congenital adrenal hyperplasia, androgen insensitivity syndrome, turner's, klinefelter, intersex, development of genitalia, classification, hermaphroditism, ambiguous genitalia, screening of CAH, swyer syndrome

1. (INTERSEX)
Part 1
DISORDERS OF SEXUAL
DEVELOPMENT
DR.PREKSHA JAIN

2. CONTENTS of Part 1
1. Development in brief
2. Introduction
3. Classifications
4. Incidence
5. 46 XX DSD
6. 46 XY DSD

3. Normal Sexual Differentiation
GENETIC SEX
GONADAL SEX
SEXUAL
DIFFERENTIATION OF
BRAIN
HORMONE
PRODUCTION AT
PUBERTY
SECONDARY SEXUAL
DEVELOPMENT
HORMONE
PRODUCTION DURING
FETAL DEVELOPMENT
SEXUAL
DIFFERENTIATION OF
EXTERNAL GENITALIA
SEX OF ASSIGNMENT &
REARING
GENDER
IDENTITY
PHENOTYPIC
SEX

4. Gonadal development

5. 46XY 46XX
INDIFFERENT GONAD
TESTIS OVARY
SRY GENE
MISPARAMESONEPHRIC DUCT
TESTOSTERONE
MESONEPHRIC
DUCT
DHT
EXTERNAL GENITALIA
ESTROGEN
PARAMESONE
PHRIC DUCT
EXTERNAL
GENITALIA
2wks later

6. Internal genital organs development

7. Leydig
cells
Sertoli
cells
Testosterone Mullerian inhibiting
factor
Wollfian duct 5a-reductase
Urogenital sinus
Regrsession of
Mullerian ducts
Male external genitalia
Male internal
Genital organs
DHT
Male development

8. 9 weeks
10 weeks
12-14
weeks

10. Urogenital sinus
Female external genitalia
. Lower part of vagina
Mullerian ducts
Female internal genital
Organs
. Most of upper vagina
. Cervix and uterus
. Fallopian tubes
Neutral
Development
Absence of androgen exposure
Female development

11. INTRODUCTION
• DISORDERS OF SEXUAL DEVELOPMENT:
Congenital conditions characterized by atypical development of chromosomal,
gonadal or phenotypic sex.
• INTERSEX
An individual in whom there is discordance between chromosomal, gonadal,
internal genital, and phenotypic sex or the sex of rearing.
• INTERSEXUALITY:
Discordance between any two of the organic sex criteria
• TRANSSEXUALITY:
Discordance between organic sex and psychological sex components.
• TRUE HERMAPHRODITISM:
Has both ovarian & testicular tissue.
• MALE PSEUDOHERMAPHRODITISM:
Has testes, but a female genotype.
• FEMALE PSEUDOHERMAPHRODITISM:
Has ovaries but a masculine genital characteristics.

12. CLASSIFICATION
Old classification
1.Sex chromosomal intersex
2.Autosomal intersex
3.Gonadal intersex
4.Hormonal intersex
5.Psychological intersex
6.Sex of rearing

13. New Classification
Disorders of gonadal (ovarian) dvp
• Ovotesticular disorder (True Hermaphroditism)
• Testicular disorder of sexual dvp (46XX male sex reversal)
• Gonadal dysgenesis
Androgen excess- Fetal origin (congenital adrenal hyperplasia)
• 21 Hydroxylase (P450c21) deficiency
• 11 β Hydroxylase (P450c11β) deficiency
• 3β Hydroxysteroid dehydrogenase deficiency
Androgen excess- Fetoplacental origin
• Aromatase (P450arom) def
• P450 oxidoreductase def
Androgen excess- Maternal (Gestational hyperandrogenism)
• Drugs
• Excess androgen production
Other disoders of genital dvp
• Cloacal extrophy
• Mullerian Agenesis (MRKH)
• MURCS
46XX DSD

14. Disorders of Gonadal (testicular) development
• Complete gonadal dysgenesis (Swyer syndrome)
• Partial Gonadal dysgenesis
• Testicular regression Syndrome
• Ovotesticular DSD
Disorders of androgen synthesis
• Steroid 5α reductase def
• 17 α hydroxylase def (P450c17)
• 3β Hydroxysteroid dehydrogenase def
• 17β Hydroxysteroid dehydrogenase def
• P450 oxidoreductase def
• Steroid acute regulatory (StAR) protein def
Disorders of Androgen Action
• Complete Androgen Insensitivity Syndrome
• Incomplete/Partial AIS
LH receptor defects
• Leydig cell hypoplasia
Disorders of AMH & its receptor
• Hernia uterine inguinale syndrome
46 XY DSD

