Müllerian agenesis

Müllerian agenesis is a congenital malformation in women characterised by a failure of the Müllerian

ducts to develop, resulting in a missing uterus and variable malformations of the vagina. It is the
second most common cause of primary amenorrhea. The condition is also called MRKH or Mayer-
Rokitansky-Küster-Hauser Syndrome, named after August Franz Joseph Karl Mayer, Carl Freiherr
von Rokitansky,Hermann Küster, and G.A.Hauser.

Signs and symptoms

A woman with this condition is hormonally normal, that is she will enter puberty with development of
secondary sexual characteristics including thelarche and adrenarche. Her chromosome constellation
will be 46,XX. Ovulation usually occurs. Typically, the vagina is shortened and intercourse may in
some cases be difficult and painful. Medical examination supported bygynecologic
ultrasonography demonstrates a complete or partial absence of the cervix, uterus, and vagina.

If there is no uterus, women with MRKH cannot carry a pregnancy. However, it is possible for these
women to have genetic offspring by in vitro fertilisation (IVF) and surrogacy. Uterine transplantation is
currently not a treatment that can be offered as the technology is still in its infancy.

Women with MRKH typically discover the condition when, during puberty years, the menstrual cycle
does not start. Some women find out earlier through surgeries for other conditions, such as a hernia.

Other, less common symptoms include kidney problems, hearing loss, and bone malformations.
Renal anomalies occur in 25-35% of females with mullerian agenesis.

Prevalence
The estimated prevalence is 1 in 5000 women.

Treatment
Although there are treatments to increase the comfort in sexual intercourse, there are none to let the
woman herself become pregnant. There are plans by UK and Swedish doctors for auterine
transplant that would allow these women to carry their own child, but no transplant has yet been
successful in producing a child. Since the women do have ovaries, women with this condition can
have genetic children through IVF with embryo transfer to a gestational carrier. Some women also
choose to adopt.

It may be necessary to use vaginal dilators or surgery to develop a functioning vagina to allow for
satisfactory sexual intercourse. A number of surgical approaches have been used. In the McIndoe
procedure[1] a skin graft is applied to form an artificial vagina. After the surgery, dilators are still
necessary to prevent vaginal stenosis. The Vecchietti procedure is a laparoscopicprocedure that has
been shown to result in a vagina that is comparable to a normal vagina in patients with Müllerian
agenesis.[2][3]
Thelarche (IPA: θilɑːki) is the first stage of secondary (postnatal) breast development, usually
occurring at the beginning of puberty in girls. Thelarche is usually noticed as a firm, tender lump
directly under the center of the nipple (papilla and areola). Thelarche is also referred to as a "breast
bud", or more formally as Tanner stage 2 breast development (Tanner stage 1 being the entirely
undeveloped prepubertal state). Thelarche may occur on one side first, or both sides simultaneously.

Adrenarche is an early sexual maturation stage in some higher primates that in humans typically
occurs at around 6 to 8 years of age. During adrenarche the adrenal cortex secretes increased levels
of androgens such as DHEA and DHEAS, but without increased cortisol levels. Adrenarche is the
result of the development of a new zone of the adrenal cortex, the zona reticularis.[1] Adrenarche is a
process related to puberty, but distinct from hypothalamic-pituitary-gonadal maturation and function.

Introduction

Background
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome consists of vaginal aplasia with other müllerian
(ie, paramesonephric) duct abnormalities.1 Its penetrance varies, as does the involvement of other
organ systems. Type I Mayer-Rokitansky-Kuster-Hauser syndrome is characterized by an isolated
absence of the proximal two thirds of the vagina, whereas type II is marked by other malformations;
these include vertebral, cardiac, urologic (upper tract), and otologic anomalies.2

In both types, the extent of vaginal aplasia varies, ranging from virtually absent to virtually
inconsequential. Mayer-Rokitansky-Kuster-Hauser syndrome usually remains undetected until the
patient presents with primary amenorrhea despite normal female sexual development. Mayer-
Rokitansky-Kuster-Hauser syndrome is the second most common cause of primary amenorrhea.
Although this condition has psychologically devastating consequences, its physiological defects can
be surgically treated. Following diagnosis, surgical intervention allows patients to have normal sexual
function. Reproduction may be possible with assisted techniques.

Pathophysiology
At approximately 5 weeks' gestation, the müllerian ducts stop developing. The skeleton, which is
derived from the embryonic mesoderm, is vulnerable to developmental disturbances at this time. The
uterus, cervix, and upper two thirds of the vagina form from the fused caudal ends of the
müllerian ducts. Fallopian tubes develop from the unfused upper ends; the renal system
simultaneously develops from the wolffian (ie, mesonephric) ducts. Ovarian function is
preserved because the ovaries originate within the primitive ectoderm, independent of the
mesonephros. Although Mayer-Rokitansky-Kuster-Hauser syndrome was previously thought to be a
sporadic anomaly, familial cases support the hypothesis of a genetic etiology and are receiving
increased attention. Although the precise gene has not yet been identified, this syndrome appears to
be transmitted in an autosomal dominant fashion, with incomplete penetrance and variable
expressivity.2

Frequency
United States

The incidence of congenital absence of the vagina is 1 per 4000-5000 female births. Mayer-
Rokitansky-Kuster-Hauser syndrome is generally thought to be a sporadic condition, and female
relatives of the patient apparently have no increased risk. However, familial clustering is reported with
increasing frequency.
Mortality/Morbidity
Mayer-Rokitansky-Kuster-Hauser syndrome has psychological consequences, but its physiological
defects are surgically treatable. Surgical correction permits normal sexual function and, possibly,
reproduction with assisted techniques.

