P&C 47b- What is Mullerian Agenesis?

Mullerian Agenesis, also known as müllerian aplasia, Mayer-Rokitansky-Küster-Hauser syndrome, or vaginal

agenesis, is a congenital disorder that affects the reproductive system in females. It is characterized by the absence
or underdevelopment of the Mullerian ducts, which are the precursors to the uterus, fallopian tubes, cervix, and the
upper two-thirds of the vagina.

Embryonic development of the Mullerian Ducts

During the 5th week of embryonic development, the

Mullerian ducts begin to form on either side of the dorsal
body wall, lateral to the Wolfian (mesonephric) ducts. The
induction and formation of the Mullerian ducts is
influenced by several factors, including the presence of
nearby tissues such as the coelomic epithelium and
mesenchyme. The exact mechanisms that regulate this
process are complex and involve a variety of signalling
pathways.

By the 6th week of development, the Mullerian ducts

begin to differentiate into distinct structures. The cranial
end of each duct forms a funnel-shaped structure called
the fimbriated ostium, which will eventually become part
of the fallopian tube. The caudal end of each duct remains
open and will become the uterine cavity. In addition to
differentiation, the two Mullerian ducts also begin to fuse
together in the midline to form a single structure called
the utero-vaginal primordium.

The utero-vaginal primordium then undergoes a process

called canalization, where it becomes hollowed out to
form a single tube called the uterovaginal canal. This
process is followed by septation, where a septum divides
the uterovaginal canal into two separate structures: the
upper part becomes the uterus and cervix, while the lower
part becomes the vagina. The septum eventually
disappears, leaving behind a single cavity in both
structures.

In addition to canalization and septation, there are several

other changes that occur during embryonic development that affect the shape and orientation of these structures. For
example, during foetal development, there is a counter-clockwise rotation of both fallopian tubes around their
longitudinal axis so that their fimbriated ends point towards each other in front of the ovary. This rotation also
results in an asymmetry between left and right fallopian tubes with respect to their length and orientation relative to
each other.

Epidemiology
Mullerian agenesis has an estimated prevalence of 1 in 4,500 female births, with no significant variation across
racial or ethnic groups. The condition is usually not diagnosed until puberty or later due to the presence of normal
secondary sexual characteristics resulting from intact ovarian function.

Mullerian agenesis is often associated with other congenital anomalies, such as renal (kidney) and skeletal
abnormalities. Approximately 30% of women with MRKHS have some form of renal anomaly, ranging from minor
abnormalities in kidney position to complete agenesis (absence) of one or both kidneys. Skeletal anomalies, such as
scoliosis (curvature of the spine) and vertebral defects, are also relatively common in women with MRKHS,
affecting up to 40% of cases.

Etiology

Genetic Factors: the specific genes responsible for the disorder have not been identified. Some studies suggest that
MRKHS may be associated with mutations in the WNT4, WNT9B, and PAX2 genes, which are involved in the
development of the reproductive system. Other research suggests that MRKHS may be linked to abnormalities in the
HOXA gene cluster, which plays a crucial role in the patterning and differentiation of the Mullerian ducts.

Environmental Factors: exposure to certain chemicals or medications during pregnancy, may also contribute to the
development of Mullerian agenesis. For example, studies have shown that exposure to diethylstilbestrol (DES), a
synthetic estrogen, during pregnancy can increase the risk of Mullerian abnormalities in female offspring. Similarly,
exposure to tobacco smoke, lead, and certain pesticides has been linked to an increased risk of reproductive tract
anomalies, including Mullerian agenesis.

Hormonal Factors: deficiencies in anti-Müllerian hormone (AMH) and/or its receptor have been implicated in the
disorder. AMH is produced by the Sertoli cells in the developing testes and plays a crucial role in the regression of
the Mullerian ducts in male fetuses. In females, AMH is produced by the granulosa cells in the ovaries and helps
regulate follicular development and ovulation.

Types of Mullerian Agenesis

There are several types of Mullerian agenesis, which can be categorized based on the specific structures affected and
the extent of the abnormalities.

1. Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

The most common type of Mullerian agenesis, which affects about 1 in 4500 female births. In this
condition, the uterus and upper two-thirds of the vagina are either underdeveloped or absent. The ovaries
and external genitalia appear normal, and individuals with MRKH syndrome have a normal 46, XX
karyotype.
2. Uterine Agenesis
Uterine agenesis is a rare type of Mullerian agenesis in which the uterus is completely absent. This
condition can occur in isolation or as part of a broader syndrome, such as MRKH syndrome. In some cases,
a rudimentary uterine structure may be present, but it is non-functional. Uterine agenesis can lead to
infertility and other reproductive complications.
3. Unicornuate Uterus
A type of Mullerian agenesis in which one side of the uterus develops normally, while the other side is
either underdeveloped or absent. This condition can lead to a range of reproductive complications,
including preterm labour, miscarriage, and malpresentation of the foetus during delivery. Individuals with a
unicornuate uterus may also have asymmetric fallopian tubes and kidneys.
4. Bicornuate Uterus
 A Mullerian agenesis in which the uterus is
shaped like a heart, with two horns or
divisions. This condition can lead to an
increased risk of miscarriage and preterm
labour. It can also cause problems during
pregnancy, such as malpresentation of the
foetus and difficulty during delivery.
Bicornuate uterus occurs in about 3% of
women and can be diagnosed through
imaging tests such as ultrasound or MRI.
5. Didelphys Uterus
A didelphys uterus is a rare type of
Mullerian agenesis in which there are two
separate uteri, each with its own cervix and
vagina. This condition can lead to
infertility or difficulties during pregnancy
and delivery. Didelphys uterus occurs in
about 1 in 3000 women and can be
diagnosed through imaging tests such as
ultrasound or MRI.

Pathophysiology

i. Abnormalities in WNT4 Gene

Expression: As mentioned earlier,
mutations in the WNT4 gene have
been identified in some cases of
MRKH syndrome. This gene
provides instructions for making a
protein that is essential for normal
female reproductive system
development. Abnormalities in
this gene can lead to abnormal
development of the Mullerian
ducts, resulting in absent or
underdeveloped uterus and vagina.
The specific mechanism by which
WNT4 mutations cause MRKH
syndrome is not fully understood
but may involve disruptions in cell
signalling pathways involved in organogenesis.
ii. Abnormalities in Hox Genes Expression: Hox (HOXA9- HOXA13) genes are a group of genes that play crucial
roles in organogenesis during embryonic development. They control patterning and differentiation along the
anterior-posterior axis of an embryo by regulating gene expression patterns along this axis. Abnormalities in
Hox gene expression patterns can lead to various congenital defects, including those affecting the positional
patterning of the fallopian tubes, uterus, uterine cervix, and upper vagina. Studies have shown that mice with
mutations in specific Hox genes show abnormalities similar to those seen in humans with MRKH syndrome,
such as absent or underdeveloped uteri and vaginas.
iii. Exposure to GALT: Müllerian agenesis has been associated with variants of the galactose-1-phosphate
uridyltransferase (GALT) enzyme; this finding suggests that increased exposure to galactose is responsible for
abnormal vaginal development.
iv. Abnormalities in MIS Gene: Mutations in either the antimüllerian hormone or müllerian inhibitory substance
(MIS) gene or its receptor gene are responsible for this disorder.

Signs & symptoms + Complications

 Absent or Underdeveloped Uterus and Fallopian Tubes

 Primary Amenorrhea
 Difficulty with Vaginal Penetration (Normal External Genitalia)
 Infertility

Complications

 Kidney Abnormalities: About 30% of individuals with MRKH have kidney abnormalities, such as
horseshoe kidney or duplicated ureters.
 Skeletal Abnormalities: Some individuals may have skeletal anomalies, such as scoliosis or vertebral
malformations.
 Hearing Loss: A small percentage of individuals with MRKH may experience hearing loss.

