That is the proposal of a new Gendercare Debate about Gender Questions:

Transsexual GD (Gender Dysphoria) may be related to MAIS (minimum androgen insensitivity syndromes), sometimes?

Waleria Torres,MS,PhD and Pedro Jurberg,PhD say it possibly may be. What do you think about?

Read Torres & Jurberg paper, presented at the 15th World Sexology Congress at Paris, 2001, and comment it. Say us what you think about the possibility the authors suggest!

Fill the form below, to send us your opinion!

Thank you

Gendercare.com

PAIS and MAIS Ligand-Selective and the Organic Ethiology of Gender Dysphorias

By Wal Torres# & Pedro Jurberg *

# Wal was a MS in sexology candidate, at UGF-Rio, Brazil
* Pedro Jurberg,PhD, is a neurobiologist from Instituto Oswaldo Cruz, Rio, Brazil.



Copyright © 2001-2002 by Genderhealth.net. All rights reserved.

Abstract:
Gender may not be defined anymore only by genitals and sex of rearing as determining factors: after David Reimer's revelation of the truth about what he suffered oppressed by sex of rearing "therapy", we need to renew our gender criterias. We propose the neuro-psychical identity as a new gender main criteria, and that gender is independent of the genital conformation because the sex hormone that determines genital external conformation is DHT, thru its action over the androgen receptor AR, but testosterone-T is the main responsible for the neural gender organization in humans. The gender discord between those two biological systems may occur, generating the dysphoria, naturally or thru a genital surgery (as in David Reimer's case). It is important to study the hormone-selective binding characteristics and expression (T-AR and DHT-AR) to know if that action in mild androgen insensitivity syndromes-MAIS and partial syndromes-PAIS explain some dysphoric situations in transsexuals (MAIS) and intersexuals (PAIS). A diagnosis test for children and youths may be developed, and gender understanding must be renewed.


Key Words: Gender identity/ gender dysphorias/ androgen insensitivity syndromes/ intersex/ transsex.






The androgen receptor (AR) is a ligand-activated transcription factor that mediates male sexual development. AR binds the two biologically active androgens, testosterone(T) and dihydrotestosterone(DHT), with high affinity (Zhou et al 1995b). AR is not tissue or ligand specific, but its action is ligand dependent. There is a database (Gottlieb et al,1998) of AR mutations. Despite AR being not ligand specific, its action may be ligand-selective. Sometimes both ligands T and DHT are uneffective; sometimes DHT is less effective; sometimes T (Gottlieb et al, 1999) .

In PAIS and CAIS (complete AIS), the action of DHT-AR is abnormal (it generates genital malformations- levels 2 to 7 in Quigley's scale--- see Quigley et al 1995); in MAIS maybe there is no problem with DHT-AR (they don't show any genital malformation- level 1 in Quigley's scale), but possibly T-AR may have important abnormalities (they show undervirilization: gynecomastia, or small penis, and/or a dysphoria, etc.). The abnormalities in T-AR are less visible and less studied than DHT-AR, because they mediate--- during fetal stage--- "more invisible processes" (Zhou et al,1995b), in more invisible tissues.

Some genital malformation or intersex don't generate gender dysphorias. Gender dysphoria means "to have an uneasiness with its genitals". CAIS don't generate dysphorias, because all tissues remain female and there is no inner discord. Some PAIS and MAIS cases also don't generate dysphorias. Gender dysphorias happens when there is a gender discord between genital and neural tissues. That situation may happens:

(1) When baby boys have their genitals mutilated, or micropenis, and are surgically transgenitalized to females and reared as girls. For example, the John/Joan case (David Reimer's), described by Nussbaum,2000;Diamond & Sigmundson,1997; Fausto-Sterling,2000; Colapinto,2000;

(2) when happens the discord between the neural gender (male) with ambiguous (female like) genitals, as in Imperato McGinley's syndromes: recognized as girls, reared as girls in all cultures and continents, later they show they are boys;

(3) some PAIS situations, when the genitals are more female, but the neural male (in most PAIS cases there is harmony between genital and neural gender, both female or male);

(4) True hermafroditism when the genital option (by surgery decision made by adults: parents, psychiatrists or surgeons) is not in accord with the child neuro-psychical gender identity (showed later by the child expression and living);

(5) "transsexuals", when the neural and genital gender are naturally in radical discord, without any visible genital external conformation problem.

