Current Topic: Gynecomastia, an Occasional Marker for M2F Transgenderism?

The Journal Of Gender Speculation

Volume 1, Number 1

Spring 2004

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Gynecomastia, an Occasional Marker for M2F Transgenderism?

RW Jasinski, MD

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CONTENTS

Abstract

Key Words

Introduction

Gynecomastia - An Occasional Marker?

Gynecomastia Associated with Transgender or Trans-sexual Variations

Excluding Concurrent Conditions or Exogenous Hormones

Excluding Social and Gender Effects of Gynecomastia

A Difficult Field, a Difficult Problem: Oldies, Moldies, or Goldies

Adolescent Gynecomastia Merits Particular Attention

Known Metabolic Disorders Could Link Transgenderism and Gynecomastia

Exceptions Prove the Rule, Maybe, Sometimes

Research Possibilities

Summary

Glossary

References

Citations

Helpful Links

Contact Information

Comment

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Copyright 2004 Robert W. Jasinski, all rights reserved

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ABSTRACT

This work reviews a wide sample of papers describing gynecomastia, its occurrence in metabolic disorders, and its presence in case vignettes or biographies of transgender biological males. It summarizes papers linking transgenderism and gynecomastia, and discusses the many impediments to evaluating such links. Increasingly subtle genetic disorders of metabolism producing gynecomastia are now being identified, and could conceivably contribute to transgenderism. Gynecomastia is suggested as a clue to underlying biological contributors to transgenderism. An extensive bibliography is offered to aid and encourage any future investigation of potential links between gynecomastia and transgenderism.

KEY WORDS

(Professional) - transgender, transsexual, gynecomastia, "congenital adrenal hyperplasia", "androgen insensitivity syndrome", aromatase, intersex, hermaphroditism, pseudohermaphroditism, AIS

(Internet) - breast, breasts, "breast enlargement", crossdressing, crossdresser, transvestite, transvestism, transvestites, genetic, endocrine, adolescent, transsexuals, transsexualism, transgenderism, transgendered, "gender identity disorder", "gender dysphoria", GID, mastectomy, mammoplasty, hermaphrodite, pseudohermaphrodite.

INTRODUCTION

Postulated biological, constitutional, or genetic contributors to transgenderism usually go unspecificied. Such factors presumably act prenatally to produce cross gender effects on the brain, especially the hypothalamus, resulting in postnatal cross gender behavior (1, 2, 3, 4, 5, 6).

For example, congenital adrenal hyperplasia in females produces variable virilization, and behavioral traits generally regarded as masculine, such as rough and tumble play, and tomboyishness, in addition to frank F2M transsexualism. (2, 7, 8, 9, 10). The evidence for biological contributors to M2F transgenderism is not as convincing. Conceivably, inherited traits that predispose to anxiety in general (D) might have some impact on the anxiety that has sometimes been ascribed to the transgender condition (E, F), as might gender, or possible transgender, related variations in the endocrine system that predispose to post traumatic stress disorder (G).

Biological contributors to transgender behavior might be found by identifying subtle cross-sexual physical traits in the transgendered, and determining whether, and how, transgender behavior might be linked to these. In effect, this means identifying a population between the non intersex transgendered, and the frankly intersexed - a subtly intersexed transgendered population. While transgenderism is often not associated with identified intersex states (11, 12), some authors state that gender change in intersexuals is higher than in the general population (13), and may not follow assigned gender in some cases (14), suggesting the possibility that past assessments of the transgendered may have overlooked subtle variants of intersex stigmata. The relation between intersex state and gender identity disorders has been controversial (15). Gynecomastia may have potential as a subtle marker trait for identification of underlying metabolic disorders or biological contributors producing transgenderism.

GYNECOMASTIA - AN OCCASIONAL MARKER?

Some reports allude to a relationship between gynecomastia and transgenderism, but these are often small studies (16, 17, 18, 19). Known metabolic and genetic conditions that produce gynecomastia also produce mixed sex/gender individuals. Transient, occult, intrauterine metabolic variations, producing prenatal cross gender brain alterations in utero, might go undetected, and yet produce postnatal cross gender behavior, and minimal postnatal physical findings like gynecomastia or undescended testes ( 2, 3, 4, 5, 20).

For example, since genetic variants in aromatase enzymes have caused gynecomastia in males, and aromatase has an important role in testosterone to estrogen conversion in the brain (21, 22, 23), potential links between aromatase, or other enzymes, causing both gynecomastia, and transgenderism, could exist. Various adrenal disorders known to produce gynecomastia, might also affect brain development (5, 24).

Since gynecomastia is a fairly common cross-sexual physical finding in a varying percentage of "normal" males (25, 26, 27) , confirming a higher rate of unexplained gynecomastia in transgender males might indicate an underlying metabolic condition that also predisposes to transgenderism.

GYNECOMASTIA ASSOCIATED WITH TRANSGENDER OR TRANS-SEXUAL VARIATIONS

Biological conditions that alter sex characteristics, including gynecomastia, might produce varying degrees of cross gender behavior, with contributions from concurrent socialization. There are some instances where gynecomastia and other intersex variations have been associated with transgender behaviors. Genetic disorders of metabolism causing gynecomastia and other intersex traits have been found both in particular genetically isolated populations , with varying degrees of associated transgenderism. Reports of a variety of intersex stigmata have been reported in studies of transgenders , and gynecomastia is also reported in clinical or biographical reports of transgendered individuals.

Relatively isolated, pure, or inbred populations generally have a greater tendency to manifest genetic disorders of metabolism, and might offer settings where detection of biological contributors to transgenderism is more likely. There are several lines of evidence suggesting associations between genetic disorders of metabolism, intersex (some with gynecomastia), and transgenderism.

Gynecomastia in Tutankhamun / Eunuchism in Akhenaten

The familial gynecomastia reported in the Akhenaten-Tutankhamun genetic line is particularly interesting. Consanguinity and the existence of incest as official practice among the Egyptians makes it all the more likely that genetic disorders of metabolism, and perhaps subtle intersex or transgender status, might be expressed (28, 29, 30, 31) in such a kindred as that of Akhenaten and Tutankhamun.

Akhenaten, the imputed (32) father of Tutankhamun, was an unusual pharaoh frequently depicted with feminine features, such as large hips and narrow shoulders (33; 34 -p171), without genitalia (35 -p104), and is thought to have had some type of eunuchoid disorder (35 -p58). Descriptions of his cloistered, sheltered life, (35 -p158), with mother closeness and father distance (35 -p57-9, 165, 233; 36), lack of forceful character (35 -p167,203), and artistic nature (35 -p234) all sound like descriptions of transgender males found in older clinical transgender literature, in works by Robert Stoller, and others. Akhenaten's reign and policies upset the traditions of the Egyptian court and religion, and after his death his works were methodically and vigorously destroyed. The unrest connected with Akhenaten's reign and death has the flavor of the instability connected with hemophilia in various European royal families in the late 19th, and early 20th century (37), perhaps reflecting the unease of any population whose ruler is perceived as defective, or who has made significant breaks with existing traditions.

Nefertiti, Akhenaten's wife, has been variously depicted with masculine character (35 -p191), strikingly similar to descriptions of women in transhomosexual couples (38, 39) who prefer males with feminine characteristics, such as enlarged breasts (40), or who prefer males with Klinefelter's syndrome (38-p173-175, 259-261). While ancient Egyptians were sometimes buried in coffins of the opposite sex (34 -p176,177), the burial of an ancient Egyptian male in a coffin built for a king's wife, has caused some to suspect that this male was Akhenaten himself (33). (The person buried in the coffin originally made for a female is variably described by different sources as having, or not having, feminine skeletal features (35 -p189-191). Such discrepancies (34, 41) illustrate how laborious, tentative, and difficult the process of determining ancient Egyptian identities and hypogonadism can be (42). Depictions of the male chest in other individuals might similarly suggest gynecomastia (J), if it were not for an adjacent simultanous rendition of the female breast, fortunately present to act as a control. )

Though artistic or religious decisions may have affected depictions of Akhenaten (30, 42, 43, 44, 45) and his genetic line, the report of familial gynecomastia in Tutankhamun and his relatives (46, 47), suggests the presence of some type of transgender or biological intersex condition in both individuals of the father-son pair of Akhenaten- Tutankhamun, similar to father-son gynecomastia reported in inherited metabolic errors that produce familial gynecomastia (16,17,48), to be discussed. The lack of male offspring in this lineage also suggests the possibility of testicular feminization, or some other intersex disorder, in this kindred (28, 29). If gene typing for metabolic disorders producing gynecomastia could be performed on mummy tissue from the Akhenaten/Tutankhamun genetic line (g32; 49 -p178; 50), perhaps the mystery of the representations of Tutankhamun and Akhenaten, their purported gynecomastia or other underlying disorder, could be solved.

