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Mullerian Anomalies By Elizabeth Diaz. Mullerian Anomalies. Introduction Embryology and Development Anomalies of the Female Ductal System Clinical Presentation, Diagnosis and Treatment. Introduction.

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Mullerian anomalies by elizabeth diaz l.jpg
Mullerian AnomaliesBy Elizabeth Diaz


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Mullerian Anomalies

  • Introduction

  • Embryology and Development

  • Anomalies of the Female Ductal System

  • Clinical Presentation, Diagnosis and Treatment


Introduction l.jpg
Introduction

  • Congenital uterine anomalies are more common than generally recognized by many practicing clinicians.

  • Prevalence in general population 1 in 201 (0.5%)

  • According to “Acien,” 2-3% of fertile women and 3% of infertile women and 5-10% of those with repeated miscarriages.

  • Distribution: 7% arcuate, 34% septate, 39% bicornuate, 11% didelphic, 5% unicornuate, 4% hypoplastic/asplastic/solid and other forms


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Introduction

  • True incidence and prevalence are difficult to assess. Why?

    • Selection bias: 0.4% nonobstetric, 8-10% recurrent pregnancy loss.

    • Nonstandardized classification systems

    • Differences in diagnostic data acquisition resulted in widely disparate estimates

    • Overall prevalence; normal fertility/infertility 1% and repeated pregnancy loss 3%.


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Why is this important?

  • Majority have no problem conceiving, but have higher rates of:

    • 1. Spontaneous Abortion

    • 2. Premature Delivery

    • 3. Infertility

    • 4. Abnormal Fetal Lie

    • 5. Dystocia at delivery

    • 6. Dysmenorrhea, endometriosis

    • 7. Cervical incompetence



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Indifferent Embryo

  • Genotype of embryo 46XX or 46XY is established at fertilization

  • Weeks 1-6 sexually indifferent or undifferentiated stage; that is genetically female and male embryos are phenotypically indistinguishable

  • Week 7 begins phenotypic sexual differentiation

  • Week 12 female or male characteristics of external genitalia can be recognized

  • Week 20 phenotypic differentiation is complete.


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Indifferent Embryo

  • Components which form the adult female and male reproductive systems are:

    1. Gonads ovaries or testes

    2. Genital Duct Systems

    Paramesonephric and Mesonephric Ducts

    3. External Genitalia


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5th week of pregnancy

Swellings on either side of the dorsal mesentery

Intermediate mesoderm forms the urogenital ridge.

Gonad develops from somatic and germ cells.

Somatic cells derived from mesonephric cells

Formation and Differentitation of the Gonads


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Coelomic epithelium and underlying mesoderm of the urogenital ridge proliferate to form the gonadal ridge

Germ cells arrive in gonadal region, stimulate coelomic epithelium and mesonephros to form primitive sex cords

Formation and Differentiation of Gonads


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Primary sex cords develop from the gonadal ridge and incorporate primordial germ cells (XX or XY genotype) which migrate into the gonad from the wall of the yolk sac.

Sex cords and germ cells essential for normal development

Gonad


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Y c’some: TDF ( testis determing factor), SRY (sex determining region), crucial for differentiation

Primary sex cords form seminiferous cords, tubuli recti, and rete testes.

Somatic cells of primary sex cords form sertoli cells and germ cells form spermatogonia

Seminiferous cords: spermatogonia and sertoli cells, which secrete Anti-Mullerian Hormone (AMH) or MIS, and ABP (androgen binding protein).

Mesoderm b/w seminiferous cords gives rise to Leydig cells, which secrete testosterone. Leydig cells have receptors for HCG, induced by HY antigen.

Development of Testes


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Development of Testes determining region), crucial for differentiation

  • Genital ridge SRY Testes

  • Primitive sex cords sertoli cells seminiferous cords

  • Seminiferous cords separated from superficial epithelium by tunica albuguinea

  • Seminiferous cords seminiferous tubules

  • Sertoli cells AMH/MIS

  • AMH ipsilateral paramesonephric regress

  • Leydig cell testosterone virilization wolffian duct epididymis, vas deferens, seminal vesicle.


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Primary sex cords develop into the rete ovarii, which degenerate.

Secondary sex cords develop and incorporate primordial germ cells

Secondary sex cords break apart and form primordial follicles, which contain primary oocytes surrounded by a layer of follicular (granulosa) cells.

Primary oocyte stage maintained until adulthood

Formation of the Ovary



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+ TDF medullary sex cords differentiate into Sertoli Cells degenerate.

