Reproduction Flashcards

Question

Describe internal sexual differentiation in males

Answer 1

- Still inside the body - do not descend until later - Producing AMH and testosterone - Mullerian ducts regress because of the AMH - Wolffian ducts keep developing because of the testosterone

Answer 2

- No AMH - Mullerian ducts therefore continue to develop - Uterine tube, uterus and vagina develop because there is no AMH - Male wolffian ducts regress because there is no tetstosterone

Answer 3

- Testosterone converted in the genital skin, tomore potent androgen DHT (DHT = dihydrotestosterone) - This conversion is by 5 alpha reductase in the skin - this just adds a H group to testosterone. Makes dihydroteststerone in the local area - In the male embryo there is testosterone circulating around, and DHT = influences formation of the external genitalia - Little or no testosterone in Females - so nothing to convert this DHT

Answer 4

- Also binds to testosterone receptor - But it is more potent than testosterone - Causes differentiation - Of the male external genitalia • Clitoral area enlarges into a penis • The labia will fuse together and will become ruggated to form the scrotum • Prostrate will form

Answer 5

- In presence of DHT you will get genital tubercle becoming phallus of penis - Urethral fold folds over on itself to make a hollow tube that becomes the shaft of the penis and folds over on itself until it becomes circular - line = marks where the urethral fold joins, and evidence of sexual differentiation

Answer 6

- External genitals are similar to begin with - Little testosterone and DHT so genital tubercle becomes clitoris and the labia = from the swellings Urethral fold becomes the opening of vagina

Answer 7

- Sexual differentiation = incomplete - Usually missing SRY gene in males - Partial / complete deletion of the second X in females + used as general description of abnormal development of gonads

Answer 8

- Phenotype and genotype do not match - May be male genotypically - And look female phenotypically

Answer 9

- Have some components of both tracts - Or have ambiguous genitalia - Sex of infant = hard to determine

Answer 10

- Androgen insensitivity syndrome AIS

Answer 11

- Gonad itself has not developed properly, which can cause other issues in development. - Sex reversal = ambiguous gender / genitals : get this with a mixture of wolffian and mullerian ducts - Testosterone would not have an effect, in ANDROGEN INSENSITIVITY SYNDROME (AIS) ○ Receptors are not responding to the high amounts of testosterone ○ AMH made, so there is regression of the mullerian ducts ○ Testosterone is not active therefore the wolffian duct, which needs testosterone to develop, will not grow - therefore no internal genitalia of any kind. ○ External genitalia = you would have female external genitalia , no external male genitals ○ DHT = also binds to testosterone receptors,

Answer 12

- 1 in 20k - Appearing totally female at birth and assigned female gender despite being XY - undescended testes - Primary amenorrhea - lack of body hair, ultrasound scan with male levels of androgen : ultrasound scan and karyotype with male levels of androgens and never responded to androgens, so appear and feel female Might even start to develop male external genitalia.

Answer 13

- Variance in incidence, as autosomal recessive and can depend on inter related marriage - Testes form. AMH and testosterone both act. This will cause the internal structures to form and the external structures do not develop. Therefore the person will appear mainly female and could have ambiguous genitalia - Degree of the enzyme block will vary - Therefore presentation also varies. What will happen at puberty: - Need to assess potential - As high testosterone level which will occur at adrenarche - And puberty - May induce virilisation

Answer 14

In turners there is just a missing chromosome = x but no y. - There is only one x chromosome - All descendants of that chromosome will have the same X suppressed - Women need 2x X chromsomes, some of the genes on the suppressed chromosome are actually needed

Answer 15

- Failure of ovarian function - "Streak" ovaries - get 2X in some cases but not in others, there are lots of morphological issues that come from only having one X • Ovarian dysgenesis • Illustrates that we need 2 X for ovarian development - The uterus + tubes are present but small, as well as other defects in growth and development - May be fertile, could have mosaicism. There is hormone support of the bones and uterus

Answer 16

- Congenital adrenal hyperplasia = the most common cause of this

Answer 17

``` - CRH ○ Corticotropic releasing hormone ○ Stimulates pituitary gland ○ To secrete ACTH - ACTH ○ Adrenocorticotropic hormone ○ Stimulates the rapid uptake of cholesterol ○ Into the adrenal cortex ○ Will upregulate the cholesterol side chain cleavage enzume § P450scc ○ Increases glucocorticoid secretion ```

Answer 18

- The completeness of the block baries - If there is an enzyme absent - Then children can be wrongly gender assigned at birth - ambiguous genitalia - Also in CAH = have to be aware of possibility of salt wasting - Due to lack of Aldesterone - which can be lethal - Need treatment with glucocorticoids to correct feedback

Answer 19

- Differentiation • Into male or female - Sexual maturation - puberty needs to have occurred - Produce + store enough egg and sperm - Right number of chromosomes in egg and sperm - Egg and sperm have to meet - sexual intercourse • I.e. in gamete transport - Creation of new individual with genes from both of the parents - Nurture individual until capable to "independent" life - Fertilisation, implantation, embryonic and placental development - nurture until capable of independent life

Answer 20

- Male and female gonadal function - This controlled by hormonal feedback by the following: • Hypothalamic and pituitary peptides • Gonadal steroids ○ And peptides - This all fits together in the Hypothalamic / Pituitary / Gonadal (HPG) axis

Answer 21

HPG AXIS is the master controller of reproduction - Controlled by feedback - Hypothalamus acts on the pituitary which act on receptors within the gonads - Feedback in negative feedback which regulates the drive from the hypothalamus to the pituitary - + feedback occurs in menstrual cycle - there is a mid cycle surge in oestrogen and LH - LH is a setup of positive feedback Hypothalamus (RH) = Gonadotrpohin releasing hormone, Kisspeptin Pituitary (SH) = follicle stimulating hormone and LH Gonad = F = oestradiol

Answer 22

- Decapeptide is synthesised - And is secreted - By specialised neurones - That are within the hypothalamus - HAS TO BE IN A PULSATILE FASHION

Answer 23

- Collective group - Of neurones - That discharge GnRH In orchestrated manner

Answer 24

- Cells in the anterior pituitary - That synthesise and secrete LH and FSH - In response to GnRH

Answer 25

- LH - FSH - Stimulate the ovary and the testis

Answer 26

- Released in a pulsatile fashion = continual release, secretion this way is key to its function - Released from special pulse generator that is within the hypothalamus

Answer 27

- In males this is around every hour or so - LH surge occurs = this causes the pulse to be more frequent - Pulse of GnRH = stimulates pulse of FSH + LH from pituitary - Pulsatile GnRH secretion is vital for the stimulation of LH and FSH - Slow frequency pulse, favours FSH release. Rapid pulse frequency, favours LH. Continuous release results in the cessation of response

Answer 28

- Synthetic GnRH is the same structure as native GnRH = stimulatory - GnRH analogues which are modified versions of GnRH = various modifications within the GnRH structures - Analogs are always used to downregulate / inhibit the GnRH structure - They work in slightly different ways - Discovery of decapeptide structure of GnRH - = development of new drugs - GnRH = synthetic but had same structure as native GnRH - GnRH analogues • Single peptide replaced in chain • Prevents breakdown by enzymes at pituitary and receptor internalisation • Longer half life • Loss of pulsatility - Can be used to stimulate or suppress release of LH / FSH - GnRH is a GPCR --> activation of signalling on binding --> stimulatiion of gonadotrophin synthesis and secretion. • Agonist = THEN dissociation of GnRH from GnRHR --> GnRHR response to next GnRH • Antagonist = uncoupling of GnRHR from Gprotein signalling --> GnRHR non responsive to GnRH

Answer 29

- Inhibition of the stimulations of gonad - By removing LH + FSH - By the loss of pulsatility - Never used for stimulation - Always used for inhibition • Testicular cancer - dependent on testosterone for growth • Uterine fibroids prior to surgery ○ Oestrogen dependent • Prevention of premature ovulation in IVF

Answer 30

- Old versions = tended to be agonists - Bind to and activate the receptor • This stimulates the massive release of gonadtrophins initially • Until the gonadotrophins in the gonadotrophs are depleted • Even receptors down regulation - Newer versions = antagonists • These will bind to and block the receptor • Without activation • Gonadarelin • Triptorelin • About £900pa for prostrate cancer

Answer 31

- HETERODIMERIC = made up of 2 different subunits - peptide hormones with common α sub-unit and specific β sub-units • β sub-unit confers specificity of action • sub-units are glycosylated - glycosylation (+ various versios of glycosylations) are required for activity - LH & FSH always released in pulses for normal reproductive function - Why pulses? • The pulses are lost in "unfit to reproduce" conditions • The correct release = dependent on extra hypothalamic and extra pituitary signals • Heterodimeric peptides –common a-subunit and hormone-specific b-subunit • N-linked carbohydrate side chains (+ O-linked in hCG) = microheterogeneity, required for biological function • Free subunits have no biological action • a-subunits are synthesized in excess with b-subunit limiting the hormone concentration Pulsatile secretion due to pulsatile GnRH release from hypothalamus but pulsatile secretion not necessary for biological activity

Answer 32

- Release of LH every 90 minutes and a smaller release of FSH - Underweight person = lose amplitude of LH pulse and there is diminishing of LH = much lower level of FSH Get downregulation of the HPG axis and therefore impairment

Answer 33

- LH = binds to receptors on the testes and stimulates the leydig cell androgen synthesis. On the ovary it causes theca cell androgen synthesism ovulation, progesterone production of CL FSH = regulates sertoli cell metabolism, follicular maturatio and granulsa cell estrogen synthesis of the ovary

Answer 34

- During puberty, first rise in secretion = during sleep - This coincides with GH rise - Sleep related rise in patients, persists in adulthood - Lost in weight loss related amenorrhoea - Delayed puberty in children with sleep disorders - "travellers amenorrhoea" = due to jet lag

Answer 35

- Gonadotrophins act via G protein coupled receptors - There are 2 x distinct receptors - There is the same secondary messenger --> cAMP - FSH low cAMP, LH high cAMP

Answer 36

- FSH receptors only on granulosa cells - Make oestrogen - LH receptors always on theca cells - cause the LH reeceptor to produce androgens • + on differentiated granulosa cells • + the corpus luteum

Answer 37

- FSH receptors on sertoli cells - Sertoli cell metabolism = spermatogenesis • Make oestrogen and AMH • FSH + LH receptors are on the Leydig cells • Makes testosterone and oestrogen

Answer 38

- LH = Stimulates androgen production, usually - FSH = always stimulates oestrogen production - And positive feedback on the hypothalamus and the pituitary

Answer 39

- Oestradiol 17beta Also oestrone

Answer 40

- Synthetic progesterones | - Are known as progestagens

Answer 41

- Androstenedione - Testosterone dihydrotestosterone

Answer 42

- When secondary characteristics develop, the primary characteristics = at birth. @ adolescence there is a growth spurt, and physiological changes. - Gonads will make mature gametes, the testes make spermatozoa and the ovaries make oocytes. - HPG axis before this is waiting for reactivation, in a quiescent state - Testes make spermatozoa - Ovaries make oocytes

Answer 43

adrenarche + gonadarche | independently regulated processes

Answer 44

- Awakening of the adrenals | - Pubic hair and axillary hair, growth in height

Answer 45

- Reawakening of the HPG axis, denoted by LH and FSH secretions

Answer 46

LH - Steroid synthesis, secondary sex characteristics FSH - Testes growth (M) - Steriod synthesis / folliculogenesis (F)

Answer 47

- Change in adrenal androgen secretion. There is a gradual rise from 8-15 years. 20 fold increase which peaks at about 20-25years. - Adrenal androgens, from the zona reticularis. Dehydro-epiandrosterona (DHEA) - Dehydro-epiandrosterone sulfate (DHEA-S) • Not taling about any other adrenal steroids = these are the only 2 adrenal steroids that are actually produced in Adrenarche - No changes in levels of cortisol, androstenedione, 11-hydroxy-androstenedione - Decline thereafter = adrenopause - We do not understand mechanisms involved in adrenarche. - Adrenal = separated into cortexes of different zones - Elevated DHEA + DHEA-S which peaks at 20-25, then there is a decline - There is no change in any other adrenal androgens - no idea what the trigger of adrenarche is yet. Can compare post natal adrenal to the one that is at the point of adrenarche = is highly differentiated - Zones = develop at different stages but we do not know what causes this

Answer 48

- Appearance of pubic / axillary hair. Induced because of adrenal androgen secretion and associated with a rise in sebum production (=acne), infection, abnormal keratinization = acne. - If before 8 years for girls or 9 years for boys = precocious.

Answer 49

- Several years after adrenarche, activation of gonadal steroid production. - This is dependent on hypothalamic GnRH. - Puberty depends on reactivation of GnRH release - Kisspeptin at the top = see this slide - HPG axis is first activated during gestation - Pulsatile GnRH remains until 1-2 years postnatally - then it is restrained

Answer 50

Reactivation of GnRH release

Answer 51

- It is made and secreted by GnRH neurones. This will stimulate the pituitary directly and the gonads. 16th gestational week activation of the HPG axis. - Pulsatile GnRH secretion in the fetus, and 1-2 years post natally. Declines until 9-10 years. - Neurones are restrained during postnatal period - 10 years or more - At puberty a gradual rise in pulsatile release of GnRH. - There is a nocturnal increase in GnRH secretion = pulse of GNRH --> pulse of LH - LH is always used as a measure for GNRH pulsatility

Answer 52

