Sex Determination, Differentiation, and Identity
http://www.100md.com
《新英格兰医药杂志》
To the Editor: We applaud Reiner and Gearhart (Jan. 22 issue)1 for highlighting the difficulties of sex assignment but would like to emphasize how their study confirms the complexity of the development of sexual identity,2 not its biologic determination.
First, the data are subject to alternative explanations. Sexual identity is internal, and thus to assess it from parents' reports is problematic. Parents may have misinterpreted behavior as reflective of sexual identity. Prenatal androgens facilitate male-typical play, but masculine play is consistent with female identity.3,4 Second, the decision by 6 of 14 subjects to reassign themselves to the male sex may have arisen not just from androgen exposure, but also in response to complex social conditions, such as a mismatch between behavior and parents' expectations or peers' stigmatization.2,5 Third, the follow-up methods were unsystematic and subjective; interviewers' expectations were probably conveyed to the participants and introduced into the scoring. This factor may have contributed to identity changes between the initial and final assessments.
These data add to, but do not resolve, the controversy about treating children with intersex conditions and those with discordance between their sexual differentiation and their physical appearance. Treatment must be based on thorough consideration of the data.
Sheri A. Berenbaum, Ph.D.
Pennsylvania State University
University Park, PA 16802
sab31@psu.edu
David E. Sandberg, Ph.D.
University at Buffalo
Buffalo, NY 14222
References
Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 2004;350:333-341.
Zucker KJ. Intersexuality and gender identity differentiation. Annu Rev Sex Res 1999;10:1-69.
Berenbaum SA, Bailey JM. Effects on gender identity of prenatal androgens and genital appearance: evidence from girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2003;88:1102-1106.
Meyer-Bahlburg HFL. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:155-171.
Meyer-Bahlburg HFL, Gruen RS, New MI, et al. Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behav 1996;30:319-332.
--------------------------------------------------------------------------------
To the Editor: The study by Reiner and Gearhart and the Perspective article by Federman1 raise important questions regarding surgical sex assignment in neonates with ambiguous genitalia and intersex conditions. The role of prenatal hormones in general development and in the sexualization of the brain must be acknowledged. Persons with the androgen insensitivity syndrome (who have an XY karyotype and testicular tissue, but breasts and female external sexual genitalia) and female sexual identity report a diminished sense of well-being and loss of energy and libido after orchiectomy with estrogen replacement. The addition of androgens to estrogen may improve their symptoms. Is there a separate androgen receptor in the brain that retains sensitivity in these women? This possibility must be explored to facilitate compassionate assistance by health professionals in the choice of sexual identity by people with unusual genitalia or karyotypes.
Arlene B. Baratz, M.D.
Androgen Insensitivity Support Group
Duncan, OK 73575
References
Federman DD. Three facets of sexual differentiation. N Engl J Med 2004;350:323-324.
To the Editor: Reiner and Gearhart report on the sexual identity of 14 genetically male patients with cloacal exstrophy. Six identified themselves as females, two had "unclear" identity, and six identified themselves as males, after learning of their genetic sex. The authors conclude that "neonatal assignment of genetic males to female sex because of severe phallic inadequacy" should be reexamined on the basis of these data.
Some important points are missing. First, the authors report that the subjects who identified themselves as males desired surgical reconstruction of a penis. However, Reiner and Gearhart and a colleague have reported elsewhere that men with bladder exstrophy had psychosexual dysfunction regarding their constructed genitalia, as well as anxiety and mood disorders.1 Time will tell whether the young participants in the current study are able to overcome such obstacles in adulthood. In addition, the authors' speculation that "prenatal androgens appear to be a major biologic factor in the development of male sexual identity" is not supported. Other groups have not reported male identity in similar children.2,3 Intersex studies also do not support their hypothesis.4,5
Claude J. Migeon, M.D.
Johns Hopkins School of Medicine
Baltimore, MD 21287
cmigeon@jhmi.edu
Gary D. Berkovitz, M.D.
