FEMALE REPRODUCTIVE SYSTEM (I)
Marylee M Kott, MD
Reading: Gartner and Hiatt pp 353, 364-372; Gartner, Hiatt, Strum pp 294-309
Learning Objectives: Identify the epithelial lining of the different areas of the female reproductive
system. Learn the general morphologic changes of the endometrium during the menstrual cycle and in
other physiologic conditions
Key Words (For all Female Reproductive System): amnion, anchoring villus, antrum, areolar, sebaceous
gland, atretic follicle, cervical canal, cervix, chorionic plate, chorionic villi, ciliated cells of the oviduct,
corona radiata, corpus albicans, corpus luteum, cortex of ovary, cumulus oophorus, cytotrophoblast,
decidua basalis, decidual cells, endocervix, endometrial glands, endometrium, menstruating stage
endometrium: proliferative stage endometrium: secretory stage, follicular cell, germinal epithelium,
granulosa cell, granulosa lutein cells, interlobular ducts, intralobular (alveolar) ducts, lactiferous duct and
sinus, mammary gland, maternal blood supply, medulla of ovary, membrane granulosa, myometrium,
nipple, oocyte, ovary, oviduct, ampulla oviduct, fimbriae oviduct, infundibulum oviduct, isthmus, peg
cells, placenta, plicae, primary follicle, primordial follicle, secondary follicle, secretory alveolus, stem
villus, stratum basalis, stratum functionalis, syncytiotrophoblast, theca externa, theca folliculi, theca
interna, theca lutein cells, uterus, vagina, zona pellucida
VULVA:
 Defined as “external female genitalia”
 External to hymen.
 Extends anteriorly to include pubis.
 Extends posteriorly to the anus.
 Extends laterally to the inguinal-gluteal folds.
 Includes: mons pubis, labia majora and minora, clitoris, hymen, the vestibule, Skene’s and
Bartholin’s glands and ducts, minor vestibular glands and the urethral meatus.
 Covered by keratinized, stratified squamous epithelium.
 Hymen is thinly keratinized on external surface, but on vaginal surface has non-keratinized
mucosa rich in glycogen.
 Mons pubis and lateral aspects of labia majora
 Changes at puberty.
 Increase subcutaneous fat and develop coarse curly hair.
 Concomitant maturation and development of sebaceous and apocrine glands.
 Lateral aspects of the labia minor and inner aspects of prepuce (which do not have hair) also
show maturation of sebaceous and apocrine glands at puberty.
 Eccrine sweat glands, which are primarily involved in heat regulation, function before
puberty.
 Labia majora contain both smooth muscle and fat.
 Labia minora are devoid of fat but are rich in elastin and vessels (erectile tissue).
 Clitoris is the descendent of the embryonic phallus
 No sebaceous, apocrine or eccrine sweat glands.
 Stroma has two conjoined corpora cavernosa which branch near the base of the clitoris
and lie along the pubic rami as divided crura.
 Bartholin’s glands are tubulo-alveolar glands
 Acini are composed of simple columnar mucus-secreting epithelium.
 Drained by a duct lined by a transitional epithelium which becomes non-keratinized
stratified squamous epithelium near its exit.
 Bartholin’s glands are equivalent to the Cowper’s glands in the male.
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Skene’s glands are composed of pseudostratified mucus-secreting columnar epithelium.
 Ducts are lined by transitional-type epithelium.
 Skene’s glands are equivalent to the prostate in male.
VAGINA:
 Wall consists of three layers
1. Mucosa (epithelium and lamina propria)
2. Muscularis
3. Adventitia
 Mucous membrane (mucosa)
A. Is thick and shows a characteristic pattern of folds (rugae) separated by furrows of variable
depth on gross examination.
 Two longitudinal (anterior and posterior) and multiple transverse furrows.
 The rugal pattern of the mucosa produces an undulating appearance on microscopic
examination, in contrast to the flat surface of the cervix.
 Consists of non-keratinized stratified squamous epithelium.
 Composed of deep (basal and parabasal cells), intermediate and superficial layers.
 Cells proliferate and mature in response to stimulation by ovarian or exogenous hormones.
 At the peak of estrogenic activity, e.g., the preovulatory phase, the vaginal mucosa
attains maximal thickness, and superficial cells containing large amounts of
intracytoplasmic glycogen predominate in vaginal smears.
 Progesterone inhibits maturation of vaginal epithelium; consequently, the intermediate
cells predominate in vaginal smears when the circulating levels of progesterone are high,
e.g., during the post-ovulatory phase of the menstrual cycle or during pregnancy.
