Gender Variant People

• Posted by Cristine Jennifer Shye. BL. B/acc December 7, 2017 4,165 views
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  Many anomalies such as AIS  (Androgen Insensitivity Syndrome) can arise causing inconsistent development between the various elements by which we know ourselves to be either a man or a women. Among the larger group embracing all these varieties, there is a small subgroup of individuals who experience gender varience The personal experience of this state is sometimes known as gender dysphoria (dysphoria means ‘unhappiness’). The impact of genetic and/or hormonal factors on their fetal development appears to cause parts of the brain to develop in a way which is inconsistent with their genitalia, gonads and, usually, with their chromosomes. This may give rise to another, rather different, example of XY women, that is, individuals whose visible physical sex appears to be that of a man, but whose brain has some female characteristics and whose gender identification is, therefore, that of a woman. Or, conversely, gender variance may occur the other way round. An individual having XX chromosomes and the visible physical sex of a female, may have some male brain characteristics and therefore, identify as a man. So the issue of one's gender identification, whether as a man or as a woman, or even neither (or both which occurs only rarely), is rooted in the brain, and is regarded by the individuals concerned, and is demonstrated by research, to be largely determined pre-birth and more or less stable thereafter.

   

  Transexualism

   

  Thus the experience of extreme gender variance is increasingly understood in scientific and medical disciplines as having a biological origin. The current medical viewpoint, based on the most up-to-date scientific research, is that this condition, which in its extreme manifestation is known as transexualism is strongly associated with unusual neurodevelopment of the brain at the fetal stage. Small areas of the brain are known to be distinctly different between males and females in the population generally. In those experiencing severe gender variance, some of these areas have been shown to develop in opposition to other sex characteristics and are, therefore, incongruent with the visible sex appearance^.

   

  Gender Variant Children

   

  Very rarely, children may express this incongruence between gender identity and the genital sex, but their discomfort is not always easy to identify. Symptoms of unease with the assigned gender role and the visible sex appearance are often only apparent to the individuals concerned and may not be understood even by them. If these children are unable to articulate their unease, their discomfort may grow through adolescence and into adulthood, as their families and society, in ignorance of their underlying gender identity, relentlessly reinforce gender roles in accordance with their physical appearance alone. However, some children are able to express a strong cross-sex identification, and sometimes insist on living in the opposite role. In particular, the increasing disgust with the development of secondary sex characteristics experienced by young people during puberty may be taken as a strong indication that the condition will persist into adulthood as transsexualism. Therefore, in carefully screened individuals, hormone blocking treatment may be given, before pubertal changes become apparent, so that these young people have more time to decide in which gender role they can achieve lasting personal comfort. There is no evidence that raising children in contradiction to their visible sex characteristics causes gender variance, nor can the condition be overridden by raising children in strict accordance with a gender role that is consistent with their visible sex. 
  
  Those who are not treated in adolescence may continue to struggle to conform; they may embark on relationships, marriages and parenthood in an attempt to lead ‘normal’ lives by suppressing their core gender identity. Ultimately, however, they may be unable to continue with the charade of presenting themselves as something they know they are not. The artificiality of their situation drives individuals to seek treatment to minimise the mismatch between the brain and the bodily appearance. They experience an overwhelming need to be complete, whole people and to live in accordance with their internal reality. Until this is achieved, the personal discomfort is such that it leads to great unhappiness and sometimes to suicidal feelings.

   

  I have been meaning to consolidate and review a rather juvenile thesis I wrote aged 16 after being told I might have a condition called Reifenstein's syndrome, a form of Androgen Insensitivity Syndrome (AIS) at the age of 15.

   

  Apart from having a penchant for dressing up in my sister’s clothes from an early age, I started noticing I was developing excess breast tissue at the age of about 14 - not the sort of breast tissue of a pre pubescent youth. More a soft feminine plumpness. AIS is not necessarily cognizant with gender dysphoria.

  After being taken to see numerous gender counselors, psychiatrists and gene specialists, finally one knew of someone else that was a specialist in AIS and Reifensteins syndrome, who referred me to the Gene clinic at Addenbrooks hospital in Cambridge. This is a rare condition, that in most cases, general GP’s and even gender therapists are unfamiliar with.

  Androgen insensitivity syndrome (AIS), also referred to as androgen resistance syndrome, is a set of disorders of sex development caused by mutations of the gene encoding the androgen receptor The set of resulting disorders varies according to the structure and sensitivity of the abnormal receptor.

  Most forms of AIS involve a variable degree of undervirilization and/or infertility in XY persons of any gender. A person with complete androgen insensitivity syndrome (CAIS) has a female external appearance despite a 46XY karyotype and undescended testes, a condition once called "testicular feminization" a phrase now considered both derogatory and inaccurate. Since 1990, major scientific advances have greatly expanded medical understanding and management of the molecular mechanisms of the clinical features of AIS.

