Reproductive System Lecture 10 PDF

Dr Yasser Abdel-Wahab (Module Coordinator) WEEK 10 Introduction to Anatomy and Physiology of the Reproductive System Aims: To give an overview of the Anatomy and Physiology of the Reproductive System Lecture Outlines: 1. The organisation of the reproductive system 2. Overview of the anat...

Dr Yasser Abdel-Wahab (Module Coordinator) WEEK 10 Introduction to Anatomy and Physiology of the Reproductive System Aims: To give an overview of the Anatomy and Physiology of the Reproductive System Lecture Outlines: 1. The organisation of the reproductive system 2. Overview of the anatomy of the male and female reproductive organs 3. Synthesis of steroid sex hormones 4. The testes, actions of testosterone and regulation of testosterone levels 5. The seminiferous tubules, spermatogenesis and the functions of sertoli cells 6. The ovaries, female sex hormones and their regulation 7. Oogenesis and follicle development 8. The ovarian phases 9. The uterine cycle 10. The hormonal control of the follicular and luteal phases 11. Interactions of the reproductive system with other organ systems Intended Learning outcomes are: Name and give brief description of the main organs and accessory structures of the male and female reproductive system Understand the synthesis of the steroid sex hormones and know the names of these hormones Appreciate and describe the main functions of testosterone. Know the general functional divisions of the testes, the cells and structure of the seminiferous tubules. Appreciate the role of the hypothalamus and pituitary gland in the regulation of testosterone levels Be able to outline the events involved in spermatogenesis, including the function of the sertoli cells Know the general functions of the female reproductive system with special reference to the ovaries Describe the actions of the female sex hormones and their regulation by the hypothalamus and anterior pituitary glands Be able to discuss oogenesis and follicle development, both prior to birth, up to puberty and from puberty onwards. Give an overview of the ovarian phases. Give an overview of the uterine cycle Describe the hormonal regulation of the ovarian phases, and the effects of estrogen and progesterone at each stage, including endocrine regulation. Give an overview of the interactions between the reproductive system and other organs systems 1  Dr Yasser Abdel-Wahab (Module Coordinator) Overview of the Reproductive System The reproductive system includes the male and female reproductive organs, which are essential for maintaining survival of the human species Reproductive system – general components include: Gonads, or reproductive organs that produce gametes and hormones. Ducts that receive and transport the gametes Accessory glands and organs that secrete fluids into the ducts of the reproductive system or into other excretory ducts Perineal structures that are collectively known as the external genitalia The main functions of the reproductive system are: Males – The Testes produce spermatozoa and androgens (male sex hormones) The spermatozoa are expelled from body in semen during ejaculation and can fertilize the female oocytes. Females – The Ovaries produce oocytes Immature ovum (eggs) – Each month one oocyte travels along uterine tube toward uterus The vagina connects the uterus with exterior of body The male reproductive system Principle components of the male reproductive system, and pathway of spermatozoa – Testes: There are 2 testes, which have a flattened egg shape about 5 cm long and 3cm wide and hang within the scrotum. They produce mature spermatozoa. Testes are covered by: An outer visceral layer called the tunica vaginalis which also lines the scrotal cavity to reduce friction between the testis and the walls of the scrotum. An inner collagen rich connective tissue layer called the tunica albuginea Septa – formed by extension of tunica albuginea into testes to divide testes into lobules Lobules – approximately 800 tightly coiled seminiferous tubules are distributed among the lobules Seminiferous tubules – sight of sperm production. – Epididymis: a coiled tube (~7 m long) bound to posterior of the testes it is the start of the reproductive tract. Spermatozoa become functional in the epididymis over about 2 weeks. – Ductus deferens: about 40 -45 cm long, this duct begins at the tail of the epididymis. Lined by thick layer of smooth muscle which performs peristaltic contractions to propel sperm and fluid. The duct enlargens (into area known as ampula) just before reaching prostate and seminal glands 2  Dr Yasser Abdel-Wahab (Module Coordinator) – Ejaculatory duct: starts at junction of seminal glands with ampula of ductus deferens, passes through the prostate gland and into the urethra. Accessory organs of the male reproductive system include: – Seminal vesicles: found on either side of the midline between posterior