Female reproductive system summary PDF

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Histology of female reproductive system, includes all material that may be included on the exam....

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FEMALE REPRODUCTIVE SYSTEM 1.

Define the ovarian follicle and know the origin of its cell types.

2.

Describe the sequence of cellular changes that characterize the development of ovarian follicles from primordial to primary to secondary to mature stages.

3.

Explain the endocrine relationships that regulate ovarian follicle maturation.

4.

Be able to relate ovarian hormone production to the histology of the ovarian follicle.

5.

Describe the structural events involved in ovulation, and the endocrine factors that regulate this process.

6.

Describe the origin, structure and function of the corpus luteum.

7.

Define follicular atresia and explain the formation and fate of corpus albicans.

8.

Describe the structural characteristics of the uterine tube and explain the endocrine factors that regulate its function.

9.

Describe the histologic structure of the uterus. Define epimetrium, myometrium, endometrium and explain the significance of the endometrial basalis and functionalis.

10.

Understand the vascular supply to the uterine wall and define the role it plays in the uterine cycle, particularly menstruation.

11.

Describe the structural changes exhibited by the uterine glands throughout the various stages of the uterine cycle.

12.

Relate the uterine cycle to the endocrine events of the ovarian cycle.

13.

Understand the structure and function of the cervical endometrium, and how cervical mucus production changes with the ovarian/uterine cycle.

14.

Describe the glandular structure of the female breast and explain the cellular mechanisms involved in milk production.

Female 1 of 10

Female Reproductive System Ovary Ovaries have a cortex and medulla - but the distinction is not always readily apparent • medulla - vascular core • cortex - ovarian follicles in various stages of development surrounded by connective tissue composed of fibroblasts and mesenchymal cells Ovarian Follicle - the fundamental functional unit of the ovary • ovarian follicles are made up of an oocyte surrounded by follicular epithelial cells that play an essential role in promoting the survival and development of the oocyte • the follicular cells start out as a single layer, but proliferate to form a multifunctional glandular epithelium called the granulosa layer • adjacent mesenchymal cells separated from the follicular epithelium by a basement membrane differentiate to form another key element of the follicle, the theca folliculi made up of two layers - the glandular theca interna and a supporting vascular layer, the theca externa

[A & B: Primordial follicles surrounded by connective tissue; D: Developing, pre-antral follicle] Origin and Fate of Oocytes During embryogenesis, germ cells migrate to the developing ovary and differentiate into oocytes that enter meiosis I, but arrest at prophase. The vast majority of oocytes undergo apoptosis before birth and attrition continues throughout life (~3.5x106 oocytes per ovary in the fetal period will yield ~ 1x106 at birth and ~2x105 at puberty). At birth a woman has all the oocytes she will ever have. Stages in the Maturation of Ovarian Follicles Ovarian follicles undergo substantial structural and functional changes during development, particularly involving the follicular epithelium. These cells are highly proliferative and produce the follicular fluid (liquor folliculi) that surrounds and nurtures the oocyte. Names of the stages in follicular development have more to do with the morphology of the granulosa layer (granulosa cells) than with characteristics of the oocyte. Conventions vary, but stages are commonly called: Primordial, Primary (pre-antral), Secondary (antral), Pre-ovulatory (Graafian or mature)

Female 2 of 10

Key Features of Named Stages in Follicular development Primordial Follicle • oocyte is immature (arrested in 1st meiotic prophase) and is surrounded by a single layer of flattened follicular epithelial cells • primordial follicles tend to be located toward the outer cortex of the ovary Primary Follicle (includes unilaminar and multi-laminar Primary Follicles) • (Note: In laboratory it can be difficult to distinguish primordial from primary follicles that have just a single layer of follicular cells. A cuboidal or rounded epithelium is characteristic of primary follicles. • the follicular epithelium proliferates to form the granulosa layer - granulosa cells are interconnected by gap junctions, suggesting synchrony in function • granulosa cells produce a prominent basement membrane separating them from the theca folliculi • the theca folliculi derives from mesenchymal cells in the surrounding connective tissue, these cells differentiate to form the endocrine theca interna and vascular theca externa • a thick zona pellucida forms between the oocyte and

granulosa cells

- composed of glycoproteins secreted by the oocyte and granulosa cells - cytoplasmic processes from the oocyte and granulosa cells extend across the zona pellucida allowing communication via gap junctions • FSH and LH act on primary (pre-antral) follicle to stimulate continued development - FSH targets granulosa cells, LH targets theca cells Secondary (Antral) Follicle – is characterized by accumulation of follicular fluid essential to nutrition, survival and continued development of the oocyte • granulosa cells generate follicular fluid that accumulates to form the follicular antrum - granulosa cells produce glycosaminoglycans (hyaluronic acid) and proteoglycans (versican) creating an osmotic gradient driving fluid movement from the vasculature of the theca externa to the antrum - creation of the antrum involves cellular remodeling within the granulosa layer

