Repro Flashcards

Question

What change in secretion occurs in adrenarche?

Answer 1

Change in adrenal androgen secretion (from zona reticularis) DHEA and DHEAS There is a gradual increase from 6-15 years with a 20 fold increase peaking at 20-25 years. - decline in DHEA/DHEAS thereafter = adrenopause - no change in other adrenal androgens - no known mechanism for trigger if adrenarche

Answer 2

Appearance of pubic/axilliary hair Induced by adrenal androgen secretion Associated with increased serum production = acne, Infection and abnormal keratinisation = acne If before 8 years (girls) or 9 years (boys) = precocious

Answer 3

GnRH is synthesised and secreted by specialist hypothalamic centres - GnRH neurones Pulsatile secretion is essential for GnRH function HPG axis is first activated at 16th gestational week - pulsatile GnRH secretion in foetus until 1-2 years postnatally web creases, reactivation at about 11 years GnRH neurones 'restrained' during postnatal period - 10 years or more At puberty a gradual rise in pulsatile rise in pulsatile release of GnRH Changes in LH secretion begin nocturnally. LH acts as a surrogate for GnRH, and LH is a lot easier to measure so this is what may be graphically represented to show changes of GnRH occurring during pubertal development.

Answer 4

- inherent maturation of 1000-3000 GnRH synthesising neurones - environmental/genetic factors - body fat/nutrition - need to be fit and healthy to reproduce and body knows this (need 17% fat for menarche and 22% to maintain female reproductive ability) - leptin - other gut hormones - kisspeptin

Answer 5

The smooth, ordered progression of changes Order of pubertal changes in uniform: age of onset, pace and duration of changes - wide inter-individual differences, average age of menarche onset (uk) is 12.5 years

Answer 6

Breasts enlarge Pubic/axilliary hair Uterus enlarges, cytology changes, secretions in response to E2 Uterine tubes Vagina Vertical changes Height Body shape HPG axis - increase in ovarian size and follicular growth Menarche - not equated with onset of fertility Fertility - in 1st year ~80% menstrual cycles anovulatory, irregular cycles

Answer 7

``` External genitalia Vas deferens Seminal vesicles and prostate Facial/body hair Pubic/axilliary hair Larynx Height Body shape Onset of fertility ```

Answer 8

- numbers represent the volume in millimetres 10th, 50th, 90th ce tiles of testicular size in boys at different ages Used to measure testis size

Answer 9

Growth hormone Oestrogen Low levels of oestrogen: linear growth and maturation High levels of oestrogen: epiphyseal fusion

Answer 10

Androgens stimulate sebum secretion and together with infection this can cause acne. Androgens can induce differentiation of vellum PSUs to terminal PSUs encouraging moustache and beard. Androgens can induce differentiation of vellum hairs to apo-PSUs encouraging increased growth in areas of pubic and axillary hair.

Answer 11

Increasing need for independence Increasing sexual awareness/interest Development of sexual personality Latter muturation = better adjustment

Answer 12

Development of any secondary sexual characteristic before the age of 8 in girls and before the age of 9-10 in boys. Precocious puberty is when puberty is when pubertal changes are early but in consonance. Gonadal-dependent (or central) precocious puberty - consonance Excess GnRH secretion - idiopathic or secondary Excess gonadotrophins secretion - pituitary tumour Gonadotrophin-independent precocious puberty - loss of consonance Testotoxicosis - activating mutation of LH receptor McCune Albright - constitutive activation of adenylyl Cyclades >>hyperactivity of signalling pathways and over production of hormones Sex steroid secreting tumour or exogenous steroids

Answer 13

Cafe au lair skin pigmentation Autonomous endocrine function - most common gonadotrophin-independent precocious puberty Fibrous dysplasia Mutations in the GNAS1 gene

Answer 14

Premature adenarche/pubarche - precocious development of pubic and/or axillary hair Also CAH/Cushings Premature thelarche - precocious breast development - can be unilateral - isolated 'cyclical' with absence of other pubertal development - other variant proceeding to precocious puberty

Answer 15

``` Auxology LH, FSH, sex steroid measurements LH response to 100 micrograph GnRH Adrenal steroids MRI scans of hypothalamic-pituitary area Ultrasound scans of pelvis ```

Answer 16

Anti-androgens 5-alpha-reductase inhibitor Aromatase inhibitor Long acting GnRH analogue

Answer 17

Absence of secondary sexual maturation by 13 years in girls or 14 years in boys

Answer 18

- affecting both growth and puberty. Approximately 90% of all pubertal delay cases - about 10 times more common in boys - secondary to chronic illness eg diabetes, cystic fibrosis

Answer 19

Low LH and FSH Kallman's syndrome Other genetic causes, hypopituitarism

Answer 20

High LH and FSH Gonadal dysgenesis, low sex steroid levels: - congenital - klinefelters and turners - gonadal dysgenesis with normal karyotype, viral eg mumps

Answer 21

``` Family history, dystrophic features, anosmia Auxology Pubertal staging Bone age estimation LH, FSH, sex steroid measurements LH response to 100 micrograms GnRH Adrenal steroids - high with tumours, precursors high with CAH MRI scans of hypothalamo-pituitary area Ultrasound scans of pelvis ```

Answer 22

Testosterone in males Oestrogens in females Oxandralone (synthetic steroid)

Answer 23

- correct process of sex determination and differentiation - sexual maturation - production and storage of sufficient supply of eggs and sperm - correct number of chromosomes in egg and sperm - actual sexual intercourse - egg and sperm have to be transported and meet - fertilisation, implantation, embryonic and placental development - once delivered/born, to nurture individual until capable of independent life

Answer 24

- hypothalamic and pituitary peptide hormones | - gonadal steroid and peptide hormones

Answer 25

Hypothalamus: (releasing hormones) gonadotrophin releasing hormone (GnRH), kisspeptin Pituitary: (stimulating hormone) FSH and LH Gonad: in females oestradiol (E2), progesterone (PS), in males testosterone (inhibins and activins)

Answer 26

Coordinate gonadal function for viable gamete production (male), growth and development (both) The u,it ate coordination of gonadal function to facilitate viable gamete production, growth and development.

Answer 27

GnRH positively drives the gonadotrope cells of the anterior pituitary where it stimulates synthesis and secretion of LH and FSH which positively stimulates the production of gonadal steroid (oestrogen positive and negative feedback, progesterone and androgens negative feedback only).

Answer 28

Decapeptide (10aa) Synthesised and secreted from GnRH neurones Secreted in a pulsatile fashion - pulse generator orchestrated Brings to the GnRH receptor (GnRHR) on gonadotrophin cells of the anterior pituitary to stimulate the synthesis and secretion of gonadotrophin hormones LH and FSH After release GnRH binds to its receptor which is a GPCR on gonadotroph cells of the anterior pituitary

Answer 29

Hypothalamic neurotransmitters

Answer 30

It binds and increases gene transcription of alpha and beta subunits of LH and FSH. These hormones are then translated, packaged and secreted from gonadotroph cells and also released in a pulsatile fashion. Pulse of GnRH also corresponds with release of LH. Lots of things regulate it.

Answer 31

GnRH pulse stimulates a pulse of LH and FSH secretion from the pituitary Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion Slow frequency pulse favours FSH release, rapid frequency favours LH release Continuous release results in cessation of response

Answer 32

Synthetic GnRH - same structure as native GnRH --> stimulatory ...... Used in the stimulation of hypothalamic pituitary axis eg delayed puberty GnRH analogues - modified GnRH peptide structure, loss of pulsatility --> inhibitory... Either agonists or antagonists ....... This is a,ways used to down regulate/inhibit the HPT axis

Answer 33

Brings to receptor Activation of signalling - GPCR Stimulation of gonadotrophin synthesis and secretion Dissociation of GnRH from receptor Responsive to next GnRH pulse as it occurs Agonists work in a similar way until we don't get the dissociation. We get a constant GnRH binding to agonist as modified in a way that prevents dissociation from the receptor. After 2-3 weeks of treatment resulting in uncoupling if GnRHR from G protein signalling. Antagonists bind to the receptor and block the receptor are all competitive inhibitors of GnRH itself.

Answer 34

Ovulation indication and IVF GnRHR/GnRH and ovarian and endometrial cancers Really and breast cancer in pre-menopausal women PCOS Endometriosis Uterine fibroids Prostrate cancer The two biggest uses in terms of clinical applications and grossing money wise is ovulation induction and IVF, and also in prostate cancer. The one controversial application is gonadal protection prior to chemotherapy. In order to try and preserve fertility in child cancer patients.

Answer 35

They are comprised of two different subunits. They have a common alpha subunit and there is a hormone specific beta subunit which confers biological specificity for each are all glycosylated. This allows recombinant heterogeneity.

Answer 36

Heterdimeric peptides - common alpha subunit and hormone specific beta subunit N-linked carbohydrate side chains and o linked in hCG - microheterogeneity required for biological function Free subunits have no biological action Alpha subunits are synthesised in excess with beta subunit limiting the hormone concentration Pulsatile secretion due to pulsatile GnRH release from the hypothalamus but pulsatile secretion not necessary for biological activity The three subunits don't have any biological activity independently. The beta subunit is the rate limiting step. Alpha is synthesised in excess and released in a pulsatile fashion. However, the pulsatile release isn't essential for their function.

Answer 37

Testis: stimulation of leydig cell androgen synthesis Ovary: theca cell androgen synthesis, ovulation, progesterone production of corpus Luteum

Answer 38

Testis: regulation of Sertoli cell metabolism Ovary: follicular maturation, granulosa cell oestrogen synthesis

Answer 39

Androgens transported from theca cells into granulosa cells under control of FSH receptor they become Oestrogens. This used AROMATASE.

Answer 40

transition from no-reproductive to reproductive state

Answer 41

- secondary characteristics develop (primary are present at birth) - adolescent growth spurt - profound physiological changes - profound psychological changes gonads produce mature gametes (testes: spermatozoa, ovaries: oocytes)

Answer 42

Adrenarche | Gonadarche

Answer 43

Originates from the adrenal and is instigated by the maturation of cells in the adrenal cortex. This results in the release of androgens from the adrenal. Changes that occur include the growth of pubs and axillary hair and growth in height. This is independently regulated.

Answer 44

Occurs following adrenarche. This is HPG driven. The synthesis and secretion of pituitary peptide hormones - LH and FSH, which activate gonadal function. LH causes secondary sex characteristics and FSH causes the growth of testis (male), steroid synthesis, folliculogenesis (female)

Answer 45