How we may evaluate those situations?

What could be a good criteria?

John Money's criteria (genital conformation and sex of rearing --- see Money & Ehrhardt 1972; Money & Tucker 1975) really isn't a good criteria: the true story of David Reimer show us John Money's model of gender identity formation was a fake and not the reality (see Diamond 1996; Diamond & Sigmundson 1997; Colapinto 2000; Fausto-Sterling 2000) --- Money and his co-workers wrote and published their opinions and not what the patient (David Reimer) really lived as gender identity, as truth-they ignored the patient's reality, publishing their opinions as truth and unfortunately being believed: they trapped doctors, sexologists and psychologists.

Considering:

(a) Our neural organization has its congenital and irreversible gender determined in a neuroendocrinal way (Imperato McGinley et al, 1979; Bonsall & Michael 1989; Resko et al 1988; McEwen, 1994, Zhou et al, 1995a; Kruijver et al, 2000);

(b) That gender neural organization generates in the foetus and baby a psychical gender identity as an emotional priming (see Damasio 1994; Torres & Jurberg 2000; and Torres & Jurberg in other article in this volume); and that

(c) rearing, culture, hormones at puberty: modulate, inhibit or reinforce, but don't determine the gender of our identity (Imperato McGinley1979; Wilson,JD, 1999);

we propose as a 1st gender classification criteria:

what determines the neural gender is prenatal T as what determines the external genitals gender is prenatal DHT: in humans as in other primates (Bonsall & Michael 1989, Resko et al, 1988). The gender identity is determined by the dynamic complex evolution and psychical expression of that neural differentiation (see the other article of Torres & Jurberg in this volume).

To evaluate properly gender in transsexual and intersexual dysphorics it is important the selective action of T-AR and DHT-AR in PAIS and MAIS, researching functional activity and gene expression not only of DHT-AR and artificial steroids-AR, but also T-AR (see Gottlieb et al 1999).

What we may today do in mosaic situations? In the genital tract (DHT-AR action) we may know , but in the neural (T-AR)?

We propose as a 2nd gender classification criteria:

in complex situations: wait the child own manifestation thru its neural system of who it is, boy or girl: they have the best neural sensor possible: their selves .

Whe propose a 3rd gender classification criteria:

When happens a dysphoria in a genetically male child, it would be important to study the child in the molecular level, with or without genital malformations , when it is feasible --- or wait and believe in the identity showed by the child.

Those 3 criterias may prevent dysphorias

when there are genital malformations, and a test procedure to evaluate dysphorias in children may be developed. When malformations don't happen we may not prevent, but we may diagnosis soon (the child show a dysphoria between 5 to 8 years old if with liberty and no social repression --- as a "sissi boy" or "effeminate gay boy", for example), and correct the children as soon as possible--- beginning with 10 to 12 years old at least, before the child will be too traumatized by society (see Cohen et al, 1997) and the body structure defformed by hormones.

The ligand-selective test may prevent consequences. If not, we will need to wait that the victim show its identity freely, before any surgery and final legal gender classification is irreversibly d etermined. It is better to sacrifice family and society, delaying the social and civil legal decision --- as Freitas, 1998 proposed --- knowing that doing this way we will prevent some children sufferings.

The ethical position we support today is:

don't define anymore gender in a rash, heteronomous and authoritary way, because that rash action may mutilate children, and originate dysphorias --- see David Reimer's and Cheryl Chase's stories and arguments (Fausto-Sterling 2000; Colapinto 2000). Therapists and surgeons know gender dysphorics by the outside only --- thinking they have problems to understand reality (see Mormont, Michel, Wauthy, 1995), when they are the only to really know and live themselves by the inside, knowing their true reality (see Freitas 1998).

Today, no result or fact is in contradiction with our 3 criterias; but first of al we need a positive confirmation of them from lab gene expression results in PAIS and MAIS intersex and transsex --- and to do that we need a molecular endocrinology lab to continue our project .

