Intersexual Humanity?
Part II (of 2): Exploration and Conclusion
{Part I is here which described early human development processes, the problem of gender as opposed to sex, and the nomenclature associated with the pathophysiology of sex and sexual development}
Spurious Genitalial Hermaphroditism
Pseudo-hermaphroditism was recognised when the gonads appeared to match the individual’s sex as informed by genetics, but presented contradictions in morphology, particularly in the external genitalia. Males may present micropenis, perineal hypospadias, oligospermia and cryptorchidism, and females may present clitoromegaly, labial hypoplasia and vaginal and uterine malformations. The extreme manifestation of phenotypical hermaphroditism is when an entirely sex-discordant phenotype is presented. This phenotypic reversal or transverse hermaphroditism is misleadingly referred to as “sex reversal”.
Pseudo-hermaphroditism in males and females somewhat corresponds to 46,XY DSD and 46,XX DSD respectively in the prevailing terminology[1]. Clinical classification is hindered by the multiple etiologies that give rise to similar phenotypes.
Hypo-Virilisation of Males
Male pseudo-hermaphroditism or under-virilisation in a genetically 46,XY individual may take several forms, and present a broad variability in phenotype.
Disorders in testicular development (gonadal determination)
Mixed male gonadal dysgenesis (GD) usually is when one gonad exists as a fibrous streak and the other is partially dysgenetic or a normal testis. 45,X/46,XY mosaicism is a frequent cause for mixed GD, as is a 46,Xi(Yq) karyotype. Partial gonadic dysgenesis is when both gonads are not entirely dysgenetic or streak. The internal genitalia show varying degrees of Wolffian and Müllerian development, and external genitalia is ambiguous. Pure or complete gonadal dysgenesis result in streak gonads and a female phenotype (Sywer’s syndrome). Most patients will be diagnosed during adolescence on account of primary amenorrhoea.
All causes of testicular dysgenesis are not known but mutations or deletions of genetic material in the Y chromosome such as SRY, steroidogenic factor 1 (SF1), SRY-box transcription factor 9 (SOX9) and MAP3K1, duplications in WNT4 and DAX1, and in autosomal genetic modifiers, may account for some incidences.
Testicular regression or “vanishing testes” syndrome, whose etiology is yet unknown but is suspected to be triggered by prenatal vascular thrombosis or testicular torsion after initial testes determination, presents variably developed internal and external genitalia and may occasionally present a female phenotype.
Disorders in androgenic function and genitalial diffentiation
Typical female phenotypes and those of undervirilisation can also result from defects in steroidogenic enzymes such as testosterone, its more potent androgenic derivative dihydrotestosterone (DHT), among others. Mutations in Sertoli cell products such as AMH or its receptor, in the synthesis and action pathways of testosterone, of upstream regulators of testosterone production are some known causes.
In the presence of normal gonads and of normal steroid biosynthesis, mutations in steroid hormone receptors can mute the effects of steroids on tissues. Mutations in the androgen receptors (AR) on the X chromosome result in androgen insensitivity syndrome (AIS). In the case of complete AIS (CAIS) a female phenotype is presented. Luteinising hormone receptor defects, and anti-Müllerian hormone and hormone receptor defects due to which a uterus and fallopian tubes may also be present, are other known factors.
Hyper-Virilisation of Females
Female pseudo-hermaphroditism is presented due to over-virilisation in a genetically 46,XX individual which causes external genitalial masculinization.
Disorders in gonadal determination and development
Testis-activating genes (such as SRY, SOX9, SOX3) could be present in a female due to translocation of a section of the Y chromosome on to an X chromosome, or to an autosome. This can cause testicular development (called testicular DSD), which could result in a male phenotype (de la Chapelle syndrome) and all degrees of genital ambiguity.
When SRY gene is not detected, the presence of SOX9 or SOX3 promoter microduplication or microdeletion may be causative. Cryptic[2] mosaicism of Yp could be a factor, and chimerae may be suspected especially if the child was conceived in vitro.