``` Dehydroepiandrosterone (DHEA) Dehydroepiandrosterone sulphae (DHEAS) ``` There is a gradual increase form 6-15 years with a 20 fold increase peaking at 20-25 years. - decline in DHEA/DHEAS thereafter = adrenopauqe - no change in other adrenal androgens - no known mechanism for trigger of adrenarche

Answer 46

- appearance of pubic/axiallary hair - induced by adrenal androgen secretion - associated with: increased serum production = acne, infection, abnormal keratinisation = acne - if before 8 (girls) and 9 (boys) it is precocious

Answer 47

- several years AFTER adrenarche (typically ~11 years of age) - reactivation of hypothalamic GnRH - activation of gonadal steroid production --> production of viable gametes and ability to reproduce

Answer 48

- synthesised and secreted by specialise hypothalamic centres - GnRH neurones - pulsatile secretion is essential for GnRH function - HPG axis is first activated at 16th gestational week: pulsatile GnRH secretion in foetus until 1-2 years postnatally when ceases, re-activation at ~11 years - GnRH neurones 'restrained' during postnatal period --> 10 years or more - at puberty a gradual ise in pulsatile release of GnRH

Answer 49

It is clear that it is a maturational event within the CNS. - inherent (genetic) maturation of 1000-3000 GnRH synthesising neurones - environmental/genetic factors - body fat/nutrition - leptin - other gut hormones - kisspeptin - What drives the central generator??? ??

Answer 50

- link between fat metabolism and reproduction - anorexia nervosa/intensive physical training: reduced response to GnRH, decreased gonadotrophin levels, amenorrhea, restored when nourished/exercise stopped

Answer 51

Certain % fat:body weight necessary for menarche (17%) and required (22%) to maintain female reproductive ability

Answer 52

- found in hypothalamic neurones | - kisspeptin receptors expressed in GnRH neurones

Answer 53

mutations of GPR54 or the gene coding for kisspeptin. - abnormal development of GnRH neurones - hypogonadism - failure to enter puberty - hypothalamic hypogonadism activating mutations of kisspeptin receptor - precocious puberty

Answer 54

smooth ordered progression of changes order of pubertal changes in uniform: - age of onset, ice and duration of changes: wide inter-individual differences - average age of menarche onset (UK) = 12.5 years

Answer 55

- breasts enlarge (thelarche) - pubic/axilliary hair - uterus enlarges, cytology changes, secretions in response to E2 - uterine tubes - vagina - cervical changes - height (earlier onset then boys, peak height velocity 9cm/y reaches at 12 years) - body shape - HPG axis (increase in ovarian size and follicular growth) - menarche (not equated with onset of fertility) - fertility (in 1st year ~80% menstrual cycles anovulatory, irregular cycles)

Answer 56

- external genitalia (increase in testiular volume >4ml, growth of penix, scrotum, scrotal skin changes) - vas deferens (lumen increases) - seminal vesicles and prostate - facial/body hair - pubic/axilliary hair - larynx (androgens - enlarge larynx, adams apple (projection of thyroid cartilage), voice deepens) - height (PHV = 10.3cm/y reached at 14 years) - body shape - onset of fertility (testosterone form leydig cells stimulates meiosis and spermatogenesis in sertoli cells, boys fertile at the beginning of puberty)

Answer 57

- measures testicular size - numbers represent the volume in millimetres - 10th, 50th, 90th centimes of testicular size in boys at different ages

Answer 58

Complex interaction between growth hormone and oestrogen. Earlier in girls - approximately 2 years biphasic effect of oestrogen in epiphyseal growth - -> low levels: linear growth and bone maturation - -> high levels: epiphyseal fusion

Answer 59

- androgens stimulate sebum secretion and together with infection this can cause acne - androgens can induce differentiation of villus PSUs to terminal PSUs encouraging moustache and beard - androgens can induce differentiation of villus hairs to apo-PSUs encouraging increased growth in areas of pubic and axillary hair

Answer 60

- increasing need for independence - increasing sexual awareness/interest - development of sexual personality later maturation = better adjustment

Answer 61

development of any secondary sexual characteristic before the age of 8 in girls, and before the age of 9-10 in boys. precocious puberty is when pubertal changes are early but in consonance. - gonadal-dependent (central) precocious puberty : consonance - gonadotrophin-independent precocious puberty : loss of consonance

Answer 62

CONSONANCE - excess GnRH secretion: idiopathic or secondary - excess gonadotrophin secretion: pituitary tumour

Answer 63

LOSS OF CONSONANCE - testotoxicosis: activating mutation of LH receptor - McCune albright: constitutive activation of adenylyl cyclase >> hyperactivity of signalling pathways and over-production of hormones - sex steroid secreting tumour or exogenous steroids

Answer 64

PREMATURE ADENARCHE/PUBARCHE - precocious development of pubic and/or axillary hairs also CAH (congenital adrenal hyperplasia)/cushings PREMATURE THELARCHE - PRECOCIOUS BREAST DEVELOPMENT - can be unilateral - isolated 'cyclical' (2 years) proceeding to precocious puberty

Answer 65

- auxology: accurate measure of height, including body proportions and weight - pubertal staging - boen age estimation - LH, FSH, sex steroid measurements LH response to 100micrograms GnRH: normal for stage of puberty in central precocious puberty, surpassed in testoxicosis - adrenal steroids: high with tumours, precursors high with CAH - MRI scans of hypothalamic-pituitary area - ultrasound scans of pelvis (uterus and ovaries)

Answer 66

- anti-androgens - 5alpha-reductase inhibitor (T --> 5a-DHT) - aromatase inhibitor - long-acting GnRH analogue (central precocious puberty

Answer 67

absence of sexual maturation by 13 years in girls (or absence of menarche by 18years) or 14 years in boys - CONSTITUTIONAL DELAY - HYPOGONADOTROPHIC HYPOGONADISM (low LH and FSH) - HYPERGONADOTROPHIC HYPOGONADISM (high LH and FSH)

Answer 68

* Affecting both growth and puberty. Approximately 90% of all pubertal delay cases. * About 10 times more common in boys. * Secondary to chronic illness eg diabetes, cystic fibrosis.

Answer 69

low LF and FSH •Kallman’s syndrome (X-linked KAL gene, GnRH migration) •Other genetic causes, hypopituitarism

Answer 70

high LH and FSH - Gonadal dysgenesis, low sex steroid levels: oCongenital – Klinefelter’s syndrome (XXY) 1:500 males, Turner’s syndrome (XO) 1:3000 girls oGonadal dysgenesis with normal karyotype, viral eg mumps

Answer 71

* Family history, dysmorphic features, anosmia * Auxology (accurate measurement of height, including body proportions, and weight) * Pubertal staging * Bone age estimation … based on above * LH, FSH, sex steroid measurements * LH response to 100µg GnRH * Adrenal steroids – high with tumours, precursors high withCAH * MRI scans of hypothalamo-pituitary area * Ultrasound scans of pelvis (uterus and ovaries)

Answer 72

- testosterone (in males) - oestrogens (females) - oxandralone (synthetic steroid)

Answer 73

- selection of a single oocyte - regular spontaneous ovulation - correct number of chromosomes in eggs - cyclical changes in the vagina, cervix and fallopian tube - preparation of the uterus - support of the fertilised dividing egg

Answer 74

The hormones produced by the follicle in the ovary which feedback to control the main production of GnRH and gonadotrophins which go on to control the whole cycle.

Answer 75

Follicular phase | Luteal phase

Answer 76

growth of follicles up to ovulation – dominated by oestradiol production from dominant follicle

Answer 77

formation of corpus luteum from the empty follicle – dominated by progesterone production from the corpus luteum

Answer 78

- Two phases separated by ovulation - Cycle begins on day 1 - first day of bleeding - Next 14 days are follicular phase – ie growth of follicle - Ovulation occurs at the end of the follicular phase - Empty follicle becomes the corpus luteum - The next 14 days are luteal phase, ie dominated by the corpus luteum - Menstruation occurs at the end

Answer 79

1. Release of negative feedback 2. Negative feedback then reinstated 3. Switch from negative to positive feedback The switching of feedback determines the control of the cycle. We start in the luteal phase which is dominated by progesterone produced from the corpus luteum which feedback back to down regulate the secretion of GnRH and gonadotrophons so it is negative feedback. In males there is constant negative feedback but in women it is more complicated. In females the negative feedback at the start of the follicular phase is released at the end of the luteal phase. The break is lifted, allowing the HPG axis to work again and this stops in the follicular phase and allows the increase of secretions again. Oestrogen is started to be produced for the growing follicle and this feeds back to reinstate the negative feedback. Towards midway through the cycle there are sustained high levels of oestrogen for the dominant follicle and the feedback switches to positive.

Answer 80

allows the selection of a single follicle

Answer 81

The exact stage of development that a follicle has to be in to be selected

Answer 82

•Raised FSH present a ‘window’ of opportunity •FSH threshold hypothesis -One follicle form the group of antral follicles in the ovary is just at the right stage at the right time… -This becomes the dominant follicle which goes on to ovulate -This is known as selection -Can be in either ovary, and doesn’t have to be alternating •Oestradiol levels rise reinstating negative feedback at pituitary causing FSH levels to fall, and this prevents further follicle growth.

Answer 83

As FSH falls, LH increases. The dominant follicle acquires LH receptors on granulosa cells. Other follicles do not, so they loose their stimulant and die. It is also thought that it has more FSH receptors than in other follicles, so it is able to catch any FSH around even if levels are really low. FSH couples maybe to their downstream signalling pathway very effectively.

Answer 84

* Theca always has LHr, never FSHr – remember LH drives androgen and progesterone production from theca * Granulosa cells have FSHr, then LHr acquired from mid-follicular phase onwards – FSH and then LH drive oestrogen production in follicular phase

Answer 85

Just be aware that all steroids originate from cholesterol and are made by sequential removal of carbon atoms by a series of enzymes (in blue) which are distributed through the cellular compartments of the follicle.

