What is gender-specific medicine and how will it help women get better medical care?

Even your immune system is female!
gender-specific medicine, gender specific medicine,

During her 2022 Supreme Court confirmation hearing, Justice Kentanji Brown Jackson was asked a surprisingly hot-button question: “Can you provide a definition for the word ‘woman’?” The now-Supreme Court Justice replied, “I can’t… I’m not a biologist.”

But does it really take a biologist to define what it means to be a woman or a man? After all, even infants as young as three months of age can distinguish between male and female faces [1]. 

Justice Jackson’s answer does point to a bit of truth, however. Certain aspects of what makes a woman a woman (or what makes a man a man) can be gleaned from scientific studies that go more than skin-deep. Gender-specific medicine (also called sex/gender-specific medicine or sex-and-gender-sensitive medicine in medical research), is a new field of science that seeks to discover exactly this: how male and female bodies differ in their disease development and response due to differences below the surface, from their hormones, to their brain structures, to their internal physiology, and even down to their DNA. In other words, gender-specific medicine recognizes (and aims to further discover) the inherent differences between men and women and the vast implications those differences have for how medicine can best treat both male and female patients 

Hormonal differences between men and women

We can’t begin a discussion about the physiological differences between men and women without first discussing the three most important sex hormones: estrogen, progesterone, and testosterone. 

Most people can name the “female hormones” (estrogen and progesterone) and the “male hormone” (testosterone). While this simple categorization is mostly correct, the reality of how these hormones operate is a bit more complex. Both men and women actually have all three of these hormones (plus dozens more), but they exist in very different amounts and have different roles in one sex versus the other. 

Men vs. women’s hormonal cycles

A woman operates on a monthly hormonal cycle predominated by the ebb and flow of estrogen and progesterone, unless she is blunting her cycle with hormonal contraceptives. When a woman has normal hormone levels and healthy ovulation, her cycles are predictable and measurable, with normal (i.e., non-painful, non-heavy) periods occurring at regular intervals. 

Men, on the other hand, do not have such predictable hormonal cycles. They do experience a 24-hour cycle of testosterone, with a peak around 9am in the morning (which, unsurprisingly, is when many workplaces begin their day — right when a man is at his maximum level of focus and energy!). But testosterone levels can also vary wildly throughout the day due to dozens of outside factors, such as a man’s level of job stress and satisfaction, if he’s recently interacted with a gun, or if his favorite sports team just won the game or not (yes, really), among many others [2][3][4].

New parents illustrate the hormonal differences between men and women

The results of hormonal differences between men and women are especially fascinating after a couple has a baby. Most obviously, the new mother is on a rollercoaster of postpartum hormone changes as her progesterone, in particular, plummets after birth. She also experiences a surge in oxytocin when she’s cuddling or breastfeeding her newborn. Oxytocin release makes women especially perceptive to the sound of their babies crying. This is why typically the mother will be the first one to wake up in the middle of the night when her newborn cries out. 

All these changes in the mom are known and unsurprising. But what about new dads? Research increasingly shows that they too undergo significant hormonal changes. Just as women’s estrogen and progesterone levels drop off after birth, fathers’ testosterone drops too. And, research suggests, as summarized here, “testosterone levels in new dads drop below the average levels of non-dads” [5]. Fascinatingly, “the more a new dad’s testosterone drops, the greater his involvement is in household chores and baby-related duties.” Oxytocin surges in new dads, too and this appears to make them more home-focused and family-oriented.      

Gender-specific medicine also seeks to shed light on how psychological differences between males and females are already present in early childhood–which may indicate that these differences are inborn

Have you ever heard it said that there is no such thing as “girl’s toys” and “boy’s toys”? While it might be true that both boys and girls can enjoy playing with a wide variety of different toys, there’s actually a reason that we typically think of a babydoll as a “girl” toy and matchbox cars as a “boy” toy. There have been many experiments done on whether or not it is a learned or innate trait for boys to prefer one type of toy and girls another [6]. Research consistently demonstrates “significant preferences for gender stereotyped toys” by around 18 months of age [6]. 

This isn’t just due to parents pushing doll houses onto their daughters and monster trucks onto their sons, either. Even young monkeys display a strong preference for wheeled toys if they’re male and plush toys if they’re female, pointing to inborn, psychological differences between the sexes [7].

The differences between male brains and female brains have important implications for psychiatric and neurological diseases 

Why does it matter if males and females exhibit differing behavioral preferences? Because these differences may be the outward expression of internal structural differences between male and female brains. 

