Congenital Malformations of the Female Reproductive System

Congenital malformations of the female reproductive system are any congenital anomalies that affect the ovaries, fallopian tubes, uterus, cervix, hymen, and/or vulva. Any of these anomalies can affect the normal reproductive and sexual functions of affected women. The cause is usually unknown. Clinically, these patients typically present with menstrual and/or fertility issues, with the exact presentation varying based on the patient’s anatomy. Diagnosis is primarily based on history, physical examination, and imaging with pelvic ultrasonography and/or pelvic MRI. Management depends on the type of defect(s) present and often involves surgical correction and/or hormone replacement. Most malformations can be managed well and have a good prognosis. Associated complications are infertility and the psychosocial and emotional impact of having “abnormal” genitalia.

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Overview

Definition

Congenital malformations of the female reproductive system are any congenital anomalies that affect the ovaries, fallopian tubes, uterus, cervix, hymen, and/or vulva. Any of these anomalies can affect the normal reproductive and sexual functions of affected women.

Epidemiology

  • Prevalence of congenital uterine anomalies (CUAs): 
    • 5.5% in unselected populations
    • 8% in infertile patients
    • 12% in patients with a history of miscarriage
    • 25% in patients with a history of infertility and miscarriage
  • Previously, there was an increased incidence of CUAs in women who were exposed in utero to the drug diethylstilbestrol (DES), which was used to treat nausea in pregnancy from the 1940s to the 1960s. This drug is no longer used, and DES-related morbidity in children is now rare. 
  • Incidence of vaginal agenesis: 1 per 5000 liveborn females

Classification

The types of congenital malformations can be classified on the basis of the affected organs. Note, true congenital malformations of the vulva are rare; an enlarged clitoris or ambiguous external genitalia is typically considered a disorder of sexual development due to testosterone exposure.

Table: Types of congenital malformations affecting the female reproductive system
OrganMalformation
Ovaries
  • Ovarian dysgenesis (streak ovaries)
  • Ovarian agenesis
  • Supernumerary ovaries
Fallopian tubesFallopian tube agenesis
Uterus
  • Septate uterus
  • Bicornuate uterus
  • Arcuate uterus
  • Unicornuate uterus
  • Didelphys
  • Uterine agenesis
Cervix
  • Cervical agenesis
  • Cervical duplication
Vagina
  • Vertical vaginal septum: obstructed hemivagina
  • Transverse vaginal septum
  • Vaginal agenesis
Hymen
  • Imperforate hymen
  • Microperforate hymen
  • Septate hymen

Anatomy and Embryology

Anatomy

The female reproductive system is divided into external genitalia and internal genitalia. The internal genitalia are located in the true pelvis and the external genitalia are present outside the true pelvis.

Table: Internal versus external female genitalia
Type of genitaliaStructures present
Internal genital organs
  • Ovaries
  • Fallopian tubes
  • Uterus
  • Cervix (technically, the lower portion of the uterus)
  • Vagina
External genital organs
  • Mons pubis
  • Clitoris
  • Labia majora and minora
  • Urethral meatus
  • Bartholin and skene glands

Embryonic origins

Table: Embryonic origins of the female reproductive organs
Embryonic structureFemale pelvic organs
Labioscrotal swellingLabia majora
Urogenital foldsLabia minora
Genital tubercleClitoris
Urogenital sinus
  • Urinary bladder
  • Urethra
  • Urethral and paraurethral glands
  • Vagina
  • Bartholin glands
Müllerian/paramesonephric duct
  • Uterus
  • Cervix
  • Fallopian tubes
  • Upper vagina
  • Hymen
Wolffian/mesonephric duct remnantGartner’s duct
Undifferentiated gonadOvary
Gubernaculum
  • Ovarian ligament
  • Round ligament
Phenotypic differentiation of the external genitalia in male and female embryos

Phenotypic differentiation of the external genitalia in male and female embryos

Image by Lecturio. License: CC BY-NC-SA 4.0
Sex differentiation

Sex differentiation

Image by Lecturio. License: CC BY-NC-SA 4.0

Overview of typical sex development

The reproductive system remains undifferentiated up to the 6th week of intrauterine life, with the presence of 2 pairs of genital ducts: the Müllerian (or paramesonephric) ducts, which will ultimately become the internal female genitalia, and the Wolffian (or mesonephric) ducts, which regress in females. 

