Understanding Obstetrics and Gynaecology

DR. LESLIE SAMUELS

April 2010

TABLE OF CONTENTS
1. Early Embryology and Placentation 2. Embryology of the Urogenital System 3. The Uterus 4. The Cervix 5. The Ovary 6. Physiology of Menstruation 7. Physiology of Labour 8. The Breast 9. Physiology of Lactation 10. The Bladder 11. Physiology of Micturition 12. Physiology of Puberty 13. Amenorrhea 14. Polycystic Ovarian Syndrome 15. Hirsutism 16. Viruses Appendix I - Blood Supply of the Pelvis

EARLY EMBRYOLOGY
Fertilization of the egg by a sperm restores the normal diploid number of the conceptus, and starts a series of mitotic divisions. Thus, the fertilized egg moves from being a single cell to a two-, four-, eight-, and then a sixteen cell structure. This ball of cells is called a morula, from the Latin word for mulberry, with which there is a resemblance (see pictures):

Each cell in a morula is genetically identical, and are called blastomeres Each cell has the potential to create the total complement of products of conception (fetus, placenta, umbilical cord, amnion and chorion); hence, they are referred to as being totipotent The overall size of the conceptus has not increased despite the cell division, because the entire structure remains confined within the zona pellucida, the thick glycoprotein shell of the egg At this point the blastomeres begin to absorb fluid from the outside environment, and to secrete this fluid between themselves. The fluid eventually coalesces into a single cavity, and the structure is now converted into a blastocyst. Cyst = a fluid filled space, lined by epithelial cells. This definition now fits the conceptus, as the blast cells line a fluid filled cavity. The increased mass of fluid within the fixed volume of the zona pellucida causes the pressure within to increase; this causes degeneration of the shell, and results in blastocyst hatching to occur Further increases in cell number now result in increases in overall size of the blastocyst At this point, the cells of the blastocyst begin to differentiate, and become specialized. This process begins with the outermost layer of cells, which differentiate into trophoblasts. The cells on the inside remain undifferentiated at this time, and are collectively referred to as the inner

cell mass. These cells can still form the amnion, amniotic fluid and the fetus, but can no longer form the placenta, as this comes from trophoblasts. Hence, they are no longer totipotent, but pluripotent. For details on further development of the placenta, please see the relevant chapter (The Placenta, Chapter ?). Differentiation now begins within the cells of the inner cell mass, leading to the development of two types of cells: the epiblast and the hypoblast. Thus, the inner cell mass is converted into a bilaminar disc. The epiblast is clustered towards the outer trophoblast, while the hypoblast faces the blastocyst cavity. (Need picture of bilaminar disc, within the early conceptus) The epiblast cells now absorb fluid from outside, and secrete it within themselves, creating a new cavity called the amniotic cavity. The epiblast cells lining the amniotic cavity are now called amniocytes. At the same time, the hypoblast cells proliferate outwards to line the blastocyst cavity, which is then called the primary yolk sac. The layer of hypoblast cells lining the yolk sac is called the exocoelomic membrane.

(Replace with an original picture) The exocoelomic membrane then produces a specialized type of tissue called the exocoelomic mesoderm. This tissue grows to completely surround both of the previous cavities, and so completely separates the bilaminar disc from the outside trophoblast cells. This tissue then degenerates centrally to form spaces (called lacunae) within itself; these spaces become confluent to form a third cavity, the chorionic cavity. The remaining mesoderm on the outer aspect (lining the cytotrophoblast) is called the extraembryonic somatic mesoderm. The remaining mesoderm on the inner aspect (lining the amniotic cavity and yolk sac) is called the

extraembryonic splanchnic mesoderm. Only one area of mesoderm remains to connect the bilaminar disc to the outside trophoblast cells: this is called the connecting stalk, and will eventually become the umbilical cord.

At this stage of embryogenesis, cells from the epiblast arrange themselves along the midline of the bilaminar disc to form a structure known as the primitive streak; these cells then invade down through the disc in the midline, dividing it into left and right halves. This structure establishes the longitudinal axis of the conceptus, and is the basis for the bilateral symmetry of the more mature organism. Additional epiblastic cells migrate down the primitive streak and create a third layer between itself (epiblast) and the hypoblast. They then continue downwards to systematically replace all the hypoblast cells with a new, third layer. Thus, the bilaminar disc

is converted into a trilaminar disc, a process called gastrulation, and the three layers are referred to as ectoderm, mesoderm, and endoderm. Ectoderm gives rise to all the outside structures, such as skin, nails, and hair, and the enamel of teeth. It also forms the brain, spinal cord, nerves of the central nervous system Endoderm produces the lining of the respiratory system and digestive tract, and generates portions of major organs such as the liver and pancreas Mesoderm forms all connective tissue, the musculoskeletal system, the cardiovascular system (heart, blood vessels, and blood itself),the genito-urinary systems, the walls of the gastrointestinal systems, and other structures

Note that there is now mesoderm inside the embryo (embryonic mesoderm), and outside the embryo (extraembryonic mesoderm), connected by the connecting stalk Since blood and blood vessels are formed from mesoderm, this establishes the potential for continuity of the embryonic/fetal circulation with that of the developing trophoblast/placenta (Insert illustration here)

Embryonic Folding During the third and fourth weeks of embryonic life (corresponding to five and six weeks after the last menstrual period, since fertilization generally occurs at day 14 of the typical menstrual cycle), the embryo converts from a flat trilaminar disc, to a tubular structure assuming the classical fetal position. Folding of the embryo occurs because of different rates of growth of the three embryonal layers, i.e. ectoderm grows faster than mesoderm, which in turn grows faster than endoderm. Consequently, folding occurs mainly at the edges of the disc: The superior edge folds forward (ventrally), to form the cephalad fold The inferior edge folds forward (ventrally), to form the caudal fold, and Both lateral edges fold forward (ventrally), to form the lateral folds. (Insert illustrations here)

These are not three separate processes, but occur simultaneously and merge into one another, and they convert the embryo into a tubular structure, with ectoderm on the outside surface, endoderm on the inside surface, and mesoderm separating the two. The only exception to this principle, that mesoderm separates ecto- and endoderm, occurs at the poles of the embryo. As previously stated, the rate of cephalocaudal growth of ectoderm and mesoderm is higher than that of endoderm, causing the head and tail folds to develop. The head fold grows forward and over the cephalad portion of the primitive gut, where it is sealed cranially at the buccopharyngeal membrane. Likewise the tail fold grows forward and over the caudal portion of the primitive gut, where it is sealed caudally by the cloacal membrane. (Insert diagram of sagittal section of embryo here to illustrate) These are the only two areas on the developing embryo where ectoderm meets endoderm directly, with no intervening mesoderm.

An invagination of the ectoderm occurs on the anterior surface of the cephalic fold. This depression is called the stomodeum, and the deepest part of this depression lies in direct contact with the cephalad end of the primitive gut. At this point, ectoderm and endoderm are in direct contact with no intervening mesoderm, and this is called the buccopharyngeal membrane. The membrane becomes perforated in the fourth week in utero, causing continuity between the two areas. Note that the stomodeum is lined by ectoderm, and the primitive gut by endoderm, explaining why the mouth is lined by stratified squamous epithelium, but the lower half to one third of the esophagus is lined by columnar epithelium. Just before the membrane ruptures, a small evagination of the roof of the stomodeum develops, just in front of the buccopharyngeal membrane. This outpouching is called Rathkes pouch, and it continues to deepen, towards the developing brain. Eventually the connection to the stomodeum is lost, and the cells of the ectoderm of the pouch develop into the adenohyophysis, or the anterior pituitary. Note that though the anterior and posterior pituitary glands form separately, they are both ectodermal in origin

Ectodermal Derivatives The ectoderm of the embryo thickens dorsally to form the neural plate, and the neural plate invaginates (i.e. folds in upon itself) to form neural groove. The continued growth of the edges of the neural groove causes them to meet and fuse in the midline, converting the groove into a tube. This process begins approximately in the middle of the embryo and continues both cranially and caudally (c.f. zipping up a suitcase with two zippers, from the middle). The openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. In human embryos, the cranial neuropore closes approximately on day 25 and the caudal neuropore on day 27 (post fertilization). This process of neural tube formation is dependent on the presence of adequate amounts of folic acid and Vitamin B12; absence may lead to neural tube defects (NTDs) Neural tube defects include open defects (anencephaly, encephalocoele,and open spina bifida), and closed defects (spina bifida occulta, meningocoele, meningomyelocoele) Folate is needed to carry one carbon groups for methylation and nucleic acid synthesis; thus, it is required for production and maintenance of new cells, and for DNA and RNA synthesis Vitamin B12 is also an important receptor in the folic acid biopathway, and studies have shown deficiency in vitamin B12 also contributes to risk of NTDs

Note that this process is occurring at gestational/menstrual age of 39 to 41 days, about six weeks. Thus, folic acid supplementation should ideally begin preconceptionally.

Mesodermal Derivatives As this folding is occurring, the mesoderm on each side of the embryo splits into three main groups: the lateral plate mesoderm, intermediate mesoderm and paraxial mesoderm. In addition, mesoderm also produces mesenchyme. Mesenchyme (also called mesenchymal connective tissue) is a type of undifferentiated loose connective tissue, the majority of which is derived from mesoderm Mesenchymal cells can migrate easily, unlike epithelial cells, which do not show great mobility Histologically, mesenchyme is composed of a prominent ground substance matrix containing a loose collection of reticular fibrils and unspecialized cells These cells are capable of developing into frequently used connective tissue, such as bone, and cartilage, as well as components of the lymphatic system, and the circulatory system

Lateral plate mesoderm is found at the periphery of the embryo. It will split into two layers, the somatopleuric mesoderm, and the splanchnopleuric mesoderm. The somatopleuric mesoderm is the outermost layer of mesoderm, closest to ectoderm; it will fuse with the ectoderm to form the dermis, subcutaneous tissues, fascia and muscle of the body wall, as well as the parietal layer of peritoneum. The splanchnopleuric mesoderm is the inner layer of mesoderm closest to the endoderm; it will fuse with the endoderm to form the walls of the abdominal viscera, and the heart and circulatory system.

The space formed by the splitting of the lateral plate (between the somato- and splanchnopleuric mesoderm) is enclosed, and forms the intraembryonic coelom, or coelomic cavity. This cavity is later divided by a mesodermal plate, called the septum transversum. The septum divides the coelomic cavity into the initial pericardial and peritoneal cavities, and the septum transversum later develops into the diaphragm. Later on, pleuropericardial folds (also from mesoderm) appear on the wall of the primitive pericardial cavity; these will eventually develop into another partition, and so form the pericardial and pleural cavities.

Finally, the upper and lower limb buds also develop from lateral plate mesoderm, in the upper thoracic and lower caudal regions, respectively.

The overlap and fusion of the lateral folds in the anterior midline produces a linear area where there is a slight increase in skin epithelial cells, including melanocytes; thus, the linea nigra is formed

Conversely, if closure of the ventral body wall fails, then ventral body wall defects, such as ectopia cordis, gastroschisis, and bladder and cloacal exstrophy, occur

The linea nigra darkens in pregnancy (compared to surrounding skin) because of the disproportionately higher number of melanocytes there, under the influence of hormones with melanin like activity, such as human placental lactogen

The intermediate mesoderm is of particular interest to the obstetrician/gynaecologist, as it represents the origin of the entire genital and renal systems (see Chapter ?: Embryology of the Renal and Genital Systems).

