Female Reproductive System Histology

• These notes are about female reproductive system histology

The Female Reproductive System

• Consists of internal organs (ovaries, uterine tubes, uterus, and vagina) located in the pelvis
• Includes external genitalia (vulva), mammary glands, and the placenta, which all play hormonal and functional roles in reproduction
• The external genitalia (vulva) includes the mons pubis, labia majora and minora, clitoris, vestibule, vaginal opening, hymen, and external urethral orifice

Cyclic Changes in the Female Reproductive System

• Female reproductive organs undergo cyclic changes from puberty to menopause due to hormonal and neural regulation
• Menarche (first menstrual cycle) occurs between ages 9-14, marking reproductive maturity
• The menstrual cycle lasts approximately 28-30 days until menopause
• Menopause occurs between 45-55 years, ending ovarian reproductive and endocrine functions, leading to reduced activity in other reproductive organs such as the vagina and mammary glands

Ovary

• Possesses two primary functions: gametogenesis (oogenesis), producing gametes (oocytes) that mature into ova, and steroidogenesis, producing steroid hormones (estrogens and progestogens)
• Steroid hormones produced in the ovary regulate postnatal growth of reproductive organs and the development of secondary sexual characteristics
• Ovaries are paired, almond-shaped organs located in the pelvis, measuring about 3 cm x 1.5 cm x 1 cm in nulliparous women
• Ovaries attach to the broad ligament via the mesovarium
• The suspensory ligament connects the ovaries to the pelvic wall, carrying blood vessels and nerves
• The ovarian ligament attaches the ovary to the uterus
• The ovarian surface is smooth before puberty but becomes irregular due to ovulation, and the ovaries shrink after menopause

Ovarian Regions and Structures

• Composed of two main regions: the medulla (central region) and the cortex (outer region)
• The medulla contains a loose connective tissue
• The medulla contains large twisted blood vessels, lymphatics, and nerves
• The cortex contains ovarian follicles embedded in cellular connective tissue with scattered smooth muscle fibers
• The ovary is covered by a germinal epithelium (cuboidal to squamous cells)
• Located beneath the germinal epithelium is the tunica albuginea, a dense connective tissue separating the epithelium from the cortex

Ovarian Follicles and Oogenesis

• Ovarian follicles provide a microenvironment for oocyte development
• The number of oogonia increases during fetal life through mitotic divisions
• By birth, there are 600,000 to 800,000 primary oocytes, arrested in prophase I of meiosis
• From puberty onward, small groups of follicles undergo cyclic maturation in parallel with the menstrual cycle, but only one oocyte typically reaches full maturity
• Over a woman's reproductive lifespan, about 400 mature ova are produced
• The majority of oocytes are lost through atresia, a process of programmed cell death that starts as early as the fifth month of fetal life
• By menopause, the remaining oocytes degenerate within a few years

Ovarian Blood Supply and Drainage

• Blood is supplied to the ovaries from two sources: the ovarian arteries and the ovarian branches of the uterine arteries
• Ovarian arteries originate from the abdominal aorta, passing through the suspensory ligaments to supply the ovaries and uterine tubes
• Ovarian branches originate from the internal iliac arteries and anastomose with the ovarian arteries
• Spiral arteries arise from the anastomotic region, becoming highly coiled as they enter the ovarian medulla
• Veins form the pampiniform plexus at the hilum, which gives rise to the ovarian vein
• Lymphatic vessels in the thecal layers surround developing follicles and corpora lutea, following the ovarian arteries to paraaortic lymph nodes in the lumbar region

Ovarian Innervation

• Innervated by the autonomic ovarian plexus
• Contains both sympathetic and parasympathetic fibers
• Parasympathetic ganglion cells are scattered throughout the medulla
• Nerve fibers follow arteries, innervating smooth muscle in vessel walls
• Sensory fibers do not penetrate the follicular basal lamina but are scattered in the ovarian stroma
• Ovarian pain is referred to the first lumbar spinal nerves due to sensory fibers reaching the dorsal root ganglia