Hostile Climate / Genetic Isolates / Consanguinity / Intersex / Gynecomastia /

Transgender Social Roles

Another potential clue to links between expression of genetic disorders, gynecomastia, other intersex conditions, and transgenderism might be found in relatively consanguinous, genetically isolated, populations where intersex conditions are well known, and where transgender behavior is observed, or transgender roles are recognized by social custom. Some authors have faild to find evidence of consanguinity among transsexuals (M). Other researchers describe a high frequency of intersexuality related to consanguinity (51). Consanguinity is also found in some of the gynecomastia producing syndromes (52, 53, 54), and is cited as a pertinent non-finding in reports of genetic disorders producing gynecomastia. Genetic disorders can produce infants who are clearly intersexed, but more subtle genetic intersex traits might produce mostly only transgender behavior, be difficult to detect, and yet be fairly frequent, since they might not severely limit fertility or survival. Thus, relatively consanguinous populations might offer productive clues to putative biological origins of transgenderism.

The co-occurence of various intersex states together with the presence of socially defined transgender roles in arctic, Middle Eastern, and American desert tribal cultures suggests the possibility that geographic or tribal isolation and inbreeding might favor the expression of genetic determinants of intersexual, and of transgender, development, particularly in hostile climates.

The past tendency of arctic and subarctic populations to be isolated for large parts of the year (g55-p281) is a social situation that could predispose to consanguinity, inbreeding, and the transgender roles and intersex syndromes found in arctic native populations. Harsh climates like the arctic, or the desert, may impose a certain level of seasonal isolation and stress upon inhabitants, creating social customs like hospitality emphasis, and perhaps also predisposing to consanguinity (54; 56; 57- p265-266; 58; 59; 60; 61; 62, B), as might lack of a rigid incest barrier (B). Tendencies to cloistering of women may be another form of isolation predisposing to consanguinity, as might any local shortage of suitors, as described with Lot's daughters and other social situations where isolation occurs (56; 63 -p105, O). The importance of maintaining clan ties and solidarity may be especially critical in hostile climates with limited resources, and would favor marriages with a greater rate of consanguinity (64, 65, B), in order to safeguard political and tribal goals. Groups isolated on the basis of caste have also shown occasional high rates of genetic disorders (37, 66 ) related to inbreeding (28, 30, 31). Groups genetically isolated on the basis of religious practice, such as the Amish, are likewise reported to have a high expression of recessively transmitted genetic disorders (50, 62, 67), and represent good populations for detecting otherwise unknown disorders (50).

For example, one subgroup of the Amish, males surnamed Beiler, and traced to Switzerland- (50 -p1282) are reported to have a tendency to be tall, and to have a missing Y chromatin body, making them mistakable for females on quinacrine fluorescence methods of karyotyping. Tallness has been reported in some transsexual cases (68 -p39; 69 -p59), and some transsexual biographies report variant results of sex chromosome testing (68-p355; L - p65) - equivocal, negative, and/or positive for female chromosomal/genetic type.

There are many examples of genetically isolated populations having intersex conditions. A high frequency of congenital adrenal hyperplasia (CAH) has been found in particularly isolated populations in Alaska, and La Reunion, France (70). 5 alpha reductase deficiency has been found in genetically isolated populations in the Dominican Republic (71), and Turkey (72). Local concentrations of subjects with 17 beta hydroxysteroid dehydrogenase deficiency have been found in the Arab population of Israel (73), with 11 beta hydroxylase found in Moroccan and Iranian Jews (74). Some studies find a remarkable percentage of Middle Eastern heritage in hypospadic populations (75). Similar effects of consanguinity in desert populations have been described for the internal form of male pseudohermaphroditism known as persistent Mullerian duct syndrome (PMDS), which produces externally normal males who also have a uterus and vagina (76).

It may not be accidental that the world's highest frequency of congenital adrenal hyperplasia (CAH) (70) is reported in theYupik tribe in particular, where the incidence is reported as one in 232 (77), but also with a high incidence of CAH in other Alaskan cultures that are remarkable for the presence of socially defined transgender roles (55; 78 -p276; 79; 80). Detailed descriptions of intersex features or behaviors (55 -p140, 141, 142, 143, 144, 146, 147, 268-284), the notion that genitals may be changed at birth or at puberty (80 -p266, 269), descriptions of birthing practices that are presumed necessary to retain a newborn's sexual features (80 -p269, 271), and the tendency for a "berdache" (81)/transgender role to appear frequently in a given family (78 -p45), all suggest potential links between genetic disorders of metabolism, and institutionalized "berdache" / intersex / intergender statuses. Among Middle Eastern traditions, a similar folk tradition concerned with intersex traits and social roles has been reported in Jewish cultures (82). Some authors (I) report Jewish, Egyptian, black, and Zambian males as relatively more prone to male breast cancer, although in some of these groups, the increased incidence of breast cancer might be attributable to the hyperestrogenism of concurrent liver disease, rather than any underlying genetic disorder.

An unusually high frequency of intersex births might lead any local culture lacking modern endocrine or surgical technology to "mainstream" such persons by creating a less stigmatizing social role for them, placing intersexual anatomy and transgender behavior on an expected, and therefore somewhat "normal", continuum (78 -p 254; 80 -p265-271). Such socially defined transgender statuses bear some similarity to the more contemporary socially recognized "guevedoces" status, in the Dominican Republic, of male pseudohermaphrodites with 5 alpha reductase deficiency (71). Transgender priesthoods in biblical times, transgender shamanic roles in arctic cultures, or the nadle role (55 -p147) seen in New World desert tribes might be examples of social roles created for such intersex or transgender persons. In the past, such roles, mediating health and well being in a complex world then beyond medical control, might fulfill functions that have in the present time shifted to the medical and scientific fields. The existence of an intersex condition and the social provision of a customary social role is not a given, however, as described in the Pokot tribe of East Africa where intersex people, if allowed to live, may be treated harshly, or ambivalently at best (83), only finding acceptance based on economic productivity (83, 84).

Any population with geographic, climatic, religious, economic, political, or other barriers to outbreeding might show higher rates of consanguinity (37, 50, 62, 66), and therefore higher rates of expression of underlying genetic disorders affecting sexual and gender development (50) - such as gynecomastia, intersex disorders, or male breast cancer. Perhaps some day the advances of the human genome project will allow the identification of the genomic equivalent of atypical inbreeding co-efficients (58, 61, 85) among persons with genetic disorders of metabolism and/or transgenderism.

Known genetic and metabolic disorders may involve intersex states, gynecomastia, and some gender variant behavior

Known metabolic and genetic disorders characterized by intersex states, some with gynecomastia (86), and transgender behaviors also suggest that gynecomastia on occasion has some relation to transgenderism.

Complete androgen insensitivity, or testicular feminization, is reported to produce feminine personalities, and a typically female phenotype (87, 88), as well as typically female breast development. Partial androgen insensitivity has produced gynecomastia, with some behavioral effects divergent from conventional masculinity (89), although one case of partial AIS reports a male gender developing, contrary to the nominally female gender of rearing (90).

Klinefelter's syndrome has an increased incidence of gynecomastia (91), and breast cancer (92, 93), and some authors report varying severity of gender difficulties in Klinefelter's patients (10; 93; 94; 95-p137; 96; 97; 98-p31).

Other hypogonadal states have also been reported in transsexual patients (95). A study of 13 patients with Kallmann's syndrome described social distress from lack of pubertal virilization (99). A report of Kallmann's syndrome in a transsexual describes four preceding operations for adolescent and post pubertal gynecomastia, performed when the patient was attempting to maintain a masculine identity (100). This patient was said to have a bloody urethral discharge, reported occasionally by other transsexual patients (100), and conceivably related to bleeding from vestigial Mullerian structures (82, 101, 102, 103, 104). Urological problems related to vestigial Mullerian structures are well known in the medical literature (105, 106, 107, 108 ). One man with persistent Mullerian structures even developed the typically female lesion of leiomyomas, or fibroids, in his enlarged uterus, which was finally discovered at age 73 during surgery for an abdominal mass and hernia (106). Perhaps these fibroids resulted from the same stimulus to Mullerian elements that produces prostate enlargement (109, 108) in normal aging males, but in any case, the finding of fibroids - tumors considered to be highly sensitive to female-typical hormone stimulation - suggests the possibility of undescribed similar pathophysiologic processes - not merely estrogenic hormone surges - ongoing in both males, and females, with uterine fibroids.

