WALLAGGA UNIVERSITY
INSTITUTE OF HEALTH SCIENCES
SCHOOL OF NURSING AND MIDWIFERY
DEPARTMENT OF NURSING
MATERNITY II ASSIGNMENT
TITLE GTD AND FEMALE CONGENITAL MALFORMATION
BY BEKAN G AND CHALTU K
NOV, 2022

COURSE OUTLINES
 Objectives
 Introduction
 Epidemiology
 Pathogenesis
 Risk factors
 Clinical manifestations
 Types of GTD
 Staging
 Investigations
 Mgt
 Post treatment surveillance
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OBJECTIVES
 At the end of the session the students will able
to:
 Define gestational trophoblastic diseases
 Discuss the pathogenesis of molar pregnancy
 Differentiate types of GTD
 Manage molar pregnancy
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INTRODUCTION
 Gestational trophoblastic disease (GTD) is a proliferative
disorder of trophoblastic cells.
 It defines a heterogeneous group of interrelated lesions
arising from the trophoblastic epithelium of the placenta.
 All forms of GTD are characterized by a distinct tumor
marker, the beta subunit of human chorionic gonadotropin
(hCG).
 The pathogenesis of GTD is unique because:
 the maternal tumor arises from gestational rather than
maternal tissue.
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INTRO…
 There are several histologically distinct types of GTD.
 Hydatidiform mole (complete or partial)
 Persistent/invasive gestational trophoblastic neoplasia
(GTN)
 Choriocarcinoma
 Placental site trophoblastic tumors
 Complete and partial hydatidiform moles are noninvasive,
localized tumors that develop as a result of an aberrant
fertilization event that leads to a proliferative process.
 They comprise 90 percent of GTD cases.
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INTRO…
 The other three categories of GTD represent malignant disease
because of their potential for local invasion and metastases.
 Malignant GTD can develop from
 Molar pregnancy or
 Gestational experience:
 spontaneous or induced abortion,
 ectopic pregnancy, or
 preterm and term pregnancy.
 Malignant transformation of trophoblastic tissue is probably
related to activation of oncogenes and inactivation of tumor
suppressor genes.
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EPIDEMIOLOGY
 The incidence of GTD varies widely in different regions of
the world.
 The incidence of hydatidiform mole ranges from 23 to
1299 cases per 100,000 pregnancies, while malignant GTD
is less common.
 North American and European countries tend to report low
rates of disease (1 per 1000 to 1500 pregnancies),
 The reason for this variation is that epidemiologic data on
GTD are limited by the rarity of the disease and
inaccurate ascertainment of the number of cases.
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PATHOGENESIS OF GTD
 Gestational trophoblastic disease (GTD) — Lesions characterized
by abnormal proliferation of trophoblast of the placenta.
 This category is comprised of benign, nonneoplastic lesions including
placental site nodule, exaggerated placental site and hydatidiform
moles as well as malignant neoplasms.
 Gestational trophoblastic neoplasia (GTN) —include:
choriocarcinoma, placental site trophoblastic tumor, epithelioid
trophoblastic tumor, and invasive moles that do not resolve
spontaneously.
 Disease diagnosed as a result of persistent elevation of hCG after
evacuation of a molar pregnancy
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PATHO…
 It is known that imprinting has a role in the development
of GTD.
 Paternal genes have more control over placental growth
while maternal genes have more control over fetal
growth.
 With excess paternal genes, there is excessive placental
or trophoblastic proliferation.
 There is also a difference between the malignant potential
of moles that are heterozygous (arising from two sperm)
and homozygous (arising from a single sperm with
duplication of DNA)
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PATHO…
 Molecular pathways that might contribute to the
development of GTD.
 Somatic point mutations and instability of mitochondrial
DNA
 Amplification and overexpression of various oncogene
products, such as c-erbB-2, c-myc, c-fms and mdm-2.
 Epidermal growth factor receptor (EGFR)
 Downregulation of tumor suppressor genes, including
p53, p21 and Rb,
 Telomerase activity and expression of cell-cell adhesion
molecules,
 Metalloproteinases, and tissue inhibitors of
metalloproteinases
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RISK FACTORS
 Extremes of age- older than age 35 and slightly
increased in those under age 20.
 History of previous GTD
 Current smoking (>15 cigarettes per day),
 Maternal blood type AB, A, or B,
 History of infertility,
 Nulliparity
 Deficiency in vitamin A
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CLINICAL MANIFESTATIONS
 Clinical manifestations of GTD include, in
decreasing order of frequency:
 Vaginal bleeding
 Enlarged uterus
 Pelvic pressure or pain
 Theca lutein cysts
 Anemia
 Hyperemesis gravidarum
 Hyperthyroidism
 Preeclampsia before 20 weeks of gestation
 Vaginal passage of hydropic vesicles
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TYPES OF GTD
 There are various histologically distinct
subtypes of GTD:
1. Benign nonneoplastic trophoblastic lesions
 Exaggerated placental site
 Placental site nodule
2. Hydatidiform mole
 Complete hydatidiform mole
 Partial hydatidiform mole
3. Gestational trophoblastic neoplasia (GTN)
 Invasive mole (chorioadenoma destruens)
 Choriocarcinoma
 Placental site trophoblastic tumor
 Epithelioid trophoblastic tumor
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TYPES….
 Clinical classification of GTD
1. Benign gestational trophoblastic disease
 Complete hydatidiform mole
 Partial hydatidiform mole
2. Malignant trophoblastic disease
 Invasive mole (chorioadenoma destruens)
 Choriocarcinoma
 Placental site trophoblastic tumor
 Epithelioid trophoblastic tumor
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PATHOLOGIC AND CLINICAL CLASSIFICATIONS FOR
GESTATIONAL TROPHOBLASTIC DISEASE
PATHOLOGIC CLASSIFICATION CLINICAL
CLASSIFICATION
Hydatidiform mole
*complete
*incomplete
Benign gestational
trophoblastic disease
Invasive mole Malignant
trophoblastic disease
Nonmetastatic
Placental site trophoblastic tumor Metastatic
Choriocarcinoma High risk Low risk
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TYPES….
I. BENIGN NONNEOPLASTIC TROPHOBLASTIC LESIONS.
 Are frequently diagnosed only as an incidental finding in a
pathology specimen after uterine curettage or hysterectomy.
1. Exaggerated placental site.
 characterized by an extensive infiltration of the endometrium and
myometrium by implantation site that occur in clusters or as single
cells.
