著者: Peter A Lee, Anna Nordenström, Christopher P Houk, S Faisal Ahmed, Richard Auchus, Arlene Baratz, Katharine Baratz Dalke, Lih-Mei Liao, Karen Lin-Su, Leendert H J Looijenga, Tom Mazur, Heino F L Meyer-Bahlburg, Pierre Mouriquand, Charmian A Quigley, David E Sandberg, Eric Vilain, Selma Witchel, Global DSD Update Consortium
雑誌名: Horm Res Paediatr. 2016;85(3):158-80. doi: 10.1159/000442975. Epub 2016 Jan 28.
Abstract/Text
The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.
© 2016 S. Karger AG, Basel.
PMID
26820577 Horm Res Paediatr. 2016;85(3):158-80. doi: 10.1159/0004･･･
著者: Peter A Lee, Christopher P Houk, S Faisal Ahmed, Ieuan A Hughes, International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology
雑誌名: Pediatrics. 2006 Aug;118(2):e488-500. doi: 10.1542/peds.2006-0738.
Abstract/Text
PMID
16882788 Pediatrics. 2006 Aug;118(2):e488-500. doi: 10.1542/peds･･･
著者: William G Reiner
雑誌名: J Pediatr Endocrinol Metab. 2005 Jun;18(6):549-53.
Abstract/Text
AIM: To compare declared sexual identity to sex-of-rearing in individuals with disorders of sexual differentiation.
METHODS: All 84 patients > or =5 years old in a pediatric psychosexual development clinic were assessed for sex-of-rearing and sexual identity. Diagnoses included 1) male-typical prenatal androgen effects but an absent or severely inadequate penis - 45 patients with cloacal exstrophy or aphallia; 2) inadequate prenatal androgens and a Y-chromosome - 28 patients with partial androgen insensitivity (pAIS), mixed gonadal dysgenesis (MGD), hermaphroditism, or craniofacial anomalies with genital ambiguity; 3) inappropriate prenatal androgen effects and a 46,XX karyotype - 11 patients with congenital adrenal hyperplasia (CAH).
RESULTS: Of 73 patients with disordered sexual differentiation and a Y-chromosome, 60 were reared female; 26 of the 60 (43%) declared female identity while 32 (53%) declared male identity including 18 (55%) with cloacal exstrophy, six (55%) with MGD, four (40%) with pAIS, one (50%) with aphallia, one (100%) with hermaphroditism, and two (67%) with craniofacial anomalies; two (3%) declined to discuss identity. Nine of 11 patients with CAH and a 46,XX karyotype were reared female and two reared male; six (55%) declared female identity and five (45%) declared male identity. Of 84 total patients, 69 were reared female, but only 32 lived as female, while 29 lived as male; four patients refused to discuss sex-of-living; parents of four patients rejected their declarations of male identity. All 15 patients reared male lived as male including two genetic females.
CONCLUSION: Active prenatal androgen effects appeared to dramatically increase the likelihood of recognition of male sexual identity independent of sex-of-rearing. Genetic males with male-typical prenatal androgen effects should be reared male.
PMID
16042322 J Pediatr Endocrinol Metab. 2005 Jun;18(6):549-53.
著者: João L Pippi Salle, Luis P Braga, Nicanor Macedo, Nicolino Rosito, Darius Bagli
雑誌名: J Urol. 2007 Oct;178(4 Pt 2):1796-800; discussion 1801. doi: 10.1016/j.juro.2007.03.167. Epub 2007 Aug 17.
Abstract/Text
PURPOSE: Management for clitoral enlargement remains controversial. New understanding of clitoral function stimulated a search for more conservative surgical approaches, such as recession or partial resection. However, these techniques risk decreasing clitoral sensation or causing painful erections. Moreover, irreversibility continues to be the principal problem that fuels patient, surgeon and societal anxiety in the management of this challenging developmental issue. We describe a new technique, corporeal sparing dismembered clitoroplasty, that dismembers the corporeal bodies and preserves all clitoral structures.
