57. Reproduction Flashcards

Question

What are some hazards to spermatazoa that may stop them from reaching the oocyte at the isthmus-ampulla junction?

Answer 1

* Haploid complement of DNA * Potential for strong motility * Receptors for the zona pellucida and egg * Ability to penetrate cumulus and zona pellucida * Ability to fuse with the egg * Ability to activate an egg

Answer 2

The physiological changes spermatozoa must undergo in order to have the ability to penetrate and fertilize an egg.

Answer 3

* In the epididymis, the sperm become mature due to changes in glycosylation -\> This allows them to be able to swim * In the female genital tract, capacitation happens -\> It relies on secretions from the prostate and seminal glands -\> There are further changes in glycosylation, activates an enzyme released in the acrosome reaction (acrosin), increases in motility, and loss of cholesterol from the sperm head

Answer 4

* Atrial natriuretic peptide (ANP) may act as a chemoattractant * Progesterone + Atrial natriuretic peptide (ANP) from cumulus cells stimulate motility & acrosome reaction

Answer 5

Secretions of seminal vesicles and prostate

Answer 6

* For 5 days after intercourse * Most in the isthmus and some in the cervix

Answer 7

* Acrosin is activated * Motility is increased * Loss of cholesterol from the sperm head

Answer 8

* A cluster of cells (cumulus cells) that surround the oocyte. * The innermost layer of these cells is the corona radiata. * This layer of cells must be penetrated by spermatozoa in order for fertilization to occur

Answer 9

Cumulus oophorus (which contains the corona radiata) secretes: * Progesterone + Atrial natriuretic peptide (ANP) -\> Stimulate motility & acrosome reaction * ANP may also attract sperm

Answer 10

* Acrosome reaction * Whiplash-like motility of the sperm

Answer 11

4 zona pellucida proteins -\> Binds to ZP3 first

Answer 12

It is the reaction when the spermatazoon binds to the zona pellucida: * Binds to the ZP3 (zona pellucida protein 3) using the ZP3 receptor on the plasmalemma * Lysins are released from the zona pellucida * The ZP2 receptor is revealed -\> This allows tighter adhesion to the zona pellucida

Answer 13

It is the reaction that occurs after the spermatazoon fuses with the zona pellucida, in order to prevent polyspermy: * Cortical granules fuse with the zona pellucida * This causes the zona pellucida to harden so that no more sperm can enter

Answer 14

Sperm penetration

Answer 15

Fertilisation causes Ca²⁺ transients in zygote: * Wave spreads from point of fertilisation * Wave initiated by PLCζ (zeta) which is on the internal membranes of sperm equator * A few waves stimulate the cortical granule reaction * Repeated waves stimulate the start of development, division etc.

Answer 16

* It takes 5 days * On the 5th day, hatching from the zona pellucida occurs * After this, implantation can occur

Answer 17

* Prior to ovulation, there is the follicular phase -\> This corresponds to the proliferative phase of the uterus * After ovulation, there is the luteal phase -\> This corresponds to the secretory phase of the uterus * Finally, there is menstruation

Answer 18

* Proliferative * Secretory * Menstrual

Answer 19

* Proliferative -\> Estrogen * Secretory -\> Progesterone

Answer 20

Proliferative phase: * Endometrium is exposed to oestrogen as a result of FSH and LH stimulating its production * Oestrogen stimulates repair and growth of the functional endometrial layer allowing recovery from the recent menstruation. Secretory phase: * Occurs after ovulation * Driven by progesterone from the corpus luteum. * Endometrial glands secrete various substances that will facilitate implantation Menstrual phase: * At the end of the luteal phase, the corpus luteum degenerates (if no implantation occurs), which results in decreased progesterone production. * This causes the spiral arteries in the functional endometrium to contract. * Endometrium is shed and exits through the vagina as menstruation.

Answer 21

* Menstruation -\> Days 0 to 7 * Proliferative -\> Days 7 to 14 * Secretory -\> Days 14 to 28

Answer 22

* Estradiol -\> Promotes proliferation and apiral artery development * Progesterone -\> Glandular secretion * Prostaglandins -\> Arterial spasm and uterine muscle spasm

Answer 23

* Basal zone -\> Not sloughed during menstruation * Functional zone -\> Sloughed during menstruation and then regenerates

Answer 24

* At the end of the luteal phase, the corpus luteum degenerates (if no implantation occurs). * The loss of the corpus luteum results in decreased progesterone production. * The decreasing levels of progesterone cause the spiral arteries in the functional endometrium to contract. * The loss of blood supply causes the functional endometrium to become ischaemic and necrotic.

Answer 25

Ovulation and receptivity of the uterus are co-ordinated

Answer 26

By preventing the degradation of the corpus luteum.