 There is no destruction of the normal endometrial glands and stroma
 It likely represents an excessive physiologic process rather than a
true lesion;
 the distinction between a normal placental site and an EPS is often
subjective.
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TYPES…. EPS
 occur in a normal pregnancy or after a first trimester abortion or
within current pregnancy.
 The associated placenta is usually normal.
 However, it occurs with increased frequency in molar pregnancies
and thus can give a clue to diagnosis of these lesions.
 The trophoblastic cells contain cytoplasm with hyperchromatic,
irregularly shaped nuclei, but fail to show mitotic activity.
 The lack of mitotic activity and association with chorionic villi is an
important clue in diagnosis, between EPS and placental site
trophoblastic tumor
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TYPES….PSN
2. Placental site nodule
 Are found in uterine curettages and cervical or
hysterectomy specimens in reproductive age patients.
 40 % located in the endocervix, 56 % the endometrium, and
4 % found in the fallopian tube,
 The intermediate trophoblastic cells of PSNs are likely
derived from
 the migratory intermediate (extravillous) trophoblasts
of the placenta.
 They represent the nonneoplastic counterpart of epithelioid
trophoblastic tumors
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TYPES….PSN
 They are occasionally found as multiple nodules
or plaques.
 They tend to have vacuolated cytoplasm and a
somewhat degenerated appearance.
 Mitotic figures are rare and usually absent.
 Histologically, the nodules are well circumscribed
and surrounded by a thin rim of chronic
inflammatory cells.
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TYPES…
II. HYDATIFORM MOLE
 Is the most common form of GTD, representing 80 % of
cases.
 Moles may be complete, partial.
 Complete and partial hydatidiform moles are
differentiated by
 karyotype,
 gross morphology,
 histologic appearance, and
 clinical features
 The development of GTN is significantly increased after
a complete mole, but only slightly increased after a
partial mole.
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TYPES…
 The microscopic appearance of hydatidiform
mole:
• Hyperplasia of trophobasitc cells
• Hydropic swelling of all villi
• Vessles are usually absent.
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TYPES…
 A sonographic findings of a molar pregnancy. The
characteristic “snowstorm” pattern is evident.
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TYPES…
 Color Dopplor facilitates visualization of the
enlarged spiral arteriesclose proximity to the
“ snow storm” appearance
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TYPES…MOLAR
A. Complete mole
 The chorionic villi of a complete mole are diffusely
hydropic and surrounded by hyperplastic, often
atypical, trophoblast
 Fetal tissue is not typically present.
 C/F-excessive uterine size for the expected
"gestational age, elevation in serum hCG , theca
lutein cysts; hyperemesis gravidarum; early
development of preeclampsia and hyperthyroidism,

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TYPES…MOLAR
 Complete hydatidiform mole demonstrating
enlarged villi of various size
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TYPES…MOLAR
 Hydatidiform mole: specimen from suction
curettage
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TYPES…MOLAR
 A large amount of villi in the uterus.
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TYPES…MOLAR
Pathogenesis of complete mole
 Most commonly has a 46,XX karyotype, with all
chromosomes of paternal origin.
 This results from fertilization of an "empty" egg (I e,
absent or inactivated maternal chromosomes) by a haploid
sperm that then duplicates (46,YY moles do not occur
because this karyotype is lethal).
 A small number (3 to 13 percent) of complete moles have
a 46,XY chromosome complement; this is thought to occur
when an empty ovum is fertilized by two sperm.
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TYPES…MOLAR
 A few complete moles have a 46,XX karyotype but develop
from fertilization of an empty ovum by two sperm,
 Because the nucleus is entirely paternal in origin, a complete
mole is actually a paternal allograft in the mother.
 Rarely, complete moles are biparental and are associated with
an autosomal recessive condition predisposing to molar
pregnancy.
 These patients often have recurrent hydatiform moles
 This defect is likely due to dysregulation of genomic
imprinting, and a mutation at the 1.1 MB region on
chromosome 19q13.4
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TYPES…MOLAR
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TYPES…MOLAR
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TYPES…MOLAR
Partial mole
 They are usually (about 90 percent) triploid (69,XXX,
69,XXY, rarely 69,XYY) due to
 the fertilization of an ovum (one set of haploid
maternal chromosomes) by two sperm (two sets of
haploid paternal chromosomes).
 The fetal or embryonic tissue that is present with a
partial mole will most commonly have a triploid
karyotype.
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TYPES…MOLAR
 Characterized by a marked proliferation of villous
trophoblast associated with hydropic swelling of the
chorionic villi.
 These pregnancies are infrequently associated with
 excessive uterine size, ovarian enlargement,
preeclampsia, hyperemesis, or hyperthyroidism
because:
 hCG levels are generally lower than those
observed with a complete mole.
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TYPES…MOLAR
 Partial hydartidiform mole
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TYPES…MOLAR
Pathogenesis
 They are usually (about 90 percent) triploid
(69,XXX, 69,XXY, rarely 69,XYY) due to:
 the fertilization of an ovum (one set of
haploid maternal chromosomes) by two sperm
(two sets of haploid paternal chromosomes).
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TYPES…MOLAR
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COMPLETE VERSUS PARTIAL MOLE
Feature Complete mole Partial mole
Incidence 1/1500 pregnancies 1/750 pregnancies
Karyotype Diploid: 46,XX (46,XY) Triploid: 69,XXX,
69,XXY (rarely
69,XYY)
Embryonic/fetal tissue Absent Present
Villi Diffusely hydropic Focal
Trophoblastic
proliferation
Hyperplastic Less trophoblastic
hyperplasia
Immuncoytochemistry hCG*, rare PLAP hcG, PLAP, p57
Uterine size Often large for dates Often small for dates
Theca lutein cysts Present in ≤25 percen Rare
Persistent mole 15 to 20 percent 3 to 5 percent
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TYPES…MOLAR
Diagnosis of Hydatidiform mole
History and physical diagnosis
• Quantitative beta-HCG( elaborates unique tumor marker
for diagnosis & follow-up)
• Ultrasound
 The classic image is of a “snowstorm” pattern in
complete mole
 focal cystic spaces in the placental tissues and an
increase in the transverse diameter of the gestational
sac in partial mole(‘honeycomb’ like placenta)
 Lutein cysts
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TYPES……GTN
III.GESTATIONAL TROPHOBLASTIC
NEOPLASIA
 The group of true gestational trophoblastic
neoplasia includes
 Invasive mole
 choriocarcinoma,
 placental site trophoblastic tumor (PSTT), and
 epithelioid trophoblastic tumor (ETT).
