Year One Semester One: Life Cycles 1.01: All’s Well That Ends Well What is the relationship between age and fertility? Males Levels of circulating testosterone tend to reduce between 50 and 60 whilst levels of circulating FSH and LH tend to increase. Although sperm production continues (well into eighties), the level of sexual activity tends to reduce with decreasing testosterone levels. The testes become softer and smaller in aging men and sperm quality reduces. The volume of sperm produced reduces, the shape becomes less effective and motility reduces. Females It is estimated that there are over 7 million potential oocytes (the term ‘eggs’ is the same as oocytes and ova) in a foetus’ ovaries. This reduces to about 1-2 million in the female infant. By puberty there will only be about 400,000 oocytes remaining. Of the eggs remaining only about 300-400 will be ovulated. The process of oocyte selection is poorly understood, during the reproductive cycle a cohort of oocytes is stimulated to begin maturation but only 1 or 2 dominant follicles complete the process and are ovulated. Follicle Stimulating Hormones (FSH) bind to the receptors in the follicular membranes of oocytes and stimulate follicular maturation, however as age progresses the remaining oocytes become increasingly resistant to FSH. Thus plasma FSH levels tend to increase several years before menopause (menopause is the cessation [end] of menses). Oestrogen levels decline as fewer follicles mature, resulting in less ovulation or perhaps no ovulation, in addition the urethral and vaginal epithelium thins. What factors influence age of first pregnancy? Social Approximately 20% of women wait until they are 35 to begin their families. Contraception is readily available; More women have careers/in work; Women are marrying later; Divorce rate remains high; Married couples are delaying having children until they are more financially secure; Many women don’t realise fertility reduces in late 20’s and early 30’s. At 30 you have a 20% chance of becoming pregnant per month, by 40 it has dropped to 5%. Physiological On average girls begin to experience puberty at around 10.5 years, beginning with breast budding – small nodules, of varying size. Then pubic hair and breasts develop. Between 12 and 13 is when girls first experience a period (first period: menarche). The whole puberty process takes approximately 3-4 years. Some girls menstruate as early as 8, others as late Andrew Gough Page 1 of 21 Year One Semester One: Life Cycles as 16. Reproductive age is generally defined as between 15 and 44, though there have been successful pregnancies beyond both extremes. What is the reproductive cycle and how does fertilization occur? The female reproductive cycle consists of: The Ovarian Cycle; The Menstrual Cycle. OVARIAN CYCLE When a female child is born, each ovum is surrounded by a single layer of granulosa cells; the ovum, with this granulosa cell sheath, is called a primordial follicle. Throughout childhood, the granulosa cells are believed to provide nourishment for the ovum and to secrete an oocyte maturation-inhibiting factor that keeps the ovum suspended in its primordial state in the prophase stage of meiotic division. Then, after puberty, when FSH and LH from the anterior pituitary gland begin to be secreted in significant quantities, the ovaries, together with some of the follicles within them, begin to grow. Enlargement of the ovum (increases 2-3 fold) Primoridal follicle Additional growth of granulosa layers Growth of 6-12 follicles each month Early primary follicle Spindle cells derived from the ovary interstitium collect in several layers outside the granulosa cells, giving rise to a second mass of cells called the theca. Theca interna cells take on epithelioid characteristics similar to those of Primary follicle granulosa cells and develop an ability to secrete addition steroid sex hormones. First meiotic division completed. Second meiotic division commences. Each of the 23 pairs of chromosomes loses Secondary follicle one of its partners which becomes incorporated into a polar body that is expelled. High levels of oestrogen inhibit FSH secretion and promotes large Graafian follicle secretion of LH. Ovulation 1. The theca externa (the capsule of the follicle) begins to release proteolytic enzymes from lysosomes, and these cause dissolution of the follicular capsular wall and consequent weakening of the wall, resulting in further swelling of the entire follicle and degeneration of the stigma. 2. Simultaneously, there is rapid growth of new blood vessels into the follicle wall, and at the same time, prostaglandins (local hormones that cause vasodilation) are Andrew Gough Page 2 of 21 Year One Semester One: Life Cycles secreted into the follicular tissues. These two effects cause plasma transudation into the follicle, which contributes to follicle swelling. Finally, the combination of follicle swelling and simultaneous degeneration of the stigma causes follicle rupture, with discharge of the ovum. MENSTRUAL CYCLE The cycle is typically 28 days but can range from 22 to 35 days; it is divided into four main phases. Copious amounts of glycogen. Andrew Gough Page 3 of 21 Year One Semester One: Life Cycles The Menstrual Phase/Menses/Menstruation Lasts roughly five days. Marked by the degeneration of the endometrial lining of the uterus – caused by constriction of spiral arteries, reducing blood flow to the endometrium depriving it of oxygen and nutrients – eventually it erupts and blood fills the uterine cavity. The endometrium thins to 1-2mm. Typically up to 50ml of blood is lost. Normally, menstrual blood does not clot due to the local release of inhibitory (anticoagulant) factors. Menses may be accompanied by uterine cramps which are due to liberation of prostaglandins from the endometrium. With the beginning of menstruation LH, estradiol and progesterone reach their lowest levels. By means of negative feedback the levels of FSH increase (in fact since day 25 of previous cycles) and another group of follicles (20 or so) are stimulated into maturing. FSH binds to receptors in the granulosa cells (nourishing cells) stimulating them to turn into cuboidal cells. 