15. SEX CHROMOSOME DSD
1. 45 XO TURNER SYNDROME & its variants
2. 47XXY KLINEFELTER SYNDROME & variants
3. 45 X/ 46 XY MIXED GONADAL DYSGENESIS/ ovotesticular DSD
4. 46 XX/ 46XY CHIMERISM/ ovotesticular DSD

16. Incidence
• A conservative estimate is that 1 in 2000 children born will be
affected by an intersex condition.
• 90 % of affected babies are due to congenital adrenal hyperplasia

17. 46XX DISORDERS OF SEXUAL
DEVELOPMENT

18. Disorder of Gonadal (ovaries)
development

19. TRUE HERMAPHRODITISM
• Ovotesticular DSD
• Mixed ovarian & testicular tissue.
• B/l ovotestes OR an ovotestis &C/l ovary or testis
• Majority 46XX, 7% 46XY, 10-40% Mosaics
• Rt- Testicular tissue, Lt- ovarian tissue
• Cause- translocation of TDF from Y to X
• Int gen- Both
• Ext gen- Ambiguous / male
• Gonadal biopsy is required for confirming diagnosis

20. TRUE HERMAPHRODITISM

21. 46 XX Sex reversal
• Testicular disorder of sexual devp
• Occurs in 1 of every 20,000 males
• Chromosomal sex (46 XX) not consistent with gonadal sex (testes).
• 2 types- Sry positive& Sry negative
• Cause-
90%- Recombination distal short arms of X & Y and transfer of sry from Y to X during male
meiosis.
10%- Sry not detected
• Int genitalia- Testes
• Ext genitalia-
Sry-negative: ambiguous
Sry positive: Normal male but hypogonadism, gynaecomastia, infertility, features of
Klinefelter but have
o Shorter (mean height, 168 cm) & more normal skeletal proportions than Klinefelter’s
patients
o Infertile lack of germ cell elements

22. 46 XX Pure Gonadal Dysgenesis
• Cause- Autosomal etiology (AR)
• Features:
• Normal female external genitalia
• Normal müllerian ducts with absence of wolffian duct structures
• Normal height
• Normal 46 XX
• Bilateral streak gonads elevated serum gonadotropins
(hypergondotropic hypogonadism)
• Sexual infantilism
• Management-
• cyclic hormone replacement with estrogen and progesterone.
• growth is basically normal so GH is not needed

23. Androgen excess-
Female Pseudohermaphroditism

24. FEMALE PSEUDOHERMAPHRODITISM
FETAL ORIGIN-
Congenital adrenal hyperplasia
• 21 -hydroxylase deficiency
• 11-hydroxylase deficiency
• 3ß-hydroxysteroid
dehydrogenase deficiency
MATERNAL ORIGIN
Gestational hyperandrogenism
• Drug
• Excess production-
Pregnancy Luteoma
Theca lutein cysts
FETOPLACENTAL ORIGIN
• Aromatase deficiency
• P450 oxidoreductase
deficiency
EXCESS
ANDROGENS

25. Mineralocorticoid
Glucocorticoid

26. Congenital Adrenal Hyperplasia
• >90% - 21 Hydroxylase def
• Basic pathophysiology-
Decrease cortisol  stimulate ACTH  adrenal hyperplasia
Increase steroid hormone proximal to enzyme block  increase androgens
• Time, duration & LEVEL of exposure of androgen determine degree of clitoral
enlargement, labial fusion, urethral & vaginal abnormalities
• <10 wk- no effect, as adrenals not functional, vg & urethra separate
• 10-12 wk- androgens  labial fusion, clitoromegaly
• 12-14 wk- limited effect if androgens rise after this
• Female ext gen not completed until 20wks, size of clitoris depends on Level of
androgens
• Ovaries, AMH normal & high local conc not achieved- Wollfian absent

28. 21-Hydroxylase Deficiency
• Most common endocrine cause of neonatal death.
• Two categories:
(1) Classical-
Salt wasters (deficiency of cortisol & aldosterone & with virilization)  severe shock
Simple virilizers (patients with virilization, but without circulatory collapse)  ambiguous gen
(2) Nonclassical (those without evidence of virilization or salt wasting)  hirsutism, Menstrual
irregularities
• 1 in 5000 live births. 2/3rd (75%) Salt wasting 1/3rd (25%) simple virilizing
• Autosomal recessive pattern
• CAUSE: 21-hydroxylase gene ( CYP-21 ) chromosome 6p
1. Non- Reciprocal gene conversions  active CYP-21 gene into the inactive gene occur in 65%
to 90% of cases of classic 21-hydroxylase deficiency (i.e., salt wasting and simple virilizing
forms) and in all nonclassic cases
2. Gene deletions are responsible for 10% to 35% of the remainder of mutations that produce
21-hydroxylase deficiency

