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 Medical Review of Human Vagina

Dr. Mohammad Oda Selman 1

Applied Embryology Department/ High Institute of Infertility Diagnosis and Assisted

Reproductive Technologies/Al-Nahrain University- Baghdad, Iraq.1

Dr. Sundus Fadhil Hantoosh 2

Training and Development Department/Research and Training Forensic DNA

Center/Al-Nahrain University-Baghdad, Iraq. 2

Dr. Ula M. Al-Kawaz 3

High Institute of Infertility Diagnosis and Assisted Reproductive Technologies/Al-
Nahrain University- Baghdad, Iraq. 3

ϭ

 Preface

This book deals with many medical aspects concerning human vagina. In this book,
rapid review on vagina involved anatomy, embryology, histology, immunology,
normal flora and infectious microbes, non-infectious diseases, environmental
conditions of vagina, benign and malignant tumors, and different stages of age and
their effects on vagina. Gynecologists can return to it as it comprises most medical
fields of this portion of female reproductive system. Not only gynecologists but also
postgraduate students who have interest in such subjects can gain considerable
benefit as it can be considered as a guide in their higher study. By reading this book,
even common educated women can know how to behave when they face any
abnormal condition during their sexual and elderly stages of life.

Ϯ

 Contents

Contents Page
Number
Introduction 4

Chapter One 8
Sexual Differentiation and Embryonic Development of
Vagina and External Genitalia
Chapter Two 20
Anatomy of Vagina
Chapter Three 28
Histology and Morphological Changes of Vagina
Chapter Four 33
Relationship Between Hormones, Vaginal Mucosa, and
Vaginal Flora
Chapter Five 37
Normal Flora of Vagina
Chapter Six 44
Vaginitis
Chapter Seven 68
Innate, Humoral and Cell-mediated Immunity
Chapter Eight 76
Oxidative Stress in Vagina
Chapter Nine 81
Vaginal Atrophy
Chapter Ten 87
Tumors of Vagina

ϯ

 Introduction

The human vagina (the word means "a sheath") is an elastic muscular canal that
extends from the cervix to the vulva. If the woman stands upright, the vaginal tube
points in an upward-backward direction and forms an angle of slightly more than 45
degrees with the uterus. The vaginal opening is at the caudal end of the vulva, behind
the opening of the urethra. The orifice of the vagina is guarded by the hymen. The
vagina lies behind the bladder and urethra and in front of the rectum and anal canal.
Its walls are collapsed: the anterior wall is some 7.5 centimeters in length, whereas
the posterior wall is about 1.5 centimeters longer. The vagina has a mucous
membrane and an outer smooth muscle coat closely attached to it. There are no
glands in the vaginal lamina propria and vaginal lubrication is provided by transudate
from the blood vessels and secretions provided by the Bartholin's glands and Skene's
gland. The membrane of the vaginal wall also produces moisture, although it does not
contain any glands.

The vagina develops from the intermediate mesoderm. The course of development of
the human genital tract is undifferentiated up to the 9th week. Both Müllerian tissue
and that of the urogenital sinus origin normally participate in the development of the
vagina.

Sex determination is the process by which the undifferentiated gonadal ridge

becomes a testis or an ovary. In turn, this leads to sexual differentiation in which
male and female genitalia and other somatic characteristics develop. Sex
chromosomes, hormones, and other factors, most of which are encoded on autosomes
determine the choice between male and female developmental paths.

The vagina is lined by nonkeratinized squamous epithelium that is responsive to

ovarian steroid hormone cycling. There is no epithelial keratin layer, but the mucosa
is protected by an acid environment resulting from bacterial growth on a glycogen
substrate supplied by the mucus.

ϰ

The vagina is responsive to estrogen cycling. At birth, the vagina exhibits the effects
of residual maternal estrogens and subsequently the lining epithelium is high in
glycogen content. During puberty, the vagina acquires mature characteristics in
response to adrenal and gonadal maturation. In women of reproductive ages, the
vaginal mucosa responds to steroid hormone cycling, exhibiting maximal thickness
and intracellular glycogen content at mid-cycle. The vagina further adapts to the
needs of pregnancy and delivery. After menopause, tissue atrophy ensues and
cervicovaginal secretions become sparse.

Lactobacilli are non-spore-forming, gram-positive rods that form an important part of

the normal human bacterial flora found in the mucosa of the vagina. They are
considered protective organisms required to maintain health by producing lactic acid
and other metabolites inhibiting growth of pathogenic organisms.

Estrogen status plays a crucial role in determining the normal state of vagina. In
prepubertal and postmenopausal states, the vaginal epithelium is thinned, and the pH
of the vagina usually is elevated (4.7 or greater). A routine bacterial culture will
demonstrate a broad variety of organisms, including skin and fecal flora. During the
reproductive years, the presence of estrogen increases the glycogen content in vaginal
epithelial cells, which in turn encourages colonization of the vagina by lactobacilli.

Vaginitis is an infectious or noninfectious inflammation of the vaginal mucosa, which

sometimes involves the vulva. Infectious vaginitis is most common in women within
reproductive ages and generally caused by the types of infection: bacterial vaginosis,
vaginal candidiasis, trichomoniasis vaginitis, aerobic vaginitis, Chlamydia infection,
gonococcal vaginitis and viral vaginitis.

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic,

cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease,
and idiopathic vaginitis.

Patients with atrophic vaginitis may have an abnormal vaginal discharge, dryness,
itching, burning, or dyspareunia. Although more common in postmenopausal women,
ϱ

sometimes it can be observed in younger premenopausal women. Vaginal atrophy
occurs when there is lack of estrogen and is characterized by the thinning of the wall
of the vagina and elevated vaginal pH.

The vaginal innate immune system represents the first line of defense against foreign
organisms and pathogenic microbes. The innate immune system-the nonspecific
portion of the immune response is well represented within this environment. An
intricate interaction between the normal vaginal flora, different immune cells and
various peptides create conditions that protect the host and thus avoid infection. Each
component contributes in such a way that homeostasis prevails; any alteration in
these components has been associated with disease processes. The components of this
defense mechanism can be divided into normal vaginal flora, antimicrobial peptides,
cytokines, and immune cells.

Antibodies are present in vaginal secretions with IgG being dominant isotype and
IgA a minor constituent. These antibodies are derived in approximately equal
proportions from serum and local production. The absence of local lymphoepithelial
sites is thought to be the cause of the poor antibody response of the vagina.

Cell-mediated immunity of vagina is key to defense against intracellular pathogens

that infect the vagina. Recent studies indicate that there are immunological
microenvironments within the female genital tract, and that immune functions are
affected by hormones as well as infections and inflammatory processes. The normal
vaginal mucosa contains few T cells and antigen presenting cells. Vaginitis cases
have increased numbers of intraepithelial CD8+ and CD4+ lymphocytes and antigen
presenting cells. The menstrual cycle and menopause have no apparent effect on
cellular localization or abundance in vaginal tissue.

Benign or malignant neoplasms of the vagina are uncommon. The frequency of

benign lesions ranges from rare to very rare. Most vaginal tumors produce no
symptoms until significant size is reached. Benign vaginal neoplasms may be divided
into cystic or solid lesions and third category best described as related conditions. As

ϲ

is true for any neoplasm, biopsy provides a definitive diagnosis. Vaginal cancer is an
uncommon disease in which cancer cells grow from the cells of the vaginal lining.
Vaginal cancer occurs when vaginal cells divide without control or order. There are
several types of vaginal cancer as squamous cell carcinoma, adenocarcinoma,
melanoma, and sarcoma. The vast majority of vaginal cancers evolve over a period of
many years. Normally, vaginal cancers affect older women between the ages of 65-70
years of age. The biggest risk factor for contracting vaginal cancer can be attributed
to the diagnosis of cervical cancer. Also, vaginal irritation and human papilloma virus
infection are attributing factors to the disease.

ϳ

 Chapter One

Sexual Differentiation and Embryonic Development of Vagina and

External Genitalia

Sex determination and manifestation begins with genetic sex determination (i.e. 46,
XX or 46, XY) that occurs at fertilization. Sex determination is the process by which
the undifferentiated gonadal ridge becomes a testis or an ovary which leads to the
development of male and female genitalia and other somatic characteristics. The
gonads do not acquire male or female morphological characteristics until the seventh
week of development.

Gonads appear initially as a pair of longitudinal ridges, the genital or gonadal ridges.
They are formed by proliferation of the epithelium and a condensation of underlying
mesenchyme. The germ cells do not appear in the genital ridges until sixth week of
development. Primordial germ cells originate in the epiblast, migrate through the
primitive streak, and by the third week reside among endoderm cells in the wall of
the yolk sac close to the allantois. During the fourth week, they migrate by ameboid
movement along the dorsal mesentery of the hindgut, arriving at the primitive gonads
at the beginning of the fifth week and invading the genital ridges in the sixth week. If
they fail to reach the ridges, the gonads do not develop. The primordial germ cells
have an inductive influence on development of the gonad into ovary or testis. During
the sixth week, cells from the coelomic epithelium form aggregates of somatic
supporting cells that completely invest the germ cells. Somatic supporting cells are
essential for germ cell development within the gonad.

ϴ

Figure (1-1): Germ cells gonad (quoted from www.google.com)

Figure (1-2): Development of gonad ovary (quoted from www.google.com).

During the sixth week and shortly after the formation of the Wolffian (male) ducts a
second pair of ducts is developed; they are the müllerian (female) ducts. Each arises
on the lateral aspect of the corresponding Wolffian (mesonephric) duct in both male
and female embryo. Paramesonephric ducts arise by the craniocaudal invaginatiion of
a ribbon of thickened coelomic epithelium extending from the third thoracic segment
caudally to the posterior wall of the urogenital sinus. Both duct systems originate
from the intermediate mesoderm which forms in the back of the embryo along the
spine and belongs to the dorsal structures. The four ducts form what is termed the
common genital cord.

ϵ

 &ŝŐƵƌĞ;ϭͲϯͿ͗

ƋƵŽƚĞĚĨƌŽŵǁǁǁ͘ŐŽŽŐůĞ͘ĐŽŵ

In the midline, the paramesonephric duct comes in close contact with the
paramewsonephric duct from the opposite side. The caudal tip of the combined ducts
projects into the postertior wall of the urogenital sinus, where it causes a small
swelling, the paramesonephric or müllerian tubercle. The mesonephric ducts open
into the urogenital sinus on either side of the müllerian tubercle.

At the end of the sixth week, the male and female genital systems appear
indistinguishable, although subtle cellular differences may already be present. In both
sexes, gerem cells and somatic support cells are present in the presumptive gonads,
and complete mesonepohric and müllerian ducts lie side by side. The ambisexual or
bipotential phase of development ends at this point. From the seventh week on, the
male and female systems pursue diversing pathways.

Shortly after the solid tip of the paramesonephric ducts reaches the urogenital sinus,
two solid evaginations grow out from the pelvic part of the sinus. These evaginations,
the sinovaginal bulbs, proliferate and form a solid vaginal plate. The vaginal plate is
ϭϬ

thought to give rise to the inferior portion of the vagina, whereas the caudal region of
the uterovaginal canal is thought to form the upper vagina. Proliferation continues at
the cranial end of the vaginal plate, increasing the distance between the uterus and the
urogenital sinus. By the fifth month, the vaginal outgrowth is entirely canalized.

The wing-like expansions of the vagina around the end of the uterus, the vaginal
fornices, are of paramesonephric origin. The vagina has a dual origin, with the upper
portion derived from the uterine canal, which developed by the fusion of the caudal
parts of the paramesonephric ducts, and the lower portion derived from urogenital
sinus. However, current molecular studies show the whole vagina is derived from the
müllerian duct with bone morphogeni8c protein4 (BMP4) reshaping the intermediate
mesoderm-derived müllerian duct into the vaginal primordium. The latter thus
exhibits different features from the uterus, including the stratified squamous
epithelium and insensitivity to anti-müllerian hormone. BMP4 induces generation of
stratified squamous epithelial cells which replace the columnar epithelium initially
exhibited in the müllerian vagina.

The vaginal plate is canalized by a process of desquamation (cell shedding), forming

the vaginal lumen. The lumen of the vagina remains separated from that of the
urogenital sinus by a thin tissue plate, the hymen, which consists of the epithelial
lini8ng of the sinus and a thin layer of vaginal cells. It usually develops a small
opening during perinatal life.

Estrogens are involved in sexual differentiation and under their influence, the
paramesonephric ducts are stimulated to form the uterine tubes, uterus, cervix, and
upper vagina. In addition, estrogens act on the external genitalia at the indifferent
stage to form the labia majora, labia minora, clitoris, and lower vagina.

Despite the fact that sex chromosomes promote the development and the
differentiation of the primary gonad, the decisive influences are the presence or
absence of testosterone and anti-Müllerian hormone production by the testis.
Testosterone which is secreted by Leydig cells from the 8th week of male embryo

ϭϭ

development, is responsible for the male differentiation of the urogenital sinus and
the male external genitalia. Anti-müllerian hormone which is secreted by Sertoli cells
of the testes during embryogenesis of the fetal male, prevents the development of the
müllerian ducts during the first 8 weeks of gestation. Anti-müllerian hormone is
named after Johannes Peter Müller who is a German scientist and was the first who
described the duct named after him, the "müllerian duct" also called the
paramesonephric duct. The term "paramesonephric" duct means beside the
mesonephric (Wolffian) duct, which is its anatomical location in early development.

In addition to the sex chromosomes that determine the choice between male and
female developmental paths, the subsequent phases of sexual development are
controlled by factors, most of which are encoded on autosomes. A single sex-
determining factor seems to control a cascade of events leading to male development.
This sex-determining transcription factor is encoded by the SRY (sex-determining
region of the Y chromosome) gene. When this transcription factor is expressed in the
somatic support cells of the indifferent presumptive gonad, male development is
triggered. This step is called primary sex determination. If the factor is absent or
defective, female development occurs. By now it must be evident why development
of the female gonad is sometimes described as the default path for the human embryo
in the absence of the SRY gene. The pro-ovarian gene wnt4 seems to play an active
role in promoting oocyte development. Wnt4 is crucial for normal female sexual
development. Wnt4 is initially expressed in the mesonephric and genital ridge
mesenchyme and is required for the initial formation of the müllerian duct in both
sexes. In addition to pro-ovarian activities, wnt4 exhibits antitestis activities. Wnt4
upregulates Dax1. Dax1 (dosage sensitive sex reversal, adrenal hypoplasia
congenito-critical region of the X chromosome gene1) is described as being an
ovarian-promoting factor because it can act as an anti-testis factor. Dax1 acts as an
"anti-testis" gene rather than as an ovarian-determining gene. Dax1 expression is also
a critical "pro-testis" factor. This is speculated that particular levels of dax1 are
required within a narrow window of time for normal gonadogenesis to occur. If Dax1

ϭϮ

levels are higher than normal (e.g. through gene duplication) or lower than normal
(e.g. the result of an inactivating mutation) abnormal testis development occurs.
Particular levels of Dax1 are required within a narrow window of time for normal
gonadogenesis to occur.

Figure (1-4): Genes and gonad differentiation (quoted from www.google.com).

Figure (1-5): Development of male and female internal genitalia. (quoted from
www.google.com).

Female differentiation of the external genitalia begins by 11 weeks of gestation (13

weeks LMP), and a well-defined female structure is present by 20 weeks of gestation
ϭϯ

(22 weeks LMP). Until the eighth week, the external genitalia grow identically for
either sex, but by the twelve weeks, for a female, a genital tubercle, a membrane
dorsally to it covering the developing urogenital opening, and labioscrotal folds
develop . The genital tubercle is formed as a result of the mesoderm extending behind
the umbilical cord, and forming the lower part of the abdominal wall and ending in a
prominent swelling, the cloacal tubercle, which after the separation of the rectum
becomes the genital tubercle. The genital tubercle develops into the phallus, the first
rudiment of clitoris.

At 14 weeks of female fetal development, the androgen receptor (AR) is not

expressed in urogenital sinus, urothelium, vaginal epithelium and müllerian ducts,
making the tissues insensitive to androgen. The fetal ovary is capable of synthesizing
estradiol as early as the 8th week of fetal age. Receptors for estradiol have been found
in the müllerian ducts, but their physiological significance is unknown as estrogens
are not necessary for the differentiation of the female internal genitalia. But the
development of the female fetal external genitalia is promoted by the absence of
androgens and by the presence of estrogens within the maternal system.