Answer 86

* Day 1 is the first day of bleeding * Menstruation lasts 3-8 days, written in notes as 7/28 or 5-6/27-32 * A regular cycle should have no more than 4 days of variation from month to month Most womens cycles are 30 days. The variation is in the follicular phase because the corpus luteum has a fixed lifespan, after 14 days it will die.

Answer 87

* Dominant follicle selected * Grows rapidly, doubling in diameter in 7 days… from 7mm to 14mm * Needs masses of growth factors, nutrients and steroids * Rapid neoangiogenesis * Oestrogen released from follicle into circulation It doesn’t only rely on oestrogen. There is a very rich vasculature in the dominant follicle allowing nutrients to be fed to it and growth can occur. There is also neoangiogenesis.

Answer 88

• Throughout the follicular phase E2 feedback was negative • At the end of the follicular phase E2 levels are raised for long enough  feedback switches from negative to positive • This causes massive release of LH from the pituitary • Exponential rise in LH in serum • Triggers ovulation cascade - Egg is released - Above result in changes in follicle cells = luteinisation ie formation of the corpus luteum - E2 production falls and P is stimulated

Answer 89

* Ovulation occurs via a cascade of events * Blood flow to the follicle increases dramatically – increase in vascular permeability increases intra-follicular pressure * Appearance of apex or stigma on ovary wall * Local release of proteases * Enzymatic breakdown of protein of the ovary wall * 18 hours after peak of LH, hole appears in follicle wall and ovulation The follicle has by now moved back to the cortex of the ovary. As they grow they move into the medulla which has a rich blood supply and as they get bigger and bigger they grow back up to cortex as they need to be able to release the oocyte from the ovarian wall. The stigma is a kind of weakness in the wall – proteases degrade the wall to allow the oocyte to be released. * Oocyte with cumulus cells is extruded from the ovary under pressure * Follicular fluid may pour into the Pouch of Douglas * The egg is ‘collected’ by fimbria of Fallopian tube * The egg progresses down the tube by peristalsis and action of cilia Egg collected by fimbria due to signal from fluid. Fluid may move into the pouch of Douglas but Fallopian tube will move around and pick up egg as it is released. Therefore, if you have fibroids or anything that means the follicular tubes are latent then may not get pregnancy as can't move to pick up the egg. The egg moves down the tubes – cilia – and hopefully meets with the sperm to be fertilised in the ampulla.

Answer 90

Ovulation “sticks” that detect the LH surge. Home ovulation methods are based on the detection of these hormone products in urine or saliva, or the changes in other body fluids such as cervical mucus in the vagina. The simplest and least expensive method is the detection of the LH surge in urine. Many women refer to this as “pee on a stick” although there are different ways of performing the test depending on the kit. Many kits are available in the drug stores. For most women, this is adequate and accurate. Ovulation occurs approximately 12 to 24 hours after the detection of the LH surge in the urine.

Answer 91

* From its formation as a primary oocyte in the fetal ovary up until ovulation, the oocyte has been arrested in the first meiotic division. * This permits the oocyte to retain all of the DNA and remain as large as possible during its long wait. * In response to the LH surge, the nucleus of the oocyte in the dominant follicle completes the first meiotic division, but it does not divide We have got to create haploid oocytes. We are in meiotic arrest as the oocyte has entered into meiosis I and stopped.

Answer 92

Undergoes meiosis I and packages all the chromosomes into astute known and the first polar body. Maintains majority of cytoplasm because we need everything that is necessary to sustain the implantation for fertilisation of the egg. The egg is now called secondary oocyte. It goes into meiosis II and arrests again. It stays in meiosis II until it is fertilised. If successfully fertilised will complete meiosis II, if not then it will be lost in menstruation.

Answer 93

* Unlike sperm we only want a single oocyte * The oocyte is the largest cell in the body (sperm are smallest… but the fastest!) * The oocyte has to support all o 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 oocyte is now on its way into the tube… will it meet a sperm? The story continues later…

Answer 94

* After ovulation the follicle collapses * The corpus luterum is formed, ‘yellow body’ * Progesterone production increases greatly, also E2 * CL contains large numbers of LH receptors * CL supported by LH and hCG… if a pregnancy occurs The second peak of E2 in the luteal phase is made by the corpus luteum

Answer 95

The uterus is mainly muscle. It has an endothelium lining which is lost each month. The sperm swim up the uterine tube and meet the egg in the ampulla.

Answer 96

- Maternal steroids increase the size of the newborn uterus - growth with height during infancy - myometrium dependent on oestradiol - corpus of uterus undergoes greater increase in size than the cervix In the newborn, the uterus has been exposed to a huge amount of oestrogen. Therefore, the uterus in the new born is disproportionately large and by the age of 4 it has shrunk to be smaller in the first place. In a menopausal woman the uterus shrinks to a similar size as it would be during puberty.

Answer 97

parous: have given birth nullparous: never given birth

Answer 98

* The outer muscular myometrium grows gradually throughout childhood * Increases rapidly in size and configuration during puberty * Changes in size through the cycle and is capable of vast expansion during pregnancy The inner layer is of circular fibres. The middle layer is figure of 8 or spiral fibres. The outer layer is longitudinal fibres. Together these produce a highly dynamic organ.

Answer 99

* Very thin in childhood. Begins to thicken at puberty * Dependent on steroids. Responds cyclically to hormone changes. Can be seen and measured on an ultrasound scan. Good ‘bioassay’ of oestradiol level * Changes in glandular and epithelial cells through the cycle. At menstruation most of the endometrium is lost * After menstruation – stromal matrix with small columnar cells with glandular extension 2-3mm thick glands are simple and straight The endometrium is the inner layer that is shed each month. The arteries supplying it become very convoluted to increase surface area and can get more nutrients in. Around a week after ovulation it is at its peak of activity it has grown the glands for adhesion factors, growth factors etc on the surface where implantation will take place. There are changes throughout the cycle and the first part of the cycle is dominated by oestrogen which causes proliferation. After ovulation the corpus luteum is producing progesterone instead which causes the differentiation of this layer eg maturation of secretory glands.

Answer 100

Proliferative phase stimulated by oestradiol from the dominant follicle. Stromal cell division, ciliated surface. Glands expand and become tortuous giving increased vascularity, neoangiogenesis also occurs. There is minimal cell division by days 12-14. When the endometrium >4mm induction of progesterone receptors occurs and there are small muscular contractions of the myometrium.

Answer 101

The secretory phase (luteal phase of ovary) 2-3 days after ovulation, the gradual rise in progesterone causes a reduction in cell division. Glands increase in tortuosity and distend – secretion of glycoproteins and lipids commences. Oedema, increased vascular permeability arterioles contract and grow tightly wound. Myometrial cells enlarge and movement is suppressed and blood supply increases.

Answer 102

The corpus luteum is stimulated by LH from the pituitary during the luteal phase. The fertilised oocyte becomes a blastocyst and produces human chorionic gonadotrophin (hCG) which acts like LH ie on LH receptor, and ‘rescues’ the corpus luteum. In the absence of this, falling levels of steroid from the corpus luteum results in menstruation.

Answer 103

* Prostaglandin release causes constriction of spiral arterioles. * Hypoxia causes necrosis * Vessels then dilate and bleeding ensues * Proteolytic enzymes released from the dying tissue * Outer later of endometrium shed, 50% lost in 24 hours, up to 80ml is considered normal. Bleeding normally lasts 4+ days * Basal layer remains and is then covered by extension of glandular epithelium * Oestrogen from the follicle in next follicular phase starts cycle off again

Answer 104

The intramural section is where uterine tube meets uterus. The outer layer is composed of of longitudinal smooth muscle fibres, and the inner layer of circular muscle fibres which continues down the tube. The inner circular muscles can squeeze tube and the outer layer can contract tube a little bit.

Answer 105

There is a secretory mucosa with two main types of cells. One is a secretory cell secreting all the nutrients for the early embryo and fertilisation and ciliated cells which waft the egg down the tube. The isthmus compared to intramural getting more and more of the secretory mucosa. When the egg gets to the ampulla, site of fertilisation, the secretory mucosa becomes very convoluted to make a huge surface area. We can see cells lining this mucosa have cilia which also secrete. This is where life starts.

Answer 106

* In uterine tubes at the start of the cycle the oestrogen is not causing proliferation but differentiation (the opposite to in the endometrium) because the two tissues have different roles and different times * Ciliated cells wave cilia and secretory cells start secreting * At the end of the first half of the cycle we get ovulation * Immediately after ovulation we want the secretion and the cilia * Hoping egg will meet sperm v soon after ovulation * If they don't meet in the first few days we don't want to continue secreting and wafting so as progesterone starts to rise, maybe in the last week before menstruation, it is probably too late for fertilisation, so progesterone undifferentiates them and causes the cilia and secretions to stop * The two organs are inversely coordinated by the menstrual cycle

Answer 107

At ovulation the egg has got to get from the ovary into the uterine tube. The fimbrae picks up the ovulated oocyte and this is why the egg doesn’t get lost.

Answer 108

Two main methods of checking if tubes are blocked Both involve passing a dye into uterus and only way out apart form cervix is through uterine tubes Can look down tube and see inside and want to seethe dye emerging from ends of fibrillated end of tubes and if it does then we know it's not blocked. If it doesn't emerge then we know the tube is blocked The other way of doing it is introducing cannula up through cervix. Fill uterus with dye. Only way out is through uterine tubes as before. The dye used is opaque to ultrasound. Instead use ultrasound scanner to detect the progress of the ultrasound opaque dye and we will know if the dye flows through the tube or not – this is a non invasive method Would use the invasive method in circumstances where we want to make a visual inspection of the inside of the pelvis – eg look for endometriosis – can't see that with ultrasound, or they may be infection or adhesions, so if we think we require a visual inspection if endometriosis is expected would use laparoscopy, if not then will probably use the quicker and cheaper and less invasive ultrasound technique

Answer 109

- Muscular structure capable of great expension - Mucosa 2-3mm thick - Many secretory glands producing mucus… protective barrier to infection, however has to allow the passage of motile sperm - Need mucus to plug the cervical os as a kind of barrier to bacteria and infection etc - Also has to allow sperm to swim through however - It does this by when the woman is ovulating the mucus becomes thinner and running, allowing the sperm to swim through it nicely - At other times in the cycle the mucus becomes stick and the sperm cant swim through

Answer 110

* Oestrogen in the follicular phase causes: change in vascularity of cervix and oedema * Mid cycle oestrogen levels cause changes in mucous to become less viscous – change in mucous composition, contains glycoproteins, glycoproteins become aligned and form microscopic channels which the sperm can swim up Oestrogen in follicular phase causes changed in vascularity and makes the mucus in the cervix more watery. Also contains glycoproteins which become aligned and form channels that the sperm can swim through. At other times is very viscous and the sperm can't get through – progesterone has this effect. Coordinated by the menstrual cycle giving a unique effect on this organ – they are all doing different things.