wall of bladder and rectum, they produce a slightly alkaline fluid which makes up about 60% of the volume of semen. – Prostate gland: small rounded muscular gland about 4cm diameter. Encircles the proximal region of urethra leaving bladder. Secretes slightly acidic prostatic fluid which makes up 20 – 30% of semen volume. – Bulbourethral glands: these round glands situated at base of penis, they are approx 10mm in diameter. Their ducts travel along penile urethra for 3-4 cm before emptying contents into urethra which neutralize acid content of urerthra before ejaculation and lubruicate the glans of the penis. – Scrotum: a thin layer of skin and underlyng superficial fascia enclose the testes and keep their temperature about 1.1oC lower than body temperature which is optimal for spermatozoa formation. The scrotum is divided internally into 2 chambers (scrotal cavities, 1 testes in each cavity) marked by raised thinkening of scrotal surface called the Raphe A narrow space separates inner surface of scotum from outer surface of testis. The dermis layer of skin contains smooth muscle layer (dartos muscle) and a deeper layer of skeletal muscle (cremastor muscle) which contract to move the scrotum closer to body or relax to move scrotum away from body to regulate temperature of the testes. – Penis: tubular organ which urethra passes. Conducts urine to exterior and when erect semen into female vagina during sexual intercourse. This diagrams show the organization of the male reproductive organs 3  Dr Yasser Abdel-Wahab (Module Coordinator) The female reproductive system Principal components of the female reproductive system include: Ovaries: pair of pink or yellowish nodular almond shaped organs near side wall of pelvic cavity. They are about 5 cm long, 2.5 cm wide and 8 mm thickness. Covered by connective tissue called tunica albuginea. Internally they have outer cortex and inner medulla, with gametes being produced in cortex. Uterine tubes (Fallopian tubes): hollow muscular tube about 13 cm long. Has 3 segment. 1. Infundibulum: expanded funnel with finger like projections which drape over surface of ovary but does not connect to ovary. Inner epithelial cells covered with cilia which beat toward ampula. 2. Ampula: middle section of uterine tube. Smooth muscle layer of ampula thickens towards uterus. 3. Isthmus: last section which connects ampula to wall of uterus. Uterus: small pear shaped organ about 7.5 cm long and up to 5 cm in diameter, located covering the superior and posterior surfaces of bladder. Function of uterus is to protect, provide nutrition and remove waste for developing foetus. The uterus has upper uterine body and lower region called cervix which extends into the vagina. The roof of the uterine body is known as the fundus. Vagina: a highly distensible elastic muscular tube about 7.5 – 9 cm long, extending from cervix to vestibule. It lies parallel to rectum and urethra runs along superior wall of vagina. This diagram summarizes the various components of the female reproductive system Accessory components of female reproductive system include: Ligaments which stabilize the position of ovaries and uterus: Ovaries, uterine tubes and uterus enclosed within a mesentery known as broad ligament. The position of the ovaries are stabilized by the mesovarium and a pair of supporting ligaments known as the ovarian ligament and the suspensory ligament. Mesovarium - a thick fold of mesentery which supports and stabilizes each ovary Ovarian ligament – extends from the uterus (near the site of attachment of the uterine tube) to the medial surface of the ovary. 4  Dr Yasser Abdel-Wahab (Module Coordinator) Suspensory ligament – extends from lateral surface of ovary, past open end of uterine tube to the pelvic wall and contains the ovarian artery and vein which enter ovary at ovarian hilum (site of attachment to mesovarium). This diagram summarizes the ligaments stabilizing the position of uterus and ovaries The Mammary glands (Breasts):  Produce and secretes milk to nourish infant during initial months of life (lactation).  The mammary glands lie in the subcutaneous tissue of pectoral fat pad close to skin of chest.  The glands contain separate lobes, containing several secretory lobules which drain into ducts.  The ducts from the lobules merge into the lactiferous duct of each lobe, which form expanded chambers called lactiferous sinus close to the nipple (small conical projection where ducts open onto body surface).  The nipple is surrounded by the areola (area of reddish-brown skin) which is grainy in texture due to large underlying sebaceous glands.  