The association of gynecomastia and urinary symptoms is not surprising. Accessory nipple development has been associated with urological anomalies, a situation which suggests some linkage mechanism between breast development, and genital anomalies, in intersex states (110, 111, 112, 113).

An African report of psychological feminization associated with kwashiorkor-induced gynecomastia, and concurrent behavioral feminization from dominant maternal and cultural socialization processes, suggests that neonatal malnutrition, gynecomastia, and psychological feminization might be linked (18, P). Whether the malnutrition in these kwashiorkor cases is comparable to intrauterine growth retardation (IUGR) in stressed pregnancies (70, 114) was not discussed, but in utero imprinting effects producing cross-sexual patterns of hepatic metabolism of sex steroids have been found (115) in rats. Starvation with refeeding also produces gynecomastia(116), variably described as due to hepatic effects (25), or to a resetting of the hypothalamo-pituitary axis to a prepubertal state (117). Effects of anticonvulsants on genital and gender development are also ascribed to alterations of liver metabolism (20). That hepatic metabolism has important sex related variations is consistent with the predominance of some liver diseases, such as primary biliary cirrhosis, in women. If sex hormone binding proteins have a role in humans similar to that in rats (23), deficiencies in binding proteins due to kwashiorkor, intrauterine growth retardation (IUGR) or starvation might all alter access of estrogen and androgen hormones, or prohormones, to the developing, or adult, brain (118), perhaps producing transgender variations.

Transgender Biographies and Clinical Vignettes and Cases Report Gynecomastia

Clinical reports and biographies of transgender people report gynecomastia and other intersex traits as well, sometimes even in the absence of a diagnosed intersex state.

Transsexual biographies and autobiographies report gynecomastia (119- p49; 120-p39; 38 -p31,58,72,109,265 ), generous chest or mammary tissues (68 -p67), and other stigmata (38 -p26,29,30,51,52,53,64,68,100,150,165,251,265); L, 119-p49; 68 -p19, 37, 44, 56, 67, 173, 208); 120- (p30,31,32,38); 121-(p29, 31,33,51,70,72); 122 -p224; 123, C - p154), also found in metabolic defects that produce cross-sexual features. Gynecomastia is sporadically and briefly reported in individual clinical transgender cases or case vignettes (96-p188; 124; 125; 126, K). Stoller's report of transsexual m2F sisters, including one with gynecomastia (96- p188-192), describes family patterns that sound similar to those described in Dawson's west African study.

A report describing letters from patients seeking SRS after the Jorgensen case, found 18% with claims of cross gender or hypogonadal physical characteristics (124).

Dr. Harry Benjamin devoted substantial discussion to categories of "intermediate" and "somatopsychic" transgender males, with breast development in the former, and the latter with a "striking" feminine appearance (122).

A study of group psychotherapy of gender identity patients (19) described previously unrevealed adolescent gynecomastia in many patients who had been thought to have been adequately evaluated, emphasizing the importance of rapport and setting in obtaining candid histories. The authors described the histories of gynecomastia as doubtful, but warranting followup. Perhaps this followup was done, but then not reported, unfortunately a common fate of negative results.

A small series by Money identified a greater than expected variant sex/gender outcome in boys with idiopathic adolescent gynecomastia (IAG), and included one boy whose father also had gynecomastia, suggesting some underlying genetic tendency in that instance (17).

A report on gynecomastia in boys (16) describes transgender tendencies in some boys with gynecomastia, although the basis for trans- or homosexual behaviors seemed related to ensuing social experience, unlike the Money article (17) which found a pre gynecomastia transgender/sexual variation. One case (16) had hypospadias, and the author astutely noted that several of his boys with gynecomastia blamed their fathers for the gynecomastia - fathers whom they themselves resembled (16) - suggesting that these fathers perhaps had both gynecomastia, and underlying genetic disorders of metabolism (48).

A description of post augmentation mammoplasties in (127) transsexual patients, reported two M2F transsexuals with previous surgical correction of adolescent gynecomastia. The cause of the gynecomastia - metabolic disorder, idiopathic or intentional estrogen dosing - was not stated, but the authors described these patients' previous mastectomies as representing a last attempt at a male role.

EXCLUDING CONCURRENT CONDITIONS OR EXOGENOUS HORMONES

Gynecomastia occurs as a normal variation in males during infancy, adolescence, old age, and with obesity, and has been associated with a multitude of drugs and conditions unrelated to transgenderism. Liver, kidney adrenal, testicular, thyroid, neoplastic, and autoimmune diseases, and starvation can produce gynecomastia (25, 116, 128, 129), as can, paradoxically, anabolic steroids taken to masculinize the body ( 130, 131, 132).

For gynecomastia to serve as a marker for underlying metabolic disorders that produce transgenderism, exogenous feminizing agents must be excluded. Exogenous estrogens, as well as anti-androgens, may derive from prenatal or postnatal accidental or environmental exposure, factitiously "accidental" exposure, and clearly intentional exposure, the latter two being a result, rather than a cause, of transgenderism.

Prenatal administration of estrogens might unintentionally produce in utero neural feminizing effects (5, 133). Cyproterone, an anti-androgen, when administered to neonatal rats, has feminized subsequent adult liver metabolism (115). Treatment of male animals with anti estrogens or aromatase inhibitors prevents normal masculine reproductive behavior (2). Similar mechanisms might apply to humans.

Accidental postnatal human exposure to feminizing substances has caused epidemic gynecomastia due to insecticides (25, 134), estrogens in meat or milk (25, 135), in morticians (136 ), and in workers in industries producing synthetic estrogens (137, 138, 139, 140, 141). Occult environmental agents have feminized alligators in the wild (142), and perhaps frogs as well (H). Perhaps some cases of gynecomastia are caused by covert environmental agents (143), with a potential for cross-gendering the developing fetal brain in ways unrelated to underlying patient genetics (5,144), or acting in concert with pre-existing genetic defects to produce feminizing effects on both brain and breast tissues. The production of intersex alterations in bees as a result of parasite infestation may be only one example of nature's ability to do the sexually unexpected (57, A).

Gynecomastia from estrogens in vaginal creams, or hair lotions, has been reported (145, 146, 147), but given the stigma of transgenderism, might have been related to factitiously "accidental" use of estrogenic substances. Stress related gynecomastia has been reported (148), but since stress can precipitate m2F transgenderism (149), covert self administration of estrogen might be present in some cases of apparent stress related gynecomastia. Alternatively, perhaps under stress, males with subclinical adrenal steroid synthetic defects undergo adrenal hyperplasia and produce more estrogenic substances due to diversion of greater amounts of substrate into branch synthetic pathways.

Gynecomastia may result from drugs intentionally taken to achieve feminization (40). The covert use of feminizing drugs (121-p77) in early adolescence (150) has been reported, even misleading a team of experienced investigators (17, 96-p80,260; 151, 152). Exogenous estrogenic effects complicate the search for gynecomastia and transgenderism as common products of unknown biological and genetic factors.

Once it develops, not all patients may desire treatment of gynecomastia, for a variety of reasons (153). Some, under pressure from their mothers, may decline mastectomy (16). Patients with previously suppressed transgenderism, upon receiving estrogen therapy for prostate cancer, might welcome the feminizing effects (69-pp 44-58).

Since transgender populations may produce histories that adhere to conventional feminine stereotypes (96), or produce breasts using estrogens (96, 150), implants (154), prostheses, or physical manipulation (155), unconfirmed histories of gynecomastia become questionable, with verification issues challenging related research. Reports of gynecomastia in transgenders could be misleading, simply representing the report of 'physiologic gynecomastia', in these instances occurring in males more likely than others to notice, report, and give it significance and meaning.

EXCLUDING SOCIAL AND GENDER EFFECTS OF GYNECOMASTIA

Besides exogenous estrogen effects, endocrine conditions producing gynecomastia might promote transgenderism by simply affecting gender role experience, without any accompanying gestational brain feminization.