 Each of these neoplasms can follow a normal
pregnancy or a molar pregnancy.
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TYPES……GTN
A. Invasive mole
 Characterized by the presence of enlarged hydropic villi
invading into the myometrium, into vascular spaces, or into
extrauterine sites.
 The abnormal villi penetrate deeply into the myometrium.
 These lesions may be differentiated from choriocarcinoma
in that they contain:
 hydropic villi along with the marked trophoblastic
proliferation.
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TYPES……GTN
 Both invasive moles and choriocarcinoma may show:
 invasion of the uterine vasculature and
 the production of secondary metastatic lesions,
particularly involving the vagina and lungs.
 Invasive moles do not often resolve spontaneously.
 it is usually only diagnosed histologically if a hysterectomy
has been performed.
 Invasion can be difficult to diagnose by curettage, as
myometrium is often not present
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TYPES……GTN
 Invasive hydatidiform mole infiltrating the
myometrium
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TYPES……GTN
B. Choriocarcinoma.
 is a highly malignant epithelial tumor.
 It can arise from any type of trophoblastic tissue (molar
pregnancy, abortion, ectopic, preterm/term intrauterine
pregnancy)
 Consists of sheets of anaplastic cytotrophoblasts and
syncytiotrophoblasts without chorionic villi.
 Choriocarcinoma following a normal gestation is often comprised of
biparental chromosomes identical to the fetus
 Postmolar choriocarcinoma is often comprised exclusively of
paternal DNA; and are aneuploid
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TYPES……GTN
 Gross specimen of choriocarcinoma
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TYPES……GTN
 Doppler image of choriocarcinoma
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TYPES……GTN
 Most lesions begin in the uterus, although ectopic
pregnancies provide extrauterine sites of origin.
 When choriocarcinoma metastasizes, the most common
sites are
 lung, brain,
 liver, pelvis, vagina,
 spleen, intestine, and kidney.
 Sometimes, when curettage is performed for an early
pregnancy loss, immature gestational tissue without villi
adjacent to regions of atypia may be encountered.
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TYPES……GTN
C. Placental site trophoblastic tumors
 is a rare, potentially malignant neoplasm originating
from extravillous (intermediate) trophoblast cells
 They can occur months to years after a pregnancy.
 PSTTs most commonly develop after a term
gestation, but also occur after any pregnancy
 presents as a proliferation of extravillous or
intermediate trophoblast in the myometrium or
endomyometrium
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TYPES……GTN
 Chorionic villi are rarely found and the typical
dimorphic pattern of choriocarcinoma is absent
 Instead, there is a characteristic pattern
consisting of a relatively monomorphic
population of predominantly mononuclear
trophoblastic cells.
 Scattered multinucleated trophoblasts are also
present as are multinucleated
syncytiotrophoblastic-like cells
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TYPES……GTN
D. Epithelioid trophoblastic tumor.
 ETT is a rare form of trophoblastic disease.
 ETTs are clinically, pathologically and prognostically
similar to PSTTs.
 ETT primarily occurs in reproductive-age women up to 18
years following a prior gestation.
 The majority of ETT occurs after a full-term pregnancy,
but about one third arise following a spontaneous
abortion or hydatidiform mole.
 Vaginal bleeding is the presenting symptom in two-thirds
of patients
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TYPES……GTN
 Serum hCG levels are elevated, but usually do not exceed 2500 milli-
international units/mL.
 Gross inspection of ETT shows a solid to cystic, fleshy, and well-
defined mass in the uterine wall, lower uterine segment, or
endocervix.
 Histologically ETT is nodular, with proliferation of smaller, more
monomorphic trophoblastic cells in comparison to PSTT.
 Molecular markers expressed on ETT by immunohistochemistry
include
 pancytokeratin, epithelial membrane antigen, cytokeratin 18,
 inhibin-a, hCG, human placental lactogen, placental alkaline phosphate, and
Mel-CAM
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TYPES……GTN
 P63 is expressed in ETT, placental site nodule,
and choriocarcinoma, but not in PSTT.
 Epithelioid trophoblastic tumor can be confused
with squamous cell carcinoma because of its
frequent involvement of:
 the lower uterine segment or endocervix, its
epithelioid histologic appearance, and
 expression of p63 and cytokeratins
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TYPES……GTN
Diagnostic criteria for Gestational Trophoblastic Neoplasia
(GTN)
 Plateau of serum ß-hCG level (<10 % drop) for four
measurements during a period of 3 weeks or longer.
 Rise of serum ß-hCG ≥ 10 % during three weekly
consecutive measurements or longer, during a period of 2
weeks or more.
 The serum / urine hCG level remains detectable for 6
months or more.
 Histological diagnosis of invasive mole, PSTT or
choriocarcinoma.
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STAGING OF GTN
 Stage I — All patients with persistently elevated
beta-hCG levels and tumor confined to the uterus.
 Stage II — The presence of tumor outside of the
uterus, but limited to the vagina and/or pelvis.
 Stage III — Pulmonary metastases with or without
uterine, vaginal, or pelvic involvement.
 Stage IV — All other metastatic sites (eg, brain,
liver, kidneys, gastrointestinal tract).
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INVESTIGATIONS
 CBC
 Blood group and RH
 Serum B-hCG (preferably) otherwise Urine hCG
 LFT and RFT
 Chest X-ray
 Ultrasound: typical sonographic features.
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MANAGEMENT OF MOLAR PREGNANCY
Immediate management.
 Open an IV line and resuscitate as required.
 Cross-match at least 2 units of blood
 Arrange for evacuation of the uterus.
 Get prepared for possible hemorrhagic shock.
 If the cervix is closed and needs dilatation use
cervical block or other analgesics.
 NB: Evacuate the uterus by suction curettage in
major OR if uterus is >14 weeks size.
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MANAGEMENT MOLAR,,,
 Infuse oxytocin 20 units in 1 L normal saline or
Ringer’s lactate at 60 drops / minute to prevent
hemorrhage once evacuation is under way.
 Provide prophylactic antibiotic
 Administer Anti-D for RH negative patients
 Submit the evacuated specimen for histo-
pathologic examination
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MANAGEMENT OF MOLAR…
Subsequent management and follow up;
 Advice for use of combined oral contraceptive
pill, implant or injectable for one year or tubal
ligation if the woman has completed her family.