Answer 27

It is part of the implantation process: * The stroma (connective tissue) in the endometrium responds to binding of the blastocyst as well as progesterone from the corpus luteum * Stroma cells differentiate into decidual cells (secretory cells) -\> These secrete lots of glycogen and mucus for immunological protection

Answer 28

* At one pole of the trophoblast, the syncytiotrophoblast and cytotrophoblast form from trophoblast cells * Syncytiotrophoblast cells are the cells that initially invade the endometrium, drawing the blastocyst into the uterine wall -\> Ruptures capillaries so creating an interface between maternal blood and embryonic fluid for passive transfer. Also secretes a lot of hCG to maintain corpus luteum * Cytotrophoblast cells line the inside of the syncytiotrophoblast and will eventually form the foetal portion of the placenta

Answer 29

* Progesterone from the corpus luteum * hCG from the synctiotrophoblast assists with this by maintaining the corpus luteum

Answer 30

* Non-Receptive -\> During times when implantation is not favourable, there are mucins that prevent the embryo from implanting * Receptive -\> During times when implantation is favourable, there are no mucins so the embryo can freely bind These states are co-ordinated with ovulation, so that ectopic implantation does not occur.

Answer 31

* Blastocyst hatches from zona pellucida and adheres to endometrium lining if it is in the receptive state (when there are no mucins on it) * Trophoblast (trophoectoderm) begins to grow into the uterine wall, forming a syncytiotrophoblast that penetrates epithelium, then basal lamina, and then starts pulling the blastocyst into the uterine wall * This triggers decidual reaction: endometrial stroma (connective tissue) responds to blastocyst AND progesterone from the corpus luteum and turns into decidual cells (secretory cells) -\> These secrete lots of glycogen and mucus for immunological protection * The uterine wall becomes more vascularised and oedematous (swollen)

Answer 32

HOXa10 (9-13) expression in stroma + endometrial glands

Answer 33

hCG (human chorionic gonadotrophin)

Answer 34

Syncytiotrophoblast cells

Answer 35

To maintain the corpus luteum so that there is continued production of progesterone.

Answer 36

* hCG is secreted by syncytiotrophoblast cells upon implantation * This hCG maintains the corpus luteum, so that it can keep producing progesterone * Progesterone means that glandular secretion in the uterine glands continues and the uterine lining is maintained * This is a positive feedback loop

Answer 37

* LH receptors in the corpus luteum * These are Gs-coupled (via cAMP)

Answer 38

hCG-h This is hyperglycosylated hCG.

Answer 39

It decreases over pregnancy.

Answer 40

It is very high at the very early stages of pregnancy (3-5 weeks), so it is a good diagnostic of preganancy at early stages.

Answer 41

* hCG -\> Syncytiotrophoblast * hCG-H -\> Cytotrophoblast

Answer 42

* In general, total hCG levels in the serum are about doubled * There are also high levels of hCG-H (heavily glycosylated hCG) may be implicated in high rates of spontaneous abortion

Answer 43

* First trimester * Very dominated by hCG * This is produced largely by the corpus luteum * Second and third trimester * All three hormones (hCG, progesterone and estrogen produced) * This is because the placenta becomes more dominant

Answer 44

It is the interface between the mother and the fetus that secretes the hormones and growth factors into the mother.

Answer 45

40 weeks from the last menstrual period (38 weeks from fertilisation)

Answer 46

Trimesters (3 month periods)

Answer 47

* \<10 days = Pre-implantation conceptus * 3-8 weeks = Embryo * \>8 weeks = Fetus

Answer 48

From 22 weeks (with high quality care)

Answer 49

In order, the fetus obtains nutrition from: 1. The small amount of yolk proteins in the oocyte 2. Secretions of the uterus and oviduct (before implantation) 3. Digestion of the uterine decidua (endometrium that is specialised for implantation) 4. Maternal blood (via placenta)

Answer 50

* Attachment of embryo to the uterus * Invasion and digestion of endometrial tissue * Transfer of: * Respiratory gases * Nutrients * Waste products * Synthesis of hormones: * To maintain pregnancy * To control fetal growth * To control maternal metabolism * To prepare for partuition * To prepare for lactation * Immunological protection of the fetus (i.e. barrier to stop the mother attacking the fetus)

Answer 51

Around 12.5kg, with most gained during the second trimester. This is due to: * Growth of the conceptus and placenta * Englargement of maternal organs * Maternal storage of fat * Increase in maternal blood and interstitial fluid

Answer 52

* Chorion (Trophoblast plus extra-embryonic mesoderm) -\> This forms the chorionic vesicle, including the placenta * Allantois -\> Endoderm lining, mesodermal covering, Forms bladder and urachus * Yolk sac -\> Site of haematopoiesis in early pregnancy; development of gut; primordial germ cells * Amnion -\> Main source of amniotic fluid in early pregnancy (later from urine, lungs, skin).

Answer 53

The placenta is essentially the interface between the maternal blood and the fetal blood: * Fetal vessels pass via the umbilical cord and form branches within villi * These villi are surrounded by intervillous spaces, which are supplied by the maternal blood * Thus, the fetal blood and maternal blood are completely separated, so the surface of the villi is required for exchange and immunological protection

Answer 54

Placental (a.k.a. chorionic) villi are villi that sprout from the chorion to provide maximal contact area with maternal blood.