29. 21-hydroxylase (P450c21) deficiency
Pituitary
ACTH
Adrenal cortex
Androgens Cortisol
Cholesterol
Pregnenolone
Progesterone
17-OH progesterone
21-hydroxylase
AndrogensCortisol

30. Classical
Salt wasting Simple virilizing
Non classical
Presentation At birth At birth (F)
Neonates, early infancy
(M)
Childhood or early adolescence
Ext genitalia
Puberty
Ambiguous genitalia (F)
(adrenogenital synd)
Adrenal insufficiency (M)
Masculinization of the untreated
female;
Pubic and axillary hair develop
prematurely
Acne
Deepening of voice
Ambiguous genitalia (F)
Young children with
early virilization (M)
Normal
Signs of hyperandrogenism
Precocious puberty
Hirsutism
Menstrual irregularities
Fertility 1.Chronic anovulation
2.Abnormalities of genital anatomy and psychosocial factors
Pregnancy Protective effect of placental aromatase from virilization of
female fetus; increase GDM
Diagnosis 1. 17 OHP levels >3500ng/dl
2. 11 deoxycortisol & 17 α hydroxypregnenolone
3. For confirmation- ACTH stimulation test (>10,000ng/dl)
4. Genotyping cells from CVS
5. Urinary 17-ketosteroids and pregnanentriol are elevated.
6. A pelvic USG for presence of mullerian tissues.
7. Neonatal screening
Not by neonatal screening
Serum 17OHP levels N or
DHEAS - N
1. 17 OHP >82 ng/dl in children
2. Adult women morning levels
<200-exclude CAH
>800- diagnostic
200-800 stimulation test(>1500)

31. Pregnenlolone
Progesterone
Desoxycorticosterone
Corticosterone
18 OH Corticosterone
Aldosterone
17 OH Pregnenlolone
17 OH Progesterone
11 Desoxycortisol
Cortisol
DeHydroEpiAndrosterone
Androstendione
Testosterone Estradiol
Cholesterol
Desmolase
3 B HSD
21 OH
11 OH
18 OH
Desmolase
3 B HSD
3 B HSD
21 OH
11 OH
21 Hydroxylase Deficiency:
90 % of CAH
1 : 5000 births
50-70 % salt wasting
Female = ambiguous,
Male =virlization

32. 11 β-Hydroxylase Deficiency
• 2nd m/c/c of CAH (1 in 1,00,000 live births)
• 5-8% cases of adrenal steroid enzyme defect.
• Types: salt wasting, simple virilizing & late-onset.
• Excess production of androgens & mineralocorticoid action of 11
deoxycorticosterone.
• Features- FEMALES
At birth- virilization of ext gen; children- precocious puberty; adolescent-
hirsutism, menstrual irrg
• 2/3rd exhibit HYPERTENSION due to 11 deoxycorticosterone.
• Mutations in the CYP-11B1 gene
• Chromosome 8q
• Diagnosis- Raised 11-deoxycortisol, 11-DOC & testosterone. ACTH stimulation
• Urinary 17-ketosteroids and 17-hydroxycorticoids are increased.

33. Pregnenlolone
Progesterone
Desoxycorticosterone
Corticosterone
18 OH Corticosterone
Aldosterone
17 OH Pregnenlolone
17 OH Progesterone
11 Desoxycortisol
Cortisol
DeHydroEpiAndrosterone
Androstendione
Testosterone Estradiol
Cholesterol
Desmolase
3 B HSD
21 OH
11 OH
18 OH
Desmolase
3 B HSD 3 B HSD
21 OH
11 OH
11 Hydroxylase Deficiency:
5 - 8% of CAH
HTN
Female = ambiguous,
Hyperpig
Male = HTN, hypokalemia

34. 3β Hydroxysteroid Dehydrogenase Deficiency
• Precursor of all steroid hormones.
• 2 types of 3β HSD enzymes-
1. Activity in placenta & peripheral tissues (skin, breast, prostate)
2. Adrenal, ovaries, testes
• Type 2 enzyme defect common.
• Pregnenolone, 17 Pregn, DHEA increased
• Types- Salt wasting & Non salt wasting.