``` - Maturational event within the CNS • Lots of things are said to implicate its starting - Inherent - genetic maturation of 1000-3000 GnRH synthesising neurones. - Environmental and genetic factors - Body fat / nutrition - Leptin - Other gut hormones - Kisspeptin ```

Answer 53

- Link between fat metabolism and reproduction - Anorexia / intensive physical training causes a reduced response to GnRH, fall in gonadotrophin levels, amenorrhea, restored when nourished and exercise stopped. - Body fat hypothesis is that, a certain % fat:body weight is needed for menarche (17%) and need (22%) to maintain female reproductive ability.

Answer 54

- A rise in leptin occurs about 2 years before puberty. This leads to increased GnRH pulsatility. - In starvation, low leptin levels. Decreased activity of HPG axis. - Obesity increases leptin and earlier puberty occurs - Low levels of Leptin, decreased LH - Receptors for leptin protein are in the hypothalamus - A permissive role for leptin, not the driver.

Answer 55

Kisspeptin / Metastin - Found in hypothalamic neurones, receptors for kisspeptin (GPR54) are expressed on GnRH neurones - Directly regulates GNRH secretion - In the arcuate nucleus

Answer 56

- Mutations of the GPR54, or gene that is coding for kisspeptin - Abnormal development of GnRH neurones leads to hypogonadism (low levels of LH + FSH gonadotrophins, so small testes and ovaries because of inactivating mutatios), failure to enter puberty - Hypothalamic hypogonadism - Activating mutations of GPR54 - precocious puberty (where the receptor is active all the time)

Answer 57

- Critical in the initiation of puberty, and reproductive function Interplay with energy homoestasis and kisspeptin

Answer 58

- Inherent genetic maturation of 1000-3000 GnRH synthesising neurones. Environmental and genetic factors. Body fat + nutriton. Leptin, and other gut hormones - Kisspeptin is critical in starting puberty + reproductive function

Answer 59

- Smooth and ordered progression of changes - order of pubertal changes is uniform - Wide inter individual differences in timing and how long each of these stages take

Answer 60

Breasts enlarge - Thelarce. 1st sign, in response to E2 Pubic / axillary hair Uterus enlarges • Secretions in response to E2 • Uterine tubes + Vagina/cervical changes • Dormant follicles start to grow and increase in size Height - Earlier onset than boys, peak height velocity (PHV) = 9cm/y • This is reached at 12 years old HPG axis - Rise in ovarian size and follicular growth Menarche - Not equated with fertility onset - First period = for the first year this might not be associated with fertility as the HPG axis is being established - Fertility - In first year there is about 80% menstrual cycles - Anovulatory, irregular cycles

Answer 61

- Numbers represent the volume in millimetres. | - Measures centiles of testicular size

Answer 62

- Androgens have different effects on the pilo sebaceous units - Terminal PSUs make the beard and mustache - If we get sebaceous gland increased secretions and infection/ abnormal keratinisation this can lead to acne

Answer 63

Growth spurt | - GH and Oestrogen in boys and girls - Complex interaction between the 2

Answer 64

- Low levels = linear growth and bone maturation - the initial growth spurt is supported by low levels of oestrogen - High levels = epiphyseal fusion (decrease in growth spurt )

Answer 65

- Smooth ordered progression of changes - Order of pubertal changes is uniform - Age of onset, pace and duration of changes - wide inter individual difference - Average age of menarche onset (UK) = 12.5yrs

Answer 66

- Can be precocious / delayed sexual maturation ○ Precocious sexual development, is development of any 2ndary sexual characteristics before the age of 8 in girls and before age 9 in boys. ○ Precocious puberty is when pubertal changes are early but in consonance- Tanner stages of puberty: scale of physical measurements of development - breasts, pubic and axillary hair growth, male genitalia.

Answer 67

Early puberty = precocious puberty (early, but in consonance) - Getting secondary sex characteristics before 8 years in girls and 9 in boys - Gonadotrophin dependent/ central precocious puberty - consonance • XS GnRH secretion : idiopathic / secondary • XS gonadotrophin secretion : pituitary tumour - Gonadotrophin independent secretion = pituitary tumour. - Gonadotrophin precocious pseudo puberty loss of consonance • Testotoxicosis : activating mutation of LH receptor • Sex steroid secreting tumour / exogenous steroids • Primary hypothyroidism (High TSH --> LH / FSH receptors)

Answer 68

• McCune Albright: mutation of alpha subi=unit of GPC activation of adenylate cyclase = hyperactivity of signalling pathways and hormone over production

Answer 69

- Small testes, absent gonadarche - Lack of FSH - Activating mutation of the LH receptor, this is a child that is 20 months old - Tanner stage 3 already though = so in mimd puberty Result of activating mutation of LH receptor which is why there is virilisation

Answer 70

- Café au lait skin pigmentation - Mutations in the GNAS1 gene - Activating mutation of LH receptor

Answer 71

- Mutation in the GNAS1 gene - Fibrous dysplasia - Autonomous endocrine function - most common gonadotrophin independent precocious puberty

Answer 72

- Premature adrenarche / pubarche - Precocious development of pubic and axillary hair, also CAH congenital adrenal hyperplasia/ Cushings. - Premature thelarche - precocious breast development • Isolated cyclical (less than 2 years) without other pubertal development • Variant (more than 2 years) proceeding to precocious puberty

Answer 73

- Auxology - meta term covering study of all aspects of human physical growth - Accurate measurements of height including body proportions and weight - Pubertal staging, bone age estimation - LH, FSH, sex steroids measurements - LH response to 100micrograms of GnRH - normal stage of puberty in central precocious puberty, suppressed in testotoxicosis. - Adrenal steroids - high in tumours, precursors high with CAH - MRI scans of hypothalamic pituitary area - Ultrasound scans of the pelvis - uterus and ovaries

Answer 74

- Antiandrogens - 5alpha reductase inhibitor - Aromatase inhibitor - Long acting GnRH analogue - central precocious puberty

Answer 75

* Affects both growth and puberty, about 90% of cases. (most common type of delay that one would see) * 10x more common in boys and 2ndary to chronic illnesses like CF, diabetes

Answer 76

* Kallmans syndrome (X linked KAL gene - GnRH neurone migration) - GnRH originate in the nasal cavity and migrate backwards into the hypothalamus * KAL mutation = neurones cannot migrate in the hypothalamus which leads to hypergonadism * (Other genetic causes, hypopituitarism) * Low levels of gonadotrophin horrmones, hyperplastic ovaries and testes which can be due to a genetic disorder

Answer 77

- Family history, dysmorphic features, anosmia, auxology - Pubertal staging - Bone age estimation - LH / FSH / Sex steroid measurements - LH response to 100micrograms of GnRH - Adrenal steroids, high with tumours, precursors high with CAH - MRI scans of hypothalamo-pituitary area - Ultrasound scans of pelvis, uterus and ovaries. - Similar to investigations of precocious puberty.

Answer 78

- Testosterone (males), oestrogens (females) - oxandralone is a synthetic steroid. - People can sometimes just go through puberty at a later stage = e.g. over exercising can make puberty be held up

Answer 79

- Goes beyond just sexual intercourse - Differentiation into male and female - Sexual maturation - Production + storage and release of sufficient supply of eggs and sperm - The right number of chromosomes in eggs and sperm - The eggs and sperm have to meet • Gamete transport - Creation of new, individual with genes from both parents - To nurture individual until capable of independent life

Answer 80

- Goes beyond just sexual intercourse - Differentiation into male and female + Sexual maturation - Production + storage and release of sufficient supply of eggs and sperm - The right number of chromosomes in eggs and sperm - The eggs and sperm have to meet • Gamete transport - Creation of new, individual with genes from both parents - To nurture individual until capable of independent life

Answer 81

1. Germs enter the gonad | 2. If the PGCs enter ovary, they will become oocytes

Answer 82

- Cells that are going to become eggs - Or sperm - Are called Primordial Germ Cells (PGC) - PGCs first identifiable in the yolk sac of the developing foetus at 3 weeks after conception, and go through many cycles of mitosis + migrate to the genital ridge in the foetus, and the genital ridge becomes the gonad Further differentiation of the PGC depend on the development of the gonad i.e. ovary or testis

Answer 83

- Germ cells become oogonia when they are in the ovary - Oogonia = egg precursors ○ Diploid, and multiply by mitosis - Once the mitosis stops, and they enter into meiosis - They are known as primary oocytes

Answer 84

- All the eggs that a woman will ever have are made at this stage - The mitotic divisions are therefore critical - Once the oogonia enter the 1st stage of meiosis no more division occurs and they become primary oocytes - The primary oocytes remains in the first phase of meiosis until it is ovulated (or dies)….maybe for 52 years!