1 = oocyte; 2 = pellucid zone; 3 = stratum granulosum; 4 = theca folliculi cells Under the influence of FSH the granulosa cells begin to secrete estradiol (an oestrogen). Estradiol stimulates LH receptors on the theca cells further increasing secretion of estradiol (through an enzyme regulated reaction: androgen precursors estradiol). This up regulation of LH prepares granulosa and theca cells for progesterone synthesis after ovulation. As estradiol levels rise, negative feedback results in a decrease of FSH secretion from the anterior pituitary. GnRH LH FSH FSH Stimulates Ovaries Growing Follicles OESTROGEN Development of female secondary sex characteristics + breasts. Increase protein anabolism. Lower blood cholesterol. Moderate levels inhibit release of GnRH, FSH and LH. Andrew Gough PROGESTERONE Anterior Pituitary LH Stimulates Ovulation Corpus Luteum RELAXIN Works with oestrogens to Inhibits contraction of prepare endometrium for uterine smooth muscle. implantation. Prepares During labour, increases mammary glands to flexibility of pubic secrete milk. Inhibits symphysis and dilates release of GnRH and LH. uterine cervix. INHIBIN Inhibits release of FSH and to a lesser extent, LH Page 4 of 21 Year One Semester One: Life Cycles The Endometrium The endometrium is divided into three histologically and functionally distinct layers. The deepest or basal layer, the stratum basalis, adjacent to the myometrium, undergoes little change during the menstrual cycle and is not shed during menstruation. The broad intermediate layer is characterised by a stroma with a spongy appearance and is called the stratum spongiosum. The thinner superficial layer, which has a compact stromal appearance, is known as the stratum compactum. The compact and spongy layers exhibit dramatic changes throughout the cycle and both are shed during menstruation; hence they are jointly referred to as the stratum functionalis. The arrangement of the arterial supply of the endometrium has important influences on the menstrual cycle. Branches of the uterine arteries pass through the myometrium and immediately divide into two different types of arteries, straight arteries and spiral arteries. Straight arteries are short and pass a small distance into the endometrium, then bifurcate to form a plexus supplying the stratum basalis. Spiral arteries are long, coiled and thick-walled and pass to the surface of the endometrium giving off numerous branches which give rise to a capillary plexus around the glands and in the stratum compactum. Unlike the straight arteries, the spiral arteries are responsive to the hormonal changes of the menstrual cycle. The withdrawal of progesterone secretion at the end of the cycle causes the spiral arteries to constrict and this precipitates an ischaemic phase that immediately precedes menstruation. The Proliferative Phase Lasts from day 6-13. A single follicle has become dominant; outgrowing others it secretes estradiol and inhibin. This reduces FSH secretion. Undeveloped follicles undergo atresia (they become atretic). The dominant follicle develops becoming ready for ovulation. The follicle begins to form a blister like bulge due to the increasing outward pressure of the filling antrum (space within the follicle). As estradiol continues to be produced, LH levels rise. Small amounts of progesterone are released before ovulation. Oestrogen stimulates repair of the endometrium, cells of the stratum basalis (B) undergo mitosis, producing the new stratum functionalis (F). Endometrium thickens to approximately 4-10mm. Ovulation By day 11-13, a huge surge in LH triggers ovulation (occurring 30-36 hours after surge). The oocyte is expelled from the follicle to be converted into a corpus luteum to facilitate progesterone secretion for rest of cycle. During the LH surge, LHG receptor bind to the LH and convert the enzymatic machinery of the granulose cells and theca cells to produce progesterone (hence early progesterone production). An inadequate surge can result in failed implantation. During the last 20 days (including 6 days of previous cycle) the primary oocyte has completed meiosis I and is now beginning meiosis II where it will stop at metaphase. Mittelschmerz is a twinge of pain felt at time of ovulation. The Post-Prevulatory Phase/Luteal Phase The period between ovulation and the next menses phase – days 15-28. Characterised by the dominance of progesterone. Progesterone production occurs rapidly after first 24 hours. If no fertilization and implantation occurs then progesterone production diminishes rapidly initiating events leading to a new cycle. The corpus luteum (life span: 13-14 days) degenerates into a corpus albicans (becomes a white fibrous streak). The loss of these ovarian hormones stimulates the action of GnRH. Andrew Gough Page 5 of 21 Year One Semester One: Life Cycles If there is fertilization and the zygote implants into the endometrium then human chorionic gonadotrophin (hCG) sustains the corpus luteum for another 6-7 weeks. FERTILIZATION