35. • Features- Symptoms of gluco & mineralocorticoid def
• FEMALES: At birth- virilized ext gen;
Late-onset- premture pubarche, signs of hyperandrogenism (mild
clitoromegaly and labial fusion)
• MALE: Incomplete masculinization
• Autosomal recessive inheritance pattern
• Diagnosis-
1. 17 α Hydroxypregnenolone, pregnenolone, DHEA, DHEAS raised
2. Most reliable criteria- serum 17 α HP levels after ACTH stimulation

36. Pregnenlolone
Progesterone
Desoxycorticosterone
Corticosterone
18 OH Corticosterone
Aldosterone
17 OH Pregnenlolone
17 OH Progesterone
11 Desoxycortisol
Cortisol
DeHydroEpiAndrosterone
Androstendione
Testosterone Estradiol
Cholesterol
Desmolase
3 B HSD
21 OH
11 OH
18 OH
Desmolase
3 B HSD 3 B HSD
21 OH
11 OH
Survival is rare due to more proximal enzyme block
Weak Androgen
3 B Hydroxy steroid DH Deficiency:

37. TREATMENT OF CAH
GOALS-
• Classical forms of CAH – provide cortisol , reduce ACTH & prevent androgen effect.
• Mothers- prevent masculinization of female fetus
• Neonates- life saving t/t, prevent virilization
• Children- to permit normal growth & sexual maturation
• Adults- hirsutism, menstrual irreg, infertility
1. PREIMPLANTATION GENETIC DIAGNOSIS IN COUPLES AT RISK- single cell removed from
6-8 cell stage embryo
2. PRENATAL TREATMENT OF MOTHERS AT RISK –
• Dexa upto 1.5mg daily divided doses
• Begin at 4-5 wks but not later than 9wk
• S/e- failure to thrive, psychomotor devp delay (neonate), severe abd striae
hyperglycemia, HTN, GI symp (mother)
• 1 in 4 female fetus benefited. Early CVS , genotyping, sex determination recommended

39. 3. NEONATAL TREATMENT: Present with ambiguity or adrenal
crisis
• Hypotension– 10-20ml/kg 0.9% saline
• Hypoglycemia – 2-4 mg/kg 10% dextrose
• Hyperkalemia- Insulin & glucose
• Withdraw a blood sample for 17OHP etc
• 50-100 mg/m2 iv hydrocort 4 hrly until stable & feeding
normally
• 0.3mg daily fludricortisone & Na Cl 1-3 g daily
4. CHILDREN: to promote growth & decrease sex steroid
production
• Hydrocort 12-18mg/m2
Long acting glucocort can cause early closure of epiphysis
• Fludrocortisone 0.05- 0.2 mg in classical 21 HD
Overt/t- impair growth, Inadeq t/t- stimulate steroidogenesis

40. • Monitor- 3mthly infants, 4-12 mthly in children
• Measure- 17OHP (400-1200ng/dl) , Androstenedione, Plasma
renin activity, growth velocity, skeletal maturation (Bone age &
growth rate )
• GnRH agonist to prevent central precocious puberty.
• ILLNESS- ppt crises – increase hydrocort 2-3 folds (100mg),
decrease gradually
• Growth hormone & long acting GnRH agonist to maximize
height.
• S/e corticosteroid- Obesity & HTN
• SURGICAL M/m- Clitoroplasty, Separation of labial folds,
Vaginoplasty.
Postponed until child is older & can participate in decision

41. 5. ADULTS: goal is to lower & maintain androgens & adr precursors
(17 OHP)
• After epiphysial closure – Long acting glucocorticoid
• Dexa 0.25-0.75mg btwn 2AM to 10 AM
• Others- Prednisone, hydrocort
• s/e- osteoporosis, cushing syndrome
• Fludrocort 0.1-0.2mg/d
6. PREGNANCY: Hydrocort dose increased
Cesarean section

42. FETOPLACENTAL ORIGIN ANDROGEN EXCESS
1.Aromatase deficiency:
• 19 c androgen to aromatic 18 c estrogen.
• Chrm 15, AR
• Female fetal virilization , low maternal estrogen
and maternal hirsutism.
• Ambiguous genitalia, 1ry amenorrhoea with
hyperandrogenism.