Answer 55

On the upper posterior aspect of the uterine wall.

Answer 56

Placenta previa: * When the placenta partially or totally covers the mother's cervix (the outlet for the uterus) * Can cause severe bleeding during pregnancy and delivery. * If you have placenta previa, you might bleed throughout your pregnancy and during your delivery.

Answer 57

* Begins with implantation (see earlier flashcards), including attachment, penetration and decidual reaction * The syncytiotrophoblast cells are fused, then maternal blood fills the lacunae in the * The cytotrophoblastic cells begin to develop and the layer buldges out, forming primary villi -\> These eventually develop into tertiary villi * Thus, the syncytiotrophoblast and crytotrophoblast form the outer lining of placental villi, which are surrounded by maternal blood

Answer 58

This is driven by the buldging of the cytotrophoblast.

Answer 59

* The trophoblast attaches to the decidua (maternal) tissue, forming an anchoring villus * The villus undergoes branching to increase SA * The cytotrophoblast becomes incomplete and the syncytiotrophoblast thins to reduce diffusion distance * Capillaries move to edge of the villus, so that they're essentially apposed to the cytotrophoblast

Answer 60

The capillaries form a convoluted knot, with a terminal dilation -\> This slows down the blood and allows for increased exchange.

Answer 61

Trophoblast

Answer 62

* Class 1 MHC antigens of paternal origin are not expressed on the membrane of trophoblast cells in contact with the maternal blood. Instead, the trophoblast expresses a specific HLA-G which interacts with maternal cells including uterine natural killer (uNK) cells to prevent rejection. * Trophoblast secretes molecules which exert some inhibition of the immune response (hCG and progesterone) * ITrophoblast produces an enzyme (IDO indoleamine 2,3-dioxygenase) that degrades tryptophan that is necessary for T-cell activation. If IDO is inhibited, allogeneic pregnancies are rejected rapidly by a T-cell mechanism * The uterine T cell population is shifted from Th1 (cell-mediated immunity) type to Th2 (antibody-mediated).

Answer 63

Fetal circulation: * **Umbilical arteries** (from the internal iliac) take blood to the placenta, where it picks up oxygen * Oxygenated blood returns to the fetus' liver via the **umbilical vein** and from there to the right atrium Mother's circulation: * Uterine arteries (branches of the internal iliac) take blood to the uterus * Spiral arteries supply the intervillous spaces * Uterine veins drain the uterus Uterine contractions allow blood to spurt in from the arteries, but close venous outflow, causing the low pressure in the intervillous space to rise. When the myometrium relaxes, veins reopen and intervillous pressure falls.

Answer 64

* Branching of villi and formation of a brush border on the syncytiotrophoblast * Decrease in diameter of villi from 140-200µm in early pregnancy to 40µm in late pregnancy * Thinning of the placental ‘barrier’ which consists of : * Endothelium and basal lamina of fetal capillary * Stroma of villus (not present in some areas of the late placenta) * Basal lamina of the cytotrophoblast * Syncytiotrophoblast

Answer 65

Peptide and protein hormones: * hCG (human chorionic gonadotrophin) * hPL (h placental lactogen) * Relaxin Steroid hormones: * Estrogens -\> Esterone, Esteriol, Estradiol * Progesterone

Answer 66

Syncytiotrophoblast cells

Answer 67

* Produced in the syncytiotrophoblast * It signals the presence of a fertilised egg, maintaining the corpus luteum and stimulating its production of progesterone * Progesterone is important in stopping the shedding of the endometrium and preventing contractions of the myometrium * This progesterone from the corpus luteum is important for the first 6-8 weeks of pregnancy, until the placenta is established and becomes the main source of progesterone (Thus, hCG levels drop around 10 weeks, but continue to be produced)

Answer 68

* Produced in the syncytiotrophoblast of the placenta * It rises in concentration in the maternal circulation between 8 and 35 weeks * Has weak GH and PRL activity -\> Therefore, increases somatic growth in the mother (e.g. breast growth) and increases milk secretion * Also has metabolic effects -\> Increases nutrient concentrations in the blood, for better supply to the fetus (e.g. increases maternal lipid breakdown)

Answer 69

Human placental lactogen

Answer 70

* Produced in the syncytiotrophoblast * Relaxes pelvic joints and ligaments and softens the cervix in preparation for partuition

Answer 71

* hPL essentially has diabetogenic effects, increasing concentrations of sugar and fatty acids in the blood for the fetus. * This can lead to gestational diabetes

Answer 72

* At first, after implantation happens, hCG from the placenta (syncytiotrophoblast) maintains the corpus luteum -\> Thus, the ovaries produce most of the progesterone at first * By the second trimester, the corpus luteum has degraded and the placenta has developed -\> More progesterone and estrogen are produced from the placenta, as hCG decreases * In the third trimester, there is very little hCG, while progesterone and estrogen peak

Answer 73

* The mother requires progesterone and estrogens for maintaining pregnancy * The mother provides the LDL cholesterol required for synthesis of these, but she lacks the enzymes to produce them, so she cannot synthesise them along * Therefore, a maternal-placental-fetal unit is required for synthesis -\> The placenta and fetal adrenal/liver provide the enzymes for progesterone and estrogen synthesis (Details of enzymes are not core)

Answer 74

The fetal zone of the adrenal gland develops to a large size unit birth, then it regresses again. It is involved in the production of weak androgens, which can then be converted to weak estrogens.