The paraxial mesoderm is the area of mesoderm that forms just lateral to the neural tube on both sides. It differentiates cranially into somatomeres and caudally into somites. The somatomeres develop into the branchial arches, which will further develop into the striated muscles of the head and neck, and cartilage, etc. Somites eventually differentiate into the axial skeleton, skeletal muscles (paravertebral, etc.), and the overlying part of the dermis.

Endodermal Derivatives As the primitive gut is being formed by inward folding, the continuity between the endoderm of the embryo, and the yolk sac cavity is progressively lost. In the middle of the folding process, while the embryo is still deriving nourishment from the yolk sac, the primitive mid-gut is connected to the yolk sac by the vitelline duct. At this point, blood cells are being made in the yolk sac and are conveyed to the embryonic circulation by the vitelline vessels. Generally, this duct obliterates during the seventh week; occasionally, this fails to occur Thus, about 2% of fetuses exhibit a type of vitelline fistula characterized by persistence of the proximal part of the vitelline duct as a diverticulum protruding from the small intestine, a Meckel's diverticulum, which is situated about two feet above the ileocecal junction, and may be attached by a fibrous cord to the abdominal wall at the umbilicus. If the entire duct remains patent, then meconium may be passed through the umbilical cord

The allantois, or urinary vesicle, arises as an endodermal evagination of the developing hindgut which projects into the connecting stalk (formed by mesoderm). It grows outwards but, in humans, only reaches a little way toward the placenta. It is surrounded by the connecting stalk, a mass of mesoderm containing blood-vessels; these vessels are pushed by the allantois through the connecting stalk into the chorionic villi, which they ramify to establish a continuous fetoplacental circulation.

As the embryo/fetus grows, the vitelline duct and yolk sac are progressively absorbed and obliterated, at the same time as the fetoplacental circulation is established. The connecting stalk is moved anteriorly by continued embryonic growth and folding, and eventually fuses with the degenerating vitelline structures. The stalk and its vessels elongate, and become covered by the amnion, to form the umbilical cord. In addition, the part of the allantois in connection with the body becomes gradually obliterated. A part of it remains as the urinary bladder, and the rest forms a fibrous cord, which runs from the apex of the bladder to the umbilicus, and is known as the urachus.

EMBRYOLOGY OF THE GENITO-URINARY SYSTEM

Most of the genital tract and renal system develop side by side within the intermediate mesoderm of the developing embryo.

THE KIDNEYS AND URETER The development of the renal system begins in the cervical region (i.e. near the neck) with the development of a series of solid cords within the intermediate mesoderm. These cords then become canalized to become tubular structures, and are collectively known as the pronephros. The pronephros has no vascular supply, so it is non-functional. The tubes of the pronephros fuse laterally to form a single duct which runs longitudinally through the mesoderm of the embryo to enter the cloaca, which is the dilated terminal portion of the primitive gut, where waste material is stored. This duct is called the pronephric duct. The tubes of the pronephros begin to degenerate shortly afterwards, but leave the pronephric duct in place. As they degenerate, the pronephric duct induces a new system of tubules develops within the intermediate mesoderm of the thoracic region of the embryo; these are collectively called the mesonephros, and they also connect with the pronephric duct, which now becomes the mesonephric duct. Unlike the pronephros, the mesonephros receives a vascular supply from the primitive aorta, and so is functional. As urine production begins, it is drained down the mesonephric duct into the cloaca; consequently, the mesonephric duct dilates and bulges inward toward the coelomic cavity, forming the urogenital ridge. The mesonephros also degenerates shortly after it is formed, but before it does so it gives off a bud just above its insertion into the cloaca. This ureteric bud branches caudally to enter the cloaca (now the urogenital sinus), where it fans out and fuses with its partner on the other side; this mesoderm from the ureteric bud goes on to form the trigone of the bladder. The cephalad portion of the ureteric bud ascends through the intermediate mesoderm. As it does so, it becomes capped by another collection of mesoderm, called the metanephrogenic blastema. As the ureteric bud grows superiorly, it obtains a blood supply from all the structures it passes, until its growth is halted due to the obstacle of the diaphragm (and the liver, on the right side).

The ureteric bud becomes the ureter, and its cephalad end branches to become the pelvis, major and minor calyceal systems, and collecting ducts of the mature adult kidney. The mesoderm of the metanephrogenic blastema becomes the parenchyma of the kidney, inclusive of the glomeruli, Bowmans capsules, proximal convoluted tubules, loops of Henle, and distal convoluted tubules. The fetal kidneys become functional by about 12 weeks gestational age. After this time, urine produced passes out to contribute to liquor formation. It is subsequently swallowed, and reabsorbed by the gut into the bloodstream. Waste can then be shunted to the placenta for disposal. Renal agenesis will result in no urine production and, therefore, in early and severe oligohydramnios In contrast, esophageal or duodenal atresia will lead to polyhydramnios, by virtue of less fluid being reabsorbed into the fetus

THE BLADDER As stated earlier, the hindgut of the embryo ends in a dilated cul-de-sac called the cloaca. The allantois, which projects out into the connecting stalk, also opens into the cloaca. The most distal aspect of the cloaca meets ectoderm directly, with no intervening mesoderm, forming the cloacal plate. With further embryonic development, the cloaca is divided by ingrowths of surrounding mesoderm, Rathkes plicae (which grow in from the sides in a medial direction) and Toureaxs fold (which grows from above the cloaca, in a caudal direction), dividing it into an anterior urogenital sinus, and a posterior anorectal canal. This wall of mesoderm forms the urorectal septum, and it also divides the cloacal plate into an anterior urogenital membrane, and a posterior anal membrane. The insertion of the urorectal septum into the cloacal plate develops into the perineal body. The urogenital sinus is divided into vesical, pelvic, and phallic portions. As the name suggests, the vesical portion of the UG sinus, along with portions of the allantois, develop into the

epithelial inner surface of the bladder. The detrusor muscle is induced to form from mesoderm surrounding the urogenital sinus. The trigone is formed from the fanning out and fusion of the mesoderm of the ureteric bud, after it inserted into the urogenital sinus. The muscle of the detrusor and the muscle of the trigone behave differently in adult life, because of their different embryonic origins; this is critical for the normal physiology of micturition. The pelvic portion of the urogenital sinus becomes the proximal urethra, and the phallic portion becomes the distal urethra, and part of the vestibule of the vagina. The proximal part of the allantois becomes obliterated, to form the urachus, or median umbilical ligament. This ligament connects with the inside of the umbilicus. If obliteration does not occur, then urine may be passed through a patent allantois and out at the umbilicus after birth.

THE UTERUS, TUBES, CERVIX AND VAGINA As the mesonephric duct is formed in the urogenital ridge, an invagination occurs on the surface of the urogenital ridge. This invagination sinks into the mesoderm below, and the upper surfaces grow together and fuse, resulting in a tubular structure within the mesoderm of the urogenital ridge. These tubes are formed using the mesonephric duct as a framework, and are called the paramesonephric (or Mullerian) ducts, and they also run caudally to insert into the cloaca (now the urogenital sinus). The paramesonephric ducts have three portions: an upper vertical segment which runs lateral to the mesonephric ducts; a horizontal middle section which crosses the mesonephric ducts; and another vertical portion running medially to the mesonephric ducts. The lower vertical portions of the paramesonephric ducts become fused in the midline, resulting in a double tubular structure with a common middle wall. This wall subsequently breaks down, leaving a single tubular structure in the midline, continuous with two open tubular structures above.

 Both the fusion of the paramesonephric ducts, and the subsequent dissolution of the intervening wall, occur in a caudocephalad direction (from the bottom upwards) This Y shaped structure is now referred to as the uterovaginal primordium, and it inserts into the posterior aspect of the urogenital sinus, immediately in front of the urorectal septum. The primordium forms the inner epithelial surfaces of the tubes, the endometrium of the uterus, the endocervical lining, and the epithelium of the upper two-thirds of the vagina. The muscular walls of the tubes and uterus, and the fibromuscular/fibroelastic walls of the cervix and vagina are again induced to form from the surrounding mesoderm. The insertion of the uterovaginal primordium into the posterior aspect of the urogenital sinus induces the proliferation of epithelium of both mesodermal origin (from the primordium) and endodermal origin (from the UG sinus), resulting in the formation of a solid vaginal plate. This plate subsequently becomes canalized, forming the epithelium of the lower one third of the vagina. The last layer of endoderm from the UG sinus is partially retained, and becomes the hymen.
1 Genital tubercle 2 Vestibule 2a UG sinus, pelvic 2b UG sinus, phallic 3 Vaginal plate 4 Perineum 5 Rectum 6 Uterovaginal canal 7 Bladder 8 Urethra

2 Vaginal vestibule 3a Uterine cavity 3b Uterine cervix (neck) 6a Vagina: The lower fourth out of endoderm 6b Vagina: The upper 3/4 out of mesoderm 9 Hymen

 Failure of dissolution of the last layer of endoderm results in an imperforate hymen Failure of canalization of the vaginal plate results in a transverse vaginal septum

THE EXTERNAL GENITALIA During the fourth week of development, a cleft develops in the midline of the cloacal plate, and is referred to as the urethral groove. This groove is flanked by a pair of mesodermal swellings called the cloacal folds, and by the sixth week of development the superior margins of the cloacal folds meet in the midline and fuse to form the genital tubercle. By this time, the cloaca has been divided by the urorectal septum into an anterior urogenital plate; consequently, the cloacal folds are now called urethral folds, and are themselves flanked by additional mesodermal swellings called the genital swellings, by week 8. In the female (i.e. in the absence of significant levels of androgens), the genital tubercle becomes the clitoris, the urethral folds become the labia minora, and the genital swellings remain unfused to form the labia majora. The labia minora enclose the vestibule of the vagina, with the urethra and vaginal introitus incorporated within it, as previously explained.

THE UTERUS
The uterus is one of the most important organs of the female reproductive system. In the female of child bearing age it responds to ovarian hormones and undergoes cyclical changes on a monthly basis, during which it prepares to receive a fertilized ovum; when this does not occur the endometrial lining is shed in the process known as menstruation. Once fertilization occurs, the uterus acts as a conduit for the fertilized ovum (through the fallopian tubes) to the endometrial cavity; provides an area for reception, housing, nourishment and protection for the developing conceptus; and expels the products of conception during parturition.

For the purpose of this discussion, only the uterine corpus (fundus and body) will be discussed. The uterine cervix is discussed separately.