In the absence of testosterone in female fetus, a deep groove forms around the phallus
and the sides of it grow dorsalward as the labioscrotal folds, which form the labia
majora, while in contrast, the labia minora arise by the continued growth of the lips of
the groove on the under surface of the phallus. The remainder of the phallus forms
the clitoris. The immature glans becomes the clitoral glans. The terminal genital
tubercle refers to the future glans. After differentiation, the corpora cavernosa of the
clitoris and of the urethra arise from the mesodermal tissue in the phallus; they are at
first dense structures, but later vascular spaces appear in them, and they gradually
become cavernous. The phallic portion of the urogenital sinus forms a vestibule in
which the urethral meatus, the vaginal orifice and the ostium of the opening of the
vestibular glands can be found. The prepuce is formed by growth of a solid plate of
ectoderm into a superficial part of the phallus; on coronal section this plate presents
the shape of a horseshoe. By breaking down of its none centrally situated cells the
ϭϰ

plate is split into two lamellae. Thus a cutaneous fold, the prepuce, is liberated and
forms the hood of the glans.

Figure (1-6): Female external genitalia. (quoted from www.google.com).

ϭϱ

Figure (1-7): Sexual differentiation of external genitalia (male to left and female to
right). (quoted from www.google.com).

A recent study using magnetic resonance imaging (MRI) has accurately measured the
dimensions of the adult vagina. Mean vaginal length from cervix to introitus was
62.7mm. Vaginal width was largest in the proximal vagina (32.5mm), decreased as it
passed through the pelvic diaphragm (27.8mm) and smallest at the introitus
(26.2mm).

ϭϲ

Abnormalities:

• Female androgen exposure in the first trimester, as in CAH, can cause major
virilization of the vagina and external genitalia. After 12 weeks, vaginal
development is unaffected and only clitoromegaly occurs.
• Administration of high doses of estrogens to pregnant women prevents the
progression of the vaginal epithelium from sinus origin. The persisting
mullerian epithelium would be responsible for the vaginal adenosis frequently
observed in girls who were submitted to high doses of estrogens in utero.
Vaginal adenosis is the deficiency of glycogen in the squamous cells
(squamous metaplasia).
• Pseudohermaphroditism is a condition of sexual ambiguity in which the
individual (pseudohermaphrodite) possesses gonadal tissue of one sex but
exhibits external phenotype of the opposite sex. Female
pseudohermaphroditism is an individual with XX karyotype, normal
development of ovaries and internal reproductive tract, but with ambiguous or
virilized external genitalia. Male pseudohermaphroditism is characterized by
the presence of a Y chromosome and testes, but the genital tract and external
genitalia are ambiguous or completely female.
• Mayer-Rokitansky-Kuster-Hauser Syndrome: (MRKH) is abnormality of
development of the female genital tract and is characterized by partial or
complete absence (agenesis) of the uterus, absent or hypoplastic vagina,
normal fallopian tubes, ovaries, normal external genitalia and normal female
chromosome pattern (46, XX). This syndrome has an incidence of
approximately 1 in 4500 newborne girls and has been associated with a
microdeletion at 17q12.
• OHVIRA Syndrome: is represented by obstructed HemiVagina and Ipsilateral
Renal Anomaly with uterine didelphysis is a syndrome due to lateral non-
fusion of the mullerian ducts with asymmetric obstruction. The presence of
vaginal septum also gives rise to other clinical conditions.

ϭϳ

 For further readings:

1- Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen's human
embryology. Churchill Livingstone. Philadelphia. 2009; pp500-525.
2- Oster H, Wilson DI, Hanley NA. Human embryo and early-fetus research. Clin
Genet. 2006;70:98-107.
3- Ulfelder H, Robboy SJ. The embryonic development of the human vagina. Am
J Obstet Gynecol. 1976; 126:769-76.
4- Bland J. About Gender: Conception and development. 1998. Internet.
5- Sizonenko PC. Human sexual differentiation. 2012. Internet.
6- Retrieved from http://en.wikipedia.org/w/index.php?title=Anti-
Müllerian_hormone&oldid=514317889

14-10-2012

The title of this subject is:

Anti-Müllerian hormone

7- Retrieved from "http://php.med.unsw.edu.au/embryology/index.php?

title=Vagina_Development&oldid=56715"

5-10-2012

The title of this subject

Vagina development

8- Retrieved from http://en.wikipedia.org/w/index.php?title=Development of the

reproductive_system&oldid=511874409

The title of this subject

Development of the reproductive system

ϭϴ

9- Klattig J, Englert C. The Müllerian duct: recent insights into its development
and regression. Sex Dev. 2007;1:271-8.

10-Cai Y. Revisiting old vaginal topics: conversion of the Müllerian vagina and
origin of the "sinus" vagina. Int.J.Dev.Biol.2009;925-934.

11-Sajjad Y. Development of the genital ducts and external genitalia in the early
human embryo. Journal of Obstetrics and Gynecology Research. 2010; 36:929-
937.

12-Home[http://www.bioportfolio.com/]" Latest PubMed Articles

[http://www.bioportfolio.com/resources/Latestpubmed]" The journal of obstetrics
and gynecology research
[http://www.bioportfolio.com/resources/pubmed/?filterfield=journal_name[+filter
val=The+journal+of+obstetrics+and gynecology+research]"Development of the
genital ducts and external genitalia in the c…

[http://www.bioportfolio.com/resources/pmarticle/90559/Development-of-The-
Genital-Ducts-And-External-Genitalia-in-The-Early-Human. Html]

13-Sadler TW. Langman's medical embryology. Lippincott Williams & Wilkins.

Philadelphia. 2010; pp 246-263.

ϭϵ

 Chapter Two

Anatomy of Vagina

The vagina (the word means "a sheath") is the canal that extends from the cervix of
the uterus within the lesser pelvis down to the vestibule between the labia minora.
The orifice of the vagina is guarded by the hymen. The hymen is a thin membrane of
connective tissue which is situated at the opening of the vagina. The hymen covers
the opening of the vagina from birth until it is ruptured during sexual or non-sexual
activity. The vagina lies behind the bladder and urethra and in front of the rectum and
anal canal. Although there is wide anatomical variation, the length of the unaroused
vagina is approximately 6 to 7.5cm (2.5 to 3 in) across the anterior wall and 9cm
(3.5in) long across the posterior wall. During sexual arousal the vagina expands in
both length and width. Its elasticity allows it to stretch during sexual intercourse and
during birth to offspring. The vagina is directed obliquely upward and backward. The
axis of the vagina forms an angle of over 90 with that of the uterus. This angle varies
considerably, depending on conditions in the bladder, in the rectum, and during
pregnancy. The cervix of the uterus projects for a short distance into the vagina and is
normally pressed against its posterior wall. There are, therefore, recesses in the
vagina at the back, on each side, and at the front of the cervix. These are known as
the posterior fornix (behind the cervix and the largest), the lateral fornices (at the
sides), and the anterior fornix (at the front of the cervix). The upper part of the
posterior wall of the vagina is covered by peritoneum or membrane that is folded
back onto the rectum to form the recto-uterine pouch. The lower part of the posterior
vaginal wall is separated from the anal canal by a mass of tissue known as the
perineal body.

The vagina is a fibromuscular tube and it is H-shaped in its central portion. The
sidewalls are suspended by their attachment to the paravaginal lateral connective
tissue from which they receive their blood supply. The vagina is lined by a stratified
squamous epithelium thrown up into rugal folds, giving the epithelium accordion-like

ϮϬ

distensibility without laceration. A dense, thin layer of elastic fibers is found
immediately beneath the epithelium. Beneath this is a well-developed fibromuscular
layer. The fibrous capsule external to this muscular coat is rich in elastic fibers and
large venous plexuses. There are no glands in the vaginal lamina propria and vaginal
lubrication is provided by transudate from the blood vessels as well as by secretions
of the Bartholin's and Skene's glands. While Bartholin's glands are identified at the 5
to 7 o'clock positions of the vestibule, Skene's glands are in the periurethral area.

Figure (2-1): Vaginal anatomy. (quoted from www.google.com).

The vagina is attached laterally to the pelvic sidewalls by condensations of

connective tissue and smooth muscle intimately adherent to the adventitia of the
vaginal blood vessels. This tends to fix it in position from side to side, and the muscle
elements supply a certain amount of tone, permitting it to adapt to changes in
pressure. In the midline, the vagina is permitted freedom in distensibility from both
bladder and rectum by the relatively avascular, vesicovaginal and rectovaginal
spaces. The rectovaginal septum is fused with the posterior vaginal wall as the
anterior lining of the rectovaginal space. The posterior vaginal wall is approximately
10cm long. Since the cervix is incorporated in the anterior vaginal wall, the length of
the anterior vaginal wall plus cervix approximates the length of the posterior wall.
The connective tissue adventitia of the vagina is continuous with that of the cervix.
The vagina is largest in its middle and upper third. The connective tissue lateral to the
lower third is attached to fibers of the pubococcygeal muscle (fibers of Luschka) and
to fibers fixing it to the perineal membrane. There are two arcus tendiei on each side
of the pelvis. The arcus tendineus levator ani (ATLA) runs from the back of the pubis

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to the ischial spine. Medial to this is the arcus tendineus fascia pelvis (ATFP).
Although there is individual variation in the distance between these two
condensations at their origin and lateral extent, they come together at the ischial
spine. There is a connective tissue bundle running between the anterior vaginal sulcus
and the arcus tendineus. The arcus tendineus is an important structure at the pelvic
sidewalls. It is a firm anchoring point used in pelvic reconstructive surgery to support
the vagina. Paravaginal repair as well as procedures using mesh kits for pelvic
reconstruction aim to restore the normal arcus-to-arcus support of the pelvic floor.

In the living healthy female, the upper vaginal axis lies in an almost horizontal plane
when the patient is in a standing position. Normal support of the vagina and the
uterus is achieved mainly by the pelvic floor muscles with the assistance of the
fibromuscular connective tissue of the vagina, also known as the "endopelvic fascia".
When the striated muscles of the pelvis are relaxed temporarily, as during micturition
or defecation, or permanently, in cases of pelvic relaxation, the connective tissue is
solely responsible for the pelvic support. The term "endopelvic fascia" was used to
describe a sheet of fibroareolar tissue following the blood supply, as a retroperitoneal
mesentery, to the visceral organs. This tissue divides the retroperitoneal space into
avascular planes. Anteriorly, the "pubocervical fascia" attaches the uterine cervix and
the vagina to the pelvic sidewalls. The posterior vaginal wall is attached to the pelvic
sidewalls by the "rectovaginal fascia". Nevertheless, this layer should not be termed
"fascia". Histologically, it is the vaginal muscularis, i.e. the subepithelial
fibromuscular layer of the vagina. For this reason, the previously called "endopelvic
fascia" will be termed "vaginal muscularis". The upper vagina lies on the rectum,
which, in turn, lies on and parallel to the levator plate. It is this almost horizontal
position of the supporting levator plate that accounts for a similar axis to the vagina.
The levator plate is formed by the fusion of the levator ani muscles posterior to the
rectum, from just behind the levator hiatus to their coccygeal insertion. The rectum,
vagina, and urethra pass through the levator hiatus. Although the cervix and upper
vagina have considerable mobility, they are more or less anchored in position over

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the levator plate by the cardinal-uterosacral ligament complex. Vaginal support, as
described by Delancey in 1992, is achieved at three different levels: Level I-the
uterosacral-cardinal ligament complex, supports the upper vagina and the uterine
cervix. LevelII- is the paravaginal support of the vaginal sidewalls to the arcus
tendineus fascia pelvis. LevelIII- is the support of the distal part of the vagina to the
perineum. Damage to the upper level of the suspensory system can give rise to
inversion of the upper vagina, often with elongation of the cervix and cul-de-sac
hernia; damage at the lower levels supporting system is more likely to be associated
with eversion of the lower vagina, including cyctocele, rectocele and descent of the
perineum.

The lower end of the vagina receives sensory fibres from the perineal and posterior
labial branches of the pudendal nerve, and (with the anterior part of the vulva) from
the ilioinguinal nerve. Autonomic nerve fibres from the inferior hypogastric plexuses
supply blood vessels, the smooth muscle of the vaginal wall and the vestibular
glands. The upper vagina is said to be sensitive only to stretch, the afferent fibres
running with sympathetic nerves.

Ϯϯ

The blood supply to the vagina is derived from several adjacent vessels, there being

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a vaginal branch of the internal iliac artery and also vaginal branches from the
uterine, middle rectal, and internal pudendal arteries, all branches of the internal iliac
artery. All these branches make good anastomotic connexions on the vaginal wall.
Veins join the plexuses on the pelvic floor to drain into the internal iliac vein.

The lymphatics of the vagina drain to external and internal iliac nodes, but the lower
part (below the hymen level) drains to superficial inguinal nodes.
Ϯϰ

Varicose veins are enlarged veins that can be blue, red, or flesh-colored. They often
look like cords and appear twisted and bulging. They can be swollen and raised above
the surface of the skin. Varicose veins are often found on the thighs, back of the
calves, or the inside of the leg. Varicose veins can also form around the vagina,
vulva, and buttocks. While vaginal varicose veins most frequently come up during
pregnancy, they can also appear on non-pregnant women. Among factors increase the
risk of vaginal varicose include increasing age, medical history, hormonal changes,
obesity, and pregnancy. During pregnancy, varicose veins can develop and become
prominent. This is partly due to the fact that during pregnancy, the weight gain that a
woman has can put increased pressure on the veins in her vaginal region. This can
cause the veins to become enlarged and engorged. Additionally, with the influx of
hormones during pregnancy, the walls of the veins can weaken, and this can also
cause them to become engorged. The extra hormones that arise during pregnancy can
have lots of physical effects all over the body, including contributing to vaginal
varicose veins. It is also possible that the fetus can compress the lower abdomen,
which can make the veins in the vulva and vagina become engorged with blood and
distended. Typically, if a woman gets vaginal varicose veins during pregnancy, she
will also notice varicose veins in her legs as well. Once a woman is no longer
pregnant, the vaginal varicose veins tend to get better. Sometimes, a rope-like vein
will appear in the vaginal area, but even this should go away with time and once the
baby has been delivered.

Vaginal varicose veins can cause itching, pain in the vulva, sensation of prolapsed,
pigmentation changes, and cosmetic differences that some women find unpleasant
and unsightly.

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 Figure (2-3): Vulval-varicose-veins (Quoted from www.google.com)

Figure (2-4): Vulval-varicose veins (quoted from www.google.com)

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For further readings:

1- Farr G. The female reproductive system.2002. Internet.

2- Irfan M. Vagina, human anatomy.2009. Internet.
3- Paul RS. Vaginal anatomy. 2012. Internet.
4- Sokol AI, Shreiky D. Clinical anatomy of the vulva, vagina, lower pelvis, and
perineum. 2008. Internet.
5- Sinnatamby CS. Last's anatomy regional and applied. China. 2011.
6- Min RJ, Rosenblatt.Varicose veins and spider veins. 2010. Internet

About vaginal varicoshttp://www.womenshealth.gov

7- About vaginal varicose veins.

http://www.all4naturalhealth.com/vaginal-varicose-veins.html

from the internet in 31-1-2013

All 4 NATURAL HEALTH.COM

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 Chapter Three

Histology and Morphological Changes of Vagina

• Histology of vagina

The vagina is a fibromuscular tubular structure 8 to 9 cm in length connected to the

uterus proximally and the vestibule of the external genitalia distally. The vagina is
derived from the embryonic mesoderm. The vagina consists of three layers: a
mucosa, a muscularis, and an adventitia. The lumen of the vagina is lined by a thick
stratified squamous nonkeratinized epithelium (150 to 200µm thick), although some
of the superficial cells may contain some keratohyalin. The vagina is responsive to
cycling. The action of estrogen on the vaginal epithelium causes augmented cell
proliferation in the basal and prabasal layers, which results in epithelial thickening.
The more superficial cells, still nucleated, become slightly more acidophilic as
ovulation approaches. The slight increase in acidophilia is considered a preliminary
sign of keratinization, but under normal circumstances vaginal epithelial cells do not
actually keratinize. The estrogen-stimulated cells also accumulate glycogen and lipid.
Naturally occurring vaginal bacterial flora metabolize the glycogen, forming lactic
acid, which is responsible for the low pH in the lumen of the vagina, especially at the
midpoint of the menstrual cycle. The lowered pH also helps to restrict pathogenic
invasion. Langerhans cells in the epithelium function in antigen presentation to T
lymphocytes housed in the inguinal lymph nodes. The lamina propria of the vagina is
composed of a loose fibroelastic connective tissue containing a rich vascular supply
in its deeper regions. It also contains numerous lymphocytes and neutrophils that
reach the lumen by passing through intercellular spaces during certain periods in the
menstrual cycle, where they participate in immune responses. Although the vagina
does not contain glands, there is an increase in vaginal fluid during sexual
stimulation, arousal, and intercourse that serve to lubricate its lining. The cervical
mucus from endocervical secretory cells (columnar epithelium) contributes to the
vaginal fluid. Vaginal lubrication is provided by transudate from the blood vessels as
Ϯϴ

well as by secretions of the Bartholin's glands (lined by columnar mucus-secreting
cells) which are identified at the 5 and 7 o'clock positions of the vestibule and highly
variable Skene's glands which are in the periurethral area.