In females, polycystic ovarian syndrome (PCOS), is a condition which can produce cross-gender physical effects such as hirsutism, analagous to gynecomastia in males. The female experience described in PCOS is similar to the patient experience reported in gynecomastia, with cross gender feelings, and even frank transsexualism described (156). Sexual and gender insecurity was found in females with PCOS, much like boys with gynecomastia. If similarly extensive studies of the male experience of gynecomastia were done, the findings might indicate that gynecomastia itself, by affecting gender role experience, can produce transgenderism.

Since social and psychological effects of gynecomastia may alter self image, gender identity, gender stress, or sexual behavior, especially at adolescence (38 -p236, 254; 91; 98-p31; 150), gynecomastia per se as a primary stimulus to transgenderism ought to be distinguished from gynecomastia and transgenderism as end results of a common biological antecedent. Transgender behaviors occurring prior to the onset of gynecomastia imply that the gynecomastia may be only one sign of an underlying disorder, and not the primary contributor to transgenderism (17).

There is little long term follow-up reported regarding cross gender effects in boys with gynecomastia, and little written about the frequency or experience of gynecomastia in transgender males. Past or present gynecomastia in transgenders may go undetected, minimized, or unreported, since gynecomastia in adolescent males is considered a normal variation. Patient memory lapse, reluctance to recall stigmatizing events, or the salience of more pressing issues may all make histories of gynecomastia difficult to obtain without a diligent search. Analogous clinical blind spots occur even with non stigmatizing symptoms, like anosmia, in Kallmann's syndrome (99). The male norm to deny pain favors underestimating gynecomastia-related stress. Even research designs specifically aimed at evaluating pubertal physical development in transgenderism (20) seem to omit questioning males about breast development. Though professionals may minimize the psychological effects of gender incongruous pubertal development, as occurs with gynecomastia, patients' psychological sensitivity to such incongruities have been described (16, 17, 91, 100, 101, 128, 157, 158). The stigma of transgenderism might inhibit identifying concomitant transgenderism in cases of gynecomastia.

Studies reporting gynecomastia in medical, and psychiatric, literature generally do not provide much detail on how gynecomastia impacts social and psychological experience, concentrating more on surgical indications, and often limiting commentary to distress as being the indication for surgical management (159, 160). Schonfeld's description (16) of gynecomastia-related social stress on gendered self image is an exception, as are some others (4, 10, 17, 89, 91, 95, 157, 158). The Schonfeld article, perhaps because it is in older, more descriptive literature, and less terse than the usual editorial brevity demanded by the space limitations of current print journals, may describe the social experience of gynecomastia better than more "up to date" literature does. Internet discussion boards, additionally, seem to be one way of collecting in depth narratives of the personal and social experience of gynecomastia (161).

A DIFFICULT FIELD, A DIFFICULT PROBLEM: OLDIES, MOLDIES, OR GOLDIES ?

A multitude of impediments make transgender research difficult in general, and make subtle biological conditions contributing to transgenderism difficult to identify.

Technical and ethical considerations limit rigorous in vivo evaluation of the critically sensitive human brain, pregnant uterus, and fetus. Uncertainty about the applicability of observations in non-primates (3, 5, 24, 90), or non-human primates (133) to humans, and about applicability of in vitro experiments to in vivo reality (162,163,164) frequently makes research results tentative (96- pp126-141). Such problems limit study of biological factors in human cross gender development to "natural experiments", where small sample sizes, concurrent social effects, and variable expression of biological defects (165) then limit definitive conclusions.

The complexity of the endocrine system, and the complexity of its maturation, with different genetic and metabolic mechanisms producing the same or similar phenotypic effects, makes research particularly demanding. Biochemical synthetic defects may appear, and disappear, at varying stages of intrauterine, prepubertal, pubertal, and post pubertal development, and may appear in adrenal, ovary, testis, placenta, brain, and peripheral tissues, potentially resulting in a Gordian knot of pathophysiology. Genetically based inhibitory effects of one genetic defect, by producing acquired deficiencies in other enzyme systems (54), can add to the confusion. Hormone receptor defects, of varying severity, add another layer of complexity.

Since transgenderism is a complex phenomenon occurring in a stigmatized, relatively hidden minority, most efforts at identifying biological factors have involved small studies often limited by concurrent estrogen effects, complex and difficult follow-up (90, 166), differing methods or patient profiles, difficulty in monitoring patient status, labile gender identification, and lack of replication. (7, 8, 95, 167, 168, 169 ).

Inhibitions to performing genital or breast exams, particularly in regard to persons regarded as particularly vulnerable (170, 171, 172) may limit clinical and scientific knowledge. Appropriate sensitivity to patients' composure (10) favors a euphemistic, minimizing, modified or empathic clinical vocabulary which can obscure a patient's medical history, potentially clouding a complete understanding of later sex related developments (173, 174). Patient confidentiality requirements may preclude the sharing of family medical history, even when potentially relevant to the individuals involved (20). Professionals, seeking efficiency and competence through subspecialization, and with proper humility about how much any professional can know, may split off parts of the patient's/subject's experience of gynecomastia, resulting in surgical literature that omits detailed gender histories, and mental health literature that doesn't describe genitals or breasts. Lack of publication space, clinical time demands, respect for patient privacy, need to limit clinical inquiry to clearly pertinent issues, professional custom, ethical codes, modesty, and fear of perception of improper conduct all weigh against the integrated approach of simultaneously delving into sexual histories and doing careful breast and genital evaluations. Such interdisciplinary splitting can promote intellectual cracks, where patient experience can be hidden, thereby obscuring associations and discoveries that might otherwise result from integrating patient lives, and data, across disciplines.

No large studies documenting an unusually high frequency of gynecomastia in the male transgender population are available. It may not be accidental that many studies describing gynecomastia in transgenders are old. Older literature (82), often limited to eyes, ears, and empathy, was forced to focus on, and describe, the patient, potentially like a psychoanalytic (96, 175 ) or grounded theory approach to research (38 -p xiv - xv,17-26; 176), mining the qualitative, raw data of human experience.

Older literature remains of value. Historically, scientific research has had the embarrassing tendency to "discover" findings noticed, and described, decades previously (82), reflecting the inevitable lacunae in any researcher's knowledge, rather than new brilliant breakthroughs.

For evaluating exceptional events where subtlety, rarity, denial, or stigma make detection less likely, a long time frame allows a better chance for events to be noticed, and patterns to be discovered. When there is a bias against candor or perception, due to societal restrictions, or individual denial, a long time frame, including older literature, allows the accumulation of chance examples from a larger mass of hidden data, providing a database where the noise of current cultural, or professional, fashion may cancel out, making it easier to detect signal.

Potentially lacking the deep data and broad experience described in the book A Feeling for the Organism (177), heavily quantitative literature may lose human being, experience, and complexity among experimental designs which necessarily prune too bare the raw data of a life, rigorously attempting to simplify, hold variables constant, and design experiments around the need to limit questions explored, so that answers have enough statistical power to be convincing (178). Scratching the surface of only a few variables may sacrifice an integrated look at the lives of the population studied.

ADOLESCENT GYNECOMASTIA MERITS PARTICULAR ATTENTION

Gynecomastia of adolescence merits particular attention because, like some transgender behavior, identified subtle genetic errors of metabolism that produce gynecomastia tend to present peripubertally.

The gynecomastia of adolescence usually resolves in a year to three, is not unduly prominent, and (26, 128) is considered a normal variant. It is variably attributed to abnormally high estrogen/androgen ratios, or elevated estrogens, but in 75% of cases is idiopathic (25 ). Severe, persistent, prominent, and therefore stigmatizing forms of gynecomastia, are more likely to be produced by a metabolic disorder. Even transient forms of gynecomastia (179) are found in kindreds with gynecomastia from documented metabolic defects (180).

Varying diagnostic thresholds probably account for a varying incidence of adolescent gynecomastia. While some observers report a high incidence of pubertal gynecomastia, these criteria may be so sensitive as to include the majority of boys (26, 27, 159). Studies reporting a high incidence of gynecomastia in boys may thus make the diagnostic criteria so sensitive as to lose discrimination, making the condition of gynecomastia normal, despite the psychological distress it may cause. Studies reporting a low incidence of gynecomastia may make too many cases normal, by writing mild cases off as normal variation, and not identifying these as potentially stigmatizing gynecomastia. If appropriately sensitive diagnostic criteria were used, a sub population of boys with unusual breast development might be found (17), in whom searching for genetic disorders of metabolism, and transgenderism, would be particularly productive. Concerns about patient suggestibility, and altering a young patient's gender identity development through the pressure of self fulfilling prophecy, might inhibit such efforts.