EMBRYOLOGY The uterus, tubes, cervix, and most of the vagina, are derived from the paramesonephric (or Mullerian) duct system. These ducts arise from an invagination (infolding) of the coelomic epithelium on the surface of the urogenital ridge, to form a groove; the surface epithelium then regrows to cover the top of the groove, resulting in a tubular structure within the mesoderm of the ridge. (see illustrations). The paramesonephric ducts, as the name implies, are developed on the framework of the mesonephric ducts, and they have three regions: a vertical upper section running lateral to the mesonephric ducts; a horizontal section which crosses the mesonephric ducts; and a lower vertical segment which runs medial to the mesonephric ducts. The medial portions of the lower vertical segments of the pair of ducts fuse in the midline, from the caudal ends upwards. Thus, a single structure with a double-barrel lower end is formed. The intervening septum then dissolves, again in a caudal to cephalic direction, leaving a single, central tube in the midline. (see illustrations). This structure is called the uterovaginal primordium, and forms the basis of the inner linings of the fallopian tubes, the endometrial glandular epithelium, the endocervical lining, and the epithelium of the vagina. The stroma and muscular and connective tissue elements of the walls of these structures are induced and formed from the surrounding

mesoderm. By week 12, the fundus rises, and the uterus assumes its mature morphologic pear shape. This entire process is completed by the 22nd week of development and results in the formation of 2 fallopian tubes, a single uterus, and the uterine cervix (and the upper two thirds of the vagina).

GROSS ANATOMY The uterus is a muscular, pear shaped, thick walled, hollow viscus, located centrally within the pelvis. It consists of four regions: The fundus, is the region which lies above the insertion of the fallopian tubes The body, which extends between the fundus and the cerix The cervix, which is the inferiormost aspect of the uterus, part of which projects into the vagina The isthmus, which is a slightly narrowed region connecting the body to the cervix

In the nulliparous, non-gravid female (and where there is no pathology present) the uterus measures approximately 8 x 5 x 3 cm, or about the size of the average womans fist. Remember 1, 2, 3 in inches for the uterine dimensions; then convert to centimeters.

The relations of the uterus are: The bladder, anteriorly The Pouch of Douglas and rectum, posteriorly The tubes, ovaries, broad ligament, and the ureters, laterally Loops of small bowel, superiorly The vagina, inferiorly

It is almost completely enveloped by peritoneum, the exception being the region lying behind the bladder, under the reflection of peritoneum which connects the bladder to the uterus, the uterovesical fold.

 During both hysterectomy and lower segment caesarean section, this fold of peritoneum must be divided, to separate the uterus from the bladder, thus helping to prevent bladder injury.

The uterus usually lies in a state of anteflexion (the axis of the body of the uterus is angled anteriorly with respect to the axis of the cervix) and anteversion (the axis of the cervix is angled anteriorly with respect to the axis of the vagina).

[Insert Picture or Diagram here]

HISTOLOGY The uterus is enveloped by peritoneum, except for the area behind the bladder (under the uterovesical fold) where it is connected to the bladder by loose connective tissue. The peritoneum enveloping the uterus extends laterally, draped over the fallopian tubes, to the pelvic side wall, as the broad ligament. The myometrium is made up of smooth muscle arranged in three main layers: Longitudinal. This layer is the most superficial. It is attached at the isthmic region, and runs up the front, over the fundus, and down the back of the body of the uterus, where it is reattached at the isthmus. Other fibres run down the cervix on the external surface, and back up to the isthmus on the internal surface. Circular. In the uterus, this layer is the deepest muscular layer, and is best developed near the uterine cornua (where the tubes insert) and at the level of the isthmus, at the internal cervical ostium (internal os). Interlacing. These fibres constitute the bulk of the uterine corpus and fundus, and run at oblique angles to each other creating a latticework of fibres; blood vessels traverse this latticework running from the superficial to deep layers of the uterus.

 Contraction of the longitudinal layer of fibres causes shortening of the fundus/body of the uterus, and aids in expulsion of uterine contents; this layer assists in all stages of labour Smooth muscle arranged in a circular fashion is found around orifices, in general, and has a sphincteric action The circular muscle at the cornua remain closed in menstruation to prevent retrograde menstruation; in contrast, the circular muscle at the internal os relaxes a little in menstruation to facilitate outflow of the menstrual effluent This fact makes it easier to insert IUCDs, just after a period, as the os remains slightly open at that time The circular muscle at the internal os remains contracted during pregnancy to keep the products of conception within the uterus; weakness/failure of the muscle at this level results in cervical incompetence During labour, the circular muscle at the internal os relaxes to facilitate cervical dilatation; damage to the muscle, with resulting fibrosis, may prevent proper dilatation, resulting in failure to progress secondary to cervical dystocia. The innermost layer of the uterus is the endometrium. The detailed appearance of the endometrium is dependent on the stage of the menstrual cycle when it is viewed, but generally it consists of a single layer of columnar epithelium, resting on a layer of connective tissue, called the stroma. Simple tubular uterine glands reach from the endometrial surface through to the base of the stroma, which also carries a rich blood supply of spiral arteries. The thickness of the stroma, the size and activity of the glands, and the number and size of the spiral arteries are all under hormonal influence, and vary according to the stage of the menstrual cycle. The endometrium can be further divided into a hormonally dependent functional layer (which grows, develops, and is shed regularly), and a hormonally independent basal layer, which is never shed, and from which the functional layer regenerates. Overzealous curettage, or inadvertent closure of the endometrial cavity with sutures (at the time of caesarean or myomectomy) may damage the basalis, and cause apposition

of raw myometrial surfaces; subsequent healing by fibrosis leads to intra-uterine synechiae (adhesions) forming, a condition called Ashermanns syndrome.

BLOOD SUPPLY The main blood supply of the uterus is via the uterine arteries, which are branches of the anterior division of the internal iliac artery. The uterine arteries cross the ureters about 2 cm lateral to the isthmus, and enter the substance of the uterus at that level. They run up the lateral surface of the uterus in a tortuous manner, and anastomose with branches of the ovarian arteries (the secondary blood supply to the uterus) within the mesosalpinx/broad ligament. The main trunks send branches anteriorly and posteriorly (the arcuate arteries), and these also send branches from superficial to deep, towards the endometrium (the radial arteries). The radial arteries branch to give the straight arteries, which supply the basalis layer of the endometrium; the hormonally dependent spiral arteries develop from these to supply the functionalis layer of endometrium, during each menstrual cycle. After delivery, contraction of the uterus, and specifically the middle latticework of fibres, results in closure of the spaces through which the radial arteries traverse. This results in external constriction of the vessels, and limits post partum blood loss, especially from the placental bed This is the main haemostatic mechanism of the post partum uterus Thus, uterine atony is the most common causes of post-partum haemorrhage (75%-80% of cases) The dual blood supply of the uterus makes it possible to do uterine artery ligation to control PPH, while still maintaining viability of the organ
Where four pedicle ligation is done (both uterine and ovarian arteries) in cases of even

more severe PPH, the uterus is maintain by the opening of additional anastomotic channels in the round ligament: the artery of the round ligament (Sampsons artery), which
is a branch of the inferior epigastric artery

The veins of the uterus drain into the Pampiniform plexus of veins which lie adjacent to the uterus, and then to the uterine veins and the internal iliac veins.

LYMPHATIC DRAINAGE The lymphatic vessels of the uterus are poorly developed, and essentially drain in three directions: One plexus is located just beneath the endometrium, and drains the body of the uterus, through the broad ligament, to the internal and external iliac nodes A small plexus of lymphatics runs superficially across the fundus, and interconnects the lymphatics of the two ovaries. This system drains via the ovarian ligaments to the para-aortic lymph nodes A small amount of lymphatic drainage occurs along the round ligament, and ends at the superficial inguinal nodes The paucity of lymphatic drainage from the uterus (along with the thick, muscular walls of the uterus) limits the spread of endometrial cancer, and confers an excellent prognosis for that particular malignancy, as it is less likely to have spread when it is detected

NERVE SUPPLY The uterus receive neurons from both the sympathetic (thoracolumbar; T12-L3) and parasympathetic (sacral; S2-S4) systems. The sympathetic roots form the abdominal aortic plexus, which then runs inferiorly to the pelvic brim to form the superior hypogastric plexus. This splits at the level of L5/S1 to form the left and right hypogastric (presacral) nerves. These nerve fibres then mix with parasympathetic sacral roots to form the left and right inferior hypogastric plexuses. These plexuses subdivides into vesical, middle rectal and uterovaginal (Frankenhauser's) plexuses. Frankenhauser's plexus lies just lateral to the uterosacral ligaments,

and nerve fibres enter the uterus by this structure. Sympathetic stimulation causes uterine relaxation; parasympathetic stimulation causes uterine contraction. The corpus, cervix and proximal fallopian tubes transmit pain through sympathetic fibers that arise from T10-L1. These fibers include neurons that are part of the uterosacral ligaments, and eventually coalesce into the presacral nerve (see above) Frankenhauser's plexus lies just lateral to the uterosacral ligaments and medial to the uterine arteries, and receives pain sensations only from the corpus and vagina Transection of the uterosacral ligaments and Frankenhausers plexus at laparoscopy (LUNA: laparoscopic uterosacral nerve ablation) can help with chronic pelvic pain Unlike presacral neurectomy (which can also help relieve central pelvic pain, but which can affect bladder and rectal function), transection of Frankenhauser's plexus during a laparoscopic uterosacral nerve division should not result in constipation or bladder distention NOTE: the presacral nerve does not receive fibers from the ovaries and lateral pelvic structures, which is why LUNA or presacral neurectomy are applicable only to midline pain; the lateral pelvis transmits pain via parasympathetic neurons ("Nervi Erigentes") arising from S2-S4

THE CERVIX
The cervix is the most inferior portion of the uterus, which projects into the vagina. The cervix serves important roles as a lymphatic organ important in maintaining the sterility of the upper genital tract in the non-pregnant female, and in maintaining a pregnancy until term, and then facilitating parturition by dilating and allowing expulsion of the products of conception. Its dynamic nature makes it susceptible to neoplastic change, and cervical carcinoma remains the most common gynaecological malignancy in developing countries, although it is arguably the most preventable.

EMBRYOLOGY The uterus, tubes, cervix, and most of the vagina, are derived from the paramesonephric (or Mullerian) duct system. These ducts arise from an invagination (infolding) of the coelomic epithelium on the surface of the urogenital ridge, to form a groove; the surface epithelium then regrows to cover the top of the groove, resulting in a tubular structure within the mesoderm of the ridge. (see illustrations). The paramesonephric ducts, as the name implies, are developed on the framework of the mesonephric ducts, and they have three regions: a vertical upper section running lateral to the mesonephric ducts; a horizontal section which crosses the mesonephric ducts; and a lower vertical segment which runs medial to the mesonephric ducts. The medial portions of the lower vertical segments of the pair of ducts fuse in the midline, from the caudal ends upwards. Thus, a single structure with a double-barrel lower end is formed. The intervening septum then dissolves, again in a caudal to cephalic direction, leaving a single, central tube in the midline. (see illustrations). This structure is called the uterovaginal primordium, and forms the basis of the inner linings of the fallopian tubes, the endometrial glandular epithelium, the endocervical lining, and the epithelium of the vagina. The stroma and muscular and connective tissue elements of the walls of these structures are induced and formed from the surrounding mesoderm. By week 12, the fundus rises, and the uterus assumes its mature morphologic pear shape. This entire process is completed by the 22nd week of development and results in the

formation of 2 fallopian tubes, a single uterus, and the uterine cervix (and the upper two thirds of the vagina).