Disorders in androgenic function and gentialial differentiation
High levels of intrauterine androgens or of androgenic precursors result in mascularisation to various degrees of the internal and external genitalia in female foetuses. Where gonads and Müllerian structures are developed normally, genital ambiguity may be caused by virilising forms of congenital adrenal hyperplasia (CAH) resulting from various gene mutations.
Foetal-placental aromatase deficiency results in elevated levels of androgenic precursors that cause virilization of mother and her foetal daughter, and infertility in her sons. Maternal ingestion or incorporation of androgens - for the purpose of “birth control” or otherwise, have also caused virilisation of female foetuses as have hormonally active maternal tumours such as luteomas, and the rare cystic ovarian condition hyperreactio luteinalis.
Mixtogonadal Hermaphroditism
The historically and histologically defined “true” hermaphroditism may be recognised within the term ovotesticular DSD[3], where both testicular tissue inclusive of seminiferous tubules or spermatozoa, and ovarian tissue inclusive of ovarian follicles or corpora albicantia is present in the individual. This may occur with the presence of one ovary and one testis (lateral), or when one (unilateral) or two ovotestis (bilateral) form within which both types of gonadal tissue are juxtaposed in that single organ. The individual may have XY or XX karyotype, the incidence being rarer in males[4]. External genitalia are usually ambiguous, though not always, and the condition may be non-syndromic.
All causes are not known, and the distinctions between genotypes or classes of human hermaphroditism does not imply that the causes for the range of conditions are distinct. In females, OT-DSD may occur due to translocation of fragments of a Y chromosome containing SRY onto an X chromosome or an autosome during paternal gametogenesis, as predominant in cases of XX testicular DSD. Duplications in SOX9 and SOX10, mutations in R-spondin1 (RSPO1), SOX3, nuclear receptor 5A1 (NR5A1), WNT4, WT1, NR2F2 may, among other factors, be determinant. In males, deletions in DMRT1, mutation in SRY and MAP3K1 have been identified[5].
In addition to genetic factors, sex chromosome disorders such as incidences of 46,XX/46,XY, 46,XX/47,XXY, and 45,X/46,XY conditions due to mosaicism[6] where some cell lines contain Yp material, or to chimerism, account for a third of instances investigated, although it might be greater if the mosaicism remained undetected. Chimerism-related DSD and genetic imprinting disorders can be expected to increase as embryonic engineering for human reproduction such as the employment of IVF technology becomes more popular[7].
Psychological disorders
Psychological disorders such as gender dysphoria - inclusive of the rapid onset version, body dysmorphia, bulimia nervosa and anorexia nervosa whether considered as individual cases or adolescent psychological epidemics, are indeed disorders of a psychological nature, mostly incident with individuals with no morphological irregularities. It suffices to mention that an anorexic girl is not fat any more than a gender dysphoric girl is male, and what is required is therapy not affirmation - and that the UN does not bully sovereign governments to legislate the right of ideologues to persecute anyone who says that she looks emaciated.
Intersexual and Intersectional
Some may contend, considering that sex-related criteria such as breast size, voice pitch, protectiveness of sons, mathematical aptitude, proclivity to aggression and the inclination to rock a doll vary across the population and may overlap between men and women, that a basis exists to suggest that everyone is intersexual – by nurture or nature, or a combination thereof. However, while an intersexual variation on the value of a parameter may exist, the sex of an individual cannot be defined through the deployment of such criteria because such characteristics while related, are not definitive.
Furthermore, while - albeit adjusted, values of body fat proportions and its transcorporal distributions in the population may be employed to declare intersexuality, such a spectrum might be discordant with that of lung capacity, vasopressin fibre density within the brain’s lateral septum and the incidence and prevalence of certain cardiac arrhythmia[8], ad infinitum, leading to a complex matrix rather than a spectrum of intersexuality that finally defines the individual rather than his or her sex.