The glands are activated during pregnancy to produce milk. This diagram shows the mammary glands, and the histological difference between inactive and active mammary glands 5  Dr Yasser Abdel-Wahab (Module Coordinator) Physiology of the reproductive system Synthesis of steroid hormones The male and female sex hormones are all synthesized from cholesterol and are steroid hormones (lipid soluble) i.e they can cross the cell membranes In males the main androgen hormone is testosterone which is produced from androstenedione. In females the hormones are estrogens (estradiol (most abundant), estrone and estriol) and progesterone Estrogens are produced by conversion of androstenedione to estrone and estriol by the enzyme aromatose or testosterone to estradiol by aromatose. The functions of these hormones will be discussed below. The male reproductive system Actions of testosterone  In the male foetus testosterone aids the functional development of the testes and penis  During puberty testosterone acts to promote secondary male characteristics such as body hair, increased musculature and body size, deepening of the voice.  Testosterone increases release of growth hormone which increase bone growth  Testosterone also influences sex drive and associated behaviour.  Testosterone is essential for spermatogenesis (development of spermatozoa). The testes The male testis is subdivided into 250 – 300 lobules by connective tissue septa (see anatomy section). Each testis contains approximately 800 seminiferous tubules which are each about 1ft long, totaling about 800 ft of seminiferous tubule/testes. The seminiferous tubules contain:  Germ cells - which produce spermatozoa.  Sertoli cells (epithelial cell lining) - which nurture spermatozoa and control their development. The seminiferous tubules have an outer connective tissue layer. The spaces between the tubules (interstitial space) contain clusters of Leydig cells 6  Dr Yasser Abdel-Wahab (Module Coordinator)  Leydig cells – synthesize and secrete testosterone and other androgens. Cross section of seminiferous tubules This diagram shows a cross section of a seminiferous tubule.  Spermatogenesis start in the spermatogonia cells (germ cells) – stem cells at the outermost layer of the tubule.  Spermatogonia divide into spermatocytes which undergo meiosis giving rise to spermatids.  Spermatids then differentiate into spermatozoa. Spermatogenesis start in the outermost layer of the tubule and proceeds towards the lumen of the tubule. As mentioned earlier Leydig cells are found in the interstitial space between the tubules. Sertoli cells – are large cell that have tight junctions joining them to the next Sertoli cells. These cell separate the tubule into an outer layer containing the spermatogonium and inner luminal layer containing spermatocytes, spermatid and spermatozoa. Regulation of testosterone secretion Reproductive function is regulated by the levels of circulating testosterone. Primarily stimulation (by neural input or low circulating testosterone levels) of the hypothalamus causes release of gonadotropin releasing factor (GRF).  GRF – causes increased synthesis and release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland.  FSH and LH act on cells in the testes to increase testosterone levels which then exert the required biological effects. For example, pre-puberty levels of testosterone are low. At puberty, neural input plus low testosterone stimulates the increase in synthesis and release of GRF which caused increased FSH, LH levels, thereby increasing testosterone and causing development of secondary male characteristics. High levels of testosterone will act on the hypothalamus and anterior pituitary to decrease GRF, FSH and LH release in a negative feedback manner. Control of testicular function As mentioned above FSH and LH act on the testes to increase testosterone. 7  Dr Yasser Abdel-Wahab (Module Coordinator) FSH – stimulates Sertoli cells to increase secretion of Inhibin and also to increase the rate of spermatogenesis LH – stimulates Leydig cells to increase synthesis and secretion of testosterone. Testosterone diffuses out of Leydig cells into surrounding tissue and acts on the Sertoli cells to enhance effect of FSH on these cells. Inhibin – raised levels of inhibin cause suppression of FSH release from the anterior pituitary (negative feedback). Spermatogenesis Spermatogenesis is the formation of new spermatozoa within the seminiferous tubules of the testes. The process takes 4 -6 days and more than 100 million spermatozoa are produced each day. There are a number of steps involved in spermatogenesis: 1. Spermatogonia cells undergo mitosis to produce 2 daughter cells (with 46 chromosomes) – one remains at the outermost layer of the tubule to maintain the germ cell line, the other moves towards the lumen of the tubule. 2. The daughter cells differentiate into primary spermatocytes (still 46 chromosomes). 3. Each primary spermatocytes undergo meiosis (special cell division involved in gamete formation only) to give rise to 2 secondary spermatocytes (with 23 chromosomes). 4. Each secondary spermatocyte undergoes further meiosis to give rise to 2 spermatids (23 chromosomes). 