 |pmid=22985232 |pmc=3479631 |language=en |issn=1064-0266}}</ref><ref>{{cite journal |last1=Nagata |first1=Jason M. |last2=Ganson |first2=Kyle T. |last3=Murray |first3=Stuart B. |title=Eating disorders in adolescent boys and young men: an update |journal=Current Opinion in Pediatrics |date=August 2020 |volume=32 |issue=4 |pages=476–481 |doi=10.1097/MOP.0000000000000911 |pmid=32520822 |pmc=7867380 |language=en}}</ref>
* [[Klinefelter syndrome]] ([[karyotype]] XXY) is the most common sex chromosome [[aneuploidy]] (occurring in ~152/100,000 births, only in males). It is often subclinical, but can cause infertility, tall stature, [[gynecomastia]] (enlargement of the breast tissue), limited facial and body hair, and [[microorchidism|small firm testicles]].<ref>{{cite journal |last1=Stormont |first1=Gavin D. |last2=Deibert |first2=Christopher M. |title=Genetic causes and management of male infertility |journal=Translational Andrology and Urology |date=March 2021 |volume=10 |issue=3 |pages=1365–72 |doi=10.21037/tau.2020.03.34 |pmid=33850772 |pmc=8039619 |language=en |doi-access=free }}</ref><ref>{{cite journal |last1=Shah |first1=K |last2=Sivapalan |first2=G |last3=Gibbons |first3=N |last4=Tempest |first4=H |last5=Griffin |first5=Dk |title=The genetic basis of infertility |journal=Reproduction |date=1 July 2003 |volume=126 |issue=1 |pages=13–25 |doi=10.1530/rep.0.1260013 |pmid=12814343 |quote=Klinefelter syndrome and the subsequent infertility phenotype caused by it are specific to males.|doi-access=free }}</ref>
==Reasons for sex differences in incidence and prevalence==
===Hypertension===
Hypertension is a worldwide disease affecting the sexes.<ref>{{cite journal |author=((NCD Risk Factor Collaboration)) |title=Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants |journal=Lancet |volume=389 |issue=10064 |pages=37–55 |date=January 2017 |pmid=27863813 |pmc=5220163 |doi=10.1016/S0140-6736(16)31919-5 }}{{cite web |last1=NCD Risk Factor Collaboration |title=Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants |url=https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31919-5/fulltext |publisher=Lancet |access-date=15 June 2024}}</ref> Women are less frequently affected by high blood pressure  . Since blood pressure rises in women after menopause,<ref>{{cite journal |last1=Izumi |first1=Yoichi |last2=Matsumoto |first2=Koichi |last3=Ozawa |first3=Yukio |last4=Kasamaki |first4=Yuji |last5=Shinndo |first5=Atsusi |last6=Ohta |first6=Masakatsu |last7=Jumabay |first7=Madet |last8=Nakayama |first8=Tomohiro |last9=Yokoyama |first9=Eise |last10=Shimabukuro |first10=Hiroaki |last11=Kawamura |first11=Hiroshi |last12=Cheng |first12=Zuheng |last13=Ma |first13=Yitong |last14=Mahmut |first14=Masum |title=Effect of Age at Menopause on Blood Pressure in Postmenopausal Women |url=https://www.sciencedirect.com/science/article/abs/pii/S0895706107002725 |journal=American Journal of Hypertension |access-date=15 June 2024 |pages=1045–50 |doi=10.1016/j.amjhyper.2007.04.019 |date=1 October 2007|volume=20 |issue=10 |pmid=17903686 }}</ref> this suggests that the cause of the sex-specific differences lies not only in possible external factors, such as lifestyle, but also in the sex hormones . It is likely due to sex hormones not external factors. One possible mechanism is the influence of the renin-angiotensin system (RAAS).<ref>{{cite journal |last1=Reckelhoff |first1=Jane F. |title=Mechanisms of sex and gender differences in hypertension |url=https://www.nature.com/articles/s41371-023-00810-4 |journal=Journal of Human Hypertension |access-date=15 June 2024 |pages=596–601 |language=en |doi=10.1038/s41371-023-00810-4 |date=August 2023|volume=37 |issue=8 |pmid=36797338 }}</ref>
Angiotensinogen (liver) is converted into angiotensin I (Ang I) by renin (kidney). Ang I is converted to angiotensin II (Ang II) by the angiotensin-converting enzyme (ACE). This binds to the Ang II type I receptor (A2T1), which causes vasoconstriction and water and sodium reabsorption in the kidneys, and in turn increases blood pressure.