Sertoli cells produce anti-mullerian hormone

- TDF cortical sex cords differentiate into oocytes and follicular cells

Lack of sertoli cells no AMH

Genetic males have testis determining factor on the sex determining region SRY of the Y chromosome. Genetic males produce Testis Determing Factor in the sex cords


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Overview degenerate.



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6 degenerate.th week, two pairs of genital ducts.

Mesonephric Duct extending from the mesonephros (Wolff’s body) to the cloaca (urogenital sinus) referred to as the Wolffian system

Second duct arises as a longitudinal invagination of coelomic epithelium on the anterolateral surface of the urogenital ridge, known as Paramesonephric or Mullerian Duct.

Genital Duct Development


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Cranial uterine tubes degenerate.

Caudal portions fuse and form the uterovaginal primordium and bring together two peritoneal folds, the broad ligament.

Initially they remain separated by a septum but later they fuse to form the uterus.

Paramesonephric Duct


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Paramesonephric ducts do not make contact with the urogenital sinus.

Paramesonephric ducts fuse with the medial wall of the mesonephric ducts.

Below the caudal tip of the uterine primordium and above the dorsal wall of the urogenital sinus, with the mesoneprhic ducts lying laterally, a collection of paramesonephric cells forms constituting the Mullerian tubercle.

Paramesonephric Duct


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Ureteral Buds urogenital sinus. :Mesonephric ducts open caudally in urogenital sinus. At caudal tip ureteral bud sprouts. Grows laterally, anteriorly and cranially becomes metanephros to form the definitive kidney


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Testis forms, the testosterone produced by leydig cells and is carried along the tubules by ABP stimulates the development of the mesonephric ducts to form the efferent ductules, epididymis, ductus deferens, and seminal vesicles. The AMH produced in Sertoli cells inhibits paramesonephric duct development.

Male Genital Duct Formation


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In ovary the absence of testosterone inhibits the development of the mesonephric ducts.

The atretic remains form the epoophoron, paraoophoron and Gartner’s ducts.

In absence of AMH, paramesonephric ducts form the female internal genital tract.

Female Genital Duct Formation


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Embryology of Vagina development of the mesonephric ducts.

  • Embryology controversial

  • Derived paramesonephric ducts vs. mesonephric ducts vs. urogenital sinus, or a combination.

  • Most accepted, superior part derived fusion paramesonephric , while inferior part arises from urogenital sinus, BUT assumes the “inductor” function of the mesonephric ducts stimulate adequate mullerian/paramesonephric development.


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Mullerian tubercle cellular condensation b/w inferior part of fused paramesonephric ducts and urogenital sinus.

Sinovaginal bulbs develop, constitute vaginal plate.

Cavity formed lined with paramesonephric epithelium, opens into the urogenital sinus and the metaplastic induction to polystratified plain epiithelium would produce the vagina.

Theory of Mullerian Tubercle.


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Studies show sinovaginal bulbs are caudal segments of mesonephric ducts.

Between these bulbs and caudally to the paramesonephric ducts, a solid epithelial structure is located contacting the dorsal wall of the urogenital sinus…the mullerian tubercle.

Inductor role of mesoneprhic duct on vagina


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Vagina derived from fused mesonephric ducts and Mullerian tubercle.

Paramesonephric ducts form uterus to external cervical os and adequate formation is induced by mesonephric ducts.

Mesonephric ducts regress cranially but at cervical os, they enlarge and form the sinovaginal bulbs.

The paramesonephric cellular condensation (mullerian tubercle ) incorporates itself in the vaginal plate formed by fusion of the two bulbs.

Cavitation allows the paramesonephric cells to line the primitive vaginal cavity with paramesonephric epithelium.

Mesonephric duct induction


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As ureteral bud sprouts from the opening of the mesonephric ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

Agenesis of mesonephric duct


Embryology of external genitalia l.jpg

Embryology of External Genitalia ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


Development external genitalia l.jpg
Development external genitalia ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • Early, similar in both sexes

  • 6th wk, three external protuberance surround cloacal membrane, the left and right genital swellings meet anteriorly to form the genital tubercle.

  • 12th wk identify difference.

  • Genital swelling labioscrotal folds scrotum or labia major

  • Genital tubercle phallus penis or clitoris


Development of external genitalia l.jpg
Development of External Genitalia ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


Female and male external genitalia l.jpg
Female and Male external genitalia ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


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Role of Dihydrotestosterone ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • Differentiation depends indirectly on gonadal secretion in male fetus.