MATERIALS AND METHODS: After obtaining full informed consent and institutional review board approval 8 consecutive patients with clitoral enlargement underwent corporeal sparing dismembered clitoroplasty. Five girls had congenital adrenal hyperplasia (Prader IV and V in 4 and 1, respectively), 1 had ovotesticular disorder of sexual differentiation and 2 had partial androgen insensitivity syndrome. One pubertal girl was tested with warm, cold and pain clitoral stimulation before and after surgery. For the clitoroplasty technique the glans and its neurovascular bundles are dissected from the corpora. The isolated corpus is then completely divided starting at the bifurcation. Each separated hemicorpus is rotated inferior and lateral, to be placed inside the labial scrotal folds. The glans is reduced by superficial excision of its epithelium and fixed to the pubic attachments. Labia minora are constructed with preputial Byars flaps. Labioplasty and vaginoplasty are then routinely performed.
RESULTS: Eight patients 6 months to 13 years old underwent this procedure. Followup was 6 to 12 months. All patients recovered well from surgery without early complications. The initial cosmetic result was good in all girls. The hemicorpora were easily palpated inside their labia majora pouches, which retained the desired cosmetic appearance following feminizing genitoplasty. All glans clitoris were preserved. The teenaged patient does not report painful erections. She has maintained clitoral sensation and is satisfied with the cosmetic result.
CONCLUSIONS: Conservative reconfiguration of the female genitalia without removing genital structures is feasible in girls with clitoral enlargement. The cosmetic appearance of the genitalia is acceptable, at least to the surgeon and parents, in that the enlarged clitoris is hidden. The physiological consequences of the current operation and any surgery in the future to reverse it are unknown. With these aspects in mind we believe that corporeal sparing dismembered clitoroplasty should be incorporated into the armamentarium of surgeons involved in the treatment of clitoral enlargement and presented as an option for feminizing genitoplasty.
PMID
17707426 J Urol. 2007 Oct;178(4 Pt 2):1796-800; discussion 1801.･･･
著者: M Nomura, S Bärtsch, H Nawata, T Omura, K Morohashi
雑誌名: J Biol Chem. 1995 Mar 31;270(13):7453-61.
Abstract/Text
Ad4BP, also known as SF-1, is a cell type-specific transcription factor regulating all the steroidogenic P-450 genes. Recently, the targeted disruption of the mouse ftz-f1 gene encoding Ad4BP/SF-1 has established its essential function in both adrenal and gonadal development and sexual differentiation. As an initial step toward understanding its role in the cascade of gene activations necessary for the differentiation of the steroidogenic tissues and the sex differentiation of the gonads, we isolated and characterized the rat ad4bp gene. A sequence analysis of the ad4bp gene revealed that another nuclear factor ELP was also transcribed from the same gene by alternative promoter usage and splicing. The promoter of the ad4bp gene showed activities in the steroidogenic cells such as Y-1 adrenocortical cells and I-10 testicular Leydig cells when examined by transient transfection assays. Using deletion analysis and site-directed mutagenesis, we identified a cis-element at the position from -82 bp to -77 bp in the 5'-upstream region. The cis-element was identical to the consensus E box element, which is the binding site for the basic-helix-loop-helix proteins. Gel mobility shift analyses revealed the amount of a binding factor to this E box in the nuclear extract prepared from the rat testes attained a maximal level 1 week after birth and then decreased dramatically thereafter, and only trace amounts were detected in adult rats. In contrast, the binding factor in the ovaries attained a maximal level just after birth and kept its level thereafter. These dimorphic expressions of the binding factor to the E box correlated well with those of Ad4BP, and thus suggested that the expression of Ad4BP, and thus suggested that the expression of Ad4BP is transcriptionally regulated through this E box element.
PMID
7706291 J Biol Chem. 1995 Mar 31;270(13):7453-61.
著者: Ryohei Sekido, Robin Lovell-Badge
雑誌名: Nature. 2008 Jun 12;453(7197):930-4. doi: 10.1038/nature06944. Epub 2008 May 4.