Answer 111

Progesterone in the luteal phase causes reduced secretion and viscous mucous (reduced water content), glycoproteins now form mesh like structure: acts as barrier, one mechanism of action of oral contraceptives. When there is high progesterone it is too late for fertilisation and the secretions become reduced and the mucus out becomes very viscous and the glycoproteins don't form nice channels for the sperm they come crossed over and meshed up so it can't get through. The oral contraceptive pill containing progesterone does this so the sperm can't pass through. This is an image from the side of the cervix. The contraceptive cap fits into the fornices of the vagina.

Answer 112

The vagina is a thick-walled tube of approximately 10cm. It is lined by specialized ‘squamous epithelial’ cells and it is a warm, damp environment containing glycoproteins.

Answer 113

- Layers of epithelial cells shed constantly and ‘flow’ downwards with the secretions - Secretions are from the cervix and transudation from vaginal epithelium – blood flow from the outside, some of the plasma transudates through the squamous epithelial cells and adds to the vaginal secretions - Secretions change with the cycle and are generally acidic providing anti-mucosal protection.

Answer 114

* Oral contraception * Barrier methods * Fertility awareness * Coitus interruptus * Oral emergency contraception

Answer 115

* IUCD/IUI/IUS * Progestogen implants * Progestogen injections * Sterilisation

Answer 116

Using hormones for many years there is the potential for cancer. There can be emotional issues as hormones can affect the brain. Introducing things inside people can get infected eg the coil. This is iatrogenic because technically the doctor has induced harm to the patients as it wouldn’t have happened to the patient if you hadn’t don’t it, even though it is for a good reason.

Answer 117

Oestrogen and progestogens. The reason there are so many is that it depends on which progestogen is present. They are in the family of progesterone and behave in the same way.

Answer 118

- On anterior pituitary and hypothalamus - Directly on the ovary - On the endometrium It keeps the hormones at a constant higher level throughout the cycle which causes negative feedback. The body thinks that you are pregnant whilst you are on the pill, so you don’t make another follicle and don’t ovulate. Oestrogen on its own causes the endometrium to proliferate but we don’t want this to happen so we give it with progestogens.

Answer 119

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

Answer 120

The combined effect on the endometrium is that it thins the lining right out so there is no proliferative or secretory phase, and so it is not receptive to implantation. Other effects are the thickening of cervical mucus and makes the fallopian tubes lazy. This stops them from contracting so transport of the sperm and the egg is delayed.

Answer 121

``` ¬ Reliable ¬ Safe ¬ Unrelated to coitus ¬ Woman in control ¬ Rapidly reversible ``` ¬ Halve ovarian cancer risks ¬ Halve endometrium cancer risks ¬ Decrease risks of colon cancer ¬ POSSIBLY helps endometriosis, fibroids, rheumatoid arthritis, premenstrual syndrome, dysmenorrhoea, menorrhagia The combined pill can just be taken non-stop without a break, and the user wont get any periods for as long as they desire.

Answer 122

- cardiovascular: arterial (HBP) and venous (clotting disorders) - neoplastic (breast, cervix, liver) - gastrointestinal (weight gain, crohns) - hepatic (jaundice, gall stones, hormone metabolism) - dermatological (chloasma, acne, erythema multiforme) - psychological (mood swings, depression, libido)

Answer 123

1. Start 1st packet 1st day of menstrual period 2. Take 21 pills and stop for a 7 days break (PFI) 3. Restart each new packet on the 8th day (same) 4. Do not start new packets late 5. If late or missed pills in the 1st 7 days, must use condoms 6. If missed pills in last 7 days, no PFI. It is especially bad to miss pills in the last or first few days. This is because then the seven say break could increase to 10 days, and this might result in ovulation.

Answer 124

Liver enzyme inducing drugs Affect metabolizing of both oestrogen and progestogen Beware rifampicin and anti-epileptics Broad spectrum antibiotics Affect enterohepatic circulation of oestrogen only (40%) If we upgrade the liver then enzymes chew up drugs then this can result in contraceptive failure.

Answer 125

Nuvaring – this is the same concept as the pill, but just not oral. - Same as COCP except vaginal delivery (ring) for 21 days - Remove for 7 days - Advantages: don’t have to take it every day - Disadvantages: don’t have to take it every day!!!

Answer 126

Implants: Implanon (ETN), Norplant (LNG) | Hormone releasing IUCD: Mirena IUS (LNG)

Answer 127

POPs: Desogestrel (Cezarette), Norethisterone, Ethynodiol diacetate, Levonorgestrel, Norgestrel Injectables: Depo Provera (MPA) (12 weekly), Noristerat (NET) All progestogens – NO OESTROGEN! The impant is a long lasting, reversible method.

Answer 128

Copper bearing intrauterine contraceptive devices are inserted into the uterus by suitably trained practitioners and may be left in situ long term and act by: - destroying spermatozoa - preventing implantation – inflammatory reaction and prostaglandin secretion as well as a mechanical effect Copper is spermicidal – it kills sperm. If there is an inflammatory reaction in the uterus this is not inclusive to implantation.

Answer 129

* Non user dependent * Immediately and retrospectively effective * Immediately reversible * Can be used long term * Extremely reliable * Unrelated to coitus * Free fro serious medical dangers

Answer 130

* Has to be fitted by trained medical personnel * Fitting may cause pain or discomfort * Periods may become heavier and painful * It does not offer protection against infection * Threads may be felt by the male Copper ones may cause periods to become heavier and more painful. The commonest switch is from the pill to this, and pill users aren’t used to having proper periods so this may seem worse than it might do otherwise. Morena is good if you already have heavy periods however.

Answer 131

* Miscarriage if left in situ if a pregnancy * Ectopics? * May be expelled * The uterus may be perforated Risks are small. The most common cause of failure is if already pregnant when it is fitted, it is best to take them out. Although in doing so this could cause miscarriage it is more likely if it's left in. Ectopic pregnancy – not true because it is so protective against all types of pregnancy, but if you do have a woman with a coil and is pregnant need to exclude ectopic first, more likely in the proportions but overall less likely cause probes not going to be pregnant. Most complications related to insertion – to be put in all the person can see is the cervix. It has to be pushed through to sit right at fundus. If doesn't get in far enough it will be expelled within first few days usually. Too far and it will go through and have to be found in abdomen. To fit it accurately the practitioner needs to know the version of uterus to get angle right. The non pregnant uterus wall is soft muscled and about 0.75 cm thick so very easy to go through. We generally know this has happened because they come back pregnant, uh oh!!

Answer 132

- current pelvic inflammatory disease - suspected or known pregnancy - unexplained vaginal bleeding - abnormalities of the uterine cavity These people should not be fitted!

Answer 133

MALE - Man in control - Protects against STIs - No serious health risks - Easily available (free at family planning clinics) FEMALE - Woman in control - Protects against STIs - Can be put in in advance and left inside after erection lost - Not dependent on male erection to work

Answer 134

- Last minute use - Needs to be taught - May cause allergies - May cause psycho sexual difficulties - Higher failure rate among some couples - Oily preparations rot rubber FEMALE - Obtrusive - Expensive - Messy - Rustles during sex - Uncertain failure rate

Answer 135

``` Diaphragm Caps • Made of latex • Fit across vagina • Sizes 55-95mm in 5cm jumps • Must be used wit spermicide and left in at least 6 hours after sexual intercourse ``` ``` Suction Caps • Made of plastic • Suction to cervix or vaginal vault • Different sizes • Must be used with spermicide and left in 6 hours or more ``` Cervical caps are not used frequently anymore. The diaphragm caps are more frequently used. They form a dome oppositely under the cervix to how you may think. They have to be used with spermicide and can be put in in advance. There is a six hour limit with the spermicide.

Answer 136

Diaphragm Caps - Woman in control - Can be put in in advance - Offers protection against cervical dysplasias - Perceived as “natural” Suction Caps - Suitable for women with poor pelvic floor muscles - No problems with rubber allergies - Very unobtrusive - Woman in control

Answer 137

Diaphragm Caps - Needs to be taught - Messy - Higher failure rate than most other methods - Higher UTI - Higher candiasis Suction Caps - Needs an accessible and suitable cervix - Higher failure rate than diaphragm - Not easy to find experience teacher

Answer 138

* 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 reach 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 1/3 will get pregnant which isn’t bad. Ovulation can be predicted if there is a regular cycle.

Answer 139

* Temperature * Rhythm * Cervix position * Cervical mucus * Persona * Lactational amenorrhoea (LAM) Persona is a urine test which is quite expensive.

Answer 140

- Non medical - Can be used in 3rd world - Allowed by the catholic church - Can result in closeness of understanding between partners

Answer 141

- Failure rate heavily user dependent - Requires skilled teaching - May require cooperation between partners - May involve limiting sexual activity - Can cause strain

Answer 142

* Postcoital pills * Up to 72 hours after unprotected sexual intercourse (UPSI) * Schering PC4 – prevents 3 out of 4 pregnancies which would have occurred Levonelle: prevents 7 out of 8 pregnancies elleOne: (ulipristal) – similar Copper bearing IUCDs – up to 5 dyas after presumed ovulation or 5 days after one single episode of UPSI at any time of the cycle. Failure is extremely rare. Now up to five days as implantation can't have worked within five days. Legally anything over five days is abort efficient. Below five days is legally contraception. Not merena for emergency contraception… Only copper.