5. Spermatids then differentiate into spermatozoa which have the typical head, mid section and tail and this stage is known as spermiogenesis 6. The mature spermatozoa are then released into the lumen of the seminiferous tubule. Spermiogenesis This diagram shows the differentiation of spermatids into spermatozoa. The nucleus becomes the main part of the head of the spermatozoa. Acrosomal vesicles and Golgi apparatus fuse to become the acrosomal cap. Centrioles of the spermatid form the neck region which fuses the head to the middle piece. Mitochondria become the middle piece of the spermatozoa. A flagellum (tail) develops. Cytoplasm is shed. 8  Dr Yasser Abdel-Wahab (Module Coordinator) These spermatozoa are immotile. They are eventually transported by peristalsis to the epididymis for final maturation to motile sperm capable of swimming towards the female oocyte. Roles of sertoli cell The Sertoli cells have a number of important functions as highlighted in this flow diagram  Maintenance of the blood-testes barrier – Adjacent sertoli cells are joined by tight junctions, and produce cell layer which produce a barrier between the interstitial fluid (communicates freely with blood) surrounding the seminiferous tubules and the fluid contained within the tubule lumen which has a very different composition. The luminal fluid is secreted by the sertoli cells and is rich in amino acids, potassium and androgens. This barrier also prevent immune destruction of spermatozoa.  Nourishment of sperm cells – they transport nutrients across blood-testes barrier to developing spermatozoa  Aiding spermiogenesis – they surround the spermatids and provide nutrients and chemical stimuli which aid differentiation into spermatozoa  Secretion of seminiferous tubule fluid – which aids flushing of spermatozoa to the epididymis.  Sertoli cells also respond to FSH and testosterone to send chemical signals to the spermatogonia cells to undergo mitosis.  They also secrete the hormone inhibin which regulates the release of FSH to control the rate of spermatogenesis.  They produce androgen-binding protein, which binds androgens in the luminal fluid. The female reproductive system The female reproductive system is not only produces female sex hormones and oocytes, but must have the ability to support and nourish developing embryos, even supporting them following birth by nourishment with milk. The female sex hormones (estrogens and progesterone) regulate activity and function of the female reproductive system including:  monthly release of one ova  Cyclical regulation of the levels of the estrogens and progesterone.  Thickening of the endometrium of the uterus and loss of this layer during menstrual cycle. 9  Dr Yasser Abdel-Wahab (Module Coordinator)  Perparation of endometrium for implantation of the fertilized ovum  Adaption in pregnancy, including maturation of mammary glands. Function of the ovaries The main functions of the ovaries are:  Production of immature oocytes (ova) by oogenesis  The monthly release of one egg (ovulation) which enters the uterine tubes and travels towards the uterus  Production and secretion of female sex hormones (estrogens and progesterone).  And also the synthesis and release of Inhibin to regulate FSH activity (similar to action in males). Actions of female sex hormones The main female sex hormones are the estrogens and progesterone. The levels of these hormones are low during childhood, but increase rapidly during puberty. Estradiol is the main estrogen which:  Causes follicular development.  Promotes development of secondary female sex characteristic during puberty (breast development, change in fat distribution, widening of hips, etc.)  Increases growth hormone secretion during puberty to increase bone growth.  Progesterone:  Promotes thickening of the endometrial layer of the uterus in preparation for a fertilized ovum.  Acts on the hypothalamus to decrease GRF release and the anterior pituitary to decrease the release of FSH and LH  Suppress contractile activity of the uterus during pregnancy.  Promotes the development of mammary glands, but suppressing lactation. Regulation of female sex hormones As in males, the regulation of circulating levels of female sex hormones is regulated by secretion of GRF from the hypothalamus which increases the release of FSH and LH from the anterior pituitary gland. 10  Dr Yasser Abdel-Wahab (Module Coordinator) FSH and LH act on cells within the ovaries to regulate synthesis and secretion of estrogens and progesterone. These cells include Granulosa cells, Theca cells of ovarian follicles and the Corpus luteum. Increased circulating progesterone causes negative feedback to inhibit the release of GRF from the hypothalamus and FSH and LH from the anterior pituitary gland. Low and high levels of estrogen can have either positive or negative feedback effects on the release of GRF, FSH and LH. Increased Inhibin levels causes negative feedback on the anterior pituitary gland to decrease FSH release. The actions of these hormones depend on the stage of the ovarian cycle and will be discussed later. Oogenesis and follicle development Oogenesis is the development of germ cells (Oogonia) into oocytes which undergo meiosis into immature ova.  