GROSS ANATOMY The cervix is a cylindrical organ which is ranges from about 4-6 cm in length, and 2-3 cm in diameter. About half of it projects from the body/isthmus of the uterus into the vagina (this portion is called the portio vaginalis), and thus, it has both a peritoneal portion and a vaginal portion, which are roughly equal in length. The cervix has a spindle shaped canal which provides continuity with the vagina inferiorly and the endometrial cavity superiorly. The canal is flattened anteroposteriorly, and is up to 5 or 6 mm wide at its widest point (near the middle). The inferior opening of the canal into the vagina is called the external os, and the superior opening into the endometrial cavity the internal os; the circular muscle in the region of the internal os is well developed, and has a sphincter-like function. The external os has no function per se, but its appearance can give info about parity: it appears slit-like in nulliparas, but somewhat rounded in multiparas. The relations of the cervix are: The body of the uterus, superiorly The vagina, inferiorly The bladder base and anterior fornix, anteriorly The uterosacral ligaments, Pouch of Douglas and rectum, and the posterior fornix, posteriorly The cardinal ligaments, ureters, and lateral vaginal fornices, laterally

The relationship of the cervix to the bladder base means that inflammation during a cervicitis can spread contiguously to the bladder base, resulting in urinary symptoms Likewise, spread of inflammatory mediators from a cystitis may cause cervical changes (and uterine activity) and lead to preterm labour Since cervical cancer spreads mainly by direct invasion (and lymphatics) knowledge of the immediate relations explains the staging of cervical cancer

HISTOLOGY The intra-peritoneal portion of the cervix is covered by a layer of peritoneum, except for the region under the uterovesical fold, behind the bladder; here it is connected to the bladder base by loose areolar connective tissue. The surface of the vaginal portion of the cervix (the ectocervix) is lined by stratified, squamous, non-keratinized epithelium. In contrast, the endocervical canal is lined by a single layer of columnar, glandular type epithelium, which is quite convoluted, and thrown into glands and crypts. Inflammation and occlusion of the mouths of these glands leads to them becoming swollen and cystic (Nabothian cysts) The convoluted nature of the cervical glands gives many potential hiding places for pathogens, making certain STIs difficult to treat (i.e. require long courses of medication) There is an area of metaplasia where one type of mature tissue changes into another, called the transformation zone (TZ); the external well demarcated edge of the transformation zone is called the squamo-columnar junction. The TZ is located wholly on the ectocervix prior to menarche, but with the influence of estrogen after menarche, it migrates to lie around the external os. In the post-menopausal woman the migration continues, such that the TZ may lie partially or wholly in the endocervical canal. The standard Ayres spatula is appropriate for Pap smears in the female of child bearing age; however, an extended tip spatula, and/or endocervical brush is better for the post menopausal female The immaturity of the TZ, in addition to its location on the ectocervix, make it more prone to persistent infection with the human papilloma virus (HPV) in very young girls; hence, the association between early age of menarche with cervical carcinoma The presence of an area of actively dividing cells, which naturally undergo metaplasia, make the cervix particularly prone to the influence of HPV, causing it to potentially

undergo neoplasia. In contrast, though men also have similar rates of HPV infection, the rate of penile cancer is significantly lower, as the penile epithelium is static The walls of the cervix are composed of variable amounts of smooth muscle, elastic fibres, and collagen fibres, embedded within an extracellular matrix composed of hyaluronic acid, chondroitin sulphate, peptidaminoglycans, and mucopolysaccharides. The smooth muscle content of the cervix is greatest at the level of the internal os, and decreases as the external os is approached. The opposite is true for connective tissue. The presence of collagen and the connective tissue elements of the normal cervix give it a firm consistency. At the end of a pregnancy (and/or after induction with misoprostol) prostaglandins cause the increased production of collagenase, elastase, hyaluronidase, and matrix metalloproteinases, which facilitate the hydrolytic degradation of the connective tissue elements. Hence, water content is increased, with a corresponding decrease in structural connective tissues, and the cervix becomes soft and more easily distensible (i.e. it is ripened).

BLOOD SUPPLY The cervix is supplied by branches of the uterine and vaginal arteries, both of which are branches of the anterior division of the internal iliac artery. Likewise, the veins from the cervix drain to vessels from both areas, culminating in the internal iliac veins.

LYMPHATIC DRAINAGE Due its function in prevention of infection of the uterine cavity by vaginal commensals (and other frank pathogens) the cervix has a rich and complex lymphatic supply. These vessels form a large plexus in the tissues immediately surrounding the cervix (the parametrium), and then drain in three main directions:

Anterior to the ureter, to eventually end in the lymph nodes surrounding the external iliac vessels

Posterior to the ureter, to eventually end in the lymph nodes surrounding the internal iliac vessels

Deep/posterior to the cervix, to end in the obturator and presacral nodes

Drainage from the common, external and internal nodes subsequently moves to the para-aortic group of nodes in the abdomen. Radical hysterectomy involves the removal of the uterus, cervix, cuff of vagina, and the parametrium, and is done with bilateral pelvic lymphadenectomy; thus all of the initial areas of spread of cervical cancer are removed, in an attempt to cure the disease

NERVE SUPPLY The cervix receives neurons from both the sympathetic (thoracolumbar; T12-L3) and parasympathetic (sacral; S2-S4) systems. The sympathetic roots form the abdominal aortic plexus, which then runs inferiorly to the pelvic brim to form the superior hypogastric plexus; this splits at the level of L5/S1 to form the left and right hypogastric nerves. These nerve fibres then mix with parasympathetic sacral roots to form the inferior hypogastric plexus: this plexus subdivides into vesical, middle rectal and uterovaginal (Frankenhauser's) plexuses. Frankenhauser's plexus lies just lateral to the uterosacral ligaments, and nerve fibres enter the uterus and cervix by this structure. The corpus, cervix and proximal fallopian tubes transmit pain through sympathetic fibers that arise from T10-L1. These fibers include neurons that are part of the uterosacral ligaments, and eventually coalesce into the presacral nerve. In addition, the endocervical canal (and especially in the region of the internal os) has been shown to have numerous free nerve endings, which conduct pain (e.g. during dilatation and curettage).

THE OVARY
EMBRYOLOGY The urogenital ridge is formed by the intermediate mesoderm stretching from the lower thoracic region down to the cloaca. The primitive gonad forms in the middle region, as a result of thickening of both the coelomic epithelium and the underlying mesoderm. The primitive gonad is consequently attached by its upper and lower poles by bands of connective tissue, called the gonadal bands, or gubernaculae (singular: gubernaculum). These structures secure the gonads cranially and caudally. Thus, there is a thickened central area of mesoderm, which eventually forms the medulla, covered by coelomic epithelium, which eventually forms the peritoneum. During early embryonic development, cells from the dorsal endoderm of the yolk sac migrate along the hindgut to the gonadal ridge. These primordial germ cells (PGCs) multiply by mitosis and once they have reached the gonadal ridge they are called oogonia (diploid stem cells of the ovary). Once they reach the ridges, they are surrounded by cells of the epithelium, and carried into the mesoderm by projections of this epithelium; thus, the first primordial follicles are formed. Around this time, the superficial aspects of the mesoderm become condensed and thicken into a poorly developed layer of connective tissue, the tunica albuginea. Thus, the four regions of the ovary are laid out: 1. 2. 3. 4. Germinal epithelium Tunica albuginea Cortex, with all the follicles, and Medulla, with all the vascular, lymphatics, and nerve structures.

At first, the mesonephros and gonadal ridge are continuous, but as the embryo grows area of the developing gonad gradually becomes pinched off from the mesonephros. However, the gonad still remains connected to the remnant of that body by a fold of peritoneum, namely the mesovarium.

The gubernaculum in the female lies in contact with the fundus of the uterus and adheres to this organ, and thus the ovary can only descend as far as to this level. In females, the upper part of the gubernaculum, together with the ovarian artery and vein form the infundibulopelvic ligament of the ovary, which suspends the ovary from the pelvic wall. The lower gubernaculum (between the ovary and the uterus) ultimately becomes the proper ovarian ligament, while the part between the uterus and the labium majus forms the round ligament of the uterus.

GROSS ANATOMY The ovaries usually appear as glistening, white ovoid structures, just lateral and posterior to the uterine body; in younger women the surface may be smooth, but it becomes somewhat scarred and pitted as time passes, due to repeated ovulation. The position of the ovary is extremely variable, and may change based on the time in the menstrual cycle, pregnancy, and/or uterine or adnexal pathology (fibroids, ovarian masses, endometriosis, adhesions, etc). The ovary generally lies on the lateral wall of the true pelvis, within the area demarcated by the bifurcation of the iliac vessels, called the Fossa of Waldeyer. Thus, it is bound superiorly and laterally by the external iliac artery, and inferiorly and medially by the internal iliac vessels. It lies just anterior to the ureter at this point, and behind the broad ligament. In young, nulliparous, non-pregnant women the ovary is ovoid, and measures about 3 x 2 x 1 cm in dimensions; in post-menopausal women the ovary becomes flattened and shrunken. It is held in place by the peritoneum of the broad ligament (to which it is attached by the mesovarium), by the ovarian ligament, and by the suspensory (infundibulopelvic) ligament of the ovary. Of note is the fact that the peritoneum of the broad ligament stops at the mesovarium and does not cover the ovary itself.

BLOOD SUPPLY The blood supply to the ovary arises from the abdominal aorta at the level of the renal arteries. The ovarian artery passes laterally, anterior to the ureter, and inferiorly into the pelvis. The ovarian artery is an extremely small vessel but supplies the ovary and anastomoses along the

fallopian tube with the uterine artery. The venous drainage of the ovary, however, often involves more than one vein, draining more blood than the artery supplies. On the right side the ovarian vein drains into the inferior vena cava, and on the left side into the left renal vein. The veins follow the route taken by the arteries.

LYMPHATICS The lymphatic drainage of the ovary reflects its origin, as the vessels drain upwards along the ovarian vessels to the para-aortic lymph nodes. Of note, the lymphatics of one ovary may also cross the fundus of the uterus to get to the other ovary, and subsequently drain to the lymph nodes.

NERVE SUPPLY The innervation of the ovary is entirely by the autonomic nervous system through the aortic plexus related to the T10 spinal cord segment. The blood supply, nerve supply and lymphatics all reach the ovary along the suspensory (infundibulopelvic) ligament.

HISTOLOGY The outer surface of the ovary is covered by a single layer of cuboidal epithelium, the germinal epithelium, which is a derivative of the coelomic epithelium seen in the developing embryo. Deep to the epithelium is a layer of poorly developed connective tissue, called the tunica albuginea. The inner region of the ovary can be divided into an outer cortex and inner medulla. The cortex is formed of follicles in various states of development, which are embedded within a loose connective tissue. The medulla consists of the same loose connective tissue, along with numerous blood vessels, lymphatics and nerves. At birth, there are approximately two million ova, within primordial follicles, distributed between the two ovaries; the egg is suspended in prophase of the first meiotic division. Of the two million ova generated before birth, most degenerate before puberty leaving about 40,000

being viable. Each month, a cohort of six to eight follicles will begin maturating, but only one generally develops into a Graafian follicle for ovulation; thus, only about 400 will pass through the complete process of maturation to ovulation, in a womans lifetime.