Figure (3-1): (the blue and red A) Stratified squamous epithelium of the vagina and
the supporting lamina propria stained by hematoxylin and eosin. The LP has two
parts: papillary (*) and reticular (**). (quoted from www.google.com).

The muscularis layer of the vagina is composed of smooth muscle cells arranged so
that the mostly longitudinal bundles of the external surface intermingle with the more
circularly arranged bundles near the lumen. A sphincter muscle, composed of skeletal
muscle fibers, encircles the vagina at its external opening.

Dense, fibroelastic connective tissue constitutes the adventitia of the vagina,

attaching it to surrounding structures. Contained within the adventitia is a rich

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vascular supply with a vast venous plexus and nerve bundles derived from the pelvic
splanchnic nerves.

• Morphological changes of vagina

The morphology and physiology of the vagina undergo characteristic age-related

changes over a lifetime.

The genitalia of the new born exhibit the effects of residual maternal estrogens. At
birth, the vaginal mucosa is glycogen rich. White or blood-tinged vaginal discharge
may be present. These estrogenic effects dissipate by the fourth postnatal week. The
vaginal epithelium loses its stratification and glycogen content, becoming much
thinner. Estrogen levels begin to fall after the neonatal period and the lowest levels
are between the ages of 3 and 8 to 9. Therefore, the vaginal epithelium is thin, less
stratified and has a low glycogen content. The vaginal epithelium is mildly
erythematous and may appear inflamed.

Pubertal changes in the vagina are induced by adrenal and gonadal maturation.
Puberty generally begins between the ages of 8 and 13 years. Gonadal maturation
usually occurs during the 2 years preceding menarche. During the maturation process,
follicular development causes estrogen production to rise. The vaginal epithelium
thickens and intracellular glycogen production begins. At the onset of puberty there is
production of a physiologic leucorrhoea. This is characteristically a milky-white or
clear mucoid discharge. This discharge is non-offensive.

During reproductive years (menarche, approximately 12 years until perimenopause),

changes in the vagina is linked to menstrual cycle and pregnancy. The vaginal
mucosa is sensitive to ovarian steroid hormone cycling. Estrogen stimulation causes
the thickness, glycogen content and parakeratosis of the vaginal epithelium to peak at
approximately mid-cycle. Cervicovaginal secretions become thicker, clearer, and
more elastic prior to ovulation. During pregnancy, an increase in total blood volume
heightens the coloration of the vagina. The connective tissue of the vagina relaxes
and the muscle fibers of the vaginal wall increase in size in preparation for delivery.
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During delivery, the perineal and vaginal musculature relaxes and the vaginal rugae
flatten to allow expansion of the vaginal tract, accommodating passage of the
newborn infant. After delivery, the vaginal introitus is wider and the fourchette
appears more flattened. Over the next 6-12 weeks, the typical morphology and
dimensions of the vaginal tract are reestablished. During the perimenopause (the
transition period to menopause) and as a result of loss of follicular activity, vaginal
dryness occur.

At menopause (1 year following final menstrual period at approximate age of 50

years old) when follicular function cease, there is a marked loss of subcutaneous fat
and vaginal mucosa atrophy. Also cervicovaginal secretions become sparse.

For further readings:

1- Makawela MR. Paediatric vaginal discharge. SA Fam Pract. 2007; 49:30-31.

2- Cervix, vagina and vestibule

http://www.siumed.edu/-dking2/erg/cervix.htm

Last updated: 13 April 2012

From internet in 22-10-2012

3- Summers PR. Vaginal anatomy. 2012. Internet.

Mhtml:file://C:\Users\DELL\Documents\Vaginal Anatomy.mht

4- Cormack DH. Essential histology. Lippincott Williams & Wilkins.

Philadelphia. 2001. p. 407.
5- Gartner Lp, Hiatt JL. Color textbook of histology. W.b. SAUNDERS
company. Philadelphia. 2001. P. 482.
6- Sokol AI, Shveiky D. Clinical anatomy of the vulva, vagina, lower pelvis, and
perineum. The Global Library of Women's Medicine. 2008. Internet.

GLOWM

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http://www.glowm.com/?p=glowm.cml/section_view&articleid=445

7- Irfan M. human anatomy. 2009. Internet.

http://sexeducation.blogspot.com/2009/09/vaginahuman-anatomy.html

8- Farage MA, Maibach HI. Morphology and physiological changes of genital

skin and mucosa. Curr Probl Dermatol. 2011;40:9-19.

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 Chapter Four

Relationship between Hormones, Vaginal Mucosa, and Vaginal Flora

Vagina of female embryo has nonkeratinized stratified squamous epithelium that is

responsive to estrogen hormone cycling. Estrogen synthesis in the foetal ovary is low
at term, but maternal estrogens cross the placenta and estrogenise the neonate. At
birth, stratified squamous epithelium of vagina exhibits the effects of residual
maternal estrogens. Mucosa is glycogen rich and becomes colonized with lactic-acid-
producing microbes, such as Lactobacillus species, within the first twenty-four hours
of birth. These vaginal microorganisms are similar to those in infant's mother.
Vaginal pH is acidic at birth. The estrogenic effects dissipate by the fourth postnatal
week. The vaginal epithelium loses its stratification and glycogen content, becoming
much thinner. Vaginal pH rises to about seven because of a relative deficiency of
acid-producing-vaginal-microbes. A variety of microbial species colonize the vagina
but at lower concentrations than in adults.

During early childhood (from one year to eight years of ages) vaginal tissue lacks
stimulation by adrenal or gonadal steroid hormones. Estrogenic levels are lowest
between the ages of three and eight to nine years. Thus vaginal epithelium thins, less
stratifies and has a low glycogen content which means vaginal tissue is atrophic,
mildly erythematous and looks inflamed. Vaginal pH is neutral or alkaline. Vaginal
flora contains skin commensals and bowel organisms with decrease in lactic-acid-
producing microbes. Due to the low estrogen levels in prepubertal girls, vaginal
mucous membrane possesses an atrophic epithelium with surface pH of 6.0 to 8.0.
Organisms commonly isolated were mixed anaerobes, Escherichia coli, diphtheroids
and coagulase-negative staphylococci. Before menarche vaginal pH is ‫ޓ‬4.5. After the
age of nine, estrogen levels begin to rise again, signaling the onset of puberty.

At puberty (from eight years to fifteen years of ages) circulating estrogens increase as
a result of follicular development which leads to proliferation of vaginal epithelial
cells and thus vaginal epithelium thickens and stratifies. Glycogen is deposited in the
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intermediate and superficial epithelial cells of vagina and lactobacilli predominate,
causing the enzymatic breakdown of cellular glycogen. Lactic acid is produced by
both bacterial metabolism and that of the epithelium. Lactic acid and hydrogen
peroxide production lowers the vaginal pH to 3.5 to 4.5. Vaginal pH frequently does
not correspond with the presence or absence of lactobacilli. These pubertal changes in
the vagina are induced by adrenal and gonadal maturation which occurs during the
two years preceding menarche. Under the influence of estrogen and progesterone,
onset of menstruation occurs (menarche). Although pH levels fall at puberty,
adolescence represents a period of hormonal instability which could affect vaginal
pH. In adolescents hormonal disturbances increases the vaginal pH and predispose to
bacterial vaginosis. Estrogen levels are lower in adolescents than in adults and
irregular menstrual cycles persist for varying periods after menarche.

During the reproductive years (menarche, approximately twelve years of age until
perimenopause), changes in vagina are linked to menstrual cycle and pregnancy.
Menstrual cycle affects the vaginal mucosa which is sensitive to estrogen, causing
mucosa epithelium thickens, increase of glycogen content and parakeratosis of the
vaginal epithelium reaching maximum at approximately mid-cycle. The pH may rise
above 4.5 at the time of menstruation, when the concentration of lactobacilli is
reduced. During pregnancy the vaginal pH may become more acidic which provides
some maternal protection for the fetus against invading microorganisms. However,
pregnancy is associated with 10-to20-fold increase in the prevalence of vulvovaginal
candidiasis. The acidic vaginal luminal pH is produced by cohabituating Doderlein
lactobacilli which produce hydrogen peroxide and secrete protons into their
immediate environment. Hydrogen peroxide production prevents vaginal colonization
with uropathogens. Lactic-acid-producing microbes are numerically dominant in
healthy women. During the reproductive years the vaginal pH in the absence of
vaginitis is 4.5 or less and this pH level is maintained by the action of estrogen on the
vaginal mucosa which supports the growth of normal vaginal bacteria that produce

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metabolic byproducts that cause the vaginal mucosa to stay acidic in the absence of
vaginitis.

During perimenopause, there is decreased number of functional follicles with less

recruitment of oocytes upon follicle stimulating hormone (FSH) stimulation. Over
time, as the aging follicles become more resistant to gonadotrophin stimulation,
circulating follicle stimulating hormone (FSH) and luteinizing hormone (LH)
increase leading to stromal stimulation of the ovary with decrease in estradiol levels.
During perimenopause, as estrogen levels decrease, blood vessels constrict and
circulation is lowered, causing potential for pain and infection in the vagina. The
reduction of estrogen during the perimenopause reduces blood circulation, which
affects vaginal lubrication. The vaginal skin dries up, and can become itchy and
irritated. Less estrogen means vaginal pH increases which ranges between 4.5 and 6.0
with mild alkalinization to about 6.5 before ovulation, and the lining of vagina thins
which create an imbalance in the good bacteria. This imbalance can leave one prone
to infection. The urethra and vaginal canal become even closer, due to the thinning
wall between them, and increased pH in the urinary tract creating the opportunity for
vaginal and urinary tract infections.

The loss of follicular activity will lead to menopause( one year following final
menstrual period, approximate average fifty years old) which is the permanent
cessation of menstruation, estrogen depletion, elevated FSH, vaginal dryness, vaginal
mucous atrophy, and rise in vaginal pH which ranges between 6 to 7.5 in the absence
of vaginitis. Alkalinization about 6.5 is associated with increased risk of vaginal
infections. Estrogen is not existent after the menopause.

Postmenopause is characterized by low estradiol level, higher FSH level, follicular

function and menstrual cycle cease, vaginal epithelium atrophies, decrease in vaginal
secretions, reducing lubrication, vaginal irritation, vaginal pH rise, increased risk of
vulvovaginitis , and prevalence of colonization by enteric organisms associated with
urinary tract infections.

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For further readings:

1- Farage MA, Maibach HI. Morphology and physiological changes of genital

skin and mucosa. Curr Probl Dermatol. Basel, Karger. 2011;40:9-19.
2- Makwela MR. Paediatric vaginal discharge. SA Fam Pract.2007;49:30-31.
3- Hay PE. Bacterial vaginosis as a mixed infection. 2009. Internet.
4- Brabin L, Roberts SA, Fairbrother E, Mandal D, Higgins SP, Chandiok S, and
et al. Factors affecting vaginal pH levels among female adolescents attending
genitourinary medicine clinics. Sex Transm Infect. 2005; 81:483-487.
5- Cailouette JC, Sharp CF, Zimmerman GJ, Roy S. Vaginal pH as a marker for
bacterial pathogens and menopausal status. Am J Obstet Gynecol. 1997;
176:1270-7.
6- Vahidroodsari F, Ayati S, Yousefi Z, Saeed S. Comparing serum follicle-
stimulating hormone (FSH) level with vaginal pH in women with menopausal
symptoms. OMJ. 2010; 25:13-16.
7- Macdonald G. Human reproduction. 2012. Internet.
8- Al-Saadi MS, Al-Windawi SM. Changes of vaginal pH in correlation with
serum FSH, estradiol and vaginal bacterial culture in premenopausal and
postmenopausal women. The Iraqi Journal of Medical Sciences. 2003; 2:370-
375.
9- Gorodeski et al. Estrogen acidifies vaginal pH by upregulation of proton
secretion via the apical membrane of vaginal-ectocervical epithelial cells.
Endocrinology. 2005; 146:816-824.

10-Miller KE. Vaginal pH for diagnosing status of menopause. Am Fam

Physician. 2005; 71:979.

11-Bilheimer S, Echenberg RJ. Perimenopause and vaginal/vulvar pain. 2003.

Internet.

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 Chapter Five

Normal Flora of Vagina

Vaginal secretions are acidic at birth and vaginal microorganisms present in the
newborn female are similar to those in her mother i.e. with corynebacteria,
staphylococci, streptococci, Escherichia coli, and a lactic acid-producing bacterium
historically named "Doderlein's bacillus" (Lactobacillus acidophilus ). Shortly after
birth, when maternaly derived oestrogen levels decline, vaginal pH rises to about 7.
Variety of microbial species colonize the vagina but at lower concentrations than in
adults and lactobacilli are absent.

In childhood, the vaginal flora contains skin commensals and bowel organisms.

Due to the low oestrogen levels in prepubertal girls, the vaginal pH is alkaline and
thus anaerobes predominate in addition to Escherichia coli, diphtheroids and
coagulase negative staphylococci.

At puberty, circulating estrogens increase, resulting in a proliferation of vaginal

epithelial cells. Glycogen is deposited in the intermediate and superficial epithelial
cells of the vagina, and lactobacilli proliferate, causing the enzymatic breakdown of
cellular glycogen. Lactic acid and hydrogen peroxide are produced, which lowers the
vaginal pH to 3.5 to 4.5. At menarch, besides vaginal domination by lactobacilli,
many other organisms may be present in lower concentrations including anaerobic
and facultative anaerobic bacteria and Candida spp. . The pH may rise above 4.5 at
the time of menstruation, when the concentration of lactobacilli is reduced.

The conditions that occur at the onset of puberty usually maintain during the fertile
years in a healthy vagina and start to change during the menopause. The estrogen
level in fertile women is believed to change during menstrual cycle, and the recovery
of the Lactobacillus varies slightly. The oestrogen level seems to be a determining
factor for colonization of lactobacilli although there is still not any convincing data.

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Some worker have now suggested the influence of race, ethnicity and other
demographic factors as playing modulating influence in the final endogenous
microbiological flora of reproductive age women. For example, it has been shown
that the occurrence of hydrogen-peroxide-producing lactobacilli, purportedly active
in antimicrobial defense, is lower in black women and that it has been reported that
the vaginal pH of black women is higher than that of white women. The composition
of the vaginal ecosystem is not static but changes over time and in response to
endogenous and exogenous influences. Variables include stage of the menstrual
cycle, pregnancy, use of contraceptive agents, frequency of sexual intercourse,
specific sexual partners, vaginal douching, use of panty liners or vaginal deodorants,
and utilization of antibiotics or other medications with immune or endocrine
activities. The most frequently isolated vaginal microbes include lactobacilli species.
The high frequency of diphtheroids in vaginal samples is suggestive of the fact that
they are constantly exposed to the external surfaces. The occurrence of Escherichia
coli, Staphylococcus aureus, and Staphylococcus epidermidis in the vagina is due to
the proximity of the vagina to the anal orifice. Other microbes can be detected in the
vagina such as Proteus species and Clostridium species.

The vaginal microbial profiles of post-menopausal women are relatively stable,

perhaps it is due to lack of menstruation which is known to cause step-dependent
variations in the microbiota. In postmenopausal women with low estrogen levels,
Lactobacillus flora is diminishing or absent. Postmenopausal women with depleted
vaginal lactobacilli are sometimes colonized by adverse microbial flora that may
cause urinary tract infection and bacterial vaginosis.