Answer 85

- Are packed into the outer layer of the ovary The cortex

Answer 86

- Oocyte arguably the most important cell in the body and will in the vulnerable 1st meiotic phase for many years - Therefore each one becomes surrounded by protective layers and protective cells In the foetal ovary, the surrounding cells condense around the oocyte and differentiate into the granulosa cells

Answer 87

- Defined as the growth and development of follicles from the earliest “resting” stages as laid down in the foetus, through to ovulation - Most of the follicles in the ovary are not growing – after puberty only a few grow each day - As the follicles start to grow, the oocyte secretes another protective acellular layer called zona pellucida….which stays attached after ovulation - Once growth of the follicles has started a second layer of cells then differentiate around the basal lamina: the theca

Answer 88

- We don’t really know or understand the factors that control the initiation of growth - Early stages = unknown FSH - Drives most folliculogenesis - Early growth = independent of FSH • Driven by local factors ○ You can tell this from FSH deficient patients ○ Or with patients that have mutations of the FSHr ○ Means that when FSH is suppressed e.g. on COCP - the follicles will continue early growth but then die When the follicle starts to grow: - Increases rapidly in diameter - Granulosa cell divisions increase - Gaps start to form in granulosa cell layers • These gaps = consist of fluid filled spaces ○ These spaces form an antrum • 2 main phases of follicle growth (labelled by absence/presence of the antrum) Follicles that have an antrum = antral, or secondary follices.

Answer 89

- The cohort of early follicles that leave the resting pool and grow continuously

Answer 90

- Fact that the follicles will not keep growing unless they get to a size where they will respond to changes in FSH which occur in the menstrual cycle

Answer 91

- The LH interacts with the LH receptor and this triggers the synthesis of androstenedione, from cholesterol. This then becomes estradiol, in reaction that is enabled by aromatase, and then the estradiol goes to the follicle. FSH binding to the FSH receptor is what binds to

Answer 92

cholesterol => progesterone => testosterone => oestradiol

Answer 93

hypothalamus makes GnRH => ant pituitary. Ant pituitary makes FSH/LH => acts on ovary. ovary produces oestrogen + progestone which acts on hypothalamus and ant.pituitary.

Answer 94

- Differentiation into male, or female - Sexual maturation - Production, storage and release of enough eggs and sperm - right # of chromosomes in eggs and sperm, plus they have to meet in gamete transport - Create new individual genes from both parents - To nurture individual until it is capable of independent life

Answer 95

- This is the selection of a single oocyte, regulator spontaneous ovulation. Correct # of chromosomes in eggs. - Cyclical changes in vagina, cervix, fallopian tube - Preparation of uterus - Support of the fertilised dividing egg

Answer 96

- Corpus luteum

Answer 97

- Progesterone = negative feedback - made by the CL, and feedbback is onto the hypothalamus and pituitary, reducing their output - Like in males there is constant negative feedback by testosterone Always negative feedback

Answer 98

1. Release of negative feedback 2. Negative feedback reinstated 3. Switch from negative to positive feedback Like a brake on the car = break is cause by progesterone, when you lift off the brake you allow it to start secreting GnRH and gonadotrophin Then start to make estrogen from the growing antral follicle which will feedback to reinstate the negative feedback = there Switching between negative and positive feedback.

Answer 99

- Progesterone declines - negative feedback. Allows hypothalamus and pituitary to start working again - Selectively raises FSH - Inter cycle rise Allows antral follicles that are at the right size to keep on growing

Answer 100

- As they grow they increase their production of oestrogen, which is made by the granulosa cells. - E2 increases, negative feedback - FSH falls (FSH turned off) - which will cause lots of the follicles to die off apart from one, which will become the dominant follicle. - Massive proliferation of granulosa cells + the amount of oestrogen, pumping oestrogen out - High sustained levels of oestrogen for about 48hrs = this then acts back on the hypothalmus and pituitary to produce positive feedback, preferentially on LH.

Answer 101

- 2 days of E2, more than 300pmol - Positive feedback when there are sustained high levels of estrogen - LH surge, which produces final maturation

Answer 102

- High progesterone - Negative feedback, low LH/FSH (from progesterones negative feedback) - P overcomes E2.

Answer 103

- Intercycle rise and fall in FSH is important because it allows selection of single follicle This happens at start to cycle because progesterone decreases = allows antral follicles to continue to grow and produce

Answer 104

- There are cohorts of follciles = ones that reach antral stage, at this part of the cycle when FSHS is low they cannot sustain their growth so will die. - When FSH is starting to rise = can contine their growth and estrogen made As FSH is falling, any other follicles that are coming across will not be able to progress

Answer 105

- When there is raised FSH, this presents a window of opportunity - FSH threshold hypothesis - one follicle from the group of antral follicles in ovary is just @ right stage @ right time. This becomes the dominant follicle which goes onto ovulate. This is known as selection. Can happen in either ovary. - One follicle becomes the dominant follicle. - Oestradiol levels rise, which reinstated negative feedback @ pituitary. This causes FSH levels to fall prevents further follicle growth - The dominant follicle survives the fall in FSH.

Answer 106

- As FSH falls, LH increases - Dominant follicle, will make LH receptors on the granulosa cells, couple much more effectively to their downstream signalling pathways - Granulosa cells need LH receptors - Other follicles do not, so they will lose their stimulant, and die.

Answer 107

- Theca always has LHr, but never FSHr - LH drives androgen + progesterone production from theca - Granulosa have FSHr, then LHr acquired from mid follicular phase, onwards. Primarily on the dominant follicle - FSH and LH drive oestrogen production in follicular phase.

Answer 108

- Aromatase in the granulosa cells and not in the theca

Answer 109

- Day 1 = 1st day of bleeding, and Menstruation = 3-8days (written as 7/28 (7 days bleeding with a regular 28 day cycle), or 5-6/27-32) - Regular cycle shouldn’t have more than 4 days variation between months - CL has a fixed lifespan - 32 day cycle would mean that you had a longer follicular phase because the luteal phase is constant.

Answer 110

- The dominant follicle is selected, and grows rapidly - it doubles in diameter in 7 days from 7mm to 14mm, large structure - Needs masses of growth factors, nutrients and steroids - Rapid neoangiogenesis (new blood vessels) - Oestrogen comes from follicle into the circulation. - Does not just rely on estrogen but relies on other growth factors and nutrients that can feed the dominant follicle and allow growth to occur

Answer 111

Theca is intact and there are follicular cells buried inside

Answer 112

- Cascade of events that causes ovulation: - Blood flow to follicle, increases massively and there is an increased in the vascular permeability increases intra follicular pressure. Follicle has moved to the apex of the ovary. Dominant follicle has to be able to release the oocyte from the ovarian wall - Appearance of the apex or stigma on the ovary wall, like a weakening that allows the release of various proteases (Local release of proteases) - Enzymatic breakdown of protein of the ovary wall. - 18hrs after the LH peak, the hold appears in the follicle wall and ovulation will occur. - The oocyte with cumulus cells = extruded from the ovary under pressure. Follicular fluid might pour into the pouch of douglas. - The egg is collected by the fimbria of the fallopian tube - Egg progresses down the tube, by peristalsis and the action of cilia. - The fallopian tube will move around and picks up the egg as it is released. If you have fibroids the follopian tubes are not patent - Egg travels down the tube and can meet a sperm that make their way up vagina and cervix. Sperms main job is to reach the egg to fertilise it. + sperm can survive for a few days

Answer 113

- Certain hormones are being detected, LH being detected

Answer 114

`- Have to grow oocyte within the follicle and have to create a haploid oocyte. In the fetus the eggs enter into meiosis 1 and then stop. This will allow the oocyte to keep all of the DNA. - From its formation as primary oocyte in the fetal ovary up until ovulation, oocyte has been arrested - in the first meiotic division - This allows the oocyte to retain all of the DNA and stay as large as possible during its long wait. - In response to the surge of LH, oocyte nucleus in the dominant follicle will complete 1st meiotic division, but it does not divide.

Answer 115

- Half of the chromosomes are put into a small package, in the egg which is called the 1st polar body - The egg is now a secondary oocyte - The 1st polar body plays no further part in the process and does not divide again - 1st polar body is extruded and then there is arrest again in meiosis 2, until it is fertilised. If it is successfully fertilised then it will complete meiosis 2. - Oocyte begins the 2nd meiotic division, but then will arrest again - There is unequal division, to keep the size because has everything that is necessary to look at preimplantation

Answer 116

What is the 1st polar body - Package which contains half of the chromosomes

Answer 117

- Unlike sperm we only want a single oocyte - The oocyte is the largest cell in the body (sperm are smallest…..but fastest!) - The oocyte has to support all of the early cell divisions of the dividing -embryo until it establishes attachment to the placenta - Spends 2-3 days in the uterine tube - So the oocytes if now on its way into the tube….will it meet a sperm? Fertilisation = will complete meiosis 2

Answer 118

* Dissected CL showing exit hole of oocyte * After ovulation, the follicle will collapse, and the corpus luteum is formed, "yellow body" because it looks yellow. * Progesterone production is greatly increased, also E2 * CL contains large number of LH receptors * CL supported by LH and hCG - if a pregnancy occurs. Has inbuilt lifespan, and dies after 14 days - if a pregnancy occurs the trophoblast will produce HCG which will maintain and support the CL.

Answer 119

- Progesterone - Supports oocyte in its journey, prepares the endometrium - Controls cells in fallopian tubes - Alters secretions of cervix Oestradiol - For endometrium

Answer 120

- If fertilisation does not occur, CL has finite lifespan of 14 days - Removal of CL is essential to initiate the new cycle - Cell death occurs, there is breakdown of vasculature, CL shrinks - Process is not well understood. - Need CL to die for the next cycle to occur

Answer 121

LL = late luteal, early follicular, mid follicular, late follicular, early luteal, mid luteal, late luteal E2 rises causes negative feedback - high sustained e2 causes LH surge, follicles dying. Big LH surge = ovulation, completion of meiosis 1, formation of the CL which is going to pump out progesterone Be able to draw and understand this and correlate this with what is going on with the follicles.