FOLLICULAR DEVELOPMENT Primordial follicles are located in the cortex just beneath the tunica albuginea. They consist of a single layer of flattened epithelial cells surrounding the oocyte. The primary follicle is the first morphological stage that marks the onset of follicular maturation. The previously flattened cells surrounding the oocyte now form a cuboidal or columnar epithelium surrounding the oocyte. Their cytoplasm may have a granular appearance, and they are for this reason also called granulosa cells. The continued proliferation of these cells will result in the formation of a stratified epithelium (with a distinct basement membrane) surrounding the oocyte. At this point, a special glycoprotein layer called the zona pellucida becomes visible. In addition, the stromal connective tissue surrounding the growing follicle becomes organised in concentric sheaths, the theca folliculi. This aspect of follicular maturation is independent of hormonal control, and takes several months to complete.

The secondary follicle is formed as small fluid-filled spaces become visible between the granulosa cells. These spaces enlarge and fuse to form the follicular antrum, which is the defining feature of the secondary follicle. The oocyte is now located eccentrically in the follicle in the cumulus oophorus (a surrounding layer of granulosa cells). The theca folliculi differentiates with the continued growth of the follicle into a theca interna and a theca externa. Vascularization of the theca interna improves, and the spindle-shaped or polyhedral cells in this layer start to produce steroid hormones, particularly androgens and estrogen. The theca externa retains the characteristics of a highly cellular connective tissue with smooth muscle cells.

The mature (a.k.a. tertiary, pre-ovulatory or Graafian follicle) increases further in size to a maximum of 18 to 20 mm (in particular in the last 12 hours before ovulation). The egg is now more or less central within the follicle, being held in the fluid of the antrum by the bridge of cumulus oophorus cells, and surrounded by a layer of granulosa cells called the corona radiata. The Graafian follicle forms a small "bump" on the surface of the ovary, where there is thinning of the capsule and a progressive restriction of the blood flow to it. The follicle finally ruptures at the stigma and the oocyte is released from the ovary into the peritoneal cavity, where it is picked up by the fimbrial end of the ipsilateral fallopian tube. At ovulation the division of the ovum is again arrested, this time at metaphase. Division proceeds only if the ovum is fertilized. All of these stages may be present in the ovary of an ovulating woman. Following ovulation the granulosa cells of the follicle are transformed into the secretory cells of the corpus luteum, which produces progesterone. If the ovum is not fertilized the corpus luteum degenerates after about ten to twelve days. The degenerating corpus luteum eventually sinks into the stroma of the ovary as a white scar, or corpus albicans.

THE PHYSIOLOGY OF THE MENSTRUAL CYCLE

The menstrual cycle is a complex series of endocrine events, involving the hypothalamus, pituitary, ovaries and the uterus. Its ultimate aim is the production of a mature egg, which may then be fertilized if sperm are present in the genital tract; thus, it forms the basis for human reproduction. The number of hormones and organs involved in the process raises the potential for abnormalities in the process to occur, and disorders associated with abnormalities of menstruation are among the most common problems seen by physicians in general, and gynaecologists in particular. In addition, understanding of the menstrual cycle forms the basis for: understanding other common pathologies (such as polcystic ovarian syndrome [PCOS], and endometriosis) understanding the principles behind contraception, and conversely, of assisted reproductive techniques

By definition, it is difficult to identify a starting point or an end to a cycle. By convention, however, it is understood that the menstrual cycle is said to begin on the first day of flow. It is subsequently divided into two stages, separated by two events. The names used to describe the phases are related to the events occurring during those phases. Thus, the following are described: The follicular phase / proliferative phase Ovulation The luteal phase / secretory phase Menstruation

THE FOLLICULAR PHASE The follicular phase of the menstrual cycle spans the first day of menstruation until ovulation. The primary goal during the follicular phase is to develop a viable follicle capable of undergoing

ovulation. As previously stated, this first phase begins with the onset of the menstrual flow. At this point the levels of circulating ovarian hormones are quite low, and so the hypothalamus and anterior pituitary are released from negative feedback. As a result, the hypothalamus secretes increasing amounts of gonadotrophin releasing hormone (GnRH) in a pulsatile manner. The increasing amount of circulating GnRH stimulates particular cells in the anterior pituitary to increase production of two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH). GnRH controls the release of both FSH and LH: low frequency pulses favour FSH release, while high frequency pulses favour LH secretion. Both FSH and LH are glycoprotein hormones, whose molecules consist of an alpha and a beta subunit. FSH and LH exert their effect primarily on the ovaries, where they stimulate a cohort of follicles, preselected from several months before. LH induces the stroma surrounding this group of follicles to become more vascular and organized, forming the theca interna and externa. This tissue actively produces androgens which diffuse in to the follicle that it surrounds. Meanwhile, under the influence of FSH, the single layer of epithelial cells (granulosa cells) surrounding the oocyte is stimulated to proliferate, forming a multilayered structure immediately surrounding the oocyte; these granulosa cells convert androgens to estrogens by aromatization. Thus, LH and FSH act on the theca and granulosa cells, respectively, resulting in the production of androgens, and subsequently of estrogens. This is called the two cell two gonadotropin hypothesis. The follicles pass through stages of maturation: Primordial follicles consist of an oocyte surrounded by a single layer of flattened epithelial cells Primary follicles have a single layer of cuboidal granulosa cells surrounding the oocyte Secondary follicles have multiple layers of granulosa cells surrounding the oocyte, and begin to form a small fluid filled cavity (called the antrum) within themselves. This fluid displaces the oocyte to an eccentric position within the follicle Further growth of the follicle is effected by an increase in number of layers of granulosa cells around the oocyte, and by an increased volume of fluid within the antrum

The tertiary follicle (also called the dominant, pre-ovulatory, or Graafian follicle) is characterized by the suspension of the oocyte in the antral fluid by a bridge of cells within the it, and by bulging of the follicle through the surface of the ovary

FSH increases the receptors for both itself and for LH, on both the thecal tissue and on the granulosa cells. This is of particular importance because as the follicles mature and more estrogen is elucidated, negative feedback causes the concentrations of circulating FSH and LH to fall. Thus, only the follicle with the most FSH receptors can survive in the environment of progressively decreasing FSH; this is the basis for the selection for the single dominant follicle produced during each cycle. The endometrium at the beginning of the menstrual cycle consists of the layer of basal endometrium only. As the levels of estrogen rise, the basal layer of endometrium is stimulated to begin intense mitotic division, and so to proliferate, resulting in the growth of a layer of tall columnar cells lining the endometrial cavity. The influence of estrogen also causes the stroma (loose connective tissue between the epithelial cells and the basal layer) to proliferate, resulting in increased thickness of the endometrial layer as a whole. The stroma also contains blood vessels, the spiral arteries; these also increase in length and branching within the stroma, and become somewhat more coiled as the proliferative phase progresses. As the endometrial epithelium grows, it is thrown into folds which delve into the stroma, forming simple tubular glands. These cells of these glands produce small amounts of glycogen within them, but it is not secreted from the cells in this phase.

OVULATION Rising levels of estrogen cause decreased levels of FSH and LH, until only one dominant follicle remains; the other follicles undergo atresia, as they cannot survive in the low FSH environment. Histologically, the Graafian follicle now consists of a large fluid filled cavity called the antrum, which contains the oocyte arrested in prophase of meiosis I, and surrounded by a layer of granulosa cells called the corona radiata granulosa cells. The oocyte is suspended centrally within the fluid of the antrum by a stalk of granulosa cells called the cumulus oophorous

granulosa cells (or simply cumulus cells). The follicle bulges through the surface of the ovary, to form a blister. Estrogen continues to be elucidated by the Graafian follicle, and levels continue to increase until they exceeds a certain threshold; at this point, through an as yet unknown mechanism, the influence on the pituitary switches from negative to positive feedback, resulting in a surge of LH, and to a lesser extent, of FSH. This LH surge causes multiple events to occur: the primary oocyte enters the final stage of the first meiotic division, yielding two cells: the larger secondary oocyte that contains all of the cytoplasmic material and a smaller, inactive first polar body Meiosis II follows at once but will be arrested in the metaphase and will so remain until fertilization the cumulus oophorous is disrupted, allowing the egg to float freely within the antral fluid the volume of antral fluid, and therefore the pressure within the follicle, increases dramatically proteolytic enzymes are secreted by the follicle that degrade the follicular tissue at the site of the blister, forming a hole called the stigma the oocyte is expelled through the stigma, into the peritoneal cavity, where it is picked up by the fallopian tube on that side Ovulation tends to occur 24 36 hours after the LH surge. The cumulus-oophorous complex is wafted along the tube by ciliary action in the ampullary region, and by peristalsis like motion in the proximal, narrower, more muscular aspect of the tube. Degeneration of the oocyte occurs after about 24 hours if fertilization does not take place.

THE LUTEAL PHASE The LH surge triggers changes in the granulosa cells of the now collapsed follicle, wherein there is ingrowth of new blood vessels, deposition of lipids within the cells the collapsed structure (granulosa and thecal cells), and a switch in sensitivity to gonadotropins (sensitivity to LH

increases; sensitivity to FSH decreases). This process is called luteinization; the structure is now referred to as the corpus luteum, and results in a decreased production of estrogens, and a significant rise in progesterone production. Progesterone concentrations rise to a peak 7-8 days following ovulation, and stabilize for a day or two. The combination of increased progesterone, coupled with the influence of the remaining estrogen, act by negative feedback to inhibit further production of pituitary hormones, effectively diminishing the support for the corpus luteum. Consequently, progesterone levels fall rapidly as the corpus luteum fails (if fertilization does not occur), reaching a nadir by the 13th or 14th post ovulatory day, when menstruation begins. Thus, the luteal phase of the menstrual cycle is relatively constant at 14 days; variation in cycle length is due to differences in the duration of the follicular phase. The initial increased levels of circulating progesterone cause cessation of mitotic activity within the endometrium, through down regulation of estrogen receptors, and by up regulation of the enzymes that degrade estrogen, so overall endometrial growth stops at that point; however, the glands and vasculature continue to develop. The glands increase production of their glycogen rich material, becoming more filled and dilated, and then more tortuous as they do so. By the middle of the luteal phase they have begun to release this product into the endometrial cavity, coating the endometrium with a nutritive substance referred to endometrial milk. Consequently, the spiral vessels have an increased demand placed on them to supply the glands with substrates, so they too become hypercoiled and dilated, as they attempt to satisfy this increased demand. The stromal cells of the endometrium also become larger and better defined, and somewhat oedematous, as the luteal phase progresses. Progesterone is necessary for the maintenance of the endometrial cellular structure, so as its levels begin to decline in the late luteal phase several things happen. Progesterone causes stabilization of the intracellular lysosomal membranes, as well as causing a down regulation of inflammatory cytokines, prostaglandins, and matrix metalloproteinases. Lysosomal stability is reduced with the withdrawal of progesterone, and the release of lysosomal phospholipases causes the increased liberation of arachidonic acid, which is then converted into prostaglandin F2alpha. This prostaglandin is the cause of the spasmodic contractions of the uterus during menstruation, which is meant to be haemostatic, but which is perceived as menstrual cramps.

Progesterone withdrawal and the consequent shift to vasoconstrictory prostaglandins also results in vasoconstriction and ischaemia of the spiral arteries; these eventually rupture, leading to worsening endometrial ischaemia, and eventual sloughing of the entire epithelial surface. Thus, the menstrual flow begins, and the cycle begins anew.