There was an inverse correlation between Lactobacillus ratio and dryness and an
increased bacterial diversity in women experiencing moderate to severe vaginal
dryness. The biotas of women who are least symptomatic with vaginal dryness have
low bacterial diversity with dominance of lactobacilli. Conversely, women with
moderate or severe dryness have a decreased abundance of lactobacilli and a large

ϯϴ

diversity in number of species detected and there is a high representation of
Prevotella timonensis, Porphyromonas, Peptoniphilus and Bacillus.

• Lactobacilli

The prevailing theory about regulation of vaginal pH postulates that the acidic
vaginal luminal pH is produced by cohabituating Doderlein lactobacilli which are
non-spore-forming, gram-positive rods. This theory is based on the finding that
the bacteria produce hydrogen peroxide and secrete protons into their immediate
environment.

Because lactobacilli can be found in the vagina of most healthy women,

acidification of the vaginal lumen is thought to result directly from bacterial
proton secretion.

The vaginal lactobacilli were originally described in the late 19th century by
German gynaecologist Albert Doderlein, who purported that the lactobacilli act as
a barrier of defense preventing other bacteria to ascend the genital tract.

Lactobacilli produce a variety of substances, such as bacteriocins and lactocins,

which are toxic to other bacterial species and lactobacilli, respectively. Lactic acid
produced by lactobacilli maintains a low vaginal pH and inhibits the growth of
pathogens. Hydrogen-peroxide (H2O2) is also an important inhibitor of anaerobic
growth, and it is thought that Lactobacillus spp. producing high levels of H2O2
provide protection against bacterial vaginosis and acquisition of sexually
transmitted infections. A recent study showed the most prevalent species was
Lactobacillus crispatus, followed by Lactobacillus jensenii. Although the
presence of lactobacilli may be used as a sign of healthy vaginal environment, the
possibility that specific strain or combinations of strains of lactobacilli being
harmful should not be ignored, especially due to their ability to produce substance
capable of inhibiting other normal vaginal microorganisms. Lactobacilli have the
ability to regulate the growth of other vaginal flora, therefore any disturbances in
lactobacilli are highly correlated with the presence of those opportunistic
ϯϵ

microorganisms. Lactobacillus plays an important role in protection of the vagina
from colonization by pathogens and this could be attributed to two main
mechanisms: blocking the attachment of pathogens to the vaginal epithelium and
by production of substances that inhibit their multiplication. However, not all
Lactobacillus strains express these properties with the same intensity, on the
contrary, there are substantial differences among species and among strains from a
single species. The normal vaginal microflora has recently been found to consist
primarily of one or more of merely four distinct species of lactobacilli, in
particular

Lactobacillus crispatus, Lactobacillus jensenii,

Lactobacillus gassrei, and Lactobacillus iners. The stability of the vaginal

microflora during pregnancy is a result of the presence of each of these index
species with the normal vaginal microflora. In pregnancy, Lactobacillus
crispatus promotes the stability of the normal vaginal microflora while
Lactobacillus gasseri and/or

Lactobacillus iners predispose to some extent to the occurrence of abnormal

vaginal microflora. Lactobacillus crispatus was more often found in the vaginal
flora of fertile women than in postmenopausal women. Most Lactobacillus
jensenii strains have been found to be equally strong hydrogen peroxide producers
as Lactobacillus crispatus. Lactobacillus jensenii is the only Lactobacillus
species for which poorer colonization resistance seemed to be correlated with
poorer colonization strength, i.e. conversion to abnormal vaginal microflora was
associated with the disappearance of Lactobacillus jensenii. Acquisition of
bacterial vaginosis was strongly associated with a lack or loss of hydrogen
peroxide producing lactobacilli.

Lactobacillus iners is a dominant part of the vaginal microbial flora when it is in

transitional stage between abnormal and normal due to treatment, physiological
changes or oestrogen levels. Lactobacillus crispatus is associated with a

ϰϬ

particularly stable ecosystem. Conversely, microflora comprising Lactobacillus
jensenii elicits intermediate stability, while vaginal microflora comprising

Lactobacillus gasseri/Lactobacillus iners is the least stable.

The vaginal lactobacilli are indeed capable of providing colonization resistance

through a variety of mechanisms. Nonetheless, failure of the lactobacilli-driven
defense often occurs, resulting in overgrowth of the vaginal epithelium by other
potentially pathogenic bacteria.

Figure (5-1): Lactobacilli from normal vaginal smear stained by Direct Gram
Stain. (quoted from www.google.com).

For further readings:

1- Brabin L, Roberts SA, Fairbrother E, Mandal D, Higgins SP, Chandiok S, and

et al. Factors affecting vaginal pH levels among female adolescents attending
genitourinary medicine clinics. Sex Transm Infect. 2005;81:483-487.
ϰϭ

2- Razzak MSA, Al-Charrakh AH, AL-Greitty BH. Relationship between
lactobacilli and opportunistic bacterial pathogens associated with vaginitis.
North Am J Med Sci. 2011;3:185-192.
3- Hay PE. Bacterial vaginosis as a mixed infection. 2009. Internet.
4- Makwela MR. Paediatric vaginal discharge. Sa Fam Pract. 2007; 49:30-31.
5- Caillouette JC, Sharp CF, Zimmerman GJ, Roy S. Vaginal pH as a marker for
bacterial pathogens and menopausal status. Am J Obstet Gynecol.
1997;176:1270-7.
6- Gustafsson RJ, Ahrne S, Jeppsson B, Benoni C, Olsson C, Stjernquist M, and
et al. The Lactobacillus flora in vagina and rectum of fertile and
postmenopausal healthy Swedish women. 2011. Internet.
7- Ekanem EI, Efiok EE, Udoh AE, Inyang-Out A. Study of the bacterial flora of
the vagina and cervix in women of childbearing age in rural community of
Niger Delta Region, Nigeria. Gynecol Obstetric. 2012;2.
8- Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa
R, and et al. Vaginal microbiome and epithelial gene array in post-menopausal
women with moderate to severe dryness. PLoSONE.2011;6.
9- Gorodeski et al. Estrogen acidifies vaginal pH by up-regulation of proton
secretion via the apical membrane of vaginal-ectocervical epithelial cells.
Endocrinology. 2005;146:816-824.

10-Verstaelen H, Verhelst R, Claeys G, Backer ED, Temmerman M,

Vaneechoutte M. Longitudinal analysis of the vaginal microflora in pregnancy
suggests that L.crispatus promotes the stability of the normal vaginal microflora
and that L.gasseri and/or L.iners are more conducive to the occurrence of
abnormal vaginal microflora. BMC Microbiology. 2009.9.

11-AQl-Saadi MS, Al-Windawi SM. Changes of vaginal pH in correlation with

serum FSH, estradiol and vaginal bacterial culture in premenopausal and
postmenopausal women. The Iraqi Journal of Medical Sciences. 2003;2:370-375.

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12-Andreu A. Lactobacillus as probiotic for preventing urogenital infection. Rev
Med Microbiol. 2004;15:1-6.

13-Gilbert GG, Bosmans E, Dekeersmacker A, Vereechen A, Spitz B.

Pathogenicity of abnormal vaginal bacterial flora. Am J Obstet Gynecol. 2000;
182:872-878.

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 Chapter Six

Vaginitis

Vaginitis is an infectious or non-infectious inflammation of the vaginal mucosa

which sometimes involves the vulva. This inflammation often causes itching,
burning, irritation, abnormal discharge, and discomfort. Vaginitis falls into many
forms: irritant, hormonal, foreign body, sexually transmitted diseases, and infective.

• Infectious vaginitis

Infectious vaginitis may be caused by bacteria, fungi, parasites, and viruses.

Among the factors favorable to vaginal infections are poor genital-anal hygiene, a
new sex partner or several of them, bathing in pools or tubs, pregnancy, diabetes,
parasitic infections, urinary or fecal incontinence, stress, congenital malformation,
frequent use of antibiotics, hormones, contraceptive preparations to be used orally
or topically and vaginal, immune system deficiency, tight clothes, nylon
underwear, using non-hygienic vaginal elements used for the application of
products and so forth.

Persistent or recurrent vaginal infections may cause daily or episodic symptoms of

itching, irritation or burning. Not all women have persistent discharge from the
vagina. An increase in vaginal pH could increase the presence of pathogens.
Abnormal vaginal pH measurement may indicate abnormal flora. Less estrogen
means vaginal pH increases and the lining of the vagina thins, which, in turn,
creates an imbalance in the good bacteria. This imbalance can leave woman prone
to infection. No significant relationship is found between the age average and the
frequency of vaginitis. A significant relationship is found between females
suffering from common vaginal infections and body mass index (BMI). There is a
significant relationship between weight and suffering from common vaginal
infections. Excessive weight causes vaginitis. It is proven there is a link between
bacterial vaginosis and psychological stress. In disturbed menstrual cycles there

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may be more days when vaginal pH is raised, facilitating overgrowth of abnormal
flora which may develop vaginitis. Women with suboptimal vaginal flora are at
increased risk for infections following gynecologic surgery. The presence of
vaginal infection leads to decrease in the number of lactobacilli that produce
H2O2 and increase colonization of the vagina by lactobacilli that do not produce
it.

Thrush (vaginal candidiasis ), bacterial vaginosis, trichomoniasis, aerobic

vaginitis, Chlamydia infection and gonorrhea are the most common causes of
vaginal infection. Other infections include genital herpes and genital warts.

Usually, vaginal discharge in post-menopausal age group is due to a lack of

oestrogens, leading to atrophic vaginitis. There is also a concomitant reduction in
the normal flora of the vagina, especially lactobacilli. These result in the
predisposition to infection.

Bacterial vaginosis is a common polymicrobial syndrome characterized by high

concentrations of aerobes and non-aerobes, absence of lactobacilli, and a high
vaginal pH. In bacterial vaginosis, the environment of the vagina shifts from a
predominance of hydrogen peroxide-producing Lactobacillus spp., such as
Lactobacillus crispatus and Lactobacillus jensenii to a
predominance of anaerobes (mainly Prevotella, Peptostreptococcuss spp.,
Eubacterium spp., Mobiluncus, Fusobacterium spp. Atopobium vaginae and
facultative anaerobic bacteria (mainly Mycoplasma spp., Gardnerella vaginalis,
non-viridans group streptococci).

An elevated vaginal pH (5.0 to 6.5) in a normally estrogenized patient almost

always associated with bacterial vaginosis. Bacterial vaginosis may be transient or
become persistent. Bacterial vaginosis is recognized as the most common cause of
abnormal vaginal discharge in women of child bearing age. The symptoms of a
thin, white or yellow discharge accompanied by a fishy smell are so characteristic
that it is surprising that bacterial vaginosis was not widely recognized until

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described as nonspecific vaginitis by Gardner and Dukes in 1955. Trimethylamine
and the polyamines putrescine and cadaverine are produced by anaerobic
metabolism, and they are thought to be responsible for the fishy smell caused by
bacterial vaginosis. Some women with bacterial vaginosis experience vaginal
irritation accompanied with a thin, watery, yellow-green discharge. Other
characteristic changes include elevated vaginal pH (‫ޓ‬4.5), formation of clue cells
which are epithelial cells that are coated with bacteria, upregulation of
inflammatory cytokines such as Interleukin (IL)-1 beta, a noticeable absence or
rare presence of white blood cells in the vaginal discharge, and a decrease in
naturally protective molecules like secretory leukocyte protease inhibitor.
Bacterial vaginosis is more common in sexually active women ranging in age
from 15-44; it is especially common after women change to a new sex partner.
Virgins can become infected with bacterial vaginosis. A study has shown
subclinical anaemia the iron shortage is a strong cause of bacterial vaginosis in
pregnant women. Most studies have found an increased prevalence of bacterial
vaginosis in women of black race compared to those of white race And in those
who report cunnilingus, smoking, and use of an intrauterine contraceptive device.
Bacterial vaginosis has also been associated with chronic douching, use of bubble
bath, antiseptic solution, and spermicide.

Figure (6-1): Bacterial vaginosis (quoted from www.google.com)

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Gardnerella vaginalis is a normal component of the human vaginal flora and
primarily is a pathogen and bacterial vaginosis is the most common condition
associated with this organism. The observation that the presence of Gardnerella
vaginalis precedes the development of bacterial vaginosis warrants consideration
of its treatment even in asymptomatic individuals. If Gardnerella vaginalis is
eradicated, perhaps the numbers of individuals who have bacterial vaginosis and
its associated disorders could be reduced.

Bacterial vaginosis strongly predisposes to the acquisition of pandemic sexually

transmitted infections, such as Neisseria gonorrhoeae, Chlamydia trachomatis,
herpes simplex virus (HSV)-2, and HIV-1 among both pregnant and non-pregnant
women.

When mucopurulent cervicitis (often caused by Chlamydia) is present, oxygen

consumption by polymorphonuclear leukocytes decreases the redox potential and
elevates vaginal pH, favouring development of bacterial vaginosis.

Pelvic inflammatory disease (PID) is associated with bacterial vaginosis. Bacterial

vaginosis is also linked to preterm delivery of low-birth weight infants, early
failure of in vitro fertilization, an increased risk of infective complications after
hysterectomy, and is associated with postpartum endometritis.

Use of hormonal contraception and condoms were both associated with lower
bacterial vaginosis risk.

Vaginal yeast infection is an infection of the vagina, most commonly due to the
fungus Candida albicans. Between 85% of vaginal yeast strains belong to
Candida albicans; Other yeasts account for up to 15% of cases and include
Candida glabrata, Candida parapsilosis, and Candida tropicalis.

Candida albicans is a part of normal flora of vagina mucus. This fungus under
special conditions such as age, diabetes, use of antibiotics, extent use of
corticosteroids, vitamin A,B,C deficiency, moisture, perspiration infectious

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diseases, cancer, use of antiobesity and cancer drugs, dressing thigh clothes, using
thigh belts, alcoholism, chronic obesity, addiction, deficiency of calcium and iron,
pregnancy, artificial proteases, such as tooth and heart valve bleeding, thoractomy,
immunosuppressive drugs, contraceptives, burning, spermicide use, oral
contraceptive use, receptive oral sex, condoms and diaphragm use, and
immunosuppression including AIDS is able to produce disease by predominating
natural immunity mechanisms of the host. Risk of vaginal candidiasis is increased
when vaginal pH is below 4.5.

Vulvovaginal candidiasis is prevalent among both sexually active and inactive

women. The bacterial vaginosis environment is not conductive to yeast
multiplications and yeast vaginitis therefore does not occur in the presence of
bacterial vaginosis. Vaginal candidiasis is not sexually transmitted disease. No
significant relationship is between suffering from vaginal candidiasis infection and
irregular menstrual cycle.

Symptoms of vaginal candidiasis include abnormal vaginal discharge, ranges from

a slightly watery, white discharge to a thick, white, chunky discharge (like cottage
cheese), pain with intercourse, painful urination, redness and swelling of the
vulva, vaginal and labial itching, and pruritis or burning.

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Figure (6-2):Vaginal yeast infection. (quoted from www.google.com)

As in adults, Candida albicans is the commonest fungal infection in prepubertal

girls. Candida infections are common under the age of two, but become less
frequent once the child is out of diapers. Recurrent vaginal candidiasis in
prepubertal girls should alert the practitioner to the possibility of conditions like
juvenile diabetes and immunosuppression.

Complications of vulvovaginal candidiasis are rare, though vulvar vestibulitis and

chorioamnionitis in pregnancy have been reported.

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with

predominance of abnormal aerobic flora. Although some pathogenic conditions
causing vaginitis are well defined like bacterial vaginosis, vulvovaginal
candidiasis, and trichomoniasis yet, 7-72% of women with vaginitis may remain
undiagnosed and such forms of abnormal vaginal flora neither considered as
normal, nor can be called bacterial vaginosis have been termed as intermediate
flora and its management differ from that of bacterial vaginosis. It is of crucial
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importance in pregnant females at risk of preterm delivery. The most organisms
associated with aerobic vaginitis are Staphylococcus aureus, Escherichia coli,
enterococci, Streptococcus pyogenes, group B streptociocci,
Pseudomonas aeruginosa, Acinetobacter spp., Staphylococcus spp.,

Listeria monocytogenes, Klebsiella pneumonia, and enteric gram negative bacilli.