University of Miami School of Medicine
Miami, FL 33136
Amy B. Wisniewski, Ph.D.
Johns Hopkins School of Medicine
Baltimore, MD 21287
References
Reiner WG, Gearhart JP, Jeffs R. Psychosexual dysfunction in males with genital anomalies: late adolescence, Tanner stages IV to VI. J Am Acad Child Adolesc Psychiatry 1999;38:865-872.
Schober JM, Carmichael PA, Hines M, Ransley PG. The ultimate challenge of cloacal exstrophy. J Urol 2002;167:300-304.
Baker Towell DM, Towell AD. A preliminary investigation into quality of life, psychological distress and social competence in children with cloacal exstrophy. J Urol 2003;169:1850-1853.
Wisniewski AB, Migeon CJ, Gearhart JP, et al. Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female. Horm Res 2001;56:3-11.
Migeon CJ, Wisniewski AB, Gearhart JP, et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 2002;110:611-611. abstract.
To the Editor: In their comprehensive review article on sex determination and differentiation, MacLaughlin and Donahoe1 state, "Germ cells are absent . . . in 'Sertoli-only' testes of infertile men who have deletions in the long arm of the Y chromosome in the azoospermia factor (AZF) regions that control spermatogenesis." However, the most common of these deletions, the AZFc interstitial deletion, is often associated with at least some degree of spermatogenesis, even in azoospermic persons; in these patients, haploid germ cells can usually be retrieved by testicular sperm extraction and used for assisted reproduction. In one study, germ cells were found in 30 of 42 patients with an AZFc deletion (71 percent), detected in the seminal fluid or at biopsy or identified after testicular sperm extraction; the most frequent pattern at biopsy in azoospermic patients was arrest of maturation.2 Very similar results have been reported in a subsequent study.3 Thus, in the majority of patients with AZFc deletions, a Sertoli-cell–only pattern is not present.
Paolo A. Tomasi, M.D., Ph.D.
Università di Sassari
07100 Sassari, Italy
ptomasi@uniss.it
References
MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med 2004;350:367-378.
Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002;17:2813-2824.
Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003;18:1660-1665.
Drs. Reiner and Gearhart reply: Let us reemphasize several points we make in our article. First, cloacal exstrophy is not an intersex condition: gonads and prenatal sex hormones (and hormone receptors) are typically normal. Removal of the testes at birth and feminizing genitoplasty were performed because historically the surgical construction of a phallus has not been feasible. Second, the primary outcome of interest was sexual identity; in our article we discuss comparable studies, but in our view, drawing parallels with studies of children with intersex conditions is fraught with difficulties. Finally, we strongly agree that treatment of children with intersex conditions — and all other children as well — should be based on thorough consideration of the data. Since data tend to be sparse in children with rare conditions (intersex conditions as well as cloacal exstrophy), longitudinal studies are important.
Regardless of their interpretation, however, our data reflect a strong trend toward transition to male sexual identity longitudinally in genetically and hormonally male subjects with cloacal exstrophy who were reared as females; those reared as males have remained male. Syndromic difficulties notwithstanding, none of the subjects living as males have had reported major depression or suicidal ideation since their transition to a male identity.
William G. Reiner, M.D.
University of Oklahoma Health Sciences Center
Oklahoma City, OK 73104
John P. Gearhart, M.D.
Johns Hopkins Medical Institutions
Baltimore, MD 21205
Drs. Donahoe and MacLaughlin reply: The statement to which Dr. Tomasi refers — in its entirety, "Germ cells are absent in the mutant strain of piebald mice and in 'Sertoli-only' testes of infertile men who have deletions in the long arm of the Y chromosome in the azoospermia factor (AZF) regions that control spermatogenesis" — is limited to infertile men with testes that contain only Sertoli cells and no germ cells. We meant to imply that the azoospermia factor region of the long arm of the Y chromosome is important for spermatogenesis. We do not discuss detailed differences in azoospermia factor subregions a, b, or c.
Patricia K. Donahoe, M.D.