 Get baseline ß-hCG within 48 hours of
evacuation.
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MANAGEMENT OF MOLAR,,,
Follow-up:
 Advise to come if she develops any or the
combination of the following danger signs: cough,
SoB, excessive vaginal bleeding, etc
 Determine serum ß-hCG every 1-2 weeks until it falls
to a normal level.
 After three consecutive normal ß-hCG level is
achieved, monitor monthly for six additional
consecutive months, at which time surveillance can be
discontinued safely.
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MANAGEMENT OF MOLAR…
 Administer single agent chemotherapy
(methotrexate or Actinomycin D) as a prophylaxis
for high risk cases who may not avail themselves for
follow up.
A. Methotrexate
 MTX: 0.4 - 0.5 mg/kg IV or IM daily for 5 days
or
 MTX: 30-50 mg/m2 IM weekly or
 MTX- Leucovorin
 MTX 1 mg/kg IM or IV on days 1,3,5,7
 Leucovorin 15 mg PO days 2,4,6,8
 High dose IV MTX / FA
 MTX 100 mg/m2 IV bolus
 MTX 200 mg/m2 12 hr infusion
 Leucovorin 15 mg q 12 hr in 4 doses IM or PO beginning 24
hr after starting MTX
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MANAGEMENT OF MOLAR….
B. Actinomycin D
 Table 1. Act D 10-12 mcg/kg IV push daily for 5
days or
 Table 2. Act D 1.25 mg/m2 IV push q 2 wks
 N.B: In places where there is no capacity to
determine serum ß-hCG for surveillance, use
urine hCG.
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MANAGEMENT OF GTN
 Non-metastatic GTD
 Low-Risk Metastatic GTD
 High-Risk Metastatic GTD
 Virtually all patients are potentially curable with
chemotherapy, especially if correctly diagnosed
and appropriate drugs are commenced early in
the course of the disease
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MANAGEMENT OF GTN
 Principles:
1) Chemotherapy
2) Surgery(resistant & persistent metastasis)-
Liver, Brain, Lung, other
3) Radiotherapy
4) Hypogastric artery embolization
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MANAGEMENT OF GTN
Treatment of Nonmetastatic GTD.
 Hysterectomy is advisable as initial treatment in
patients with non-metastatic GTD who no longer wish
to preserve fertility
 This choice can reduce the number of course and
shorter duration of chemotherapy.
 Adjusted single-agent chemotherapy at the time of
operation is indicated to eradicate any occult
metastases and reduce tumor dissemination.
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MANAGEMENT OF GTN
 Single-agent chemotherapy is the treatment of
choice for patients wishing to preserve their
fertility.
 Methotrexate(MTX) or Actinomycin-D
 Treatment is continued until three consecutive
normal hCG levels have been obtained and two
courses have been given after the first normal
hCG level.
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MANAGEMENT OF GTN
Treatment of Low-Risk Metastatic GTD.
 Single-agent chemotherapy with MTX or Actinomycin-D is
the treatment for patients in this category
 If resistance to sequential single-agent chemotherapy
develops, combination chemotherapy would be taken
 Approximately 10-15% of patients treated with single-
agent chemotherapy will require combination chemotherapy
with or without surgery to achieve remission
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MANAGEMENT OF GTN
 Methotrexate:
1- 0.4mg/Kg IM/wk/5days, repeat Q2wks(10%
failure rate).
2- 1mg/Kg/IM on days(1,3,5,7), alternate with
folinic acid 0.1mg/Kg IM on days(2,4,6,8), after
24hrs of MTX
3- 50mg/M2 IM weekly(30% failure)
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MANAGEMENT OF GTN
 Actinomycin-D:
1- 12mcg/Kg IV/day/5days repeat Q2 weeks(8%
failure)
2- 1.25mg/M2 IV Q2weeks(20% failure)
3- MTX 250mg iv over 12hrs(EMA-CO regimen) –
30% failure
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MANAGEMENT OF GTN
Treatment of High-Risk Metastatic GTD.
 Multiagent chemotherapy with or without adjuvant
radiotherapy or surgery should be the initial treatment
for patients with high-risk metastatic GTD
 EMA-CO regimen formula is good choice for high-risk
metastatic GTD
 MAC(MTX,Actinomycin-D, Cytoxan/chlorambucil)-
alternative to EMA-CO(risk of leukemia)
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MANAGEMENT OF GTN
 Resistant to EMA-CO: EMA-EP, EMA-PA
 Resistant to EMA-EP: Taxol with cisplatin alternating
with Taxol-etoposide or Taxol-5FU or ICE or BEP
 Adjusted surgeries such as removing foci of
chemotherapy-resistant disease, controlling
hemorrhage may be the one of treatment regimen
 Brain metastasis: Increase MTX dose in EMA-CO
to1gm/M2, alkalinize urine by iv bicarbonate
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MANAGEMENT OF GTN
 Radiotherapy: Brain & Liver metastasis
Can be given with chemotherapy.
1- Brain:- 300 rads/day/5days/week X2weeks-
3000 rads total
2- Liver:- 200 rads/day/5days/week X 2weeks-
2000 rads total
•
Pelvic artery embolization- intractable hemorrhage
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POST TREATMENT SURVEILLANCE
 Monitoring of patients with stage I, II, or III
GTN consists of weekly beta-hCG measurements
until the level is undetectable for 3 weeks,
followed by monthly titers until the level is
undetectable for 12 months.
 Women with stage IV disease are followed for 24
months because of the greater risk of late relapse.
 Patients are encouraged to use effective
contraception during the entire surveillance period
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REFERENCES
 William text book of obstetrics 26th edition,
2022.
 FMOH management protocol on selected
obstetrics topics for hospitals 2020.
 William text book of gynecology 4th edition,
2020
 DC Dutta text book of GYNECOLOGY 8th edition
2015
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CONGENITAL MALFORMATION OF
GENITAL TRACK

COURSE OUTLINE
 Objectives
 Normal embrology
 Mullerian anomalities
 Cervical anomalities
 Fallopian tube anomalities
 DSD
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OBJECTIVES
 At the end of the session the students will able
to:
 Differentiate different mullerian anomalities
 Define DSD
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NORMAL EMBRYOLOGY
 The urogenital tract is functionally divided into the
urinary system and genital system.
 The urinary organs include the kidney, ureters, bladder,
and urethra.