Less well known is that Ang II can also bind to Ang II type II receptor (A2T2) or be converted by angiotensin-converting enzyme II (ACE II) into angiotensin III (Ang III), which binds to MAS receptors.<ref>{{cite journal |last1=Miller |first1=Amanda J. |last2=Arnold |first2=Amy C. |title=The renin-angiotensin system and cardiovascular autonomic control in aging |journal=Peptides |pages=170733 |doi=10.1016/j.peptides.2021.170733 |date=1 April 2022|volume=150 |pmid=34973286 |pmc=8923940 }}</ref> Both A2T2 and MAS receptors trigger vasodilation.<ref>{{cite journal |last1=Reckelhoff |first1=Jane F. |title=Mechanisms of sex and gender differences in hypertension |url=https://www.nature.com/articles/s41371-023-00810-4 |journal=Journal of Human Hypertension |pages=596–601 |language=en |doi=10.1038/s41371-023-00810-4 |date=August 2023|volume=37 |issue=8 |pmid=36797338 }}</ref>
Animal experiments have shown that female ovariectomised mice treated chronically with testosterone have increased blood pressure (mean arterial pressure ~180mmHg) compared to female mice from the control group (~155mmHg).<ref>{{cite journal |last1=Reckelhoff |first1=Jane F. |last2=Zhang |first2=Huimin |last3=Srivastava |first3=Kumud |title=Gender Differences in Development of Hypertension in Spontaneously Hypertensive Rats: Role of the Renin-Angiotensin System |url=https://www.ahajournals.org/doi/pdf/10.1161/01.hyp.35.1.480 |journal=Hypertension |pages=480–3 |doi=10.1161/01.HYP.35.1.480 |date=January 2000|volume=35 |issue=1 |pmid=10642345 }}</ref> This difference was reduced by ACE inhibition (enalapril (250 mg/L)) in both groups to a similar level ( ~115mmHg).<ref>{{cite journal |last1=Miller |first1=Amanda J. |last2=Arnold |first2=Amy C. |title=The renin-angiotensin system and cardiovascular autonomic control in aging |journal=Peptides |pages=170733 |doi=10.1016/j.peptides.2021.170733 |date=1 April 2022|volume=150 |pmid=34973286 |pmc=8923940 }}</ref> It can therefore be assumed that male androgens have an high increasing influence (up to 25mmHg in middle blood pressure) on angiotensinogen.<ref>{{cite journal |last1=Miller |first1=Amanda J. |last2=Arnold |first2=Amy C. |title=The renin-angiotensin system and cardiovascular autonomic control in aging |journal=Peptides |pages=170733 |doi=10.1016/j.peptides.2021.170733 |date=1 April 2022|volume=150 |pmid=34973286 |pmc=8923940 }}</ref>
=== Autoimmune diseases (Sjögren's syndrome) ===
In [[Autoimmune disease|autoimmune diseases]], like [[Sjögren syndrome|Sjögren's syndrome]] (SS), the body produces hyperreactive [[Autoantibody|autoantibodies]] against the salivary and lacrimal gland tissue. This results in symptoms like dry mouth and dry eyes.