Conception is the fertilization of an ovum by a spermatozoon, this typically occurs in the ampulla or isthmus of the uterine tubes. Movement of the ovum along the tube is mediated by gentle peristaltic action of the longitudinal and circular smooth muscle layers of the oviduct wall; this is aided by a current of fluid propelled by the action of the ciliated epithelium lining the tube. The mucosal lining of the Fallopian tube is thrown into a labyrinth of branching, longitudinal folds, a feature that is most prominent in the ampulla, At the time of ovulation, the infundibulum moves so as to which is the usual site of overlie the site of rupture of the follicle; finger-like fertilisation. projections called fimbriae extending from the end of the tube envelop the ovulation site and direct the ovum into the tube. Contractions of the uterine musculature help to accelerate sperm to its destination. This is stimulated by prostaglandins in seminal fluid and oxytocin secreted from the woman’s posterior pituitary gland during her orgasm. The journey can take anything from 30 minutes to 2 hours. Dozens of sperm must reach the ovum because a single sperm cannot penetrate the corona radiata. The oocyte is much larger than a spermatozoon because it’s suspended in metaphase II of meiosis II. The acrosome (structure at head) of a spermatozoon contains enzymes such as hyaluronidase which breaks bonds between adjacent follicle cells. Dozens of sperm need to release this enzyme to enable fertilization. The acrosomal head ruptures when a spermatozoon binds to a sperm receptor on the zona pellucida. The enzyme acrosin then helps the spermatozoon make a path towards the surface of the oocyte. They then fuse together. The spermatozoon is absorbed into the oocyte cytoplasm. This results in inactivation of the sperm receptors. The zona pellucida hardens and helps prevent polyspermy – which leads to a zygote unable to develop. Meiosis II also completes. Andrew Gough Page 6 of 21 Year One Semester One: Life Cycles Nuclear materials of ovum and spermatozoon both swell forming pronuclei and migrate to the centre where they fuse, amphimixis, with the formation of the 46 chromosome zygote. How does a pregnancy test work? The urine test detects the hormone: human chorionic gonadotrophin (produced in the syncytiotrophoblast – outer layer – of growing placenta), hCG, and the levels rise sharply in the early period of pregnancy. However the structure of LH and hCG are closely related (both LH and hCG share an -subunit – a peptide formed by chromosome 6, found on some hormones) and a test must take account for this overlap in structure; hence the concentration of hCG must be high to evoke a positive test result to avoid a false-positive result. The test is an immunoassay test. There are several antibody binding sites on the hormone hCG and its free subunits. Once one antibody binds to one site, a second (tracer) antibody binds to a distant site and is labelled with a blue dye. How does the oral contraceptive pill work? There are two types of oral contraceptive pill. Combined Oral Contraceptive Pill Oestrogen and Progesterone. Progesterone Only Pill The ‘minipill’ – may be started immediately after delivery as it has no effects on lactation. Must be taken same time of the day each day. Progesterone suppresses LH secretion and in turn ovulation. Thickens cervical mucus and alters fallopian tube peristalsis – makes the endometrium hostile to implantation and the cervix relatively impermeable. Oestrogen suppresses FSH secretion. Also acts as an adjuvant to progesterone by increasing the number of progesterone receptors. What are the general symptoms of pregnancy? Symptoms include: Tiredness; Indigestion; Constipation; Sore breasts; Sickness; *Abdominal Pains*. Gastrointestinal Changes Earliest symptoms of pregnancy include nausea/morning sickness. It appears a main reason is to do with elevated hCG and progesterone levels causing relaxation of the smooth muscle in the GI tract and stomach. The transit time from stomach and small bowel increases significantly by 15-30%. The heartburn/gastric reflux are associated with the increased emptying time and the sphincter muscle at the gastroesophageal junction and increase intra-abdominal pressure as gestation increases. Constipation is also common; Andrew Gough Page 7 of 21 Year One Semester One: Life Cycles this is due to unfamiliar pressure on the bowel system and also by reduced motility elsewhere in bowel and increased absorption of water. Breast Changes The breasts grow in size rapidly during the first 8 weeks of pregnancy as well as the nipples becoming larger and more mobile. Tiredness One possibility is anaemia, a condition arising due to reduced oxygenation of the blood. Whilst the numbers of red blood cells do increase during pregnancy the plasma volume also does and so it can become diluted. Also there are the normal reasons such as increased weight to support and also a pregnant woman may find her sleep patterns are poor due to other symptoms she is experiencing. *Abdominal Pains* Mild abdominal pain can be normal during early pregnancy. As progesterone softens ligaments and relaxes muscles in the body, it may cause the round ligaments which suspend the enlarging uterus, to stretch and cause pain. These feel like pulling sensations in the right and left lower quadrants of the abdomen and are very annoying; however the pain subsides during the second and third trimesters. Pain is often more pronounced on right due to usual dextro(-to the right)rotation of the gravid (carrying developing young) uterus. Preeclampsia