 The lamina propria is loosely textured and contains elastin and a rich venous and lymphatic
network.
 The vaginal mucosa contains no glands.
 Surface is lubricated by fluids, which pass directly through the mucosa, and by cervical
mucus.
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Muscularis - composed of smooth muscle fibers arranged in an outer longitudinal layer and an
inner layer with a spiral-like course which appears in microscopic sections as somewhat circular
in direction.
Adventitia - thin coat of dense connective tissue adjoining the muscularis. It merges with the
stroma which connects the vagina to the adjacent structures.
THE UTERUS:
Anatomy: Divided into corpus, isthmus (lower uterine segment) and cervix. The vagina is fused
circumferentially and obliquely around the distal part of the cervix dividing it into upper, supra-vaginal
and lower, vaginal portion.
 Cervix:
 Is composed of an admixture of fibrous, muscular, and elastic tissue.
 Fibrous connective tissue is the predominant component.
 Non-keratinizing stratified squamous epithelium lines the vaginal portion of the cervix
(ectocervix or exocervix).
 Is referred to as the native portio epithelium.
 Is remodeled by proliferation, maturation, and desquamation during the reproductive
period.
 Estrogen in general stimulates this process while progesterone inhibits maturation of
the upper midzone level of the epithelium.
 The mature cervical epithelium is similar to the vagina epithelium but under normal
conditions lacks the rete pegs seen in the vagina.
 It is divided into three zones:
1. The basal or the germinal cell layer - responsible for the continuous epithelial
regeneration.
2. The midzone or the stratum spinosum - dominant portion of the epithelium.
3. The lower third of the midzone, parabasal layer, also contribute to the epithelial
growth.
 Cells that are involved in a process of ascending maturation occupy the upper portion of
the midzone.
 They are referred to as intermediate cells when exfoliated.
 They do not divide.
 The superficial zone contains the most mature cell population.
 Are glycogen-rich.
 The upper superficial cells virtually lack desmosomes, which explains their loose
attachment and easy desquamation.

Columnar Epithelium lines the cervical canal (endocervix)
 Consists of a single layer of mucin-producing columnar epithelium, which lines the surface
and its cleft-like infolding (glands).
 Cells have basally placed nuclei and tall, uniform, finely granular cytoplasm filled mucinous
droplets.
 Mitoses are not seen under normal conditions.
 Does not show obvious morphologic changes during the menstrual cycle, however, its
viscoelastic secretory product, the cervical mucus, is subject to profound cyclic changes.
 Secretions are profuse, watery, and alkaline, facilitation sperm penetration under estrogen
stimulation.
 Secretions are scant, thick, and acidic, and contain numerous leukocytes and act as a barrier
for sperm penetration during the post-ovulatory phase (progesterone).
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Transformation Zone:
 Defined as the area on the cervix where the glandular tissue (columnar epithelium) is being
replaced by squamous epithelium.
 The junction between the two types of epithelium is labeled the squamocolumnar junction.
 The exposed endocervical tissue is often referred to as “ectropion”.
 Zone moves between ectocervix and endocervix at different stages of life:
 Birth - endocervical mucosa resides on the exocervix (ectocervix) in two thirds of the
infants, but quickly moves back into the anatomic endocervical canal where in most girls
it remains until menarche.
 Puberty - the endocervical mucosa again moves out onto the ectocervix, usually more
predominantly on the anterior portion than on the posterior part.
 After menarche - ectropion occurs throughout the reproductive years and there is
gradual replacement of the endocervical mucosa by squamous epithelium.
 perimenopausal - the squamocolumnar junction is usually concealed within the
endocervical canal above the external os
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Two mechanisms are thought to be operative in transforming the endocervical mucinous
epithelium into squamous epithelium:
1. Squamous epithelialization: The direct ingrowth of the mature native squamous
epithelium from the ectocervix.
2. Squamous metaplasia: The proliferation of undifferentiated sub-columnar reserve cells
of the endocervical epithelium and their gradual transformation into a fully mature
squamous epithelium. Has a random distribution within the ectropion, reflecting its
asynchronous development.
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Nabothian cysts are formed when the orifices of endocervical clefts become obliterated by
the proliferating surface squamous epithelium. When the obstructed clefts are adjacent to
each other “tunnel clusters” will be formed.
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The clinical identification of the transformation zone is important because almost all cervical
squamous neoplasia and their precursors begin in this area.
