Genital system anomalies (1): Hermaphroditism

Embryology Course, Second year, Faculty of Medicine, Damascus University

1. Genital System Anomalies (1)
www.marwanalhalabi.com
Marwan Alhalabi
Professor of Reproductive Medicine and Infertility,
Damascus University
Head of Assisted Reproduction Unit, Orient Hospital
President of Middle East Fertility Society
President of Syrian Society of Obstetricians and Gynecologists

2. SRY-gene (TDF)
Short arm of Y chromosome
Bipotential
Gonad
2 X chromosomesReceptors
For H -Y antigen
OVARYTESTES
Present Absent
Gonadal development

3. Indifferent
embryo
Weeks 1-6 sexually indifferent or
undifferentiated stage
Week 7 begins phenotypic sexual
differentiation.
The sex of the fetusmay be discerned
by ultrasound as early as 12 weeks
gestation.
However, it can be determined with 95-
100% accuracy only at or after 20
weeks.

5. Paramesonephricor
Mullerian Duct
develops lateral to
the Mesonephric
”wolffian“Duct
At 6THweek gestation

6. •The middle and caudal parts of the
Mullerianducts undergoes medial
migration and fusion.
•The cranial 1/3 → tubes.
•The middle 1/3 → uterus and cervix.
•The caudal 1/3 → upper 3/4 of vagina.

7. •The cranial 1/3 → tubes.
•The middle 1/3 → uterus and cervix.
•The caudal 1/3 → upper 3/4 of vagina.

8. 2 main Principle
•Internal genital organs develop in close
association with urinary tract So gross
malformation of uterus and tube are
commenalyassociated with anomalies of
kidney and ureter.
•Development of gonads is separate from that
of the ducts So functional ovary are usually
present when uterus, vagina are absent

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

10. Leydig
cells
Sertoli
cells
Testosterone Mullerian inhibiting
factor
Wollfian duct5a-reductase
Urogenital sinus
Regression of
Mullerian ducts
Male external genitalia
Male internal
Genital organs
DHT
TESTIS
Male development

11. Hermaphroditism
(inter sexuality)

12. Ambiguous genitalia is a condition in which an infant's
external genitals don't appear to be clearly either male or
female. In ambiguous genitalia, a baby's genitals may not
be well formed or the baby may have characteristics of
both sexes. In a baby with ambiguous genitalia, the
external sex organs may not match the internal sex organs
Definition

13. Hermaphroditism

14. 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, hypospadiacphallus and
unilaterally undescended gonad.
•An enlarged phallus with
bilaterally impalpable gonads.
•An enlarged phallus and a vagina
in the same infant.
Ambiguous Genitalia at Birth

15. 1:2000new born mainly (more than 95%) is
due to congenital adrenal hyperplasia.
Incidence:

16. 1. Virilizationof geniticallyfemale fetus
(Female pseudohemaphroditism).
Classification Of Intersexuality
2. Incomplete musculinizationof geniticallymale
fetus (Male pseudohermaphroditism).

17. EXCESS FETAL ANDROGENS
Congenital adrenal hyperplasia
•21-hydrxylasedeficiency
•11-hydroxylase deficiency
•3ß-hydroxysteroid
dehydrogenase deficiency
EXCESS MATERNAL ANDROGENS
•Maternal androgen secreting tumors (ovary, adrenal)
•Maternal ingestion of
androgenic drugs
Female Pseudohermaphroditism

18. •The commonest cause of genital
ambiguity at birth
•21-Ohas deficiency is most common
form
•Autosomal reccessive
•Salt wasting form may be lethal in
neonates
•ÇSERUM 17OH-progesterone
(21OHase)
•ÇSERUM deoxycorticosterone, 11-
deoxycotisol (11-OHase)
Congenital adrenal hyperplasia

19. -Testosterone
-Synthetic progestins
-Danocrine
-Diazoxide
-Minoxidil
-Phenytoin sodium
-Streptomycin
-Penicillamine
Drugs with Androgenic side effects
ingested during pregnancy

20. Femalepseudohermaphroditism(causedby
congenitaladrenal hyperplasia)

21. Failure to produce testosterone
gPure XY gonadal dysgenesis
(Swyer’ssyndrome)
gAnatomical testicular failure
(testicular regression syndrome)
gLeydig-cell agenesis
gEnzymatic testicular failure
Failure to utilize testosterone
g5-alpha-reductase deficiency
gAndrogen receptor deficiency
* Complete androgen
Insensitivity (TFS)
* Incomplete androgen
Insensitivity
Male pseudohermaphroditism
(XY-FEMALE)

22. Testicular feminization syndrome
46-XY/SRY
TESTIS _AMH
Testosterone
5-µ-reductase
DHT
Absent androgen
receptors
Male
Internal
Genitalia
Female
External
Genitalia
Incomplete form aAmbiguous genitalia

23. •Thepresenceofbothovarianandtesticulartissuein
thesameindividual,(Truehermaphroditism).
•Chromosomalabnormality…..(Mixedgonadal
dysgenesis(45,X0/46,XY)
Classification of Intersexuality

24. • 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 mullerianand wolffianderivates
• Phenotype is variable
• Gonadal biopsy is required for confirming diagnosis
OvotesticularDSD
(True Hermaphroditism)