Female 3 of 10

• theca interna cells are now differentiated and a critical cooperation develops between theca interna cells and granulosa cells - LH stimulates production of androgens (eg. androstenedione) by theca interna cells - FSH stimulates conversion of androgens to estrogens by granulosa cells, and the estrogens in turn stimulate granulosa cells to proliferate - de novo synthesis of estrogens by theca interna cells is minimal • FSH and estrogen prime the granulosa cells to be responsive to LH (i.e. induce synthesis of LH receptors), a necessary step for the follicle to enter the pre-ovulatory phase • during the secondary follicle stage the oocyte attains full size (~150-200 µm) Pre-Ovulatory Follicle (Graafian or mature follicle) • follicle becomes very large (can be > 1cm) • a rim of granulosa cells (corona radiata) remains adherent to the zona pellucida • a stalk of granulosa cells (cumulus oophorus) holds the oocyte near the wall of the follicle • cytokines released by the oocyte induce functional heterogeneity in the granulosa cells - corona radiata and stalk cells increase production of hyaluronic acid while mural cells remain responsive to LH in preparation for their post-ovulation role in the corpus luteum • oocyte completes first meiotic division, casts first polar body, enters meiosis II and arrests at metaphase (to continue following fertilization) - granulosa cells produce a factor (oocyte maturation factor) that inhibits the secondary oocyte from premature continuation of meiosis Ovulation A surge in LH levels is essential for ovulation to take place and must occur after both the theca interna cells and granulosa cells have expressed LH receptors, or the follicle will fail and undergo atresia. • granulosa cells secrete factors that promote weakening of the ovarian stroma to permit expansion of the growing follicle, with greater activity nearing ovulation - plasminogen activator converts circulating plasminogen to plasmin (fibrinolysin), a trypsin-like protease that weakens the surrounding connective tissue • increased collagenase activity aided by focal ischemia weakens the connective tissue capsule at the point of contact with the follicle • oocyte surrounded by corona radiata cells breaks free from the follicle wall and is released to the surface of the ovary

Female 4 of 10

Corpus Luteum The granulosa cells that remain with the post-ovulatory follicle and the surrounding theca interna cells undergo a rapid transformation to a new endocrine structure. • the layer of granulosa cells becomes folded, and in response to LH they enlarge to become granulosa lutein cells - these cells acquire steroid secretory morphology and initiate production of progesterone • theca interna cells become theca lutein cells and continue production of estrogen precursors for conversion by the granulosa lutein cells – TL cells also produce progesterone • cells of the corpus luteum proliferate, supported by vascularization of the clot within the lumen and the growth of new capillaries from the theca externa

Luteolysis is degeneration of the corpus luteum • if pregnancy does not occur, the corpus luteum of menstruation will persist 10-14 days sustained by LH and FSH - progesterone (produced by the corpus luteum) exerts negative feedback on LH, so if pregnancy does not occur the CL will fail by a mechanism involving ischemia, infiltration by macrophages and apoptosis • the corpus luteum of pregnancy is maintained by chorionic gonadotrophin from the fetus Follicular Atresia • ovarian follicles can undergo degeneration at any stage of development and often times retain eosinophilic remnants of the zona pellucida and basement membrane (glassy membrane) • the largest collagenous scars in the ovary (corpus albicans) are derived from corpora lutea

Female 5 of 10

Uterine Tubes (Oviducts, Fallopian Tubes) Muscular tubes (~12 cm long) supported by the broad ligament and extending from the body of the uterus to the ovary Four segments: interstitial segment isthmus ampulla infundibulum

pierces the uterine wall medial 1/3 of the oviduct dilated intermediate segment expanded, lateral portion bears osteum and has finger-like fimbriae