Diagnosis/ Investigations

1) Clinical Evaluation:
- Menstrual history: Absence of menstruation by the age of 16 is a key indicator.
- Sexual development: Delayed puberty, absence of breast development, or other signs of hormonal
imbalance.
- Pelvic examination: This helps assess the presence or absence of a cervix and vagina.
- Breast examination: Evaluates breast development and signs of oestrogen production.
- External genitalia: Examines the appearance of the external genitalia for any abnormalities.
2) Imaging Studies:
- Ultrasound: A pelvic ultrasound is the initial imaging test. It can visualize the uterus, ovaries, and
fallopian tubes. In Müllerian agenesis, the uterus and cervix will be absent, and the ovaries may be
present but may appear smaller than normal.
- Magnetic Resonance Imaging (MRI): MRI provides a more detailed view of the pelvic anatomy and
can confirm the absence of the uterus and cervix. It can also assess the length of the vagina and
identify any other associated anomalies.
- Hysterosalpingography (HSG): This procedure involves injecting a contrast dye into the uterus and
fallopian tubes to visualize them on X-ray. It is not typically used in Müllerian agenesis as the uterus is
absent.
3) Hormonal Testing:
- Hormone levels: Blood tests can measure hormone levels, such as follicle-stimulating hormone (FSH),
luteinizing hormone (LH), and oestradiol. These tests help assess ovarian function and oestrogen
production.
- Karyotype: A karyotype is a test that examines the chromosomes to rule out any genetic abnormalities
that may be associated with Müllerian agenesis.
4) Genetic Testing: While Müllerian agenesis is often sporadic, genetic testing can be considered to identify
potential genetic causes, especially if there is a family history of the condition.
5) Other Investigations:
- Kidney function tests: Some individuals with Müllerian agenesis may have associated kidney
abnormalities, so kidney function tests may be recommended.
 - Cardiovascular evaluation: Some individuals with Müllerian agenesis may have associated heart
defects, so a cardiovascular evaluation may be recommended.

Treatment

The primary goals of treatment for Müllerian agenesis are:

a. Achieving sexual function: This includes addressing vaginal agenesis and enabling sexual intercourse.
b. Enabling pregnancy: While biological pregnancy is not possible due to the absence of a uterus, options like
adoption, surrogacy, or egg donation can be explored.
c. Addressing psychological well-being: The diagnosis of Müllerian agenesis can be emotionally challenging.
Providing support and counselling is crucial for managing the psychological impact.
I. Vaginal Reconstruction:
- Vaginoplasty: This surgical procedure creates a functional vagina using various techniques. The most
common method involves creating a vaginal canal using a skin graft from the labia majora or buttocks.
- Dilatation: This non-surgical approach involves using dilators to gradually stretch the existing vaginal
opening. It is often used in cases of partial vaginal agenesis.
- Vaginal Reconstruction with a Tissue Expander: This involves inserting a tissue expander into the
vaginal canal, which is gradually inflated over time to create a larger space.
II. Hormone Therapy:
- Oestrogen Replacement Therapy: This is often prescribed to promote secondary sexual characteristics
like breast development and regulate menstrual cycles.
- Progesterone Therapy: This can be used to induce a withdrawal bleed, mimicking a menstrual cycle.
III. Fertility Options:
- Adoption: This allows individuals with Müllerian agenesis to experience parenthood.
- Surrogacy: A surrogate mother carries the pregnancy for the individual with Müllerian agenesis.
- Egg Donation: Eggs from a donor are fertilized with the partner’s sperm and implanted in a surrogate
mother.
IV. Psychological Support:
- Counselling: This can help individuals cope with the emotional and psychological impact of the
diagnosis.
- Support Groups: Connecting with others who have similar experiences can provide valuable support
and understanding.
V. Ongoing Management:
- Regular Gynaecological Check-ups: These are essential for monitoring the reconstructed vagina and
addressing any potential complications.
- Hormone Monitoring: Regular hormone levels checks are necessary to ensure optimal hormone
replacement therapy.

Differential Diagnosis

 Imperforate hymen: A condition where the hymen is completely closed, preventing menstrual flow.
 Vaginal septum: A condition where a wall divides the vagina.
 Androgen insensitivity syndrome: A condition where the body is unable to respond to male hormones,
leading to female external genitalia but absent internal reproductive organs.
REFERENCES

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Available from: https://emedicine.medscape.com/article/273534-overview

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Genetik. 2018 Feb 21;30(1):3–11.

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Management, And Treatment. Obstetrics and gynecology [Internet]. 2018;131(1):e35–42. Available from:
https://www.ncbi.nlm.nih.gov/pubmed/29266078