Towards a Scientifically Sound Analysis of the Problem of Gender Dysphoria

towards a scientifically sound analysis of the problem of gender dysphoria

In contemporary society, many have advocated conceptions of sexual identity that deviate substantially from the universal historical understanding of sex as related to reproductive purpose.[1] Several tenuous arguments have been put forward for abandoning a rigid binary definition of man and woman and for embracing a more fluid meaning of these terms.[2] This has included the introduction of the concept of “gender” as distinct from “sex,” and sometimes conflating the two.[3]

Within this context, physicians are confronting a rising number of adolescent children who express a perceived gender identity that is discordant with their sex. By some estimates, including a recent survey of the Pew Institute, nearly 5% of young adults now claim a sex-discordant or non-binary gender identity.[4] Many in this category experience significant morbidities including depression, anxiety, substance abuse, and eating disorders.[5] Elevated rates of suicidal ideation and attempts are the most concerning symptoms of the anguish these individuals experience.[6] Better understanding of the etiology of this condition and the development of interventions that provide real and lasting alleviation of associated suffering are urgently needed. Rather than perpetuating the ongoing politicization of medical practice, a rigorous and objective scientific analysis of sex-gender incongruence can provide a starting point for a productive path forward. Critical appraisal of the published literature and consideration of basic anthropological principles expose a multitude of limitations, weaknesses, and outright errors in this highly contentious social dialogue.

The terminology used in such discussions has undergone considerable development over the past decade. It is therefore necessary to define with precision the scientific understanding of sex, i.e., of sexual differentiation. As an objective biological trait, sexual differences are intrinsically oriented toward specific roles in the conception and development of new members of a species. Both males and females contribute genetic information in distinct yet complementary ways. Males have the role of delivering sperm produced by testes, and the father’s unique DNA contained therein, to a female. Females have the role of receiving this male genetic information to join with the mother’s genetic information contained in ova produced by ovaries. For humans, gestation of this new living being occurs within the body of the female. Following birth, both sexes participate in the rearing of offspring to the point at which they reach physical and intellectual competency for successful reproduction. As with the initial act of copulation, there are biological differences between sexes that contribute to success in distinct maternal and paternal roles in reproduction and child rearing. Examples include differences in lean versus adipose tissue mass oriented toward protective versus nutritive goals.[7] In this respect, societal roles that encompass gender expression are integral to the process of bringing males and females together in sexual union and raising children.

The dissociation of sexual interactions and reproductive telos serves as a basis for assertions that sex occurs along a continuum. A highly probable hypothesis for the genesis and evolution of this distorted portrayal of sexual identity is the widespread acceptance and use of contraceptive agents. The rare existence of individuals who are born with a disorder of sexual development[8] that leads to genital ambiguity does not change basic understanding of sex. It is an objective biological fact that there are only two types of gonads: testes and ovaries, which participate in the generation of new human life. In the majority of cases of genital ambiguity, genomic testing, radiological imaging, and measurement of sex steroid hormone levels, together with identification of environmental influences affecting the normal process of pre-natal sexual differentiation, allows accurate determination of sexual identity.[9] For most severely affected people, reproductive potential is absent or significantly impaired.[10] Proper diagnosis and prompt medical treatment can be lifesaving in conditions such as congenital adrenal hyperplasia.[11] For some, this can also aid efforts to preserve or restore fertility.

For the medical profession, recognition of sex as a biological variable is necessary to assess both disease risk and response to medications.[12] Requirements by the United States National Institutes of Health to include both males and female subjects in research studies reflect this necessity.[13] Failure to do so because of the use of gender as a replacement for sexual identity, or because of the conflation of the two, introduces serious risk of adverse outcomes and failure to achieve the ultimate goal of medicine, the restoration of health. In this regard, it is important to recognize that nearly all of the individuals presenting to gender clinics for medical treatment of gender dysphoria have normally formed and functioning sexual organs prior to the initiation of hormonal and surgical interventions intended to align the appearance of the body to self-perceived sexual identity.