Answer 122

- There is an intercycle rise in FSH that is followed by a slow decline - Slow rise in LH in follicular phase to exponential mid cycle rise - 2 peaks in oestradiol - different shapes Single luteal phase rise in progesterone

Answer 123

Oral contraception, barrier methods, fertility awareness, coitus interruptus, oral emergency contraception

Answer 124

- IUCD / IUI / IUS | - Progesterone implants, progestogen injections, sterilisation

Answer 125

- Cardiovascular, neoplastic, emotional, infection, allergic, Iatrogenic (harm) - Potential for cancer and infection

Answer 126

- Childbirth related, abortion related, social costs, economic costs

Answer 127

Childbirth related, abortion related, social costs, economic costs

Answer 128

- Non interference - Population growth - Control of women

Answer 129

- Can be ostrogen or progesterone - Oestrogen: - EthinylOestradiol contained in all pills: 20,30,35,50 micrograms. - Progesterones: Old gen progesterones : norethisterone + levonorgestrel New gen progesterones: desogestrel, gestodene, and norgestiate Latest = drospirenone Depends on which progestagens, in the family and behaves most like that: engineered molecules. Starting to use newer ones

Answer 130

- Oestrogens act, at high levels on the anterior pituitary and the hypothalamus - Directly on the ovary, and cause negative feedback. Do not make another follicle and ovulate. - On the endometrium - Estrogen alone will cause the endometrium to proliferate, which we do not want to happen - really good negative feedback and the HPA axis - Endometrium = combined effect is to thin the lining, not receptive to implantation. Thickens cervical mucus, makes fallopian tubes lazy aand makes them stop contracting - If used properly then it is in the order of 1 in 500 get pregnant using this - Fertility comes back within 10 days of not taking the pill - endometrium thins and is not proliferating all the time which reduces risk of cancer - Heavy and painful periods = good treatment for this too, can take it forever, can affect venous or arterial side of the heart - check blood pressure as some people get hypertension while on the pill - Not a problem unless you get another CVS risk factor

Answer 131

- Progesterones act on the anterior pituitary and hypothalamus - Directly on the ovary - On the endometrium - On the fallopian tubes On the cervical mucus

Answer 132

1. Contraceptive - reliable, safe, unrelated to coitus, woman is in control, and is rapidly reversible. 2. Non contraceptive - halve ca ovary, halve ca endometrium, decrease ca colon, helps with endometriosis, fibroids, rheumatoid arthritis, premenstrual syndrome, dysmenorrhoea, menorrhagia.

