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Fetal Sex Differentiation-Fundementals of Cancer Cytogenetic-Lecture Handout, Exercises of Cancer Cytogenetics

Sree Chitra Tirunal Institute of Medical Sciences and TechnologyCancer Cytogenetics

This lecture handout was designed and distributed by Prof. Akhilesh Kulkarni at Sree Chitra Thirunal Institute of Medical Sciences and Technology. This is part of Cancer Cytogenetic course. It includes: Normal, Abnormal, Sexual, Fetal, Embrionic, Urogenital, Androgen, Syndromes, Reseptor, Genitalia

Typology: Exercises

2011/2012

Uploaded on 08/01/2012

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IN SUMMARY
HST 071
NORMAL & ABNORMAL SEXUAL DIFFERENTIATION
Title: Fetal Sex Differentiation – Postnatal Diagnosis and Management of
Intersex Abnormalities
By: Patricia K. Donahoe, M.D.
Marshall K. Bartlett Professor of Surgery, Harvard Medical School
Director, Pediatric Surgical Research Laboratories, MassGeneral Hospital for
Children
1. Embryonic development of the urogenital ridge
A. Congenital abnormalities produced by molecular defects
2. Germ cell development
A. Germ cell selection from embryonic stem cells
B. Development, migration, and homing of germ cells
C. Meiosis and mitosis of XX and XY germ cells
D. Somatic cell nuclear transfer (SCNT) using oocytes
E. Oocytes from embryonic stem cell lines; presidential/Melton
F. Male germ cell development from embryoid bodies
G. Epigenetic erasure (methylation of DNA; acetylation of histones)
3. Development of the reproductive tracks (Mullerian and Wolffian)
A. Role of Mullerian Inhibiting Substance
4. Development of external genitalia
A. Role of 5α reductase and dihydrotestosterone
5. Pathogenesis (molecular defects) of intersex abnormalities
A. Excessive androgen syndromes
Congenital Adrenal Hyperplasia – Female pseudohermophroditism
B. Chromosomal abnormalities
1. pure gonadal dysgenesis
2. mixed gonadal dysgenesis
3. true hermophroditism
C. Deficient Androgen Syndromes - Male pseudohermaphroditism
1 testosterone deficiency
2 androgen receptor deficiency
3 5 Alpha reductase deficiency
6. Female reconstruction
7. Male reconstruction
62
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IN SUMMARY

HST 07 1

NORMAL & ABNORMAL SEXUAL DIFFERENTIATION

Title: Fetal Sex Differentiation – Postnatal Diagnosis and Management of

Intersex Abnormalities

By: Patricia K. Donahoe, M.D.

Marshall K. Bartlett Professor of Surgery, Harvard Medical School

Director, Pediatric Surgical Research Laboratories, MassGeneral Hospital for

Children

1. Embryonic development of the urogenital ridge

A. Congenital abnormalities produced by molecular defects

2. Germ cell development

A. Germ cell selection from embryonic stem cells

B. Development, migration, and homing of germ cells

C. Meiosis and mitosis of XX and XY germ cells

D. Somatic cell nuclear transfer (SCNT) using oocytes

E. Oocytes from embryonic stem cell lines; presidential/Melton

F. Male germ cell development from embryoid bodies

G. Epigenetic erasure (methylation of DNA; acetylation of histones)

3. Development of the reproductive tracks (Mullerian and Wolffian)

A. Role of Mullerian Inhibiting Substance

4. Development of external genitalia

A. Role of 5α reductase and dihydrotestosterone

5. Pathogenesis (molecular defects) of intersex abnormalities

A. Excessive androgen syndromes

Congenital Adrenal Hyperplasia – Female pseudohermophroditism

B. Chromosomal abnormalities

1. pure gonadal dysgenesis

2. mixed gonadal dysgenesis

3. true hermophroditism

C. Deficient Androgen Syndromes - Male pseudohermaphroditism

1 testosterone deficiency

2 androgen receptor deficiency

3 5 Alpha reductase deficiency

6. Female reconstruction

7. Male reconstruction

62

IN SUMMARY HST 07 1

NORMAL & ABNORMAL SEXUAL DIFFERENTIATION

SEXUAL DIFFERENTIATION

NORMAL SEXUAL DIFFERENTIATION

  • Embryo has bisexual potential, each gonad can develop into either testis or ovary
  • Orderly sequence needed for normal sexual differentiation of gonads, internal ductal

system, and external genitalia

  • Psychosocial issues in intersex disorders may have more serious ramifications than

physical ambiguity and sterility  delivering child with ambiguous genitalia should be

considered medical emergency

  • Differences between male and female fetuses:
    • Testicular determinant genes must be present and active for testicular