  • Chromosomal sex → determines gonadal sex → determines phenotypic sex
  • Until 6 weeks of gestation, sex development is identical and nonbinary; developing structures include:
    • Nonbinary, bipotent, undifferentiated gonads
    • Wolffian and Müllerian ducts (initially, both are present in both sexes)
    • Urogenital sinus
    • The genital tubercle, genital swellings, and genital folds 
  • The genes present at fertilization will determine how the developing bipotent gonads differentiate (e.g., into a testis or an ovary)
  • The developing gonads will then secrete hormones:
    • The presence and/or absence of specific hormones will determine how the remaining structures differentiate.
    • In general, female organs and structures are the “default” phenotype if specific genes and hormones are not present to stimulate male differentiation.

Sex organs and characteristics

  • Gonads: develop on the basis of the karyotype/genes present
    • Testes: 
      • Develop when sex-determining region of the Y chromosome (SRY gene) is present
      • Secrete testosterone and anti-Müllerian hormone (AMH)
    • Ovaries: develop when X chromosome is present and/or SRY gene is absent 
    • Ovotestis: gonad containing both ovarian and testicular tissue found in patients with true hermaphroditism
  • Müllerian structures: differentiate from the Müllerian (paramesonephric) ducts when AMH is absent
    • Uterus
    • Fallopian tubes
    • Upper ⅓ of the vagina
  • Wolffian structures: differentiate from the Wolffian (mesonephric) ducts in the presence of testosterone
    • Epididymis
    • Vas deferens
    • Seminal vesicles
    • Ejaculatory ducts
  • External genitalia: develop from the undifferentiated genital tubercle, genital swelling, and genital folds on the basis of the presence or absence of testosterone
    • Male: testosterone → penis and scrotum
    • Female: lack of testosterone → clitoris, labia majora, labia minora
  • Secondary sexual characteristics: develop on the basis of the hormonal milieu at puberty
    • Androgenic characteristics: due to the presence of testosterone and/or dihydrotestosterone (DHT)
      • Pubic and axillary hair
      • Facial and body hair in an androgenic distribution and quality (dark and coarse)
      • Deepening of the voice
      • ↑ Muscle mass
    • Estrogenic characteristics: due to the presence of estrogen
      • Breast development
      • Wider hips

Development of congenital malformations

  • Ovarian anomalies: due to defects in gonadal development
  • Müllerian anomalies:
    • Anomalies of the uterus, cervix, upper vagina, and fallopian tubes
    • Develop due to defects in:
      • Formation/extension of the ducts
      • Midline fusion of the ducts
      • Regression of the midline walls  (leaving midline divisions)
  • Lower vagina: defects in development of the urogenital sinus/sinovaginal bulbs
  • Vulva and clitoris: abnormal hormonal environment, typically considered a disorder of sexual development rather than a true congenital anomaly

Congenital Malformations of the Ovaries

Types of ovarian and fallopian tube malformations

  • Ovarian agenesis: failure of the ovary to form
  • Ovarian dysgenesis (also called “streak ovaries”): 
    • Abnormal and dysfunctional, small hypoplastic ovaries
    • Associated with Turner syndrome
  • Supernumerary ovary: an extra ovary
  • Fallopian tube agenesis: failure of a fallopian tube to form

Clinical presentation

The ovaries are the primary source of estrogen production in women. Without properly functioning ovaries, estrogen is not produced in significant quantities. 