A recent Stanford University study used Artificial Intelligence (AI) to determine whether the functional organization of human brains differ consistently between men and women. “Sex is an important biological factor that influences human behavior, impacting brain function and the manifestation of psychiatric and neurological disorders,” the researchers wrote. “However, previous research on how brain organization differs between males and females has been inconclusive” [8]. 

After combing through large multi-cohort fMRI (functional MRI) datasets, the researcher’s “deep learning” AI tool was able to tell with almost perfect accuracy if a brain was male or female, just by analyzing how each brain was organized and structured. The researchers concluded: “Our findings underscore the crucial role of sex as a biological determinant in human brain organization, [and] have significant implications for developing personalized sex-specific biomarkers in psychiatric and neurological disorders.”

Gender-based medicine examines why women’s heart attack symptoms differ from men’s  

But our sex-based differences don’t simply reside in our brains! Gender-specific medicine is important for treating the rest of the body, too–and not just those parts that fall under the “bikini view,” as Dr. Marianne Legato, founder of The Foundation for Gender Specific Medicine and pioneer of gender-specific medicine, puts it [9]. 

For example, one important area of gender-specific medicine that researchers are finally beginning to examine is also the deadliest killer of Americans: heart disease. Although heart disease is often more closely associated with men, it’s actually the number one killer of both men and women. In fact, more women die of the disease than men every year. 

Heart disease also presents differently in men versus women, largely due to the fact that male hearts are larger, while female hearts beat faster and have narrower blood vessels. Men are also prone to plaque buildup in their largest arteries, while women tend towards buildup in the smallest blood vessels. This is why heart attacks do not look the same for men and women — men get the classic chest pain, whereas women might experience chest pain but will also probably have nausea, sweating, vomiting, and pain in their neck, jaw, throat, abdomen, or back. 

Female hormones impact the cardiovascular system too

In fact, after menopause, women’s risk for cardiovascular disease increases fourfold from their premenopausal risk. Men tend to develop cardiovascular disease a full decade before women and this may be because (until menopause) women’s reproductive hormones protect them from heart disease [10]. 

Concerningly, women who have endometriosis don’t appear to enjoy the heart disease protection that women without endometriosis do [11]. Premenopausal women with endometriosis are at increased risk of heart disease like menopausal women who don’t have endo [12] .

Female and male immune systems differ, with sex-specific differences in infection and autoimmunity 

Because women’s bodies must accommodate foreign organisms (that is, growing babies!), it should come as no surprise that women’s immune systems also differ from men’s, which can have sex-specfic implications for a host of immunity-related health concerns.. 

Interestingly, women have stronger immune responses to most kinds of infections than men do, meaning that men are more susceptible to parasitic or bacterial infections [13]. Higher levels of testosterone also promote parasite breeding, making fighting off these kinds of infections particularly challenging for men. 

Why women are more likely to experience autoimmune disease

On the flip side, women are more likely to develop autoimmune disorders, with as many as 4 out of 5 autoimmune sufferers being female. Autoimmune disorders include Hashimoto’s, Rheumatoid arthritis, multiple sclerosis (MS), lupus, and many more. 

The reason for this comes down in part to our very genes. Men have XY chromosomes while women have XX. Researchers have connected a genetic process in females called X-chromosome inactivation with autoimmunity, which is why lupus, thyroid, and other autoimmune problems are so much more common in women (though autoimmunity is still possible in men with their single X chromosome) [14]. 

Having a second X chromosome also gives women a genetic predisposition toward developing inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis) at higher rates [15]. What’s more, females with this disease often report a worse quality of life than male patients. 

Gender-specific medicine aims to improve how doctors treat both men and women 

Medicine still has a long way to go in understanding all of the ways men and women differ in the response to (or development of) various disorders and diseases. But it’s becoming increasingly clear that, when caring for female patients, doctors cannot merely add mammograms for breast cancer prevention and pap smears for cervical infections – and then proceed to more or less treat them in the same way as their male patients. Heart disease, autoimmunity, cancers, and even diabetes can all look different in men and women, and we still have much to understand about the sex-specific variations in these diseases [16].

Although Supreme Court Justice Jackson might be wrong in her assessment that only a biologist can distinguish between men and women, medical researchers do have a responsibility to further examine the differences between the two sexes beyond the visibly obvious. Men and women are innately different, not just in our hormones and reproductive parts, but in every tissue and cell of our bodies. Both sexes deserve doctors who can help them prevent and treat disease according to their sex — taking into the fact that men and women are uniquely designed, with unique medical needs. 