Varying thresholds for mastectomy/mammoplasty (128, 159), and varying opinion about how common, and how psychologically significant, gynecomastia is, imply that physicians may minimize gynecomastia, making it seem an insignificant factor in gender identity.

While adolescent gynecomastia seems far removed from intrauterine events, a subtle biochemical abnormality might predispose a male to both adolescent gynecomastia and to gender developmental anomalies during the course of normal, stressed, or otherwise atypical fetal development.

KNOWN METABOLIC DISORDERS COULD LINK TRANSGENDERISM AND GYNECOMASTIA.

Many genetic disorders of metabolism producing gynecomastia demonstrate a wide variety of manifestations, severity, and organs of expression (48, 52, 53, 74, 162, 165, 180, 181, 182, 183, 184, 185, 186, 187,188), sometimes blending into the "normal" population when mild (74, 153, 162, 165, 180, 183, 184, 185, 187, 188, 189). Age of onset (109) may not always be uniform for a given metabolic disorder. This protean variability makes detection of subtle metabolic variants, and then linking them to transgenderism, difficult, and might allow such linkages to persist undetected. Single determinations of hormones have failed to detect significant shifts in testosterone/estrogen ratios (148), illustrating how such effects might be invisible to any but the most rigorous endocrine investigation (54).

Undiagnosed drug exposures, other teratogenic influences, and subtle genetic disorders of metabolism all might combine and interact to produce transgenderism (20), while their acting in concert might make it that much harder to discern any single causative agent.

Known metabolic disorders with potential impact on both gynecomastia and transgenderism include estrogen excess disorders, androgen synthesis deficiencies, and androgen insensitivity disorders. Although there is evidence to suggest that defects in the androgen receptor are more likely to cause feminine gender role behavior in males than are enzyme defects (88), enzyme defects that cause gynecomastia are included below for purposes of completeness in a field where much remains unexplained, controversial, or subjec to caveats.

Estrogen excess disorders

Aromatase is an enzyme that converts testosterone to estradiol. Disorders with increased aromatase activity produce more estrogen, resulting in gynecomastia (21, 22, 23, 48, 164, 190, 191, 192, 193 ). The aromatase excess syndrome may be genetically heterogeneous, and can affect both males and females. Females may be short, with isosexual precocity and macromastia (48).

In males, aromatase excess produces familial gynecomastia and slows pubertal maturation. Gynecomastia in these cases begins prepubertally, at adrenarche, when adrenal androgen precursors become available to aromatase action, rather than occurring later, as found in adolescent pubertal gynecomastia (190).

Aromatase inhibitors feminize the sexual behavior of male rats (23). Conceivably, aromatase inhibition, reducing intracellular estrogen in the brain, might have effects similar to excessive peripheral aromatase that could reduce levels of testosterone, available to the developing brain, for conversion to estrogen..

The persistence of aromatase activity until birth (192), and its occurrence in cases of adolescent gynecomastia, suggests a mechanism that might account for gynecomastia at birth, and at adolescence in some persons. Boys born with gynecomastia may also be more likely to have both gynecomastia at adolescence (179), and have transgenderism, a potential research question that favors a multidisciplinary approach.

Mixed Androgen Synthetic Deficiency/Estrogen Excess

Some forms of congenital adrenal hyperplasia, or adrenogenital syndromes, depending on their severity, can result in increased estrogens, decreased androgens, or a combination of these. These include 3 beta HSD deficiency, 11 beta hydroxylase deficiency, 17 ketosteroid reductase, and 17 hydroxylase deficiency.

Stress stimulates adrenocortical function (194), and produces adrenal crisis in persons with impaired adrenal function, affecting levels of adrenal precursors and metabolites (9, 101, 160). Fetuses or persons with occult, marginal adrenal synthetic deficiencies might, under stress and subsequent adrenal stimulation, develop precursor accumulations behind a partial enzymatic block, diverting adrenal androgens to estrogen synthesis (25), and producing feminizing effects (70, 160, 182, 195). If the testes were also involved in an enzymatic defect, testosterone deficiency might also contribute to transgender brain alterations. Gooren's study of gynecomastia in males under stress (148) might also apply to conditions of stressful in utero development (24), such that pre-existing enzyme synthetic defects in stressed pregnancies might affect both brain and breasts, producing transgenderism in utero, gynecomastia at birth, and gynecomastia again at adolescence, under stress. Newborns with gynecomastia may conceivably be more likely to have had stressful fetal environments, and might also have a higher frequency of conditions that divert corticosteroid precursors to estrogen synthesis, two research questions that might be considered. Alternatively, perhaps fetal testosterone insufficiency fails to inhibit breast anlage, resulting in gynecomastia at a later date (160).

17 beta hydroxysteroid dehydrogenase, or 17 ketosteroid reductase deficiency, involves failure to metabolize androstenedione, a weak androgen, to testosterone, and estrone to estradiol, though there are multiple forms of the enzyme. Increased estrogens from extragonadal aromatization of precursor accumulations prior to the enzymatic defect may account for the common presence of gynecomastia in this disorder (25). Classical forms of this deficiency may present as male pseudohermaphroditism. Most are raised as girls (73), have female or ambiguous external genitalia, but virilize at puberty and often take a male sex role (153). Others may undergo feminizing surgery (73). Late onset or milder variants in males may produce only gynecomastia, oligospermia, decreased libido, impotence, or varicocele, the genitals remaining normal (52, 153, 186) . Testosterone is normal or reduced, and estrogens normal or increased (52, 153). Affected females may present as polycystic ovarian disease, breast hypotrophia, clitoral enlargement, modest virilization, amenorrhea, or hirsutism, probably on the basis of low ovarian secretion of estradiol, and high (for females) levels of circulating extragonadal testosterone (186). Short stature, diabetes mellitus, and thyroid disease were found among many relatives in one study (52).

11 beta hydroxylase deficiency (74, 195, 196), in more severe forms, is remarkable for pubertal gynecomastia, with increased estradiol from peripheral aromatization of adrenal androgens, and slightly increased testosterone (195). Endogenous mineralocorticoids bound to androgen receptors, may produce an acquired, rather than genetically inherent, androgen insensitivity, similar to spironolactone effects (195). Arterial hypertension also occurs in both sexes (196). Ambiguous genitalia, premature pubarche, hirsutism, polycystic ovaries, tall stature, and ameno- or oligmenorrhea were found in girls (74, 196). Boys may have pseudoprecocious puberty, neonatal salt wasting, and crytporchidism, tall stature, and acne (74).

17 alpha hydroxylase deficiency, with 18 hydroxylase deficiency has been reported in a complete male pseudohermaphrodite with a thyroid nodule, severe hypertension, hypokalemia, lack of secondary hair, primary amenorrhea, bilateral abdominal testes, and sporadic muscle weakness. She had minimal breast development, with testosterone levels below normal (197).

Gynecomastia commonly occurs in 3 beta HSD deficiency (25), due to increased estrogen production from adrenal androgens (160), as well as decreased testosterone synthesis (25), or perhaps from the failure to inhibit breast anlage during fetal life, due to testosterone deficiency, which then only later results in gynecomastia (160).

The defect may involve only the adrenal gland (187), both adrenal and the testis (53), or the breast (187). Forms involving the adrenal rather than the testis may have normal testosterone (187). ACTH stimulation testing is important in diagnosis (187). At gene analysis, minor mutations may be distinguishable from controls only by meticulous attention to denaturing gradient gel electrophoresis conditions (183).

3 beta HSD deficiency (53, 160, 184, 187, 189 ) can be partial or complete. In the late onset variety, it has presented with gynecomastia, infertility, varicocele, or hypogonadism as late as age 24. (187, 189).

Severe forms of 3 beta HSD can result in classical salt wasting, glucocorticoid deficiency, and incomplete masculinization, with children raised as females from birth. The most obvious presentation is male pseudohermaphroditism (183). Most male cases of 3 beta HSD show partial masculinization, 2nd or 3rd degree hypospadias, and partial fusion of labioscrotal folds, but with fertility sometimes preserved in severe cases (183, 187). Less severe types may produce male pseudohermaphroditism, hypospadias, gynecomastia, or late onset virilization (160, 183). Absence of gynecomastia in salt wasting forms is rare (53). Non salt wasters have been reported to not have gynecomastia (53). Infertility may be found in postpubertal men with testicular 3 beta HSD deficiency, normal peripheral testosterone, and without gynecomastia or other abnormalities (184).