Answer 133

``` Aterial: - Progesterone, HBP, smoking Venous: - Oestrogen- VTE clotting disorders - DVT, PE, migraine Slight increased risk of getting a thrombosis in the leg. Reduces ovarian cancer. On pill = do not use condoms, can get HPV ```

Answer 134

- Breast, cervix, liver

Answer 135

- COH / insulin metabolism, weight gain, chrons disease

Answer 136

- Hormone metabolism, congenital nonhaemolytic jaundices, gall stones

Answer 137

- Cholasma, acne, erythma multiforme

Answer 138

- Mood swings, depression, libido.. Pill = can affect psyche

Answer 139

- Start 1 packed 1st day of a menstrual period, take 21 pills and stop for 7 day break - Start each packed on 8th day - Do not start new packets late - If late or missed pills in the 1st 7 days, use condoms - If missed pills in the last days, 7 days no PFI

Answer 140

1. Liver enzyme inducing drugs - Affect metabolising of both oestrogen and progesterone - Rifampicin and anti-epileptics, upgrade the liver and make it metabolise more= get failure of the pill, 40% pill recycling is via the gut 2. Broad spectrum antibiotics - Affect enterohepatic circulation of oestrogen only (40%)

Answer 141

- Same as the combined oral contraceptive pill. Apart from fact there is vaginal delivery (ring) for 21 days, which you remove for 7 days, nuva ring - Advantage is that you do not have to take every day - Disadvantage is that you do not have to take it everyday!

Answer 142

- Implants = implanon (ETN), norplant (LNG) Hormone releasing IUCD = mirena IUS (LNG), can deliver directly into the uterus and sits inside the uterus

Answer 143

- POPs - Desogestrel (cerazette) - norethisterone, • Ethynodiol diacetate • Levonorgestrel • Norgestrel - Injectables - Depo Provera (MPA) 12 weekly - Noristerat (NET)

Answer 144

- Why cerazette is so good - it's as effective as COCP. There is no estrogen, Cis like breastfeeding. Favourable side effect profile. Bleeding = predictable + controlled as COCP. Forgot to take combined pill in the morning , can take in a 12 hr window. In old progesterone only pill, need to take within 3.

Answer 145

- Copper bearing sets up local inflammatory reaction and is literally spermicidal. Implantation = need a controlled local reaction. Can be inserted or removed. - Intrauterine contraceptive device that is inserted into the uterus by trained doctor and left in situ long term. Destroy spermatozoa (spermicide) - Prevent implantation - inflammatory reaction + prostaglandin secretion as well as a mechanical effect.

Answer 146

- Benefits are that it is not user dependent, immediately and retrospectively effective, immediately reversible, long term use, reliable, unrelated to coitus, free from serious medical dangers.

Answer 147

- Ortho - Multiload - Nova T - GyneFix

Answer 148

- Mirena: this is abs. fixed because the drug runs out after 5yrs

Answer 149

- Negatives are that you need a trained doctor to insert it, which can be uncomfortable to do. Can make periods heavier and more painful, does not offer infection protection, threads may be felt by the male.

Answer 150

- Risks are that miscarriage can occur if left insitu in pregnancy, may be expelled and uterus may be perforated. - if in luteal phase of pregnancy. Always take out if possible.

Answer 151

- Absolute contraindications: current pelvic inflammatory disease, suspected / known pregnancy, unexplained vaginal bleeding, abnormalities of uterine cavity.

Answer 152

- Man is in control, protects against STIs, no serious health risks, easily available (free)

Answer 153

- Woman in control, protects against STIs, can be put in in advance and left inside after erection is long - Not dependent on male erection to work as they sit inside the woman

Answer 154

- Last minute use, needs to be taught, can cause allergies, psychosexual difficulty, higher failure rate in some couples, oily preparations rot rubber - Live sperm in secretions before men ejaculate = wear during all sexual contact

Answer 155

Obtrusive, expensive, messy, rustles during sex, uncertain failure rate.

Answer 156

- Latex, fit across the vagina, sizes 55-95mm in 5cm jumps | - Must be used with spermicide + left in at least 6 hours after sex

Answer 157

- Woman in control, can be put in advance, offers protection against cervical dysplasias, percieved as natural.

Answer 158

- Needs teaching, messy, higher failure than most other methods, Higher UTI, higher candiasis

Answer 159

- Plastic, suction to cervix or vaginal vault. Different sizes, must be used with spermicide and left in for 6hrs+

Answer 160

- Suitable for women with poor pelvic muscles, no problems with rubber allergies, unobtrustive, woman in control

Answer 161

- Needs accessible and suitable cervix, higher failure rate than diaphragm, not easy to find experienced teacher.

Answer 162

- Prediction of ovulation 14/7 before period, sperm can survive 5 days in female tract - ova can survive 24 hours. - Ova are fertilised in the fallopian tube and take 4 days to get to the uterus and implant - Cervical mucus is receptive to sperm around the time of ovulation - Use periodic abstinence / alternative contraception to avoid pregnancy - Time intercourse to pre ovulatory phase to conceive.

Answer 163

- Up to 72 hrs after unprotected sex - Prevents 3/4 pregnancies that WOULD have occurred - Levonelle - prevents 7/8 pregnancies: 2 tablets each, containing 750 micrograms of Levonorgestrel. 1.5mg one dose - ellaOne (Ulipristal) - similar - Schering PC4 = lower failure rate in 1st 24hrs. N+V in some women - Contraindicated during focal migraine attack - Levonelle 2 = lower failure rate in the 1st 24hrs. Little nausea, only contraindicated in women that take potent liver enzyme medication (AntiTB) Ella one (ulipristal)

Answer 164

- Copper bearing IUCDs - Up to 5 days after presumed ovulation, or 5 days after 1 single episode of UPSI @ any time of cycle. Failure is really rare!

Answer 165

- Act by postponing ovulation in the first part of the cycle - Act by preventing implanation in the 2nd part of the cycle

Answer 166

- Copper IUCDs - Copper kills sperm in the 1st part of the cycle - Device prevents implantation in 2nd part of the cycle.

Answer 167

- Ulipristal acetate, - New selective progestagen receptor modulator (SPeRM) - Up to 120 hours, RR 0.58 pregnancy vs Levonelle Possible slightly higher side effect profile = GI symptoms mainly.

Answer 168

- 2 tablets each, with 750 micrograms - Only risk of this if if you are maybe already pregnant - Given in the first half of the cycle = pushes ovulation back and 2nd half of the cycle, works in a different way and probably works in stopping implantation because it stops the endometrium. Occasionally can do more than 24h. • All of them with ideal use will only cause 1/100 women per year

Answer 169

- Produce + Store sperm - Produce hormones that can regulate spermatogenesis - They lie in the scrotum - That is outside the body cavity - The optimum temperature for sperm production = 1.5-->2.5 degrees celcsius below body temperature - Overheating of testes = reduces sperm count

Answer 170

- Well vascularised - Well innervated - The normal volume of the testes is about 15-25ml - This can be measured by the orchiometer

Answer 171

- Using a orchiometer

Answer 172

- Tubules = lead to area on 1 side, called the rete - Rete = leads to epidymus + vas deferens - Testis = 90% seminiferous tubules • This is the site of spermatogenesis - 600m long, in each testis - The tubules are tightly coiled

Answer 173

- Made up of tall and columnar endothelial cells - That are called sertoli cells - Between these, lying on basement membrane = primary germ cells - Or spermatogonia - Spaces that are between the tubules are filled with: • Blood + lymphatic vessels • Leydig cells • Interstitial fluids

Answer 174

- Open to allow passage of spermatogonia prior to completion of meiosis. - Divides into luminal and adluminal compartment. - Protects the spermatogonia from immune attack. - Allows specific enclosed environment for spermatogenesis which is filled with secretions from Sertoli cells.

Answer 175

1. All laid down in fetus 2. Begin meosis - to make the oocyte 3. Cant make more oocytes by mitosis 4. Finite supply

Answer 176

1. Spermatogonia = laid down in fetus 2. Begin mitosis to make the spermatocyte 3. Or divide mitootically, to make more spermatogonia 4. Infinite supply

Answer 177

- Leydig cells contain LH receptors and primarily convert cholesterol into androgens. ○ Intra-testicular testosterone levels are 100x those in plasma. - Androgens cross over to and stimulate Sertoli cell function and thereby control spermatogenesis. - Sertoli cells contain FSH receptors and convert androgens to oestrogen. - FSH establishes a quantitatively normal Sertoli cell population, whereas androgen initiates and maintains sperm production

Answer 178

- Vasodilation of the corpus cavernosum. - Partial constriction of the venous return. - Autonomic nervous system causes co-ordinated contractions of vas deferens and glands. Sympathetic nervous system control - Movement of sperm into epididymus, vas deferens, penile urethra - Expulsion of the glandular secretions Parasympathetic control - Erection and evacuation of urethra

Answer 179

- 300 million sperm produced per day on average. • 3,500 per second so 9 million during this lecture approximately 120 million in average ejaculate - Normal ejaculate volume is 1.5ml - 6ml. • around one third to just over a teaspoon full - Initial portion of the ejaculate is most sperm rich. 99.9% lost before reaching ampulla of the uterine tube • around 120,000 sperm get near to egg, only one enters - Seminal fluid consists of secretions from: seminal vesicles, prostate, bulbo-urethral gland combined with epididymal fluid

Answer 180

Ø Clear viscous secretion that is high in salt = pre ejaculate This is a fluid that helps to lubricate the urethra for the spermatozoa to pass through + neutralises traces of acidic urine

Answer 181

- Secretions comprise 50-70% of the ejaculate. - Contains proteins, enzymes, fructose, mucus, vitamin C and prostaglandins. - High fructose concentrations provide energy source. High pH protects against acidic environment in vagina.

Answer 182

- Secretes milky or white fluid roughly 30% of the seminal fluid. - - Protein content is less than 1% and includes proteolytic enzymes, prostatic acid phosphatase and prostate-specific antigen which are involved in liquefaction. - High zinc concentration 500–1,000 times that in the blood is antibacterial.

Answer 183

- 5 micrometres

Answer 184

- Continuous from puberty - Long and complex process that has lots of errors - Want to produce high numbers - Many small sperm, compared to 1 large oocyte - Process is driven by FSH and testosterone

Answer 185

- Made by testes, and adrenal cortex. - Testes (leydig cells of the testes secrete testosterone C19) - Adrenal cortex (ACTH) + ovary - Made from cholesterol, C27 in Leydig cells

Answer 186

- Androsterone and its 5beta isomer, etiocholanolone, made by the body as testosterone metabolites

Answer 187

- Androsterone and its 5beta isomer, etiocholanolone - Produced in the body as metabolites of testosterone - Androsterone is inactive metabolite of testosterone.

Answer 188

- There are different degrees of negative feedback inputs that alter the secretion rates of FSH and LH - GnRH (trophic hormone) --> release of FSH and LH (gonadotrophins) from the gonadotrophs of anterior pituitary - Effects of FSH in females and males - triggers growth + recruitment of immature ovarian follicles in the ovary in females. - In males it initiates + promotes spermatogenesis

Answer 189

Effects of LH in females and males: - Females, LH triggers ovulation and the development of corpus luteum (a temporary endocrine structure which secretes progesterone, oestrogen); - Males, it stimulates the production of testosterone by leydig cells

Answer 190

Control of FSH and LH release: - These processes are controlled by the size and frequency of GnRH pulses, as well as by feedback from androgens and oestrogens and by factors released by sertoli cells. - It is thought some low-frequency GnRH pulses causes FSH release, while a high-frequency GnRH pulse may stimulate LH release – further research needed to clarify this.

Answer 191

Inhibin B (heterodimeric protein): - produced by granulosa cells in the ovary; - suppresses synthesis and secretion of the FSH. It is probably produced in a specific pattern in response to gonadotropin stimulation - may plays an important role in the regulation of the hypothalamic-pituitary-gonadal axis during childhood and puberty. - Overall, inhibin downregulates FSH synthesis and inhibits FSH secretion.

Answer 192

- Acts via Sertoli cells to initiate and maintain spermatogenesis - Reduces the secretion of GnRH - Inhibits LH secretion - Induces the differentiation of epididymis, vas deferens, seminal vesicles, ejaculatory duct - Induces male secondary sex characteristics; opposes action of oestrogen on breast growth - Stimulates erythropoietin secretion - to treat anaemia; hereditary angioneurotic oedema (episodic swelling of the extremities, face, abdominal viscera or airway); osteoporosis; wasting - Provokes boisterous play; may enhance sex drive and aggressive behaviour - Anabolic – induces bone growth an cessation of bone growth

Answer 193

- Some males foetal tissues need testosterone to differentiate - Testosterone - internal genitalia, (epididymis, vas deferens, seminal vesicles and prostrate), libido, sex drive. - Prostrate, penis need DHT

Answer 194

- External genitalia to develop into the male form - Enlargement of penis and prostrate at puberty - Facial hair and acne, temporal hairline recession. Females = andreogens are not there so the external genitalia develop into female form. Tissues need receptors to respond, otherwise testicular feminisation will occur when genetic males appear as females.

Answer 195

- On avg males are taller than females - Males = greater muscularity, shoulder girdle than females, stronger bone growth, greater shoulder to pelvic girdle ratio, GH secretion than females - heavier skull, larger hands and feet, strong and often dark hair growth on face, limbs and body, hair on head receeds and baldness often occurs with increased hairlines elsewhere - Pubic hair = triangle with base down, continues with abdo + chest hair. - Prominent subcutaneous veins because of lack of subcutaneous fat - Increased growth of larynx, deep voice, penis, testicles and scrotum enlarge

Answer 196

- In many cases, several androgens (e.g. testosterone, nandrolone, oxymetholone and stanozolol, etc) are used for prolonged periods - Testosterone and other anabolic steroids such as nandrolone, stanozolol have nitrogen, calcium, sodium and water-retaining actions → hypertension and oedema - Cholestatic jaundice: anabolic steroids (nandrolone, stanozolol) may lead to liver cancer - Headache, anxiety, depression - Premature closure of epiphyses of long bone in boys - Suppression of gonadotrophin (FSH & LH) release with testicular regression and reduced spermatogenesis - Androgens (e.g. testosterone) causes virilisation - Hirsutism, male pattern baldness, acne - Gynaecomastia – due to conversion of testosterone to oestrogens by aromatase Virilisation = the development of male physical characteristics (e.g. deep voice, body hair, and muscle bulk) in a female or precociously in a boy, due to excess production of androgens. Development of breasts in boys, ca - Can be drug-induced - e.g. cimetidine, spironolactone, ketoconazole, marihuana may cause it - May arise pathologically due to damage to the endocrine system leading to excessive oestrogen production, e.g. sertoli cell tumour - Anti-oestrogens are not always effective; testosterone may cause regression Examples of anti-oestrogens: anastrozole, clomiphene, and formestane

Answer 197

- GnRH is synthetic and can be given - administration must be by a pump and given intermittently to avoid being desensitised + down regulation - GnRH agonist analouges, like gosrelin, busrelin • Desensitise after an initial surge of LH + FSH release, and act as antagonists, cause reduction in testosterone in the long term = prostrate and breast cancers, endometriosis, assisted conception • GnRH antagonists (cetrorelix, ganirelix) - causes no initial surge in LH + FSH so better. - Human chorionic gonadotrophin (LH mainly) - Synthetic or from urine of pregnancy women, - Given IM for 3-6 months to stimulate testicular development in hypogonadism, to initiate spermatogenesis, or testicular descent - cryptochidism. - Used with human menopausal gonadotrophin (FSH/LH = 1:1) to induce ovulation

Answer 198

- Goserelin, busrelin

Answer 199

- Testosterone is converted in most target cells, except in muscle cells --> to DHT - DHT + testosterone bind to the same receptor - Testosterone receptor complex = less stable - DHT being formed allows the amplification of the actions of testosterone - Treatment of prostrate cancer makes use of this pathway - DHT promotes hair loss - male pattern baldness may be treated with 5a reductase inhibitors - LH and FSH are gonadotrophins - Male urogenital structures like epididymis, vas deferens and seminal vesicles are differential from the Wolffian duct