 The reproductive organs are the gonads, ductal system,
and external genitalia.
 The female urogenital tract develops from multiple cell
types that undergo important spatial growth and
differentiation.
 Both the urinary and genital systems develop from
intermediate mesoderm
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CONT…
 During initial embryo folding,-
 urogenital ridge-
 longitudinal ridge and
 develops along each side of the primitive
abdominal aorta.
 the urogenital ridge divides into
the nephrogenic ridge and
 the genital ridge(the gonadal ridge)
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CONT…
 At approximately 60 days of gestation, the
nephrogenic ridges develop into
 the mesonephric kidneys and
 paired mesonephric ducts(wolffian ducts.)
 The mesonephric ducts connect the mesonephric
kidneys to cloaca(opening into which the embryonic
urinary, genital, and alimentary tracts join).
 The paired paramaontphric ducts(the mullerian
ducts), develop from invagination of the coelomic
epithelium at approximately the sixth week.
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CONT…
 The cloaca is divided by formation of the urorectal septum
by the seventh week and is separated to create the
rectum and the urogenital sinus.
 The urogenital sinus is considered in three parts:
1. The cephalad or vesicle portion, which will form the
urinary bladder;
2. The middle or pelvic portion, which creates the female
urethra;and
3. The caudal or phallic part, which will give rise to the
distal vagina and the greater vestibular (Bartholin)
glands and paraurethral glands.
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CONT…
Gonadal Determination.
 Mammalian sex is determined genetically.
 Individuals with X and Y chromosomes usually develop as
males, whereas with two X chromosomes develop as
females
 The epithelium proliferates, and cords of epithelium
invaginate into the mesenchyme to create primitive sex
cords.
 In both 46,XX and 46,XY embryos, the primordial germ
cells are first identified as large polyhedral cells in the
yolk sac.
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CONT…
 Sexual determination is the development of the genital ridge
into either an ovary or testis.
 This depends on the genetic sex produced at fertilization,
when the X-bearing oocyte is penetrated by either an X- or
Y-chromosome-bearing sperm.
 In humans, the gene named the sex-determining region of
that Y (SRY) is the testis-determining factor.
 In the presence of SRY, gonads typically develop as testes.
 Other genes are important for normal gonad development and
include SOX9, SF-1, DMRTJ, GATA4, WNT4, WTJ, DAXJ,
and RSPOJ.
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CONT…
 Mutations in any of these genes may lead to abnormal
sexual determination.
 In males, cells in the medullary region of the primitive sex
cords differentiate into Sertoli cells-form the testicular
cord
 Testicular cords are identifiable at 6 weeks and consist
of these Sertoli cells and tighty packed germ cells.
 During early development, Sertoli cells begin secreting
antimullerian hormone (AMH), also called mullerian
inhibitory substance (MIS).
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CONT…
 This gonadal hormone causes regression of the ipsilateral
paramesonephric (miillerian duct) system, and this
involution is completed by 9 to 1 0 weeks' gestation.
 In the female embryo, without the influence of the SRY
gene, the bipotential gonad develops into the ovary.
 The pathways regulating female sex determination have
remained incompletely defined, but WNT4, WTI, FoxL2,
and DAXJ genes are important for normal development
 Development is first characterized by the absence of
testicular cords in the gonad.
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CONT…
 The primitive sex cords degenerate, and the
mesothelium of the genital ridge forms
secondary sex cords.
 These secondary cords become the granulosa
cells that band together to form the follicular
structures that surround the germ cells.
 Germ cells that carry two X chromosomes
undergo mitosis during their initial migration to
the female genital ridge.
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DEVELOPMENT OF THE GONADS AND DUCTAL SYSTEMS IN
MALE (A) AND FEMALE (B) EMBRYOS.
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CONT…
Ductal System Development
 Sexual differentiation of the mesonephric (wolffian) and
paramesonephric (mullerian) ducts begins in week 7 from
the influence of gonadal hormones (testosterone and
AMH) and other factors.
 In the male, AMH forces paramesonephric regression, and
testosterone prompts mesonephric duct differentiation
into the epididymis, vas deferens. and seminal vesicles.
 In the female, a lack of AMH allows mullerian ducts to
persist.
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CONT…
 During paramesonephric duct elongation,
homeobox(Hox) genes determine developing duct.
 HoxA9 is expressed at high levelsin areas destined
to become the fallopian tube
 HoxA10 and HoxA11 are expressed in the developing
uterus
 Mesonephric and paramesonephric duct systems
become enclosed in peritoneal folds that later give
rise to the broad ligaments of the uterus
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CONT..
 Urogenital sinus is formed by fusion of the two distal
portions of the mullerian ducts.
 The fused ducts form a tube called the urovaginal canal.
 By 12 weeks, mesonephric duct regress from lack of
testosterone.
 The uterine corpus and cervix differentiate, and the
uterine wall thickens.
 The vagina forms partly from the miillerian ducts and
partly from the urogenital sinus
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CONT…
 Specifically, the upper two thirds of the vagina
derive from the fused mullerian ducts.
 The distal third of the vagina develops from the
bilateral sinovaginal bulb, which are cranial
evaginations of the urogenital sinus.
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CONT…
External Genitalia
 By 6 weeks' gestation, three external
protuberances have developed surrounding the
cloacal membrane.
 the left and right cloacal folds, which meet
ventrally to form the genital tubercle
 With division of the cloacal membrane into anal
and urogenital membranes, the cloacal folds
become the anal and urethral folds, respectively
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CONT…
 Between the urethral folds, the urogenital sinus extends into the
surface of the enlarging genital tubercle to form the urethral
groove.
 The genital tubercle elongates to form the phallus in males and the
clitoris in females
 In the male fetus, DHT forms locally by the 5a:-reduction of
testosterone.
 DHT prompts the anogenital distance to lengthen, the phallus to
enlarge, and the labioscrotal folds to fuse and form the scrotum
 Sonic hedgehog (SHH) is a gene that regulates urethral
tubularization in males at 14 weeks' gestation
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CONT…
 Specifically, DHT and SHH expression promote the
urethral folds to merge and enclose the penile urethra.
 In the female fetus, without DHT, the anogenital distance
does not lengthen, and the labioscrotal and urethral folds
do not fuse.
 The genital tubercle bends caudally to become the clitoris,
and the distal urogenital sinus becomes the vestibule of
the vagina.
 The labioscrotal folds create the labia majora, whereas
the urethral folds persist as the labia minora.