Estrogens and Progestogens

• Estrogens promote the development and maturation of reproductive organs
• Estrogens promote secondary sex characteristics, and mammary gland growth
• Progestogens prepare the uterus for pregnancy and support mammary gland development for lactation
• Both hormones (estrogens and progestogens) regulate the menstrual cycle, preparing the uterus for implantation
• If fertilization does not occur, the endometrium degenerates, leading to menstruation

Uterine Tubes

• Paired structures transporting the ovum from the ovary to the uterus
• Provide an environment for fertilization and early embryonic development (up to the morula stage)
• One end opens into the peritoneal cavity and the other communicates with the uterine cavity
• Each tube is 10-12 cm long and consists of four segments: infundibulum, ampulla, isthmus, and uterine parts
• Infundibulum is funnel-shaped, located near the ovary, opens into the peritoneal cavity, and has fimbriae that guide the ovum into the tube
• The ampulla is the longest segment of the fallopian tube, and is the site of fertilization
• Isthmus is narrow and medial, adjacent to the uterus
• The uterine (intramural) part is short and is within the uterine wall that opens into the uterine cavity

Histological Structures of the Uterine Tube

• The wall of the uterine tube consists of three layers: serosa (peritoneum), muscularis, and mucosa
• Serosa (peritoneum) is the outer layer consisting of mesothelium and connective tissue
• Muscularis has and inner circular layer and an outer longitudinal layer, aiding in peristalsis
• Mucosa is the inner layer with longitudinal folds that is most prominent in the ampulla, lined with simple columnar epithelium containing ciliated and nonciliated cells
• Ciliated cells are abundant in the infundibulum and ampulla and enlarge and produce cilia (ciliogenesis) to propel the ovum toward the uterus
• Estrogens increase the rate of the ciliary beat
• Ciliated cells lose their cilia (deciliation) during luteolysis
• Nonciliated (peg) cells secrete nutritive fluid for the ovum and secretory activity is stimulated by estrogens
• The infundibulum consists of numerous fingerlike projections of mucosal tissue called fimbriae
• The ampulla and the isthmus are lined by mucosal folds projecting into the lumen of the tube
• The isthmus has fewer mucosal folds than the ampulla
• A peristaltic contraction of the muscular wall (with an inner circular-spiral layer and an outer longitudinal layer), as well as the ciliary activity of the lining epithelial cells, propel the oocyte or fertilized egg/embryo toward the uterus
• Estrogen stimulates ciliogenesis, thus increasing ciliated cells
• Progesterone increases secretory (peg) cells
• The epithelium undergoes cyclic hypertrophy during the follicular phase and atrophy in the luteal phase

Uterus

• A hollow, pear-shaped organ located in the pelvis between the bladder and rectum
• Plays a crucial role in embryonic and fetal development, expanding significantly during pregnancy
• Measures approximately 7.5 cm in length, 5 cm in width, and 2.5 cm in thickness in a nulliparous woman

Anatomical Regions of the Uterus

• The body, which is the upper, larger portion, with a flat anterior surface and a convex posterior surface, and a fundus which is the rounded part above the uterine tube attachment
• The cervix, which is the lower, barrel-shaped portion connected to the vagina via the external os and to the uterus via the internal os

Uterine Wall Layers

• Endometrium, the innermost mucosal layer that undergoes cyclic changes during the menstrual cycle
• The endometrium consists of the stratum functionale (thick part shed during menstruation) and the stratum basale (a deeper layer that regenerates the endometrium)
• Myometrium is the thick muscular layer with three indistinct layers, functioning as a syncytium for uterine contractions, that undergoes hypertrophy and hyperplasia during pregnancy
• Perimetrium is the outer serous layer composed of mesothelium and connective tissue, continuous with the pelvic peritoneum
• The endometrium thickens and prepares for implantation each month
• If fertilization does not occur, the stratum functionale is shed as menstrual flow (lasting about 3-5 days), marking the start of a new cycle
• The uterine artery gives rise to arcuate arteries, which branch into radial arteries supplying the basal layer
• Spiral arteries, influenced by estrogen and progesterone, regenerate and degenerate with each cycle
• During pregnancy, the uterus expands due to smooth muscle hypertrophy, an increase in connective tissue, and collagen remodeling
• After delivery, the uterus returns close to its original size, though some structural changes remain