Oogenesis begins before birth in the developing female foetus (usually starting at about three months of foetal development).  Oogonia undergo mitosis to form approx 6 million Oogonia clones  These then begin to prepare for meiosis becoming primary oocytes, but complete meiosis does not occur by freezes or arrests (meiotic arrest).  They remain in this phase until puberty.  Some of these cells are surrounded by granulose cells to become primary follicles, the rest degenerate in a process known as Atresia At birth there are approx 2 million primary follicles remaining in the ovaries. During childhood there is continued Atresia such that by puberty only ~400,000 primary follicles remain in the ovaries. From puberty until menopause:  Each month a group of primary follicles is activated. The granulosa layer thickens and outer connective tissue cells differentiate into an outer layer of Thecal cells.  FSH stimulates the development of fluid filled Antrum within the granulosa layer and the primary follicles become secondary follicles. 11  Dr Yasser Abdel-Wahab (Module Coordinator)  10 -25 secondary follicles develop further for about 7 days after which one of these (dominant follicle) will become the mature follicle.  The remaining follicles do not develop beyond this stage and will undergo Atresia.  The antrum become larger and the follicle become known as the Graafian follicle.  LH stimulates the primary oocytes to now undergoes meiosis to form the secondary oocyte which breaks free of the granulosa wall of the antrum and floats in the growing antrum.  The follicle will reach 2 -2.5 cm in diameter.  At ovulation the Graafian follicle ruptures releasing the antral fluid and the secondary oocyte, which then enters the uterine tube.  The remaining ruptured follicle becomes a gland known as the corpus luteum which secretes estrogen, progesterone and inhibin. The diagram below shows the development of the follicles, release of the oocyte (ovulation) and formation of the corpus luteum as discussed above Ovarian phases There are two ovarian phases which generally cycle over 28 days, but can be between 21 and 35 days:  The follicular phase – involving the maturation of the follicles as discussed above. Usually about 14 days and starts on day 1 of the menstrual cycle. This phase ends at ovulation.  The luteal phase – commences with the rupture of the Graafian follicle at ovulation. During this phase the corpus luteum releases estrogen and progesterone which prepare the endometrium of the uterus for implantation of a fertilized ovum. 12  Dr Yasser Abdel-Wahab (Module Coordinator)  If the ova is not fertilized then the corpus luteum degenerates to the corpus albicans, which causes a decline in circulating estrogen and progesterone levels. This prepares the uterus for menstruation and the ovary for the start of the next follicular phase.  If the ovum is fertilized and implants in the uterine wall, then the corpus luteum dose not degenerate. The Uterine Cycle (changes in uterine endometrium) The lining of the uterus is also subject to variation during the follicular and luteal phases and this is known as the uterine cycle which has 3 phases: 1. The proliferative phase: starts after menstruation. The development of the primary and secondary follicles causes increased estrogen secretion. Estrogen stimulates and promotes growth of the endometrium by proliferation of the endothelial cells lining the uterus. There is also increase in the number of spiral arteries to enrich blood supply to the functional endometrium. 2. Progestational or Secretory phase: starts after ovulation. The endometrium thickens and secretes uterine milk which is rich in glycogen. This phase is stimulated by increasing levels of progesterone and also estrogen, secreted from the corpus luteum. The cervical mucus thickens and may eventually form a plug between the uterus and vagina to protect a developing embryo from the external environment. This phase continues until the corpus luteum degenerates. 