David T. MacLaughlin, Ph.D.
Massachusetts General Hospital
Boston, MA 02114
maclaughlin@helix.mgh.harvard.edu
First, the data are subject to alternative explanations. Sexual identity is internal, and thus to assess it from parents' reports is problematic. Parents may have misinterpreted behavior as reflective of sexual identity. Prenatal androgens facilitate male-typical play, but masculine play is consistent with female identity.3,4 Second, the decision by 6 of 14 subjects to reassign themselves to the male sex may have arisen not just from androgen exposure, but also in response to complex social conditions, such as a mismatch between behavior and parents' expectations or peers' stigmatization.2,5 Third, the follow-up methods were unsystematic and subjective; interviewers' expectations were probably conveyed to the participants and introduced into the scoring. This factor may have contributed to identity changes between the initial and final assessments.
These data add to, but do not resolve, the controversy about treating children with intersex conditions and those with discordance between their sexual differentiation and their physical appearance. Treatment must be based on thorough consideration of the data.
Sheri A. Berenbaum, Ph.D.
Pennsylvania State University
University Park, PA 16802
sab31@psu.edu
David E. Sandberg, Ph.D.
University at Buffalo
Buffalo, NY 14222
References
Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 2004;350:333-341.
Zucker KJ. Intersexuality and gender identity differentiation. Annu Rev Sex Res 1999;10:1-69.
Berenbaum SA, Bailey JM. Effects on gender identity of prenatal androgens and genital appearance: evidence from girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2003;88:1102-1106.
Meyer-Bahlburg HFL. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:155-171.
Meyer-Bahlburg HFL, Gruen RS, New MI, et al. Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behav 1996;30:319-332.
--------------------------------------------------------------------------------
To the Editor: The study by Reiner and Gearhart and the Perspective article by Federman1 raise important questions regarding surgical sex assignment in neonates with ambiguous genitalia and intersex conditions. The role of prenatal hormones in general development and in the sexualization of the brain must be acknowledged. Persons with the androgen insensitivity syndrome (who have an XY karyotype and testicular tissue, but breasts and female external sexual genitalia) and female sexual identity report a diminished sense of well-being and loss of energy and libido after orchiectomy with estrogen replacement. The addition of androgens to estrogen may improve their symptoms. Is there a separate androgen receptor in the brain that retains sensitivity in these women? This possibility must be explored to facilitate compassionate assistance by health professionals in the choice of sexual identity by people with unusual genitalia or karyotypes.
Arlene B. Baratz, M.D.
Androgen Insensitivity Support Group
Duncan, OK 73575
References
Federman DD. Three facets of sexual differentiation. N Engl J Med 2004;350:323-324.
To the Editor: Reiner and Gearhart report on the sexual identity of 14 genetically male patients with cloacal exstrophy. Six identified themselves as females, two had "unclear" identity, and six identified themselves as males, after learning of their genetic sex. The authors conclude that "neonatal assignment of genetic males to female sex because of severe phallic inadequacy" should be reexamined on the basis of these data.
Some important points are missing. First, the authors report that the subjects who identified themselves as males desired surgical reconstruction of a penis. However, Reiner and Gearhart and a colleague have reported elsewhere that men with bladder exstrophy had psychosexual dysfunction regarding their constructed genitalia, as well as anxiety and mood disorders.1 Time will tell whether the young participants in the current study are able to overcome such obstacles in adulthood. In addition, the authors' speculation that "prenatal androgens appear to be a major biologic factor in the development of male sexual identity" is not supported. Other groups have not reported male identity in similar children.2,3 Intersex studies also do not support their hypothesis.4,5
Claude J. Migeon, M.D.
Johns Hopkins School of Medicine
Baltimore, MD 21287
cmigeon@jhmi.edu
Gary D. Berkovitz, M.D.
University of Miami School of Medicine
Miami, FL 33136
Amy B. Wisniewski, Ph.D.