  • Testosterone acts locally on the tubules but not directly on the external genitalia.

  • Hormonal action is exerted by dihydotestsoterone (DHT) formed from testosterone by the 5 alpha reductase enzyme.

  • DHT causes external genitalia to become a penis and scrotum and induces development of prostate


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Anomalies of Female Ductal System ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


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Mullerian Anomalies ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


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Classification System: American Fertility Society ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


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Classification into 3 groups: ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)Based on similar embryonic development defects and clinical presentation

  • 1. Agenesis of uterus/vagina: Rokitansky-Kuster-Hauser Syndrome.

  • 2. Defects in Vertical Fusion (obstructive or non-obstructive)

  • 3. Lateral Fusion defects (obstructive or non-obstructive).


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Revised Classification System ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • “Acien” proposed embryological classification.

  • 1.Agenesis of urogential ridge absence kidney, ovary, fallopian tube, hemiuterus, hemivagina.

  • 2. Isolated Mullerian anomalies (probably also induced by minor mesonephric defect) affect:

    • A. Paramesonephric uterine and/or tubal anomalies

    • B. Mullerian tubercle agenesis or atresia vagina.

    • C. All Paramesonephric derivatives Rokitansky-Kuster-Hauser syndrome.

      3. Anomalies urogenital sinus urogenital membrane (imperforate hymen).


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Revised Classification System ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • 4. Mesonephric anomalies, with absence opening in urogenital sinus and forming ureteral bud. Usually uterine anomaly, b/c lack of inductor function of mesonephric duct, as well as unilateral renal agenesis and ipsilateral blind vagina

  • 5. Combination of above malformations


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RKH Syndrome: Diagnosis ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • Expected Menarche

  • Difficult to differentiate from imperforate hymen

  • No uterus on exam, U/S, MRI, Laparoscopy, IVP

  • Confused with Androgen Resistance Syndrome with shallow pouch and no uterus.

  • Determine karyotype.


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RKH Syndrome: Etiology ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • Molecular mechanisms for differential development:

    Hox-9, 10, 11, 13 are expressed along the length of mullerian ducts. Alteration of HOX genes may give rise to mullerian anomalies


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RKH Syndrome: Treatment ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • Goal is to restore normal sexual function through creation of neovagina.

  • Nonsurgical:

    • 1. Frank technique: Pressure to perineal dimple.

    • 2. Ingram method: Bicycle seat stool.

      Surgical: Create neovagina

      1. McIndoe operation: Skin graft between

      rectum/bladder

      2. Sigmoid vaginoplasty:

      3. Vecchietti operation: transabdominal approach.


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Vertical Fusion Defects: obstructive and non-obstructive ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)

  • Incomplete cavitation of the vaginal plate formed by the down-growing mullerian ducts and the up-growing urogenital sinus. Can be considered in two categories:

  • 1.Imperforate Hymen

  • 2.Transverse Vaginal Septum


Vertical fusion defects l.jpg
Vertical Fusion Defects ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


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Transverse Vaginal Septum ducts in the urogenital sinus, the absence or distal agenesis of a mesonephric duct would result in an absence of its opening to the sinus ( the origin of the blind vagina) and in an absence of the ureteral bud on that side. Thus, the definitive kidney would fail to develop (ipsilateral renal agenesis)


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Cyclic pelvic pain due to hematocolpos hematometria, or hematosalpinx

Bulging hymeneal membrane or a blind-ending pouch on exam.

Pelvic/Rectal exam, U/S, MRI

Rarely urologic anomalies.

Tx: Cruciate incision

Imperforate Hymen: Diagnosis/ Treatment



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Transverse Vaginal Septum: Presentation/Diagnosis hematosalpinx

  • Cyclical pain due to hematocolpos or hematometria.

  • Blind-ending pouch.

  • No bulging at outlet, hydromucocolpos or hematocolpos, rectal exam or U/S, MRI.

  • Incidence 1 in 2100 to 1 in 72000.

  • Thickness varies and site varies in vaginal canal.

  • 19% lower 1/3, 35% middle third, 46% upper third.


Transverse vaginal septum treatment l.jpg
Transverse Vaginal Septum: Treatment hematosalpinx

  • Aspirate fluid

  • Transverse incision and identify cervix

  • Indwelling stent

  • Normal coital function after excision

  • Pregnancy rates: More likely 40-50% especially if septum in lower or middle third of vagina.