and eclampsia About 5 per cent of all pregnant women experience a rapid rise in arterial blood pressure to hypertensive levels during the last few months of pregnancy. This is also associated with leakage of large amounts of protein into the urine. This condition is called preeclampsia or toxaemia of pregnancy. It is often characterized by excess salt and water retention by the mother's kidneys and by weight gain and development of oedema and hypertension in the mother. In addition, there is impaired function of the vascular endothelium, and arterial spasm occurs in many parts of the mother's body, most significantly in the kidneys, brain, and liver. Both the renal blood flow and the glomerular filtration rate are decreased, which is exactly opposite to the changes that occur in the normal pregnant woman. The renal effects also include thickened glomerular tufts that contain a protein deposit in the basement membranes. During normal placental development, the trophoblasts invade the arterioles of the uterine endometrium and completely remodel the maternal arterioles into large blood vessels with low resistance to blood flow. In patients with preeclampsia, the maternal arterioles fail to undergo these adaptive changes, for reasons that are still unclear, and there is insufficient blood supply to the placenta. This, in turn, causes the placenta to release various substances that enter the mother's circulation and cause impaired vascular endothelial function, decreased blood flow to the kidneys, excess salt and water retention, and increased blood pressure. Eclampsia is an extreme degree of preeclampsia. Andrew Gough Page 8 of 21 Year One Semester One: Life Cycles How does an egg implant outside of the uterus? An ectopic pregnancy presents a major problem for women of child bearing age. It is a result of a flaw that allows the conceptus to implant and mature outside the endometrial cavity, which ultimately ends in death of the foetus. The condition can be life-threatening. In the USA ectopic pregnancy accounts for 9% of all pregnancy related deaths. This abnormally implanted gestation grows and draws its blood supply from the site of abnormal implantation. As the gestation develops organ rupture becomes a potential because only the uterine cavity is designed to expand and accommodate a foetus. Essentially anything hampering the migration of the embryo (a conceptus up to 8 weeks) to the endometrial cavity could predispose a woman to ectopic pregnancy. Pelvic Inflammatory Disease – Cause: antecedent (existed before) infection caused by chlamydia – resulting in asymptomatic (not producing indications) cervicitis – inflammation of the cervix. Gonorrhoea causes inflammation of mucous membrane. A history of salpingitis (inflammation of the fallopian tube) increases risk four fold. History of ectopic pregnancy. Prior tubal surgery Age 35-44, a three fold risk compared to 15-24 years, this may be due to reduced myoelectrical activity at fallopian tubes. Salpingitis isthmica nodosum – protrusions into the fallopian tubes from the tubal epithelium in the myosalpinx (muscular lining of uterine tube). 80% of ectopic pregnancies are in the ampulla followed in turn by the isthmic segment, then the fimbriae. Abdominal ectopic pregnancies are rare, occurring in about 1.2% of cases. Ovarian and cervical sites represent 0.2% each. Symptoms: Pain; Absence of menstruation (amenorrhea); Vaginal Bleeding; Only 50% of patients present this triad of symptoms. What happens in the first trimester of pregnancy? Starts from fertilization and lasts 12 weeks (three months = trimester). Cleavage A series of cell divisions that sub-divides the cytoplasm of the zygote. There is the initial division forming two cells – the pre-embryo and is completed 30 hours after fertilization. Subsequent divisions occur every 10-12 hours. After three days the morula stage is reached and there is a clump of blastomeres (these cells produced by mitotic divisions). Andrew Gough Page 9 of 21 Year One Semester One: Life Cycles There is a hollow cavity called the blastoceole, the trophoblast is the outer layer – the insulator and supplier of nutrients. The inner cell mass is a group of cells at one end of the blastocyst – this will form the embryo. Implantation The blastocyst releases enzymes that erode through the zona pellucida, which is shed in a process known as hatching, from here on also: hCG begins to be secreted from the trophoblast. The blastocyst becomes fully exposed to the glycogen rich fluid contents of the uterine secreted by its endometrium. The blastocyst enlarges and as it obtains more nutrients. When fully formed the blastocyst contacts the endometrium and implantation occurs. On contact, the trophoblast cells divide rapidly increasing the thickness of the trophoblast layer, cells closest to the interior remain intact – cellular trophoblast; however the cell membranes of cells closer to the endometrium break down and nuclei filled cytoplasm is left – the syncytial (sin-SISH-al) trophoblast, which erodes a path through the uterine epithelium by secreting (that special enzyme) hyaluronidase. When the uterine lining heals the blastocyst becomes detached from the uterine cavity and has burrowed in – the functional layer is where development occurs. Generally implantation is into the fondus. The syncytial trophoblast continues to expand and erodes glands within the endometrium releasing nutrients – these nutrients are then distributed to the underlying cellular trophoblast and inner cell mass. The nutrients assist embryo development. Trophoblastic extensions grow