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SUMMARY
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SUMMARY
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SUMMARY
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MÜLLERIAN ABNORMALITIES
 are often asymptomatic and therefore
unrecognized.
 They may affect a young woman due to pain at
the time of menarche, or a woman's
obstetric and/or gynecologic health.
 The incidence of congenital uterine anomalies is
difficult to determine since
 many women with such anomalies are not diagnosed,
especially if they are asymptomatic.
 Uterine anomalies occur in 2 to 4 percent of
fertile women with normal reproductive
outcomes.
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MÜLLERIAN ABNORMALITIES
 Classification of Müllerian anomalies according to the
American Fertility Society classification system.
1) Type I: "Müllerian" agenesis or hypoplasia
2) Type II: Unicornuate uterus
3) Type III: Uterus didelphys
4) Type IV: Uterus bicornuate
5) Type V: Septate uterus
6) Type VI: Diethylstibestrol-related anomalies
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MÜLLERIAN ABNORMALITIES
Müllerian Agenesis (Class I)
 are caused by müllerian hypoplasia or agenesis.
 These developmental defects can affect the
vagina, cervix, uterus, or fallopian tubes
 May be isolated or coexist with other müllerian
anomalies.
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MÜLLERIAN ABNORMALITIES
Vaginal Abnormalities.
 The most profound and may be isolated or associated
with other müllerian anomalies.
 The Mayer- Rokitansky-Küster-Hauser (MRKH)
syndrome, in which upper vaginal agenesis is typically
associated with uterine hypoplasia or agenesis.
 The obstetrical significance of vaginal anomalies
depends greatly on the degree of obstruction.
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MÜLLERIAN ABNORMALITIES
 With MRKH syndrome, a functional vagina can be
created, but uterine agenesis proscribes
childbearing.
 However, ova can be retrieved for in vitro
fertilization (IVF) and carriage by a surrogate
mother.
 Congenital septa may form longitudinally or
transversely, and each can arise from a fusion or
resorption defect.
 Alongitudinal septum divides the vagina into
right and left portions.
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MÜLLERIAN ABNORMALITIES
 It may be complete and extend the entire vaginal
length.
 A partial septum usually forms high in the vagina
but may develop at lower levels.
 These septa are often associated with other
müllerian anomalies.
 A transverse septum poses an obstruction of
variable thickness.
 It may develop at any depth within the vagina,
but most lie in the lower third.
 Septa may or may not be perforate, and thus
obstruction or infertility is possible.
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MÜLLERIAN ABNORMALITIES
II. Uterine Abnormalities
 Assessing an accurate population prevalence is
difficult because the best diagnostic techniques are
invasive.
 The prevalence found with imaging ranges from 0.4
to 10 percent.
 In a general population, the most frequent finding is
arcuate uterus, followed in descending order by
 septate,
 bicornuate,
 didelphic, and
 Unicornuate
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MÜLLERIAN ABNORMALITIES
Unicornuate Uterus (Class II)
 General population estimates cite an incidence of
1 case in 4000 women.
 only one uterine horn is present
 Instead, an underdeveloped rudimentary horn
may be present.
 The rudiment may or may not communicate with
the dominant horn and may or may not contain an
endometrium-lined cavity.
 With noncommunicating types, the rudiment may
lie near the uterus or may lie anywhere along the
embryological migration path of the
paramesonephros.
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MÜLLERIAN ABNORMALITIES
 Importantly, 40 percent of affected women will
have renal anomalies.
 Pregnancies developing in the main horn carry
significant obstetrical risks.
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MÜLLERIAN ABNORMALITIES
 Ectopic pregnancy, correctly termed a cornual
pregnancy, can develop within a rudmentary horn.
 The rudimentary horn pregnancy displays:
1. No continuity between the cervical canal and
gestational sac,
2. Myometrium surrounding the gestation,
3. PAS-associated hypervascularity surrounding
the gestational sac, and
4. A vascular pedicle connecting the main horn
and the sac’s surrounding myometrium.
 Treatment is surgical and removes the
rudimentary horn and in situ pregnancy
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MÜLLERIAN ABNORMALITIES
Uterine Didelphys (Class III)
 This anomaly arises from incomplete fusion that
results in
 two entirely separate hemiuteri,
 two cervices, and
 usually two vaginas or a longitudinal vaginal
septum
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MÜLLERIAN ABNORMALITIES
 Uterine didelphys may be isolated or part of a
rare triad with an obstructed hemivagina and
ipsilateral renal agenesis (OHVIRA), also known
as Herlyn-Werner-Wunderlich syndrome.
 it is considered in a fetus with renal agenesis
and a cystic pelvic mass, which reflects
hydrometrocolpos
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MÜLLERIAN ABNORMALITIES
Bicornuate Uterus (Class IV)
 This fusion anomaly results in two hemiuteri.
 The central myometrium runs either partially or
completely to the cervix.
 A complete bicornuate uterus may extend to the
internal cervical os
 Have a single cervix (bicornuate unicollis) or reach
the external os (bicornuate bicollis).
 As with uterine didelphys, a coexistent longitudinal
vaginal septum is common.
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MÜLLERIAN ABNORMALITIES
Septate Uterus (Class V)
 With this anomaly, a resorption defect leads to a
persistent complete or partial longitudinal
uterine septum.
 In the rare, an asymmetric longitudinal septum
creates a sequestered noncommunicating
hemicavity that acts similar to a rudimentary
horn
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MÜLLERIAN ABNORMALITIES
Arcuate Uterus (Class VI)
 This malformation is a mild deviation from the
normally developed uterus.
 Most consider this anomaly benign, but some
have found excessive second-trimester losses,
preterm labor, and malpresentation.
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MÜLLERIAN ABNORMALITIES
Diethylstilbestrol-related Abnormalities (Class
VII).
 In the 1960s, a synthetic nonsteroidal
estrogen—diethylstilbestrol (DES)— was used to
treat threatened abortion, preterm labor,
preeclampsia, and diabetes.
 Moreover, women exposed as fetuses carry
increased risks for vaginal clear cell
adenocarcinoma, cervical intraepithelial
neoplasia, and vaginal adenosis
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MÜLLERIAN ABNORMALITIES
 Women exposed in utero can also show a cervix
or vagina with a transverse septum,
circumferential ridge, or cervical collar.
 Uteri are potentially smaller or have a T-shaped
cavity.
