Psuedohermaphroditism

1. Psuedohermaphroditism Erin Moseley

2. Pseudohermaphroditism - Male (MPH) • Incomplete masculinization of the external genitalia in a male (46XY) karyotype. • If the testes form only partially and the production of androgen and Mullerian inhibitor is incomplete, there will be only partial masculinization of the external genitalia as well as incomplete inhibition of the development of the vagina, uterus, and Fallopian tubes.

3. Pseudohermaphroditism - Male • A rare autosomal recessive disorder of genetic (XY) males. • Ambiguous external genitalia appearing in adolescence. - Characterized by a clitoris-like phallus, bifid scrotum, and urogenital sinus with a blind vaginal pouch. -Testes are undescended pre-pubescently, are usually located in the abdomen, inguinal canals, or scrotal folds. • Causes initial misdetermination of sex at birth.

4. Male Pseudohermaphroditism The gonads are testicles which are usually retained. The tubular components are basically female. The external genitalia are mainly of the female type with an enlarged clitoris, or may be vestigial penile development.

5. Pseudohermaphroditism - Female • A virilized female • Masculinization of the external genitalia by an abnormal source of androgen • Internal genitalia are normal, such as the vagina and uterus.

6. Female Hermaphroditism The gonads are ovaries and the accessory sex organs are predominantly male.

7. Signs & Tests • Male chromosomes -- X,Y • High testosterone and luteinizing hormone level in blood • Low or absent sperm count • Testicular biopsy shows no mature sperm despite normal precursors • Decreased or absent vas deferens (the tubes through which sperm exit the testes) • Partial development of female gonads/sex organs • Decreased ability to bind androgen in cell culture tests • Mutations in the androgen receptor gene • Family history of affected males who share a common, unaffected female relative consistent with X-linked recessive inheritance

8. Symptoms • Abnormal male genitalia, including undescended testes; scrotum that is small, with a line down the middle (bifid) or incompletely closed; small penis and hypospadias (penis tethered to underlying skin) • Breast development in males at time of puberty • Lack of fertility • Decreased body hair and beard with normal pubic and armpit hair

9. Causes and Risks This disease is one of a spectrum of diseases that are due to loss of normal response to the male sex hormones, called androgens (of which testosterone is the best known). In this genetic disease, the affected gene codes for the androgen "receptor." This is the key protein inside cells that receives the androgen hormone and instructs the cell how to respond to androgen hormones.

10. LOCATION Location- Chromosome X Address- Xq12

11. CGAGATCCCGGGGAGCCAGCTTGCTGGGAGAGCGGGACGGTCCGGAGCAAGCCCAGAGGCAGAGGAGGCGACAGAGGGAAAAAGGGCCGAGCTAGCCGCTCCAGTGCTGTACAGGAGCCGAAGGGACGCACCACGCCAGCCCCAGCCCGGCTCCAGCGACAGCCAACGCCTCTTGCAGCGCGGCGGCTTCGAAGCCGCCGCCCGGAGCTGCCCTTTCCTCTTCGGTGAAGTTTTTAAAAGCTGCTAAAGACTCGGAGGAAGCAAGGAAAGTGCCTGGTAGGACTGACGGCTGCCTTTGTCCTCCTCCTCTCCACCCCGCCTCCCCCCACCCTGCCTTCCCCCCCTCCCCCGTCTTCTCTCCCGCAGCTGCCTCAGTCGGCTACTCTCAGCCAACCCCCCTCACCACCCTTCTCCCCACCCGCCCCCCCGCCCCCGTCGGCCCAGCGCTGCCAGCCCGAGTTTGCAGAGAGGTAACTCCCTTTGGCTGGAGCGGGCGAGCTAGCTGCACATTGCAAAGAAGGCTCTTAGGAGCCAGGCGACTGGGGAGCGGCTTCAGCACTGCAGCCACGACCCGCCTGGTTAGGCTGCACGCGGAGAGAACCCTCTGTTTTCCCCCACTCTCTCTCCACCTCCTCCTGCCTTCCCCACCCCGAGTGCGGAGCCAGAGATCAAAAGATGAAAAGGCAGTCAGGTCTTCAGTAGCCAAAAAACAAAACAAACAAAAACAAAAAAGCCGAAATAAAAGAAAACGAGATCCCGGGGAGCCAGCTTGCTGGGAGAGCGGGACGGTCCGGAGCAAGCCCAGAGGCAGAGGAGGCGACAGAGGGAAAAAGGGCCGAGCTAGCCGCTCCAGTGCTGTACAGGAGCCGAAGGGACGCACCACGCCAGCCCCAGCCCGGCTCCAGCGACAGCCAACGCCTCTTGCAGCGCGGCGGCTTCGAAGCCGCCGCCCGGAGCTGCCCTTTCCTCTTCGGTGAAGTTTTTAAAAGCTGCTAAAGACTCGGAGGAAGCAAGGAAAGTGCCTGGTAGGACTGACGGCTGCCTTTGTCCTCCTCCTCTCCACCCCGCCTCCCCCCACCCTGCCTTCCCCCCCTCCCCCGTCTTCTCTCCCGCAGCTGCCTCAGTCGGCTACTCTCAGCCAACCCCCCTCACCACCCTTCTCCCCACCCGCCCCCCCGCCCCCGTCGGCCCAGCGCTGCCAGCCCGAGTTTGCAGAGAGGTAACTCCCTTTGGCTGGAGCGGGCGAGCTAGCTGCACATTGCAAAGAAGGCTCTTAGGAGCCAGGCGACTGGGGAGCGGCTTCAGCACTGCAGCCACGACCCGCCTGGTTAGGCTGCACGCGGAGAGAACCCTCTGTTTTCCCCCACTCTCTCTCCACCTCCTCCTGCCTTCCCCACCCCGAGTGCGGAGCCAGAGATCAAAAGATGAAAAGGCAGTCAGGTCTTCAGTAGCCAAAAAACAAAACAAACAAAAACAAAAAAGCCGAAATAAAAGAAAA Gene Sequence