around the endometrial capillaries and soon maternal blood percolates through these extensions known as lucnae. Blood flow increases as endometrial veins and arteries are penetrated, roughly at day 9. As separation between the inner cell mass and trophoblast increases a fluid filled chamber called the amniotic cavity forms. When the amniotic cavity first appears, the cells of the inner cell mass are arranged into an oval that is two cells thick. By day 12 a third layer begins to form through gastrulation – specific cells are moving towards a central area known as the primitive streak, this layer of poorly organised cells is known as the mesoderm layer and is sandwiched between the ecto- and endo- (cells closest to the blastoceole) derm layers. These layers are known as germ layers. The oval three layered sheet becomes known as the embryonic disc. The germ layers all have very distinct fates. For instance the endoderm layer contributes the urinary bladder and mesoderm layer contributes all components of the cardiovascular system. Ectoderm Mesoderm Endoderm Primitive streak Andrew Gough Page 10 of 21 Year One Semester One: Life Cycles Germ layers also participate in the formation of some extraembryonic membranes: The Yolk Sac – Begins life as a layer of cells spread out around the outer edges of the blastoceole to form a complete pouch. As gastrulation proceeds, the mesodermal cells migrate around this pouch and complete the formation. Blood cells form within this sac and it soon becomes an important place for blood cell generation. The Amnion – The ectodermal layer increases in size and the ectodermal cells spread all over the amniotic cavity. Mesodermal cells form a second layer, the amniotic cavity contains amniotic fluid. The Allantois – Begins life as an out pocketing of the endoderm near the base of the yolk sac. The free endodermal tip then grows towards the edge of the blastocyst, surrounded by a mass of mesodermal cells, and will later form the urinary bladder! The Chorion – consists of two layers: an outer formed by the ectoderm or trophoblast and an inner by the mesoderm. Blood vessels develop inside the mesoderm of the chorion. This is the first step towards a functional placenta. By the third week the mesoderm extends along the core of each trophoblastic villus forming chorionic villi in contact with maternal tissue. Blood starts flowing through these villi in the third week when the embryonic heart starts to beat. As the villi enlarge more maternal blood vessels are eroded and blood now moves more slowly through the complex lucnae formed by the syncytial trophoblastic extensions known as lucnae. Maternal blood re-enters maternal veins and there is no mixing of maternal and foetal blood due to the trophoblast. Placentation At first the entire blastocyst is surrounded by chorionic villi and the chorion continues to th enlarge. By the 4 week the embryo, amnion and yolk sac are suspended within an expansive, fluid filled chamber. The body stalk, the connection between embryo and chorion, contains the distal portions of the allantois and blood vessels that carry blood to and from the placenta. The narrow connection between the endoderm of the embryo and the yolk sac becomes known as the yolk stalk. The placenta does not continue to enlarge indefinitely. Regional differences in placental organization begin to develop as placental expansion creates a prominent bulge in the endometrial surface. The relatively thin portion of the endometrium no longer participates in nutrient exchange and chorionic villi in this region disappear – this becomes known as the decidua capsularis. Placental functions are now concentrated in the deeper region known as the decidua basalis. The rest of the uterine endometrium, which has no contact with the chorion, is called the decidua parietalis. As the end of the trimester approaches the foetus moves farther apart from the Andrew Gough Page 11 of 21 Year One Semester One: Life Cycles placenta but remains in contact by means of the umbilical cord, which contains the allantois, placental blood vessels and the yolk sac. Hormones releases by the placenta include: hCG – Acts like LH promoting secretion of progesterone, which maintains the endometrial lining. A number of hormones which convert mammary glands to an active status. Relaxin – increase the flexibility of the pubic symphysis, dilation of cervix and suppresses oxytocin by the hypothalamus and delays the onset of labour contractions. Progesterone and Oestrogen – Progesterone maintains the endometrial lining and continue the pregnancy. Towards the end of the pregnancy oestrogen stimulates labour and delivery. Embryogenesis Shortly after gastrulation the body of the embryo separates from the rest of the embryonic disc. Internal organs start to form. Folding and differential growth of the embryonic disc produces a bulge that projects into the amniotic cavity. This projection is known as the head fold. Similar movements lead to the tail folds. The embryo is now physically and developmentally distinct from the embryonic disc and extraembryonic membranes. The first trimester establishes the base for organogenesis. What pregnancy services are available? Before becoming pregnant a woman should speak to their GP about any regular medication they are taking. Once a woman believes she is pregnant she should see her physician to maximise pre-natal care and to minimise risks of birth defects and complications. This should be done by the tenth week. Blood screening, starting pre-natal vitamin supplements and early detection of problems are better accomplished