 The extension and limits of the precursor lesions coincide with the distribution of the
transformation zone.
 Visualized directly by colposcopic examination.
 Biopsy or local destruction of the lesion may be curative if non-invasive.
During the reproductive period, the transformation zone is located on the exposed portion of
the cervix and can be visualized with the aid of the colposcope.
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Cervical Stroma:
 Mainly fibrous tissue admixed with elastin through which run a few strands of smooth
muscle.
 At the upper end of the endocervix the superficial fibrous stroma blends imperceptibly into
the endometrial stroma of the lower uterine segment.
 Decidualization of the stroma, either patchy or diffuse, occurs in about one-third of pregnant
women.
 Normally populated by lymphocytes as part of the mucosa associated lymphoid tissue
(MALT). Secrete mainly immunoglobulin A.
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Endometrium:
 Undergoes cyclic morphologic and physiologic changes during the reproductive period.
 These are particularly evident in the upper two-thirds of the mucosa, the so-called
functionalis layer.
 Morphologic alterations are minimal in lower one-third, the basalis layer, as well as most of
the lining of the lower uterine segment and cornual regions.
 Has an abundant vascular supply originating from the radial arteries of the subjacent
myometrium which:
 Penetrate the endometrium at regular intervals and give rise to the basal arteries.
 And, the arteries in the functionalis layer are referred to as spiral arterioles.
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Consists of surface epithelium and stroma containing simple tubular glands that sometimes
branch.
 The epithelial cells are simple columnar and are a mixture of ciliated and secretory cells.
 The epithelium of the endometrial glands is similar to the surface epithelium, but ciliated
cells are rare in the base of the glands, except in perimenopausal stage (Ciliary
metaplasia).
The endometrial stroma underlying the surface epithelium and present between the glands is
a specialized connective tissue which responds to the hormonal changes during the
endometrial (menstrual) cycle.
 During the proliferative phase, the stromal cells are small and have a scant cytoplasm.
 During the secretory phase, progesterone stimulation causes the stromal cells to enlarge
and assume rounder margins (pre-decidual cells).
The endometrial cycle follows a precisely scheduled series of morphologic and physiologic
events characterized by proliferation, secretory differentiation, degeneration, and regeneration
of the uterine lining.
 Epithelial, stromal, and presumably endothelial cells are controlled by cyclically released
ovarian estradiol and progesterone.
 Mediated through specific receptors which are concentrated in nuclei.
 Estradiol promotes the synthesis of both estrogen and progesterone receptors.
 Progesterone inhibits the synthesis of estrogen receptor.
THE ENDOMETRIAL CYCLE:
 PROLIFERATIVE (FOLLICULAR) PHASE (6TH TO 14TH DAYS):
 Follows the menstrual phase (see below).
 Preovulatory endometrium is characterized by proliferation of glandular, stromal and
endothelial cells leading to an increase in the volume of the uterine mucosa.
 The changes are under the influence of estrogen which increases DNA synthesis.
 The maximal number of endometrial cells engaged in DNA synthesis is seen between cycle
days 8 and 10.
 Corresponds to maximal mitotic activity, peak plasma estrogen levels and maximal
concentration of estrogen receptors.
 Daily morphologic changes are not sufficiently obvious to permit accurate dating during
the proliferative phase.
Uterus. Follicular phase.
SECRETORY (LUTEAL) PHASE (15TH TO 28TH DAYS):
 Following ovulation the estrogen-primed endometrium undergoes rapid secretory differentiation
under the influence of progesterone.
 The first sign of secretory activity in the endometrium is the development of subnuclear
cytoplasmic vacuoles.
 Progesterone stimulates the gland cells to secrete glycoproteins.
 The glands become highly coiled, and the epithelial cells accumulate glycogen (cytoplasmic
vacuoles).
 Later glycoprotein secretory products dilate the lumens of the glands.
 The endometrium reaches its maximum thickness (5mm) as a result of secretions and edema.
 The elongation and convolution of the spiral arterioles continues and they extend into the
superficial portion of the endometrium.
 The stromal cells assume their pre-decidual appearance.
 Later, the endometrium is infiltrated by “stromal granulocytes”.
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The morphologic changes are very reliable for accurately dating the endometrium.
A.
B.
Uterus. Luteal phase.
MENSTRUAL PHASE (1ST TO 5TH DAYS):
 A normal menstrual period lasts 3 to 5 days.
 The endometrial mucosa rapidly degenerates and 50% of the endometrial detritus is expelled in
the first 24 hours of menses.