43. 2.P450 oxidoreductase deficiency:-
• Chrm 7
• 46 XX (female virilization) & 46XY (incomplete male
virilization)
• Partial deficiencies in 21 hydroxylase, 17, 20 lyase & to less
extent 17 alpha hydroxylase ,aromatase.
• Cortisol levels usually Normal, Raised 17OHP, Low DHEA &
andrestenedione
• Female Virilization in utero by “backdoor androgen pathway”

45. MATERNAL ORIGIN ANDROGEN EXCESS
 Gestational hyperandrogenism
 Hirsutism, temporal balding, clitoromegaly,deepning of voice in
pregnant women.
 Early pregnancy exposure- labioscrotal fusion & clitoromegaly of
female fetus
 > 12wks- clitoromegaly
1. DRUGS-
• Danazol for endometriosis
• Progestins for threatened/ recurrent abortions
Testosterone Diazoxide
Minoxidil Danocrine
Phenytoin sodium Streptomycin
Penicillamine

46. 2. EXCESS ANDROGEN PRODUCTION-
• M/c/c- Luteomas & Theca lutein cysts
• Pelvic USG – All theca lutein cyst & ½ Luteomas are bilateral
• Surgery rarely needed as regress after delivery.
a) PREGNANCY LUTEOMA- Hyperplastic masses of lutenized cells
6- 10 cm in size
1/3 rd – maternal hirsutism
no risk to female fetus if mother not virilized
regress after delivery
b) THECA- LUTEIN CYST - Associated with increased hCG
10-20% with GTD
10- 15 cm
30% hirsute or virilize

48. OTHER DISORDERS
1. CLOACAL EXTROPHY- rectum, vg, urinary tract single orifice,
omphalocoele, imperforate anus
2. MRKH
3. MURCS- Mullerian renal cervico thoracic somatic dysplasia

49. 46 XY DISORDERS OF SEXUAL
DEVELOPMENT

50. Disorders of Gonadal (testes)
Development

51. Complete Gonadal Dysgenesis
(SWYER SYNDROME)
• Streak gonads with no AMH nor androgens
• Int gen & ext gen – female
• Cause- 10-15% Sry inactivation
• Features- Delayed puberty, 1ry amenorrhea, normal pubic
hair & normal int , ext gen
• Treatment- Gonadectomy soon after diagnosis
Female sex assignment
Estrogen for breast devp
Cyclic E & P for sexual maturation
Pregnancy by donor oocytes (IVF)

52. Partial Gonadal Dysgenesis
• Varieties of genetic mutations –
Single gene disorders (WT1, SRY, SF1, SOX9 etc)
Chrom Aberrations (Wnt4, Dax1, DMRT1)
• Mullerian struct absent or present
• Ext Gen female/ ambiguous/ male
• Other devp anomalies

53. Testicular Regression Syndrome
• Developmentally normal testes during but fetal life
regressed / lost later
• Unilateral/ bilateral
• Partial/ Complete absence of testicular tissue
• Normal male Ext Gen
• Cause- Might be catastrophic event (torsion)
• Features- Late in pregnancy- Int & Ext Gen virilize, anorchia,
small phallus, incomplete masculinization

54. Disorders of Androgen Synthesis

55. 5 α Reductase Deficiency
• AR, Type 2 enzyme defect
• Testosterone  DHT Blocked  impaired virilization
• 46XY with severe perineal hypospadias (phallus size btwn penis & clitoris,
chordee tethering phallus into perineum, urethra on perineum, small vg)
• Ext Gen- Female
• Int Gen- Male
• Testes in inguinal canal/ labia majora/ scrotum & impaired spermatogenesis
• Virilize to varying degrees at puberty
• Breast like normal male (contrast to AIS)
• Less body hair, less temporal hairline recession, no acne (Less DHT)
• Females- Body hair reduced, delayed menarche

56. urogenital sinus with separate
urethral and vaginal openings,
and posterior labioscrotal fusion
clitoromegaly with marked
labioscrotal fusion and small
vaginal introitus

57. Diagnosis -
• Infants with ambiguous genitalia , Adolescents phenotype
• serum hormone profile (normal testosterone, increased TT/DHT ratio > 10
infants, >20 in children & adults)
• hCG stimulation test- measure testosterone & DHT before & after (3rd & 6th
day) administration of 1500 IU/m2 hCG
Management- Sex assigned according to sex of rearing & psychological sex .
• Female- Gonadectomy , Clitoroplasty, Vaginoplasty, Estrogen t/t at puberty or
after gonadectomy
• Male- Hypospadias & cryptoorchidism correction, Testosterone t/t