Women with aerobic vaginitis have redder, inflamed vagina. Ulcerations that
occur, particularly on the anterior fornix, resemble lesions seen in patients with
desquamative vaginitis. They have a foul-smelling discharge, but the smell is not
fishy. They are not itchy, but about 10% of those with severe form of condition
have dyspareunia. Vaginal pH is above 6. McDonald et al (1994) found
Escherichia coli and group B streptococci to be the important pathogens
associated with mid-trimester pregnancy losses, alongside the classic bacterial
vaginosis organisms.

Figure (6-3):Vaginal fluid from patients with aerobic vaginitis. (quoted from
www.google.com).

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Children like to explore and pathogenic organisms can be introduced from other
parts of the body. Haemophilus influenza, group A and B haemolytic streptococci
and Streptococcus pneumonia are commonly isolated in vaginal infections of
children. Infections in the genital tract of children may follow infection in the
respiratory tract or skin. Infections by respiratory pathogens tend to cause a
yellowish to greenish purulent vaginal discharge.

Wiping the perineum from anus to vagina causes faecal contamination of the
vagina. Recurrent bouts of gastroenteritis, especially common in
immunocompromised children, may result in recurrent infections. Shigella
flexneri is an unusual cause of infection in young children. It causes
mucopurulent, sometimes bloody vaginal discharge. Escherichia coli infection
causes a thin, watery foul smelling discharge. Infections may follow an episode of
diarrhoea.

Trichomonas vaginalis is an anaerobic, flagellated protozoan, a form of

microorganism. The parasitic microorganism is the causative agent of vaginal
trichomoniasis. Vaginal trichomoniasis is a sexually transmitted infection which
can occur in females if the normal acidity of the vagina is shifted from a healthy,
semi-acidic pH (3.8-4.2) to a much more basic or alkaline one (5-6) that is
conductive to Trichomonas vaginalis growth. Vaginal trichomoniasis accounts for
no more than 10% of all cases of vaginitis, and it appears to be decreasing since
the introduction of metronidazole.

It is classified as sexually transmitted disease, although transmission is possible by

other means if the organism is protected from desiccation-for example, in dirty
washcloths or towels and contaminated water. Nonsexual transmission is thought
to be uncommon. Vaginal trichomoniasis is associated with gonococcus and
Chlamydia infections, and like them has been associated with seroconversion to
HIV-positive status.

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Women with vaginal trichomoniasis often experience copious, greenish-yellow
forthy discharge that can lead to irritation and painful intercourse. In addition,
clinical presentations involve vulvovaginal erythema, itching, and punctate
hemorrhagic cervical lesions which are considered pathognomonic of
trichomoniasis, but are seen in only about 2% of cases. Other symptoms of vaginal
trichomoniasis include preterm delivery, low birth weight, and increased mortality
as well as predisposing to HIV infection, discomfort during sex, pain when
passing urine, occasionally stomach pains, and cervical cancer.

Figure(6-4): Trichomonas vaginalis infection. (quoted from www.google.com)

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Enterobius vermicularis (pinworm) is a common infestation in young girls. It
causes a severe pruritis, associated with a thin colourless discharge.

Females with altered vaginal flora but without bacterial vaginosis may be at risk
for sexually transmitted infections. Females at risk for sexually transmitted disease
acquisition more commonly test positive for Neisseria gonorrhoeae and
Chlamydia trachomatis if they have bacterial vaginosis.

Women vagina colonized with H2O2-producing lactobacilli are less likely to be

infected with a sexually transmitted disease than are women without lactobacilli.
The influence of body mass index is little effect on sexually transmitted disease.

Chlamydia infection is caused by the sexually transmitted bacterium

Chlamydia trachomatis. Chlamydia can cause pain when passing urine, long-term
pelvic pain, and infertility. However, it may produce no symptoms in women. It
has also been associated with low birth weight babies and premature delivery.

Figure (6-5): Chlamydia trachomatis infection of vagina. (quoted from

www.google.com).

The bacterium responsible for gonorrhea is Neisseria gonorrhoeae. The main

symptoms for gonorrhea are vaginal discharge and pain passing urine, but there
may be no symptoms in the early stages. Untreated, gonorrhea can lead to pelvic
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infection, with abdominal pain, painful sex, and a general feeling of being unwell.
Damage to the Fallopian tubes can result in reduced fertility and an increased risk
of ectopic pregnancy.

Figure (6-6): Gonnorhea and an abundance of vaginal discharge which may

change to a yellow or greenish color. (quoted from www.google.com)

A vaginal discharge may be the only manifestation of a sexually transmitted

disease in an abused child. In a study, all the girls with Neisseria gonorrhoeae or
Trichomonas vaginalis had vaginal discharge. Two thirds of those with Chlamydia
trachomatis also had a vaginal discharge. Neisseria gonorrhoeae infection
produces a purulent thick yellow discharge. Trichomonas is expressed clinically as
a forthy, watery-yellow or green discharge. Children born to mothers infected with
Chlamydia may carry the organism for up to 18 months.

The herpes infection is caused by the herpes simplex virus being passed during
sex. The virus lies dormant in the body and it is common to get repeated attacks.
These are generally milder than the first attack. Vaginal herpes infection can cause

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spots on the labia, clitoris, and pubic area. These look like blisters, ulcers, or
chapped areas. People often have flu-like symptoms, fever, and pain passing urine
for about a week when first infected. A pregnant woman can transmit herpes
infection to her baby during delivery. Severe damage to the baby's nervous system
can result. The virus is most infectious during an attack, so avoiding sexual
activity at this time lessens the chance of passing it to others. Beyond the neonatal
period, the presence of herpes in children indicates a need to look for sexual
abuse. Infected children with herpes present with painful vulvar eruptions
associated with a thin, watery vaginal discharge.

Figure (6-7): Herpes simplex virus infection. (small fluid-filled blisters on the
outside of the vagina that burst leaving small painful sores).(quoted from
www.google.com).

Genital warts appear as small round lumps on or around the genitals. They are
caused by the human papilloma virus (HPV), which is passed by skin-to-skin
contact. Exposure to human papilloma virus increases the risk of developing
cervical cancer.
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Figure (6-8): Genital warts in and around the vagina of a woman infected with
human papilloma virus (quoted from www.google.com).

• Noninfectious vaginitis

Noninfectious vaginitis are noninfectious causes of vaginal discharge.

Cytolytic vaginosis is a condition where the vagina is overrun with Lactobacillus.

Lactobacilli are good bacteria that live in the vagina and they normally do not
cause any problems and therefore cytolytic vaginosis is not classified as an
infection. Cytolytic vaginitis is characterized by overgrowth of lactobacilli and
cytolysis of squamous cells, including presence of cytoplasmic fragments and
intact cells with naked nuclei. The condition occurs when the delicate balance of
the vagina is interrupted, causing overgrowth of lactobacilli. The cause is
uncertain but may include reaction to intravaginal medications or other products
such as tampons. Repeated use of antibiotics or antifungals can trigger it.
Symptoms often mimic vulvovaginal candidiasis and may include a white, cheesy
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discharge. Other symptoms are present as vulvar itching and redness, pain when
urinating and pain during intercourse. Vaginal pH ranges from 3.5 to 5.5.
Recurrences during luteal phase of the menstrual cycle have been described.

Figure (6-9): Cytolytic vaginosis. (quoted from www.google.com).

Desquamative inflammatory vaginitis is an uncommon vaginitis characterized by

profuse purulent discharge with epithelial cell exfoliation. Generally occurring in
perimenopausal or postmenopausal women, desquamative inflammatory vaginitis
causes burning, varying amounts of vestibular and vaginal erythema, dyspareunia,
and an abnormal yellow or green discharge. The vaginal pH is elevated. Some
cases may correspond to a disorder within the spectrum of lichen planus. Although
streptococcal species, including group B streptococci, are found in more than 90%
of affected women, this does not mean that desquamative inflammatory vaginitis
is caused by streptococcal species. Microscopy reveals large amounts of
polymorphonuclear cells and parabasal cells. This condition is easily mistaken for
trichomoniasis; however, in cases of desquamative inflammatory vaginitis, no
motile trichomonads are present and cultures for Trichomonas vaginalis are
negative.

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Figure (6-10): Desquamative inflammatory vaginitis. (quoted from
www.google.com).

A number of studies have shown that vaginal immune response causes some cases
of recurrent vaginitis. IgE antibodies to Candida albicans, seminal fluid
components, pollen, and contraceptive spermicides have been identified in vaginal
fluids of women with recurrent vaginitis. In many instances, presence of
prostaglandin E2 in the vagina and detection of eosinophils in vaginal smears
were also observed.

Exposure to allergen in the vaginal lumen is followed by the transport of this

allergen through the interepithelial channels and its interaction with mast cell-
bound specific IgE. This induces mast cells degranulation and the release of
histamine and other inflammatory mediators, causing symptoms of allergic
vaginitis. In addition, histamine is a potent inducer of prostaglandin E2 from
macrophages which suppresses cell-mediated immune response. Unlike bacterial
infections, in which humoral immunity is an important component of defense,
protection against yeast is dependent on the cellular immune system. The resulting

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symptomatic candidal vaginitis would be a secondary consequence to a primary
allergic vaginitis.

The physiologic features that allow a selective accumulation of allergens in the

vaginal lumen, their passage through the interepithelium channels, and the
subsequent binding to specific IgE on mast cells in the subepithelium basal lamina
could explain the newly characterized occurrences of allergic vaginitis. The routes
of vaginal sensitization would be by direct or indirect contact.

Hormone secretion is influenced by immunologic factors and vice-versa.

Regulation of mucosal immunity in the female reproductive tract through the
reproductive cycle is well established. Endocrine changes regulate the levels of
IgA and IgG in the uterine and vaginal secretions. As expected, the vaginal
epithelium, interepithelium channels, and lymphoid cell concentration are all
influenced by the menstrual cycle, which can be divided into four phases: (1)
menstruation, (2) preovulatory phase (proliferative), with a predominance of
estrogen, (3) periovulatory phase, when both estrogen and progesterone are active,
and (4) postovulatory phase (luteal), with a predominance of progesterone which
remains until the next menstruation.

Immunosuppressive effects of vaginal lavage fluids collected during menstruation

and in the periovulatory phase may indicate an attenuation of normal immune
surveillance and enhanced susceptibility to infections and allergic reaction during
these periods. Immunosuppression during the periovulatory phase may also be a
mechanism for attenuation of a woman's immune response to spermatozoa.

Some studies show that progesterone favors the development of T-helper cells
producing Th2 type cytokines which are responsible for the IgE-mediated
hypersensitivity reactions. The immune response to Candida albicans and
therefore the ability of this organism to proliferate and undergo the asymptomatic
yeast to-germ tube transition is influenced by high levels of progesterone. This

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explains the fact that the incidence of allergic reactions and candidal vaginitis is
most common in the late luteal phase, just prior to menstruation.

Besides direct contact, allergens, such as pollens, dust mite, and latex could be
systemically absorbed after inhalation. This kind of sensitization has recently been
demonstrated in patients with atopic dermatitis and may also be valid for allergic
vaginitis. In these cases, there are an increased number of eosinophils in the
vaginal smear. In the majority of cases of allergic vulvovaginitis due to inhalants,
the patients were children who have not developed Candida vaginitis because
there was no estrogen in the vagina, essential for the overgrowth of the yeast.

Food or drug compounds as walnuts, banana, and penicillin may accumulate in the
vagina and induce allergic reactions in susceptible women. This may occur by
ingestion or contact with the semen of a partner who had ingested the
incriminating food or drug. Drugs may also affect the vagina and vulva for
mechanisms other than type I hypersensitivity reaction. Examples are fixed drug
eruption, contact dermatitis and pemphigoid lesion.

Bernstein et al proposed that patients with seminal plasma allergy can be

classified into two groups, localized and systemic, depending on the character of
the symptoms. There is a greater prevalence of self-reported food allergy among
women with semen allergy. This suggests that there is reaction to seminal plasma
proteins that cross-react with other common exogenous proteins (possibly foods)
to which they may have been previously sensitized. It has been clearly
demonstrated that the systemic responses to human seminal plasma are
immunologically mediated by the production of IgE antibodies. The disease is
generally allergic and type I mediated, but type III and IV have also been reported.
Clinical manifestations of postcoital arthritis, rash, hemorrhagic proctitis, bullous
fixed drug eruption, and contact dermatitis after coitus have been described, with
their respective diagnostic proofs. Repeated episodes of asthma after unprotected
sexual intercourse were due to semen. Male factors increasing the risk for semen
allergy in women seem to be vasectomy, chronic illness, and infections. Female
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factors include pregnancy, infections, gynecologic surgery, and insertion of
intrauterine devices. A high degree of HLA sharing between affected women and
the partner has been suggested as a causal factor of the disease.

Natural rubber allergy is reported worldwide and it is responsible for a broad

spectrum of allergic symptoms ranging from mild reactions to severe anaphylaxis.
It may determine type I or IV hypersensitivity reactions as a consequence of
contact with latex used in condoms, diaphragms, surgical gloves, diagnostic and
surgical procedures. Inhaled latex has also been reported to provoke vaginal
pruritus. Unfortunately, some women present a concomitant allergy to semen and
latex.

There is evidence incriminating Candida albicans as a potent allergen. Both the

protein and carbohydrate fractions of the yeast contain allergens. IgE against
Candida albicans and clinical symptoms of allergy have been demonstrated in the
lungs, nose, and skin. In 1988, Witkin et al identified Candida albicans specific
IgE in vaginal washes. In 1994, Regulez et al identified Candida albicans IgE
antibodies in vaginal washes of women with acute Candida vaginitis-like, in
whom the yeast was not identified in vaginal cultures. Allergy is an important
pathogenic factor in recurrent vaginal candidiasis.

Parasiets may cause several kinds of allergic reactions as asthma and urticaria.
Parasitosis due to Enterobius vermicularis (pinworm) is very common, especially
in children. The migration from the anus to the vagina may cause an irritative and
allergic vaginitis that may induce eosinophilia and high total serum IgE
antibodies.

Immunoglobulin E anti-nonoxynol-9, the active component of spermicide jellies

has been demonstrated in vaginal washes from women suffering from chronic
vaginitis. Furthermore, studies have demonstrated that nonoxynol-9 was toxic to
lymphocytes and macrophages and significantly inhibited their function.

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Allergic contact dermatitis is an important, but often unrecognized factor in vulvar
pruritus and can be caused by a great number of substances in our environment.
Irritant contact dermatitis can occur as a result of friction and trauma, or due to the
use of corrosive chemicals. It should be emphasized that these compounds may be
in use by the patient or her partner as topical medications, K-Y jelly, perfumes,
hygiene sprays, soaps, bubble-bath, nail polish, sanitary napkins, soaps and
detergents used in underwear washing, saliva, newsprint, colophony, and textiles.

Figure (6-11); Allergic contact dermatitis. (quoted from www.google.com).

Atopic dermatitis can also affect the vulva. It is characterized by severe pruritus,
xerosis of the skin, and particularly lichenification.

Urticaria may sometimes affect the female genital tract. Erythematous pruritic
skin lesions tend to be evanescent in the labia maiora, labia minora, and clitoris.
Angioedema may also be present and can occur in the vagina.

There are patients complaining of allergy from their husband's sweat.

Dermographism may occur in the vulva and worsened by the use of tight
underwear. Dermographism that occurs only after sexual intercourse is not a rare
condition and it may be associated with exercise-induced (by the sexual
intercourse) urticaria.

Drug eruption in the genitalia is sometimes seen in the allergist's office. The
characteristic lesion is well delineated, round or oval, mildly pruritic or may

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produce a burning sensation. It is considered to be virtually pathogenomonic of
drug hypersensitivity. Drugs most commonly implicated include phenolphthalein,
analgesics/antipyretics, barbiturates, penicillins, sulfonamides, tetracycline, and
minocycline.

Finally it is important to mention four risk factors associated with allergic

vulvovaginitis which comprise sexual intercourse, exaggerated personal hygiene
habits, dressing pattern including wearing tight clothing in association with nylon
or lycra underwear and jeans, and physiologic factors as depression.

For further readings:

1- Razzak MSA, Al-Charrakh AH, AL-Greitty BH. Relationship between

lactobacilli and opportunistic bacterial pathogens associated with vaginitis. North
Am J Med Sci. 2011;3:185-192.

2- vaginitis.