development to begin ; ovarian determinant genes must be present at later stages

 absence of testicular determinants, ovarian development will begin regardless

of genetic sex of embryo

  • Male sexual differentiation depends on endocrine function of testes

(testosterone, DHT, and MIS); female internal and external genital development

occurs in absence of ovarian hormones

  • Note: Mullerian female; Wolffian male

MALE SEXUAL DIFFERENTIATION

  • Initial switch seems to be Y-chromosome SRY gene
  • Primordial germ cells travel to genital ridge, become enveloped by developing

seminiferous tubules

  • Sertoli cells at base of seminiferous tubules
  • Sertoli cells produce MIS (Mullerian inhibiting substance)  arrest of development of

Mullerian system

  • Leydig cells appear and produce androgens
  • DHT has significantly greater potency than testosterone
  • Wolffian development due to testosterone because no 5-alpha-reductase to convert to

DHT

  • External genital masculinization due to DHT (5-alpha-reductase present)
  • Competent androgen receptor needed for masculinization
  • Mullerian and Wolffian systems are local and unilateral
    • Remove one testis, that side develops Mullerian
  • External genital development begins week 9, completed in early middle trimester
  • Testicular descent week 32, gubernaculums “pulls” testis toward scrotum

FEMALE SEXUAL DIFFERENTIATION

  • Ovarian development begins in absence of testicular or ovarian determinant genes
  • Mullerian development begins and continues unless arrested by MIS
  • External genitalia will feminize in absence of androgens
  • Ovaries contain 6 million germ cells by 20 weeks

63

IN SUMMARY HST 07 1

NORMAL & ABNORMAL SEXUAL DIFFERENTIATION

  • Translocation of SKY, not genes controlling sperm production
  • Male phenotype, infertile

CONGENITAL ADRENAL HYPERPLASIA

  • Most common and serious abnormality of sexual differentiation, seen in 46XX
  • Deficiency of 21-hydroxylase or (less commonly) 11b-hydroxylase or 3b-hydroxysteroid

dehydrogenase

  • Cortisol production limited  ACTH overproduction  accumulation of cortisol precursor

and androgens

  • High fetal adrenal androgens adversely influence external genitalia in female but not

male fetuses  virilization

  • Ranges from clitoromegaly and mild labioscrotal fusion through hypospadias
  • Bilateral undescended gonads with ambiguous penile development, think CAH
  • Tall children, short adults because of premature epiphyseal fusion
  • Skin hyperpigmentation because of high melanocyte stimulating hormone (MSH)
  • 21 - OH deficiency:
    • Salt wasting and simple virilization
    • Males infants more likely to be undiagnosed and develop salt-wasting crisis than

females, because normal phenotype at birth

ANDROGEN EXCESS SYNDROME

  • In utero exposure to endogenous maternal or exogenous androgens can cause

masculinization of the external genitalia

  • Placenta can aromatize native androgens, except DHT, to estrogen and prevent

masculinization

  • Luteoma of pregnancy: androgen producing tumor

IDENTIFICATION AND EVALUATION OF INTERSEX DISORDERS

  • Sex of rearing = label of male or female given at birth
  • Gender identity = one’s own feelings of sexuality
  • Ambiguous genitalia caused by intersex disorder may include: minimal clitoromegaly,

isolated cryptorchidism, hypospadias, overt ambiguity

  • If gender is in question, best to withhold decision on sex of rearing
  • Can say “sexual development of this infant is incomplete; after a few studies it will be

easy to determine whether the baby is a boy or girl”

65

HST 07 1

Content removed due to copyright restrictions. Please see:

��MacLaughlin, D. T., and P. K. Donahoe. "Sex Determination and Differentiation."

N Engl J Med. 350, no. 4 (January 22, 2004

Erratum in N Engl J Med. 351, no. 3 (July 15 , 2004): 306.:

Comment in N Engl J Med. 350, no. 4 (January 22, 2004 ): 323-4.

Engl J Med. 350, no. 21 (May 20, 2004 ): 2204-6, author reply 2204-6.

FUNDAMENTAL QUESTIONS

1. How does the genital tract of a female fetus develop?

2. How does the genital tract of a male fetus develop?

3. What is the role of MIS?

4. What is the role of SRY?

5. How does mullerian agenesis occur?

6. What is a pseudohermaphrodite?

7. What is the role DHT in male development?

8. What is the androgen insensitivity syndrome?

9. What can congenital adrenal hyperplasia cause? Why?

10. What is the workup for CAH?

11. What is a true hermaphrodite? A pseudohermaphrodite?

12. What is androgen excess syndrome?

66

IN SUMMARY

SEXUAL DIFFERENTIATION

68