The gender distribution in Sjögren's syndrome is heavily skewed towards women, with a ratio of 16:1 in the UK.<ref name=":1">{{Cite journal |last1=Brandt |first1=Jessica E. |last2=Priori |first2=Roberta |last3=Valesini |first3=Guido |last4=Fairweather |first4=DeLisa |date=2015-11-03 |title=Sex differences in Sjögren's syndrome: a comprehensive review of immune mechanisms |journal=Biology of Sex Differences |volume=6 |issue=1 |pages=19 |doi=10.1186/s13293-015-0037-7 |doi-access=free |pmid=26535108 |pmc=4630965 |issn=2042-6410}}</ref> Various reasons have been suggested, but the evidence is not strong. One common reason is the hormonal differences between women and men. In women, [[estrogen]] dominates, as does the hormone [[progesterone]] during pregnancy. [[Androgen|Androgens]] (e.g. [[testosterone]]) are only present in small quantities. In men, testosterone, an androgen, dominates, and estrogen is only present to a small extent. Estrogen stimulates the immune system more than androgens. Accordingly, it stands to reason that an autoimmune reaction, which is based on a hyperreactive immune sensitivity to autoantigens, can manifest itself much more easily in women.
In Sjögren's syndrome, [[B cell|B cells]] and [[Interferon|interferons]] are of particular importance. Generally, hormone receptors are expressed on immune cells (e.g., B cells), such as the [[estrogen receptor]] (ER-alpha/ß) or the [[androgen receptor]]. These receptors are [[Steroid hormone receptor|steroid hormone receptors]], i.e., they influence gene expression in the nucleus of the immune cells.
Pregnancy, including hormonal changes, appears to increase the risk of developing SS and also exacerbate the course of the disease if it is already present. During pregnancy, more hormones than just estrogen are secreted that also have an immune system-stimulating effect, such as [[prolactin]]. So, an overstimulated immune system seems to be the result.
On the other hand, estrogen protects glandular cells and prevents them from cell death. [[Menopause]] causes a decreased level of hormones like estrogen and thus reduces the protective effect on glandular cell health. Increased [[apoptosis]] (cell death) and inflammatory effects on damaged and aged cells are the result. As a result, there is an increased level of autoantibodies against the glandular cells. Estrogen is important, but only in the right amount. The study showed that the prevalence of women developing SS after menopause is quite higher than before menopause. This leads to the assumption that the protective effect of estrogen on glandular tissue is more important than the stimulation effect on B cells for the development of SS.<ref name=":1" />
Another study investigated the hormonal influence on the pathogenesis of autoimmune diseases, including SS. Female mice had their ovaries removed to investigate the effect of missing estrogen on the pathogenesis of SS.<ref name=":2">{{Cite journal |last=Xuan |first=Yuhao |date=2024 |title=Impact of sex differences on the clinical presentation, pathogenesis, treatment and prognosis of Sjögren's syndrome |url=https://doi.org/10.1111/imm.13740 |journal=Immunology |volume=171 |issue=4 |pages=513–524 |doi=10.1111/imm.13740 |pmid=38156505 }}</ref> In this study, low estrogen levels promoted apoptosis and the formation of apoptotic bodies and microparticles containing membrane antigens. These are recognized as pathogens via [[Toll-like receptor|TLR]] (toll-like receptors) of the dendritic and B cells, which then secrete increased levels of [[Interferon type I|INF]] alpha/ß and [[Cytokine|cytokines]]. These cytokines stimulate other immune cells (e.g., DC, T-cells), which can lead to autoreactivity and thus to an autoimmune reaction.
In men, the preliminary stage of testosterone, DHT ([[dihydrotestosterone]]), is synthesized from testosterone in one simple step. DHT has an anti-apoptotic effect on the glandular tissue. In women, DHEA ([[dehydroepiandrosterone]]) takes over this task. Synthesizing this product in women is much more complex and involves several steps that are difficult to ensure when estrogen levels are low (menopause, etc.). This might be another reason for increased apoptosis and the pathogenesis of SS in women compared to men.
Another key player in the pathogenesis of SS is [[Interferon type I|INF1]]. It is stimulated by estrogen receptor interaction. INF1 ensures a higher level of autoantibodies and inflammatory cytokines. A study has shown that interferon type I and type II are more pronounced in women than in men. <ref name=":1" />That might be a reason for the increased level of autoantibodies and prevalence of SS in women.