  Importantly, advocacy groups for this and other intersex conditions have increased public awareness and spurred acceptance and understanding of the variable nature of gender identity. The value of accurate and scientifically detailed information for patients is now emphasized, with physicians no longer automatically recommending traditional surgical corrections, with elective options now viewed as a possible but no longer necessary intervention for ambiguous conditions.

  The incidence of complete AIS is about in 1 in 20,000. The incidence of lesser degrees of androgen resistance is unknown. It's been suggested by various authorities that it could be either more common or less common than complete AIS. Evidence suggests many cases of unexplained male infertility may be due to a mild degree of androgen resistance.

  Because the Androgen Insensitivity Syndrome gives rise to misleading between the genetic and the phenotypic gender, the convention is to designate a 46,XX individual as a genotypic female, and an 46,XY as a genotypic male. According to this convention, a person with Androgen Insensitivity Syndrome is a phenotypic female with a chromosomal genotype

  The Androgen Insensitivity Syndrome has been linked to mutations in AR, the gene for the human Androgen Receptor, located at Xq11-12 (i.e. on the X chromosome). Thus, it is an X-linked recessive trait, causing minimal or no effects in 46,XX people. Most individuals born with AIS have inherited their single X chromosome with its defective gene from their mother and may have siblings with the same disorder. Generally, inherited mutations effect siblings similarly, though different syndromes may occasionally manifest from the same mutation (carrier testing is now available for relatives at risk when a diagnosis of AIS is made in a family member).

  Over 100 AR mutations causing various forms of AIS have been recorded. The milder forms of AIS (4 and 5 in the list below) are caused by a simple missense mutation with a single codon/single amino acid difference, while complete and almost complete forms result from mutations that have a greater effect on the shape and structure of the protein.

  About one third of cases of AIS are new mutations rather than familial. A single case of CAIS attributed to an abnormality of the AF-1 coactivator (rather than AR itself) has been reported. Understanding the effects of androgen insensitivity begins with an understanding of the normal effects of testosterone in male and female development. The principal mammalian androgens are testosterone and its more potent metabolite, dihydrotestosterone (DHT).

  The androgen receptor (AR) is a large protein of at least 910 amino acids. Each molecule consists of a portion which binds the androgen, a zinc finger portion that binds to DNA in steroid sensitive areas of nuclear chromatin, and an area that controls transcription.

  Testosterone diffuses from circulating blood into the cytoplasm of a target cell. Some is metabolized to estradiol, some reduced to DHT, and some remains as testosterone. Both T and DHT can bind and activate the androgen receptor, though DHT does so with more potent and prolonged effect. As DHT (or T) binds to the receptor, a portion of the protein is cleaved. The AR-DHT combination dimerizes by combining with a second AR-DHT, both are phosphorylated, and the entire complex moves into the cell nucleus and binds to androgen response elements on the promoter region of androgen-sensitive target genes. The transcription effect is amplified or inhibited by coactivators or corepressors.

  Although testosterone can be produced directly and indirectly from ovaries and adrenals later in life, the primary source of testosterone in early fetal life is the testes, and it plays a major role in human sexual differentiation. Before birth, testosterone induces the primary sex characteristics of males. At puberty, testosterone is primarily responsible for the secondary sex characteristics of males.

  The most common cause of AIS are point mutations in the androgen receptor gene resulting in a defective receptor protein which is unable to bind hormone or bind to DNA. Prenatal effects of testosterone in 46,XY fetusIn a normal fetus with a 46XY Because the Androgen Insensitivity Syndrome gives rise to misleading between the genetic and the phenotypic gender, the convention is to designate a 46,XX individual as a genotypic female, and an 46,XY as a genotypic male. According to this convention, a person with Androgen Insensitivity Syndrome is a phenotypic female with a chromosomal genotype of 46,XY. karyotype, the presence of the SRY gene induces testes to form on the genital ridges in the fetal abdomen a few weeks after conception.

  By 6 weeks of gestation, genital anatomies of XY and XX fetuses are still indistinguishable, consisting of a tiny underdeveloped button of tissue able to become a phallus, and a urogenital midline opening flanked by folds of skin able to become either labia or a scrotum.

  By the 7th week, fetal testes begin to produce testosterone and release it into the blood. Directly and as DHT, testosterone acts on the skin and tissues of the genital area and by 12 weeks of gestation, has produced a recognizable male, with a growing penis with a urethral opening at the tip, and a perineum fused and thinned into a scrotum, ready for the testes.

  Evidence suggests that this "remodeling" of the genitalia can only occur during this period of fetal life; if not complete by about 13 weeks, no amount of testosterone later will move the urethral opening or close the opening of the vagina. For the remainder of gestation, the principal known effect of testosterone and DHT is continued growth of the penis and internal wolffian derivatives (part of prostate, epididymis, seminal vesicles, and vas deferens).

  Early postnatal effects of testosterone in 46,XY infant’s Testosterone levels are low at birth but rise within weeks, remaining at normal male pubertal levels for about 2 months before declining to the low, barely detectable childhood levels. The biological function of this rise is unknown. Animal research suggests a contribution to brain differentiation.