RELATED INFORMATION GnRh is a peptide hormone produced and released by specialized neurones in the preoptic area of the hypothalamus The hypothalamus constantly secretes GnRH after puberty, and always does so in a pulsatile manner, but the amount varies throughout the cycle by virtue of the frequency and amplitude of these pulses This pulsatility is required for the normal action of GnRH; constant elevated levels of GnRH causes a transient flare of activity in the pituitary, followed by a down regulation of receptors, and therefore reduced production of pituitary hormones GnRH levels are regulated through negative feedback by estrogens and androgens, primarily; progestins have a lesser effect The GnRH producing neurons also have insulin receptors on them; stimulation of these receptors by increased circulating insulin, or insulin like growth hormone, leads to a high frequency GnRH secretion

FSH, LH, TSH, and hCG all share the same alpha subunit; their biological activity varies based on the structure of the beta subunits hCG and LH function very similarly. Thus, hCG replaces the function of LH if an egg is fertilized and implanted, and maintains the endometrium (and therefore the pregnancy) until the end of the first trimester, when the trophoblastic production of progesterone is enough for self-maintenance

THE PHYSIOLOGY OF LABOUR

Labour is defined as regular uterine activity (contractions), which leads to progressive cervical change (dilatation and effacement), resulting in eventual expulsion of the products of conception.

THE ANATOMY OF THE BREAST

GROSS ANATOMY The breasts are fairly symmetrical double organs. The breasts reach normal size between 16 and 19 years, and the mature, non-pendulous, adult breast lies between the second and sixth ribs in the vertical axis, and between the sternal edge and the mid-axillary line in the horizontal axis. Breast tissue also projects into the axilla as the axillary tail of Spence. The breast comprises three major structures: skin, subcutaneous tissue, and breast tissue, which is composed of both epithelial and stromal elements. The epithelial components are branching ducts which connect the structural and functional units of the breast (the lobules) to the nipple. The stroma, which comprises the majority of the breast volume in the non-lactating state, is composed of adipose and fibrous connective tissue. The skin of the breast is thin, and contains hair follicles, sebaceous glands, and exocrine sweat glands. In the lower part of the breast the skin forms a groove (sulcus submammalis). The nipple areola complex has abundant sensory nerve endings, sebaceous and apocrine sweat glands, but not hair follicles. The areola is circular and pigmented, measuring 15 to 60 mm in diameter. The Morgagni tubercles, which are located near the periphery of the areola, are elevations formed by the openings of the ducts of the Montgomery glands, large sebaceous glands that represent an intermediate stage between sweat and mammary glands. The superficial pectoral fascia envelops the breast, and is continuous with the superficial abdominal fascia (of Camper). The undersurface of the breast lies on the deep pectoral fascia, covering the pectoralis major and serratus anterior muscles. Connecting these two fascial layers are fibrous bands (the Cooper suspensory ligaments) that represent a natural means of support for the breast.

HISTOLOGY Each gland drains into a small collecting ductule, and groups of these glands and ductules drain into bigger ducts. Groups of these glands and their duct systems from lobules, and groups of

lobules subsequently form lobes (usually 15-20). Each lobe originates embryologically from a secondary bud, and therefore has its own draining duct, and these ducts converge toward the areola, just beneath which each one expands to form a dilated region (sinus lactiferus), and then again become contracted and narrow before opening at the nipple. Lobes and its ducts are radial aligned around the nipple.

BLOOD SUPPLY The principal blood supply of the breast is derived from the internal thoracic/internal mammary artery. Approximately one-third of the blood supply (mainly to the upper outer quadrant, and deeper regions, respectively) is provided by the lateral thoracic arteries, and the underlying intercostal arteries. The veins of the breast describe an anastomotic circle round the base of the nipple, called the circulus venosus. From this, large branches transmit the blood from the medial part of the breast into internal thoracic veins, and from the lateral part of the breast into lateral thoracic vein and intercostal veins. Thus, the venous drainage ultimately follows the arterial supply.

LYMPHATIC DRAINAGE The lymphatic drainage of the breast is through both superficial (subepithelial and subdermal) and deep lymphatic vessels, and the lymph flows unidirectionally from the superficial to the deep plexus. Lymph flow from the deep subcutaneous and intramammary vessels moves centrifugally toward the axillary and internal mammary (IM)/parasternal lymph nodes. Approximately 3 percent of the lymph from the breast is estimated to flow to the IM chain (these are the only lymph vessels that pass by axillary lymph nodes), whereas 97 percent flows to the axillary nodes. It is important to mention that this drainage to the axillary nodes occurs to both ipsilateral and contralateral lymph nodes.

NERVE SUPPLY Intercostal nerves innervate the breast. Branches of the supraclavicular nerves also innervate part of the superior part of the breast.

PHYSIOLOGY OF LACTATION
Mammogenesis Development of the human breast begins during week 4 of fetal life, when a thickening of ectoderm occurs from the region of the axillae to the inguinal region, in a curvilinear fashion (curved medially). This is called the mammary ridge, or milk line, and it subsequently regresses so that the thickened ectodermal tissue remains in the thoracic region only, where the mammary gland then develops. Failure of regression of part of the ridge may result in accessory nipples (polythelia = more than two nipples), +/- breast tissue (polymastia), at any point on the mammary ridge. The ectoderm then grows downwards into the underlying mesoderm as a solid diverticulum, to form a primary mammary bud; this bud then forms 15-20 branches (secondary buds), which continue to grow and branch within the mesoderm. Each secondary bud eventually results in the formation of a lobe of the adult breast, which is drained by a single lactiferous duct; hence, there are 15-20 lobes in each breast. The branching of the secondary buds is influenced by the presence of maternal hormones, such as progesterone, growth hormone, insulin-like growth factor, estrogen, prolactin, adrenal corticosteroids, and tri-iodothyronine. These hormones support the growth of the ectodermal tissue, and as the branches grow and thicken, their cores become distanced from the hormonal supply; these cells then undergo death by apoptosis, and their degradation results in canalization of the buds to form ducts.

The fibrous connective tissue, Cooper ligaments, and fat of the mammary gland develop from the surrounding mesoderm. The in-growth of the ectoderm also stimulates the mesoderm surrounding the original area of ectodermal proliferation, creating the nipple with circular and longitudinally oriented smooth muscle fibers. The surrounding areola is formed by the ectoderm during the fifth month of gestation.
At birth, the breast rudiment is formed by 15 to 20 primitive ductal elements located beneath the nipple-areola complex. In the pre-pubertal years, these ducts exhibit relatively slow but steady growth and branching, with canalization into additional ductal structures. No true glandular elements are present at this point. In boys, breast development ceases at this stage.

At puberty, in females, the production of increased levels of estrogen and progesterone cause an increase in growth and development of the epithelial/ductal tissue. The ends of the ducts proliferate to form club shaped terminal end buds, and further branching occurs from these structures, and from the sides of pre-existing ducts (lateral buds). Additional adipose and connective tissue is deposited at this time as well, resulting in an increase in breast size and shape. The Tanner staging system describes the development of the breast during puberty. Stage I refers to the pre-pubertal breast, where the there is no elevation of the breast compared to the surrounding skin, and all the breast tissue is located beneath the nipple-areola complex. In stage II, the breast bud forms as a result of growth of glandular tissue located under the areola; the areola consequently begins to widen, but the surface contour of the breast remains continuous with that of the surrounding skin, and all the breast tissue remains located beneath the nipple-areola complex. In stage III, the breast begins to become more elevated, and breast tissue extends beyond the borders of the areola, which continues to widen but remains in contour with surrounding breast. At stage IV, there is further increase in breast size and elevation, and the areola and nipple form a secondary mound projecting from the contour of the surrounding breast (i.e. areolar surface becomes elevated above that of the surrounding skin). Stage V represents final adult size: the areola returns to the contour of the surrounding breast, with a projecting central nipple. As previously stated, growth of breast tissue is caused by the progressive branching of the ductal/epithelial elements within the stroma of the breast, to eventually form tiny ductules. When these ductules reach the limit of the fat pad of the breast laterally and/or in the deep tissue, or begin to encroach on branches from adjacent lobes, then growth ceases and the distal ends of the ductules develop into alveolar buds. Special cells called cap cells are located in growing ducts and ductules, and in alveolar buds, and they differentiate into the acinar cells of the mature alveolus, the luminal ductal epithelium, as well as the myoepithelial cells surrounding the alveoli and ducts. The cluster of these alveolar buds and the surrounding ductules form the lobules of the breast. Multiple lobules drain to a single lactiferous duct; this group of lobules forms a breast lobe. Lobule formation is apparent within one to two years after the onset of the menses. Thereafter, glandular development is variable. When an average of 11-12 alveolar buds/ductules cluster around a terminal duct, they form the type 1 (virginal) lobule. The changing levels of estrogen and progesterone during subsequent menstrual cycles stimulate the type 1 lobules to sprout new alveolar buds and evolve to more mature structures called type 2 and type 3 lobules. Full differentiation of the mammary gland

towards its maximal degree of branching and secretory activity (type 4 lobules) is a gradual process, and is only fully achieved with the advent of a term pregnancy.

The development of the alveoli and maturation of the epithelium that occurs in response to the hormonal changes of pregnancy is known as stage II mammogenesis, and progesterone plays a vital role during this phase. The maximum branching capability of the breast is expressed during this period, and the epithelial cells of the alveoli mature/differentiate to form secretory acini; this represents a terminal outgrowth that marks the full extent of glandular differentiation. Fully differentiated secretory acini are characterized by their ability to synthesize and secrete milk proteins (caseins) and lipids.

The breast attains its maximum development in pregnancy in two distinct phases, characteristic of the early and late stages of pregnancy. Ductular sprouting predominates in the first trimester, under the influence of estrogen, while lobular formation exceeds ductal sprouting in the second and third trimesters, under the influence of progesterone. At this stage, proliferation of new acini is reduced, and the lumen of already formed units becomes distended by the accumulation of secretory material or colostrum. Just before and during labour there is a final phase of mitotic activity within the mammary gland, and by this point, the glandular component of the breast has increased to the point where the breast is composed primarily of epithelial elements, with very little stroma. These changes persist throughout lactation. Estrogens are considered to play the major role in promoting proliferation of the breast epithelium, by stimulating DNA synthesis and promoting bud formation. These activities are mediated by a nuclear estrogen receptor (ER alpha), which activates transcription of specific genes. Progesterone acts in conjunction with estrogen to regulate breast development through its specific receptor (PR) on breast epithelial cells. Type 1 lobules contain the most receptors for estrogen, and consequently display the highest level of proliferative activity. This is mainly seen in the breasts of young nulliparous females. With progressive differentiation into type 2 and 3 lobules, under the hormonal influences of the menstrual cycle, and with increasing parity, due to the effect of placental hormones, there is a concomitant reduction in estrogen receptors and in proliferative activity. These biologic differences may have profound implications for cancer risk. Since the highest proliferative

capacity is present in type 1 lobules, these structures are more likely to undergo neoplastic transformation, and this supports the observation that type 1 lobules are the site of origin of ductal carcinomas. This also somewhat explains the protective effect of full term pregnancy from the development of ductal carcinomas of the breast (since more differentiation has occurred, less type 1 lobules exists). In contrast, women who have multiple first trimester losses are at increased risk of breast carcinoma, as there has been increased proliferation of ductal elements, without the progressive development and maturation of the glandular elements, which occurs later in the pregnancy.