References:

ALLEN,LS; HINES,M; SHRYNE,JE; GORSKY,RA (1989)---Two sexually dimorphic cell groups in the human brain, Journal Neuroscience 9(2), 497-506, 1989;

BONSALL,RW & MICHAEL,RP (1989)--- Pretreatments with 5alfa dihydrotestosterone and the uptake of testosterone by cell nuclei in the brains of male rhesus monkeys, Journal Steroid Biochemistry, 33(3),405, 1989;

CLARK,AS; MAcLUSKY,NJ; GOLDMAN-RAKIC,PS (1988)--- Androgen binding and metabolism in the cerebral cortex of the developing rhesus monkey, Endocrinology, 123(2),932,1988;

COHEN, de RUITER,C; RINGELBERG,H; COHEN-KETTENIS,PT (1997)--- Psychological functioning of adolescent transsexuals: personality and psychopathology, Journal of Clinical Psychology, 53(2), 187-196, 1997;

COLAPINTO,J (2000)--- As Nature Made Him --- Portuguese translation: Sexo Trocado- a hist�ria real do menino criado como menina, Ediouro, 2001;

DAMASIO,AR (1994)---Descarte's Error--- Portuguese translation: O erro de Descartes,, Cia das Letras, 1996;

DIAMOND,M (1996)--- Prenatal predisposition and the clinical management of some pediatric conditions, Journal of Sex & Marital Therapy, 22(3) 1996;

DIAMOND,M & SIGMUNDSON, HK (1997)--- Sex reassignment at birth: long-term review and clinical implications, Archives of Pediatric Adolescent Medicine. 151, 298-304, 1997;

EHRHARDT,AA & MEYER-BAHLBURG,HFL (1981)---Effects of prenatal sex hormones on gender related behavior---Science, v211, pp1312, 1981.

FAUSTO-STERLING,A (2000)---The Five Sexes, Revisited, The Sciences, 19-23,July/ August 2000;

FREITAS,MC (1998)---Meu Sexo Real: a origem inata, som�tica e neurobiol�gica da transexualidade, Editora Vozes, 1998;

FREUD,S---3 ensaios sobre a teoria da sexualidade (1905), Ed. Stand. Bras., vol VII, Imago,1972;

GOTTLIEB,B; LEHVASLAIHO,H; BEITEL,LK; LUMBROSO,R; PINSKY,L; TRIFIRO,M (1999) --- The androgen receptor gene mutation database, Nucleic Acids Research 26(1),234, 1998;

GOTTLIEB,B; PINSKY,L; BEITEL,LK; TRIFIRO,M (1999)---Androgen Insensitivity, American Journal of Medical Genetics (Semin. Med. Genet.) 89: 210-217, 1999;

IMPERATO-McGINLEY,J; PETERSON,RE; GAUTIER,T; STURLA,E (1979)--- Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5-alfa-Reductase deficiency, The New England Journal of Medicine, 300(22) 1233-1237, 1979;

KRUIJVER,FPM; ZHOU,JN; POOL,CW; HOFMAN,MA; GOOREN,LJG; SWAAB,DF (2000) --- Male to female transsexuals have female neuron numbers in a limbic nucleus, The Journal of Clinical Endocrinology and Metabolism, 85(5), 2034-2041, 2000;

McEWEN,B (1994) --- How do sex and stress hormones affect nerve cells? Annals New York Academy of Sciences, 1-18, 1994;

MIGEON,CJ; BROWN,TR; LANES,R; PALACIOS,A; AMRHEIN,J�; SCHOEN,EJ (1984) --- A clinical syndrome of mild androgen insensitivity, Journal of Clinical Endocrinology and Metabolism, 59(4), 672-678, 1984;

MONEY,J; HAMPSON,JG; HAMPSON,JL (1955)---Hermafroditism: recommendations concerning assignmentt of sex, change of sex, and psychologic management, Bulletin of the Johns Hopkins Hospital 97, 284-300, 1955;

MONEY,J & ERHARDT,AA (1972)---Man and woman; boy and girl: The differentiation and dimorphism of sexual identity from conception to maturity, Johns Hopkins University Press, 1972;

MONEY,J & TUCKER, P (1975) --- Sexual signatures: on being a man or a woman, Portuguese translation as " Os pap�is sexuais"by Editora Brasiliense, 1981;

MONEY,J (1994)--- The concept of gender identity disorder in childhood and adolescence after 39 years, Journal of Sex & Marital Therapy, 20 (3), 163-177, 1994;