Answer 143

Levonelle 2 consists of 2 tablets each containing 750 micrograms of Levonorgestrel. 1.5mg is one dose. The earlier it is taken, the higher the effectiveness. PC4 • Lower failure rate in 1st 24 hours • Causes nausea and vomiting in many women • Contraindicated during focal migraine attack Levonelle 2 • Lower failure rate in 1st 24 hours • Very little nausea • Only contraindicated in women taking very potent liver enzyme medication (anti TB) elleOne – 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 144

PC4 and Levonelle 2 - Act by postponing ovulation in 1st part of the cycle – so beware! - Act by preventing implantation in 2nd part of the cycle?? Copper IUCDs - Copper kills sperm in 1st part of the cycle - Device prevents implantation in 2nd part of the cycle The copper coil is the best emergency contraception, and it almost never fails. It can be used up to 120 hours after when you expect them to ovulate if you believe them about them not lying to you and have a reliable cycle and reliable dates and this is the only time you could go a bit over 120 hours.

Answer 145

We can clip off the fallopian tubes. This takes about 10 minutes to do but it is still not completely reliable. Male clips can also be done, but even then 1/2000 will fail. They are easier, safer and more reliable to do men clip then women.

Answer 146

* Produce sperm and store it * Produce hormones which regulate spermatogenesis * Lie in scrotum outside body cavity… optimum temperature for sperm production 1.5-2.5*C below body temperature. Overheating of testes reduced sperm count. * Well-vascularised, well-innervated * Normal volume of testis approximately 15-25ml

Answer 147

* Tubules lead to an area on one side called rete * Rete leads to epididymis and vas deferens * Testis is 90% seminiferous tubules, site of spermatogenesis * 600m long in each testis! Tubules are tightly coiled Each lobule contains a tightly curled up tube. There are two or three hundred of these, each containing 400-600 seminiferous tubules. That’s nearly a mile of tubules in the testes!!

Answer 148

Spermatogonia are male stem cells that can divide mitotically to replenish themselves. Also commit to meiosis. They nestle between sertoli cells and move towards the lumen as they develop into cells. Once in the lumen they move along the seminiferous tubule until it gets to the rete testis. It then ends up in the epididymis. Leydig cells are the testosterone producing cells

Answer 149

* 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 Sertoli cells form tight junctions between each other. Tight junctions close behind and infront of sperm. They were therefore in an adluminal compartment and have an outside world outside of the testis. As the sperm are developing they are in an adluminal compartment. They are highly specialised with growth factors and signalling molecules etc

Answer 150

There is a blood testes barrier, similar to the BBB. The immune system therefore never sees the inside of the testes. When the vas deferens is snipped in hysterectomy the sperm are shown to the immune system for the first time, and the man might make antibodies to his own sperm. Therefore, this may decrease the effectiveness of reverse hysterectomy and cause sub-fertility

Answer 151

* Walls of tubule made up of tall columnar endothelial cells sertoli cells * Between these lying on the basement membrane are primary germ cells or spermatogonia * Spaces between the tubules are filled with blood and lymphatic vessels, leydig cells and interstitial fluid

Answer 152

There is a new cycle approximately every 16 days, the entire process takes approximately 74 days. 1. Mitotic proliferation of spermatogonia 2. Meiosis and development of spermatocytes 3. Spermiogenesis, elongation, loss of cytoplasm, movement of cellular contents Movement into the lumen is controlled by sertoli cell secretions. Factors produced by sertoli cells are required for development. The main thing is that the whole process seems to occur in stages. They replenish themselves by dividing mitotically remaining diploid. A small proportion of them end up committed to undergoing meiosis and when this happens they are then called spermatocytes, not spermatogonia – they are all undergoing meiosis I and II. When they have completed meiosis they become spermatids. The rest of the development is them becoming sperm – they lose their cytoplasm, grow their tail, etc.

Answer 153

* 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 converts androgens to oestrogen. * FSH establishes a quantitatively normal Sertoli cell population, whereas androgen initiates and maintains sperm production. If we ever have to measure testosterone in a lab we need to distinguish between free and bound testosterone. Testosterone still has feedback to reduce it, as it does in the female.

Answer 154

* 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 the sperm into epididymis, vas deferents and penile urethra, expulsion of the glandular secretions * Parasympathetic control: erection and evacuation of urethra

Answer 155

* 300 million sperm produced per day on average: 3500 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% is lost before reaching the 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, bulbourethral gland combined with epididymal fluid

Answer 156

The bulbourethral gland produces a clear viscous secretion high in salt, known as pre-ejaculate. This fluid helps to lubricate the urethra for spermatozoa to pass through, neutralising traces of acidic urine

Answer 157

The 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 the vagina

Answer 158

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 500-1000 times that in the blood is antibacterial

Answer 159

A mature sperm is kind of a missile. It has haploid DNA in head. Sperm is the smallest cell in body and the egg is the largest. All the machinery needed is in the egg. The spermatids have mitochondria to produce lots of energy for swimming but even they don't get into the egg or are discarded by the egg. All mitochondria are identical to your mothers, and all you get from father is the haploid DNA.

Answer 160

Behind the sperms head is a mitochondrial sheath producing a huge amount of ATP to be used as energy. That energy is used to flick the tail and this happens by nine pairs of fibres with two in the middle turning all the way down the length of the sperm tail. There are pairs of strings going all the way down it. These cause the tail to flap around and that is how the sperm swims. This is the Axoneme.

Answer 161

The acrosome is a bag over head of sperm full of enzymes and as spermatids approaches egg it bursts and the enzymes cut through surface of egg so the sperm can get their head right onto surface and fuse with it.

Answer 162

If you take freshly ejaculated sperm and put it on egg they won't be able to fertilise it, they have to undergo two processes. The first thing taking between four and eighteen hours is they change some of the constituents of the membrane this is called capacitation – don't want the sperm getting straight in the female and then into uterus and exploding prematurely, the bursting of the bag and releasing of the contents and the fusion etc is called the acrosome reaction.

Answer 163

* Prostatic and seminal vesicle secretions comprise seminal fluid which coagulates. Prevents loss, later liquefied. * Movement through the cervical mucus removes seminal fluid, abnormally morphological sperm and cellular debris.

Answer 164

• Cervical mucus is less viscous in the absence of progesterone allowing sperm to pass. • Sperm can inhibit 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 165

• The passage through the uterus is not well understood, currents set up by the uterine or tubal cilia may have a role. • Chemoattractants released from the oocyte cumulus complex may have a role in attracting the sperm. Sperm become hyperactivated. Forceful tail beats with increased frequency and amplitude mediated by Ca2+ influx via CatSper channels

Answer 166

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 and changes in membrane composition must occur before the acrosome reaction can occur

Answer 167

Acrosome reaction occurs in contact with the cells surrounding the egg; the acrosomal membrane on the sperm head fuses releasing enzymes that cur through the outer layers of cumulus surrounding the egg. Acrosin bound to the inner acrosomal membrane digests the zona pellucida so the sperm can enter

Answer 168

• 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. • Oocytencumulus complex extruded out and caught by fimbrae of uterine tube. Theca and granulosa become mixed

Answer 169

Progesterone - Makes the endometrium secretory and receptive to implantation - Supressed cilia into uterine tubes one oocyte has already passed - Makes cervical mucus viscous again to prevent further sperm penetration Oestradiol - Helps to maintain endometrium in luteal phase (causes proliferation in follicular phase)

Answer 170

- If fertilisation does not occur, CL has an inbuilt finite lifespan of 14 days - Regression of CL essential to initiate new cycle - Fall in CL-derived steroids causes inter-cycle rise in FSH - Cell death occurs, vasculature breakdown, CL shrinks - Over time it becomes a corpus albicans

Answer 171

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

Answer 172

protect egg, secrete mucus matric projections into plasma membrane.

Answer 173

secreted by egg around projections. at LH surge projections withdrawn

Answer 174

1st meiotic division resumes and completed

Answer 175

1. Sperm release enzymes to cut through cumulus and bind to ZP triggering acrosome reaction 2. Acrosome reaction, sperm enzymes cut through ZP and sperm fuses with plasma membrane 3. Sperm taken in by phagocytosis, tail and mitochondria left behind 4. Movement of cortical granules in egg and release of contents hardens the oocyte coat and prevents polyspermy

Answer 176

After meiosis I the oocyte has 23X chromosomes, but 2 copies of each chromosome arranged as sister chromatids. The sperm binds to the ZP before penetrating it and fusing with the oocyte membrane. This causes and increase in Ca2+ triggering the completion of meiosis II expelling the second polar body. The sperm nuclear membrane breaks down, the chromatin decondenses and chromosomes separate. 4-7 hours after fusion the two sets of haploid chromosomes become surrounded by distinct membranes forming pronuclei. 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 177

• The fertilised egg has 2pronuclei. This is the first sign of fertilisation. • The developing embryo contains 6-8 cells 3 days after fertilisation. Five days after fertilisation it is called a blastocyst and has approximately 100 cells

Answer 178

The myometrium consists of 3 layers of smooth muscle. - Outer longitudinal fibres - Middle figure of eight shaped fibres - Inner circular fibres The fibres are organised so that contraction causes an increase in uterine pressure forcing and contents towards the cervix. It acts as a natural ligature to prevent blood lost

Answer 179

* Myometrium is spontaneously active – myogenic * Spontaneous contractions are highly sensitive to neurotransmitters, hormones (oestrogen and progesterone) * Progesterone inhibits contraction * Oestrogen induces contraction * Remember: increase in 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

Answer 180

- Myometrium is innervated by sympathetic nerves (not parasympathetic) - Myometrium contains both alpha and beta receptors - Stimulation of alpha produces contraction - Stimulation of beta2 produces relaxation

Answer 181

1. Myometrium is myogenic – ‘pacemaker’ mechanism 2. Myometrium contains 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 cells through gap junctions – made of connexion proteins 4. Uterus behaves as a ‘syncytium’ – electrical connected cells 5. These mechanisms are affected by hormones eg oestrogen increase expression of gap junctions to promote contraction

Answer 182

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

Answer 183

* Similar to other smooth muscle tissue * Contraction is caused by an increase in ]Ca2+]i * Increase force production is proportional to an increase in [Ca2+]i * Each action potential will cause in incremental increase in [Ca2+]i but also there are mechanisms lowering [Ca2+]I – eg Ca extrusion. Changes in [Ca2+]I will be the resultant effect of these processes 1. Low concentrations of stimulants of ICCs increase slow wave frequence producing increased frequency of SMC contractions 2. Higher concentrations increased frequency of Aps on top of slow waves (ie peak [Ca2+]I increased) producing both increased frequency and force of SMC contractions 3. Higher concentrations still increased plateau of slow wave producing prolonged sustained SMC contractions 4. Large concentrations hypertonus where there is incomplete relaxation – Ca extrusion processes not effective