Answer 75

* Pituitary, thyroid and adrenal glands increase in size: * Increased cortisol production * Increased T3 and T4 * Parathyroid glands increase in size to control calcium homeostasis

Answer 76

* Growth of uterus and preparation of the uterus for partuition * Growth of breasts (along with progesterone) * Increase in blood volume -\> Via sodium retention, reduced water excretion, and vasodilation * Connective tissue effects -\> Makes the body more pliable

Answer 77

* Nausea + Constipation * Reduces bladder and ureter tone (increased micturition) * Reduces distolic pressure and causes vasodilation * Maintains the uterus in a quiescent state (so that the fetus is not lost) * Relaxes cardiac sphincter -\> Leads to heart burn * Alters taste and appetite

Answer 78

* Signalling pregnancy (e.g. hCG preserves the corpus luteum) * Maintaining pregnancy: (e.g. Progesterone to maintain uterine quiescence, Estradiol for uterine growth) * Converting maternal metabolism to the pregnant state (e.g. hPL increases maternal lipid breakdown to provide the fetus with energy * Preparing for & initiation of parturition (e.g. Estradiol induces production of contraction-associated proteins by the myometrium, stimulates production of oxytocin receptors; and increases the excitability of the myometrium * Stimulating myometrial contractions and modifying the cervix for parturition (e.g. Placental prostaglandins) * Preparing for lactation (e.g. Estradiol stimulates development of the duct system of the mammary gland; Progesterone causes development of the alveoli, hPL has a lactogenic action, developing the secretory potential of the breast alveoli -\> However, during pregnancy, production of milk is suppressed by the high levels of progesterone and estradiol)

Answer 79

* Simple diffusion -\> Small molecules, ions, unconjugated non-polar molecules * Facilitated diffusion -\> Glucose, Some fatty acids * Secondary active transport -\> Amino acids * Carrier mechanisms involving specific receptors on the syncytiotrophoblast brush border: * For large molecules: e.g. immunoglobulins (may involve receptor-mediated endocytosis) * To concentrate substances in the fetal circulation: e.g. Fe, Ca, Cu, glucose, vitamin B12, folate, riboflavin, vitamin C, amino acids, some hormones (Note: Most proteins are not transported but are synthesized from amino acids by the placenta or fetus)

Answer 80

* Although the placenta can produce progesterone from cholesterol, it does not have the key enzymes necessary to produce estradiol from cholesterol * Instead it uses the weak androgen dehydroepiandrosterone (DHEA) which is synthesized in the fetal adrenal gland. * This is converted by the placenta in part to estradiol. * However, it is also 1,6-hydroxylated by the liver, to yield a steroid which is converted by the placenta to estriol, a weak oestrogen which is the main oestrogen secreted in the urine. Some estrone is also formed.

Answer 81

* It increases throughout pregnancy, then falls near term. * This means that pregnancies that go over term are at much higher risk of placental insufficiency

Answer 82

* Some mothers, in late pregnancy, develop very high ABP which causes renal damage (albumin appears in the urine) and oedema. * It is most common in first pregnancies in lower socio-economic groups. It is also most likely if there is a large placental mass as with multiple fetuses or a ‘hydatidiform mole’ (a tumour of trophoblast with no fetus present). * The blood pressure can rise so high and so fast that, on occasion, the mother may suffer convulsions or even death. * The cause is still unclear, but an abnormality of placental spiral arteries, which fail to dilate normally, is thought to restrict uteroplacental blood flow and causes placental ischaemia.

Answer 83

* Ultrasound and MRI -\> Used to examine the fetus morphologically * Amniocentesis -\> Sampling of amniotic fluid at 16-20 weeks pregnancy, followed by culture of fetal cells are cultured and karyotyped to check for chromosomal abnormalities, single gene disorders, and signs of spina bifida. * Chorionic villus sampling -\> Used for diagnosis of: * Chromosomal abnormalities * Single gene disorders * Transplacental virus infection (eg. Rubella) * Fetal blood grouping (eg. Rh).

Answer 84

* Abnormal implantation site -\> ‘Placenta praevia’ is where the placenta covers cervical outlet (risk of fatal haemorrhage) * Abnormal shape: peripheral attachment of cord * Hydatidiform mole: non-invasive tumour of trophoblast * Choriocarcinoma: invasive malignant tumour of trophoblast 4 * Placental insufficiency: functional insufficiency leading to fetal malnutrition; smoking causing uterine vasoconstriction.