58. 3β-Hydroxysteroid Dehydrogenase Deficiency
• incomplete masculinization with salt-wasting  impaired aldosterone and
cortisol synthesis
• a small phallus, hypospadias with labioscrotal fusion, a urogenital sinus, and a
blind-ending vaginal pouch. Testes are often scrotal, and wolffian ducts
develop normally
• diagnosis: increased levels of 3β-hydroxysteroids (pregnenolone, 17-
hydroxypregnenolone, and DHEA)
17α-Hydroxylase Deficiency
• conversion of pregnenolone and progesterone to 17-hydroxypregnenolone
and 17-hydroxyprogesterone
• impaired cortisol production ACTH hypersecretion  increased DOC,
corticosterone, and 18-hydroxycorticosterone in the adrenals
• These mineralocorticoids  salt and water retention, HTN, and hypokalemia
• FEMALE- 1ry amenorrhea, delayed puberty, hypergonado hypogonadism, HTN
hypokalemia
• MALE- Ext g- female, Int Gen- Male & Intraabd testes
• T/t- Glucocort, Estrogen therapy

60. 17,20-Lyase Deficiency
• cortisol and ACTH secretion are normal aldosterone normal  no HTN
• ambiguous rather than totally female genitalia at birth
• suspect this dx if absent müllerian derivatives and no defect in glucocorticoid or
mineralocorticoid synthesis.
17β-Hydroxy steroid Dehydrogenase Deficiency
• Most common hereditary defect in testosterone synthesis
• Type 3 convert Androstenedione  androgen, testosterone
• Male- normal int gen & undescended testes, Ext gen- female (blind vagina)
At puberty  Virilization phallic growth and male secondary sexual characteristics
• Diagnosis- Androstenedione  increased to 10 to 15x normal
Testos/ Androstn <0.8- 0.9 after hcg stimulation
• T/T- Gonadectomy, Estrogen therapy (if reared as F)

61. P450 Oxidoreductase deficiency-
As described earlier
StAR protein deficiency- Chrm 8p
• Congenital Lipoid Adrenal Hyperplasia
• Rarest & severest form of CAH
• Def of all adr & gonadal steroid hormones, raised ACTH, Adr hyperplasia,
cholesterol ester accumulation
• Infants- Severe adrenal insufficiency
• Male- Ext g is female, a blind-ending vaginal pouch
intra-abdominal, inguinal, or labial testes
absence of mullerian structures & Wolffian ducts are present but rudimentary
• Female- Normal genitalia & puberty
• T/t- Gluco & mineralo
• Abdominal CT scan- large, lipid-laden adrenal glands

62. Disorders of Androgen Action
ANDROGEN INSENSITIVITY SYNDROME

63. Complete Androgen insensitivity syndrome
• Testicular Feminization syndrome
• 1 in 20,000 to 1 in 60,000 males
• Chrm Xq12 (X linked recessive)
• Normal testes  AMH  suppress mullerian & descent of testes up to inguinal
canal
• Ext G- Female, Axillary & Pubic hair absent, Breast enhanced, Good height
• Presentation- Female with 1ry amenorrhea 2% of female with hernia
• Unequivocal female gender identity androgen resistance of brain tissue
• Serum Testos N/raised, LH increased, FSH normal, Estrogen raised, DHT decreased
• T/t- Hormone therapy, Vaginoplasty, Gonadectomy  after puberty (16-18 yrs)
• Low (5-10%) risk of seminoma or gonadoblastoma before puberty
• Testis produces estradiol  helps feminization

65. Incomplete Androgen Insensitivity
• Reduced number of normally functioning androgen receptors
• Normal receptor number but decreased binding affinity

67. Reifenstein
Syndrome

68. Infertile Male
• Mildly under masculinized & infertile
• Normal Ext & Int G, normal testes, some gynecomastia
• 10% men with azoospermia / severe oligospermia have Partial AIS
• Decreased androgen receptor binding to DHT in genital skin fibroblasts
Diagnosis of AIS- Most reliable method- sequence AR gene

69. 5α-reductase Complete Incomplete Reifenstein Infertile
Inheritence Autosomal
recessive
X-linked
recessive
X-linked
recessive
X-linked
recessive
X-linked
recessive
Spermatoge
nesis
Decreased Absent Absent Absent Decreased
Mullerian Absent Absent Absent Absent Absent
Wolffian Male Absent Underdevp Male Male
External Female Female Female
clitoromegaly
Male
hypospadias
Male
Breasts Male Female Female Gynecomastia M (Gynecomastia)

70. MANAGEMENT OF INCOMPLETE AIS
• Appropriate gender assignment- Size of phallus & feasibility of constructing male
urethra
• Hormone therapy- Estrogen therapy for female after puberty.
Female Children- consider growth percentile, velocity, bone age, target
height & predicted adult height.
Boys- with Reifenstein syndrome – High dose testosterone
Adult men- Might improve masculinization
• Psychological support- early disclosure
• Gonadectomy- Earlier to prevent virilization at puberty (F) & maximise
function(M)
• Reconstructive surgeries
• Gynecomastia in men – mastectomy (Risk of breast ca raised in Reifenstein)