For medical interventions that are intended to alleviate the suffering of people who experience sex-gender incongruence to have potential for success, it is important to recognize and critically assess the scientific premises and hypotheses that underlie proposed treatments. Until recently, the prevailing understanding was that sex-discordant gender identity represents disordered psychological perceptions. Integral to this premise is understanding and acceptance of normal formation and function of the body. Formal diagnosis of this condition previously reflected this perspective. As recently as 1994, with the publication of the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),[14] an individual who experienced a perception of their sexual identity discordant with their sexual anatomy was understood to have gender identity disorder (ICD10 diagnosis F64.2).[15] Accordingly, medical providers directed therapeutic efforts toward understanding the basis of psychological distress and actively worked to reintegrate sex and gender identity.

Yet, despite these efforts toward sex-gender identity re-integration, practitioners recognized that some individuals with this experience persist in a sex-discordant gender identity. Based upon empirical observation that the majority of pre-pubescent children who experienced gender dysphoria had spontaneous realignment of gender and sexual identity,[16] some have advocated for an expectant approach (i.e., “watchful waiting”). With the lack of an objective biological test to identify those who persist versus desist in sex-discordant gender identity, it is felt best to support affected individuals on their developmental journey without any pre-conceived desire for a particular outcome. While desistence is not a specific goal, advocates of this approach consider this as a positive outcome since it obviates inducing a lifelong medical dependency coming from altered sexual anatomy. An important component of the expectant approach is the provision of care to address any co-morbid psychiatric conditions. This approach has become more difficult to follow within legal and educational structures that encourage “social affirmation,” which includes the practice of allowing affected individuals to change their names, pronouns, and dress and to have access to sex-segregated facilities according to gender identification. Emerging data indicate that socially affirmed children are more likely to experience persistence of gender dysphoria beyond the start of puberty, in contrast to the historical observation of desistance.[17]

In contrast to the cautious expectant approach, several professional societies including the American Academy of Pediatrics,[18] the American Medical Association,[19] and the American Psychological Association[20] endorse uncritical social affirmation and directed efforts to alter the appearance of the body to conform to an individual’s self-perception of sexual identity. These organizations often present this gender-affirming medical approach as the only prudent option for affected adolescents. Foundational to this affirmation-only paradigm is the premise that with sex-discordant identity the mind is functioning normally and the physical appearance of the body is defective. Accordingly, psychotherapy to address the emergence of gender dysphoria is actively discouraged as a barrier to receiving hormones to stop normally timed puberty and the introduction of sex steroids of the opposite sex.[21]

Efforts to provide scientific evidence of a “brain in the wrong body” have failed to prove this ideologically constructed hypothesis.[22] On the one hand, scientific investigation has revealed structural and functional differences between male and female brains and many have used these data as a basis to understand sex-influenced differences in behavioral traits.[23] However, such studies have at best shown sex-influenced average differences in gene expression, neuronal structure, and signaling responses. The wide overlap in these brain characteristics between males and females makes it impossible to determine sex or gender identity based upon these findings.[24] Furthermore, such studies fail to appreciate that neuronal plasticity (i.e., the ability of the brain to change in response to external stimuli) may significantly influence these structural and functional observations.[25]

Inherent limitations and weaknesses in study design and interpretation continue to plague the field of “gender medicine” in efforts to assess the relative risk versus benefit of the affirmation model. Frequent unrecognized or unacknowledged deficiencies of the published literature include small sample size, lack of control groups, short duration of follow-up, high subject dropout rates, and lack of randomized trial design.[26] Critical assessment of the papers published in this area also reveals highly prevalent biases. Non-probability and convenience sampling such as internet-based surveys introduce selection bias.[27] Questionnaires that require participants to recall memories of prior events introduce recall bias as these memories may be incomplete or inaccurate.[28] Knowledge of the investigator’s aim in conducting the study introduces demand bias (a.k.a. the “good subject” effect).[29] Finally, the conduct of experiments to support existing beliefs or the ignoring of information that contradicts existing belief results in observation bias. Rather than seeking to find evidence to reject the null hypothesis, many investigators appear to have started with a predetermined conclusion and have sought to find evidence to support this conclusion. Furthermore, in propagating the results from such studies, advocates of the affirmation model endorse unjustified claims of causal relationships in studies with cross-sectional design where data can only show associations between intervention and outcome.