Answer 200

- 5 alpha reductase - Converts testosterone to DHT - Type 1, 5 alpha reductase - scalp and skin - Type 2, 5 alpha reductase - genital skin, prostrate - Deficiency in 5alpha reductase, testes develop - but without prostrate - external genitalia look like those that are female and they will be raised as girls. - Clitoris gets larger "penis at 12 syndrome" - Increase in LH and testosterone levels at puberty - Mutation in the type 2 5 alpha reductase leads to male pseudohermaphroditism, which is common in parts of the Dom. Republic - Not enough metabolism of DHT may cause prostatic hyperplasia.

Answer 201

- 5alpha reductase

Answer 202

- Fall in sensitivity to androgens - XY male fetus has external genitalia and retained testes, but no female internal genitalia - Testes are surgically removed, patient is put on oestrogen therapy @ puberty - If mild with male type external genitalia, give high dose testosterone - helps to improve 2ndary sexual characteristics - Assign patient to gender on which they feel more comfortable

Answer 203

- Cannot convert testosterone to DHT - Which leads to XY baby with female external genitalia - Raised as girl until puberty, @ puberty there is increased testosterone causes the development of external male genitalia, and 2ndary sexual characteristics also develop - Some might adopt normal male role post puberty.

Answer 204

1. Mutation in the androgen receptor gene | 2. 5alpha reductase deficiency

Answer 205

- Adrenal cortex produces androstenedione, which can get converted to testosterone and DHT - Adrenal hyperplasia = virilisation with alteration of genitalia to male type in females (ambiguous genitals) - For boys: premature puberty • Deep voice, enlarged penis, small testes, pubic and axillary hair appear early - For girls: abnormal genital development • Ambiguous genitalia + severe acne - Cytoperone and androgen antagonists can be used

Answer 206

- Caused by inherited genetic defect that limits production of one of the many enzymes (e.g. 21-hydroxylase deficiency) the adrenal glands use to make cortisol. - Most of the problems of congenital adrenal hyperplasia are due to a lack of cortisol, (helps regulate BP, stress, glucose regulation etc. - Kids with congenital adrenal hyperplasia may also experience: - Excess production of androgens, e.g. testosterone: early puberty in boys, short height, abnormal genital development in girls and severe acne. - A lack in the adrenal glands' production of aldosterone: causes low blood pressure, lower sodium level and higher potassium level.

Answer 207

- Androgen deficiency - Delayed puberty - Promotes erythropoiesis - Useful for gynaecomastia, angioedema, baldness, endometriosis, menorrhagia (heavy and prolonged periods) mastalgia (breast pain) - Diethylstilboestrol is synthetic oestrogen, inhibits release of gonadotrophin in prostate cancer without supporting the growth of the prostrate cells.

Answer 208

- Methyltestosterone - Male infertility associated with hypogonadism - Useful for gynaecomastia, angioedema, baldness, endometriosis, menorrhagia (heavy and prolonged periods) mastalgia (breast pain) - Diethylstilboestrol is synthetic oestrogen, inhibits release of gonadotrophin in prostate cancer without supporting the growth of the prostrate cells.

Answer 209

- Androgen derivative - Not converted to oestrogen - Feedback inhibition of gonadotrophin and GnRH - Has antioestrogenic + antiprogestagenic effects • Side effects = acne, deep voice, hirsutism, vaginal dryness, breasts get smaller, changes in libido, amenorrhoea, hot flushes - Useful for gynaecomastia, angioedema, baldness, endometriosis, menorrhagia (heavy and prolonged periods) mastalgia (breast pain) - Diethylstilboestrol is synthetic oestrogen, inhibits release of gonadotrophin in prostate cancer without supporting the growth of the prostrate cells.

Answer 210

- Cyproterone acetate. Inhibits peripheral androgen receptor - Uses suppress initial surge effects of goserelin + buserelin - Acne, hirsutism, virilisation in women - Precocious puberty in boys

Answer 211

- Delayed puberty (15-17years) - Testes will not make enough testosterone in response to LH primary - Where there is not enough pituitary hormones (FSH + LH) or pituitary dysfunction (2ndary)

Answer 212

- Chromosome abnormalities - Like Kleinfelters XXY syndrome - Deficient, negative feedback @ hypothalamic pituitary levels with high levels of LH and FSH as a result - Treatment = testosterone and GH, Puberty might take 2yrs to reach completion - Continuous administration of testosterone = premature closure of epiphyses of long bones - dose of 4-6months, stop and assess to avoid reduced final height

Answer 213

- Deficiency of hypothalamic/pituitary level - Low levels of GnRH + low levels of FSH and LH (Kallmans syndrome) - Treatment = giving Gonadorelin (synthetic GnRH) or LH and FSH - Their effects on spermatogenesis takes months to develop in post pubertal patients.

Answer 214

- Testitoxicosis - Delayed puberty - Deviations from pubertal age, that happens too early or too late - needs to be investigated or treated

Answer 215

- Retained testes - 97% descend around birth and 99% by one year - Failure of the testes to descend can potentially lead to testicular tumour formation and infertility - Drug treatment or surgical remedy

Answer 216

- If has not already happened at pubertal age

Answer 217

- Impairs masculinisation of genitalia | - Secondary sexual characteristics fail to develop at puberty

Answer 218

- Androgen antagonists - Like cyroproterone acetate - Reduces libido in sex offenders, to treat their hypersexuality - informed consent needed

Answer 219

- Inhibition of 5a reductase, reduces the levels of DHT levels at the hair follicles while increasing testosterone levels - Can result in hair regrowth.

Answer 220

- Inhibits peripheral androgen receptors | - Prostatic hyperplasia / treat prostatic cancer

Answer 221

- Gosrelin, buserelin - Can be continously give, to suppress Leydig cell function - Desensitisation and down regulation of receptors - This causes a fall in LH and FSH - Treat and manage prostatic cancer

Answer 222

- Cetrorelix and ganirelix - Block release of LH and FSH - Regression of Leydig cells

Answer 223

- Ethinyloestradiol and diethylstilbestrol | - Decreased androgen dependent prostrate cancer (local and metastatic cancer)

Answer 224

- Flutamine - Nilutamide • Also used after surgical castration - Bicalutamide - Compete with testosterone and DHT, blocks their action - Useful for prostrate cancer

Answer 225

- Finasteride, dutasteride - Inhibit androgen dependent prostatic cancers - By suppressing the prostrate cancer cells

Answer 226

- Enlargement of prostrate in older men, causes urinary obstruction - Treatment by 5alpha reductase blocker - finasteride inhibits type 2. - This inhibits the conversion of testosterone to DHT, which causes shrinkage of the prostrate, utility of dutasteride is unclear - inhibits type 1 & 2. - Other agents for benign prostrate hypertrophy, alpha 1 blockers, tamsulosin, alfuzosin, acts to relax smooth muscle component of prostrate.

Answer 227

- Used by bodybuilders + athletes - Large doses might be effective in increasing muscle mass and athletic performance in some people. - Attempts to separate anabolic from virilsing effects of anabolic steroids have not been successful - All anabolic steroids virilse.

Answer 228

- Fall in testicular size and sperm count, hepatotoxicity with cholestasis, hepatitis or hepatocellular tumours - Increased LDLs and fall in HDLs. Leads to vascular disease - Changes in libido, regression of testes with suppression of spermatogenesis - Increased aggression, weight gain, acne - Stanozolol, nandrolone, other anabolic steroids can be detected in urine of athletes abusing these drugs.

Answer 229

- There is evidence that hypogonadal men will not regain fertility while taking testosterone. Some reports also suggest that sexual function returns to normal in castrated or severely hypogonadal men who undergo treatment with exogenous androgens - Erectile function is probably androgen-dependent

Answer 230

- NO is produced nerve endings and endothelial cells in the spongy erectile tissue, the corpus cavernosum of the penis. - The physiologic mechanism of erection of the penis involves release of NO in the corpus cavernosum during sexual stimulation. - An erection is an involuntary action controlled by the autonomic nervous system (sympathetic and parasympathetic pathways). In general, sympathetic stimulation leads to the constriction of smooth muscle surrounding the arteries and parasympathetic stimulation induces smooth muscle relaxation. - When stimulated sexually, the sympathetic stimulation of the penis decreases and the parasympathetic stimulation increases and releases NO.

Answer 231

- Treatment with exogenous androgens, may produce clinical improvement in signs of hypogonadism - but may not improve sexual function PDE5 inhibitors - Like sildenafine, tadalafil, vardenafil - Release of NO during sex stimulation - NO --> activates guanylate cyclase --> releases c GMP from GTP - C GMP then causes the relaxation of smooth muscle that lines the blood vessels, and inflow of blood occurs - Tumescence, erection - Incidence of priapism is low - Generally without effect until stimulation begins - Side effects = headaches, vasodilation, flushing, fall in BP, disturbances of colour vision because of PDE6 inhibition in the retina, do not take with nitrate drugs.

Answer 232

- cGMP causes the smooth muscle to relax, which causes an inflow of blood which then leads to an erection. cGMP is then hydrolysed back to the inactive GMP by phosphodiesteras type 5 (PDE5). - cGMP modulates Ca2+ entry into sarcoplasmic reticulum – reduces Ca2+ availability

Answer 233

Ø Potent + highly selective PDE5 inhibitor Ø Blocks hydrolysis of cGMP (by occupying its active site) Ø Prolongs Cgmp mediated smooth muscle relaxation (erection) but arousal + stimulation are important in its mode of action

Answer 234

Other treatments for erectile dysfunction: - Surgically implanted inflatable prostheses - Negative suction devices will engorge the penis, causing erection – the erection is maintained by a tight ring at the base - Injection of phentolamine, prostaglandin E1 (alprostadil) or papavarine into the Crus of the penis prior to intercourse, may cause priapism. - The agents relax the vasoconstrictor tone of the penile arteries - The absence of α-adrenoceptor activation helps to maintain penile erection - Relax the blood vessels so that blood can flow more easily Draw back of above agents = Priapism

Answer 235

1. Is coagulated - Prostatic and seminal vesicle secretions comprise seminal fluid which coagulates. - Prevents loss, later liquefies. - Movement through cervical mucus removes seminal fluid, abnormally morphological sperm and cellular debris.

Answer 236

2. Passes into the cervix - Cervical mucus is less viscous in the absence of progesterone allowing sperm to pass. - Sperm can inhabit cervical crypts which may form a reservoir. Some evidence of thermotaxis, but mechanism not yet elucidated. Sperm survive 24-48 hours in the female.

Answer 237

- Passage through uterus not well understood ○ Currents set up by uterine or tubal cilia may have a role. - Chemoattractants released from the oocyte cumulus complex may have a role in attracting the sperm. - Sperm = 50µm - Reproductive tract = 20cm - 200,000 times sperm length - Equivalent to 400km (250 mile) run.

Answer 238

- Capacitation is partly achieved by removing the sperm from the seminal fluid, also uterine or tubal fluid may contain factors which promote capacitation. - Biochemical rearrangement of the surface glycoprotein initiates whiplash movement of the tail- sperm increasing swimming speed. - The modified sperm membrane becomes capable of the acrosome reaction once it encounters the oocyte. - In the acrosome reaction the acrosomal membrane on the sperm head fuses releasing enzymes that cut through the outer layers of cumulus surrounding the egg. This only occurs in close proximity to the egg

Answer 239

- LH spike causes resumption of meiosis and ovulation. Converts the primary - oocyte to secondary oocyte plus 1st polar body. - Basement membrane breaks so blood pours into the middle. - Oocyte cumulus complex extruded out and caught by fimbrae of uterine tube. - Theca and granulosa become mixed.

Answer 240

Makes the endometrium secretory and receptive to implantation. Supresses cilia in uterine tubes once oocyte has already passed. Makes cervical mucus viscous again to prevent further sperm penetration

Answer 241

Helps to maintain endometrium in luteal phase (causes proliferation in follicular phase).

Answer 242

- This is what happens when fertilisation does not occur - CL has finite lifespan (that is 14 days long) - Regression of the CL = essential to initiate a new cycle - Fall in CL derived steroids, causes inter cycle rise in FSH - Cell death will occur - Vasculature breakdown - CL will shrink Over time it will become a corpus albicans

Answer 243

1. Selection of a single follicle and oocyte. 2. Regular spontaneous ovulation. 3. Correct haploid number of chromosomes in the oocyte. 4. Cyclical changes in the vagina, cervix and uterine tubes, to enable egg transport and sperm access. 5. Preparation of the endometrium of the uterus to receive the fertilised egg. 6. Support of the implanting embryo and endometrium by corpus luteum progesterone. 7. Initiating a new cycle if fertilisation does not occur.

Answer 244

1. The sperm binds to zona pellucida => this triggers acrosome reaction 2. Acrosome reaction - sperm enzymes cut through the ZP + sperm will fuse with the plasma membrane 3. Sperm is taken in by phagcytosis, tail & mitochondria are left behind Movement of cortical granules in contents hardens the oocyte coat and prevents polyspermy

Answer 245

- Penetration by the sperm is the signal for the oocyte to complete the second meiotic division. • It divides unequally expelling the second polar body. - Entry of the sperm causes oocyte intracellular calcium to increase. - Oocyte completes meiosis II and expels second polar body. - The sperm nuclear membrane breaks down, the chromatin decondenses and chromosomes separate. - Between 4 and 7 hours after fusion the two sets of haploid chromosomes become surrounded by distinct membranes forming pronuclei and these haploid structures synthesise DNA in preparation for the first mitotic division. - The pronuclear membranes break down and the mitotic metaphase spindle forms with the chromosomes assuming their position at its equator. - Mitosis is completed and the one cell zygote becomes a two cell embryo.

Answer 246

- When sperm enters the oocyte = this will cause Ca2+ waves which produces 3 direct effects 1. Cortical granules will fuse with the Zona Pellucida to block polyspermy 2. Nucleus of sperm transformation to male pronucleus 3. Completion of MII expulsion of 2nd polar body => production of the female pronucleus - The pronucleii will then come together, membranes will break down - Alignment of chromosomes on spindle = MITOSIS - This = 2 cell embryo

Answer 247

- Output • To cope with increased respiration • And cardiac ouput - Storage • For the fetus • For labour and puerperium

Answer 248

- Increased consumption and reduced usage - Mainly laid down in anterior abdominal wall - Utilised later in pregnancy and puerperium

Answer 249

- Need increased levels in the blood in the 2nd trimester - Active transport across placenta - As fetal energy source - Fetus stores some in the liver 1st trimester = maternal reserves - The pancreatic beta cells will increase in # • Therefore plasma insulin will increase • More into the tissues • Laid down as stores and used by the muscle • Fasting serum glucose will decrease 2nd trimester - Fetal reserves - Hpl = causes insulin resistance - Ie less glucose into the stores - Increase in serum glucose - More will cross the placenta - But can cause diabetes

Answer 250

- There are increases in respiratory centre sensitivity to co2 - Thoracic anatomy changes - ribcage is displaced upwards and the ribs will flare outwards ○ Both of these factors will cause one to breathe more deeply ○ Therefore the minute volume will increase by 40% 1. Arterial Po2 increases by 10% 2. PCO2 decreases by 15-20%

Answer 251

E2 and progesterone will act on the renin angiotensin system | fetus, placenta, plasma volume, mammary gland, uterine muscle, placenta, amniotic fluid, oedema

Answer 252

- Increased efficiency - Of iron absorption from the gut - Haemodilution - Apparent anaemia = as concentration of Hb falls

Answer 253

- Fetal blood - Increased Hb and altered in type • Leads to increased o2 binding ○ Oxygen given up by maternal Hb - Smoking will increase maternal carboxy-Hb - This is MORE permanent - And reduces the increased binding - Which will lead to fetal hypoxia

Answer 254