71. LH Receptor Defects
• AR
• Inactivating mutation in LH/hCG receptor gene  Leydig cell
hypoplasia  decrease testosterone production
• Mullerian – Absent (Normal AMH)
• Wollfian – Impaired (Decreased Testos)
• Testes – Undescended (require IGF3 & Testos, both by Leydig)
• Phenotype – Completely N female to nearly N Male
• At puberty - Females present with 1ry amenorrhea, sexual infantalism,
Pubic hair & Breast Absent
• LH raised & testosterone decreased

72. Disorders of AMH & its Receptor
• Hernia uterine inguinale syndrome
• AR
• AMH receptor gene defect  mullerian persists
• AMH gene 45%, AMHR2 receptor gene 39%, No mutation detected
15%
• Normal male Int & Ext Genitalia ,
• Cryptorchid testes &
• Inguinal hernia containing Mullerian structures during hernia repair
• M/M- Require orchidopexy
• Vas deferens are in close proximity to the uterus and proximal
vagina not to remove  to preserve fertility
• Malignancy of retained müllerian structures has not been reported

73. THANK YOU…to be continued

75. TRUE HERMAPHRODITISM
• Gonads :
- ovary one side and testis on the other or
- bilateral ovotestis
• Karyotype :
46,XX most common(57%); XY(13%) and XX/XY(30%)
• Internal genitalia :
Both mullerian and wolffian derivates
• Phenotype is variable
•

76. XX XY
XX O X Y
XXX XO XXY YO
OVUM SPERMATOZOON
NON-DISJUNCTION

77. Turner’s Syndrome (45,XO)
 1 in 2500 live births
 60% are 45,XO and 40% are mosaics
 No oocytes remain in the ovaries, which
become streaks
 Ovum donation for those with bilateral streaks
 33% - 60% have structural or positional
abnormalities of the kidney
 horseshoe kidney = 10%,
 duplication or renal agenesis= 20%
 malrotation= 15%
 multiple renal arteries = 90%
 Four classic features:
 female phenotype
 short stature
 lack of secondary sexual characteristics
 a variety of somatic abnormalities:
Cubitus valgus
Wide spaced nipples
Broad chest (shield)
Webbed neck
Short stature
peripheral edema at birth, short 4th metacarpal,
hypoplastic nails, multiple pigmented nevi,
coarctation of the aorta, and renal anomalies

78. Characteristics
1. Short slender female less than 5 ft.
2. Secondary sexual ratio altered
3. Breast B0 or B1
4. Body hairs absent
5. Shield chest,webbing of neck,cubitus
valgus
6. CVS abnormalities (aortic
stenosis,coarctation of aorta)
7. Urinary abnormalities
8. Mental retardation
9. External genitalia poorly developed.
10. Uterus and tubes –hypoplastic
11. Internal gonads-agenetic or
dysgenetic
12. Primary ovarian failure
13. Colour blindness and multiple navi
on skin
14. Hashimoto’s thyroiditis,Addison’s
disease and vitiligo are common.
15. Anormality of lymphatic system
may sometimes cause gross swelling
of thelegs in the child or adult.

79. Seminiferous Tubule Dysgenesis (Klinefelter's
syndrome) Syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased
gonadotropin levels, and small, firm testes, 47,XXY karyotype
 nondisjunction during meiosis
 1 of 1000 liveborn males
 associated with 48,XXYY; 49,XXXYY; 48,XXXY; 49,XXXXY; 46,XY/47XXY
 Gynecomastia can be quite marked at pubertal development
 8 X risk for breast carcinoma compared with normal males
 Seminiferous tubules degenerate and are replaced with hyaline
 After birth tubules are aplastic and functionless so sterility is the rule.
 decreased androgens prevents normal secondary sexual development
 poor muscle development, the fat distribution is more female than male.
 Normal amounts of pubic and axillary hair, but facial hair is sparse.
 Patients tend to be taller than average, due to disproportionately long legs
 Predisposed to malignant neoplasms of extragonadal germ cell origin.
 Androgen supplementation to improve libido & reduction mammoplasty

80. Klinefelter's syndrome

81. 46,XY Complete Gonadal Dysgenesis
 Characterized by :
 normal female genitalia
 well-developed müllerian structures
 bilateral streak gonads
 nonmosaic karyotype
 Ambiguity of genitalia is not an issue
 Sexual infantilism is the primary clinical problem
 present in their teens with delayed puberty
 An abnormality of the Sry gene function, or loss of another gene
downstream from Sry that is necessary for SRY protein action
 LH elevated  clitoromegaly
 30% risk of germ cell tumor development by age 30 years
 gonadoblastoma is most common
 embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, and immature teratoma
have also been reported
 Management  removal of both streak gonads and proper cyclic hormone
replacement with estrogen and progesterone