Answer 184

* 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 increased oxytocin release, increased oxytocin receptors, increased gap junctions * Oxytocin is only effective at term

Answer 185

- low concentrations of syntocinon/oxytocin increase frequency and force of contractions - high concentrations cause hypertonus - may cause fatal distress

Answer 186

- induction of labour at term; doesn't soften cervix | - treat/prevent postpartum haemorrhage

Answer 187

* PGE2 (vasodilator) and PGF2alpha (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 increase frequency/force of contractions, increased hap junctions, soften cervix, increase synthesis of oxytoxin * PGs are effective in early and middle pregnancy * Dinoprostone (PGE2), carboprost (PGF2aloha) are agonists

Answer 188

- induction of labour; before term - induce abortion - postpartum bleeding - softening the cervix concern: dinoprostone can cause systemic vasodilation

Answer 189

* Ergot – fungus that grows on some cereals (eg rye) and grasses * Contains array of potent agents eg 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 alpha-adrenoceptors, 5-HT receptors? Uses - post-partum bleeding – NOT induction

Answer 190

these drugs may be used in premature labour - beta1-adrenoceptor stimulants - Ca channel antagonists - oxytocin receptor antagonists - COX inhibitors

Answer 191

* Relax uterine contractions by a direct action on the myometrium * Used to reduce strength of contractions in premature labour, delay delivery by 48 hours – allow corticosteroids to be given to enhance lung maturation * May occur as a side effect of drugs used in asthma

Answer 192

eg nifedipine (used in hypertension) or magnesium sulphate

Answer 193

eg NSAIDs decreased prostaglandin production - why NSAIDs are useful to treat dysmenorrhoea and menorrhagia

Answer 194

* Increase in size of the uterus * Increased etabolic requirements of the uterus * Structureal and metabolic requirements of fetus * Removal of fetal waste products * Provision of amniotic fluid * Preparation for delivery and puerperium

Answer 195

- Energy balance - Respiratory system - Cardiovascular system - Gastrointestinal system - Urinary system - Endocrine system

Answer 196

* Maternal steroids: placenta takes over ovarian (CL) production around week 7 * Placental peptides: hCG, hPL, GH * Placental and fetal steroids: progesterone, oestradiol, oestriol * Maternal and fetal pituitary hormones: GH, thyroid hormones, prolactin, CRF Essentially the main ones are steroids and peptides. hCG at the beginning produces hPL which is the equivalent of GH. CL stops functioning around week 7 and there are different sorts of oestrogens. There is an increase in thyroid function to up the metabolic rate. The woman will start producing prolactin which is involved in breast development, and CRF which is a pituitary hormone

Answer 197

* Renin/angiotensin system – fluid balance, BP control * Respiratory centre * GI tract * Blood vessels – massive vasodilation when pregnant * Uterine myometrial contractility

Answer 198

12.5-13kg ideally keep to less than 13kg: failure to gain or sudden change needs monitoring there is extra fluid in the intra and extravascular compartments

Answer 199

Need to increase energy: - Output: to cope with increased respiration and cardiac output - And storage: for fetus, for labour and puerperium Gain in fat and protein stores 4-5kg: - Increased consumption and reduced use - Mainly laid down in anterior abdominal wall - Utilised later in pregnancy and puerperium

Answer 200

350 kcal/day mid gestation 250 kcal/day late gestation 75% fetes and uterus, 25% respiration (H&L)

Answer 201

* Need increased levels in the blood in the second trimester * Active transport across placenta as fetal energy source * Fetus stores some in the liver 1st Trimester Maternal Reserves Pancreatic beta cells increase in number = plasma insulin increases so more into tissue (laid down as stores and used by muscle), fasting serum glucose decreases 2nd trimester fetal reserves hPL causes insulin resistance ie less glucose into stores = increae in serum glucose = more crosses placenta but can cause diabetes Doesn’t just diffuse across the placenta easily. The baby will only function well on glucose – need to keep it in aerobic respiration. The mother needs to get ore sugar across the placenta as well as providing for herself. Women become insulin resistant when pregnant and this is completely normal, they are not diabetic. They get around this by increasing insulin level and overcome the resistance. They get more resistant and the pregnancy goes on. As it gets worse and worse there is a slight tendency for serum sugars to go up a bit and then there is a better concentration gradient to get it across the placenta. This still doesn’t make you diabetic! But… if they are already susceptible this could tip you into diabetes

Answer 202

Oestrogen and progesterone – mineralocorticoid manner. We retain sodium in the kidneys and drag water with it. 80-90% of women will get swollen ankles by the end of their pregnancy. We have to be careful when giving women IV fluids because of retention

Answer 203

Oxygen consumption is increased. With all the physiological changes we get increased sensitivity it CO2. The natural tendency in this situation is to over breathe to get rid of the excess CO2. The women breathe longer and deeper per breath. The blood gases will show high pO2 and low CO2. This is good because it means that when the blood reaches the placenta the O2 can go across easily as there is a high concentration gradient, and the CO2 can get back into the mothers blood because again there is a high concentration gradient. This will occur at around 3 months of pregnancy

Answer 204

The woman will make more red cells. If we check the concentration, the red cell mass will have gone up, divided by the Hb content which will have gone up even more, meaning that the red cell volume goes down. The gut gets better at absorbing iron as more is needed for both the mother and the baby. The reference rage of anaemia changes in pregnancy. However, anaemia should still be investigated as you normally would, but it is normal for the concentration to fall – you just want to know the cause. White cell count increases in pregnancy and platelet levels fall by 10-15% in pregnancy. Because of all the extra oestrogen, women make more clotting factors in the liver (2,7,9,10) which makes you hypercoagulable

Answer 205

Expanding uterus: - Pushes heart round - Changes in ECG and heart sounds Increased cardiac output: - Increased heart rate and stroke volume - Begins as early as 3 weeks to maximum of 40% at 28 weeks - For maternal muscle and fetal supply There is high volume but low pressure in the system. We end up with changes in an ECG reading. Everything has shifted to the left in the heart a little bit. We can get flow murmurs due to the high volume. The cardiac output foes up by 40-50% (plasma volume has increased) – stroke volume has increased. Heart rate may go up a little bit – not normal if it is above 90 though. These effects are maximal by about 28 weeks. For people with underlying cardiac disease, pregnancy can show this up, as the heart can’t cope with the increased stroke volume – it is exacerbated

Answer 206

- Uterus - Placenta - Muscle - Kidney - Skin Blood pressure will decrease, therefore the peripheral resistance goes down loads. This allows the blood to go everywhere it needs to. Principally progesterone is involved in this, causing a massive relaxation.

Answer 207

Progesterone causes a general smooth muscle relaxation – so pregnant women get heartburn and constipation

Answer 208

Supplementation is advised of 400micrograms/day up to week 12. Deficiency is linked to spina bifida – neural tube defect. ( folic acid --> DNa production, growth, blood cels --> uterus, placental, fetus) Folic acid is very important in DNA production. Women are advised to take supplements 3 months before they even come off the pill to get pregnant etc. However 50:50 pregnancies and planned vs unplanned, so this isn’t always possible

Answer 209

- Swollen kidneys, hydronephrosis, hydroureters - Floppy untoned urinary system - This is normal - Pregnant women also pee a lot more – extra flow going through kidneys 40-50%, therefore urea and creatinine are really low (if they are high, or ‘normal’ there is something wrong) - Pregnant women are more prone to UTIs because there is more stasis in the system The uterus enlarges within the pelvis and compresses the bladder (increased urinary frequency), the uterus then lifts out of the pelvis which relieves this, and then the baby’s head descends onto the bladder again, reducing its volume

Answer 210

There is a huge increase in muscle mass (x20), a hug eincrease in blood flow and the placenta and uterus are 1/6 of the total increase. There is a hug eincrease in muscle VOLUME, not muscle cells. This is called uterine hypertrophy. The uppr part of the cervix is incorporated from 34 weeks. The lower uterine segment is formed from the isthmus. We do lower segment caesareans because there is less vascularity in this area as it is thinner, more fibrous and less muscular

Answer 211

* Primary function is to retain the pregnancy * Increase in vascularity * Tissue softens and turns bluer from 8 weeks changes in connective tissue, begins gradual preparation for expansion * Proliferation of glands mucosal layer becomes half of mass, great increase in mucus production, protective… ie anti-infective We want a firmly closed cervix to act as a barrier to ascending infection from the vagina. The uterine myometrium is quiescent and doesn’t contract. In labour we want the reversed situation. We want an active myometrium which will squeeze the baby does, and to make the cervix soft to open up and let it out. Progesterone makes the thick mucus plug on the cervix, like in the pill. This acts as part of the anti-infective barrier, keeping the baby in a sterile environment. When the woman goes into labour prostaglandins act at the cervix so that it becomes soft, the collagen is broken down and it will open

Answer 212

* Dramatic and rapid fall in steroids on delivery of the placenta * Most endocrine-driven changes return to normal rapidly * Urerine muscle rapidly looses oedema but contracts slowly: never returns to pre-pregnancy size * Removal of steroids permits action of raised prolactin on breast As soon as the baby is delivered, the steroid levels plummet. Everything is back to normal by 6 weeks, many things returning to normal within hours/days. The uterus will never go quite back to the size it was before the first baby however. Prolactin is also allowed to work on the breasts for breastfeeding following delivery due to the removal of steroids

Answer 213

cells of blastocyst that invade endometrium and myometrium (D5-6), secrete betaHCG

Answer 214

that which becomes the placenta

Answer 215

layer that becomes the amniotic sac

Answer 216

The egg and sperm meet in the ampulla of the fallopian tubes. The cilia in the tubes waft it towards the uterus then. At 8 cells big it is called a morula (can no longer count the individual cells). The cellular component moves to one side and we get formation of the blastocyst around day 5. There is a thin membrane around it. The blastocyst has to hatch out of the zona and on cell to cell contact with the endometrium it will implant. If this happens too early it wont occur, and if it happens too late it will result in ectopic pregnancy

Answer 217

* Free living blastocyst reliant on cytoplasm inherited from the oocyte (maternal) * Histiotrophic; blastocyst is bathed in uterine secretions * Haemotrophic; vascular contact between mother and foetus