ACOG PRACTICE BULLETIN

Clinical management guidelines for

Obstetrician-gynecologists

Number 72, May 2006

Got from the internet in 11-2012

3- Ramirez H, Paniagan A, Salgad G, Lopez P. Fluconazole-Tinidazole

combination for the treatment of vaginal infections, composition thereof and
preparation and use of same. 2004. Internet.

4- Center for Women's Health

A National Center of Excellence in Women's Health Program in Vulvar Health

The title is :

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Chronic infection

Got from the internet in 20-11-2012

The program in Vulvar Health OHSU Center for Women's Health

Last updated 2007.

www.ohsuwomenshealth.com/vulva/

5- Al-Saadi MS, Al-Windawi SM. Changes of vaginal pH in correlation with

serum FSH, estradiol and vaginal bacterial culture in premenopausal and
postmenopausal women. The nIraqi Journal of Medical Sciences. 2003;2:370-375.

6- Bilheimer S, Echenberg RJ. Perimenopause and vaginal/vulvar pain. 2003.

Internet.

7- Mirian AMR, Keshavarz D, Hashemi JH, Gazvini SM. Factors vulvovaginal

referred to medical centers in Qazvin. The Journal of Qazvin University of
Medical Sciences. 2007;11:35-9.

8- valiani M, Zolfaghari M, Nazeemi M, Pirhadi M, Ebrahimian S. The

relationship between family planning methods, individual hygiene, and the women
referring to selected health centers in Isfahan city. I J N M R. 2011;16:83-92.

9- County S. Vaginitis information sheet. 2000. Internet.

10- Pendergraft JS. Bacterial vaginosis. 2010.

Reproductive health

http://www.womenscenter.com/

got from internet in 17-3-2010

11- Brabin L, Roberts SA, Fairbrother E, Mandal D, Higgins SP, Chandiok S, and
et al. Factors affecting vaginal pH levels among female adolescents attending
genitourinary medicine clinics. Sex Transm Infect. 2005;81:483-487.
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12- Hudson T, Kochan L. Vaginitis: two common causes bacterial vaginosis and
atrophic vaginitis. 2005. Internet.

13- Eschenbach Da, Thwin SS, Patton DL, and et al. influence of the normal
menstrual cycle on vaginal tissue, discharge, and microflora. Clin Infect Dis.
2000;30:901-907.

14- Mumtaz S, ahmad M, Aftab I, Akhtar N, ul Hassan M, Hamid A. Aerobic

vaginal pathogens and their sensitivity pattern. J Ayub Med Coll Abbottabad.
2008;20:113-117.

15- common vaginal infections.

BUPA

Health Insurance

Supported by www.healthwise.org.hk

Got from internet in 11-2012

16- Goh PSC. An outpatient approach to vaginal discharge. The Singapore Family
Physician. 2010. Internet.

17- Hay PE. Bacterial vaginosis as a mixed infection. 2009. Internet.

18- Verstraelen H, Delanghe J, Roelens K, Blot S, Claeys G, Temmerman M.

Subclinical iron deficiency is a strong predictor of bacterial vaginosis in early
pregnancy. BMC Infectious Diseases. 2005;5.

19- caillouette JC, Sharp CF, Zimmerman GJ, Roy S. Vaginal pH as a marker for
bacterial pathogens and menopausal status. Am J Obstet Gynecol. 1997;176:1270-
7.

20- Bacterial vaginosis.

http://en.wikipedia.org/wiki/Bacterial vaginosis

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Categories: Sexually transmitted diseases and infections | Gynecology|Sexual
health

Got from internet in 17-3-2010

21- Amaya RA, Al-Dossary F, Demmler GJ. Gardnerella vaginalis bacteremia in

a premature neonate. Journal of Perinatology. 2002;22:585-587.

22- Wiesenfeld HC, Hillier SL, Krohn MA, Landers DV, Sweet RL. Bacterial
vaginosis is a strong predictor of Neisseria gonorrhoeae and

Ghlamydia trachomatis infection. Clinical Infectious Diseases. 2003;36:663-8.

23- Vorvick L. Vaginal yeast infection. 2011. Internet.

24- Spinillo A, Capuzzo E, Gulminetti R, and et al. Prevalence of and risk factors
for fungal vaginitis caused by non-albicans species. Am J Obstet Gynecol.
1997;176:138-41.

25- Bayat M, Kousha A, Saraji AA, Rohani SR, Nissiani M. Study effectsof some
kinds of standard essences over two microorganisms

( Candida albicans and Gardnerella vaginalis ) related to leucorrhoea disease as

in vitro. World Applied Sciences Journal. 2008;5:418-421.

26- French L, Horton J, Matousek M. Abnormal vaginal discharge using office

diagnostic testing more effectively. The journal of Family Practice, 2004;53:805-
814.

27- Thulkar J, Kriplani A, Agarwal N. Utility of pH test and whiff test in

syndromic approach of abnormal vaginal discharge. Indian J Med Res.
2010;131:445-448.

28- Moodley P, Connolly C, Sturn AW. Interrelationships among human

immunodeficiency virus type 1 infection, bacterial vaginosis, trichomoniasis, and
the presence of yeast. The Journal of Infectious Diseases. 2002;185:69-73.

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29- Makwela MR. Paediatric vaginal discharge. SA Fam Pract. 2007;49:30-31.

30- Baker B. aerobic vaginitis looks like BV, but requires different Tx. 2000.
Internet.

31- Garber GE. The laboratory diagnosis of Trichomonas vaginalis. Can J Infec
Dis Med Microbiol. 2005; 16:35-38.

32- Nagelkerke NJD, Berusen RMD, sgaier SK, Jha P. Body mass index, sexual
behavior, and sexually transmitted infections: an analysis using the NHANES
1999-2000 data. 2006. Internet.

33- Karpasea-Jones J. Cytolytic vaginosis. 2011. Internet.

Cytolytic Vaginosis, University of Virginia Student Health-

http://www.virginia.edu/studenthealth/Cytolytic%20Vaginosis.pdf

Got from the internet in 11-2012

34- Moraes PSA, Taketomi EA. Allergic vulvovaginitis. Ann Allergy Asthma
Immunol. 2000;85:253-267.

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 Chapter Seven

Innate, Humoral and Cell-mediated Immunity

The vaginal environment is a common site of infections. The vaginal innate immune
system represents the first line of defense against foreign organisms and pathogenic
microbes. It is known that the vaginal innate immune system works as a guardian,
keeping the vagina in homeostasis. The loss of this balance has been associated with
increase in susceptibility to infections, especially sexually transmitted infections, and
importantly to adverse outcomes during normal pregnancy. The components of innate
defense mechanism can be divided into normal vaginal flora, antimicrobial peptides,
cytokines, and immune cells. All these components interact in order to maintain
homeostasis. Any alteration in these components has been associated with disease
processes.

The vagina is a non-sterile mucosal surface that is colonized by normal flora. The
principal constituents of the vaginal flora are Lactobacillus species that produce lactic
acid and hydrogen peroxide, which in turn maintains a low vaginal pH and prevents
infections such as vulvovaginal candidiasis and bacterial vaginosis. The vaginal
mucosa must retain the capacity to respond to pathogens while tolerating the normal
flora at this site, largely consisting of Lactobacillus species. The tolerance to normal
flora established at this site may contribute to poor immunoresponsiveness. The
normal flora itself is an innate immune defense, by competing with pathogens and
generation of an acidic vaginal pH and hydrogen peroxide. The slight acidic pH
within the vagina makes it inhospitable for pathogenic organisms. The absence of
normal lactobacilli in the vagina has shown to be a strong indicator of the presence of
sexually transmitted diseases such as trichomoniasis, Chlamydia trachomati,
Neisseria gonorrhoeae, and syphilis. Bacterial vaginosis is associated with an
increase in the incidence of HIV (human immune virus) infection. One of the
possible mechanisms attributed to this increased risk in HIV infection, is the more
basic vaginal pH and the increased CD4+ vaginal lymphocyte activation which lead

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to increase in adherence and survival of the human immune virus. Disruption of the
normal flora by anaerobic bacteria is termed bacterial vaginosis. Donders et al.
recently introduced the term aerobic vaginitis which is defined as an inflammatory
state characterized by the overgrowth of aerobic microorganisms as Escherichia coli.
This entity differs from bacterial vaginosis in that vaginal lactate levels are severely
depressed. This pathogenic state is also associated with higher production of IL-6,
IL-1ß and leukemia inhibitory factor.

Pathogens are recognized by the certain components of the innate immune system
through receptors called pattern-recognition receptors, which recognize specific
patterns on the surface of these organisms. One major family of pattern-recognition
receptors are the Toll-like receptors (TLRs), capable of recognizing fungi, viruses,
and bacteria. The vagina is lined by a stratified squamous non-keratinized epithelium.
This epithelium expresses Toll-like Receptors which recognize broadly conserved
microbial molecules and serve as critical sensors of infection. TLR2 and its partners
TLR1 and TLR6, which in combination (TLR1/2 and TLR2/6) recognize lipopeptides
present on both Gram-positive and Gram-negative bacteria. TLR4 recognizes
lipopolysaccharide of Gram-negative bacteria; and TLR5, which recognizes flagellin,
a component of the flagellum responsible for bacterial motility.

Trichomonas vaginalis is recognized by TLR4 on vaginal epithelial cells. Both TLR2

and TLR4 are involved in the immune response against Chlamydia. TLRs may be
implicated in the pathogenesis of preterm labor. Stimulation of these TLRs triggers
secretion of the chemokine IL-8, which in turn recruits neutrophils to the vaginal
mucosa to combat infection, as well as production of antimicrobial peptides such as
human Beta Defensin-2 (hBD-2), which can directly inhibit bacteria.

In addition to epithelial cells, the role of dendritic cells (called Langerhans Cells
when present in the epidermis) in detecting vaginal pathogens has been explored.
Dendritic cells function primarily as antigen-presenting cells (APCs), and play a key
role in linking the innate (e.g. inflammation) and adaptive (e.g. antibodies, cell-
mediated immunity) arms of the immune response. Dendritic cells in the vaginal
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mucosa utilize TLR9 to recognize Herpes Simplex Virus-2 and stimulate interferon
expression to combat this pathogen. In contrast, TLR stimulation increases the
susceptibility of these cells to HIV infection. In addition to epithelial cells and
dendritic cells, the innate immune system has a rich network of cellular components
such as stromal fibroblasts, various phagocytes (macrophages and neutrophils), mast
cells, eosinophils, basophils, and natural killer (NK) cells which all play an important
role in natural protection against pathogenic organisms. The recruitment of
neutrophils to the vaginal mucosa causes elimination of pathogens through
phagocytosis and their oxidative burst. Neutrophils are required for defense against
Trichomonas infection. In contrast, during vulvovaginal candidiasis the symptoms of
infection are mediated by vaginal neutrophil influx that is unable to clear the
pathogen. In the absence of infection or inflammation, the cervical transformation
zone is the area where antigen-presenting cells are most abundant. By contrast, the
vaginal epithelium is rather void of antigen-presenting cells. This fact suggests the
conclusion that the cervix is the area of the major area of induction of immunity in
the genital tract. These cells seem to be under hormonal control. Estradiol, the
predominant form of estrogen found in women of reproductive age, inhibits the
antigen presentation done by these cells in the vaginal stroma. This inhibitory effect
is thought to be mediated by the action of TGF-ß produced locally by vaginal cells.

In response to recognition of bacterial pathogens, the vaginal mucosa mobilizes a

variety of defenses. Antimicrobial proteins, including lysozyme, lactoferrin, and
small antimicrobial peptides such as defensins are secreted in response to infection.
Defensins are a family of antimicrobial peptides expressed by epithelial cells
leukocytes. In humans, the best characterized are the Į-defensins, termed human
neutrophil peptides 1-3, and human ß-defensins1-3. The Į-defensins are usually
released by extravasated neutrophils at sites of inflammation. Both Į- and ß-
defensins have been shown to have anti-HIV activity. Vaginal epithelial cells
constitutively produce human ß-defensin-1 (HBD-1), and produce HBD-2 after TLR
stimulation with microbial products. Concentrations of Į- and ß- defensins from

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cervicovaginal lavage can vary greatly throughout the menstrual cycle and this
change in concentration is evidence that levels of estrogen can influence the
operational status of the vaginal innate immune system.

Lactoferrin expression is increased during bacterial vaginosis and infection by

Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis.
Lactoferrin limits infections by sequestering iron, an essential nutrient, away from
pathogens.

Secretory leukocyte protease inhibitor (SLPI) is another antimicrobial peptide, with

antiprotease activity. It is produced by macrophages and epithelial cells and has a
range of antimicrobial activities, including activity against HIV. SLPI seems to be
under hormonal control i.e. estrogen.

Another immune peptide is termed elafin. It is also an antiprotease protein and is

produced by epithelial cells and neutrophils. Because of its particular antiprotease
activity, it is thought to primarily protect the epithelium from damage caused by
neutrophil activity.

Calprotectin is a peptide produced by epithelial cells, cervical glands, and

neutrophils. It has been found to have antimicrobial properties.

Other important components of the vaginal innate immune system are the cytokines.
Cytokines are small soluble protein molecules that serve as mediators of
inflammation, activation, differentiation and chemotaxis. They are produced by a
variety of cells and are present in abundance in the lower genital tract secretions. The
presence of certain cytokines, such as IL-1Į, IL-1ß, IL-6 and TNF, has served as a
marker for inflammation in a large body of research. In women diagnosed with
bacterial vaginosis, the concentration of IL-1Į in the cervical mucus rises with an
increase in the concentration of bacterial endotoxin in the vaginal fluid. Once
bacterial vaginosis has been effectively treated with antibiotics, levels of IL-1Į, IL-
1ß, and ILO-8 in cervical secretion decrease, which demonstrating the direct
relationship between the presence of infection and abnormal cervical cytokine levels.
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Not all pathogens of the lower genital tract elicit a cytokine response. Neisseria
gonorrhoeae, the organism responsible for gonococcal infections, appears to elude a
local immune reaction. Levels of IL-1, IL-6, IL-8 and Il-10 in genital secretions were
not elevated in patients with confirmed cases of gonorrhea, although serum levels did
demonstrate a rise.

Interferon, a well-known systemic cytokine, has also been found to have properties
within the local vaginal immunity. Some groups have reported an increased
concentration in interferon in vaginal swabs of women diagnosed with bacterial
vaginosis.

Antiviral responses in the vaginal tract are found to be due to type-III IFNs produced
by vaginal dendritic cells.

Another cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), has

both local and systemic effects and plays a role in vaginal immunity. GM-CSF has
the ability to recruit dendritic cells to elicit an immune response. After an infection
with Chlamydia, epithelial cells in the lower genital tract release IL-1Į which then
stimulates the release of GM-CSF locally, thus implicating it in normal response of
the vaginal immune system.

Complement allows for the recognition of pathogens by immune cells. Complement

recognizes infectious agents using three different molecules: C1q, mannose-binding
lectin (MBL), and C3. Alterations in MBL predispose women to vulvovaginal
candidiasis.

Almost all components of the innate immune system undergo some change during
pregnancy. The normal vaginal flora tends to shift throughout gestation. The aerobic
bacteria in the vagina remains constant throughout pregnancy, but the detection of
anaerobic bacteria seems to decrease during the late third trimester with a return to
normal levels 6-weeks postpartum. In normal pregnancy, there may be alteration in
the concentration of several cytokines in the genital tract. Increasing concentrations
of IL-1ß are found during the course of pregnancy. Levels of the anti-inflammatory
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cytokine IL-10 in the cervicovaginal fluid are found to be reduced during the first
trimester, likewise levels of proinflammatory cytokine, IFN-ɭ, IL-2 and anti-
inflammatory IL-4 are reported as decreased during the second trimester. Pregnant
women are less likely to have detectable IL-6 and IL-8, and that the concentrations of
these molecules drop during the second trimester. Some levels of cytokines do not
return to pregnancy levels at the end of the third trimester and indicate maternal
physiological changes in preparation for the labor and delivery process. The
concentration of some antimicrobial peptides is frequently altered in pregnancy. SLPI
concentrations are increased during pregnancy. It is significant to demonstrate that
various adverse pregnancy outcomes, especially the link with a ratio of 3.0 for PTB,
have been associated with alterations in the innate immune system of the lower
genital tract.

Figure (7-1): The major components involved in vaginal innate immunity. (quoted
from www.google.com).