sooner Andrew Gough Page 12 of 21 Year One Semester One: Life Cycles rather than later. What is spotting and what are its causes? Spotting or bleeding during pregnancy can be serious and should always be investigated. About a quarter of women experience some spotting or bleeding in early pregnancy. About half of these women miscarry. Spotting is very light bleeding, similar to what you may have at the beginning or end of a period. It can very in colour from pink to red to brown. Causes: There is greater blood supply to cervix so there may be spotting after a smear test, internal exam or sex. Implantation – burrowing egg into the wall of the uterus. Miscarriage or ectopic pregnancy, especially likely if there is abdominal pain or cramping. Infections – vaginal infection or STI. This can cause an inflamed cervix susceptible to bleeding. Placental problems or premature labour, e.g. placenta previa (low-lying placenta), placental abruption (placenta separates from uterus), late miscarriage or premature labour (classed as mid pregnancy – 37 weeks). Normal labour – a mucus discharge that’s tinged with blood after 37 weeks is most likely just a sign that the mucus plug has dislodged and the cervix is beginning to soften or dilate, in preparation for pregnancy. Sex Hormones. Hormone Details Follicle Stimulating Hormone (FSH) Origin: anterior pituitary Endocrine target: Testes and ovaries. Function: Promotes follicle development in females and, in combination with luteinising hormone, stimulates the secretion of oestrogens by ovarian cells. In males, FSH stimulates sustentacular cells, specialised cells in the tubules where sperm differentiate. Regulation: Inhibited by inhibin. Regulated by GnRH. Luteinising Hormone (LH) Origin: anterior pituitary Endocrine target: Testes and ovaries. Function: Induces ovulation. Promotes the secretion by the ovaries of oestrogens and the progestins (such as progesterone). In males it Andrew Gough Page 13 of 21 Year One Semester One: Life Cycles stimulates the production of sex hormones by the interstitial cells of the testes. Regulation: Regulated by GnRH. Progesterone Origin: ovary (corpus luteum); placenta Function: Preparation of uterus for pregnancy; maintenance of pregnancy; development of alveolar system in mammary glands. Regulation: The corpus luteum is formed under LH stimulation and the lipids contained within it are used to form progesterone. Placenta produces sufficient amounts of progesterone to maintain the endometrial lining and continue pregnancy. Oestrogen Origin: ovary, testis, and placenta Function: Stimulating bone and muscle growth. Development of secondary female sex characteristics: Hair growth; voice pitch; broad pelvis; mons pubis (fatty layer overlying pubic symphysis). Affecting CNS – e.g. affect sex drive in hypothalamus. Initiating growth and repair of endometrium. Regulation: FSH and LH stimulate. Inhibin Origin: Sustentacular cells of the testes; follicular cells of ovaries Endocrine target: anterior pituitary gland. Function: Inhibit secretion of FSH. Regulation: Stimulated by FSH from anterior pituitary gland. Human Chorionic Gonadotrophin Hormone (hCG) Origin: Corpus luteum Function: Maintains the integrity of the corpus luteum and promotes continued secretion of progesterone – appears in blood stream soon after implantation. The presence of hCG reduces after 3-4 months however by now the placenta actively secretes both oestrogens and progesterones. Andrew Gough Page 14 of 21 Year One Relaxin Semester One: Life Cycles Origin: Corpus luteum and placenta Function: Increase the flexibility of the pubic symphysis; permitting the pelvis to expand during delivery. Causes dilation of cervix and suppresses the release of oxytocin by the hypothalamus – delaying onset of labour contractions. What is spermatogenesis? SOME ANATOMY The testes is divided into lobules (division or lobe) and seminiferous tubules are distributed throughout. THERE ARE THREE PROCESSES Mitosis Spermatogonia (primitive male reproductive cells) undergo cell divisions through life. One daughter cell from each division is pushed towards the lumen of the seminiferous (producing sperm) tubule. These cells then differentiate into primary spermatocytes. Andrew Gough Page 15 of 21 Year One Semester One: Life Cycles Meiosis In the seminiferous tubules meiotic divisions take place. The spermatocytes become spermatids – undifferentiated (no distinguishable characteristics) male gametes. Interphase between divisions I and II is short with no replication. Four haploid gametes are produced known as spermatids. In anaphase I the tetrads (2 pairs of matched chromosomes – where crossing over may take place) separate. The daughter cells receive both the maternal and paternal chromosome. Increasing variety results from the random assortment of parental and maternal chromosomes. Cytokinesis does not occur – ensuring therefore that nutrients can be supplied and that cells develop in synchrony. M = myofibroblasts; SA = spermatogonia type A; SB = spermatogonia type B; S1 = primary spermatocytes; S3 = spermatids; S4 = spermatozoa; St = Sertoli cells. Spermiogenesis Each spermatid matures into a single spermatozoon, or sperm. Developing spermatocytes undergoing meiosis and spermatids undergoing spermiogenesis are not free in the seminiferous tubules. Instead they are surrounded by the cytoplasm of the sustentacular/Sertoli (support – protect sperm because their antigens would initiate an Andrew Gough Page 16 of 21 Year One Semester One: Life Cycles immune response) cells. Spermatids gradually develop the appearance of mature