  • Without estrogen:
    • No endometrial proliferation → primary amenorrhea
    • No egg development → infertility
    • No secondary sex characteristics (e.g., breast development) at puberty
  • Note: Only 1 ovary needs to be present in order to have normal fertility and menstrual function:
    • Abnormalities in and/or absence of a single ovary is typically asymptomatic and clinically irrelevant.
    • Excess ovarian tissue or an extra ovary (a supernumerary ovary) are also typically asymptomatic, though they may present with some menstrual irregularities.
  • Fallopian tubes anomalies:
    • Fallopian tubes are Müllerian structures (like the uterus), so tubal anomalies are typically associated with uterine anomalies on the same side.
    • Isolated unilateral fallopian tube agenesis is possible and likely asymptomatic, assuming the contralateral side is normal.
    • Isolated bilateral fallopian tube agenesis is technically possible and would be asymptomatic until it presents with infertility, but this generally isn’t seen.

General diagnosis and management principles

  • Imaging: 
    • Ultrasonography: Diagnosis of any ovarian abnormality is best made by pelvic ultrasound (1st test).
    • MRI may contribute additional information.
  • Karyotype should be obtained.
  • Laboratory (screening tests for amenorrhea):
    • Follicle-stimulating hormone (FSH): secreted by the pituitary gland; will be ↑ trying to stimulate the abnormal/absent ovaries to work
    • Estradiol: will be ↓ (unable to be synthesized by the abnormal/absent ovaries)
    • This combination of ↑ FSH + ↓ estradiol localizes the issue to the ovaries (as opposed to the uterus or hypothalamus).
  • Management typically involves:
    • Hormone replacement therapy (HRT) if ovaries are nonfunctional
    • Surgical excision of abnormal ovaries/ovarian tissue due to ↑ risk of malignancy with streak ovaries
    • Fertility is often possible through assisted reproductive technology (ART):
      • Requires donor egg/donor embryo for nonfunctional ovaries
      • In vitro fertilization (IVF) for fallopian tube anomalies

Summary and comparison

Table: Comparison summary of congenital malformations of the ovaries
Streak ovariesOvarian agenesis
Definition
  • A form of ovarian dysgenesis (malformed and dysfunctional ovaries)
  • Associated with Turner syndrome (45X,0)
  • Congenital absence of both ovaries
  • Unilateral agenesis is reported but is exceedingly rare.
Clinical presentation
  • Primary amenorrhea
  • Little to no secondary sex characteristics (↓ estrogen)
  • Features of Turner syndrome: short stature, webbed neck, wide-spaced nipples, cardiac anomalies
  • Primary amenorrhea
  • No secondary sex characteristics (no estrogen)
Diagnosis
  • Ultrasonography: rudimentary or nonvisible ovaries
  • Karyotype: 45X,0
  • Ultrasonography: absent ovaries
  • Karyotype: 46X,X
  • Laboratory: ↑ FSH, ↓ estradiol
Management
  • Surgical excision (oophorectomy) due to high risk of malignancy
  • HRT
  • HRT
  • Psychosocial therapy
  • Fertility: Pregnancy is possible via donor egg or embryo and ART.
ART: assisted reproductive technology
FSH: follicle-stimulating hormone
HRT: hormone replacement therapy

Congenital Malformations of the Uterus and Cervix

Overview of uterine malformations

  • The uterus forms from the Müllerian ducts, which fuse in the midline to create the uterus, cervix, and upper vagina. Therefore, initially, these structures are divided down the midline before this midline septum regresses. 
  • Types of defects:
    • Lateral fusion defects: occur when the midline septum fails to regress, resulting in vertical septa and divided or “duplicated” cavities
    • Vertical fusion defects: result in transverse, obstructive defects (typically in the vagina)
    • Hypoplasia or agenesis: failure of an organ or tissue to fully develop (hypoplasia) or complete absence of the organ (agenesis)
  • Types of CUAs:
    • Arcuate uterus
    • Septate uterus
    • Bicornuate uterus
    • Unicornuate uterus
    • Uterus didelphys
    • Uterine agenesis
  • Patients with CUAs are at increased risk for additional anomalies:
    • Renal (20%–30%, typically ipsilateral to the CUA) 
    • Skeletal
    • Abdominal wall
Malformations of the uterus

Malformations of the uterus

Image by Lecturio. License: CC BY-NC-SA 4.0

Characteristics of the congenital uterine anomalies

Aside from uterine agenesis, CUAs are all caused by lateral fusion defects. Frequencies of each specific anomaly (out of all CUAs) are noted in parentheses.