Cervix Structure and Response

• Cervix is the lower part of the uterus, connecting it to the vagina through the endocervix
• Cervix differs from the rest of the uterus in both structure and function
• Cervical Endometrium is approximately 2-3 mm thick
• Cervical Endometrium contains large, branched glands, unlike the rest of the uterine endometrium, that lacks spiral arteries
• Unlike the endometrium, the cervical mucosa does not shed during menstruation
• Cervical glands undergo functional changes under ovarian hormone influence
• At mid-cycle, mucus secretion increases 10-fold, becoming less viscous to facilitate sperm migration
• At other times, mucus restricts sperm passage, ensuring synchronization with ovulation
• The ectocervix (vaginal part) is covered by stratified squamous epithelium
• The endocervix (cervical canal) has mucus-secreting columnar epithelium
• The transformation zone is the transition site between these epithelia, located outside the external os during reproductive years, and before puberty and after menopause, it moves inside the cervical canal
• The endocervix is lined by simple columnar epithelium
• The endocervix forms deep mucus-secreting crypts, resembling tubular glands
• Some endocervix crypts may become occluded, forming Nabothian cysts (cysts of Naboth)
• Located in the stroma is a dense irregular connective tissue with some smooth muscle, and abundant blood vessels
• Secretory activity in the endocervix is regulated by estrogens and is maximal at ovulation
• The cervical mucus lubricates the vagina during intercourse and also forms a protective barrier against bacteria
• Mucus becomes less viscous, hydrated, and alkaline, facilitating sperm migration during the ovulation phase
• Contains Na+, K+, Cl-, leading to a fernlike crystallization pattern, often used clinically to predict ovulation
• Mucus becomes highly viscous and acidic, which inhibits sperm penetration and reduces viability in the post-ovulation phase

Vagina

• A fibromuscular tube that connects the internal reproductive organs to the external environment
• Composed of three layers, a mucosal layer, muscular layer, and adventitial layer
• Mucosal layer is lined with stratified squamous, nonkeratinized epithelium, and contains rugae (transverse folds) and connective tissue papillae projecting into the epithelium
• Cervical mucus and vestibular glands provide vaginal lubrication because the this layer lacks glands
• The lamina propria has two regions, and outer loose connective tissue (highly cellular) and a deeper dense connective tissue (contains thin-walled veins, resembling erectile tissue)
• Lymphocytes and leukocytes (especially neutrophils) infiltrate the mucosa, increasing around menstruation
• Muscular Layer is composed of two smooth muscle layers: the outer longitudinal (thicker, continuous with the uterus) and inner circular (less distinct)
• Bulbospongiosus muscle fibers are present at the vaginal opening
• The Adventitial Layer is divided into inner dense connective tissue (with elastic fibers for strength and elasticity) and outer loose connective tissue (rich in blood vessels, lymphatics, and nerves)
• The vaginal wall lacks glands, so moisture is maintained by mucus from the uterine, endocervical, and Bartholin's glands
• Estrogen stimulates the differentiation of the vaginal epithelium
• At ovulation, the epithelium is fully differentiated, and acidophilic squamous cells predominate (visible in Pap smears)
• After ovulation, Progesterone increases, leading to a decline in squamous cells and the appearance of basophilic polygonal cells, along with neutrophils and lymphocytes