Lactogenesis Lactogenesis refers to development of the ability to secrete milk, and involves activation of the mature alveolar cells. It takes place in two stages, secretory initiation and secretory activation. Stage I lactogenesis (secretory initiation) generally occurs during the second half of pregnancy, when the high levels of circulating progesterone cause complete maturation of the breast glandular tissue (type 4 lobular formation; secretory acini). However, these high hormonal levels also inhibit actual milk production in normal quantities. Small amounts of milk containing lactose and casein may be secreted in the second half of pregnancy, and some (usually multiparous) women are able to express colostrum. Stage II lactogenesis (secretory activation) is marked by the onset of copious milk production after delivery. This stage is triggered by the rapid decline in progesterone that follows delivery of the placenta, and requires the presence of elevated levels of prolactin and cortisol, as well as insulin.

Lactation, or galactopoiesis, is the process of continued secretion of copious milk. It requires regular removal of milk and stimulation of the nipple, which triggers prolactin release from the anterior pituitary gland and oxytocin from the posterior pituitary gland. Prolactin is produced by the anterior pituitary and released into the circulation. The regulation of prolactin levels in the plasma is controlled by the dopaminergic system.

 When prolactin is abnormally high (usually due to a micro- or macroadenoma of the pituitary), dopaminergic agonists such as bromocriptine may be used in therapy. In contrast, during lactation induction, drugs which have an anti-dopaminergic action (such as metoclopramide and domperidone) may be used to increase endogenous prolactin levels
Prolactin binds to cell receptors in the glandular tissue of the breast, and causes the synthesis of mRNA for milk proteins. It also mediates the increased production of lactose, and various lipids. Lactose is a disaccharide unique to milk, and is the primary determinant of milk volume as it is the major osmotic component of milk. Lactose is formed by lactose synthetase within the Golgi complex from glucose and galactose, and as it is formed water is drawn in to maintain osmotic equilibrium. The Golgi membrane and its vesicles are both impermeable to lactose. Contents of the vesicles are released into the milk compartment by exocytosis.

During pregnancy, high estrogen levels cause increased activity of the prolactin producing cells of the anterior pituitary. Consequently, prolactin levels rise greatly during pregnancy, peaking at up to 20 times normal at term. These levels remain elevated for months if breastfeeding is commenced and continued, but eventually decrease to normal even if weaning does not occur. Note that although the levels of prolactin fall, the volume of milk does not. In contrast, if breastfeeding is avoided, prolactin levels normalize within two to three weeks. The high levels of prolactin seen in the first few months of breastfeeding cause suppression of the hormonal axis which runs the menstrual period; hence, lactational amenorrhea occurs. In terms of numbers, this is one of the most common methods of contraception practiced world wide, particularly in poor/developing countries
Despite the fact that estrogens cause this increase in circulating prolactin, the high levels also cause a decrease in the ability and/or affinity of prolactin to bind its receptor on the glandular epithelium of the breast. After the placenta is delivered, however, the affinity of prolactin for its receptor rises by 7 to 8 fold, enabling lactation to occur. Subsequent to this, continued milk production (galactopoiesis) is facilitated by the stimulation of the breasts by the suckling infant: suckling causes increased afferent

stimulation to the pituitary, which maintains a high prolactin level. This firmly establishes lactation, and facilitates continuation of milk production.

Milk Ejection The alveoli are surrounded by a basket-like network of myoepithelial cells and blood vessels. Tactile stimulation of the nipple-areolar complex, in addition to prolactin release, leads to the increased production and release of oxytocin from the hypothalamic paraventricular nuclei to be stored in the posterior pituitary. Suckling at the breast stimulates the pituitary to release oxytocin into the blood, and upon delivery to the breast alveoli the hormone interacts with its receptor on the myoepithelial cells. The myoepithelial cells surrounding the alveoli then contract, forcing milk into the ducts from the alveolar lumens and out through the nipple. Contraction of ductal myoepithelium results in the ducts expanding rapidly to facilitate milk flow. Oxytocin also causes contraction of the uterus at these times. This aids in uterine involution, but is often experienced by the mothers as painful cramping. Opiates and B endorphins released during stress can block the release of oxytocin, resulting in delay of the "milk let down" reflex.

Cessation of Lactation After initial lactogenesis, sustained milk production is reliant on removal of milk on a regular basis; failure to remove milk disrupts milk production. Mechanism #1: The accumulation of milk within the alveolus causes distension and an elevation in pressure/tension in the breast (c.f. breast engorgement). This may cause an interruption in blood flow to the glandular elements, causing a reduction in supply of hormonal support and diminished substrate provision to the glands. Mechainsm #2: A sufficient increase in intra-mammary pressure may lead to disruption of the connections between glandular cells and their attachment to the basement membrane, thus disrupting the synthesis and secretion of milk components.

Mechanism #3: Galactopoiesis may be inhibited by a protein known as feedback inhibitor of lactation (FIL). This milk protein is synthesized by epithelial cells of the breast in response to increased intramammary pressure, and works by reversible down regulation of cell-surface prolactin receptors. The post-partum woman weans by gradually increasing the interval between feeds, and by not manually expressing milk during this time. The increasing duration of the breast being full results in decreased milk production (as outlined above), and eventually in involution of glandular tissue. The patient with an infant that is not with her immediately after birth (e.g. admitted to the nursery) must be encouraged to express milk regularly to initiate, and then maintain, galactopoiesis. If this is not established within the first week after birth, then it becomes significantly more difficult for successful lactation to be accomplished, as prolactin levels, and breast milk production, will rapidly decline.

THE URINARY BLADDER

The urinary bladder is a muscular, distensible, hollow viscus that serves to collect and store urine produced by the kidneys, until it can be expelled at an appropriate time and place; this expulsion of urine is called micturition, or urination. Proper bladder function is made possible by a complex series of voluntary and involuntary processes; abnormalities of anatomy of the bladder, its immediate relations, or both, may lead to a number of clinically and psychosocially important issues, such as incontinence of urine. Thus, a thorough understanding of this organ is crucial to prevent, diagnose and successfully manage problems related to it.

EMBRYOLOGY In the early stages of development, there is no separation of the urinary and alimentary tracts. A common chamber, known as the cloaca, forms in the caudal region of the fetus. This expanded region of the gut, now a potential receptacle for feces, urine, and reproductive products, absorbs the stem of each mesonephric duct, whereupon the remainder of the duct and the ureter acquire separate openings into it. It next subdivides into a rectum behind and a urogenital sinus in front. The sinus, in turn, will specialize into the urinary bladder and the urethra. At the caudal end of the cloaca, ectoderm lies directly over endoderm (with no intervening mesoderm) forming the thin cloacal membrane. As development progresses, a septum forms (Toureux's fold) dividing the hind gut from an anterior chamber, the urogenital sinus. This septum extends in a caudal direction. Two tissue folds arise from the lateral sides of the cloaca (Rathke's plicae). These folds move medially toward each other to complete the separation of the hind gut (anal canal) from the urogenital sinus. Tourneux's folds and Rathke's plicae together form the uro-rectal septum. The cloacal plate then gets divided into an anal membrane and a urogenital membrane with a perineal body in between. The mesonephric duct empties into the urogenital sinus. The urogenital sinus and the allantois enlarge to form the

urinary bladder. The distal ends of the mesonephric ducts become incorporated into the urinary bladder. The urogenital sinus then has three parts: the vesical portion (which becomes the urinary bladder), the pelvic portion of the urogenital sinus which becomes the proximal urethra in the female, and the the phalic portion of the urogenital sinus which becomes the vestibule and part of the urethra and vagina in the female.

After birth, the allantois degenerates and becomes the urachus forming the median umbilical ligament. The transitional epithelium of the bladder develops from endoderm of the urogenital sinus. The detrusor forms from surrounding mesoderm. The trigone of the bladder forms from the distal expansion of the two caudal ends of the ureters (which are also of mesodermal origin); this difference in embryological origin explains the difference in function in adult life.

GROSS ANATOMY The size and shape of the bladder depend on its state of fullness. When empty, it has the form of a somewhat flattened tetrahedron, with the vertex tilted forward (c.f. the bow of a ship); thus, it has four surfaces (superior, inferolateral x 2, and posterior) and four angles (apical, lateral x 2, and inferior). The apex of the bladder is connected to the umbilicus by the median umbilical ligament, which is the embryological remnant of the urachus. The lateral apices are connected to the ureters, and the edges bound by the lateral umbilical ligaments, which are the embryological remnants of the umbilical arteries. The inferior angle is connected to the

urethra. The triangular area formed between the insertion of the ureters and the entrance to the urethra is called the trigone; this region is important for embryological, anatomical and physiological reasons. The urinary bladder has a volume of less than 30 mls when empty, and 300-350 mls of urine when filled to the level where urination commonly takes place; a full adult bladder may holds as much as 500 mls of urine under physiological circumstances, and even more (upwards of 2 liters) when pathologically distended. The superior surface of the bladder is covered by peritoneum, and is flat or concave when the bladder is empty. The continuous layer of peritoneum which reflects from the superior surface of the bladder to the anterior surface of the uterus is called the uterovesical fold. As it fills, this surface rises, such that when the bladder is maximally filled it assumes a dome shape, and may be easily palpated in the abdomen. It is related to the body of the uterus (which is generally anteverted to lie slightly above it), and to loops of small bowel which lie in the pelvis. The posterior surface of the bladder is attached to the anterior surface of the uterus by loose areolar connective tissue, below the level of the uterovesical fold. This surface is also known as the trigone of the bladder. It is also closely related to the cervix, in its inferior aspect. The relationship of the cervix to the bladder base means that inflammation during a cervicitis can spread contiguously to the bladder base, resulting in urinary symptoms. The inferolateral surfaces of the bladder are related to the symphysis pubis and pubovesical ligament by the retropubic fat pad. The inner surface of the bladder is - generally - loosely attached to the muscular walls, and appears to be thrown into folds when the bladder is empty; when the bladder is full, the surface appears smooth. However, the epithelium of the trigone is firmly bound to the underlying muscle, and always appears smooth.

HISTOLOGY The bladder has four layers: serous, muscular, submucous, and endothelial. The serous layer is partial, as only the superior surface, and a small amount of the inferolateral surfaces, are lined by peritoneum. The muscle of the bladder wall, the detrusor, is composed of smooth muscle fibres arranged in three layers: outer longitudinal, middle circular/oblique, and inner longitudinal. The outer longitudinal fibres originate from the posterior surface of the pubic symphysis, and pass in a sling like fashion over the inferolateral surfaces, across the superior surface, and down the posterior surface, to attach to the anterior wall of the vagina. The fibers of the middle circular layer are thin and poorly developed, except for around the internal urethral orifice, where they are thick and well developed to form the internal urethral sphincter. The internal longitudinal layer is thin, and poorly developed except near the ureters; as the ureters enter the bladder obliquely, contraction of these fibres during micturition helps to prevent vesico-ureteral reflux. The submucous layer is composed of loose areolar tissue which is connected (loosely) to the muscle and (much more closely) to the endothelium. It facilitates the sliding of the endothelium over the muscle layer during distension/emptying of the bladder. The endothelium of the bladder is transitional, appearing as stratified columnar cells when it is empty; cuboidal when partially filled; and squamous when distended. The endothelium of the bladder is continuous with that of the ureters above (up to the level of the pelvis and calyces), and the urethra below.