  • Arcuate (18%):
    • Smooth fundal contour
    • Slight midline, often broad, fundal cavity indentation
    • Often considered a normal variant because it is not associated with adverse pregnancy outcomes
    • Patients are typically asymptomatic and these are incidental findings.
  • Septate uterus (35%):
    • Complete lateral fusion of the Müllerian ducts with incomplete regression of the midline septum
    • Smooth fundal contour
    • A thin dividing band of tissue, typically consisting of myometrium covered by endometrium that is usually vascularized
    • Varying amounts of fibrous and muscular tissue and degrees of vascularization 
    • May be partial, complete, or extend into the vagina:
      • Partial septum (known as a subseptate uterus): The septum spares the cervix
      • Complete septate uterus: The septum extends down to the cervix.
      • Septate uterus and vagina: The septum extends through the cervix into the vagina.
  • Bicornuate (26%):
    • Partial (rather than complete) fusion of the Müllerian ducts 
    • Indented fundal contour with moderately separated endometrial cavities
    • 1 cervix
    • May be partial or complete (which extends all the way to the cervix)
  • Unicornuate (10%):
    • Due to hypoplasia or agenesis of 1 of the Müllerian ducts
    • A single uterine horn is present, with an otherwise “normal” cavity, fallopian tube, and cervix.
    • The failed duct may be completely absent or may present as a rudimentary horn: 
      • Rudimentary horns may or may not communicate with the uterus.
      • Noncommunicating rudimentary horns may still have hormonally active endometrial tissue that lacks an outflow tract → presents with severe dysmenorrhea or chronic pelvic pain
  • Didelphys (8%): “double uterus”
    • Failure of Müllerian duct fusion resulting in duplicated reproductive structures
    • 2 separate uteri, each with its own cervix (2 cervixes seen on speculum exam)
    • 75% also have a septate vagina.
    • 15%–20% also have other associated unilateral anomalies:
      • Examples: obstructed hemivagina, ipsilateral renal agenesis
      • Anomalies are on the right side in 65% of cases.
  • Uterine agenesis (3%):
    • Also known as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome
    • Varying degrees of uterine hypoplasia including (most commonly) complete absence of the uterus, cervix, and upper vagina
    • Also includes cervical agenesis

Clinical presentation

The clinical presentation of anomalies depends on the underlying malformations:

  • Due to abnormal uterine walls (e.g., poorly vascularized uterine septum) and/or cavity shape:
    • Recurrent pregnancy loss
    • Infertility
    • Preterm delivery
    • Breech presentation
    • Placental abruption
  • Due to complete obstruction or obstructed portions of the uterine outflow tract:
    • Cyclic pain
    • Vaginal or pelvic mass
  • Due to agenesis:
    • Primary amenorrhea
    • Infertility

Diagnosis

In general, all patients with primary amenorrhea, pelvic pain, infertility, and/or recurrent pregnancy loss should have pelvic imaging, which is how CUAs are typically diagnosed. Methods include:

  • Pelvic ultrasonography:
    • 1st-line test for imaging the uterus, cervix, and ovaries
    • Can delineate the external uterine contour well
    • Cannot visualize anatomy within the uterine cavity
  • Pelvic MRI: 
    • Can aid in diagnosis when ultrasonography is inconclusive
    • Can delineate both the internal and external uterine contours (e.g., can differentiate between septate and bicornuate uteri)
  • Saline-infusion sonography (SIS):
    • Sterile fluid is injected into the uterine cavity through a catheter. The fluid distends the uterine cavity to allow real-time ultrasound images to be obtained.
    • Allows for assessment of the internal uterine cavity (in addition to all images obtained on traditional ultrasonography, like the external uterine contour as well)
    • Can identify septa, polyps, and submucosal fibroids
  • Hysterosalpingography:
    • A fluoroscopic exam in which dye is injected into the uterine cavity and allowed to fill and spill from the fallopian tubes
    • Provides information about the inner contours of the uterine cavity and patency of the fallopian tubes
    • Does not provide information about the external uterine contour
Bicornuate uterus

Hysterosalpingogram (HSG) showing a bicornuate uterus

Image: “HSG of secondary infertility patient showing bicornuate uterus” by Muhammad Usman Aziz, MBBS, FCPS (Radiology). Senior Registrar, Department of Radiology, Liaquat National Hospital, National Stadium Road, Karachi, Pakistan. License: CC BY 3.0
Table: Imaging diagnosis of congenital uterine anomalies
External uterine contourInternal uterine contour
Arcuate uterusSmooth fundal contour
  • Minimal fundal indentation < 1.5 cm
  • Indentation is broad (> 90°).
Septate uterusSmooth fundal contour, or indentation of < 1 cm
  • 2 closely separated endometrial cavities
  • Fundal indentation > 1.5 cm
  • Angle of indentation < 90°
Bicornuate uterus
  • Indented fundal contour ≥ 1 cm
  • 1 cervix
2 moderately separated endometrial cavities
Didelphys
  • Deeply indented fundal contour
  • 2 cervixes
2 widely separated endometrial cavities

Management

  • Any obstructed areas should be surgically opened and/or resected to allow for full efflux of menstrual fluid.
  • Uterine septa are typically resected hysteroscopically.
  • Surgical repairs of bicornuate and didelphys anomalies are highly complex and rarely done since it is unclear whether they truly improve pregnancy outcomes (which would be the only indication for such a repair).
  • Isolated cervical agenesis:
    • Consider medical management for menstrual suppression until patient desires conception via ART:
      • Continuous use of combined estrogen/progestin therapy (e.g., oral contraceptive pills)
      • Progestin-only therapy
      • Gonadotropin-releasing hormone (GnRH) agonist (continuous GnRH suppresses FSH, inducing a menopause-like state)
    • Surgical management:
      • Hysterectomy
      • Reconstructive surgeries to allow for menstruation (increased risks)

Congenital Malformations of the Vagina and Hymen

Development of vaginal and hymenal anomalies

  • Like uterine anomalies, vaginal anomalies are due to:
    • Agenesis/hypoplasia
    • Lateral fusion defects → resulting in vertical septa
    • Vertical fusion defects → resulting in transverse septa
  • The hymen is a transverse membrane made of fibrous connective tissue: 
    • The embryologic junction of the sinovaginal bulbs and the urogenital sinus
    • Normally perforates, becoming patent in fetal life → creates a connection between the vaginal lumen and the external genital structures
    • Failure of perforation can result in hymenal anomalies.

Types of vaginal anomalies

  • Longitudinal vaginal septum:
    • May be partial or complete (coming all the way down to the vaginal introitus)
    • Obstructed hemivagina: when a longitudinal septum joins the lateral wall, creating an obstructed area of vagina
    • Typically occurs in conjunction with a uterus didelphys
  • Transverse vaginal septum: 
    • May include “windows,” called fenestrations, that allow for slow menstrual efflux
    • Or may be completely obstructive
  • Vaginal agenesis:
    • Agenesis of the upper vagina (MRKH syndrome): 
      • The cervix, uterine body, and fallopian tubes are also typically absent.
      • Ovaries (non-Müllerian structures) are usually present and normal.
    • Agenesis of the lower vagina: 
      • Due to abnormal development of the sinovaginal bulbs 
      • Müllerian ducts are normal. Upper vagina, cervix/uterus, fallopian tubes and ovaries are all typically present and normal.
Congenital vaginal anomalies