25. True
Hermaphroditism

26. •Presence of one functioning X
Chromosome
•1 in 2500 females. Mosaicism45 X/46 XX
(10%) or 45 X/46 XY (3%)
•Oocytes degenerate leaving streak gonads
(in broad lig.) at birth
•Reduced Oestrogen, Raised FSH/LH. No
pubertal development.
Features:
1. Female Phenotype
2. Short Stature
3. No Secondary Sexual
Characteristics
4. Somatic Abnormalities
-Webbed Neck
-Broad Chest
-Short Ring finger
Renal Anomalies:
90% Multiple Renal Arteries
20% Renal agenesis/Duplication
15% Malrotation
10% Horseshoe kidney
Gonadal Dysgenesis
Turners Syndrome (45 X0)

27. Turner syndrome”ovarian dysgensis”

28. Karyotype 45,X (60%)
(45,X/46,XX, structuralabnormalitiesofX chromosome)
Shortstature(finalheight142-147cm)
Gonadaldysgenesis-streak gonad & sexual infantilism
Skletalabnormalities& dysmorphic face
Cardiacand kidneymalformation
Autoimmune ds : Hashimoto’s thyroditis, Addison’s ds
Mild insulin resistance & hearing loss
Lymphedema
Essential hypertension
No mentaldefect
Impairmentofcognitivefunction: mathematical ability↓
Visual–motor coordination, spatial-temporal processing↓
H. Tuner, 1938
Turner syndrome”ovarian dysgensis”

29. Turner syndrome”ovarian dysgensis”

30. *Enlarged clitoris looks like a small penis
*Urethral opening can be along, above, or below surface of the
clitoris
*Labiamay look like a scrotum
*Infant may be thought to be a male with testiclesthat have not
descended
*Lump of tissue may be felt in the labia, making it look like a scrotum
with testicles
AmbiguousGenitaliain GeneticFemales

31. *Smallpenisthatlookslikeanenlargedclitoris
*Urethralopeningmaybealong,above,orbelowthepenis
Canbeaslowasontheperineum,makingtheinfantappearto
befemale
*Possiblyasmallscrotumthatisseparated,lookslikelabia.
*Testiclesthatarenotdescendedareacommonoccurrence
AmbiguousGenitaliain GeneticMales

32. *Impaired Testicle Development
*Congenital Adrenal Hyperplasia (CAH)
Can impair production of male hormones
*Androgen Insensitivity Syndrome
Developing genital tissues don't respond normally to male
hormones
Possible Causes for Males

33. *Congenital adrenal hyperplasia (CAH)
Can cause the adrenal glands to make excess male hormones.
CAH-most common cause of DSD
*Prenatal Exposure to Substances with Male Hormone Activity
Example: Anabolic Steroids
*Tumors
Rare, but a tumor may produce male hormones
Possible Causes for Females

34. What does it look like?

35. 1) True hermaphrodism
2) Female pseudo-hermaphrodism
3) Male pseudo-hermaphrodism
4) Testicular feminization
5) Ovarian hypoplasia

36. Case 1
Hermaphroditism

37. True Hermaphroditism
•In most patients, the external genitalia are ambiguous but masculinized to variable degrees, and 75% are raised as male
•Internal ductal development are influenced by ipsilateral gonad
•Fallopian tubes are consistently present on the side of the ovary
•a vas deferens is always present adjacent to a testis
•Fallopian tube is present with 66% of ovotestes, vas or both in 33%
•Most have urogenital sinus and and uterus
•80% of those raised as male have hypospadias and chordee
•Ovaries usually on left in normal position, testis usually on right and located anywhere along path of descent
•60% of gonads palpable in canal or labia are ovotestes

38. •GENERAL GIUDELINES
•Medical and social emergency
•Avoid immediate declaration of sex
•Proper counselling of the parents
•Team management; obstetrician,
neonatologist, pediatric endocrinologist,
genetistand pediatric surgeon.
Management Of Newborn With Ambiguous
Genitalia

39. Before surgeryAfter surgery
Management Of Ambiguous Genitalia

40. THANK YOU
FELLOWS !

41. Acknowledgement

43. 43
Thank you

44. Ambiguous genitalia
•Physical examination
•Pelvic ultrasonography
•Hormonal studies
•Examination of a buccalsmear for sex chromatin
•Karyotyping
•And consultation with specialists

45. Female pseudohermaphroditism
•Genetic females (45,XX)
•Ovaries but with secondary sexual characteristics or external genitalia
resembling those of a male
•Caused by masculinization occurring in utero (Androgens)
•Presenting with ambiguous genitalia.
•Ex. Congenital adrenal hyperplasia
ØDefect in production of cortisol.
ØExcessive adrenal androgens must be produced to overcome the
decrease in cortisol production.
ØEnlargement of the clitoris is the most conspicuous abnormality

49. the diagnosis is not suspected until signs of salt-wasting
develop a week later, due in particular to the lack of aldosterone.
When the external genitalia are ambiguous is necessary to
investigate for the presence of a uterus and ovaries. The
diagnosis can be confirmed when levels of serum
testosterone result to be extensively increased while anti
mullerianhormone is not present.

50. Male pseudohermaphroditism
Androgen insensitivity
•Genetic males (45,XY)
•Deficit in testosterone production or action
•These individuals have testes, but their genital ducts and
external genitalia are female
•Occur with varying degrees of virilizationand müllerian
development
•Ex. 5-alpha-reductase deficiency

51. Quigley scale
•Grade 1 includes individuals whose external genitalia are fully masculinized,
condition that correspond to mild androgen insensitivity syndrome.
•Grade 6 and 7 includes individuals whose external genitalia are fully
feminized.

55. True hermaphroditism
•Dual gonadal development occurs, either in the form of an
ovotestisor as a separate ovary and testis
•Most true hermaphrodites have some degree of both
female and male development internally and externally
•The extent to which masculinization occurs depends on the
relative amount of testicular tissue and its relative
contribution of testosterone