82. Mixed gonadal dysgenesis (MGD)
 Characterized by a unilateral testis, often intra-abdominal
 Contralateral streak gonad
 Persistent müllerian structures with varying inadequate masculinization
 Most are 45,XO/46,XY, the most common form of Y chromosome mosaicism
 Second most common cause of ambiguous genitalia after CAH
 Dysgenetic or streak gonad is associated with ipsilateral mullerian derivatives (uterus,
fallopian tube)
 Well-differentiated testis with functional Sertoli and Leydig cells will have ipsilateral
wolffian but no mullerian ducts
 no germ cells so infertility is the rule
 Increased risk of developing gonadoblastoma or dysgerminoma of 15% to 20%
 Also increased risk for Wilm’s tumor .
 Endocrine function of testis is normal post-pubertally
 fetal testis dysfunction may account for ambiguous genitalia
 90% to 95% of 45,X/46,XY mosaicism have normal-appearing male genitalia

83. Bilateral dysgenesis of testes( Swyer
Syndrome)
XY karyotype with mutation in SRY gene.
Fibrous bands in place of gonads.
Female internal and external genitalia
presents with primary amenorrhea and lack of
secondary development at puberty.
To prevent neoplasia removal of band areas is
advocated as diagnosis is made.

84. Anorchia
XY individual with infantile umambiguous
male external genitalia and male wolffian
ducts and lack mullerian ducts.
No detectable testes, early testes did occur
but was not sustained in sufficient amount or
duration to develop normal size phallus.
Also known as “disappearing testis
syndrome”.

85. Noonan syndrome
Inheritence autosomal dominant
Both affected male and females have normal
chromosome complements and normal gonadal
function.
The phenotypic appearance is that of a patient
with turner syndrome. The cardiac lesions are
different, pulmonic stenosis as opposed to aortic
coarctation.
These are fertile.

86. AMBIGUOUS GENITALIA AT
BIRTH
The external genital organs look
unusual, making it impossible to
identify the sex of the newborn
from its outward appearance.
Any one of the following :
 A small, hypospadiac phallus
and unilaterally
undescended gonad.
 An enlarged phallus with
bilaterally impalpable
gonads.
 An enlarged phallus and a
vagina in the same infant.

87. MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
GENERAL GIUDELINES
Medical and social emergency
Avoid immediate declaration of sex
Proper counselling of the parents
Team management; obstetrician,
neonatologist, pediatric endocrinolgist,
genetist and paediatric surgeon.

88. MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
DIAGNOSIS
History : pregnancy; family
Detailed examination : abdomen; pelvis;
external genitalia; urethral and anal
openings.
Federman’s rule: a palpable gonad below the
inguinal ligament is testes until proven
otherwise

89. MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
Investigations
• Rule out cong. Adrenal hyperplasia: Serum electrolytes; 17-
OHP level and urinary levels of 17-ketosteroids
• Karyotype ( buccal smear; blood)
• Pelvic US and sometimes MRI or Genitogram
• Skin biopsy; fibroblast culture to measure 5alpha-reductase
activity or dihydrotestosterone binding
• Laparoscopy
• Gonadal biopsy (laparotomy)

90. Sex assignment
1)Phallus length- Male gender assignment :
- stretched phallus > 2.5 cm
- erectile tissue
- lack of severe hypospadias
Female gender assignment :
- clitoris < 1cm
- cervix and uterus present.
2) Degree of labioscrotal fold fusion
In difficult cases; sex assignment should be
to the sex which can be surgically made to be
adequate for coitus

91. DDx Algorithm

92. SURGICAL CONSIDERATIONS
 Phallic / clitoral reduction if the assigned sex is female, before 3 years
of age
 Removal of intra-abdominal gonads / streaks in newborns carrying Y
chromosome
 Vaginal construction / repair is better performed around puberty

93. Before surgery After surgery

94. GONADECTOMY

95. VAGINAL CREATION

96. Vaginal dilatation

97. McIndoe Vaginoplasty

98. William’s vulvo-vaginoplasty

99. Colovaginoplasty

100. Transsexualism
 Transsexualism occurs when a person strongly
believes that he or she belong to the opposite sex.
 This is typically a lifelong feeling and results in
varied degrees of physical/external changes
 These patients should be referred to the psychiatrist

101. THANKYOU