- The expanding uterus will push the heart around - Changes in the ECG and heart sounds - Increased cardiac output - Increased heart rate and stroke volume - This begins as early as 3 weeks to maximum 40% at 28 weeks For maternal muscle and fetal supply

Answer 255

- Increased CO and vasodilation due to steroids - Reduced peripheral resistance - Increased flow to: • Uterus • Placenta • Muscle • Kidney • Skin - Neoangiogenesis - Including extra capillaries in the skin (spider naevi) - To assist with heat loss

Answer 256

- Steroids, will lead to: 1. Appetite and thirst 2. Reduced gastrointestinal tract motility ==> constipation 3. Relaxes the lower oesophageal sphincter ==> acid reflux

Answer 257

- Supplementation is advised, 400 micrograms a day up to week 12 - Deficiency is linked to spina bifida - neural tube defect

Answer 258

- Urinary tract will dilate and relax, this will cause an increase in rate of UTI + may persist - Kidney has an increased blood flow, and increased filtration rate ○ This will lead to increased clearance of creatinine, urea, and uric acid

Answer 259

- Uterus gets larger within the pelvis - This will compress the bladder = frequency - Uterus will lift out of the pelvis - Baby head will descend onto the bladder again, reducing volume

Answer 260

- Huge rise in muscle mass x 20 - Huge increase in the blood flow - Placenta and uterus = 1/6 of total

Answer 261

- The main function of the cervix = retaining the pregnancy - Increase in vascularity - Tissue will soften and turn more blue from 8 weeks onwards - There are changes in connective tissue • Begins gradual preparation for expansion - Proliferation of glands • Mucosal layer becomes half of the mass • Great increase in mucus production • Protective ○ I.e. is anti-infective

Answer 262

- Dramatic and rapid fall in steroids - On delivery of the placenta - Most endocrine driven changes will return to normal, rapidly - Uterine muscles will rapidly loose oedema - But will contract slowly • Never will return to pre pregnancy size - Removal of steroids will permit action of raised prolactin on the breast

Answer 263

- Implantation - Development of extraembryonic structures - Hormone production essential for normal development and growth - Clinical disorders

Answer 264

- Cells of the blastocyst, that invade the endometrium and myometrium (day 5-6) - Secrete BetaHCG (human chorionic gonadotrophin)

Answer 265

- Becomes placenta

Answer 266

- Layer, that becomes amniotic sac.

Answer 267

1. Fertilised egg 2. 4 cell embryo 3. 8 cell embryo 4. Blastocyst Hatching blastocyst

Answer 268

- Free living blastocyst, reliant on cytoplasm inherited from the oocyte - maternal - Histiotrophic; blastocyst is bathed in uterine secretions - Haemotophic, vascular contact between mother and fetus

Answer 269

- Day 6 is the window of implantation (24-36h), Day 10 is when the trophoblast produces BetaHCG.

Answer 270

- When there is maternal recognition of pregnancy

Answer 271

- Progesterone production - Plus decidualisation is under progesterone - Which is vital until placental steroidogenesis is established

Answer 272

- It is under progesterone, and vital until placental steroidogenesis is established

Answer 273

1. Apposition 2. Attachment 3. Invasion

Answer 274

- There is a narrow window of time, when endometrium receptive to the embryo. Key balance of progesterone and oestrogen. - Come hither, LIF/EGF/IL11 - "Go away" Muc1 - There is a complex molecular cross talk between the embryo, and the endometrium

Answer 275

- There is a 3 way conversation between the uterus, ovary and conceptus - The conceptus signals its presence to the mother

Answer 276

- Basis of urinary pregnancy tests - Beta subunit, qualitative - Serum beta HCG - is quantitative. This is useful for monitoring early pregnancy complications, like ectopic pregnancy, miscarriage.

Answer 277

- Beta HCG maximal by 9-11 weeks - Maintains corpus luteum - Continued progesterone production - Corpus luteum is not necessary beyond 5-6 weeks.

Answer 278

Steroidogenesis - Oestrogens, progesterone, HPL, cortisol Nutrition - O2, CHO, fats, amino acids, antibodies, vitamins, minerals Waste removal - CO2, urea, NH4, minerals Barrier - Bacteria, viruses, drugs - The placenta is good because it has a huge maternal uterine blood supply, low pressure - Huge reserve in function, huge surface area that is in contact with maternal blood - Highly adapted, efficient transfer system

Answer 279

- There are 4 key steps of building the placenta 1. Trophoblast differentiation 2. Trophoblastic invasion of decidua + myometrium 3. Remodelling of the maternal vasculature in the utero placental circulation 4. Development of the fetal vasculature within the villi

Answer 280

Homeostasis - Temperature , fluid, ions Development - Vital for development of certain structures, like the limbs and lungs Protection - Physical and barrier - e.g. ascending infection

Answer 281

- Miscarriage - 15% - Ectopic pregnancy, hydatidiform mole - Transfer of other substances, like drugs, toxins and infections - Failed trophoblast invasion + remodelling - Placental insufficiency (10%) - Pre eclampsia - 5% pregnancies - Excessive invasion - Placenta acreta, percreta, - Choriocarcinoma

Answer 282

- Polyhydramnios - Oligohydramnios - Premature rupture of membranes

Answer 283

- Placental steroids, maternal steroids, fetal steroids, placental protein hormones

Answer 284

- Progesterone, oestrogen, cortisol

Answer 285

- Placental from 6-9 weeks onwards, 200mg per day by late pregnancy. Decidualisation (corpus luteum), smooth muscle relaxation, uterine quiescence - Mineral corticoid effect, cardiovascular changes - Breast development

Answer 286

- E3>E2>E1 - oestriol > oestradiol > oestrone - Feto placental unit - Rely on androgens, from the fetus and maternal adrenals - Development of uterine hypertrophy - Metaboli changes (insulin resistance) - cardiovascular changes - Breast development

Answer 287

- Placental CRH + Cortisol, both increase from T2 onwards - Cortisol = metabolic changes, insulin resistance, fetal lung maturity - CRH, is potentially involved in labour initation (placental biological clock)

Answer 288

- CRH - placental biological clock

Answer 289

Human placental lactogen (HPL) - Similar to GH, metabolic changes, insulin resistance, possibly has a role in lactation Prolactin - Predominantly maternal anterior pituitary, increases throughout pregnancy, breast development for lactation. - There are lots of uncertain functions in human pregnancy, v complex interactions between the mum, placenta and fetus - Most hormones cross placenta and are raised in maternal blood - Changes in binding proteins as well.

Answer 290

- Period of time from changes in menstrual pattern to menopause.

Answer 291

- Permenant cessation, of mestruation, because of loss of ovarian follicular function - Amenhorrhoea (stopped periods) for 12 months. It is a retrospective diagnosis. Could still potentially ovulate and still get pregnant. - Tired, periods stop

Answer 292

- No consistent definition - Period of changing ovarian function, which comes before the menopause by 2-8 years - Premature ovarian failure, menopause at less than 40 y/o

Answer 293

- Hot flushes/flashes are an ongoing symptom. - Fall in cycle length, because of reduced follicular phase - Mean 4 years prior to final menstrual period - some women get irregular periods, with amenorrhoea, heavy periods and also longer gaps between. V variable. - 1 year before menopause = hot flushes (4/5 minutes of profuse sweating) + therefore disturbed sleep because of falling oestrogen - Dry vagina (therefore pain during sex), impaired fertility - because of fewer periods. - Also around age of other rubbish stuff happening like children leaving, parents dying etc.

Answer 294

- Reduced follicular phase

Answer 295

- Reduced follicle count, none or few at menopause, reduced granulosa cell number, reduced granulosa cell function, increased chromosomal abnormality of oocyte. - Only have a few 100 follicles, a lot of follciles never make it to be released and die - a lot of the follicles that never get recruited into the menstrual cycle die as well. - Granulosa cells are hormone producing factories. Decline in number and quality which has consequences for the cycle + number of FSH receptors on the cells and their ability to produce estrogen as well.

Answer 296

- Thought to involve serotonin, so SSRIs appear to reduce the prevalence of hot flushes - Also about thermoregulatory control = in menopausal women, range of temperatures that your body can tolerate will fall which triggers vasodilation at a lower temperature compared

Answer 297

- Increased apoptosis of follicles - could be to do with the repair - Ovarian environment - like smoking, reduces age @ menopause by mean of 2 years, and shorter transition - Accelerated follicular loss • This is Anti Mullerian Hormone declines, FSH increases, and there is increased follicular recruitment. AMH inhibits FSH. Ability of the granulosa cells to make AMH declines.

Answer 298

- 30% fall in the granulosa cells in older women - Fall in inhibin B production, from granulosa cells in follicular phase - which allows higher FSH levels - As you get through the menopaise, you are more likely to have anovulatory cycles = decreased inhibin A normally produced in luteal phase - allows higher FSH. Don’t have enugh estrogen to allow LH surge. Have period for a few weeks of high FSH, high estrogn (enough to cause breast tenderness) but not enough for the follicle to actually release. No corpus luteum. Still get endometrial build up as you normally would - not a normal period, there will be very heavy bleeding! - Fall in FSH receptors and sensitivity impairs recruitment dominant in follicle - Impaired secretion growth factors and other signalling pathways - survival factors, oestrogen, progesterone.

Answer 299

- Older women have fewer granulosa cells (30% less) than younger women

Answer 300

- Decline in inhibin B production, granulosa cells - Leads to elevated FSH in follicular phase - Earlier elevated levels of oestrogen production and earlier LH surge

Answer 301

- Oestrogen production - Stimulated earlier in the cycle by elevated FSH but may not reach levels high enough to induce GnRH surge - This is due to impaired granulosa cell function - Ovulation = delayed or does not occur

Answer 302

- Longer oestrogen stimulation of endometrium - never get the dominant follicle being recruited. - Oestrogen levels may be higher than in women under 35

Answer 303

- Transitory increases oestrogen

Answer 304

- Fall in oestrogen levels (this happens closer to the actual menopause.) - Disturbance in serotonin levels - Resets thermoregulatory nucleus, and leads to heat loss.

Answer 305

- AMH levels first sign of declining ovarian function - Inhibin B declines about 2 years before the FMP - FSH levels are variable between each cycle, but increase towards menopause - LH increases but later in menopause - Oestrogen levels fall close to the menopause - Adrenal + ovarian androgen levels decline with age - from 20s, but not related to menopause - No progesterone production after menopause.

Answer 306

- AMH levels are the 1st sign of declining ovarian function. Inhibin B falls about 2 years before FMP. FSHs vary each cycle but increase towards menopause. LH increases later in menopause. Oestrogen levels fall close to the menopause. Adrenal and ovarian androgen levels decline with age from 20s, but not related to menopause. No progesterone production after menopause.

Answer 307

- Consequence of impaired production of growth factors / survival factors from the granulosa cells (increased disorders of the chromosomes) - Increased aneuploidy - chromosomal disorder - Increased oocyte abnormality impairs follicle recruitment, even with climphene - Resultant : anovulatory cycles, and increased miscarriage rate

Answer 308

- Being able to tell when women are going to have the menopause. Ovarian volume as proxy for number of follicles, or antral follicle count. - Response to ovarian stimulation, see how many follices are recruited if you stimulate the ovary - antral follicle count - Anti mullerian hormone - useful for family planning or use of IVF

Answer 309

- Anti Mullerian Hormone - is the one that decreases first in a womans reproductive life.

Answer 310

- Progesterone | - Is not made at all after menopause

Answer 311

- Urinary incontinence is not associated with menopause | - Hot flushes are associated.

Answer 312

* start w lowest dose possible.* - Oestrogen 80% efficacy at reducing hot flushes. Lower doses 60% efficacy so worth starting with low dose. - But not everyone can take estrogen so can use Gabapentin (modulatory nerve conduction), has a beneficial effect on hot flushes, but = addictive - Patient centred - woman should be clear about the indication, the risks and benefits, and have a plan for review. - Always use progesterone for 13 days for women with a uterus. Bear in mind: need contraception if less than 1 year amenorrhoea. Start with low doses. Minimise unwanted effects, such as mastalgia, nausea. Risks = low for short term use - For women with hot flushes in their 50s, the risks are really low.

Answer 313

- Hyperplasia is found in 56% of women who use unopposed oestrogens, ~3% develop carcinoma. - Protection obtained by 10-13 days of progesterone. - Best protection obtained by continuous combined oestrogen and progesterone, though may get break through bleeding and not good for women whose periods have not stopped.

Answer 314

- Sertraline = best treatment for thrombotic stroke (brain blood clot) - It is a SSRI and seeems to reduce hot flushees - Do not want to give someone estrogen who has had a thrombotic stroke

Answer 315

Could be any of the following; - Oestrogen and progesterone tablets with monthly break - Continuous oestrogen and progesterone tablets - Oestrogen patches and intrauterine progesterone secreting coil should be the treatment of choice! - Oestrogen patches and progesterone tablets - Tibolone tablets ○ Depends on cost and choice

Answer 316

- Prevents ALZ

Answer 317

- There is non-significant increase in ovarian carcinoma in users of combined HRT - Milli women study reports - RR of 1.2, for HRT usage

Answer 318

- Biphosphonates - Raloxifene - Calcium and vitamin D - Strontium - Other agents that are being investigated, teriparatide, a peptide fragment of parathormone - Simvastatin, leptin - Phyto oestrogens and manipulation of the RANK L gene - antioxidants

Answer 319

- Micronised progesterone vs. synthetic progesterones - RCTs looking @ ischaemic heart disease in women, around the menopause - Critical period theories for IHD, and ALZ - but may not ever be able to precisely predict risks for each woman

Answer 320

- Bleeding again 13 months after last menstrual period would not be normal - This is an important symptom of: cancer, until proven otherwise. Anyone with bleeding needs endometrial biopsy to see if they have got cancer :(

Answer 321

- 3 smooth muscle layers - Outer longitudinal fibres - Middle, figure of 8 shaped fibres - Inner circular fibres - Organised so that contraction causes an increase in uterine pressure - Which will force the contents towards the cervix - Acts as natural ligature - To prevent blood loss

Answer 322

- Myometrium is spontaneously active – myogenic - Spontaneous contractions are highly sensitive to neurotransmitters, hormones (oestrogen and progesterone) • Progesterone – inhibits contraction • Oestrogen – induces contraction Remember: Oestrogen/Progesterone ratio during parturition - Non-pregnant uterus: weak contractions early in cycle, but strong contractions during menstruation - Pregnant uterus: weak and uncoordinated in early pregnancy, but strong and co-ordinated at parturition - ANS Innervation - Myometrium is innervated by sympathetic nerves (not parasymapathetic) - Myometrium contains both a and b receptors - Stimulation of a produces contraction - Stimulation of b2 produces relaxation

Answer 323

1. Myometrium is myogenic - ‘pacemaker’ mechanism 2. Myometrium contain pacemaker cells - Interstitial Cells of Cajal (ICCs), which initiate and coordinate contractions 3. Electrical activity generated in ICCs pass from smooth muscle cell to smooth muscle cell through gap junctions - made of connexin proteins 4. Uterus behaves as a ‘syncytium’ – electrical connected cells 5. These mechanisms are affected by hormones, e.g. oestrogen increase expression of gap junctions to promote contraction

Answer 324

1. Electrical activity generated in ICCs pass from smooth muscle cell to smooth muscle cell through gap junctions - made of connexin proteins 2. Uterus behaves as a ‘syncytium’ – electrical connected cells 3. These mechanisms are affected by hormones, e.g. oestrogen increase expression of gap junctions to promote contraction

Answer 325

1. low wave: slow depolarisation produced by pacemaker cells (ICCs) 2. Electrical activity spreads via gap junctions to SMCs – activates action potentials in SMCs: upstroke of APs are carried by Ca2+ ions through VGCCs which leads to increase in [Ca2+]i ® contraction 3. Slow waves/SMCs are modulated by neurotransmitters/hormones

Answer 326