Perhaps most concerning is the unwillingness to acknowledge ongoing equipoise (i.e., uncertainty about the relative therapeutic merits of different treatments) for achieving the goal of alleviating suffering from gender dysphoria. Affirmation advocates falsely assert that randomized trials are unethical in the “gender medicine” field. An erroneous conception of randomized controlled trial design contributes to this accusation. Specifically, the perception is that a control arm would receive no intervention. However, in properly designed and conducted randomized controlled clinical trials, both arms of a study receive the same degree of care apart from the independent variable tested.

Recently, several European countries including Sweden, Finland, and the United Kingdom have recognized that the scientific evidence frequently referenced to support the affirmative approach is weak and that serious questions remain about long-term efficacy in preventing suicide. These countries have shifted to a more cautious approach that prioritizes psychological testing and treatment.[30] In the United States, rather than seeking high-quality evidence, there continues to be high reliance on eminence-based treatment recommendations by medical societies and dismissal of the concerns raised by the European systematic reviews. The presumed authority of these medical associations fails to recognize that such pronouncements have generally come from small special interest panels within these organizations, where many members often have inherent biases and conflicts of interest.[31] While battles are currently being fought in courtrooms, state legislatures, and on social media, there remains an opportunity to more fully engage the scientific community in efforts to better understand the etiology of sex-discordant gender identity. This can aid in the design and conduct of high-quality clinical trials to test the relative safety and efficacy of novel approaches to treating gender dysphoria that preserve sexual integrity.

In acknowledging current errors in understanding sexual identity and misuse of basic scientific principles in efforts to promote an ideological agenda, it is essential to remember the inherent dignity of the people who experience a sex-discordant experience of gender identity. While their individual struggles may be unique and varied, all are ultimately seeking to be understood and loved. With appreciation that what is discovered by faith is not in contradiction with what can be learned by reason,[32] which is the rightful domain of science, the nature of this love can be illuminated in and through our sexuality. Beyond the reproductive purpose of sex is a much deeper reality of sexual complementarity that can only find fulfillment in that which exists outside of the individual male or female person.[33] Search for a scientifically sound solution to the problem of gender dysphoria will be well served by keeping sight of this reality.

[1] H. Breithaupt, “The science of sex”, EMBO Rep. 2012 May 1; 13 (5) 394. doi: 10.1038/embor.2012.45. PMID: 22546705; PMCID: PMC3343355; P.A. Aashta, T.C. Arbor, K. Krishan, Embryology, Sexual Development. 2022 Sep 8. In: StatPearls [Internet]. (Treasure Island, FL: StatPearls Publishing, 2022) Jan–. PMID: 32491533, accessed 1/15/23.

[2] C. Ainsworth, “Sex redefined”, Nature. Feb 19; 518 (7539) 288-91. doi: 10.1038/518288a. PMID: 25693544.

[5] F. Pinna, P. Paribello, G. Somaini, A. Corona, A. Ventriglio, C. Corrias, I. Frau, R. Murgia, S. El Kacemi, G.M. Galeazzi, M. Mirandola, F. Amaddeo, A. Crapanzano, M. Converti, P. Piras, F. Suprani, M. Manchia, A. Fiorillo, B. Carpiniello; Italian Working Group on LGBTQI Mental Health. “Mental health in transgender individuals: a systematic review”. Int. Rev. Psychiatry. 2022 May-Jun; 34 (3–4) 292-359. doi: 10.1080/09540261.2022.2093629. PMID: 36151828.

[7] J.D. Finley, A. Sodergren, C. Buskmiller, L.J. Welch, P.W. Lappert, P.W. Hruz,. Sexual Identity: The Harmony of Philosophy, Science, and Revelation. (Steubenville, OH: Emmaus Road Publishing, 2022).