13. AccessionNumber Nucleotide Codon Insertion Phenotype Reference CI962560 52 C Androgen insensitivity syndrome 1 CI994028 542 60 A Androgen insensitivity syndrome 2 CI993488 617 85 A Androgen insensitivity syndrome 3 CI920926 966 202 ATCC Androgen insensitivity syndrome 4 CI941827 215 G Androgen insensitivity syndrome 5 CI962561 2011 553 ACTATTAC Androgen insensitivity syndrome 6 CI000491 848 A Androgen insensitivity syndrome 7 Examples of Insertion Mutations

14. Protein Sequence SEQUENCE 919 AA; 98988 MW; 93B096927740B6FF CRC64; MEVQLGLGRV YPRPPSKTYR GAFQNLFQSV REVIQNPGPR HPEAASAAPP GASLLLLQQQ QQQQQQQQQQ QQQQQQQQET SPRQQQQQQG EDGSPQAHRR GPTGYLVLDE EQQPSQPQSA LECHPERGCV PEPGAAVAAS KGLPQQLPAP PDEDDSAAPS TLSLLGPTFP GLSSCSADLK DILSEASTMQ LLQQQQQEAV SEGSSSGRAR EASGAPTSSK DNYLGGTSTI SDNAKELCKA VSVSMGLGVE ALEHLSPGEQ LRGDCMYAPL LGVPPAVRPT PCAPLAECKG SLLDDSAGKS TEDTAEYSPF KGGYTKGLEG ESLGCSGSAA AGSSGTLELP STLSLYKSGA LDEAAAYQSR DYYNFPLALA GPPPPPPPPH PHARIKLENP LDYGSAWAAA AAQCRYGDLA SLHGAGAAGP GSGSPSAAAS SSWHTLFTAE EGQLYGPCGG GGGGGGGGGG GGGGGGGGGG GGEAGAVAPY GYTRPPQGLA GQESDFTAPD VWYPGGMVSR VPYPSPTCVK SEMGPWMDSY SGPYGDMRLE TARDHVLPID YYFPPQKTCL ICGDEASGCH YGALTCGSCK VFFKRAAEGK QKYLCASRND CTIDKFRRKN CPSCRLRKCY EAGMTLGARK LKKLGNLKLQ EEGEASSTTS PTEETTQKLT VSHIEGYECQ PIFLNVLEAI EPGVVCAGHD NNQPDSFAAL LSSLNELGER QLVHVVKWAK ALPGFRNLHV DDQMAVIQYS WMGLMVFAMG WRSFTNVNSR MLYFAPDLVF NEYRMHKSRM YSQCVRMRHL SQEFGWLQIT PQEFLCMKAL LLFSIIPVDG LKNQKFFDEL RMNYIKELDR IIACKRKNPT SCSRRFYQLT KLLDSVQPIA RELHQFTFDL LIKSHMVSVD FPEMMAEIIS VQVPKILSGK VKPIYFHTQ

15. ANDROGENRECEPTOR Structure of Protein

16. Genetic Research The effect of testosterone replacement on the psychological well-being of 20 women with CAIS. Women randomly received a skin patch containing active testosterone or a dummy placebo. The testosterone was administered as an adhesive patch applied daily. A new patch system was used in this study - one that is usually used in men with testosterone deficiency. After 8 weeks the treatment will be swapped so that all women with receive testosterone at some time. The entire study will take place over the course of 16 weeks. All volunteers will continue their usual estrogen replacement therapy during the trial.