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CERVICAL ABNORMALITIES
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 Developmental abnormalities of the cervix
include:
 partial or complete agenesis,
 duplication, or a longitudinal dividing septum.
 Complete agenesis is incompatible with
pregnancy.
 surgical correction by uterovaginal anastomosis
successfully relieves outlet obstruction

FALLOPIAN TUBE ABNORMALITIES
 The fallopian tubes develop from the unpaired
distal ends of the müllerian ducts.
 Congenital anomalies include:
 Accessory ostia,
 Complete or segmental Tubal agenesis, and
 Several embryonic cystic remnants.
 The most common is a small, benign cyst
attached by a pedicle to the distal end of the
fallopian tube—the hydatid of Morgagni.
 In other cases, benign paratubal cysts may be of
mesonephric or mesothelial origin
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DISORDERS OF SEX DEVELOPMENT
 Formerly, Disorders or differences in sex development
(DSD} were subdivided as those:
1) associated with gonadal dysgenesis,
2) associated with undervirilization of 46,)CY individuals,
and
3) associated with prenatal virilization of 46,XX
subjects.
 Proposed classification ofDSDs are:
A. sex chromosome DSDs,
 45,XTurne,.a
 47,XXY Klinefelte,.a
 45,X/46,XY Mixed gonadal dysgenesis
 46,XX/46,XY Ovotesticular DSD
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CONT…
B. (46,)CY DSDs, and
 Testicular development
 Pure gonadal dysgenesis
 Partial gonadal dysgenesis
 Ovotesticular
 Testis regression
 Androgen production or action
 Androgen synthesis
 Androgen receptor
 LH/hCG receptor
 AMH
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CONT…
C. 46,XX DSDs
 Ovary development
 Ovotesticular
 Testicular
 Gonadal dysgenesis
 Androgen excess
 Fetal
 Maternal
 Placental
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CONT…
Others
 Hermaphroditism
 Ambiguous genitalia
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SEX CHROMOSOME DISORDERS OF SEX DEVELOPMENT
Turner Syndromes
 usually caused by loss of part or all of an X-chromosome
 occurs in approximately 1/2,500 live female births.
 caused by de novo loss or severe structural abnormality of
one X chromosome in a phenotypic female.
 It is the most common form of gonadal dysgenesis that leads
to primary ovarian insufficiency.
 Most affected fetuses are spontaneously aborted.
 Nearly all affected patients have short stature.
 This results from lack of one copy of the SHOX gene(Short Stature
Homeobox-containing Gene), which resides on the short arm of the X
chromosome
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CONT…
PATHOGENESIS
 Maternal X is retained in two-thirds of patients with
Turner syndrome and the paternal X in the
remaining one-third.
 More than one-half of all patients with Turner
syndrome have a mosaic chromosomal complement
(eg, 45,X/46,XX)
 Mosaicism with a normal cell line in the fetal
membranes may be necessary for adequate placental
function and fetal survival
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CONT..,
 The identification of mosaicism depends directly upon the method of
ascertainment.
 It varies from 34 percent with conventional cytogenetic
techniques,
 60 percent with fluorescence in situ hybridization techniques and
 74 percent in a study in which reverse transcriptase polymerase-
chain-reaction assays were used.
 Some patients with Turner syndrome lack only part of one sex
chromosome, and the Turner syndrome phenotype can be seen with
of structural abnormalities, such as
 isochromosomes, or
 terminal deletions.
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CONT…
 A rare but very informative class of Turner syndrome
includes patients who have deletions of the Y
chromosome that remove the testes-determining gene,
SRY;
 these individuals develop as females
 Short stature is the only clinical finding invariably
associated with the 45,X karyotype;
 it also is the only phenotypic abnormality present in virtually
100 percent of patients.
 Karyotypic abnormalities may also correlate with the
presence of hypothyroidism
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CONT…
 Some patients are not diagnosed until adolescence,
when they present with short stature, prepubertal
female genitalia, and primary amenorrhea.
 The uterus and vagina are normal and are capable of
responding to exogenous hormones.
 Have a structural abnormality of the second X
chromosome or have a mosaic karyotype, such as
45,X/46,XX.
 More than half of the girls with this syndrome have
chromosomal mosaicism
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CHARACTERISTIC FINDINGS OF TURNER SYNDROME
 Height 142-147 cm
 Micrognathia
 Epicanthal folds
 Low-set ears
 Shield-like chest
 Cubitus valgus
 Renal abnormalities
 Aorta coarctation
 Diabetes mellitus
 High-arched palate
 Hearing loss
 Webbed neck
 Absent breast
development
 Widely spaced areolae
 Short fourth
metacarpal
 Autoimmune disorders
 Autoimmune
thyroiditis
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CONT…
CLINICAL MANIFESTATIONS
Physical findings
Skeletal growth disturbances
 Short stature
 Short neck
 Short metacarpals
Lymphatic obstruction
 Webbed neck
 Low posterior hairline
 Rotated ears
 Edema of hands/feet
 Severe nail dysplasia
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CONT…
Ovarian failure
 The ovaries in Turner syndrome cxrsally consists:
 small amounts of connective tissue and no follicles or
 only a few atretic follicles ("streak gonads")
 Most affected women have no pubertal development
and primary amenorrhea,
 Some develop normally and then have secondary
amenorrhea,
 While occasionally others have no morphologic
defects and achieve normal stature.
 The gonadal dysgenesis may be caused by
accelerated apoptosis rather than abnormal germ
cell formation.
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CONT..
Short stature
 the most common clinical feature of Turner
syndrome
Renal anomalies
 most commonly horseshoe kidney, followed by
abnormal vascular supply
 Anomalies associated with obstruction of the
ureteropelvic junction can produce clinically
significant
 hydronephrosis or
 pyelonephritis
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Cardiovascular disease
 due to risk of cardiovascular malformations, renal
abnormalities, and hypertension
 coarctation, aortic valvular disease, aortic dissection,
hypertension, Neck webbing
Osteoporosis
 due to both ovarian failure and possibly
haploinsufficiency for bone-related X-chromosome
genes
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DIAGNOSIS
 Karyotype analysis
 Y chromosome mosaicism
 Serum thyrotropin (TSH)
 Echocardiography or Magnetic resonance imaging
 Blood glucose, serum creatinine, and urinalysis
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Management
 Estradiol initiation at ages 11 or 12 years, the use of
transdermal estradiol, and gradual dose increases
over 2 to 3 years (International Turner Syndrome
Consensus Group).