[8] L. Sax. “How common is intersex? a response to Anne Fausto-Sterling”, J. Sex Res. 2002 Aug; 39 (3)174-8. doi: 10.1080/00224490209552139. PMID: 12476264.

[9] P.A. Lee, A. Nordenström, C.P. Houk, S.F. Ahmed, R. Auchus, A. Baratz, K. Baratz Dalke, L.M. Liao, K. Lin-Su, L.H. Looijenga III, T. Mazur, H.F. Meyer-Bahlburg, P. Mouriquand, C.A. Quigley, D.E. Sandberg, E. Vilain, S. Witchel; Global DSD Update Consortium. “Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care.” Horm. Res. Paediatr. ; 85 (3) 158-80. doi: 10.1159/000442975. Epub Jan 28. Erratum in: Horm. Res. Paediatr. ; 85 (3) 180.

[10] J.P. Van Batavia, T.F. Kolon, “Fertility in disorders of sex development: A review,” J. Pediatr. Urol.  Dec; 12 (6) 418–425. doi: 10.1016/j.jpurol..09.015. Epub Nov 3. PMID: 27856173.

[11] P.W. Speiser, R. Azziz, L.S. Baskin, L. Ghizzoni, T.W. Hensle, D.P. Merke, Meyer-Bahlburg, W.L. Miller, V.M. Montori, S.E. Oberfield, M. Ritzen, P.C. White; Endocrine Society. “Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline,” J. Clin. Endocrinol. Metab. 2010 Sep; 95 (9) 4133–60. doi: 10.1210/jc.2009-2631.

[12] A. Bhargava, A.P. Arnold, D.A. Bangasser, K.M. Denton, A. Gupta, L.M. Hilliard Krause, E.A. Mayer, M. McCarthy, W.L. Miller, A. Raznahan, R. Verma, “Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement”, Endocr. Rev. 2021 May 25; 42 (3) 219–258. doi: 10.1210/endrev/bnaa034. PMID: 33704446; PMCID: PMC8348944.

[14] DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, by the American Psychiatric Association, ISBN 0-89042-061-0, (Washington, DC: American Psychiatric Association, 1994).

[15] World Health Organization (WHO). (1993). The ICD-10 classification of mental and behavioural disorders. World Health Organization.

[16] K.D. Drummond, S.J. Bradley, M. Peterson-Badali, K.J. Zucker, “A follow-up study of girls with gender identity disorder”, Dev. Psychol. 2008 Jan; 44 (1) 34-45. doi: 10.1037/0012-1649.44.1.34. PMID: 18194003; T.D. Steensma, J.K. McGuire, B.P. Kreukels, A.J. Beekman, P.T. Cohen-Kettenis, “Factors associated with desistence and persistence of childhood gender dysphoria: a quantitative follow-up study,” J. Am. Acad. Child Adolesc. Psychiatry. 2013 Jun; 52 (6) 582-90. doi: 10.1016/j.jaac.2013.03.016. PMID: 23702447. D. Singh, S.J. Bradley, K.J. Zucker, “A follow-up study of boys with gender identity disorder”, Front. Psychiatry. 2021 Mar 29; 12:632784. doi: 10.3389/fpsyt.2021.632784. PMID: 33854450; PMCID: PMC8039393.

[17] K.J. Zucker, “The myth of persistence: Response to “Critical commentary on follow-up studies and ‘desistance’ theories about transgender and gender non-conforming children,” by Temple Newhook et al. (2018). International Journal of Transgenderism, 19 (2) 231–245.

[18] J. Rafferty, Committee on Psychosocial Aspects of Child and Family Health; Committee on Adolescence; Section on Lesbian, Gay, Bisexual, and Transgender Health and Wellness, “Ensuring Comprehensive Care and Support for Transgender and Gender-Diverse Children and Adolescents”. Pediatrics. 2018 Oct; 142 (4) e20182162. doi: 10.1542/peds.2018-2162. Epub 2018 Sep 17. PMID: 30224363. AMA APA.