The presentation in females is generally less striking, and may be without clinical symptoms or signs (183). Female homozygotes may appear normal when young, but adult heterozygotes of the same kindred have been found to have a "variable reduction" in ovarian function (183). Clitoral enlargement, oligomenorrhea, delayed menarche, miscarriage, premature menopause, and fertility problems may be found (183). Late onset 3 beta HSD was found in female relatives of male patients with 3 beta HSD deficiency, and in 13% of women presenting with peri or post pubertal hirsutism or acne (187).

Androgen resistance disorders

Androgen resistance syndromes, due to defects in the androgen receptor, include complete or incomplete androgen insensitivity syndromes, and Reifenstein's syndrome, and can also cause gynecomastia (89, 162, 165, 180, 182, 185, 188).

Phenotpyic expression ranges from complete testicular feminization and a frankly female phenotype, to partial forms of androgen insensitivity with congenital external genital undermasculinization, hypospadias, pubertal subvirilization (minimal facial and body hair) and gynecomastia. Milder variants show male external genitalia, with or without gynecomastia, or with infertility and oligo- or azoospermia as the sole abnormality (165, 182).

Partial AIS manifesting only as azoospermia, oligospermia, and infertility, accounted for up to 40% of cases of male infertility in one study (162), and showed no elevations of testosterone or LH (162). Random blood sampling can be insufficient to demonstrate abnormal testosterone and LH levels (162, 165), making subtle receptor defects harder to detect.

One affected family had low ejaculate volume, small prostate, and bilateral gynecomastia, but with preserved fertility (180). Another series had decreased spermatogenesis, gynecomastia, limited body hair, short penile length, and small prostate size, but otherwise normal male phenotype, with testosterone levels above normal (185). In another kindred, the men were fertile, but with undervirilization, gynecomastia, high pitched voice, diminished beard and body hair, small but normal penis, and low semen volume (188). Pubertal gynecomastia in 4 cousins was associated with unambiguous male genitalia, limited body and facial hair, high voice pitch, and minimal acne (165).

Combined disorders with defects in androgen receptors or androgen synthesis.

Combined defects such as partial AIS and 5 alpha reductase deficiency in a kindred has also been reported (181). One brother with a male gender orientation had been raised as girl until age 5, had mastectomy at age 15, and then married and adopted a child. Other brothers had severe penile hypospadias, bifid scrotum, gynecomastia, minimal virilization, and a high pitched voice. A sister had sparse pubic and axillary hair. Testosterone values were normal or elevated, with low or normal plasma DHT.

Such additive multiple minimal defects of different types might cause phenotypic alterations out of proportion to any single hormonal abnormality that might detected by other than the most rigorous endocrine assessments.

Idiopathic disorders

Unspecified conditions (27), lumped under the label "idiopathic" (25), produce gynecomastia in 75% of cases, and may somehow contribute to transgenderism as well.

EXCEPTIONS PROVE THE RULE, MAYBE, SOMETIMES

Some intersex disorders produce male pseudohermaphrodites, with predominantly female phenotpyes, and rearing as females from birth. Gender change to the male role at puberty has been reported in several of these syndromes.

In a case of 3 beta HSD deficiency (53), an XY patient born with ambiguous genitalia was raised as a girl, but virilized at puberty, lacked breast development, and made a gender role change to male at age 17. His similarly affected cousin, with ambiguous genitalia, had phallic amputation at age 7, and bilateral orchiectomy, but developed breasts after estrogen treatment at age 13, and maintained a female gender at age 24. Because the first patient had strong virilization at puberty, without gynecomastia, this may be an exception that emphasizes the importance of socially salient secondary sex characteristics, such as virilization, and lack of breasts, in maintaining a gender identity congruent with genetic status (160).

In multiple cases of 5 alpha reductase deficiency (13, 71), breasts were lacking at puberty, and these male pseudohermaphrodites, previously raised as girls, usually made a change to a male gender, even against social pressure.

In a case of partial AIS with a move to a male gender role (181) after an initial 5 years of being raised as a girl, even though breasts developed, this was preceded by 4 operations for hypospadias, reflecting a serious commitment to living as a male. Another case of partial AIS, a 46X,Y nominal daughter with clitoromegaly at birth, normal sized vagina, masculine childhood, and with pubertal feminization and breast development, ultimately chose a male role, suggesting that AIS may not be invariably linked to a feminine gender identity (90).

In 17 ketosteroid reductase deficiency, even though most are raised as girls, the onset of pubertal virilism leads to many taking a male role (153).

While these cases suggest that presumptive in utero feminization, with postnatal female socialization, are sometimes not enough to produce a solid feminine gender identity, they may also emphasize the importance of breasts and other secondary sex characteristics as particularly powerful, and, unlike genitals, socially salient, markers of sex and gender. Such a social salience effect would be consistent with the general societal enthusiasm for augmentation mammoplasty, and the enhancement and display of breasts to best advantage. Since nursing an infant is a prolonged and conscious choice, perhaps the breast is a stronger insignia of femininity than the uterus. In combination with virilization, lack of breasts may have displaced these boys with intersex disorders from a previous female role. The finding of gender identity transposition in some Klinefelter's patients, who have near normal genitalia, but who frequently have breast development, also suggests that the socially evident body may at times have more weight than the genitalia in affecting gender development.

RESEARCH POSSIBILITIES

The following steps might help identify potential linkages between transgenderism and gynecomastia.

1. Careful studies of gynecomastia in transgenders, and transgenderism in gynecomastia, like that of Kitzinger (156) in polycystic ovarian syndrome (PCOS), or like those of Schonfeld (16), and Money (17), might be replicated, with longer followups and more comprehensive interviewing to detect any associated metabolic disorders, and their stigmata. Web based surveys of the social and medical factors in gynecomastia, if done in a detailed, careful fashion (161), because of their relative anonymity, could conceivably obtain better data than face to face interviews. Careful gender histories, family histories, and histories attentive to reproductive, and primary and secondary sex characteristics, when combined, might yield information not obtainable when gender and medical histories remain segregated. This might be enhanced by informed and complete medical examinations.

Whether gynecomastia causes alterations in self image, incongruities in social role, and gender role stress resulting in transgenderism, or whether it is linked to more global underlying metabolic variants that produce both gynecomastia and transgenderism, might be discerned if studies interested in the antecedents of transgenderism attend to and document physical variations like gynecomastia, as well as the social and psychological experience of gynecomastia. Given that the borderline between normal and abnormal gynecomastia is a grey area even for experienced clinicians, research on gynecomastia in transgender populations might document associated teasing, assaults, or the use of appliances or clothing that emphasize visibility, or limit the discomfort, of gynecomastia, since the social salience and response to the gynecomastia might be as, or more, important than the gynecomastia itself in producing transgenderism, and recalled social experience may be the most objective finding that subjects have the experience to discern.

2. To reveal undisclosed gynecomastia or transgenderism, a sufficiently supportive setting might be difficult to achieve in a busy clinic, or in a large, rigorous, scientifically and technically perfect, but impersonal, study. Perhaps only clinicians with established rapport, doing very directed studies, or transgenders themselves, in the fashion of other insiders from "hidden" populations (198), are best positioned to get such information.

3. Genetically inherited biological contributors to transgenderism might be suspected from careful family histories. Family members may not show identical manifestations of the same metabolic deficiency, and therefore comprehensive questioning about associated physical stigmata of intersex disorders, variants such as varicoceles or undescended testes (153), functional stigmata like infertility ( 153, 162, 52, 184, 188), or behavioral stigmata of transgenderism, might identify cases where gynecomastia and transgenderism have strong biological origins.

4. Adolescents with idiopathic gynecomastia, and those with gynecomastia from genetic disorders of metabolism are not the only groups that might offer clues to biological origins of transgenderism. Males who develop breast cancer (92, 199, 200), or who have other disease processes known to be more common in women (164), might have a greater than average chance of being predisposed to transgenderism, if there really are any constitutional factors involved in transgender behavior. Male patients who have had breast ultrasound, or mammography, because of breast complaints, might have a higher frequency of transgenderism, and merit further attention. Mammography also offers the important advantage of distinguishing mere fatty breasts from the hyperplasia of ductal or glandular elements found in gynecomastia, a common problem with the physical diagnosis of gynecomastia.