spermatozoa. At spermination a spermatozoon loses its attachment to the sustentacular cell and enters the lumen of the seminiferous tubule. The whole process of spermination takes 9 weeks. What happens during labour?! The goal of labour is parturition, the forcible expulsion of the foetus. During true labour, each labour contraction begins near the top of the uterus and sweeps in a wave toward the cervix. The contractions are strong and occur at regular intervals. During most of the months of pregnancy, the uterus undergoes periodic episodes of weak and slow rhythmical contractions called Braxton Hicks contractions. These contractions become progressively stronger toward the end of pregnancy; then they change suddenly, within hours, to become exceptionally strong contractions that start stretching the cervix and later force the baby through the birth canal, thereby causing parturition. This process is called labour, and the strong contractions that result in final parturition are called labour contractions. Based on experience with other types of physiological control systems, a theory has been proposed for explaining the onset of labour. The positive feedback theory suggests that stretching of the cervix by the foetus’s head finally becomes great enough to elicit a strong reflex increase in contractility of the uterine body. This pushes the baby forward, which stretches the cervix more and initiates more positive feedback to the uterine body. Thus, the process repeats until the baby is expelled. There are two known types of positive feedback which increase uterine contractions during labour: 1. Stretching of the cervix causes the entire body of the uterus to contract, and this Andrew Gough Page 17 of 21 Year One Semester One: Life Cycles contraction stretches the cervix even more because of the downward thrust of the baby's head. 2. Cervical stretching also causes the pituitary gland to secrete oxytocin, which is another means for increasing uterine contractility. Dilation Stage Begins with the onset of true labour, as the cervix dilates and the foetus begins to move toward the cervical canal. This stage is highly variable in length but typically lasts 8 or more hours. At the start of this stage, the labour contraction last up to half a minute and occur t intervals once every 10-30 minutes. Frequency steadily increases. The amniochorionic membrane breaks at some point (waters break). Expulsion Stage The cervix is pushed open by the approaching foetus and dilation it completed. Contractions reach maximum intensity occurring at 2-3 minute intervals and lasting a full minute. Expulsion continues until the foetus has emerged from the vagina; in most cases this lasts less than 2 hours. The arrival of the newborn is called delivery. Placental Stage Muscle tension builds in the walls of the partially empty uterus and the organ gradually decreased in size. The uterine contraction tears the connections between the endometrium and the placenta. In general, within an hour of delivery, the placental stage ends with the ejection of the placenta accompanied by a loss of blood, however as maternal blood volume has increased greatly during pregnancy, this blood loss can easily be tolerated. Placental production Oestrogen Relaxin Foetal Growth Distortion of the myometrium Maternal oxytocin release at posterior pituitary Increased excitability of uterine musculature Increased prostaglandin production positive feedback Foetal oxytocin release Labour Contractions Andrew Gough Page 18 of 21 Year One Semester One: Life Cycles What are the female and male sexual functions? MALES The most important source of sensory nerve signals for initiating the male sexual act is the glans penis. The glans contains an especially sensitive sensory end-organ system that transmits into the central nervous system that special modality of sensation called sexual sensation. The slippery massaging action of intercourse on the glans stimulates the sensory end-organs, and the sexual signals in turn pass through the pudendal nerve, then through the sacral plexus into the sacral portion of the spinal cord, and finally up the cord to undefined areas of the brain. Impulses may also enter the spinal cord from areas adjacent to the penis to aid in stimulating the sexual act. For instance, stimulation of the anal epithelium, the scrotum, and perineal structures in general can send signals into the cord that add to the sexual sensation. Psychic Element of male sexual stimulation Appropriate psychic stimuli can greatly enhance the ability of a person to perform the sexual act. Simply thinking sexual thoughts or even dreaming that the act of intercourse is being performed can initiate the male act, culminating in ejaculation. Indeed, nocturnal emissions during dreams occur in many males during some stages of sexual life, especially during the teens. Integration of the male sexual act in the spinal cord The male sexual act results from inherent reflex mechanisms integrated in the sacral and lumbar spinal cord, and these mechanisms can be initiated by either psychic stimulation from the brain or actual sexual stimulation from the sex organs, but usually it is a combination of both. Stages of male sexual act Penile Erection – erection is caused by parasympathetic impulses that pass from the sacral portion of the spinal cord through the pelvic nerves to the penis. Nitric oxide is released, believed to assist in vascular dilation. For erection to occur the arterial blood flow is rapid and the venous outflow is partially occluded. High blood pressure causes ballooning of erectile