Answer 85

* The concept is that a person's health can be largely affected by the conditions they face when they are still a fetus * For example, risk of Type 2 diabetes and hypertension is affected by fetal conditions. * Those born underweight have a reduced life expectancy. This is in part due to long-term programming of the glucocorticoid stress axis, which becomes chronically overactive.

Answer 86

* The uterus grows at the same rate as the conceptus, so there is little stretching until the very end of pregnancy. * Progesterone is essential for uterine quiescence: * Acts on the muscle cells directly * Acts on chorionic enzymes (which prevent the accumulation of activating prostaglandins from reaching the myometrium) * Reduces the numbers of oxytocin receptors within the uterine muscle. * The prostaglandin produced before term is largely prostaglandin I which relaxes smooth muscle On the other hand, estrogen (estradiol) is the main hormone causing growth of the uterine muscle. It also stimulates development of contraction-associated proteins and oxytocin receptors to prepare the smooth muscle for parturition.

Answer 87

Do it -\> Use practical in week 4 of Michaelmas.

Answer 88

* Syncytiotrophoblast cells: * Initially invade the endometrium, drawing the blastocyst into the uterine wall and rupturing capillaries so that there is an interface between maternal blood and embryonic fluid for passive transfer. * Also secretes a lot of hCG to maintain corpus luteum. * Cytotrophoblast cells: * Line the inside of the syncytiotrophoblast and buldge out to form placental villi for transfer

Answer 89

They are the spaces between the chorionic (placental) villi, which fill with maternal blood and allow for exchange.

Answer 90

It is the inner lining of the uterus, where the blastocyst implants.

Answer 91

* Amnion -\> A membrane that covers the embryo when it is first formed. It contains the amniotic fluid, used for protection. * Chorion -\> The outermost fetal membrane. It contains chorionic fluid, usd for protection. Chorionic villi (a.k.a. placental villi) are used for exchange with the mother.

Answer 92

* The term given to the uterine endometrium at the site of implantation where signaling transforms the uterine stromal cells (fibroblast-like) into decidual cells. * Functions: * Exchanges of nutrition, gas, and waste with the gestation * Protects the pregnancy from the maternal immune system * Hormone production

Answer 93

* They are divisions of the placenta, separated by septa, only visible from the maternal side. * Each cotyledon consists of a main stem of a chorionic villus as well as its branches and subbranches.

Answer 94

* Uterine glands tubular glands of the endometrium * They secrete [INSERT HORMONES]

Answer 95

* A gelatinous substance within the umbilical cord, largely made up of mucopolysaccharides (hyaluronic acid and chondroitin sulfate). * It acts as a mucous connective tissue, important in the protection of the vessels in the umbilical cord.

Answer 96

* Progesterone + Relaxin -\> Decrease contractility * Estrogens -\> Increase contractility * Corticotrophin-releasing hormone (CRH) * Adrenocorticotropic hormone (ACTH) * Prostaglandins -\> Increase contractility * Oxytocin -\> Used to induce labour * Prolactin (PRL)

Answer 97

* They are all derived from cholesterol, which is provided by the mother * The placenta converts the cholesterol to progesterone (via pregnenolone) -\> Decreases contractility * The fetus converts cholesterol to DHEA-S and 16-OH DHEA-S, which are used to synthesis weak estrogens -\> Increase contractility This makes sense because as the fetus grows, the uterus needs to increase contractility for childbirth.

Answer 98

* Fetus must be fullyt mature, with developed lungs, gut and liver -\> This is dependent on cortisol * Uterus must begin synchronised contraction -\> Dependent on intracellular calcium increases, mediated via prostaglandin and oxytocin action. Synchronicity is due to gap junctions and estrogens. * Relaxant effects of progesterone must be stopped -\> Dependent on change in the progesterone receptors * Cervix must allow passage -\> Prostaglandins cause collagen breakdown

Answer 99

* Fetal hypothalamus produces corticotrophin-releasing hormone (CRH): * This leads to increased ACTH secretion from the fetal pituitary * This in turn leads to increased fetal adrenal production of cortisol and DHEA-S * The cortisol leads to maturation of the lungs, liver and gut, as well as stimulating release of CRH from the placenta -\> This acts on the fetal pituitary again, completing the feedback loop * Maternal cortisol also stimulates CRH production in the placenta * The DHEA-S is converted to estrogens in the placenta, ready for action in the uterus * There is remodelling of the uterus, driven by irritation of the cervix, which leads to increased contractility: * Although estrogens and progesterone in plasma changes little at term, their intracellular receptors on the uterus change. This inhibits progesterone action and favours estrogen action, which has 2 effects: 1. Leads to increased prostaglandin action via: * Increased synthesis in the uterus * Decreased breakdown * Prostaglandin receptor activation * Prostaglandins stimulate contraction by favouring a rise of calcium levels in the uterine smooth muscle cells. They also soften the uterine cervix. 2. Leads to an increase in oxytocin receptors in the uterus * Oxytocin leads to formation of gap junctions within the uterus, for synchronised contractions. It is worth noting that the ultimate kickstart for labour to begin is irritation of the cervix and stretch of the uterus (leading to the Ferguson reflex).