Point
Human beings vary in innumerous ways, not just eye colour, nose shape, archery skill or the capacity to appreciate Strauss’ An der schönen blauen Donau. Such intra-species variations do not suggest a myriad of species, specific to each factor or otherwise. Neither does suffering from phenylketonuria or Huntingdon’s disease make the patient less human on some humanically diverse spectrum. Likewise, an overlapping variation in the propensity to engage in lethal violence does not make us inter-special with chimpanzees, nor does the existence of a minority of individuals with sickle cell disease suggest that blood oxygen capacity is intervolumetric and lies on a spread outside of 1.34 ml O2/g(haemoglobin).
Bricks are cuboid and tyres are round, and chips in the bricks and nails in the tyres do not create new classes of shapes for these items to belong to, not even when the brick has all its edges chipped off. Syphilis and gonorrhoea do not extend the nature of human skin to include the presence of a variety of pustules, which is a biological disease condition. In as much as a man with a cleft lip is a man, and a woman with a six-toed foot is a woman, they remain men and women with biological disorders - albeit not in the area of sex or sexual development.
Even in sexual development, in the instances of genitalial, gonadal and genetic variations or in abnormalities and faults related to puberty and fertility - with their roots in meiotic or post-conception chromosomal or genetic aberrations, the sex of the individual concerned as determined at their origin, is in most cases knowable through thorough karyotyping. Indeed, irrespective of gonadal differences, males and females have constitutional differences in the operation of genes which exert genome-wide regulatory effects that are not mediated by the gonads[9], and this may explain the difference, inter alia, between male and female immunoreactivity.
Ambiguity does arise in the ascertainment of an individual’s sex, in the inherent cases of male/female chimerism, perhaps in monosomy-related mosaicism, and arguably even when some Y translocation has occurred. However, situations where determination of the individual’s sex as male or female is not possible, as much as those conditions where it is possible but the histological outcome is discordant, are all indeed deviations, all of a biological pathophysiological - not sociological, political or ideological, nature, and does not repudiate the reality of a dioecious and thereby gonochoric species.
Irrespective of what defects or errors were encountered at syngamy or thereafter at any time during our lives, that could have caused an inflationary dissipation of even the idea of sex, the stable genetic sex determination enabled during meiotic gametogenesis and requisite bigametal fertilisation ensures that rectification occurs in every cycle of reproduction to conserve the two sexes and even require a father and mother for the purpose on account of persistent epigenetic imprinting. This natural cyclic correction or regeneration of sex-related degeneration - even chaos, that may occur during the course of each generation, ensures that human beings will perdure as man and woman, made for each other.
[1] The incidence of live births is estimated at 1 in 20,000 for 46,XY DSD, and 1 in 14–15,000 (mainly congenital adrenal hyperplasia) in 46,DSD . Pang SY, et al., Pediatrics. 1988; 81:866–874.
[2] Cells that can be stimulated to divide rapidly in culture such as skin fibroblasts and peripheral lymphocytes are frequently used in karyotyping.
[3] OT-DSD is a subset of DSDs with incidence estimated at circa 1 in 100,000 live births, or in 2-10% of all DSD (Kilberg, M. et al., Pediatr Endocrinol Rev. 2019 17(2), 110–116). 1 in 83,000 (or 0.0012%) live births is a commonly quoted figure.
[4] XY OT-DSD is reported as ~7% of the sum.
[5] Disorders of Sex Development, Ch. 16 of Yen & Yaffe’s Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, 8th Ed, 2018.
[6] Genetic mosaicism describes the presence of two or more cell lineages with different genotypes arising from a single zygote due to a post-zygotic mutation in a single individual. In contrast, distinct cell lines derived from different zygotes defines chimerism. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615857/)
[7] https://open.substack.com/pub/dreshandias/p/embryonic-engineering?r=1qgpbn&utm_campaign=post&utm_medium=web
[8] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.319893; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC101202/pdf/20011200s00005p265.pdf
[9] DeCasien et al., Biology of Sex Differences (2022) 13:43