[20] American Psychological Association. “Guidelines for psychological practice with transgender and gender nonconforming people”, Am. Psychol. Dec; 70 (9) 832-64. doi: 10.1037/a0039906. PMID: 26653312.

[21] A. Kumar, U.O. Amakiri, J.D. Safer, “Medicine as constraint: Assessing the barriers to gender-affirming care”, Cell Rep. Med. 2022 Feb 15; 3 (2) 100517. doi: 10.1016/j.xcrm.2022.100517. PMID: 35243420; PMCID: PMC8861822.

[22] J. Ristori, C. Cocchetti, A. Romani, F. Mazzoli, L.Vignozzi, M. Maggi, A.D. Fisher, “Brain sex differences related to gender identity development: genes or hormones?” Int. J. Mol. Sci. 2020 Mar 19; 21 (6) 2123. doi: 10.3390/ijms21062123. PMID: 32204531; PMCID: PMC7139786; E. Luders, F.J. Sánchez, C. Gaser, A.W. Toga, K.L. Narr, L.S. Hamilton, E. Vilain, “Regional gray matter variation in male-to-female transsexualism”, Neuroimage. 2009 Jul 15; 46 (4) 904-7. doi: 10.1016/j.neuroimage.2009.03.048. Epub 2009 Mar 31. PMID: 19341803; PMCID: PMC2754583; J.N. Zhou, M.A. Hofman, L.J. Gooren, D.F. Swaab, “A sex difference in the human brain and its relation to transsexuality”, Nature. 1995 Nov 2; 378 (6552) 68-70. doi: 10.1038/378068a0. PMID: 7477289.

[23] M. Ingalhalikar, A. Smith, D. Parker, T.D. Satterthwaite, M.A. Elliott, K. Ruparel, H. Hakonarson, R.E. Gur, R.C. Gur, R. Verma, “Sex differences in the structural connectome of the human brain”, Proc. Nat. Acad. Sci. Jan 14; 111(2) 823-8. doi: 10.1073/pnas.1316909110. Epub 2013 Dec 2. PMID: 24297904; PMCID: PMC3896179.

[25] N.W. Tien, D. Kerschensteiner, “Homeostatic plasticity in neural development”, Neural Dev. 2018 Jun 1; 13 (1) 9. doi: 10.1186/s13064-018-0105-x. PMID: 29855353; PMCID: PMC5984303.

[26] P.W. Hruz, “Deficiencies in scientific evidence for medical management of gender dysphoria”, Linacre Q. 2020 Feb; 87 (1) 34-42. doi: 10.1177/0024363919873762. Epub 2019 Sep 20. PMID: 32431446; PMCID: PMC7016442.

[27] S. Tyrer, B. Heyman, “Sampling in epidemiological research: issues, hazards and pitfalls”, B. J. Psych. Bull.  Apr; 40 (2) 57-60. doi: 10.1192/pb.bp.114.050203. PMID: 27087985; PMCID: PMC4817645.

[28] S.S. Coughlin, “Recall bias in epidemiologic studies”, J. Clin. Epidemiol. 1990; 43 (1) 87-91. doi: 10.1016/0895-4356(90)90060-3. PMID: 2319285.

[29] A.L.Nichols, J.K. Maner, “The good-subject effect: investigating participant demand characteristics”, J. Gen. Psychol. 2008 Apr; 135 (2) 151-65. doi: 10.3200/GENP.135.2.151-166. PMID: 18507315.

[32] Pope John Paul II, Encyclical Letter, Fides et Ratio, of the Supreme Pontiff John Paul II: To the Bishops of the Catholic Church on the Relationship between Faith and Reason. United States Catholic Conference, 1999.

[33] Pope John Paul II, Man and Woman He Created Them: A Theology of the Body. Translated by Michael Waldenstein. Second ed. (Boston, MA: Pauline Books & Media, 2006).