Androgens generally have stimulating effects on the production of the lipid layer in the tear film and oral [[Mucous membrane|mucosa]].<ref name=":2" /> Androgens increase the level of [[Integrin|integrins]] alpha1 and 2, which promote the differentiation of mesenchymal [[Stem cell|stem cells]] into acinar cells. In the absence of androgens, this differentiation and regulation are defective. In SS, the conversion of testosterone to DHT (in men) or DHEA (in women) in the lacrimal glands is defective. The enzymes are not functional. This means that the lipid layer, which is important for maintaining moisture in the mouth and on the eyes and providing protection against pathogens, is missing. This could be a leading reason for symptoms like dry mouth and dry eyes.
Another study investigated the effects of gene expression of the [[Sex chromosome|sex chromosomes.]]<ref>{{Cite journal |last1=Liu |first1=Ke |last2=Kurien |first2=Biji T. |last3=Zimmerman |first3=Sarah L. |last4=Kaufman |first4=Kenneth M. |last5=Taft |first5=Diana H. |last6=Kottyan |first6=Leah C. |last7=Lazaro |first7=Sara |last8=Weaver |first8=Carrie A. |last9=Ice |first9=John A. |last10=Adler |first10=Adam J. |last11=Chodosh |first11=James |last12=Radfar |first12=Lida |last13=Rasmussen |first13=Astrid |last14=Stone |first14=Donald U. |last15=Lewis |first15=David M. |date=May 2016 |title=X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome |journal=Arthritis & Rheumatology |language=en |volume=68 |issue=5 |pages=1290–1300 |doi=10.1002/art.39560 |issn=2326-5191 |pmc=5019501 |pmid=26713507}}</ref> Normally, one [[X chromosome]] is inhibited in women ([[Barr body]]). However, not completely. Some of the genes of the inhibited X chromosome are still (single or double) expressed, including genes relevant to the immune system. This is supposed to ensure better immunity, among other things, but also results in a higher risk of autoimmunity.
The study has shown that the prevalence of SS in triple-X individuals is 2.9 times higher than in healthy women and 41 times higher than in healthy men, despite physiological hormone levels. This suggests an involvement of the double gene expression of the 2nd X chromosome in the pathogenesis of SS,<ref name=":2" /> which could also affect XX genotype women. An explanation how the double gene expression, which can also be normal, can be manifesting investigated another study.
Another study investigated the influence of a [[Long non-coding RNA|long non coding RNA]] protein, called [[XIST]], which is a leading factor of the double X chromosome expression.<ref>{{Cite journal |last=Dou |first=Diana R. |date=2024-02-01 |title=Xist ribonucleoproteins promote female sex-biased autoimmunity |url=https://doi.org/10.1016/j.cell.2023.12.037 |journal=Cell |volume=187 |issue=3 |pages=733–749 |doi=10.1016/j.cell.2023.12.037 |pmid=38306984 |pmc=10949934 |pmc-embargo-date=February 1, 2025 }}</ref> XIST is only present in women where it is inactivating genes of the second “restoring” X chromosome. Dysfuncitonal XIST proteins seem to be a leading cause of higher prevalence of autoimmune diseases of women, so as in SS.
Furthermore, [[Microbiota|intestinal microbiome]] differences, elevated levels of certain [[MicroRNA|miRNAs]], and [[microchimerism]] during pregnancy are discussed and investigated as possible risk factors in the pathogenesis of SS.<ref name=":2" />
== See also ==
{{Portal|Medicine}}
* [[Andrology]]
* [[Gynaecology]]
* [[Health equity]]
* [[Men's health]]
* [[Obstetrics and gynecology]]
* [[Reproductive medicine]]
* [[Sex differences in humans]]
* [[Women's health]]
== Notes ==
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== References ==
{{Reflist}}
{{Human group differences}}
{{DEFAULTSORT:Sex And Illness}}
[[Category:Human diseases and disorders]]
[[Category:Sex differences in humans|Medicine]]