Answer 218

* Day 6 – “window of implantation” (24-36hours) * Day 10 – trophoblast produces betaHCG * BetaHCG – “maternal recognition of pregnancy” * Maintenance of the corpus luteum – progesterone production * Decidualisation under progesterone * Vital until placental steroidogenesis established If the timing is wrong, nothing will happen. BetaHCG is almost identical to LH and it binds to the corpus luteum to keep it alive. The first 7 weeks of pregnancy are completely dependent on the ovarian production of steroids - -> apposition - -> attachment - -> invasion

Answer 219

* Narrow window of time when endometrium receptive to the embryo * Key balance of progesterone and oestrogen * ‘come hither’ LIF/EGF/IL 11 * ‘go away’ Muc1

Answer 220

- basis of urinary pregnancy tests – βsubunit (qualitative) - serum βHCG (quantitative) useful for monitoring early pregnancy complications eg ectopic pregnancy, miscarriage It is maximal by 9-11 weeks, this is because we only really need it for the first 7 weeks. Serum βHCG from the blood is used to measure how much

Answer 221

- maximal by 9-11 weeks - maintains corpus luteum - continues progesterone production - CL not necessary beyond 5-6 weeks The level almost doubles every other day. When it has completed its job at around 7 weeks it goes back down. However, the level doesn’t go back to 0 until the pregnancy is over. If the level is slow rising, the pregnancy might be ectopic

Answer 222

* Steroidogenesis: oestrogens, progesterone, HPL, cortisol * Nutrition: oxygen, CHO, fats aminoacids, antibodies, vitamins, minerals * Removal of waste: CO2, urea, NH4, minerals * Barrier: bacteria, viruses, drugs, etc Rubella gets across the placenta easily and can cause harm.

Answer 223

* Huge maternal uterine blood supply – low pressure * Huge reserve in function * Huge surface area in contact with maternal blood * Highly adapted and efficient transfer system

Answer 224

* Differentiation of the trophoblast * Trophoblastic invasion of decidua and myometrium * Remodelling of the maternal vasculature in the utero-placental circulation * Development of foetal vasculature within villi Synccytiotrophoblasts are the first primary layer that invades. The cytotrophoblast is secondary and follows with cells. Third is the mesoderm, the extraembryonic mesoderm which derives all the blood vessels. These are the three layers of invasion out into endometrium

Answer 225

There is a transfer between maternal and foetal blood occurring across the membrane. It is sort of like a bowl of maternal blood with fingers going into it, with layers o gloves and the exchange occurs across the glove. They branch. This increases surface area in contact with the maternal blood. It moves straight across and the layer is one cell thick. In theory we shouldn’t get any mixing of foetal and maternal blood. In reality however there is a little bit of mixing

Answer 226

- homeostasis - temp, fluid, ions - vital for development of certain structures e.g. limbs, lungs - protection - physical and barrier e.g. ascending infection

Answer 227

These are the ectodermal, endodermal and mesodermal. The ectodermal layer gets cranial and caudal enlargement of the cord and this drags the amniotic sac with it, pulling it round. As the fold gets more and more, the yolk sac disappears up inside so the sac can come the whole way round and that is how the baby ends up inside the sac

Answer 228

* Miscarriage – 15% (40%?) pregnancies! * Ectopic pregnancy * Hydatidiform mole – get excessive trophoblastic activity, get far too much placenta, some can be cancerous * Transfer of other substances – drugs, toxins, infections * Net effect of placental insufficiency is the baby is underperfused and gets growth restriction * Failed trophoblast invasion and remodelling * Placental insufficiency10% * Pre-eclampsia – 5% pregnancies * Expressive invasion * Placenta acreta, percreta * Choriocarcinoma

Answer 229

* Polyhydramnios – excessive fluid in the cavity * Oligohydraminios * Diabeti – high sugars, passed across to baby, baby produces a lot of insulin, pee out a lot, amniotic fluid is essentially foetal urine. If they produce less urine they are not likely to be growing properly. * Premature rupture of membranes – can possibly be a result of ascending infection if the cervix has not acted as a god barrier

Answer 230

- progesterone - oestrogen - cortisol

Answer 231

* Placental from 6-9 weeks onwards * 200mg/day by late pregnancy * decidualisation (CL) * Smooth muscle relaxation – uterine quiescence * Mineralocorticoid effect – cardiovascular changes * Breast development

Answer 232

* E3>E2>E1 (oestriol>oestradiol>oestrone) * Feto-placental unit * Rely on androgens form foetus and maternal adrenals * Development of uterine hypertrophy * Metabolic changes (insulin resistance) * Cardiovascular changes * Breast development In the oestrogens a hydroxyl group is added each time, each time with it getting more potent. We cant make oestrogen without androgens

Answer 233

- Similar to GH - Metabolic changes – insulin resistance - Possibly some role in lactation

Answer 234

- predominantly maternal anterior pituitary - increases throughout pregnancy - breast development for lactation

Answer 235

period of time from changes in menstrual pattern to menopause

Answer 236

the permanent cessation of menstruation due to loss of ovarian follicular function (amenorrhoea for 12 months)

Answer 237

no consistent definition. a period of changing ovarian function which precedes the menopause by 2-8 years

Answer 238

* Initially reduced cycle length due to reduced follicular phase * Mean 4 years prior to final menstrual period: some women experience irregular periods, with episodes of amenorrhoea * Around year before menopause, or later, hot flushes and disturbed sleep due to declining oestrogen levels * Dry vagina * Some women have no menstrual irregularity prior to the menopause * Impaired fertility

Answer 239

- reduced follicle count - non or few at menopause - reduced granulose cell number - reduced granulose cell function - increased chromosomal abnormality of oocyte

Answer 240

increased follicular death (apoptosis), ovarian environment: eg smoking reduces age at menopause by mean of 2 years and shorter transition

Answer 241

anti-mullerian hormone declines, follicle stimulating hormone increases, increased follicular recruitment

Answer 242

- 30% decrease in granulosa cells in older women c/w younger - decrease inhibin B production from granulosa cells in follicular phase (allows higher FSH levels) - anovulator cycles lead to decreased inhibin A normally produced in luteal phase (allows higher FSH) - decreased FSH receptors and sensitivity impairs recruitment dominant follicle - impaired secretion growth factors and other signalling pathways, survival factors, oestrogen and progesterone

Answer 243

Shortened cycle (early MT): decline in inhibin B production (granulosa cells) leads to elevated FSH in follicular phase, earlier elevated levels of oestrogen production and earlier LH surge Delayed/absent ovulation (late MT): oestrogen production is stimulated earlier in the cycle by elevated FSH but may not reach levels high enough to induce GnRH surge (due to impaired granulosa cell function). Consequently, ovulation delayed or doesn’t occur. Also relative FSH insensitivity due to fewer receptors in granulosa cells. Fewer follicles to recruit. No inhibin A and so FSH rises. Heavier periods: longer oestrogen stimulation of endometrium – oestrogen levels may be higher than in women ages under 35. Breast tenderness: transitory increases oestrogen Hot flushes: decreased oestroge levels disturbance serotonin levels. Resets thermoregulatory nucleus and leads to heat loss.

Answer 244

- AMH levels first sign of declining ovarian function - Inhibin B declines ~2 years before FMP - FSH levels variable each cycle but increase towanrds menopause - LH increases but later in menopause - Oestrogen levels fall close to the menopause - Adrenal ad ovarian androgen levels decline with age (from 20s) but not related to menopause - No progesterone production after menopause

Answer 245

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

Answer 246

- smoking status - ethnicity - maternal age - several candidate genes - surgery/chemotherapy

Answer 247

- Ovarian volume as proxy for number of follicles (or antral follicle count) - Response to ovarian stimulation – antral follicle count - Anti-mullerian hormone - Useful for planning family/or including older women in IVF * Removed ovaries * Re-implanted fragments of stimulated ovary near fallopian tube * Stimulated follicular development * Removed eggs * 27 women – 1 live birth * hippo signalling system * Akt stimulator treatment

Answer 248

anti-mullerian hormone

Answer 249

progesterone

Answer 250

• Oestrogen 80% efficacy at reducing hot flushes. Lower doses 60% efficacy so worth starting with low dose • Patient centred – woman should be clear about the indication, the risks and benefits, and have a plan for review • Consider individual risks • Always use progesterone for 13 days for women with a uterus • Need contraception is less then one year amenorrhoea • Start with low doses to minimise unwanted effects, such as mastalgia, nausea • Risks are low for short term use --> can increase risk of alzheimers, urinary incontinance, ovarian cancer

Answer 251

* 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 252

hormone replacement therapy

Answer 253

- 70% treatment of hot flushes - 58% prevention osteoporosis - 20% for prevention heart disease - 8% prevent memory loss - 12% improve sex - 23% prevent irritability - 38% feeling tired - 41% at suggestion of the doctor

Answer 254

* bisphosphonates * ? raloxifene (SERM) * calcium and vitamin D * strontium * other agents currently being investigated: teriparatide (a peptide fragment of parathormone), simvastatin, leptin, phyto-oestrogens and manipulation of RANKL gene, anti-oxidants

Answer 255

- smoking - physical activity - BMI and nutrition - Cardiovascular risk management - Mammography and cervical cytology

Answer 256

- Micronised progesterone vs synthetic progesterones - RCTs looking at ischaemic heart disease in women around the menopause - ‘critical period’ theories for IHD and Alzheimers… but… could we ever precisely predict risks for individual women? - Will another RCT looking at long term outcomes be mounted?