Wall of the oviduct is made up of three layers • mucosa – highly folded lamina propria forms convoluted channels lined by a simple columnar epithelium having two cell types - ciliated cells have long, very active cilia that beat toward the uterus - estrogen drives ciliogenesis and stimulates ciliary activity, while progesterone has an opposite effect - Peg cells secrete nutrients to support the oocyte and factors that promote sperm capacitation - the lamina propria is a highly vascular loose connective tissue that contains considerable smooth muscle, particularly in the fimbriae. Contraction of these cells and movement of the fimbriae (and mucosal folds) is very active at ovulation. • muscularis – is made up of two (or more) interwoven layers of smooth muscle, an inner circular/spiral layer and an outer longitudinal layer - peristaltic contraction of the muscularis is directed toward the uterus • serosa – is lined by mesothelium

Female 6 of 10

Uterus The uterus is composed of two main portions, the body (or corpus) lined by a mucosa (endometrium) capable of supporting implantation of a conceptus, and the cervix a specialized mucous gland that projects into the vagina. Layers of the uterine wall • epimetrium (outermost) - serosa and adventitia • myometrium (middle) - interlacing bundles of smooth muscle - cells undergo hypertrophy and hyperplasia during pregnancy - unwanted contraction during pregnancy is blocked by the hormone relaxin, produced by ovarian granulosa lutein cells and by the placenta - contraction at parturition is regulated by oxytocin • endometrium (innermost) - uterine mucosa - the endometrium of the uterine body (but not the cervix) is classified functionally as two layers - the functionalis is shed at menstruation, while the basalis is retained and functions to regenerate the endometrium. There are no structural features to distinguish the boundary between the basalis and functionalis Uterine Vasculature The pattern of arterial supply to the endometrium is key to the concept of cyclical renewal of the uterine mucosa (menstruation and the uterine cycle). • arcuate arteries are located within the myometrium • radial arteries originate in the myometrium and enter the basalis of the endometrium • straight (basal) arteries supply the endometrial basalis • spiral (coiled) arteries – extend from the basalis to the functionalis of the endometrium - these are heavily muscular vessels that grow during the uterine cycle and play a key role in inducing ischemia at menstruation

Female 7 of 10

Histological Changes During in the Uterine Cycle A substantial portion of the endometrium (functionalis layer) is shed at menstruation leaving behind a layer (basalis of the endometrium) that undergoes resurfacing, growth and maturation in preparation for implantation. The structural and functional changes involved are driven by a variety of cytokines and ovarian hormones, with estrogen and progesterone playing a major role. The uterine cycle starts with menstruation and is typically described as four phases. Menstrual phase (~days 1-5) - initiated by ischemia Proliferative phase (~days 6-15) - driven by estrogen (and progesterone) Secretory phase (~days 16-28) - dependent on progesterone Premenstrual or ischemic (duration ~1 day) The endometrium (uterine mucosa) is composed of uterine glands surrounded by a vascular lamina propria (endometrial stroma). - uterine glands are tubular type, commonly branched and are lined by simple columnar epithelium • Menstrual phase - the functionalis is shed, but the base of uterine glands is retained in the stratum basalis • Proliferative phase - the torn endometrium is resurfaced by outgrowth of epithelial cells from the base of glands, accompanied by proliferation of cells in the surrounding stroma - the uterine glands lengthen and coil and the epithelial cells accumulate glycogen - the spiral (coiled) arteries grow toward the functionalis • Secretory phase - as the endometrium thickens the stroma becomes edematous - the uterine glands become swollen and tortuous, and the epithelium releases glycoprotein-rich products into the lumen - the spiral arteries elongate • Ischemia leads to menstruation - when pregnancy does not occur and the corpus luteum degenerates, estrogen and progesterone levels fall triggering a series of events ultimately targeting the vasculature - prostaglandins released in the stroma trigger vasoconstriction of the spiral arteries - endometrial stroma loses fluid, lymphocytes and macrophages invade the stroma - the spiral arteries open and close intermittently ischemia  hypoxia  cell lysis  hemorrhage to debride the functionalis