3. The menstrual phase: This is the shedding of the uterine lining (endometrium). It is prompted by rapid decline in estrogen and progesterone levels due to degeneration of the corpus luteum. The outer endometrium layer degenerates as the spiral arteries constrict cutting off blood and nutrient supply. The weakened arteries eventually rupture and the degenerated tissue and blood are lost through the vagina. This diagram summarizes the uterine cycle and changes in the endometrium 13  Dr Yasser Abdel-Wahab (Module Coordinator) Corpus luteum / menstruation As discussed above, the corpus luteum secretes estradiol and progestrone and the rising levels of these hormones cause the alteration of the endometrium to make it suitable to receive a fertilized ovum. However, if fertilization does not occur then the corpus luteum degenerates, the levels of estradiol and progesterone rapidly decline and menstruation occurs. Hormonal control of the ovarian cycle Follicular phase 1 (early-mid follicular phase)  High levels of progesterone and estrogen inhibit the release of GRF from the hypothalamus and FSH and LH from the anterior pituitary.  The levels of estrogen and progesterone are low at the start of the follicular phase due to degeneration of the corpus luteum.  As levels are low then the release of GRF, FSH and LH are not suppressed and levels of these hormones start to increase.  FSH: o stimulates proliferation of Granulosa cells of the primary and secondary follicles increasing the size of the follicles o stimulates differentiation of outer connective tissue cells of follicle into Thecal cells o Thecal cells have LH receptors  LH: o Stimulate ovulation Follicular phase 2 [Endocrine] (late phase)  The Thecal cells respond to the increase in LH, by increasing the synthesis and release of androgens  These androgens diffuse to the granulosa cell were they are converted to estrogens by aromatase  FSH stimulates the granulosa cells to secrete estrogen and also increases the release of inhibin. 14  Dr Yasser Abdel-Wahab (Module Coordinator)  Estradiol travels in the circulation to the uterus were it causes proliferation and growth of the endometrium.  The ever increasing inhibin levels in this phase inhibit FSH release from the anterior pituitary gland  The increase in estrogen levels now have a positive effects on the hypothalamus to increase the release of GRF and thus increase the release of LH to increase follicular development and further enhance the estradiol levels (however levels of FSH decline due to actions of inhibin).  Estrogen also causes the expression of LH receptors on the granulosa cells  Estrogen increases the number of progesterone receptors on endometrial cells.  LH then begins to act on the granulosa cells to release chemical which induce the oocyte to undergo meiosis; to cause a decrease in estrogen release and increase in progesterone levels from granulosa cells; and to secrete enzymes which break down the wall of the follicle for ovulation to occur. Follicular phase / luteal phase  As mentioned above, FSH prepares the follicles for maturation and response to actions of LH.  LH prepares the Graafian follicle for ovulation by increasing enzyme secretions which breakdown the wall of the follicle to allow release of the ovum.  The estradiol and inhibin released by the granulosa cells of the follicles feedback on the hypothalamus and anterior pituitary to alter FSH and LH release.  Inhibin causes decline in FSH and this may lead to degeneration of follicles which do not become the dominant follicle. In turn there is a decrease in estrogen levels due to the degeneration of these follicles.  After ovulation the luteal phase commences with the ruptured follicle becoming the corpus luteum.  The corpus luteum secretes increasing amounts of estrogen and progesterone, causing the levels of these hormones to increase.  Initially the levels of estrogen are low as the production by the corpus luteum is not sufficient to make up for the decline due to degeneration of follicles.  Progesterone prepares the uterine endometrium as discussed earlier, by binding to the progesterone receptors on the endometrial cells.  The low estrogen inhibits LH release, causing a decline in LH levels.  Progesterone inhibits the positive effects of estrogen on release of LH and FSH from the anterior pituitary, causing a progressive decline in LH and FSH levels even in the presence of increasing estrogen levels secreted by the corpus luteum. As progesterone prepares the uterus for implantation of fertilized ovum (embryo) during the luteal phase, if fertilization and implantation occurs, the corpus luteum remains and the levels of progesterone and estrogen remain high. 15  Dr Yasser Abdel-Wahab (Module Coordinator) If no fertilization occurs, then the corpus luteum degenerates (12-14 days after ovulation) and the cycle starts again. Interaction of the reproductive system with other organ systems The diagram below summarizes the interaction of the reproductive system with the other body systems Reading Lists:  Martini FH & Nath JL, Fundamentals of Anatomy and Physiology, San Francisco, Pearson Benjamin Cummings. Martini’s Fundamentals of Anatomy and Physiology was specially selected for this module on the basis of the quality of the textbook, the inclusion of the valuable Fundamentals of Anatomy and Physiology. It comes with Interactive CD-ROM and supporting WWW site (freely accessible to students purchasing this text). 16