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Intersexual Humanity – A Critique by Dr Eshan Dias




October 13, 2023 (Updated)


Interduction [sic]


Some contend and often assert that “gender” is synonymous with sex, frequently ingenuously, sometimes not, while others concede that sex is a biological reality and gender is a subjective even delusional socio-political construction which might even mean temperament or personality. To unveil and understand the distinction is capital since beyond its materiality, its implications are vast, the failure of which to grasp, and indeed wrestle with, lead to abysmal consequences. Clarity is required regarding biological sex and sociological gender, as well as regarding physiological disorders of sex and sexual development and of psychological disorders such as “gender” dysphoria and body dysmorphia.


The ideas of the gender spectrum, gender fluidity, gender transition, gender identity, gender expression, and deviant behaviours and lifestyles related to the gender mélange - at times considered as deriving from erotic or even romantic orientations and inclinations, need also to be understood, particularly with respect to the vigorous and militant systemisation of gender mainstreaming. Gender ideology, perilous in itself, has its political activists demanding privilege under the guise of gender equality that would eliminate associated and alleged gaps, biases, stereotypes, and discriminations - and the enlightened and the influential appear to be lapping up such square roots of -1 with abandon.


The “I” in the string of letters starting with the sodomic and polyamoric LGB of the rainbow sequence, is interposed inter Q & A presupposedly forming a group of those who possess ambiguous genitals - and perhaps also those who simply identify as such, if any do. Whether all who present abnormal genitalia wish to be included in this group or not, and what special rights are campaigned for, are separate matters. Questions may arise as to whether the material possession of spurious genitals, irrespective of the degree of malformation, empowers those thus possessed to establish a whimsical gender to identify into, and whether such biological phenomena - grounded in reality, provide a basis to formulate queer theories of gender. Of more importance is whether the spectrum of genital presentations ipso facto justify the theory of a spectrum of sexes that constitute the individuals of our species.


Sex


The sex of a human being specifies whether the individual in question is a male or a female. Genes, chromosomes, genomes, cells, tissues, organs and even physical characteristics and psychological traits might be referred to as male and female, or masculine and feminine. Secondary sexual characteristics such as facial hair, wide hips, muscularity, mammae, long vocal folds or the mensus, could be associated particularly with one sex than with the other. Likewise, even with tertiary sexual parameters such as a proficiency at chess, a nurturing instinct, spacial intelligence, vulnerability to Parkinsons’s disease, neurotism or an attraction to physics. However, a distinction needs to be made between these entities, processes, aptitudes and inclinations which, albeit usually at the extremes, can be sectioned sexually - and the sex of a human being.


Hermaphroditus of Greek myth was a fusion of a male and a female, who embodied both male and female attributes and qualities. Hermaphroditism in biology is the occurrence of both male and female reproductive organs in the same individual organism - and thereby of male and female gametes when sexually mature and if healthy, and it is the norm inter alia for most angiosperms, bryozoans and trematodes. Human individuals with evident genitalial ambiguity were called hermaphrodites.


Sex Origination


“The head of the spermatozoon binds to the zona pellucida, and its apical body the acrosome releases its contents that degrade it locally and thence the oocyte surface membrane the oolemma, creating confluence between the two cells. The oocyte is thenceforth penetrated by the haploid paternal gamete. Cytoplasmic continuity is enabled through this fusion of their membranes, and the two become one. Instantaneous electrical depolarisation of the membrane and subsequent morphological change in the zona pellucida triggered by cortical granule exocytosis into the perivitelline space acts to prevent a competing spermatozoon from gaining entry. This one that the two became is referred to as the primordial embryo and all the genetic material necessary for the new individual is now within a single plasmalemma. At this point in the process of fertilisation, a new male or female human being has been procreated, who did not exist before”1


Genes, chromosomes, genome


From the very instance of our origin, in the union of male paternal and female maternal gametes, we are either male or female in sex, depending on whether we inherit an X or a Y chromosome from our father. We cannot survive as a species, unless there are male and female gametes, produced in male and female gonads of male and female parents which unite to conceive of a male or female child. Human reproduction is not only bigametal, but only two mating types exist – male and female.