References:

[1] Pickron CB, Cheries EW. Infants’ Individuation of Faces by Gender. Brain Sci. 2019 Jul 11;9(7):163. doi: 10.3390/brainsci9070163. PMID: 31373332; PMCID: PMC6680589.

[2] Hirokawa K, Miwa M, Taniguchi T, Tsuchiya M, Kawakami N. Moderating effects of salivary testosterone levels on associations between job demand and psychological stress response in Japanese medical workers. Ind Health. 2016 Jun 10;54(3):194-203. doi: 10.2486/indhealth.2015-0113. Epub 2015 Dec 1. PMID: 26632120; PMCID: PMC4939866.

[3] Klinesmith, Jennifer et al. “Guns, testosterone, and aggression: an experimental test of a mediational hypothesis.” Psychological science vol. 17,7 (2006): 568-71. doi:10.1111/j.1467-9280.2006.01745.x

[4] Bernhardt, P C et al. “Testosterone changes during vicarious experiences of winning and losing among fans at sporting events.” Physiology & behavior vol. 65,1 (1998): 59-62. doi:10.1016/s0031-9384(98)00147-4

[5] Gettler, Lee T et al. “Longitudinal evidence that fatherhood decreases testosterone in human males.” Proceedings of the National Academy of Sciences of the United States of America vol. 108,39 (2011): 16194-9. doi:10.1073/pnas.1105403108

[6] Serbin, L. A., Poulin-Dubois, D., Colburne, K. A., Sen, M. G., & Eichstedt, J. A. (2001). Gender stereotyping in infancy: Visual preferences for and knowledge of                gender-stereotyped toys in the second year. International Journal of Behavioral Development, 25(1), 7-15. https://doi.org/10.1080/01650250042000078

[7] Williams CL, Pleil KE. Toy story: why do monkey and human males prefer trucks? Comment on “Sex differences in rhesus monkey toy preferences parallel those of children” by Hassett, Siebert and Wallen. Horm Behav. 2008 Aug;54(3):355-8. doi: 10.1016/j.yhbeh.2008.05.003. Epub 2008 May 22. PMID: 18586246; PMCID: PMC2755553.

[8] Ryali, Srikanth et al. “Deep learning models reveal replicable, generalizable, and behaviorally relevant sex differences in human functional brain organization.” Proceedings of the National Academy of Sciences of the United States of America vol. 121,9 (2024): e2310012121. doi:10.1073/pnas.2310012121

[9] Legato MJ. Rethinking Gender-Specific Medicine. Women’s Health. 2006;2(5):699-703. doi:10.2217/17455057.2.5.699

[10] Maas AH, Appelman YE. Gender differences in coronary heart disease. Neth Heart J. 2010 Dec;18(12):598-602. doi: 10.1007/s12471-010-0841-y. PMID: 21301622; PMCID: PMC3018605.

[11] Blom JN, Velez MP, McClintock C, Shellenberger J, Pudwell J, Brogly SB, Bougie O. Endometriosis and cardiovascular disease: a population-based cohort study. CMAJ Open. 2023 Mar 7;11(2):E227-E236. doi: 10.9778/cmajo.20220144. PMID: 36882211; PMCID: PMC10000901.

[12] Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. Endometriosis and Risk of Coronary Heart Disease. Circ Cardiovasc Qual Outcomes. 2016 May;9(3):257-64. doi: 10.1161/CIRCOUTCOMES.115.002224. Epub 2016 Mar 29. PMID: 27025928; PMCID: PMC4940126.

[13] vom Steeg LG, Klein SL (2016) SeXX Matters in Infectious Disease Pathogenesis. PLoS Pathog 12(2): e1005374. https://doi.org/10.1371/journal.ppat.1005374

[14] Brooks WH, Renaudineau Y. Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus. Front Genet. 2015 Feb 16;6:22. doi: 10.3389/fgene.2015.00022. PMID: 25763008; PMCID: PMC4329817.

[15] Lungaro L, Costanzini A, Manza F, Barbalinardo M, Gentili D, Guarino M, Caputo F, Zoli G, De Giorgio R, Caio G. Impact of Female Gender in Inflammatory Bowel Diseases: A Narrative Review. J Pers Med. 2023 Jan 17;13(2):165. doi: 10.3390/jpm13020165. PMID: 36836400; PMCID: PMC9958616.

[16] Szalat A, Raz I. Gender-Specific Care of Diabetes. Women’s Health. 2007;3(6):735-764. doi:10.2217/17455057.3.6.735

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