Congenital vaginal anomalies:
Left: Uterus didelphys with a longitudinal vaginal septum
Middle: Uterus didelphys with a longitudinal septum and obstructed hemivagina
Right: Normal uterus with a transverse vaginal septum

Image by Lecturio. License: CC BY-NC-SA 4.0

Types of hymenal anomalies

  • Imperforate hymen
  • Microperforate or cribriform perforations
  • Septate
Malformations of hymen

Normal parous hymen compared to common hymen malformations, including microperforate, septate, cribriform, and imperforate hymens

Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical presentation

  • Completely obstructive anomalies (e.g., transverse vaginal septa, vaginal agenesis, imperforate hymen):
    • Inability to fully penetrate the vagina during: 
      • Tampon insertion
      • Intercourse
      • Physical exam
    • If a functional uterus and ovaries are present, at menarche patients also experience:
      • Severe dysmenorrhea 
      • Cyclic or chronic pelvic pain
      • Vaginal mass or bulge
  • Incomplete obstructions (e.g., septate hymen, obstructed hemivagina) present with similar pain symptoms and:
    • Irregular bleeding
    • Prolonged bleeding
  • All vaginal and hymen anomalies can also present with pain during intercourse (known as dyspareunia).
  • Longitudinal vaginal septum versus septate hymen:
    • Bleeding despite using a tampon → longitudinal vaginal septum
    • Inability to remove a tampon after it is inserted → septate hymen. Because the tampon is thin in the applicator, it can fit through 1 side, but it expands once deployed and cannot be removed.

Diagnosis

  • Diagnosis is typically achieved with a pelvic exam and ultrasonographic imaging.
  • MRI can be used to differentiate between a high transverse septum and cervical/uterine agenesis.
  • All patients with vaginal and hymenal anomalies should undergo pelvic imaging to look for associated uterine anomalies.
  • On imaging, obstructive lesions may demonstrate:
    • Hematocolpos: accumulation of menstrual blood in the vagina
    • Hematometra: accumulation of blood in the uterus

Management

  • For septa and hymenal anomalies: surgical resection
  • For vaginal agenesis:
    • Vaginal dilators used regularly can achieve good functional length (for intercourse) in a majority of patients.
    • Specialized complex surgical procedures exist to create a neovagina if desired by the patient for penetrative intercourse.

References

  1. Marc R Laufer, Alan H DeCherney (2021). Congenital uterine anomalies: clinical manifestations and diagnosis. UpToDate. Retrieved June 25, 2021, from https://www.uptodate.com/contents/congenital-uterine-anomalies-clinical-manifestations-and-diagnosis
  2. Marc R Laufer, Alan H DeCherney (2021). Congenital uterine anomalies: surgical repair. UpToDate. Retrieved June 25, 2021, from https://www.uptodate.com/contents/congenital-uterine-anomalies-surgical-repair
  3. Marc R Laufer (2021). Congenital anomalies of the hymen and vagina. UpToDate. Retrieved June 25, 2021, from https://www.uptodate.com/contents/congenital-anomalies-of-the-hymen-and-vagina
  4. Marc R Laufer (2020). Benign cervical lesions and congenital anomalies of the cervix. UpToDate. Retrieved June 25, 2021, from https://www.uptodate.com/contents/benign-cervical-lesions-and-congenital-anomalies-of-the-cervix
  5. Northwell Health (2021). Congenital anomalies of the female genital tract. https://www.northwell.edu/obstetrics-and-gynecology/conditions/congenital-anomalies-of-the-female-genital-tract
  6. Aurora M Miranda, Rebecca Heuer Schnatz (2018). Female reproductive organ anatomy. UpToDate. Retrieved June 25, 2021, from https://emedicine.medscape.com/article/1898919-overview

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