Race
Mayer-Rokitansky-Kuster-Hauser syndrome has no racial predisposition.

Sex
Mayer-Rokitansky-Kuster-Hauser syndrome only affects females.

Age
Mayer-Rokitansky-Kuster-Hauser syndrome is a congenital disorder that is present at birth. However,
it may remain undiagnosed until adolescence or early adulthood.

Clinical

History
The following may be observed in patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome:

• Primary amenorrhea and possible cyclic abdominal pain

○ These symptoms are common in individuals with Mayer-Rokitansky-Kuster-Hauser
syndrome.
○ The patient undergoes puberty with normal thelarche and adrenarche; however,
menses do not begin.
○ Patients may report cyclic abdominal pain due to cyclic endometrial shedding without
a patent drainage pathway.
○ Because ovarian function is normal, patients experience all bodily changes
associated with menstruation and puberty.
• Infertility
○ Patients who do not undergo evaluation for primary amenorrhea often seek clinical
attention for infertility. However, patients rarely proceed to infertility evaluation without
ever having had a menses due to Mayer-Rokitansky-Kuster-Hauser syndrome.
○ Although the ovaries function normally, the fallopian tubes may be closed, and the
uterus is often anomalous.
• Inability to have intercourse
○ The degree of vaginal aplasia can vary from complete absence to a blind pouch.
○ The more shallow the canal, the greater the likelihood of the patient having
dyspareunia.
• Renal malformations
○ Absence or ectopia of the kidneys is common. Diagnosis can lead to discovery of
renal anomalies.
○ Some patients present with a history of voiding difficulties, urinary incontinence, or
recurrent urinary tract infections (UTIs).
 • Vertebral anomalies: Skeletal findings range in severity and clinical importance. Scoliosis is
the most common of the skeletal anomalies.
Physical
• Normal secondary female sexual characteristics are present after puberty.
• Height is normal.
• Speculum examination of the vagina may be impossible or difficult because of the degree of
vaginal agenesis.
• The vulva, labia majora, labia minora, and clitoris are normal.
• A palpable sling of tissue may be present at the level of the peritoneal reflection.
Causes
• The cause of Mayer-Rokitansky-Kuster-Hauser syndrome is unknown, and no known gene is
linked to this condition.
• A postulation is that the müllerian duct system ceases development during gestational days
44-48.
Workup

Laboratory Studies
• Chromosomal analysis is essential to exclude karyotypic abnormalities of the X chromosome
(eg, Turner syndrome). Turner syndrome does not cause Mayer-Rokitansky-Kuster-Hauser
(MRKH) syndrome. However, a karyotype is needed to rule out androgen insensitivity
syndrome (AIS) because these gonads need to be resected.
• Other chromosomal aberrations may include a 46,XY karyotype, which suggests a form of
AIS.
• Normal circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
indicate appropriate ovarian function. Human chorionic gonadotropin (hCG) levels are
negative and are not checked. Testosterone levels can be assayed and are in the normal
female range for Mayer-Rokitansky-Kuster-Hauser syndrome and in the normal male range
for AIS.
Imaging Studies
• Ultrasonography
○ An excellent imaging modality for Mayer-Rokitansky-Kuster-Hauser syndrome,
ultrasonography requires no radiation and is noninvasive and inexpensive.
Ultrasonography easily depicts the upper level of the vagina and the length of its
obstruction.
○ Ultrasonography can also be used to identify uterine duplications and tubal
obstruction.
○ Ultrasonography simultaneously allows assessment of the kidneys and bladder for
abnormalities and visualization of some vertebral anomalies.
• MRI
○ MRI provides excellent images of superficial and deep tissue planes.
○ MRI can clarify inconclusive ultrasonography results concerning cavitation of the
uterus.
 ○ MRI improves assessment of subperitoneal structures and detects the presence of a
cervix.
○ MRI can be used to image the spine if vertebral anomalies are suspected as can
plain films
○ MR urography (MRU) is an excellent imaging modality for visualization of both the
reproductive and the urinary anatomy, as well as for function.
• Laparoscopy
○ Laparoscopy provides only indirect assessment of uterine cavitation. Hysteroscopy
(examining inside the endometrial cavity) confirms cavitation; however, MRI is also
a great method for this. Laparoscopy is used in patients who also present with
abdominal pain to evaluate and possibly resect the müllerian horn.
○ Therapeutic laparoscopic surgery can also be performed in the same setting.
○ Laparoscopy is the preferred procedure when uterine remnants or endometriosis
cause cyclic pelvic pain requiring excision.
• Pyelography
○ Perform intravenous pyelography to assess renal structure.
○ Retrograde pyelography can be used to asses the renal collecting system, and does
not require intravenous contrast injection.
○ This technique requires cystoscopy.
Histologic Findings
• The uterine anlage may have unilaterally functioning endometrial tissue; bilateral function is
rare.
• Hematometra develops and may lead to endometriosis.
• The myometrium appears thinner than usual.
Treatment