  • Goal is to relieve cyclic abdominal pain and prevent development of endometriosis



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Lateral Fusion Defects hematosalpinx

  • Most common type of mullerian defects

  • The resulting organs are either asymmetric or symmetric and obstructed or nonobstructed.

  • Result from failure of formation of one mullerian duct, migration of a duct, fusion of the mullerian ducts, or absorption of the intervening septum. Defective resorption of the septum between the fused mullerian ducts results in a uterine septum, which may extend either partially down the uterus or the full length to the cervix. This is the most common uterine defect.


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Obstructive Defect of Lateral Fusion: hematosalpinxFailure of lateral fusion of two mullerian ducts and failure of one duct to communicate with the outside, thus unilateral obstruction. Uterus didelphys with obstructed hemivagina with ipsilateral renal agenesis


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Inductor role of mesonephric duct hematosalpinx

Absence of ureteric bud, no ureter/kidney

Distal agenesis, no opening into urogenital sinus, therefore blind vagina

Agenesis of Mesonephric Duct


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Dysmenorrhea, abd pain, vaginal masses, intermittent foul odor, mucopurulent discharge, endometriosis

IVP generally shows renal agenesis on obstructed side.

Dx is difficult: U/S, HSG, MRI

Tx: excision of septum or excise obstructed uterine horn to prevent endometriosis or pregnancy in rudimentary horn

Obstructed Lateral Fusion: Presentation/Dx/Tx.



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Lateral Fusion defects without obstruction septum with bilateral obstruction


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Two mullerian ducts fail to fuse, thus duplication of system.

Generally limited to uterus and cervix (uterine didelphys and bicollis (two cervices), although duplication of vulva, bladder, urethra, vagina and anus may also occur

Generally have good reproductive outcomes.

A septated vagina may occur in 75% of cases and may cause difficulty with intercourse or vaginal delivery.

Uterine didelphys


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Resection of septum: metroplasty or hysteroscopic resection of septum

Obstructed hemivagina and ipsilateral renal agenesis will have regular menses, but pain.

Uterine didelphys with complete vaginal septum


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Didelphic Uterus of septum


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Didelphic Uterus: of septumU/S at 9 weeks, then at 15 weeks



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Unicornuate Uterus of septum

  • Reproductive potential is essentially normal; high risk for infertility, endometriosis, PTL, breech presentations

  • No septum, no intervention.

  • Asymmetric lateral fusion defect.

  • One cavity normal with fallopian tube and cervix, while the failed mullerian duct has various configurations.

  • Affected mullerian duct may not develop or develop partially as horn or an anlager. It may or may not communicate.

  • Most rudimentary horns are asymptomatic, others contain functional endometrium that is shed cyclically. If the rudimentary horn is obstructed (without communication to the other uterus or cervix), the women may develop cyclic pain and may require surgical excision of the obstructed horn.

  • DX: HSG, IVP, U/S, MRI,

  • TX: Typically no treatment.


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1. Unicornuate 2. Unicornuate with uterine horn (not containing an endometrial cavity) not fused to unicornuate uterus


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1. Unicornuate with uterine horn (no endometrial cavity) fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Unicornuate with communicating uterine horn fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Bicornuate and Septate Uterus fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Bicornuate: fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused

Fundus indented

Partial fusion of mullerian ducts

Variable degree of separation of uterine horns that can be complete, partial or minimal

HSG won’t dx, need laparoscopy

Minimal reproductive problems, however can have pregnancy loss, PTL, etc.

Septate:

Normal external surface, need laparoscopy to dx

Defect in canalization or resorption of midline septum between mullerian ducts.

Septum can cause infertility, recurrent midtrimester loss

Tx: resection of septum hysteroscopically or hysteroscopic metroplasty

Bicornuate and Septate Uteri


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Septate Uterus: Partial and Complete fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Septate Uteri fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Bicornuate Uterus fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Bicornuate uterus with unilateral pregnancy fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused


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Summary fused to unicornuate uterus 2. Unicornuate uterus with noncommunicating horn containing endometrial cavity not fused

  • Understanding the embryologic origin of the defect of mullerian anomalies is key to its correct diagnosis

  • Presentation: obstetrical problems, dysmenorrhea, amennorhea

  • Dx: Pelvic/Rectal exam, U/S, HSG, Laparoscopy, Hysteroscopy, MRI

  • Tx: Resection of septum or horn


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