``` Ø There is an increase in Calcium levels Ø =Ca2+ calmodulin Ø Myosin light chain kinase Ø Myosin light chain actin / myosin Ø Contraction ``` - This is all triggered because of the action of ion channels, which increases membrane excitability - and thus will lead to depolarisation

Answer 327

• Similar to other smooth muscle tissue (Review 1st year lectures) • Contraction is caused by an increase in [Ca2+]i • Increase force production µ increase in [Ca2+]i • Each action potential will cause an incremental increase in [Ca2+]i but also there are mechanisms lowering [Ca2+]i – e.g. Ca extrusion. Changes in [Ca2+]i will be the resultant effect of these processes 1. Low concentrations of stimulants on ICCs ® slow wave frequency producing frequency of SMC contractions 2. Higher concentrations ® frequency of APs on top of slow waves (i.e. peak [Ca2+]i ) producing both frequency and force of SMC contractions 3. Higher concentrations still ® plateau of slow wave producing prolonged sustained SMC contractions 4. Large concentrations ® Hypertonus where there is incomplete relaxation – Ca extrusion processes not effective

Answer 328

Nonapeptide hormone - synthesised in hypothalamus and released from the posterior pituitary gland - Released in response to suckling and cervical dilatation – role in parturition? - Syntocinon is a synthetic version - Action is dependent on oestrogen - Oestrogen (released at later stages of parturition) produces oxytocin release, oxytocin receptors, gap junctions - Oxytocin is only effective at term

Answer 329

Uses - Induction of labour at term – doesn’t soften cervix - Treat / prevent post-partum haemorrhag

Answer 330

Pharmacological actions - Low concentrations of syntocinon/oxytocin increase frequency and force of contractions - High concentrations cause hypertonus – may cause fetal distress

Answer 331

- PGE2 (vasodilator) and PGF2a (vasoconstrictor) synthesised in myo- and endometrium – promoted by oestrogens - May have a role in dysmenorrhoea (severe menstrual pain, menorrhagia (severe menstrual blood loss) and parturition (birth) - Act together to coordinate frequency/force of contractions, gap junctions, soften cervix, synthesis of oxytocin - PGs are effective in early and middle pregnancy Dinoprostone (PGE2), Carboprost (PGF2α) are agonists

Answer 332

``` Uses Induction of labour – before term Induce abortion Postpartum bleeding Softening the cervix ``` Concern – Dinoprostone can cause systemic vasodilatation

Answer 333

Ergot - fungus that grows on some cereals (e.g. rye) and grasses Contains array of potent agents e.g. ergometrine, ergotamine (both based on LSD moiety), histamine, tyramine and Ach When ingested ® ergotism, gangrene, convulsions and abortion Action Powerful and prolonged uterine contraction - but only when myometrium is relaxed Mechanism Stimulation of a-adrenoceptors, 5-HT receptors? Uses Post-partum bleeding - NOT induction

Answer 334

- Used in premature labour b2-adrenoceptor stimulants = e.g. Salbutamol Relax uterine contractions by a direct action on the myometrium Used to reduce strength of contractions in premature labour, delay delivery by 48 hrs – allow corticosteroids to be given to enhance lung maturation May occur as a side effect of drugs used in asthma Ca channel antagonists e.g. nifedipine (used in hypertension) or magnesium sulfate Oxytocin receptor antagonists e.g. Atosiban COX inhibitors e.g. NSAIDs (¯ prostaglandin production) – why NSAIDS are useful to treat dysmenorrhoea and menorrhagia

Answer 335

Induction of labour at term Oxytocin Induction of labour/termination in early term Prostaglandins (not Oxy – no oxy receptors) Post-partum bleeding Prostaglandins, ergots Prevent premature birth b2-adrenoreceptor agonists, Ca channel blockers, MgSulfate Oxytocin inhibitors

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