 The functionalis becomes gradually detached from the underlying basalis.
 Starts from the fundus and extends toward the isthmus.
 The degenerating epithelium covering the surface of the aggregated stromal cells gives rise to the
so-called stromal balls.
 Tissue shedding is followed by regeneration (re-epithelialization) which occurs by extension of
the residual glandular epithelium over the denuded surface.
Uterus. Menstrual phase
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Gestational Endometrium:
 The secretory phase endometrium undergoes further morphophysiologic development to
provide an appropriate environment for the conceptus.
 Between days 22 and 28 the endometrium displays hypertrophic and hypersecretory features.
 The endometrium is characterized by:
 Glandular ferning with epithelial and intraluminal secretions.
 Exaggeration of these changes produces the so-called Arias-Stella reaction in which the
epithelial cells exhibit marked nuclear pleomorphism and hyperchromatism
 Transmucosal decidual reaction.
 Contains the implantation site (intrauterine pregnancy) which is composed of thick walled
vessels showing fibrinoid changes and is infiltrated by trophoblastic cells.
 The implantation site is the only reliable histologic sign of early pregnancy in which
chorionic villi may not have developed yet.

Inactive Endometrium:
 The mucosa is as thick as early to mid-proliferative phase endometrium but is devoid of
morphologic features of active proliferation or secretion.
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Such changes are usually found in the early postmenopausal years when ovarian hormonal
stimuli have decreased to levels not sufficient to induce endometrial proliferation.
Atrophic Endometrium:
 The mucosa is thin and measures about half or less the thickness of the basal layer of cyclic
endometrium.
 The glands are oriented parallel to the surface.
 The lining epithelium is low and cuboidal.
 The glands may become cystically dilated.
 The stroma is often collagenized.
8.
Myometrium:
 The bulk of the myometrium is comprised of smooth muscle cells, but an important
contribution is made by extracellular components such as collagen and elastin.
 Consists of 3 layers:
1. Outer longitudinal muscle layer,
2. Inner circular submucosal muscle layer.
3. Interposed thick middle layer.
 It is richly populated by vessels and composed of randomly interdigitating fibers.
 During pregnancy the uterus undergoes a 20-fold increase in size and weight both by
hypertrophy and to a lesser extent by hyperplasia.
1. Appears to be largely prompted by estradiol.
2. Progesterone probably functions to inhibit uterine contraction during gestation.
9. Serosa:
 About ¾ of the uterus is covered by a flat mesothelial lining.
 The remaining is the adventitia that connects the uterus to the surrounding organs.
THE FALLOPIAN TUBE (OVIDUCT):
1. Anatomy:
 Extends from the area of its corresponding ovary anteriorly and medially to its terminus in the
posterosuperior aspect of the uterine fundus.
 At the ovarian end opens into the peritoneal cavity and is composed of about 25 irregular fingerlike extensions, the fimbriae.
 The fimbriae attach to the expanded end of the tube, the infundibulum, which is about 1 cm long
and 1 cm in diameter distally.
 The infundibulum narrows gradually to 4 mm in diameter and merges medially with the
ampullary portion of the tube, which extends about 6 cm, passing anteriorly as it loops around
the ovary.
 At a point characterized by relative thickness of the muscular wall, the isthmic portion begins and
extends some 2 cm from the uterus.
 Within the myometrium, the interstitial portion extends as a 1 cm intramural segment until it
joins the extension of the endometrial cavity at the uterotubal junction.
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2. Histologically the fallopian tube is composed of three layers:
a. The mucosal layer: lies directly on the muscularis.
consists of a luminal epithelial lining and a scant underlying lamina propria.
The number of mucosal folds (plicae) increases from about six in the interstitial portion to a
dozen or more in the isthmus.
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In the ampulla, the plicae are frond-like and delicate with both secondary and tertiary branches
present; the infundibular plical pattern is similar.
The mucosa is lined by a simple columnar epithelium which is composed of the ciliated,
secretory, and the intercalary or peg cells. A few lymphocytes are also present in the lining.
The epithelium exhibits changes associated with the menstrual cycle.
During the proliferative phase, as a response to increased estrogen levels, the cilia increase in
number and height.
During the secretory phase the cilia decrease in number and height while the secretory cells
actively secrete into the lumen.
The lamina propria contains vessels and spindle or angular stromal cells which may become
decidualized in about 10% of pregnancies.
 The muscularis is composed of smooth muscle bundles roughly arranged into inner circular
and outer longitudinal layers.