MORMONT,C; MICHEL,A; WAUTHY,J --- Transsexualism and Connection with Reality: Rorschach data, in Rorschachiana - Yearbook of the International Rorschach Society , Hogrefe & Huber Publishers, vol 20, pg 172-187, 1995;

NEWMAN,SW (2000)--- The medial extended amigdala in male reproductive behavior: A node in the mammalian social behavior network, Annals of the New York Academy of Sciences, 242-257, 2000;

NUSSBAUM,E (2000)--- A question of gender, Discover Magazine, Jan 2000;

OGAWA,S; LUBAHN,DB; KORACH,KS; PFAFF,DW (1997)--- Behavioral effects of estrogen receptor gene disruption in male mice, Proceedings of the National Academy of Sciences of the USA, 94,1476-1481, 1997;

OGAWA,S; ENG,V; TAYLOR,J; LUBAHN,DB; KORACH,KS; PFAFF,DW (1998b)--- Roles of estrogen receptor-alfa gene expression in reproduction related behaviors in female mice, Endocrinology, 139 (12), 5070, 1998b;

OGAWA,S; WASHBURN,TF; TAYLOR,J, LUBAHN,DB; KORACH,KS; PFAFF,DW (1998a)--- Modification of testosterone dependent behaviors by estrogen receptor-alfa gene disruption in male mice,Endocrinology, 139(12), 5058, 1998a;

OGAWA,S; CHAN,J; CHESTER,AE; GUSTAFSSON,J�; KORACH,KS; PFAFF,DW (1999)--- Survival of reproductive behaviors in estrogen receptor-beta gene deficient (?erko) male and female mice, Proceedings of the National Academy of Sciences of the USA, 96(22), 12887-12892, 1999;

PHOENIX,CH; GOY,RW; GERALL,AA; YOUNG,WC (1959)--- Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig--- Endocrinology, 65, pp. 600-667, 1959;

QUIGLEY,CA; DeBELLIS,A; MARSCHKE,KB; EL-AWADY,MK; WILSON,EM; FRENCH,FS (1995)---Androgen receptor defects: historical, clinical and molecular perspectives, Endocrine Reviews, 16(3), 271-321, 1995;

RESKO,J; CONNOLLY,PB; ROSELLI,CE (1988)--- Testosterone 5-alfa-reductase activity in neural tissue of fetal rhesus macaques, Journal Steroid Biochemistry, 29(4), 429-434;1988;

SWAAB,DF & FLIERS,E (1985)--- A sexually dimorphic nucleus in the human brain, Science 228, 1112; 1985;

TORRES,WF & JURBERG,P (2000)--- Ser homem ou ser mulher: a identidade neuro-ps�quica de g�nero como fator determinante, Scientia Sexualis, 6(3), 2000;

TORRES,WF & JURBERG,P (2001) --- Gender Identity: A dynamical neuro-psychical process, paper presented at the 15th World Congress of Sexology, Paris, that same volume, 2001;

WILSON,JD; GRIFFIN,JE; GEORGE,FW (1980)--- Sexual differentiation: early hormone synthesis and action, Biology of Reproduction, 22, 9-17;1980;

WILSON,JD, GRIFFIN,JE, RUSSEL,DW (1993) --- Steroid e-alfa-redutase 2 deficiency, Endocrine Reviews, 14(5), 577, 1993;

WILSON,JD (1999)--- The role of androgens in male gender role behavior, Endocrine Reviews, 20(5), 726-737;1999;

ZHOU,JN; HOFMAN,MA; GOOREN,LJG; SWAAB,DF--- A sex difference in the human brain and its relation to transsexuality, Nature, 378, 68-70, 1995(A);

ZHOU,ZX ; LANE,MV; KEMPPAINEN,J�; FRENCH,FS; WILSON,EM--- Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability, Molecular Endocrinology, 9(2), 208-218, 1995(B).