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Antibodies are present in vaginal secretions, with IgG being the dominant isotype and
IgA a minor constituent. These antibodies are derived in approximately equal
proportions from serum and local production. IgG and IgA secreting plasma cells are
scarce in the vagina. The absence of local lymphoepithelial sites, such as the Peyer's
Patches in the gastrointestinal tract, is thought to be the cause of the poor antibody
response of the vagina. In general, protective antibody responses are not observed for
this site, underlying the recurrent and chronic nature of many vaginal infections.

Cell-mediated immunity (CMI) is the key to defense against intracellular pathogens

as viruses. The normal vaginal mucosa contains few T cells and APCs. The menstrual
cycle and menopause have no apparent effect on cellular localization or abundance in
the vagina. Mucosal tissues sequester the largest proportion of T lymphocytes in the
body. T cells and APCs are present throughout the human vaginal mucosa.

Inflamed vagina contains higher concentrations of several IEL, subpopulations

(TIA1+, CD8+T cells; CD4+T cells; and CD103+ lymphocytes) in comparison to
noninflamed tissues. Further, immature immune cell phenotypes, characteristically
found in the stroma, i.e., CD45RA and CD62 L, are also present in higher
concentrations in inflamed tissues. In contrast, fewer CD1a+ dendritic cells are found
in the epithelium of inflamed vaginal mucosa. CD57+ and CD56+NK cells kill virus-
infected as well as neoplastic cells, and are important first line mediators of immune
defense at a number of mucosal sites. Lastly, the human immune system is well-
equipped to detect and destroy virus –infected cells, using dendritic cells, T cells and
NK cells among others to do this.

For further readings:

1- Menez-Figueroa H, Anderson B. Vaginal innate immunity. Expert Rev of

Obstet Gynecol. 2011; 6:629-641.
2- Hilbert DW. Vaginal mucosal immunity. The Laboratorian. 2011;4. Internet.
3- Lyersen MB, Ank N, Melchjorsen J, Paludan SR. Expression of type III
interferon (IFN) in the vaginal mucosa is mediated primarily by dendritic cells

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 and displays stronger dependence on NF-kappa B than type 1 IFNs. J Virol.
2010; 84:4579-86.
4- Mura S, Kawana K, Schust DJ, Fujii T, Yokoyama T, Lwasawa Y and et al.
CD1d, a sentinel molecule bridging innate and adaptive immunity, is
downregulated by the human papillomavirus (HPV)ES protein: a possible
mechanism for immune evasion by HPV. J Virol. 2010; 84:11614-23.
5- Pudney J, Quayle AJ, Anderson DJ. Immunological microenvironments in the
human vagina and cervix: mediators of cellular immunity are concentrated in
the cervical transformation zone. Biology OF REPRODUCTION. 2005;
73:1253-1263.

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 Chapter Eight

Oxidative Stress in Vagina

Oxidative stress is an imbalance between prooxidants and antioxidants, with the

former prevailing. In a healthy body, ROS (reactive oxygen species) and antioxidants
remain in balance. Oxidative stress occurs when the generation of reactive oxygen
species and other radical species exceeds the scavenging capacity by antioxidants of
antioxidative agents in organism, due to excessive production of reactive oxidagen
species and/or inadequate intake or increased utilization of antioxidants.

Oxidants are generated in three main ways: (i) as a by-product of the bacterium's own
metabolic processes, (ii) as a key element of the innate immune response, and (iii) as
a result of response to other factors within the host environment that promote
oxidative stress, such as metal ions or commensal organisms that generate oxidants.

In normal cell function reactive oxygen species (ROS) is generated constitutively by

non-phagocytic cells and in response to injury, trauma or infection by phagocytic
cells.

The most commonly found and discussed oxidants in biological systems are the
reactive oxygen species (ROS), which include the superoxide anion (O2-·), hydrogen
peroxide (H2O2), and the hydroxyl radical (OH·), and the reactive nitrogen species
(RNS), which include nitric oxide (NO) and peroxynitrite (ONOO-). In addition,
sulfur- and chlorine- containing compounds are generated by antimicrobial effector
cells. The primary source of reactive oxygen species (ROS) is molecular oxygen
(O2). In aerobic cells, during electron transport, about 10% of reducing equivalents
from NADH leaks to produce superoxide (O2-·) hydrogen peroxide (H2O2). These
diffuse out of mitochondria and form the starting materials for subsequent generation
of ROS through a serial one electron acceptor process. RNS (NO) also fuel ROS
generation through a similar interaction with cytochrome c oxidase to give rise to O2-
·/H2O2 or react with O2-· to generate peroxynitrite (ONOO-).

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Under normal conditions, scavenging molecules known as antioxidants convert ROS
to H2O to prevent overproduction of ROS. There are two types of antioxidants in the
human body: enzymatic antioxidants, also known as natural antioxidants, which are
composed of superoxide dismutase, catalase, glutathione peroxidase and glutathione
reductase and non-enzymatic antioxidants, which are also known as synthetic
antioxidants or dietary supplements as antioxidant vitamins and minerals such as
vitamin C, vitamin E, selenium, zinc, taurine, hypotaurine, glutathione, beta carotene,
and carotene.

In oxidative stress, excess ROS (O2-·, H2O2, OH·) are involved in three main
activities:

a. Causing damage to cellular macromolecules (DNA, protein and membrane

lipids) due to their chemical reactivity.
b. Causing changes in membrane potential, within the inner mitochondrial
membrane directly causes mitochondrial permeability transition (MTP) and
c. Acting as a sink for cellular antioxidants.

Lactobacilli are a major component of the normal vaginal flora; this organism has
been implicated as one of the factors controlling the growth of other organisms in
that locale. Among the properties of most vaginal strains of lactobacilli is their
ability to release H2O2 in appreciable amounts in vitro. The H2O2 formed by
H2O2-generating bacteria can be autoinhibitory or be toxic to adjacent bacteria,
fungi, viruses, or mammalian cells, particularly in the presence of peroxidase and
a halide. The peroxidase uses the H2O2 of microbial origin to oxidize the halide,
forming the corresponding hypohalous acid or halogen, which has potent toxic
properties. Peroxidase activity has been detected in the vaginal fluid of most
women in amounts adequate to serve as the catalyst of the peroxidase-mediated
antimicrobial system in vitro, and the association of the vaginal overgrowth of a
number of microorganisms with a decrease in or loss of H2O2-generating
lactobacilli in the vagina in patients with bacterial vaginosis is compatible with a
requirement for microbial H2O2 production for local host defense. Hydrogen
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peroxide causes oxidative stress in bacterial cells, at least partially by oxidizing
sulphydrals, and by oxidizing free ions to produce hydroxyl radicals that react
with nucleic acids. The bactericidal effect of hydrogen peroxide is notably
enhanced in the acidic vaginal environment by the presence of myeloperoxidase
and halides, which are very abundant in the uterine mucus, especially during
ovulation. Lactobacillus spp. are believed to control the microflora by
production of hydrogen peroxide, bacteriocins, organic acids (e.g.1-lactate) and
nitric oxide. H2O2-producing Lactobacillus spp. inhibit Neisseria gonorrhoeae
growth and decrease catalase activity. Women with inhibitory strains of
lactobacilli are less likely to be infected with Neisseria gonorrhoeae.
Metabolism of 1-lactate (produced by lactobacilli) by Neisseria gonorrhoeae also
greatly enhances oxygen consumption, and this in turn may increase levels of
endogenous reactive oxygen species. Human immunodeficiency virus (HIV)-1 is
among the pathogens that can be inactivated by the peroxidase-H2O2-halide
system, and lactobacilli can provide the hydrogen peroxide for this effect.

The importance of the thioredoxin system as one of the major antioxidant defense
mechanisms in Trichomonas vaginalis, which causes vaginal trichomoniasis, was
confirmed by showing that the parasite responds to environmental changes
resulting in increased oxidative stress by upregulating thioredoxin and thioredoxin
peroxidases levels. Sequence data indicate that the thioredoxin reductase of
trichomonads differs fundamentally in structure from that of its human host and
thus may represent a useful drug target.

Mechanisms for coping with oxidative stress are crucial for the survival of all
organisms, particularly obligate human pathogens, which are routinely exposed to
oxidative killing by the host and inhabit an environment of unremitting oxidative
stress. Defense against oxidative stress are increasingly being recognized as
playing an important role in virulence.

A greater understanding of the oxidative stress response of microbial pathogens

may aid the future development of treatment and prevention strategies for disease
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caused by organisms because they possess a diverse range of defense mechanism
for sensing, avoiding, and removing oxidants.

References:

1- Quaye IK. Oxidative stress in human health and disease. In: Priti R. Editor.
Insight and control of infectious disease in global scenario. Croatia: In
Tech; 2012. P. 97-120.
2- Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female
reproduction. Reproductive biology and endocrinology. 2005; 3. Internet.
3- Lazar L. The role of oxidative stress in female reproduction and pregnancy.
In Lushchak V. Editor. Oxidative stress and diseases. Croatia: In Tech;
2012. P. 313-336. Internet.
4- Hracsko Z, Safar Z, Orvos H, Novak Z, Pal A, Varga IS. Evaluation of
oxidative stress markers after vaginal delivery or caesarean section. In vivo.
2007; 21:703-706. Internet.
5- Seib KL, Wup HJ, Kidd SP, Apicella MA, Jennings MP, McEwan AG.
Defenses against oxidative stress in Neisseria gonorrhoeae : a system
tailored for a challenging environment. Microbiology and molecular
biology reviews. 2006; 70: 344-361.
6- Klebanoff SJ, Watts DH, Mehlin C, Headley CM. Lactobacilli and vaginal
host defense: activation of the human immunodeficiency virus type 1 long
terminal repeat, cytokine production, and NF-kB. The journal of infectious
diseases. 1999; 179: 653-60.
7- O'Hanlon DE, Moench TR, Cone RA. BMC Infectious Diseases. Volume
11. 2011.

http://creativecommons.org/licenses/by/2.0

biomedcentral.com/bmcinfectdis/article/10.1186/1471/2334/11/200

The electronic version of this article is the complete one and can be found
online at: http://www.biomedcentral.com/1471-2334/11/200
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published 19 July 2011.

8- Schwebke JR, Burgess D. Trichomoniasis. Clinical microbiology reviews.

2004; 17:794-803.

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 Chapter Nine

Vaginal Atrophy

Vaginal atrophy, also known as vulvovaginal atrophy, is a condition that most

women experience much later in life. It is defined as an irreversible involution of the
mucous membranes and tissues of the vagina following the drop in estrogen that
commonly occurs in women during menopause. Estrogen levels begin to fall as the
menopause approaches. However, it can also develop during breast-feeding or
whenever the body decreases its production of estrogen. Aside from menopause and
breast-feeding, there are other factors that can cause decrease a woman's estrogen
levels resulting in vaginal atrophy. These factors include: stress, depression,
strenuous exercise, removal of the ovaries, and hormones that can affect a woman's
estrogen levels. Radiation and chemotherapy treatments to the pelvic area can also
result in lower estrogen levels. In addition, certain medications, such as
antihistamines, parasympathomimetics, and tricyclic antidepressants, can cause
significant dryness, that leads to vaginal atrophy. Women using anti-estrogen
medications, such as aromatase inhibitors for adjuvant treatment of breast cancer, are
more likely to experience severe symptoms of vaginal atrophy. It is important to
mention that patients with sjögren's syndrome have insufficient moisture throughout
their reproductive years that, despite adequate estrogen levels, can cause vaginal
dryness. Among risk factors that can lead to vaginal atrophy are: women who are not
sexually active, never giving vaginal birth, following child birth, and antiestrogen
medications as leuprolides, danazol, medroxyprogesterone, nafarelin, or tamoxifen.
Also smoking which limits blood circulation that can affect the amount of oxygen
that travels to the vagina and has an effect on estrogens in the body can cause vaginal
atrophy.

Estrogens are mainly produced by the ovaries. The urogenital sinus in the embryo is
the anlage of the trigone, urethra, and distal vagina and vulva; these are the structures
(which are of endodermal origin) that have the highest concentration of estrogen

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receptors in the female body. The upper vagina and other Mullerian elements (ie, the
uterus) are of mesodermal origin and, as such, they are not as exquisitely sensitive to
estrogen. Estrogen is responsible for maintaining the health of tissues within the
vagina, keeping them well lubricated to minimize irritation and also to make sexual
intercourse more comfortable. In markedly hypoestrogenic women (serum estradiol
‫ޒ‬10pg/ml) the vulva and vagina can be shown to exhibit early involutional change
within 12-24 months. Estrogen deficiency is the major cause of vaginal function
decline with age. This is supported by the fact that estrogen levels decline while
estrogen receptors in the vagina are unregulated after menopause. Among changes
correlated with declining estrogen are: vaginal length and diameter shrink, the
vaginal fornices disappear, and the rugal folds of the vagina are lost.

Typical findings on external genital exam include sparse pubic hair, decreased turgor
and elasticity of the vulva, fusion of the labia minora and eversion of the urethral
mucosa. The vaginal exam shows pale, smooth, shiny mucosa that may be friable and
bleed with minimal trauma. The vagina may be dry or there may be watery to
serosanguinous discharge. Fissure, diffuse or patchy erythema, petechiae, or visible
vessels are common findings. Cystocele, rectocele, or uterine prolapsed may also be
present.

Prior to menopause, the vaginal lining appears plump, bright red, and moist. As
estrogen levels decline, the lining of the vagina becomes thinner, drier, light pink to
bluish in color and less elastic. Vaginal atrophy leads to decreases in the size of the
uterus, ovaries, vaginal canal and vulva. Vaginal atrophy leads to the breakdown of
collagen, smooth muscle and elastin in the vagina. Blood flow to the vagina is also
reduced, leading to decreased transudation during sexual arousal as well as increased
risk of trauma and pain.

With age, the vaginal walls become less elastic, less rigid, and will considerably
thinner. If this happens, the vagina will become shorter. Progressive loss of vaginal
secretions, marked vaginal ischemia, thinning of the epithelial surface, and decreased
subcutaneous fat occur in the majority of older women due to loss of estrogen
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stimulation to the genitalia. With aging, vaginal secretions compose mainly of
vaginal transudate with some contribution from desquamated cells from the upper
genital tract (vagina, oviduct, endometrium), endocervical glands, and Bartholin's
glands. There is a decrease in quantity of vaginal secretions from a production rate of
3-4g/4h to 1.7g/4h. The physiopathological condition of vaginal atrophy is sustained
by a thinning of the mucous membrane epithelium, with a reduction in secretions of
the glandular epithelia in turn due to reduced hydration and loss of vaginal texture
and elasticity.

There are several symptoms to watch out for when dealing with vaginal atrophy as
dryness, irritation, burning sensation especially when urinating, hurried urination,
high susceptibility to urinary tract infections, urinary incontinence, bleeding after
intercourse, vaginal discharge, pain during sexual intercourse, and vaginal itching.

Typically, the vaginal pH during menopause tends toward values considerably higher
than those observed during fertility. Since vaginal atrophy has a direct effect on the
acidic environment of the vagina, there is a higher risk of infection, or vaginitis.

Vaginal atrophy can also cause sores, cracks and other abrasions around the vaginal
wall due to dryness and sensitivity.

Vaginal prolapsed can also happen. This means the whole vagina can drop out of its
position. This sometimes causes incontinence. The symptom could be swelling on the
opening of the vagina. The back wall can also have bulges.

The homologous of the urogenital sinus in the embryo (the urethra, trigone and distal
vagina and vulva) are extremely sensitive to estrogen deficiency and contraction of
the introitus becomes problematic. While lubricants may diminish dryness, it is the
involutional contraction of the introitus that predisposes women to progressively
worsening dyspareunia (pain during intercourse) and sexual dysfunction. The upper
two-thirds of the vagina is far less affected by atrophy as compared with the
compromise occurring at the fourchette. The vestibule actually loses much of its
concavity and, as the introitus contracts, it becomes somewhat of a narrowed, fibrotic
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channel or tunnel. This early atrophic change at the introitus, rather than the vagina
itself, is clinically quite important as it pertains to dyspareunia. This indicates that
vaginal atrophy result in reduced frequency of intercourse and major coital
dysfunction, including dyspareunia and postcoital bleeding.

The main form of prevention for vaginal atrophy is maintaining regular sexual
activity. This can help increase blood flow to a woman's vagina. The increased blood
flow can be used as a countermeasure to the lack of lubrication affecting vaginal
tissues.