 The serosa: composed of a flat mesothelial lining covering the tube. Walthard rests are
urothelial metaplastic foci (arising from the mesothelial cells) commonly found in the serosa
of the fallopian tube and rarely in the ovarian surface epithelium and pelvic peritoneum. They
are solid but may become cystic.
FEMALE REPRODUCTIVE SYSTEM (I) LABORATORY
SLIDE 22, VAGINA:
The vagina is lined by a non-keratinized stratified squamous epithelium. The superficial cells contain
large amounts of intracytoplasmic glycogen. Their cytoplasm is clear or “empty” because glycogen is
washed out (water-soluble) during tissue preparation. The surface has an undulating appearance
reflecting the mucosal folds (rugae). The lamina propria is loosely textured.
The muscularis is composed of smooth muscles fibers. The arrangement of the fibers into outer
longitudinal and inner circular layers many not be easily seen in the slides. Also the amount of fibrous
tissue is increased in the section because the sample was taken from a patient with uterine prolapse. No
glands are present in the vagina.
SLIDE 77, UTERINE CERVIX:
Follow the mucosal lining:
The ectocervix (portio vaginalis) is lined by a non-keratinized stratified squamous epithelium. The
superficial cells have intracytoplasmic glycogen (clear cytoplasm).
The endocervical surface and the infoldings (glands) are lined by a simple columnar mucin-producing
epithelium. The cytoplasm is light blue. The nuclei are small and present in the basal portion of the cells.
A few ciliated cells may be found in the lining.
The transformation zone has numerous patches lined by a non-keratinized stratified squamous
epithelium reflecting either squamous re-epithelialization or squamous metaplasia. Some of these patches
of squamous epithelium occlude the openings of the endocervical infoldings leading to the formation of
Nabothian cysts.
The lamina propria has numerous lymphocytes. The wall of the cervix has a few smooth muscle
bundles.
SLIDE 78, UTERUS (PROLIFERATIVE ENDOMETRIUM):
The endometrium is composed of glands and stroma. The lower portion of the endometrial mucosa is
slightly bluer than the superficial portions.
The lower portion is the basalis that usually exhibits minimal morphologic changes during the
endometrial cycle.
The superficial two-thirds of the endometrium, the functionalis, has tubular (straight) glands with
minimal tortuosity. They are lined by a simple columnar epithelium that may be pseudostratified in some
areas. Numerous mitoses are present, reflecting the proliferative activity. Some of the lining cells, close
to the surface openings of the glands may have cilia.
The stroma is composed of cells with minimal cytoplasma and small round or oval nuclei. Mitoses
may be seen in stromal cells.
The endometrial-myometrial junction is somewhat sharp. The myometrium is composed of smooth
muscle fibers and contains numerous large vessels. The serosa may not be present on your slide.
SLIDE 79, UTERUS (SECRETORY ENDOMETRIUM)
The endometrial-myometrial junction is indistinct as compared to the previous slide. This is due to
“penetration” of some of the endometrial glands and the surrounding stroma into the underlying
myometrium. This is a benign condition known as adenomyosis.
The endometrium is thicker than in the previous slide. The glands are more numerous and they are
tortuous. The lining has numerous infoldings, giving them a serrated or saw-toothed appearance. No
mitoses are present in the lining cells. Some of the lumens contain an eosinophilic secretion.
Prominent spiral arterioles may be present in the stroma close of the surface. A “cuff” of predecidual stromal cells surrounds many of these arterioles. The pre-decidual cells are larger than the
stromal cells seen in the previous slide. They have a pale pink cytoplasm. Some of the glands in the
basalis do not show these changes.
SLIDE 80, FALLOPIAN TUBE
Some of the slides may have two lumens in one section due to the tortuous course of some portions of the
oviduct. The mucosal layer lies directly on the muscularis. It is composed of luminal epithelial cells
and scanty lamina propria. The lining is simple columnar. Many of the lining cells have prominent cilia.
Some of the cells are non-ciliated. A few slender and darkly stained intercalary, or peg cells are present
among the other cells. Also a few lymphocytes are present within the lining. The lamina propria
contains a few lymphocytes. The muscularis is composed of smooth muscle fibers that are poorly
organized into outer longitudinal and inner circular layers. The serosa has a smooth flat mesothelial
lining. Some of the slides may contain a few cystically dilated structures beneath the serosa. These are
Walthard rests. They are lined by a transitional-type epithelium that may become attenuated