Paris, June 2001
Universidade Gama Filho- Rio, Brazil
WF Torres supported by Capes.
Presented at the 15th World Congress of Sexology, Paris 2001


M.I., researcher, opinion:

Dear Wal,
I agree with you philosophy that the brain is not sexually neutral, but I don't agree that MAIS will be related to GID. Instead, I think that the DAX-1 gene is involved, and I am gathering strong evidence which supports this.
As you know, duplication of the DAX-1 gene on the X chromosome can result in XY individuals becoming female, with ovarian tissue, uterus, and female phenotype (not the AIS syndrome, but the less familiar XY sex reversal syndrome-XY gonadal dysgenesis). Smaller duplications result in an ambiguous phenotype. I believe that even smaller duplications, will reult in the brain remaining female, without the genitals being involved. Of course, it may not be the duplication of DAX-1 material, but deletion which may cause GID. This is because it is PUZZLING to researchers that deletion of DAX-1 has been known to cause hypogonadotropic hypogonadism in XY persons. Nobody knows why BOTH the addition AND subtraction of DAX-1 sequences lead to ambiguous sexuality. BUT,

(1) Benjamin originally described 40% of his m to f's to have hypogonadism! So, I think this fits well with the finding of DAX-1 and HH.

(2) Deletions in DAX-1 have been reported in Kallman's Syndrome, a syndrome of hypogonadotropic hypogonadism with anosmia (lack of sense of smell), which has been reported to co-exist with GID.

(3) Furthermore, there are genes on the second X chromosome, which escape X inactivation in person's with a second X chromosome (eg., XX females, and XXY Klinefelter's). Jan Walinder noted in his 1967 thesis, that about 5% of m to f's were chromatin positive (had a form of Klinefeleter's). This is 25 times HIGHER than the 1/500 average of Klinefeleter's in the general male population. So, genes which escape X inactivation create a vulnerability to GID. The DAX-1 region ESCAPES X inactivation! It is located at Xp21-Xp22.3. Interestingly, the H-Y antigen reports which correlated with transsexuality (but were never replicated) showed a gene controllong H-Y antigen to be at Xp22.3! I do not believe that MAIS genes (which are located at Xq13) escape X inactivation. So, XXY, XXXY, XXXXY, persons, etc., would have the AR genes inactivated on ALL of the extra X chromosomes, and would therefore not show the increasing vulnerabiltiy found for, by Walinder in these subjects, if AR genes were directly involved. Also, Loehlin and Martin's 1999 report on AR repeat polymorphisms did not correlate with the degree of femininity in their study of this in women.

(4) FURTHERMORE, and of GREAT significance, DAX-1 has now been shown to inhibit AR function!! See the following report:

Holter, E., et. al. (2002) Inhibition of androgen receptor (AR) function by the reproductive nuclear orphan receptor DAX-1. Mol. Endocrinol. Mar;16(3):515-528.

The authors report:

"In this study, we have identified the androgen receptor (AR) NR3C4 as a novel target for DAX-1. We show that DAX-1 potently inhibits ligand-dependent transcriptional activation as well as the interaction between the two receptors involve the N- and C-terminal activation domains of AR. We provide evidence for direct interactions of the two receptors that involve the N-terminal repeat domain of DAX-1 and the C-terminal ligand-binding activation of AR. Moreover, DAX-1, known to shuttle between the cytoplasm and the nucleus, is capable of relocalizing AR in both cellular compartments, suggesting that intracellular tethering is associated with DAX-1 inhibition. These results implicate novel inhibitory mechanisms of DAX-1 action with a particular relevance for the modulation of androgen-dependent gene transcription in the male reproductive system."

(5) Lastly, DAX-1 receptors are expressed in the human brain!!!

Thus, I believe DAX-1, and its regulation of AR will be crucial for understanding GID.

Thank you M.I. for your answer. Surely, the human brain is not sexually neutral. But we dont know today what are the ways GI remains female or is masculinized. DAX-1 problems? Perhaps. AIS problems? Perhaps too. Perhaps sometimes DAX-1, sometimes MAIS hormone selective problems.... what I intend to show is:

First: The brain, in a basal and congenital way, has a determined gender, that generates the GI.

Second: Transsexual GD probably is related to MAIS... or perhaps sometimes to DAX-1... and possibly to other factors, we ignore today. So, we need to research those possibilities.

Unfortunately, based in FReud's and Money's old ideas, no Research Center study transsexuality at that level, seriously, because transsexuality is a "moral".... or "psychological" problem....

Thank you for your very interesting opinion, M.I.!

Would you like to say us your opinion about those subjects?