Answer 100

They spike just before parturition.

Answer 101

It is important in the fetus: * Stimulates maturation of the lungs, liver and gut * Stimulates the release of CRH from the placenta -\> CRH is important as an initiator of many downstream effects involved in parturition

Answer 102

* Placental CRH levels rise toward term and CRH levels at 16-20 weeks roughly predict when a woman will give birth. * High CRH levels are associated with premature labour; low levels usually indicated delayed parturition.

Answer 103

Ferguson reflex

Answer 104

* Parturition is properly initiated by irritation of the cervix and stretch of the uterus * Sensory fibres convey information about stretch via the spinal cord to the hypothalamus * This stimulates the production (in the hypothalamus) and release (in the posterior pituitary) of oxytocin * Oxytocin binds to oxytocin receptors on the uterus that have been induced by estrogen in preparation for pregnancy * This leads to uterine contraction and increased prostaglandin secretion * Prostaglandins also increase uterine contraction, but also stimulate changes in progesterone receptor ratios, decreasing the inhibitory effect of progesterone * Decreased activity of progesterone leads to reciprocal increases in prostaglandins and increase uterine contractions * This completes the positive feedback loop and also stimulates increased stretch of the uterine wall (which reciprocally induces contractions)

Answer 105

It is worth noting that the oxytocin induces uterine contraction in a variety of ways, as shown in the previous slide.

Answer 106

* Estrogens (and decreased progesterone action) prepare the uterus for contraction by increasing contractility and inducing oxytocin receptors on the uterus, as well as increasing prostaglandins that loosen the cervix * CRH appears to be the signal of readiness for parturition * Stretch of the cervix and uterus appear to be what ultimately triggers parturition * Parturition itself is sustained by the Ferguson reflex, involving oxytocin and prostaglandins that stimulate uterine contraction

Answer 107

* Early in pregnancy, prostaglandins that cause smooth muscle relaxation predominate * During parturition, prostaglandins that stimulate contraction are induced by oxytocin acting on the uterus * It leads to uterine contraction and changes in the progesterone receptor ratios (so that progesterone action is decreased)

Answer 108

* Its action is induced by: * Increased production triggered by uterine contraction * Increased receptor expression on the uterus * It leads to uterine contraction and prostaglandin secretion by the uterus

Answer 109

PGF and PGE

Answer 110

PGF and PGE induce uterine contractions, and are therefore used in terminations of pregnancy.

Answer 111

1. Estrogen binds to its receptor intracellularly 2. This leads to changes in transcription and increased production of oxytocin receptors and PLA₂ 3. Oxytocin receptors are inserted into the cell membrane 4. Oxytocin receptors and PLA₂ lead to increased prostaglandin synthesis 5. Prostaglandins and oxytocin receptors lead to an increase in intracellular calcium 6. This stimulates muscle contraction

Answer 112

It goes from an anti-inflammatory to a pro-inflammatory state.

Answer 113

Ergometrine -\> A smooth muscle stimulant

Answer 114

Most of these are induced by the secretion of glucocorticoids which increase markedly towards term. They include: * Production of surfactant in the lungs -\> To allow lung expansion when air is first breathed * Changes to gut and liver enzymes to allow the fetus to metabolise its post-natal milk diet

Answer 115

* Preterm -\> The fetus is not yet prepared for extrauterine life * Post-term -\> Continued fetal growth and placental insufficiency pose problems for both delivery and fetal nutrition

Answer 116

* Found in the subcutaneous fat * Develops along axillary-to-groin line, but only remains in the breast area. Tail of Spence is part of the breat tissue that extends into the armpit. * Blood supplied/drained by axillary and internal thoracic vessels * Lymphatics drain to axillary nodes (mostly) and internal thoracic nodes (more minor)

Answer 117

* Before pregnancy, there are few ducts and alveoli * Estrogen causes the duct system to develop * Progesterone causes the alveoli to develop * Human placental lactogen (hPL) has lactogenic action, developing the secretory potential of the mammary glands * Estrogen and progesterone suppress milk production during pregnancy * After birth, prolactin stimulates lactation and further breast growth * After weaning, the breast regresses

Answer 118

There is a tubulo-alveolar with 12-20 galactopoetic (milk-producing) lobules each emptying into a common lactiferous duct which opens onto the nipple.

Answer 119

Adrenal steroids are also important in the development of the mammary glands.