Further, the oogamic union of both father’s and mother’s gametes are requisite due to genetic imprinting2 during parental gametogenesis with epigenetic methylation tags which persist through the life of the individual begotten, whereby certain genes can only parent-specifically monoallelically be expressed in the offspring.


Early Sexual Development


Gonads/ genitals


While other factors expressed earlier primes gonadal development towards a testis-forming pathway in males, during late embryohood when males are nigh seven weeks old, a unique protein transcription factor that is encoded by the sex determining region Y (SRY) gene on the short arm of the Y chromosome, in a complex interaction with DAX1 which is required for ovary formation and found on the X chromosome, activates the bipotential undifferentiated proto-gonad which has developed from the genital ridge formed earlier, into specialisation into testis.


Many factors and mechanisms of gonadogenesis are yet unknown, and several autosomal genes such as follistatin (FST) are known to be necessary for proper ovary formation. These processes constituting testis and ovary organogenesis, dependent particularly on presence or absence of paternal genes, is misleadingly called “sex determination”, since it is a gonadal determination driven by already determined genetics – although the term may be applicable to some species of reptiles, fish or insects who do not possess a stable genetic sex determination mechanism.


Histology/ Anatomy


The developing testis in males thereafter secretes hormones that trigger the structural differentiation of internal and external genital organs and ducts, including development of the epididymis, vas deferens and seminal vesicles, and phallus growth and testical descent. The absence of testosterone and anti-Müllerian hormones (AMH) from testicular tissue, were testis present, prevents regression of Müllerian structures and enables development of female genitalia such as the labia, clitoris, vagina, uterus and the oviducts. These processes which are governed by hormones, are misleadingly called “sex differentiation”, since it is a genitalia differentiation. The differentiation of external genitalia proceeds during foetal development.


Sexual Maturity


Secondary sexual characteristics, clearly distinct from the primary characteristics which are the genitalia inclusive of the gonads, and reproductive capability, develop consequent to the onset of puberty.


Errors


In the multi-factoral, multi-dimensional interlinked coordinated complexity of processes that constitute the awesome phenomena of and preceding our origination, and of consequent growth and development, mistakes and defects do occur. Children conceived with more grievous conditions on account of these, often die before birth3, and those who are born may sustain a plethora of disorders, some of which are related to sexual development, of which some manifest dubiety with regard to sex in the observation of the external genitalia, and some individuals may be justifiably referred to as ambisexual or even mixtosexual. The rare instances of human beings being born with congenital biological sex-ambiguous conditions of various types and degrees – whether observed genitalial or ingrained genetic, arise due to several combinations of causes.


Ambiguous external genitalia may be visually observed prenatally or at birth. When not phenotypically obvious and other suggestive symptoms are absent, disordered sexual development conditions may be diagnosed or become evident due to irregularities such as precocious or retarded adrenarche, or during puberty on account of gynaecomastia or scarcity of pubic hair. Likewise in adulthood, diagnosis may take place when investigating infertility, a prevalent symptom. Apart from anatomically evident, palpable and histologic information, hormone level measurements - such as of Sertoli and Leydig cell function, can be indicative, and imaging, cytogenic analysis and molecular studies can provide further diagnostic and etiological information.


Phenotypic abnormality results from irregularity in hormone-driven processes, and these in turn derive from cytogenetic irregularities some of which regulated gonadogenesis. Diagnosis for the etiologies of the pathophysiological condition faced by individuals who present these anomalous phenotypes is important where determination of treatment is concerned, and also to discern their sex. Other disease conditions such as inter alia renal failure, mental retardation, tumorigenesis, and α-thalassemia, may also occur concurrent with disordered sexual development and these traits - often associated with particular genes or chromosomal conditions, might be collatable and define respective syndromes.