Abstract/Text
The mammalian Y chromosome acts as a dominant male determinant as a result of the action of a single gene, Sry, whose role in sex determination is to initiate testis rather than ovary development from early bipotential gonads. It does so by triggering the differentiation of Sertoli cells from supporting cell precursors, which would otherwise give follicle cells. The related autosomal gene Sox9 is also known from loss-of-function mutations in mice and humans to be essential for Sertoli cell differentiation; moreover, its abnormal expression in an XX gonad can lead to male development in the absence of Sry. These genetic data, together with the finding that Sox9 is upregulated in Sertoli cell precursors just after SRY expression begins, has led to the proposal that Sox9 could be directly regulated by SRY. However, the mechanism by which SRY action might affect Sox9 expression was not understood. Here we show that SRY binds to multiple elements within a Sox9 gonad-specific enhancer in mice, and that it does so along with steroidogenic factor 1 (SF1, encoded by the gene Nr5a1 (Sf1)), an orphan nuclear receptor. Mutation, co-transfection and sex-reversal studies all point to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate Sox9 and then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Our results open up the field, permitting further characterization of the molecular mechanisms regulating sex determination and how they have evolved, as well as how they fail in cases of sex reversal.
PMID
18454134 Nature. 2008 Jun 12;453(7197):930-4. doi: 10.1038/natur･･･
著者: Maki Fukami, Yuka Wada, Kanako Miyabayashi, Ichizo Nishino, Tomonobu Hasegawa, Agneta Nordenskjöld, Giovanna Camerino, Christine Kretz, Anna Buj-Bello, Jocelyn Laporte, Gen Yamada, Ken-Ichirou Morohashi, Tsutomu Ogata
雑誌名: Nat Genet. 2006 Dec;38(12):1369-71. doi: 10.1038/ng1900. Epub 2006 Nov 5.
Abstract/Text
46,XY disorders of sex development (DSD) refer to a wide range of abnormal genitalia, including hypospadias, which affects approximately 0.5% of male newborns. We identified three different nonsense mutations of CXorf6 in individuals with hypospadias and found that its mouse homolog was specifically expressed in fetal Sertoli and Leydig cells around the critical period for sex development. These data imply that CXorf6 is a causative gene for hypospadias.
PMID
17086185 Nat Genet. 2006 Dec;38(12):1369-71. doi: 10.1038/ng1900･･･
著者: Michiko Nakamura, Maki Fukami, Fumihiro Sugawa, Mami Miyado, Katsuya Nonomura, Tsutomu Ogata
雑誌名: PLoS One. 2011 Apr 29;6(4):e19123. doi: 10.1371/journal.pone.0019123. Epub 2011 Apr 29.
Abstract/Text
BACKGROUND: MAMLD1 is known to be a causative gene for hypospadias. Although previous studies have indicated that MAMLD1 mutations result in hypospadias primarily because of compromised testosterone production around the critical period for fetal sex development, the underlying mechanism(s) remains to be clarified. Furthermore, although functional studies have indicated a transactivation function of MAMLD1 for the non-canonical Notch target Hes3, its relevance to testosterone production remains unknown. To examine these matters, we performed Mamld1 knockdown experiments.
METHODOLOGY/PRINCIPAL FINDINGS: Mamld1 knockdown was performed with two siRNAs, using mouse Leydig tumor cells (MLTCs). Mamld1 knockdown did not influence the concentrations of pregnenolone and progesterone but significantly reduced those of 17-OH pregnenolone, 17-OH progesterone, dehydroepiandrosterone, androstenedione, and testosterone in the culture media. Furthermore, Mamld1 knockdown significantly decreased Cyp17a1 expression, but did not affect expressions of other genes involved in testosterone biosynthesis as well as in insulin-like 3 production. Hes3 expression was not significantly altered. In addition, while 47 genes were significantly up-regulated (fold change >2.0×) and 38 genes were significantly down-regulated (fold change <0.5×), none of them was known to be involved in testosterone production. Cell proliferation analysis revealed no evidence for compromised proliferation of siRNA-transfected MLTCs.
CONCLUSIONS/SIGNIFICANCE: The results, in conjunction with the previous data, imply that Mamld1 enhances Cyp17a1 expression primarily in Leydig cells and permit to produce a sufficient amount of testosterone for male sex development, independently of the Hes3-related non-canonical Notch signaling.
PMID
21559465 PLoS One. 2011 Apr 29;6(4):e19123. doi: 10.1371/journal･･･