Answer 120

* Prolactin -\> Milk secretion * Oxytocin -\> Milk ejection

Answer 121

Milk production: * Produced by mammary epithelial cells that are on top of myo-epithelial cells and a capillary -\> Stimulated by prolactin * Amino acids, glucose and galactose are taken up into the epithelial cells from the capillary, while water, leukocytes and ions pass via the paracellular route (and also transcellular route for water and ions) * Within the epithelial cells, proteins (e.g. casein and lactalbumin) are synthesised in the RER, then secreted in vesicles * Fats are produced in the SER, then secreted in vesicles * Immunoglobulins are secreted into the milk via transcytosis (vesicular transport through the cell) Milk ejection: * Due to contraction of myo-epithelial cells * Stimulated by oxytocin

Answer 122

* It is produced by the anterior pituitary * It acts on the PRL receptors on the mammary glands, stimulating lactation * PRL levels rise up to 20-fold during pregnancy, but its action is inhibited by the high levels of estrogen and progesterone * It secretion is also inhibited by dopamine

Answer 123

Dopamine inhibits PRL release, so dopamine agonists can be uesd to inhibit lactation.

Answer 124

* It is the initial secretion from the mammary glands after birth, later giving way to milk. * It is dense in carbohydrates, proteins and immunoglobulins for passive immunity

Answer 125

* Prolactin -\> Natural contraceptive that decreases fertility * Parathyroid hormone -\> Mobilises maternal calcium for the baby * Calcitonin -\> Protects against excessive calcium loss

Answer 126

* Prolactin alters GnRH output from the hypothalamus, reducing GnRH pulses. * In this way, lactation suppresses ovulation and so prevents a further pregnancy which would create excessive metabolic demand on the mother.

Answer 127

* Suckling causes reflex neural input to the hypothalamus * Aside from increasing oxytocin release, this leads to decreased dopamine secretion * Decreased dopamine secretion leads to decreased inhibition of prolactin release from the anterior pituitary gland

Answer 128

* The production of milk that is unrelated to childbirth * This can be caused by: * Tumours of the PRL-releasing cells in the anterior pituitary * Antipsychotic drugs (e.g. haloperidol) used to treat schizophrenia -\> These may suppress dopamine-mediated inhibition of PRL release * It can be treated using radiation therapy for cancers or dopamine receptor agonists

Answer 129

* Infertility is an issue that affects many men and women * Controlling fertility is also important due to the rapidly growing population

Answer 130

* Implantation * Injection * Oral * Patches * Uterus/vagina

Answer 131

* Include injected or oral steroids that inhibit FSH & LH by enhancing negative feedback on the brain and pituitary * There are a few varieties of oral contraceptive pill. * These tend to include synthetic estrogens and progestagens

Answer 132

No, it is the response to withdrawal of the pill.

Answer 133

Prevent implantation by giving a high dose of a synthetic progesterone receptor modulator (levonorgestrel) (or previously, a synthetic estrogen) within 72 hours of unprotected intercourse: * High dose estrogen -\> Thought to act by speeding movement of the conceptus through the fallopian tube to reach an unprepared uterus – it has now been superceded. * Progesterone receptor modulator levonorgestrel -\> Thought to act either (a) by preventing ovulation and/or (b) by thickening cervical mucus to reduce/prevent sperm entry. Doesn’t seem to act on the endometrium to prevent implantation.

Answer 134

Around 95%

Answer 135

* Intrauterine devices (IUDs) -\> Typically copper, which affects the uterine environment and prevents implantation * Intrauterine systems (IUSs) -\> Carries a progesterone receptor modulator Can use IUSs as a ‘morning-after’ device containing progesterone receptor modulator. Can also use progesterone receptor antagonist (RU486) to block implantation, and prostaglandin to evacuate uterus.

Answer 136

All possible methods decrease testosterone, which has too many side effects to be viable.

Answer 137

* A male “pill” is in development * It involves desogestrel (synthetic progestagen) + monthly testosterone injections * This stops testis making androgens and blocks sperm production

Answer 138

It involves cutting the vas deferens -\> So the patient can still ejaculate, but there is no sperm in the semen.

Answer 139

Anti-sperm antibodies

Answer 140

* Plant extracts -\> Cannabis (hemp seeds), Gossypol (cotton) * Heatt * Blocking neural control of vas, emission, ejaculation

Answer 141

* 35% male * 35% female * 20% both * 10% idiopathic

Answer 142

HPG (Hypothalamo-pituitary-gonadal)

Answer 143

You have to determine where in the HPG (hypothalamo-piuitary-gonadal) axis there is a problem, so it can be corrected.

Answer 144

Diagnosis: * Use GnRH itself for defects * Use kisspeptin to test its receptors on the anterior pituitary Treatment: * Supply GnRH -\> Pulsatile (in cases of delayed puberty, as in Kallmann syndrome) or long-acting (to synchronise cycles for IVF

Answer 145

* Supply FSH/LH, although this can be problematic because no human recombinant of these and therefore the animal FSH/LH supplied can elicit antibody production * Cannot use testosterone since the dose required is too high

Answer 146

* Sperm donation -\> Although sperm donors have reduced since new laws reducing anonymity have been introduced * Cryoprotection of semen, spermatozoa, spermatids -\> This is done in cancer patients who know that their * Spermatagonia transplant (experimental!) * Intra-Cytoplasmic Sperm Injection (ICSI) -\> Insertion of a single spermatozoon into an oocyte in vitro * Round Spermatid Injection (ROSI) -\> Insertion of a spermatid into an oocyte in vitro (less successful)