Answer 257

* Testes and adrenal cortex secrete androgens – steroid sex hormones * Adrenal cortex (ACTH), and ovary * Testes (leydig cells of testes) secrete testosterone * Testosterone is synthesised from cholesterol in leydig cells

Answer 258

Androsterone and its 5β-isomer, etiocholanolone, are produced in the body as metabolites of testosterone. Androsterone is an inactive metabolite of testosterone. In circulation testosterone can bind to sex steroid-binding globulin, albumin

Answer 259

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 that 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 260

A 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 and may play an important role in the regulation of the hypothalamic-pituitary-gonadal axis during childhood and puberty. Overall, inhibit down regulates FSH synthesis and inhibits FSH secretion

Answer 261

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

Answer 262

Differentiation of some male foetal tissues requires testosterone and DHT - Testosterone internal genitalia (epididymis, vas deferens, seminal vesicles and prostate) - DHT acts on external genitalia to develop into male form: enlargement of the penis and prostate at puberty, facial hair and acne, temporal hairline recession Hairline in children and adults: • In females, these androgens are absent, so the external genitalia develop into female form • The tissues need the receptors to respond, otherwise testicular feminization (genetic males appear as females) develops - height - muscularity - bone growth - deep voice - pubic hair

Answer 263

In many cases, several androgens (e.g. testosterone, nandrolone, oxymetholone and stanozolol, etc) are used for prolonged periods and their continuous use can cause: ¥ Hypertension and oedema: testosterone and other anabolic steroids such as nandrolone, stanozolol have calcium, sodium, and water-retaining actions ¥ Cholestatic jaundice: anabolic steroids (nandrolone, stanozolol) may lead to liver cancer ¥ Suppression of gonadotrophin (FSH & LH) release with testicular regression and reduced spermatogenesis ¥ Virilisation; hirsutism; male pattern baldness; acne ¥ Premature closure of epiphyses of long bone in boys ¥ Gynaecomastia – due to conversion of testosterone to oestrogens by aromatase

Answer 264

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 excel production of androgens

Answer 265

* Used by body builder and athletes * Large doses may be effective in increasing muscle mass/athletic performance in some individuals * All anabolic steroids virilise * Attempts to separate the anabolic form virilising effects of anabolic steroids have been unsuccessful

Answer 266

- Decreased testicular size and sperm count - Hepatotoxicity with cholestasis, heptatitis or hepatolcellular tumours - Increased LDL and decreased HDL vascular disease - Changes in libido, regression of testes with suppression of spermatogenesis - Increased aggression - Weight gain - Acne

Answer 267

• Testosterone is converted in most target cells (except in muscle) to dihydrotestosterone (DHT) • DHT and testosterone bind to same receptor, but testosterone-receptor complex is less stable • DHT formation allows amplification of the actions of testosterone - Treatment of prostate cancer makes use of this pathway - DHT promotes hair loss, so male pattern baldness may be treated with 5alpha-reductase inhibitors

Answer 268

LH and FSH

Answer 269

5alpha-reductase converts testosterone to DHT - Type I 5alpha-reductast: scalp and skin - Type II 5alpha-reductase: genital skin, prostate DHT is required for masculinization of external genitalia in utero. * Deficiency in 5aloha-reductase: testes develop, but without prostate; external genitalia resemble those of females (raised as girls) * Clitoris enlarges (“penis-at-12-syndrome”) * Increased LH and testosterone levels at puberty * Mutation in type II 5alpha-reductase male pseudohermaphroditism – common in parts of Dominican republic Inadequate metabolism of DHT may cause prostatic hyperplasia; acne, hirsutism??

Answer 270

failure to convert testosterone to DHT results in XY baby with female external genitalia. - May be raised as a girl until puberty - At puberty, increased testosterone causes the development of external male genitalia and secondary sexual characteristics - Some may adopt normal male role post-puberty

Answer 271

21-hydroxylase deficiency secretion of excess male hormones by the adrenal gland, causing CAH In the adrenal gland, cholesterol is turned into a precursor called pregnenolone, then several enzymes complete the production of aldosterone, cortisol, and androgens. Deficiency in 21-hydroxylase leads to inadequate amounts of aldosterone and cortisol (red). Other substances that do not need the defective enzyme are produced in excess (black). This enzyme deficiency is inherited and is the most common cause of congenital adrenal hyperplasia (CAH).

Answer 272

* Adrenal cortex produces androstenedione which can be converted to testosterone and DHT * Adrenal hyperplasia causes the secretion of excess male hormones virilisation with alteration of genitalia to male-type * for girls: ambiguous/female genitalia, and severe acne * for boys: premature puberty (deep voice, enlarged penis, small testes, pubic and axillary hair appear early) Cyproterone and androgen antagonists can be used. 17-ketoreductase converts androstenedione to testosterone 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

Answer 273

- low BP - lower sodium levels - higher potassium levels

Answer 274

- gonadorelin - can be given for CAh, but administration must be by pump and given intermittently to avoid desensitisation and down-regualtion

Answer 275

- goserelin - Mbuserelin - desensitise after an initial surge of LH and FSH release and act as antagonists - cause reduction in testosterone in the long term - prostate and breast cancers, and endometriosis

Answer 276

- cetrorelix - ganirelix - cause no initial surge in Lh and FSH, so better (used in IVF)

Answer 277

- LH mainly - Synthetic or from urine of pregnant women - Given I.M. for 3-6 months to stimulate testicular development in hypogonadism to initiate spermatogenesis or testicular descent (cryptorchidism) - Used with human menopausal gonadotrophin (FSH/LH -1:1) to induce ovulation

Answer 278

* Precocious puberty (testoxicosis) or delayed puberty: significant deviations from pubertal age (occurring either too early or too late), must be investigated and treated * Cryptorchidism (retained testes): 97% descend around birth and 99% by 1 year. Failure of testes to descend can potentially lead to testicular tumour formation and infertility drug treatment or surgical remedy * Initiate spermatogenesis, if it has occurred spontaneously at pubertal age * Androgen-insensitivity syndromes: impairs masculinisation of genitalia; secondary sexual characteristics fail to develop at puberty * Premature baldness: DHT is implicated in baldness. Inhibition of 5alpha-reductase maintains testosterone levels, which can result in regrowth of hair

Answer 279

* Testosterone: androgen deficiency, delayed puberty * Mesterolone (methyltestosterone): male infertility associated with hypogonadism * Danazol: an androgen derivative, but not converted to oestrogen – feedback inhibition of pituitary gonadotrophin and GnRH decreased release of LH and FSH in both sexes, has antioestrogenic and antiprogestongenic effects (inhibits testicular and ovary function directly)

Answer 280

delayed puberty (15-17 years); testes fail to produce adequate testosterone in response to LH (primary) or where there is a deficiency of pituitary hormones (FSH/LH) or pituitary dysfunction (secondary)

Answer 281

chromosomes abnormalities (eg Klinefelter’s (XXY) syndrome – deficient negative feedback at hypothalamic pituitary levels with consequent high levels of LH and FSH) - Treatment: testosterone (and GH); puberty may take 2 years to reach completion - Note that continuous administration of testosterone premature closure of epiphyses of long bones – so better to dose for 4-6 months, stop and assess to avid reducing final height

Answer 282

deficiency of hypothalamix/pituitary level – low levels of GnRH and also low levels of FSH and LH (eg kallman’s syndrome) - Treatment: five gonadorelin or LH and FSH – it may take months for their effects on spermatogenesis to develop in post-pubertal patients

Answer 283

A condition that describes a male born with at least one extra female chromosome. While some men may have no issues related to the syndrome, some may experience hypogonadism, reduced fertility or infertility, ↓or no facial hair, gynaecomastia, small penis and cognitive impairment, May be treatment: testosterone if the man wants more masculine appearance and reduction mamoplasty for those with gynaecomastia. IVF may be a good option to pursue for men who want to father children

Answer 284

inhibits peripheral androgen reeptors

Answer 285

- precocious puberty in boys - to suppress initial surge effects of goserelin and Mbuserelin - acne, hirsutism and virilisation in women

Answer 286

Enlargement of prostate in older men causes urinary obstruction. Urinary obstruction is painful

Answer 287

- Use 5alpha-reductase blocker – inhibits conversion of testosterone to DHT shrinkage of prostate - Finasteride has better utility as inhibits type II 5alpha-reductase - Dutasteride has unclear utility as inhibits types I and II of 5alpha-reductase Other agents for benign prostate hypertrophy: α1 blockers (tamsulosin, alfuzosin): acts to relax smooth muscle component of prostate

Answer 288

* Cyproterone acetate: inhibits peripheral androgen receptors * Prostatic hyperplasia or treat prostatic cancer * GnRH analogues (goserelin and buserelin) can be given continuously to suppress leydig cell function (desensitization and down-regulation of receptors decreased LH and FSH levels) – treat and manage prostatic cancer * GnRH antagonists (cetrorelix and ganirelix): block release of LH and FSH regression of leydig cells * Oestrogens (ethinyloestradiol and diethylstilbestrol): decreased androgen-dependent prostate cancer (local and metastatic cancers) * Anti-angdrogens: eg flutamide – compete with testosterone and DHT and blocks their action * Usegul for prostate cancer * 5alpha-reductase inhibitors: finasteride, dutasteride * suppress prostate cancer cells * inhibit androgen-dependent prostatic cancers

Answer 289

¥ Consistent inability to sustain an erection of sufficient rigidity for sexual intercourse ¥ 40-70 year olds; nerve damage, endocrine disease, depression, therapeutic/recreational drug use, atherosclerosis ¥ There may be insufficient blood flow to allow erection, and penetration Androgens have always been assumed to play a major role in male erectile function because: ¥ There is a decrease in serum testosterone levels with ageing in healthy men Ð But the decline in testosterone that occurs with ageing may not always produce erectile dysfunction. ¥ Castration usually causes a decline in sexual function ¥ Exogenous testosterone does not lead to an improvement in erectile function in those with erectile dysfunction ¥ Some patients with normal testosterone levels have erectile dysfunction and if given exogenous androgen therapy report improvement in erectile function. ¥ Erectile function is probably androgen-dependent

Answer 290

Treatment of exogenous androgens may produce clinical improvement in the signs of hypogonadism but may not improve sexual function. PDE5 inhibitors: eg sildenafil - Release of NO during sexual stimulation - NO activates guanylate cyclase (GC) which releases cGMP from GTP - cGMP causes the relaxation of smooth muscle lining of blood vessels (inflow of blood occurs) - tumescence (erection) - incidence of priapism is low - generally without effect until stimulation begins Side effects: headache, vasodilation, flushing, decreased BP, disturbances of colour vision due to inhibition of PDE6 in the retina; do not take with nitrate drugs

Answer 291

Sildenafil is a potent and highly selective inhibitor of PDE5 - blocks cGMP hydrolysis by occupying its active site - prolongs cGMP-mediated smooth muscle relaxation erection, but arousal/stimulation is important in its mode of action

Repro Flashcards

(317 cards)