Female 8 of 10

Uterine Cervix The cervix is composed of two portions, the endocervix (endocervical canal) and the ectocervix. The cervical canal is lined by simple columnar epithelium and its mucosa has elaborate mucous glands. The ectocervix projects into the vagina and is lined by a thick stratified squamous epithelium continuous with the lining of the vagina. - the cervical endometrium (mucosa) undergoes only modest changes during the uterine cycle and is not shed at menstruation, as the vasculature remains stable - the mucosa of the endocervix has longitudinal folds (plicae) - the mucous glands of the cervix are branched type, often dilated and may form cysts (nabothian cysts) Cervical mucus – plays a critical role in reproduction - mucus production and composition changes during the uterine cycle under the influence of estrogen and progesterone - at mid-cycle, estrogen stimulates secretion of hydrophilic mucins producing a watery mucus that promotes sperm motility. Sperm swim along strings of mucus to reach the uterus. - cervical mucus contains bactericidal agents such as lysozyme, and can trap pathogens - at late-cycle, under the influence of progesterone mucin levels decline, the mucus is less hydrated and sperm penetration is lower The properties of cervical (and salivary) mucus can be exploited in natural family planning. • ferning is a distinctive, leaf-like crystallization pattern created when “fertility promoting” mucus is dried on a microscope slide • spinnbarkeit is the stretchability of mucus, as between the finger tips or two slides. Mucus under the influence of progesterone has a lower stretchability (low spinnbarkeit) than the more hydrated mucus produced under the influence of estrogen Ectocervix The transformation zone between the endocervix and ectocervix shows an abrupt change in epithelium from simple columnar (cervical) to stratified squamous (vaginal). This is a frequent site of dysplasia, neoplasia and invasive carcinoma and is a key area sampled during a diagnostic cytology Pap (Papanicolaou) smear.

Vagina - the vaginal mucosa is lined by a thick stratified squamous (non-keratinizing) epithelium that undergoes cytologic changes during the uterine cycle. The cells accumulate glycogen in response to estrogen. Breakdown of glycogen (to lactic acid) released by sloughed cells produces an acidic environment that helps keep bacterial proliferation in check. - there are no glands in the lamina propria. The mucosa is moistened by cervical mucus. - the muscularis of the vagina has somewhat poorly defined circular and longitudinal layers of smooth muscle

Female 9 of 10

Mammary Gland The mammary gland is a compound tubuloalveolar gland consisting of 15-25 separate lobes having a lacteriferous duct that leads to a dilated lactiferous sinus at the nipple.

• Mammary duct system - lactiferous ducts are lined by a stratified cuboidal epithelium - smooth muscle forms a sphincter (circularly oriented bundles of cells) guarding the opening of each lactiferous sinus at the nipple • Secretory units of the breast - secretory elements called mammary alveoli form as outgrowths from small ducts that branch from the lactiferous ducts and are composed of clusters of cuboidal cells (mammary gland epithelium) responsible for milk production - myoepithelial cells are found closely associated with the mammary gland epithelium and play a role in stimulating the release of milk products into the lumen of the mammary alveoli Mechanisms of secretion in the release of milk products The constituents of breast milk are released by several secretory mechanisms. - proteins (casein, α-lactalbumin, and parathyroid hormone-related peptide PTH-RP) are packaged in membrane bound secretory granules and released by regulated merocrine secretion

Female 10 of 10

- lactose is released by constitutive exocytosis - lipids (triglycerides, cholesterol) are released enclosed by a rim of cytoplasm, apocrine secretion - secretory IgA synthesized by adjacent plasma cells is transported to the lumen via vesicular transcytosis - in addition to these main constituents breast milk contains factors (lysozyme, mucins, latoferrin) that help regulate the intestinal flora of the infant Hormonal regulation of breast structure and function - at puberty, estrogen (in the presence of prolactin) stimulates development of lactiferous ducts - alveolar buds (precursors to mammary alveoli) form and regress with each ovarian cycle - in pregnancy, multiple hormones (estrogen, prolactin, placental lactogen, progesterone) stimulate substantial development of the lactiferous ducts and mammary alveoli - during lactation, milk secretion is stimulated by prolactin (and oxytocin) Regulation of milk let-down during nursing Release of milk from the breast involves feedback at the level of the hypothalamus and pituitary. - suckling stimulates the release of oxytocin which in turn stimulates the myoepithelial cells associated with secretory cells of mammary alveoli to contract promoting secretion - afferent signals to the CNS trigger supression of release of prolactin-inhibitory hormone from the hypothalamus, leading to an increase in prolactin levels stimulating lactation - multiple neuroendocrine factors work ...