17. Genetic Research - Personality traits and platelet monoamine oxidase (MAO) activity were studied in 22 women, 17-34 years old, with prenatal virilization due to congenital adrenal hyperplasia (CAH) (21-hydroxylase deficiency) and 22 healthy controls. The CAH group differed significantly on two of the eight scales of the Karolinska Scales of Personality (KSP), which have earlier shown significant gender differences. Both differences were in the masculine direction, with a high, male level, score for Detachment and a lower score for Indirect Aggression. The Detachment scale reflects distance in social relations, and has earlier been shown to be strongly gender differentiating. There was no significant difference in platelet MAO activity between the CAH group and the controls. Although an influence of psychosocial factors cannot be excluded, the results suggest a possible association between prenatal androgen exposure and the high Detachment score for the CAH group. Gender differences in empathy, affiliation motivation, intimacy and maternal behavior may be relevant parallels

18. Genetic Research Nine female adolescents with female pseudohermaphroditism resulting from virilizing congenital adrenocortical hyperplasia (CAH) were studied in terms of gender identity, sex-role behavior, psychological adjustment, and psychosexual development. A group of adolescents with chronic illness was used as a control. The Draw-A-Person, the Bem Sex-Role Inventory, Rorschach, TAT, and a questionnaire reviewing peer and romantic activities were administered to both groups. The two groups were comparable on measures of general personality greater bodily concerns. Sex-role identity for both groups was near the adolescent girl norms for both Femininity and Masculinity, with virilized CAH girls showing slightly higher Androgyny scores. Significant differences were found on gender identity as measured by greater differentiation of the drawn male figure as well as a trend toward drawing the male figure first. The CAH females also showed consistent patterns of psychosocial delay in dating and sexual relations as compared to the control group. Gender identity in this group appears to be mediated by body image. The resulting ambivalence may be evidence of feelings of incompetence, leading to resistance to social interactions and goals involving intimacy and nurturance.

19. Prenatal Diagnosis & Treatment • Prenatal diagnosis done by molecular genetic analysis using DNA extracted from chorionic villus cells in the amniotic fluid. • Analysis of fetal P450c21B genes can determine 21 OH deficiency. ( Congenital Adrenal Hyperplasia) • Causitive mutations can be identified on 95% of Chromosomes using Southern blot analysis and selective amplification of the CYP21B gene by polymerase chain reaction.

20. Prenatal Diagnosis &Treatment • Prenatal prediction of CAH deficiency allows doctors to prevent virilization of affected female fetus • Treatment begins in the 5th week of gestation. • Mothers are given 20-25 kg of dexamethasone per day until fetus is delivered. • Three fourths of treated cases respond successfully with female born with either normal genitalia or only mildly virilized genetalia.

21. Post Natal Treatment • -Male gender identity and hormone replacement therapy • Some evidence suggests that DHT therapy administered prior to puberty may increase penile size. DHT therapy is ineffective once puberty starts, probably because it merely suppresses and replaces the endogenous production of testosterone, maintaining a normal total serum level. • Most males virilize adequately for normal sexual function without replacement. The unaffected less active 5-ARD type 1 enzyme may provide adequate activity for this; or, even with the lower level of receptor binding, the large amount of testosterone produced at puberty may suffice for this masculinization.

22. Post Natal Treatment • -Female gender identity and hormone replacement therapy • After gonadectomy, which should be performed prior to puberty and usually is performed in the newborn period, start hormone replacement therapy at an appropriate age. • Many endocrinologists use an arbitrary bone age of approximately 13 years; starting therapy too early causes premature epiphyseal fusion. • Other endocrinologists start measuring luteinizing hormone (LH) and follicle-stimulating hormone (FSH) when the individual is aged approximately 10 years and begin therapy when the gonadotropins begin to rise. • Either ethinyl estradiol or conjugated estrogens can be used initially. • Progesterone usually is not added in the absence of a uterus.