External Genitalia

• The female external genitalia is referred to as vulva
• They are covered by stratified squamous epithelium
• Structures included are the: Mons Pubis, Labia Majora, and the Labia Minora
• Mons Pubis: A rounded prominence area, which covers the pubic symphysis, containing subcutaneous adipose tissue and covered with pubic hair
• Labia Majora: Two large folds of skin that contain smooth muscle (similar to the dartos muscle) and subcutaneous fat; The outer surface is covered in pubic hair, with an inner hairless inner surface, containing sebaceous and sweat glands.
• Labia Minora: Hairless, pigmented skin folds on the vestibule; it’s core is connective tissue with elastic fibers and blood vessels; and it has sebaceous glands that are large

Additional Structures of the External Genitalia

• The Clitoris is an erectile structure, homologous to the penis that contains two corpora cavernosa and a glans clitoris
• It is covered by a thin skin layer forming the prepuce, with numerous sensory nerve endings
• The Vestibule is positioned between the labia minora and is lined with stratified squamous epithelium
• Lesser vestibular glands (Skene's glands) are near the clitoris and urethral orifice in the vestibule
• Greater vestibular glands (Bartholin's glands), also in the vestibule, are homologous to male bulbourethral glands, and secrete lubricating mucus
• A block in the Bartholin's gland duct will result in swelling and an infection called bartholin's cyst, that requires drainage surgically

Hymen and Urethra

• Hymen: a thin fibrous membrane marking the boundary between internal and external genitalia
• This membrane type has a keratinized external surface and a nonkeratinized, glycogen-rich internal surface
• Urethral meatus opens near the clitoris
• Paraurethral (Skene's) glands surround the meatus, lined by pseudostratified columnar epithelium
• Bartholin's glands: Near the lower vagina, they secrete mucus, and connect to the vagina via a transitional epithelium-lined duct
• Lined by pseudostratified columnar epithelium, transitioning to stratified squamous epithelium near the meatus
• Elastic fiber-rich connective tissue supports the muscle layers

Mammary Glands

• Modified tubuloalveolar apocrine sweat glands that develop under hormonal influence and undergo structural changes throughout life
• Glands are inactive until pregnancy, when estrogen and progesterone begin influencing components (corpus luteum, later placenta)
• Milk secretion begins after birth, triggered by prolactin (PRL)
• Milk ejection is stimulated by oxytocin from the neurohypophysis
• Functional gland tissue regresses at menopause and is replaced by fat and connective tissue

Anatomy of the Mammary Glands

• Each consist of 15–20 lobes divided into terminal duct lobular units (TDLUs)
• Lactiferous ducts open at the nipple, with each duct having a lactiferous sinus beneath the areola
• The nipple is highly pigmented and consists of keratinized stratified squamous epithelium with smooth cells for nipple erection
• Nipple contains sebaceous, sweat, and Montgomery glands (produce protective secretions discouraging microbial growth), causing an increase of pigmentation at puberty and pregnancy

Terminal Duct Lobular Unit and Pregnancy

• Basic functional unit of mammary glands
• It’s structural changes depend on both pregnancy and menstrual cycles, especially in terminal ductules
• Undergo structural changes during menstrual cycle with slight proliferation and regression of epithelial cells
• First trimester structural shifts is an epithelial cell and myoepithelial proliferation
• Second trimester results in alveolar differentiation from the terminal ductule and immune inclusion into stroma
• Third trimester shifts into alveolar maturation, secretory cell hypertrophy, and secretory accumulation

Mammary Gland Secretions

• During milk production are both protein and lipids involving specific secretions
• Merocrine protein secretion is involved with apocrine lipids
• Colostrum is involved immediately after birth in the first instance of milk
• Hormone regulation of mammary glands involves estrogen, for pubital stage, and progesterone for puberty
• Estrogen promotes lactiferous duct proliferation for menstrual follicular phases
• Progesterone promotes luteal phases that result in alveolar growth and stromal edema for breast tenderness
• Mammary gland atrophy occurs at menopause due to a drop of ovary stimulus with associated hormone output
• Secretory cells will degenerate within TDLUs in menopause which leads to only ductile structures making a similar structure to that of the male breast
• Fibroblasts are also impacted, degrading also to elastic and collagen