tissue. Lubrication – parasympathetic stimulation causes urethral glands and the bulbourethral glands to secrete mucous. This mucus flows through the urethra during intercourse to aid in the lubrication during coitus (sexual intercourse). Emission and ejaculation – the culmination of the sexual act. When the stimulus becomes extremely intense the reflex centres of the spinal cord begin to emit sympathetic impulses from T-12 and L-2 – this initiates emission, the forerunner of ejaculation. The vas deferens and ampulla contract causing expulsion of sperm into the internal urethra. Then contractions of the coat of the prostate gland followed by the seminal vesicles expel prostatic and seminal fluid into the urethra also. The filling of the internal urethra with Andrew Gough Page 19 of 21 Year One Semester One: Life Cycles semen elicits sensory signals that are transmitted through the pudendal nerves to the sacral regions of the cord giving a sense of fullness in the internal genital organs. Sensory signals further excite rhythmical contraction of the ischiocavernosus and bulbocavernosus muscles that compress the bases of the penile erectile tissue. A wave-like sequence of contractions results in ejaculation of semen from the urethra. Rhythmical contractions of the pelvic muscles and even some of the body trunk cause thrusting movements of the pelvis and penis which also help propel the semen into the deepest recesses of the vagina and perhaps even into the cervix. At termination of this, the male orgasm, sexual excitement is terminated within 1 to 2 minutes and erection ceases, a process called resolution. FEMALES Thinking sexual thoughts can lead to female sexual desire, and this aids greatly in the performance of the female sexual act. Such desire is based largely on a woman's background training as well as on her physiological drive, although sexual desire does increase in proportion to the level of sex hormones secreted. Desire also changes during the monthly sexual cycle, reaching a peak near the time of ovulation, probably because of the high levels of oestrogen secretion during the prevulatory period. Local sexual stimulation in women occurs in more or less the same manner as in men because massage and other types of stimulation of the vulva, vagina, and other perineal regions can create sexual sensations. The glans of the clitoris is especially sensitive for initiating sexual sensations. As in the male, the sexual sensory signals are transmitted to the sacral segments of the spinal cord through the pudendal nerve and sacral plexus. Once these signals have entered the spinal cord, they are transmitted to the cerebrum. Also, local reflexes integrated in the sacral and lumbar spinal cord are at least partly responsible for some of the reactions in the female sexual organs. Female erection and lubrication Located around the introitus (entrance, i.e. to the vagina) and extending into the clitoris is erectile tissue almost identical to the erectile tissue of the penis. This erectile tissue, like that of the penis, is controlled by the parasympathetic nerves that pass through the nervi erigentes from the sacral plexus to the external genitalia. In the early phases of sexual stimulation, parasympathetic signals dilate the arteries of the erectile tissue, probably resulting from release of acetylcholine, nitric oxide, and vasoactive intestinal polypeptide (VIP) at the nerve endings. This allows rapid accumulation of blood in the erectile tissue so that the introitus tightens around the penis; this aids the male greatly in his attainment of sufficient sexual stimulation for ejaculation to occur. Parasympathetic signals also pass to the bilateral Bartholin's glands located beneath the labia minora and cause them to secrete mucus immediately inside the introitus. This mucus is responsible for much of the lubrication during sexual intercourse, although much is also provided by mucus secreted by the vaginal epithelium and a small amount from the male urethral glands. This lubrication is necessary during intercourse to establish a satisfactory massaging sensation rather than an irritative sensation, which may be provoked by a dry vagina. A massaging sensation constitutes the optimal stimulus for Andrew Gough Page 20 of 21 Year One Semester One: Life Cycles evoking the appropriate reflexes that culminate in both the male and female climaxes. Female Climax When local sexual stimulation reaches maximum intensity, and especially when the local sensations are supported by appropriate psychic conditioning signals from the cerebrum, reflexes are initiated that cause the female orgasm, also called the female climax. The female orgasm is analogous to emission and ejaculation in the male, and it may help promote fertilization of the ovum. Indeed, the human female is known to be somewhat more fertile when inseminated by normal sexual intercourse rather than by artificial methods, thus indicating an important function of the female orgasm. There is evidence to suggest that the rhythmic contraction of the perineal muscles increases uterine and fallopian tube motility. It’s also possible that the dilation of the cervical canal may be due to orgasm. In addition to the possible effects of the orgasm on fertilization, the intense sexual sensations that develop during the orgasm also pass to the cerebrum and cause intense muscle tension throughout the body. But after culmination of the sexual act, this gives way during the succeeding minutes to a sense of satisfaction characterized by relaxed peacefulness, an effect called resolution. Andrew Gough Page 21 of 21