Medical Care
• Although evaluation of patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome can
be performed on an outpatient basis, surgical repair requires admission.
• Medical and surgical care are essential for capacity for sexual intercourse, and genital
appearance. In rare cases, fertility may be possible. Using assisted reproductive techniques,
women with Mayer-Rokitansky-Kuster-Hauser syndrome can become pregnant by having
oocytes harvested, fertilized, and implanted in a surrogate.
Surgical Care
The ideal repair provides the patient with an unscarred vagina that allows sexual functioning. Excision
of uterine anlage can also prevent endometriosis and resultant ovarian function impairment.

• Frank technique or perineal dilation

○ The only nonsurgical option, this technique is successful in motivated patients willing
to spend time to create a neovagina using the molds. Patients apply progressive
pressure to the perineum using a bicycle-seat stool to hold a dilator in place. They
need to be frequently examined to be sure they are dilating the vagina and not the
urethra.
 ○ Because this technique is self-administered, compliance may be poor in patients with
a vaginal dimple or no vagina because these patients may experience discomfort and
abandon the dilator. However, this is often an indication of future compliance with
vaginal dilators and molds in the postoperative period.
• McIndoe technique
○ The most common surgical procedure used for vaginal reconstruction is the McIndoe
technique. The technique involves the following steps:
 A split-thickness skin graft is the most popular tissue for vaginal replacement.
Skin from the thigh or buttocks is preferable. Sometimes knowing the patients
tan lines is helpful in hiding the donor graft site.
 Using a blunt dissection, create a pocket between the urethra and rectum.
 After covering a cylindrical stent with the skin graft, place it into the potential
space. Fix the graft into place by attaching cut edges of the skin incision to
recreate the introitus. The labia majora are then sutured loosely together to
hold in the mold. A Foley catheter is placed, and the patient is given a low
residue diet and placed on modified bed rest.
 About one week later, remove the stent. Irrigate the neovagina and cauterize
any areas of granulation tissue with silver nitrate sticks.
 Have the patient use a mold or dilator in the neovagina every day and night
for 3 months, followed by nightly insertion for 3 more months to prevent
contraction.
○ Disadvantages of this procedure include scarring at the donor site, neovaginal
stenosis, and the need for long-term dilation.
• Williams vaginoplasty
○ Williams vaginoplasty uses a vulval flap to make a vaginal tube.
○ Although this simple procedure does not damage the urethra or rectum, dilation is
needed for a lengthy period, and the neovagina has a physiologically abnormal angle.
• Rotational flap procedures
○ Rotational flap procedures use the pudendal thigh, gracilis myocutaneous, labia
minora, and other fasciocutaneous flaps.
○ Disadvantages of these techniques include extensive skin scarring at the donor graft
site and the need for patient diligence in postsurgical dilation.
• Intestinal neovagina
○ This technique uses an isolated segment of bowel for vagina
○ The isolated segment retains its vascular supply via intact mesentery.
○ Sigmoid is generally the preferred bowel segment, as it can most easily be mobilized
to the perineum in a tension-free manner.3
○ Patients who have undergone this reconstructive technique report a high degree of
satisfaction.4
• Vecchietti technique
○ Exerts continuous progressive pressure by an acrylic olive passed through the
potential neovaginal space and the abdominal wall.
 ○ A traction device is placed into the peritoneal cavity and gradually draws the olive
upward over a period of days to weeks. This gradually lengthens the vaginal vault.
○ This technique is now performed laparoscopically.

Müllerian duct

Müllerian ducts (or paramesonephric ducts) are paired ducts of the embryo that run down the
lateral sides of the urogenital ridge and terminate at the mullerian eminence in the primitive urogenital
sinus. In the female, they will develop to form the fallopian tubes, uterus, and the upper portion of the
vagina; in the male, they are lost. These ducts are made of tissue of mesodermal origin.

Development
Müllerian ducts are present on the embryo of both sexes. Only in females do they grow and develop
into reproductive organs. They degenerate in males, but the adjoining Wolffian ducts develop into
male reproductive organs.

Regulation of development
The development of the müllerian ducts is controlled by the presence or absence of "AMH", or Anti-
müllerian hormone (also known as "MIF" for "müllerian-inhibiting factor", or "MIH" for "müllerian-
inhibiting hormone").

The testes produce

Disturbances
AMH and as a
male can lead The ducts disappear except for the
result the
embryogene topersistent vestigialvagina masculina and
development of the
sis müllerian duct the appendix testis.
müllerian ducts is
syndrome.
inhibited.

female The absence of Disturbance in The ducts develop into the

embryogene AMH results in the the upper vagina,cervix, uterus andovid
 development
development of may result in
female uterine absence
sis reproductive (Mullerian ucts.
organs, as noted agenesis)
above. or uterine
malformations.