5. Increasingly subtle presentations of metabolic defects are being discovered as more powerful genetic tools are found. Sufficiently sensitive genetic screening methods (70, 183) could allow investigators to identify undetected genetic causes of cross gender physical traits, and behaviors, previously undiscovered among the "normal" population. Gene typing could allow a rigorous search for variant genes in patients with gynecomastia (183) or transgenderism. If genetic typing could be done inexpensively, it might allow numerically large studies that are otherwise too expensive to perform .

6. Looking more closely at populations with higher rates of genetic isolation or consanguinity, gynecomastia, and transgenderism, might make it easier to identify genetic traits that produce subtle intersex states or transgenderism.

7. Collaboration between geneticists, neonatologists, sex researchers, pediatricians, neuroscientists, endocrinologists, and mammographers could identify cases with gynecomastia for detailed study, creating an environment where neither gynecomastia, transgenderism, nor their potential links and causes would be overlooked.

SUMMARY

If unrelated causes of gynecomastia can be identified and excluded, and if diagnostic criteria are sufficiently precise and sensitive to allow meaningful diagnosis, gynecomastia might become a valuable clue to underlying biological contributors to transgenderism.

Identifying underlying metabolic disorders causing both gynecomastia and transgenderism requires excluding exogenous feminizing agents, excluding psychological reactions to the social experience of gynecomastia per se, and excluding causes of gynecomastia unrelated to transgenderism. Many sources refer to gynecomastia in transgender populations, but further investigation with the advantage of newer genetic, endocrinological, or imaging tools, might identify previously unsuspected linkages. Adolescent gynecomastia in particular is likely to be a fertile condition for identifying such linkages. Interpersonal rapport is probably key to being able to identify such cases, and therefore, despite advances producing powerful biomedical technology, talking to the patient or subject retains its traditional importance.

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GLOSSARY

The descriptions below are general, rather than scientifically rigorous, and are intended to assist the interested lay person to obtain a general understanding of the text.

3 beta HSD deficiency - diminished activity of the enzyme 3 beta hydroxysteroid dehydrogenase; an enzyme important in the early stages of steroid synthesis. Non classic defects may be common. Classic defect incidence uncertain. Results in decreased corticosteroids, mineralocorticoids, and sex steroids.

5 alpha reductase deficiency - diminished activity of the enzyme 5 alpha reductase, an enzyme important in conversion of testosterone to the even more potent androgen DHT or 5 alpha dihydrotestosterone.

5 DHT - 5 alpha dihydrotestosterone

11 beta hydroxylase deficiency - diminished activity of the enzyme 11 beta hydroxylase; occurs in 1:100,000 general population. Results in diminished mineralo- and glucocorticoids, with hypertension.

17 alpha hydroxylase deficiency -diminished activity of the enzyme 17 alpha hydroxylase, which acts early in the path of steroid synthesis, and results in deficiency of sex hormones and corticosteroids. Spares mineralocorticoids.

17 ketosteroid reductase (aka 17 dehydrogenase, aka 17 beta hydroxysteroid dehydrogenase ) deficiency -diminished activity of the enzyme 17 ketosteroid reductase, which acts to convert androstenedione and dehydroepiandrosterone (DHEA) to testosterone.

18 hydroxylase deficiency -diminished activity of the enzyme 18 hydroxylase; results in diminished aldosterone synthesis.

Abdominal testes - testes that remain in the abdomen, more like an ovary, and do not descend normally into the scrotum; can be seen in intersex states.

ACTH - adrenocorticotropic hormone, secreted by the pituitary gland; stimulates the adrenal gland to produce steroid hormones.

Adrenal - hormone secreting glands which lie superior to each kidney, producing a variety of critically important hormones.

Adrenarche - onset of mature adrenal function, results in the development of axillary, pubic, and other body hair.

Amenorrhea - lacking normal menses.

Androgen - one of the variety of hormones which produce visible masculinizing effects, such as beard growth, decreased voice pitch.

Androgen insensitivity syndrome (AIS) - a variably severe condition due to non responsiveness of cellular receptors to androgens, resulting in variable degrees of feminizing features; when complete, can result in a nearly normal female appearance, except for internal genitals.

Androstenedione - a precursor hormone on the path to producing testosterone.

Anlage - structures which are the beginnings of other structures which are to follow.

Anomalies - unusual variations from expected normal structure or function.

Anosmia - limited capacity of the sense of smell.

Anticonvulsants - medications given to diminish the frequency and severity of seizures.

Aromatase - an enzyme which converts testosterone to estrogen, which if unusually active can have feminizing effects.

Aromatization - the biochemical reaction which converts testosterone to estrogen.

Augmentation mammoplasty - a surgical procedure to increase the apparent size of the breast.

Autoimmune diseases - diseases where antibodies produced by its own immune system react against an organism to cause disease.

Axillary - referring to the armpit.

Berdache - a term, sometimes controversial as to its meaning and proper application, describing, in a variety of First American tribes, biological males who assumed various aspects of female roles.

Bifid scrotum - a scrotum which is divided into two portions, and therefore intermediate in appearance between a normal scrotum and normal labia.

Clitoral - referring to the clitoris or the female analog of the male phallus.

Clitoromegaly - enlargement of the clitoris, occurring in some masculinizing conditions.

Congenital adrenal hyperplasia -a family of disorders due to a variety of enzyme deficiencies like those above, which generally results in lower amounts of normal steroid hormones, and increased production of their precursors, causing a variety of effects due to inadequate normal hormone levels, and excessive precursor levels.

Congruent - in accord with, not in conflict.

Consanguinity - the state of having excessive inbreeding as might occur in parent-child, sibling, or cousin pairing, and which tends to bring out otherwise hidden genetic traits.

Crytporchidism - the state where the testes are not in their normal location in the scrotum, such as in abdominal testes.

Denaturing gradient gel electrophoresis - a technique for genetic analysis and typing of genes.

Endocrine - having to do with the hormone producing, or endocrine, glands of the body.

Endocrinologist - a person who studies the endocrine system.

Endogenous - produced from within, such as endogenous hormones produced by the endocrine organs of any given organism.

Ejaculate - the material achieved by seminal emission, or the act of achieving seminal emission.

Enzymes - proteins which are essential to catalyze chemical reactions in the body.

Estradiol - one of the more common and important varieties of estrogens.

Estrogen - the class of hormones which produce visibly feminizing effects, and so are thought of as female hormones.

Estrone - an estrogen generally thought of as less active than estradiol.

Exogenous - derived from sources outside an organism, such as hormones or medications ordered by prescription.

Extragonadal - derived from a source outside the gonads, or sex hormone producing organs such as the testes or the ovaries.

F2M - a biological female assuming variations of male or masculine status, role, gender, sex organ appearance and function.

Factitiously - occurring unnaturally, by some type of artifice or method, rather than spontaneously.

Familial gynecomastia - the tendency for breast enlargement in males to be inherited along a family line.

Genital - having to do with the organs of reproduction.

Gestational - having to do with gestation, that is, the pregnant state.

Gynecomastia - breast enlargement in males.

Glucocorticoid deficiency - deficiency in the glucocorticoid hormones produced by the adrenal gland, responsible for glucose regulation, stress reactions, and other functions.

Gordian knot - an incredibly complex knot found in a conquered city, that Alexander the Great despaired of untying. In frustration, he cut it through with his sword.

Guevedoces - Spanish for eggs, or testicles, at age twelve, used to describe male pseudohermaphrodites who virilize at puberty.

Hepatic - relating to the liver.

Hirsutism - the development of hairiness, especially facial and body hair, and especially in women.

Homozygote - having two identical alleles, or variations, of a particular gene, and generally tending to produce more severe alterations or abnormalities in structure or function.

Hypogonadal - states of low gonadal function, often associated with limited development of normal secondary sex characteristics and appearance.

Hypokalemia - low potassium levels in the blood.

Hypospadias- a defect of the underside or ventral aspect of the penis at birth, often resulting in the urinary opening being at any location along the underside of the penis.

Hypothalamo-pituitary axis - the linked functioning of the pituitary gland to the hypothalamus in the brain just above it, in order to regulate hormone production.

Hypothalamus - a portion of the brain which controls many basic and regulatory drives in animals, such as eating, reproduction, etc.

Hypotrophia - minimal growth.

Idiopathic - of unknown cause. Latin for I " don't know" why.

Impotence - male inability to achieve erection.

Imprinting - a disproportionately powerful and persistent effect of early training which occurs during a period of life of an organism, when the organism is particularly responsive and vulnerable to such training.