  Pubertal effects of testosterone in 46,XY children At puberty, many of the early physical changes in both sexes are androgenic (adult-type body odor, increased oiliness of skin and hair, acne, pubic hair, axillary hair, fine upper lip and sideburn hair).

  As puberty progresses, later secondary sex characteristics in males are nearly entirely due to androgens (continued growth of the penis, maturation of spermatogenic tissue and fertility, beard, deeper voice, masculine jaw and musculature, body hair, heavier bones). In males, the major pubertal changes attributable to estradiol are growth acceleration, epiphyseal closure, termination of growth, and (if it occurs) gynecomastia.
  Variations produced by androgen insensitivity.

  Although many distinct mutations have been discovered, the spectrum of clinical manifestations has been divided into six phenotypes, which roughly correspond to increasing amounts of androgen effect due to increasing tissue responsiveness. It should be emphasized that some affected persons will have features that fall between the phenotypes described.

  1. Complete AIS (CAIS): completely female body except no uterus, fallopian tubes or ovaries; testes in the abdomen; minimal androgenic (pubic or axillary) hair at puberty.

  2. Partial or incomplete AIS (PAIS): male or female body, with slightly virilized genitalia or micropenis; testes in the abdomen; sparse to normal androgenic hair; mild to partial(MAIS)

  3. Reifenstein syndrome: obviously ambiguous genitalia; small testes may be in abdomen or scrotum; sparse to normal androgenic hair; gynecomastia at puberty.

  4. Infertile male syndrome: normal male genitalia internally and externally; normal male body or possible female androgyny, normal virilization and androgenic hair; reduced sperm production; reduced fertility or infertility.

  5. Undervirilized fertile male syndrome: male internal and external genitalia with micropenis; testes in scrotum; normal androgenic hair; sperm count and fertility normal or reduced.

  6. X-linked spinal and bulbar muscular atrophy: normal or nearly normal male body and fertility; exaggerated adolescent gynecomastia; adult onset degenerative muscle disease.

  SYMPTOMS OF CAIS

  If a 46,XY fetus cannot respond to testosterone or DHT, only the non-androgenic aspects of male development begin to take place: formation of testes, production of testosterone and anti-müllerian hormone (AMH) by the testes, and suppression of müllerian ducts.

  The testes usually remain in the abdomen, or occasionally move into the inguinal canals but can go no further because there is no scrotum. AMH prevents the uterus and upper vagina from forming. The testes make male amounts of testosterone and DHT but no androgenic sexual differentiation occurs. Most of the prostate and other internal male genital ducts fail to form because of lack of testosterone action.

  A shallow vagina forms, surrounded by a normally-formed labia. Phallic tissue remains small and becomes a clitoris. At birth, a child with CAIS appears to be a typical girl, with no reason to suspect an incongruous karyotype and testosterone level, or lack of uterus.

  Childhood growth is normal and the karyotypic incongruity remains unsuspected unless an inguinal lump is discovered to be a testis during surgical repair of an inguinal hernia, appendectomy, or other coincidental surgery.

  Puberty tends to begin slightly later than the average for girls. As the hypothalamus and pituitary signal the testes to produce testosterone, amounts more often associated with boys begin to appear in the blood. Some of the testosterone is converted into estradiol, which begins to induce normal breast development. Normal reshaping of the pelvis and redistribution of body fat occurs as in other girls. Little or no pubic hair or other androgenic hair appears, sometimes a source of worry or shame. Acne is rare.

  As menarche typically occurs about two years after breast development begins, no one usually worries about lack of menstrual periods until a girl reaches 14 or 15 years of age. At that point, an astute physician may suspect the diagnosis just from the breast/hair discrepancy. Diagnosis of complete AIS is confirmed by discovering an adult male testosterone level, 46,XY karotype, and a shallow vagina with no cervix or uterus.

  Hormone measurements in pubertal girls and women with CAIS and PAIS are similar, and are characterized by total testosterone levels in the upper male rather than female range, estradiol levels mildly elevated above the female range, mildly elevated LH levels, normal FSH levels, sex hormone binding globulin levels in the female range, and possibly mild elevation of AMH. DHT levels are in the normal male range in CAIS but reportedly in the lower male range in PAIS. Interpretation of hormone levels in infancy is more complex and cannot be as easily summarized for this article. Androgen receptor testing has become available commercially but is rarely needed for diagnosis of CAIS and PAIS but more so for MAIS when ambiguity is more likely.

  To all intents and purposes, visibly at birth having normal genitalia I was perceived as a male. I received my test results from the Gene Clinic at Addenbrooks hospital in Cambridge 3 days after my 16th birthday, which I mentioned in my contribution to the then running article ''coming out'' in an earlier edition of the Tribune. I have recently been invited back to Addenbrooks to take part in DNA gene testing relating to my original gender dysphoria as recent studies indicate there might be links relating to what generally is considered a mental abnormality, and might in some cases actually be related to an abnormality in the make up of one’s DNA.

  © Cristine J Shye