BLOOD SUPPLY The bladder is supplied by the superior and inferior vesical arteries, which are branches of the anterior division of the internal iliac artery. The obturator, inferior gluteal, uterine and vaginal arteries also supply small visceral branches to the organ.

The veins form a complex plexus on the infero-lateral and posterior surfaces, and eventually drain into the internal iliac veins.

LYMPHATIC DRAINAGE The lymph vessels from the superior part of the bladder pass to the external iliac lymph nodes. Those from the inferior part of the bladder pass the internal iliac lymph nodes. Some lymph vessels from the neck region of the bladder drain into the sacral or common iliac lymph nodes.

NERVE SUPPLY The bladder receives neurons from both the sympathetic (thoracolumbar; T12-L3) and parasympathetic (sacral; S2-S4) systems. The sympathetic roots form the abdominal aortic plexus, which then runs inferiorly to the pelvic brim to form the superior hypogastric plexus; this splits at the level of L5/S1 to form the left and right hypogastric nerves. These nerve fibres then mix with parasympathetic sacral roots to form the inferior hypogastric plexus: this plexus subdivides into vesical, middle rectal and uterovaginal (Frankenhauser's) plexuses. The afferent fibres from the bladder are concerned with the awareness of distension and pain. They pass back to the CNS via both the sympathetic and parasympathetic nerves. The efferent fibres to the bladder are both parasympathetic and sympathetic. The parasympathetic fibres are motor to the detrusor and inhibitory to the internal sphincter. The sympathetic fibres cause constriction of the internal sphincter and inhibit the detrusor muscle.

THE PHYSIOLOGY OF MICTURITION

Micturition is defined as the normal process by which urine is expelled from the bladder, through the urethra, and into the external environment. It is a reflex activity in the neonate and young infant, but comes under voluntary control in healthy older children and adults. Micturition results from a complex series of neuromuscular events, and is therefore dependent on normal form and function of the organs and support structures in and around the bladder, as well as those in the central and peripheral nervous system. Pathology in either system may lead to problems such as urinary incontinence, or urinary retention. Micturition can be divided into two phases: passive and active.

The Passive Phase The passive phase of micturition results in filling of the bladder. Urine is produced at ~ 1 ml/hr, and as the bladder is filled there is relaxation and passive stretching of the detrusor muscle fibres. This relaxation is maintained by sympathetic activity (mediated through receptors in the smooth muscle of the detrusor), and results in an increase in bladder volume, without a great increase in intra-vesical pressure, until the bladder is relatively close to its maximum capacity. Simultaneously, the muscle of the trigone, particularly at the level of the internal urethral sphincter, is kept tonically contracted; this is also mediated by the sympathetic nervous system though -receptors. The different embryological origin of the smooth muscle of the detrusor vs. the trigone, results in different activity (relaxation vs. contraction) mediated by the same sympathetic stimulation Lastly, the muscle of the external urethral sphincter is also kept contracted, maintaining its forward pull on the bladder neck and proximal urethra, and thus maintaining the posterior urethro-vesical angle. In combination with the elastic tissue within the urethra itself, and the external pressure applied to the urethra by the surrounding vascular arcades, the sum of all

these actions is to keep the intravesical pressure less than that of the intra-urethral pressure; thus, urine will not flow outwards, and continence is maintained. Within the walls of the bladder are mechanoreceptors which are sensitive to changes in the stretch of and pressure across the bladder wall. They relay afferent impulses to the brain via small myelinated A fibres, through the sacral roots S2-S4. As the bladder is filled, the rate and intensity of the receptors firing increase; these impulses are passed up the lateral spinothalamic tracts to the pons, and then to the cerebral cortex. Thus, the sensation of bladder filling is brought to the conscious level. Unmyelinated C fibres also supply the bladder, but these are mainly involved in the transmission of nociceptive (painful) signals, such as during a cystitis.

Active Phase When the rate and intensity of the afferent signals to the sacral segment of the spinal cord (aka the sacral micturition center) exceed a certain threshold, the active phase of micturition begins. This phase essentially involves reversal of the previous neuromuscular activities. Thus: Sympathetic relaxation of the detrusor is stopped, and parasympathetic stimulation causes detrusor contraction Sympathetic contraction of the internal urethral sphincter is also stopped, so the sphincter opens The external urethral sphincter and pelvic floor are also relaxed, causing loss of the posterior urethro-vesical angle (essentially unkinking the proximal urethra) and causing funneling of the bladder neck, and a drop in intra-urethral pressure Urine flow begins when intravesical pressure exceeds the intraurethral pressure. At this time, the contraction of the bladder causes an even greater increase in intravesical pressure, further stimulating the afferent flow from the receptors in the detrusor. This results in even greater efferent stimulation to the bladder, and even stronger detrusor contraction.

When the bladder is almost empty the intravesical pressure drops, and the afferent stimulation to the nervous system is lost. The efferent parasympathetic flow is halted, the sympathetic relaxation to the detrusor (and tone to the trigone) is re-established, and the posterior urethrovesical angle is restored by contraction of the external sphincter and pelvic floor. Thus, the intra-urethral pressure once again exceeds the intravesical pressure, and urine flow ceases. The understanding of the autonomic innervation of the bladder forms the basis for the pharmacological management of certain types of incontinence, with anticholinergic/anti-muscarinic agents (e.g. Detrusitol/tolterodine), and/or with agonists (e.g. clonidine). In contrast, men with benign prostatic hyperplasia and outflow tract obstruction may be given -blockers (e.g. tamsulosin/Flomax), to facilitate urine flow So, in summary, the sympathetic nervous system regulates the process of urine storage in the bladder. -receptors are responsible for mediating relaxation of the bladder with filling, whereas -receptors are responsible for tonically contracting the internal sphincter during bladder filling. In contrast, the parasympathetic nervous system controls bladder contractions and the passage of urine, via smooth muscle cholinergic receptors, to produce bladder contraction. Somatic efferent motoneurons that innervate the external striated urethral sphincter muscle and the pelvic floor musculature are located in the sacral spinal cord, commonly referred to as Onufs nucleus. The external sphincter is under voluntary control and normally contracts in response to coughing/laughing/sneezing, or to the Valsalva maneuver, or when a person actively tries to prevent or halt urine flow.

The main reflex center controlling micturition is located in the rostral pontine tegmentum (the pontine micturition center). Afferents to the PMC run through the dorsal tracts and the spinothalamic tract, and convey impulses from the bladder to the thalamus and finally to the sensory areas of the cerebral cortex. The efferent pathway from the PMC passes through the lateral funiculus of the spinal cord, inhibits the thoracolumbar sympathetic nucleus and the pudendal nerve nucleus (Onufs nucleus) in the sacral cord, and excites the parasymapathetic

nucleus in the sacral cord. Inhibition of the sympathetic nucleus and pudendal nerve nucleus induces relaxation of the bladder neck (the internal urethral sphincter) and the external urethral sphincter, respectively, while parasympathetic stimulation causes detrusor contraction. Pontine control of the micturition reflex allows sufficient detrusor contraction to facilitate complete emptying of the bladder. The pontine continence center (PCC) exists ventrolateral to the PMC. Stimulation of the PCC inhibits bladder contraction and promotes the activity of the external urethral sphincter. Higher brain areas than the pons that influence the micturition reflex have been found. These include the cerebellum, periaquedactal gray in the midbrain, substantia nigra, red nucleus, thalamus, hypothalamus, amygdaloid body, and cerebral cortex (sensorimotor cortex, median or ventral aspects of the frontal lobe, etc.) However, the only region of the cerebral cortex consistently associated with detrusor dysfunction when damaged is the superior frontal gyrusseptal area. Lesions in this area interfere with voluntary inhibition of the pontine detrusor reflex center. Excitatory and inhibitory areas for micturition are often located side by side and many of these areas project to the PMC , and/or the PCC. Since the main switches for the micturition reflexes are located in the pons, and in the spinal cord, the cerebral cortex exerts voluntary control by turning these switches on or off as needed. For continence to be consciously maintained, the cerebrum stimulates the PCC, while it inhibits the PMC. In contrast, for micturition to occur, the cerebrum switches off the inhibitory projections to the PMC, as well as the excitatory projections to the PCC.

APPENDIX I - THE BLOOD SUPPLY TO THE PELVIS

The internal iliac artery, as its name suggests, supplies most of the tissues on the inside of the pelvis. It arises from the bifurcation of the common iliac artery, at the level of the sacroiliac joints. It runs for about 4 cm before it divides into an anterior and a posterior division. As it runs, it is anterior to the internal iliac vein, posterior to the ureter, and medial to the external iliac vein (near the bifurcation). It forms a part of the Fossa of Waldeyer, making it also related to the ovary. The internal iliac artery has 12 branches, 6 parietal and 6 visceral. The visceral branches are: The umbilical arteries (obliterated, in the adult) The superior vesical arteries The inferior vesical arteries The uterine arteries The vaginal arteries The middle rectal arteries

The parietal branches are: the iliolumbar arteries* lateral sacral arteries* obturator arteries superior gluteal arteries* inferior gluteal arteries internal pudendal arteries

*The iliolumbar, lateral sacral, and superior gluteal arteries arise from the posterior division of the internal iliac artery. After ligation of the internal iliac arteries, such as in the management of severe post partum haemorrhage, the pelvic organs remain viable because of the presence of extensive anastomoses between the circulation of the internal iliac with that of the external iliac/femoral and abdominal aorta, via many other connecting vessels.

 The superior and inferior vesical arteries anastomose freely with each other, while the inferior anatomoses with the middle rectal artery. This in turn anastomoses with the superior rectal, which is a direct continuation of the inferior mesenteric artey, from the abdominal aorta. The uterine artery anastomoses with the ovarian artery in the mesosalpinx. The ovarian (gonadal artery), of course, is a branch of the abdominal aorta. The vaginal artery anastomoses with the uterine artery above (and is sometimes a branch from it, as opposed to directly from the internal iliac), and branches of the middle rectal artery posteriorly. The middle rectal artery anastomoses with the superior and inferior rectal arteries. The superior rectal is a continuation of the inferior mesenteric, a branch of the abdominal aorta. The superior gluteal artery forms part of the trochanteric anastomosis, around the head of the femur, where it is joined by the inferior gluteal, and the medial and lateral femoral circumflex arteries. The inferior gluteal artery forms part of the cruciate anastomosis, in the hip joint, where it is joined by the lateral and medial femoral circumflex arteries, and a branch from the profunda femoris. All of the latter are branches of the femoral (external iliac) artery. The lateral sacral arteries anastomoses with the median sacral artery, a branch/continuation of the abdominal aorta. The iliolumbar arteries anastomoses with the fifth/last lumbar artery (from the abdominal aorta). The internal pudendal arteries anatomose with the superficial and deep external pudendal arteries (branches of the femoral artery), via its branch, the perineal artery. The obturator artery (by means of its pubic branch) with the vessel of the opposite side, and with the inferior epigastric artery (branch of the external iliac) and medial circumflex femoral artery (branch of profunda femoris).