Answer 147

(Johnson, 1993): * The principle behind sorting sperm into male and female is the fact that the X chromosome is larger than the Y, so that there is 2.8% more DNA in female sperm * “Microsort” uses a modified fluorescence-activated cell sorter to separate male and female sperm stained with the non-damaging fluorochrome bisbenzimide based on DNA content (not colour as in diagram)

Answer 148

* FSH & LH assays -\> If normal, may suggest poor corpus luteum formation in conjunction with effects on progesterone levels * Measure circulating anti-Mullerian hormone -\> Secreted by primary follicles and therefore indicates how many follicles remaining (when they run out, it marks infertility) * Ultrasound of ovaries

Answer 149

Surgery can be used to treat: * Endometriosis (growth of the endometrium outside the uterus) * Incompetent cervix (which has a risk of spontaneous abortion) * Congenital uterine abnormalities

Answer 150

If there are problems with the sperm getting through the Fallopian tube, semen can be introduced into the vagina or uterus by GIFT (Gamete Intra-Fallopian Tube injection) or ZIFT (Zygote Intra-Fallopian Tube injection). However, this has been largely superceded by IVF.

Answer 151

* GnRH analogues are used to block LH surge (GnRH is usually an agonist, but here the analogue is an antagonist), which synchronises the cycle * FSH & LH and/or clomiphene (oestrogen receptor modulator) are used to stimulate follicle formation/ripening * Oocytes are collected under ultrasound guidance * Follicle are stored and culture Note that the oocytes can also be collected earlier in their maturation without using all of these complex hormones, which is known as in vitro maturation. This is less effective but has fewer side effects.

Answer 152

* Improving collection methods for collecting oocytes * Improving culture conditions * Screening individual blastocyst cells for aneuploidy, etc. * Selecting only appropriate blastocysts for transfer

Answer 153

A cell is obtained from the early blastocyst or a polar body is taken from the fertilised oocyte. It is then checked for genetic abnormalities.

Answer 154

All of the early stages can be preserved, up to the early embryo.

Answer 155

* Used to prevent mitochondrial diseases * If the mother has a mitochondrial disease, her fertilised egg can be taken and both the paternal and maternal pronuclei can be removed. * These can then be inserted to an enucleated zygote. * It was approved for use in the UK in December 2016.

Answer 156

* Oxytocin * Vasopressin

Answer 157

They are peptide hormones.

Answer 158

Maternal behaviour

Answer 159

* Courtship * Aggression * Territorial defense * Paternal care of young * Pair bonding (Mostly in males)

Answer 160

* Oxytocin antagonists (e.g. atosiban) block oestrogen-controlled maternal behaviour such grooming (Fahrbach, 1985) * Radioactive oxytocin administration shows that oxytocin receptors are denser in monogamous vole brains * Oxytocin KO mice show a lack of maternal behaviour, including percentage of scattered pups, effects on the latency to retrieve scattered pups and latency of crouching over the pups. Oxytocin receptor KO mice also have impaired social recognition (Takayanagi, 2005) * Oxytocin KO male mice have social amnesia, which involves the mice being unable to recognise mice that they have encountered 10 minutes earlier (Ferguson, 2000) * Mating of male priarie vole mice leads to increased oxytocin and vasopressin levels, which leads to pair bonding, parental care and aggression to male (Wang, 1994) * Vasopressin antagonist blocks mating-induced aggression (Winslow, 1993) * Vasopressin increases aggression in prairie but not meadow voles (Young, 1997) * Vasopressin induces pair bonding in prairie voles but not meadow voles (Young, 1999) * In situ hybridisation can be used to find the location of vasopressin receptors -\> Vasopressin receptor is denser in the ventral pallidum of monogamous voles (Young, 1997) * Viral expression of V1a receptor in meadow vole gives it “prairie” characteristics (Lim, 2004) * Homozygosity in the 334 RS3 allele upstream of the vasopressin receptor transcription start site is associated with marital problems (Walum, 2008) * Intranasal administration of oxytocin increases trust in humans (Kosfeld, 2005) * Oxytocin may be a potential treatment for autism (Andari, 2010)

Answer 161

* Starvation * Severe exercise * Emotional stress

Answer 162

* Central: * Damage to the inhibitory system of the brain (due to infection, trauma, or irradiation) * Hypothalamic cancers producing pulsatile gonadotropin-releasing hormone (GnRH) * Peripheral: * Endogenous and exogenous sources of sex steroids

Answer 163

* Malnutrition * Various systemic diseases * Defects of the reproductive system (hypogonadism) * Lack of responsiveness to sex hormones

Answer 164

* The depletion of the ovarian reserve causes an increase in circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels because there are fewer oocytes and follicles responding to these hormones and producing estrogen. * The ovaries produce less oestrogen and progesterone.