Johns Hopkins School of Medicine
Baltimore, MD 21287
References
Reiner WG, Gearhart JP, Jeffs R. Psychosexual dysfunction in males with genital anomalies: late adolescence, Tanner stages IV to VI. J Am Acad Child Adolesc Psychiatry 1999;38:865-872.
Schober JM, Carmichael PA, Hines M, Ransley PG. The ultimate challenge of cloacal exstrophy. J Urol 2002;167:300-304.
Baker Towell DM, Towell AD. A preliminary investigation into quality of life, psychological distress and social competence in children with cloacal exstrophy. J Urol 2003;169:1850-1853.
Wisniewski AB, Migeon CJ, Gearhart JP, et al. Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female. Horm Res 2001;56:3-11.
Migeon CJ, Wisniewski AB, Gearhart JP, et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 2002;110:611-611. abstract.
To the Editor: In their comprehensive review article on sex determination and differentiation, MacLaughlin and Donahoe1 state, "Germ cells are absent . . . in 'Sertoli-only' testes of infertile men who have deletions in the long arm of the Y chromosome in the azoospermia factor (AZF) regions that control spermatogenesis." However, the most common of these deletions, the AZFc interstitial deletion, is often associated with at least some degree of spermatogenesis, even in azoospermic persons; in these patients, haploid germ cells can usually be retrieved by testicular sperm extraction and used for assisted reproduction. In one study, germ cells were found in 30 of 42 patients with an AZFc deletion (71 percent), detected in the seminal fluid or at biopsy or identified after testicular sperm extraction; the most frequent pattern at biopsy in azoospermic patients was arrest of maturation.2 Very similar results have been reported in a subsequent study.3 Thus, in the majority of patients with AZFc deletions, a Sertoli-cell–only pattern is not present.
Paolo A. Tomasi, M.D., Ph.D.
Università di Sassari
07100 Sassari, Italy
ptomasi@uniss.it
References
MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med 2004;350:367-378.
Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002;17:2813-2824.
Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003;18:1660-1665.
Drs. Reiner and Gearhart reply: Let us reemphasize several points we make in our article. First, cloacal exstrophy is not an intersex condition: gonads and prenatal sex hormones (and hormone receptors) are typically normal. Removal of the testes at birth and feminizing genitoplasty were performed because historically the surgical construction of a phallus has not been feasible. Second, the primary outcome of interest was sexual identity; in our article we discuss comparable studies, but in our view, drawing parallels with studies of children with intersex conditions is fraught with difficulties. Finally, we strongly agree that treatment of children with intersex conditions — and all other children as well — should be based on thorough consideration of the data. Since data tend to be sparse in children with rare conditions (intersex conditions as well as cloacal exstrophy), longitudinal studies are important.
Regardless of their interpretation, however, our data reflect a strong trend toward transition to male sexual identity longitudinally in genetically and hormonally male subjects with cloacal exstrophy who were reared as females; those reared as males have remained male. Syndromic difficulties notwithstanding, none of the subjects living as males have had reported major depression or suicidal ideation since their transition to a male identity.
William G. Reiner, M.D.
University of Oklahoma Health Sciences Center
Oklahoma City, OK 73104
John P. Gearhart, M.D.
Johns Hopkins Medical Institutions
Baltimore, MD 21205
Drs. Donahoe and MacLaughlin reply: The statement to which Dr. Tomasi refers — in its entirety, "Germ cells are absent in the mutant strain of piebald mice and in 'Sertoli-only' testes of infertile men who have deletions in the long arm of the Y chromosome in the azoospermia factor (AZF) regions that control spermatogenesis" — is limited to infertile men with testes that contain only Sertoli cells and no germ cells. We meant to imply that the azoospermia factor region of the long arm of the Y chromosome is important for spermatogenesis. We do not discuss detailed differences in azoospermia factor subregions a, b, or c.
Patricia K. Donahoe, M.D.
David T. MacLaughlin, Ph.D.
Massachusetts General Hospital
Boston, MA 02114
maclaughlin@helix.mgh.harvard.edu