Figure (9-1): A 67 years old woman demonstrating loss of elasticity and constriction
of vulvovaginal tissue.(quoted from www.google.com).

Women should be counseled to avoid tight-fitting clothing, synthetic undergarment,

and contact irritants such as scented soaps and feminine hygiene products. Regular
use of vaginal moisturizers (such as Replens) can help relieve vaginal itching and
irritation, while water-or silicone-based personal lubricants (such as Astroglide or
Eros) during intercourse can reduce dyspareunia. Estrogen-based treatment restores
vaginal epithelium, pH, and moisture, and should be considered when non-hormonal
treatments fail.

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For further readings:

1- Alessandro D, Milani G, Milani M. Postmenopausal vaginal atrophy: non-

hormonal therapy with a moisturizing bioadhesive gel.

08-0132_tr00E_M2volXIIIno2 2003, pg 14-16. Doc

2- Cenzonl M. Vaginal atrophy. 2012.Internet.

3- Aging and the vagina.

http://www.revirgination.net/vagina-aging.html

got from internet 9-11-2012

4- Stöppler MC, Nettleman MD. Vaginal dryness and vaginal atrophy. 2012.
Internet.

MedicineNet.com

5- Nachtigall L, Nachtigall M, Goren J, Loewenstein J. Update on vaginal

atrophy. 2005. Internet.
6- Kaunitz AM. Sexual pain and genital atrophy: breaking down barriers to
recognition and treatment. 2001. Internet.
7- Utian WH. The neglected symptom: vaginal dryness. 2002. Internet.
8- Johnston SL, Farreli SA. The detection and management of vaginal atrophy. J
Obstet Gynecol. 2004;26:503-8.
9- Hobenbaus MH. Vulvovaginal atrophy: a common-and-commonly overlooked-
problem.

Medicine and Health/RHODE ISLAND.

2011;94:138-140.

10-Freedman MA. Vaginal pH, estrogen and genital atrophy. 2008. Internet.

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11-Bachmann GA, Notelovitz M, Gonzalez SJ, Thompson C, Morecraft BA.
Vaginal dryness in menopausal women: clinical characteristics and nonhormonal
treatment. Clinical Practice in Sexuality. 2012;7. Internet.

12-Marzejon KW. Low estrogen levels lead to inflammation. 2005. Internet.

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 Chapter Ten

Tumors of Vagina

A vaginal tumor is an abnormal growth of tissue in the vagina. Vaginal cancer is an

uncommon disease in which cancer cells grow from the cells of the vaginal lining.
Vaginal cancer occurs when vaginal cells divide without control or order. Normally,
cells divide in a regular manner. If cells keep dividing uncontrollably when new cells
are not needed, a mass of tissue, called a growth or tumor, forms. The term cancer
refers to malignant tumors, which can invade nearby tissue and spread to other parts
of the body. A benign tumor does not invade or spread. Benign tumors can still create
problems by pressing on surrounding tissue, it is rare that one would be life-
threatening.

Tumors of the vagina are generally classified into squamous, glandular, melanocytic,
and mesenchymal neoplasms.

Benign tumors of the vagina are usually cystic arise from the mesonephric or
paramesonephric ducts and are usually an incidental finding on examination of the
anterolateral wall of the vagina (Gartner's duct cyst). An ulcerative lesion may occur
at the site of direct trauma, following an inflammatory reaction caused by prolonged
retention of a pessary or other foreign body, or, occasionally, following a chemical
burn. Granulomatous venereal diseases seldom affect the vagina. Endometriosis that
penetrates the cul-de-sac of Douglas into the upper vagina cannot be differentiated
from cancer except by biopsy.

Many benign conditions may masquerade as neoplastic lesions and only through
colposcopy and biopsy will the precise nature be ascertained. Benign vaginal
neoplasms may be divided into cystic or solid lesions and a third category best
described as related conditions.

Cystic tumors involve Gartner's duct cyst, paramesonephric duct cyst, inclusion cyst,
and endometriosis.
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Gartner's duct cysts develop as a result of incomplete regression of the mesonephric
or wolffian duct during fetal development. When present, these cysts may be
multiple, and are located submucosally along the lateral aspects of the upper vagina.
Histologic evaluation reveals nonsecretory, columnar epithelium.

Paramesonephric duct cysts are lined with secretory epithelium resembling

endocervix or fallopian tube, suggesting müllerian origin. These cysts may be found
anywhere in the vagina and frequently contain mucus.

Figure (10-1): Vulvar cystic mass. Paramesonephric duct cyst or Gartner's duct cyst.
(quoted from www.google.com).

Inclusion cysts of the vagina result from mucosa trapped in the submucosal area by
surgical procedures such as episiotomy, colporrhaphy, or trauma including child
birth. These cysts are lined with squamous epithelium and contain keratin and
squamous debris. Foreign- body reaction and inflammation surround the cyst.

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Figure (10-2): Inclusion cyst of vagina. (quoted from www.google.com).

Endometriosis in the vagina may develop at the site of a previous operation or as

primary implants. Nodularity of the posterior vaginal fornix may represent
endometriotic implants of the posterior cul-de-sac and may eventually erode or grow
into the vaginal mucosa.

Figure (10-3): Endometriosis cyst of vagina. (quoted from www.google.com).

Solid tumors include leiomyoma, fibroepithelial polyp, condyloma acuminatum, and

rare lesions.

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Vaginal leiomyomas or fibromyomas are rare lesions usually located in the anterior
vaginal wall. These lesions are benign smooth muscle neoplasms, usually solitary and
in many cases asymptomatic. Histologically, they resemble leiomyoma of other
origins. Proposed sites of origin include vaginal smooth muscle, local arterial
musculature, or smooth muscle of the bladder or urethra.

Figure (10-4): Leiomyoma of anterior vaginal wall, with pedicle. (quoted from
www.google.com).

Fibroepithelial polyps of the vagina are uncommon and usually asymptomatic. In

infants and young girls, sarcoma botryoides must be ruled out. Fibroepithelial polyps
of the vagina are usually small and may be multiple. During pregnancy, these lesions
may become enlarged, very edematous, and bizarre in appearance. Histologically, the
polyps are composed of a squamous epithelial surface with a fibrovascular stalk and
edematous stroma. Proposed etiologies include stromal proliferation or granulation
tissue reaction as a result of local injury.

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Figure (10-5): Vaginal fibroepithelial polyp in a newborn girl. (quoted from
www.google.com).

Condyloma acuminatum represents the clinical manifestation of human papilloma

virus infection. These lesions may be associated with condylomata of the cervix and
vulva or appear only as vaginal lesions.

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Figure (10-6): Condyloma acuminatum (venereal warts) of vagina. (quoted from
www.google.com).

Among rare lesions is prolapsed of the fallopian tube into the vagina following
hysterectomy and it may be alarming as the edematous fimbria may appear very
much like a well-differentiated adenocarcinoma to the unsuspecting. In addition,
hemangiopericytoma, neurofibromas, mixed cell tumors, granular cell myoblastoma,
myxoma, rhabdomyoma, and benign cystic teratoma are neoplasms found in the
vagina.

Related conditions involve urethral caruncle and diethylstilbestrol associated changes

of the vagina.

Urethral caruncles present as localized, red, friable lesions at the urethral meatus.
They are generally seen in the postmenopausal women and are thought to result from
a localized area of prolapsed of the urethral mucosa with secondary inflammatory
changes.

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Figure (10-7): Urethral caruncle. (quoted from www.google.com).

Diethylstilbestrol (DES) associated changes of the vagina that show nonmalignant

structural changes of the cervix and vagina include cockscomb, cervical collar,
cervical hood, pseudopolyp, and hypoplastic cervix have been described in 25-48%
of in utero DES exposed women. Vaginal epithelial changes, predominantly adenosis
have been reported in 34-65% of in utero exposed women. Adenosis may be
described as the retention of müllerian-derived granular epithelium in the vagina after
vaginal embryogenesis is completed. Recently, vaginal adenosis has been reported as
a result of laser therapy of the vagina for condyloma or dysplasia. This should not be
confused with DES related adenosis.

The benign vaginal lesions are estrogen dependent. Malignant conversion is

extremely rare. When large, symptoms can include vaginal discharge or bleeding,
dyspareunia, or urinary retention.

Vaginal cancer usually begins with precancerous changes. Precancerous lesions in the
vagina are often called vaginal intraepithelial neoplasia (VAIN). Intraepithelial
means that the precancerous cells are only in the lining layer of the vagina (the
epithelium). But these changes may develop into invasive vaginal cancer in some
women. It is estimated that 9 of every 10 truly premalignant lesions of the vagina

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occur in women over 40 years of age. Also the incidence of such lesions may be
rising in younger women, possibly a reflection of the increased incidence of infection
with human papilloma virus generally noted in the younger population. Vaginal
premalignant lesions are classified as VaIN 1, 2, or 3, corresponding to mild,
moderate or severe dysplasia, respectively. VAIN1 is the thinnest, while VAIN3 is
the thickest and also called carcinoma in situ or stage 0 vaginal cancer. There is now
a trend to classify these lesions as low grade or high grade intraepithelial neoplasia
based on their histology. The propensity of these lesions to progress to a higher grade
is less well established than for CIN, but evokes the same concern.

Vaginal cancer is a rare type of cancer that forms in the vaginal tissue in women.
Several risk factors for vaginal cancer have been identified which involve being 60 or
older, smoking, human papilloma virus (HPV) infection, human immunodeficiency
virus (HIV) infection, vaginal pessary use which is a device used to treat a uterine
prolapse, diethylstilbestrol (DES) exposure which is used to prevent miscarriage and
studies show that women whose mothers were given DES while pregnant are at a
greater risk of developing vaginal and a few other cancers, history of cervical cancer,
history of precancerous conditions in the cervix or vagina, vaginal adenosis when
cells lining the vagina look like those found in the cervix and uterus, early
hysterectomy, and prior radiation.

The third edition AJCC (the American Joint Committee on Cancer) staging for
cancers of the vagina states:

Stage I vaginal cancer is defined as tumor confined to vagina with no lymph node
metastases.

Stage II vaginal cancer is defined as tumor which invades paravaginal tissues but not
to pelvic wall with no lymph node metastases.

Stage III vaginal cancer is defined as tumor extending to pelvic wall, or either tumor
confined to the vagina or tumor with lymph node metastases, invading paravaginal
tissues.
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Stage IV vaginal cancer is defined as either tumor invasion of the mucosa of the
bladder or rectum or extension beyond the true pelvis.

Primary cancers of the vagina are rare, representing approximately 3% of

gynecologic cancers. Approximately 85% are squamous cell cancers, and the
remainders , in decreasing order of frequency, are adenocarcinomas, sarcomas, and
melanomas. A tumor should not be considered a primary vaginal cancer unless the
cervix is uninvolved or only minimally involved by a tumor obviously arising in the
vagina. By convention, any malignancy involving both cervix and vagina that is
histologically compatible with an origin in either organ is classified as cervical
cancer.

Secondary carcinoma of the vagina is seen more frequently than primary vaginal
cancers. Secondary, or metastatic, tumors may arise from cervical, endometrial, or
ovarian cancer, breast cancer, gestational trophoblastic disease, colorectal cancer, or
urogenital or vulvar cancer. Extension of cervical cancer to the vagina is probably the
most common malignancy involving the vagina.

The majority of invasive malignant lesions present with a clinically apparent lesion.
The colposcopist may observe granular red lesions, white epithelium with or without
abnormal vessels, ulceration, tumor formation and intraepithelial or subepithelial
hemorrhage in invasive lesions. Most of these cancers are squamous, although
adenocarcinoma and others (melanoma) are reported.

Squamous cell carcinoma may be ulcerative or exophytic. It usually involves the

posterior wall of the upper third of the vagina, but may be multicentric. Direct
invasion of the bladder or rectum may occur. The incidence of lymph node
metastases is directly related to the size of the tumor. The route of nodal metastases
depends on the location of the tumor in the vagina. Tumors in the lower third
metastasize primarily to the inguinal lymph nodes. Cancers of the upper vagina,
which is the most common site, metastasize in a manner similar to cancer of the
cervix. The lymphatic drainage of the vagina consists of a fine capillary meshwork in

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the mucosa and submucosa with multiple anastomoses. As a consequence, lesions in
the middle third of the vagina may metastasize to the inguinal lymph nodes or
directly to the deep pelvic lymph nodes.

Figure (10-8): Squamous cell carcinoma-vagina. (quoted from www.google.com).

Figure (10-9): Signs of vulval squamous cell carcinoma. (quoted from

www.google.com).

Melanomas and sarcomas of the vagina metastasize like squamous cell cancer,
although liver and pulmonary metastases are more common. Nevi rarely occur in the
vagina; therefore, any pigmented lesion of the vagina should be excised or biopsied.
The anterior surface and lower half of the vagina are the most common sites. Grossly,
the tumors are usually exophytic and described as polypoid or pedunculated with
secondary necrosis.
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Figure (10-10): Malignant melanoma of the vagina. (quoted from www.google.com).

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Figure (10-11):Nodules of epidemic Kaposi's sarcoma of vagina. (quoted from
www.google.com).

Sarcomas of the vagina occur in children younger than 5 years of age and in women
in the fifth or sixth decades. Embryonal rhabdomyosarcomas or sarcoma botryoides,
replace the vaginal mucosa of young girls and consist of polypoid, edematous,
"grapelike" masses that may protrude from the vaginal introitus. Leiomyosarcomas,
reticulum cell sarcomas, and unclassified sarcomas occur in older women. The upper
anterior vaginal wall is the most common site of origin.

Clear cell adenocarcinomas arise in conjunction with vaginal adenosis, in recent

years, has been detected most frequently in young women with a history of exposure
to diethylstilbestrol (DES) in utero. Adenosis vaginae and adenocarcinoma do occur
in sexually mature and postmenopausal women. Metastatic adenocarcinoma to the
vagina may arise from the urethra, Bartholin's gland, the rectum or bladder, the
endometrial cavity, the endocervix, or an ovary, or it may be metastatic from a distant
site. Hypernephroma of the kidney characteristically metastasizes to the anterior wall
of the vagina in the lower third.
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Figure (10-12): Vagina Clear Cell Adeno CA 1. Tubules, ductules, and cystic spaces.
(quoted from www.google.com).

Figure (10-13): Vaginal clear cell adenocarcinoma. (quoted from www.google.com).

Vaginal cancer is often asymptomatic, discovered by routine vaginal cytologic

examination, and confirmed by biopsy after delineation of the location and extent of
the tumor by colposcopy.

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Symptoms of vaginal cancer include: bleeding or discharge not related to menstrual
periods, pain or difficulty when urinating, pain during intercourse, pain in pelvic area,
new or worsening constipation, weight loss, and a mass in the vagina that may be felt.

For further readings:

1- Vorick L J. 2012. Internet.

Medline Plus

A service of the U.S. National Library of Medicine

NAIH National Institutes of Health

2- Treatment options for precancerous lesions in the vagina.

Women's Cancer Network. 2013.

info@foundationforwomenscancer.org.

3- Dolson L. A guide to gynecologic tumors. 2001. Internet.

4- Larsen J, Davis G. Vaginal colposcopy: colposcopic clues for the identification
of benign and malignant disease. 2012. American Society for Colposcopy and
Cervical Pathology.

The Society for Lower Genital Tract Disease since 1964.

5- Beahrs OH, Henson DE, Hutter RVP, Myers MH. AJCC Cancer staging
manual. American Joint Committee on Cancer. Philadelphia. Lippincott. 1988.
6- Crowther ME, Lowe DG, Shepherd JH. Vaginal cancer. 2012. Internet.
7- Fayed L. Vaginal cancer risk factors. Risk factors you should know about.
2011. Internet.
8- Delmore JE. Benign neoplasms of the vagina. Glob. libr. women's med. 2008.
Internet.
9- Vaginal cancer

(Cancer of the vagina)

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Got from internet in 1-1-2013

Resources:

American Cancer Society

http://www.cancer.org/

Gynecologic Cancer Foundation

http://www.thegcf.org/

Canadian Resources:

Canadian Cancer Society

http://www.cancer.ca/

Canadian Women's Health Network

http://www.cwhn.ca/

10-Chieng D, Hui P.Cytology and surgical pathology of gynecologic neoplasms.

Humana Press. 2011. P15. Internet.

http://www.springer.com/978-1-60761-163-9

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