In utero - occurring in the uterus, as in pregnancy.

In vitro - occurring in glass, that is, in the laboratory or in some laboratory vessel.

In vivo - occurring in the living organism.

Intersex - Having physical development intermediate between male and female.

Intracellular - within the substance of a cell or cells.

Intrauterine -within the uterus, especially during a pregnancy.

Isosexual precocity - earlier than usual development of sex linked characteristics of a person's own sex.

Jorgensen, Christine - one of the first and most widely publicized transsexuals.

Kallmann's syndrome - a syndrome consisting of variable degrees of anosmia, hypogonadism, and other abnormal findings.

Klinefelter's syndrome - a male with an extra X chromosome, giving XXY sex chromosomes, and generally having a particular characteristic appearance, but frequently having gynecomastia.

Kwashiorkor - a nutritional protein deficiency disease, especially of the newborn and young child in Africa.

Labioscrotal folds, partial fusion of - partial fusion of the labia, or lips of the vaginal opening, can produce an appearance with some resemblance to the scrotum.

LH - luteinizing hormone, released by the pituitary gland, induces secretion of testosterone by the testes, and estrogen by the ovaries.

Libido - the intensity of sex drive.

M2F - a biological male assuming variations of female or feminine status, role, gender, sex organ appearance and function.

Macromastia - a disorder characterized by unusually large breasts, to the point of distress.

Mammographers - persons evaluating the breasts using Xray or radiographic imaging methods, usually looking for malignancy.

Mammoplasty - a surgical procedure to alter an existing condition of the breast.

Mastectomy -surgical removal of breast tissue.

Menarche - the onset of menstruation.

Menses - menstrual periods

Menstrual -having to do with menstruation.

Metabolites -those compounds that result from biochemical reactions involving a precursor chemical or hormone as substrate.

Mineralocorticoids - those steroids secreted by the adrenal gland that serve to regulate electrolytes and water retention, and therefore affect blood pressure.

Mullerian - having to do with the primitive fetal precursors of the mature female genital tract.

Neonatal - relating to the period at or immediately adjacent to the moment of birth.

Neoplastic - having to do with malignancy.

Oligmenorrhea - small amounts of menses.

Oligospermia - small amounts of sperm.

Orchiectomy - surgical removal of the testes.

Partial enzymatic block - an incomplete defect in an enzyme along a given hormonal synthetic pathway, which may or may not be compensated for, and may or may not allow normal hormonal levels to be achieved, but which often results in high levels of precursors.

Peripheral aromatization - the conversion of testosterone to estrogen in non endocrine sites, such as fat or muscle.

Peripubertally - at or around the time of puberty.

Phallic - having to do with the penis, or phallus.

Phenotype - the physical appearance, structure, or function produced by a given genotype or genetic heritage.

Polycystic ovarian disease - a disorder characterized by ovaries enlarged by multiple cysts, scanty or no menses, and often with hirsutism and obesity.

Postnatal - after birth.

post augmentation mammoplasty - after surgical breast enlargement.

Precursors - the hormones or compounds from which other hormones are made by the body.

Prenatal - prior to birth

Primary amenorrhea - the condition of never having had a menstrual period.

Primary biliary cirrhosis - a disease of the liver which is much more common in women than men, not related to alcoholic cirrhosis.

Primates - the class of animals including the monkeys, apes, and humans.

Prostheses - devices used to simulate or produce the appearance or function of various body parts.

Protean - characterized by a large number of variable appearances.

Pseudohermaphrodites - persons with physical and sexual features contradicting the person's gonadal type, unlike true hermaphrodites, who do have both ovary and testis tissue.

Pseudoprecocious puberty - puberty characterized by early maturation of breasts or pubic hair, but without early maturation of genitals.

Pubarche - the time of first onset of maturing of the various genital and body hair appearances.

Pubertal - having to do with puberty.

Pubic - having to do with the region of the pubis, at and adjacent to the genitals.

Reifenstein's syndrome - an incomplete form of androgen insensitivity syndrome, producing significant, but incomplete feminization of genitals and breasts.

Salt wasting - the loss of salt in the urine due to deficiency of mineralocorticoids, found in various forms of congenital adrenal hyperplasia.

Scrotum- the loose sac of skin holding the testicles of the male.

Sex hormone binding proteins - proteins in the blood which bind sex hormones, changing the amount of hormone which is free to be metabolically active.

Somatopsychic - having to do with body and psychological features.

Sonographic - having to do with the use of ultrasound to produce images for medical diagnosis.

Spermatogenesis - the process of sperm production.

Spironolactone - a drug to control hypertension, but which also has anti-androgen activity.

SRS - sexual reassignment surgery, or "sex change" surgery

Stigmata - physical characteristics or results of some given condition.

Synthetic defects - defects, limits, or abnormalities in the pathway for synthesis of a hormone.

Testicular feminization - the most severe form of androgen insensitivity syndrome which results in a near complete female external appearance, though lacking a uterus and ovaries.

Teratogenic - having the effect of inducing an abnormality or deformity during the fetal development of an individual.

Testosterone - one of the major male hormones.

Transgender - some variation from the usual and expected congruence between genitals, chromosomes, and behavior.

Transsexual - a person having a sufficiently strong identification with the opposite sex that varying degrees of cross sex anatomy and lifestyle are sought.

Urethral - having to do with the urethra, or the conduit carrying urine from the bladder to the outside. In the male, the penis comprises the majority of the urethra.

Varicocele - a collection of distended and convoluted veins found in the scrotum adjacent to the testis.

Vestigial - being left over from a preceding time, or phase of development.

Vignettes - small short descriptive stories or summaries of medical cases.

Virilism - having to do with the production of masculine features, most evident when seen in a female.

Virilization - producing masculine features, especially if seen in a female.

___________________________________________________________________________

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CITATION (MLA)

Jasinski, Robert. "Gynecomastia, an Occasional Marker for M2F Transgenderism?" The Journal of Gender Speculation Vol 1, number 1, Spring 2004. http://www.oocities.com/gmapop04

CITATION (APA)

Jasinski, Robert. (2004). Gynecomastia, an Occasional Marker for M2F Transgenderism? The Journal of Gender Speculation, Vol.1, No.1. [online]. Available HTTP: http://www.oocities.com/gmapop04

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HELPFUL LINKS (WITH PERMISSION)

http://www.ifas.org.au - International Foundation for Androgynous Studies, Inc.

http://www.gynecomastia.org - Gynecomastia.org (contains an excellent survey)

http://www.hbigda.org - Harry Benjamin International Gender Dysphoria Association

http://www.isna.org - Intersex Society of North America

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CONTACT

gmapop04@yahoo.com

No copies of any sort may be produced without the express, written authorization of the author.

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COMMENT

The Journal of Gender Speculation (JGS), is a non-peer-reviewed, occasional serial publication offering information and opinion of a speculative nature, pertinent to gender issues, and of potential stimulus value to the scientific community, or to non scientists interested in gender issues. These conjectures are heavily referenced so that interested readers can trace, rebut, or substantiate the line of thought for themselves. Verification tasks are best left to professionals who are in a better position to perform such work, while JGS will concentrate on the stimulating part of any science - making up stuff that might be true, and maybe useful. Mail from readers is a welcome contribution to this effort.

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Current topic: Gynecomastia, an Occasional Marker for M2F Transgenderism?

This particular article will be of interest to clinicians who want a referenced guide to literature specifically concerned with gynecomastia, intersex, and transgenderism. Clinicians, anthropologists, and geneticists may find the article useful as a referenced stimulus to studying intersex states in genetic isolates, particularly those in hostile climates, and how such populations might be productive for the study of biological origins of transgenderism. Transgendered people may find that this work provides some insights into their own lives, perhaps bringing understanding of conditions overlooked by medical professionals. Gender activists may find interesting those articles that describe how intersex states blend into the "normal" population. Egyptologists may find the referenced scientific articles on gynecomastia useful in investigating the purported cross-sexual features, including gynecomastia, of Tutankhamun and Akhenaten.

While the purpose here is to provide serious work that will be of some practical or theoretical usefulness, the title of this journal emphasizes the normal difficulty, uncertainty, ambiguity, incompleteness and tentativeness involved in most scientific work. It is probably healthy to have a little humility, and skepticism, even (and especially?) about the most serious efforts.

THIS COPY IS AFTER PRECEDING COPY SENT IN FOR COPYRIGHT REGISTRATION !!! 1