Terminology


Scotsman James Young Simpson in 1849 published a treatise on hermaphroditism in the Cyclopaedia of Anatomy and Physiology where, while acknowledging many preceding classifications ancient and modern, he classified human hermaphroditic malformations into “true” and spurious hermaphroditism, including respective sub-divisions. The Germanic Theodor Albrecht Edwin Klebs in 1876 in his Handbuch de Pathologischen Anatomie, proposed a similar but different system, and employed the term pseudo-hermaphroditism (scheinzwitterbildung) in males and females. Definitions were established based on histological criteria related to internal and external genitalia to assess the heterogeneity of phenotypes.


In clinical literature proceeding 2005, abnormal and ambisexual external genitalial presentations and mixtogonadal conditions remain recognised but have been absorbed within the umbrella of Disorders of so-called Sex Development (DSD), which nomenclature admits congenital conditions of atypical chromosomal, gonadal or anatomical development4, and confers new names to them. The scope of the term DSD extends diagnosis beyond histology and anatomy to cytogenetic and endocrine criteria, and focus on etiology over phenotype, although comparable presentations occur due to multiple causes and likewise common causes may present a variety of phenotypes. DSD encompasses isolated urogenital anomalies as well as multi-organ syndromes. Much remains unknown or not understood and perhaps half of the DSD conditions cannot yet be molecularly explained.


Within this definition of DSD and its gonadal deemphasis, sex chromosomal abnormalities such as the aneuploid chromosomal constitutions that give rise to Trisomy X, Klinefelter5 and Jacobs syndromes and their variants, and the multi-etiological Turner6 syndrome, are included. Sex chromosome aneuploidies generally do not present ambiguous genitalia and ambiguity regarding the sex of the individual, nor are they sexual development disorders of a gonadus disparilis nature. However, individuals with Klinefelter and Jacobs syndrome may present gynaecomastia in late puberty due to hormonal imbalance, and mosaical forms of Turner and Klinefelter karyotypes may present ambiguous genitalia and may give rise to both testicular and ovarian tissue formation in a single individual.


With pathophysiological conditions concerning sexual development, medical even surgical intervention may be meet in extreme situations. It might even be prudent to confer a sex for practical rearing and social purposes. Indeed, the expression “sex assigned at birth” is only meaningful with reference to phenotypic hermaphrodites, but it remains an assignation unless the assignment is found to concur sufficiently with the ontological reality.


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 terminology7. 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. Cryptic8 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 DSD9, 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 males10. 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 identified11.


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 mosaicism12 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 popular13.


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 arrhythmia14, 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 gonads15, 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.


On the “Dr Eshan is Curious” substack:

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Notes:

  1. https://dreshandias.substack.com/p/when-do-i-begin

  2. https://www.geneimprint.com/site/genes-by-species.Homo+sapiens.imprinted-All

  3. Monosomy X, a chromosomal abnormality with a 45,X karyotype is commonly found in children aborted spontaneously.

  4. Lee PA, et al., Consensus statement on management of intersex disorders. Pediatrics. 2006;118: E488–E500.

  5. Males have additional copies of the X chromosome in Klinefelter syndrome, usually 47, XXY, and more rarely 48, XXXY and 49, XXXXY. Mosaical conditions such as 47,XXY/ 46,XY and 47,XXY/46,XX also do arise.

  6. These symptoms predominantly honour the American Turner, but historically and in other geographies recognise also Ullrich of Germany, the female Bonnevie of Norway, and even Šereševskij of Russia and Morgagni of Italy

  7. 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.

  8. Cells that can be stimulated to divide rapidly in culture such as skin fibroblasts and peripheral lymphocytes are frequently used in karyotyping.

  9. 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.

  10. XY OT-DSD is reported as ~7% of the sum.

  11. Disorders of Sex Development, Ch. 16 of Yen & Yaffe’s Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, 8th Ed, 2018.

  12. 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/)

  13. https://open.substack.com/pub/dreshandias/p/embryonic-engineering?r=1qgpbn&utm_campaign=post&utm_medium=web

  14. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.319893; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC101202/pdf/20011200s00005p265.pdf

  15. DeCasien et al., Biology of Sex Differences (2022) 13:43

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