 Progesterone is added after 2 years of treatment or
with onset of breakthrough bleeding.
 Ensure adequate calcium intake (1.2 g/day).
 Encourage weight-bearing exercise.
 Check bone mineral density every three to five years
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KLINIFELTER SYNDROME (47,XXY)
 which occurs in 1 in 600 births or in 1 to 2 percent of all
males.
 are tall, undervirilized males with gynecomastia and small,
firm testes.
 They have significantly reduced fertility from
hypogonadism due to gradual testicular cell loss that
begins shortly after testis determination.
 These men carty higher risks for germ cell tumors,
osteoporosis, hypothyroidism, diabetes mellitus, breast
cancer, and cognitive and psychosocial problems.
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 The 47,XXY karyotype results from nondisjunction
of the sex chromosomes and can be maternal or
paternal in origin.
 Male newborns with the 47,XXY karyotype are
phenotypically normal, with normal male external
genitalia and no apparent dysmorphic features.
 The major clinical manifestations of Klinefelter
syndrome include tall stature, small testes, and
infertility (azoospermia) that become noticeable
after puberty.
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CONT…
 Patients with Klinefelter syndrome are at
increased risk for psychiatric disorders, autism
spectrum disorders, and social problems.
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CHROMOSOMAL OVOTESTICULAR
 Several karyotypes can create a coexistent ovary and
testis, and thus ovotesticular DSD is found in all three
DSD categories.
 may arise from a 46, XX/46,XY katyotype.
 an ovary, testis, or ovotestis may be paired
 a picture of mixed gonadal dysgenesis shows a streak
gonad on one side and a dysgenetic or normal testis on the
other.
 The phenotypic appearance ranges from undervirilized
male to ambiguous genitalia to Turner syndrome stigmata.
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46,XY DISORDERS OF SEX DEVELOPMENT
 Insufficient androgen exposure of a fetus destined to be a
male leads to 46,XY DSD, formerly called male
pseudohermaphroditism.
 The katyotype is 46,XY, and testes are frequently present.
 The uterus is generally absent as a result of normal
embryonic AMH production by Sertoli cells.
 These patients are most often sterile from abnormal
spermatogenesis and have a small phallus that is inadequate
for sexual function.
 Etiology of from abnormal testis development or abnormal
androgen production or action.
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46,XY GONADAL DYSGENESIS
 Abnormal gonad underdevelopment includes
 pure or complete, partial, or mixed 46,XY gonadal dysgenesis
 These are defined by the amount of normal testicular tissue and
katyotype.
Pure gonadal dysgenesis( Swyer syndrome, )
 results from a mutation in SRYor in another gene with testis-
determining effects (DAXJ, SF-1, CBX2)
 This leads to underdeveloped dysgenetic gonads that fail to produce
androgens or AMH.
 the condition creates a normalprepubertal female phenotype and a
normal miillerian system due to absent AMH.
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Partial gonadal dysgenesis defines those with
gonad development
 intermediate between normal and dysgenetic testes.
 Depending on the percentage of underdeveloped
testis, wolffian and mi.illerian structures and genital
ambiguity are variably expressed.
 Mixed gonadal dysgenesis
 One gonad is streak and the other is a normal or a
dysgenetic testis.
 Of affected individuals, a 46,XY katyotype is found
in 15 percent
 The phenotypic appearance is widen ranging as with
partial gonadal dysgenesis
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ABNORMAL ANDROGEN PRODUCTION OR ACTION
 In some cases, 46.XY DSD may stem from
abnormalities in:
1) Testosterone biosynthesis,
2) Luteinizing hormone (LH) receptor function,
3) AMH function, or
4) Androgen receptor action.
 The sex steroid biosynthesis pathway can suffer
enzymatic defects that block testosterone
production,
 Depending on the timing and degree of blockade,
undervirilized males or phenotypic females may
result.
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CONT…
 Abnormal action of 5α-reductase type 2 enzyme
impairs conversion of testosterone to DHT and
blunts virilization.
 Second, hCG/LH receptor abnormalities within
the testes can lead to Leydig cell hypoplasia and
decreased testosterone production.
 Disorders of AMH and AMH receptors result in
persistent müllerian duct syndrome (PMDS).
 Last, the androgen receptor may be defective
and result in androgeninsensitivity syndrome
(AIS).
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 Those with complete androgen-insensitivity
syndrome (CAIS) are phenotypically normal
females.
 Girls often present at puberty with primary
amenorrhea.
 External genitalia appear normal; pubic and
axillary hair are scant or absent; the vagina is
markedly shortened; and the uterus and fallopian
tubes are absent.
 However, these individuals develop breasts
during puberty due to conversion of androgen to
estrogen
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46,XX DSD
 This DSD group may stem from abnormal ovarian
development or from excess androgen exposure.
1. Abnormal Ovarian Development.
 Disorders of ovarian development in those with a
46,XX complement include:
i. Gonadal dysgenesis,
ii. Testicular DSD, and
iii. Ovotesticular DSD.
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46,XX DSD
 46,XX gonadal dysgenesis, similar to Turner
syndrome, streak gonads develop.
 These lead to hypogonadism, prepubertal normal
female genitalia, and normal müllerian structures.
 However, other Turner stigmata are absent.
 46,XX testicular DSD, several genetic
mutations lead to testis-like formation.
 Most commonly, defects stem from SRY
translocation onto one paternal X chromosome.
 Less often, other genes with testis-determining
effects are activated.
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46,XX DSD
 46,XX ovotesticular DSD, individuals possess a
unilateral ovotestis with a contralateral ovary or
testis, or bilateral ovotestes.
 Anoverexpression of SOX genes, which are
testis promoting, or deficient ovarian promoting
genes are implicated.
 Phenotypic findings depend on the degree of
androgen exposure.
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46,XX DSD
2. Androgen Excess.
 The prior term was female
pseudohermaphroditism.
 In affected individuals, the ovaries and female
internal ductal structures such as the uterus,
cervix, and upper vagina develop.
 The embryonic clitoris, labioscrotal folds, and
urogenital sinus are commonly affected by
elevated androgen levels.
 Virilization may range from modest clitoromegaly
to posterior labial fusion and a phallus with a
penile urethra.
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REFERENCES
 William text book of obstetrics 26th edition,
2022.
 William text book of gynecology 4th edition,
2020
 DC Dutta text book of GYNECOLOGY 8th edition
2015
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