22/3 Flashcards

Question

Misoprostol

Answer 1

Synthetic PGE1 and PGE2 receptor agonist - G-protein coupled reception. Reproductive organs: Collagenase activity causing breakdown within cervical stroma Myometrial smooth muscle contraction Reduction in cervical tone Gatroprotection Inhibits gastric parietal cell acid secretion Increases bicarbonate production

Answer 2

Misoprostol 800mcg Then Misoprostol 400mcg every 3 hours until the pregnancy has passed (Note 3 hours if no mife or if mife and 12-24)

Answer 3

Oral doxycycline 100mg BD for 3-7 days Rectal metronidazole 1g for one dose Amoxicillin 500mg TDS 5 days

Answer 4

Risk Factors RPOC Increased maternal age Raised BMI Prev CS (2 or more) Abnormal placentation Bleeding disorders > 20/40 Management Bimanual compression Uterotonics Oxytocin Misoprostol Carbeprost (Haemabate) Re-aspiration Intrauterine tamponade Senior/MDT review

Answer 5

Fetal material/amniotic fluid inadvertently enters the maternal circulation --> systemic inflammatory response and disseminated intravascular coagulation leading to cardiovascular collapse, acute hypoxia, major haemorrhage and end organ ischaemia Classic triad: hypoxia hypotension coagulopathy Management: CPR with anaesthetic and intensive care input

Answer 6

If no infection: Uterine size <14/40 Misoprostol 400mcg SL/V/B or 600mcg orally OR Uterine evacuation Uterine size >14/40 Misoprostol 400mcg SL/V/B every 3 hours OR Uterine Evacuation with Abx cover If infection present (unwell) Urgent surgical evacuation and abx cover Combination of ampicillin 0.5–1g every 6 hours, metronidazole 500mg every 8 hour and gentamicin 120mg daily

Answer 7

non-sensitised RhD-negative individuals From 12/40 med or any gestation surg Provided within 72 hours of the abortion <12/40 Minimum dose 250iu indicated within 72 hours Test for FMH not required 12-20/40 Minimum dose 250iu indicated within 72 hours Test for FMH not required After 20/40 Minimum dose 500iu indicated within 72 hours Test for FMH is required

Answer 8

Primordial germ cells undifferentiated stem cells that develop into gametes originate in endoderm of yolk sac (migrate to ridges wk5) undergo mitosis in gonad to become.. Primary ooctyes (gonadotrophin-independent) enter meiosis at wk12 - stop at prophase 1 single layer of flat granulosa cells --> primordial follicle Latent phase, then during repro years FSH and LH are produced in pulsatile manner Granulosa cells become cuboidal and increase in number. Gap junctions develop between granulosa cells and oocyte+granulosa cells. Secondary (gonadotrophin-dependent) FSH causes an increase in the number of granulosa cells --> promote differentiation of stromal cells into theca cells --> differentiate into two distinct areas: the theca interna (androgens) and the theca externa (support). Tertiary/ antral Formed when antrum (fluid filled spaces) appear. The antrum contain plasma as well as factors secreted by the granulosa cells (e.g. oestrogen and growth factors). Graafian As more fluid builds up and the antrum enlarges, the developing follicle is known as a graafian follicle.

Answer 9

Peptide Water-soluble

Answer 10

arcuate nucleus of the hypothalamus

Answer 11

LH --> theca cells: androstenedione and testosterone FSH --< granulosa cells: aromatase and inhibin B Androstenedione and testosterone diffuse from theca --> granulosa: converted to 17 beta-oestradiol by aromatase (via aromatisation) As it grows, neg feedback on FSH and LH Reduced FSH - only enough to stimulate one follicle (dominant follicle with most FSH receptors) Growth of dom follicle (also insulin like growth factor and vascular endothelial growth factor to aid in developing the dominant follicle)

Answer 12

Heterodimeric protein hormones secreted by granulosa cells of the ovary; Sertoli cells of the testis selectively suppress the secretion of FSH (late follicular phase) and also have local paracrine actions in the gonads 2 homologous subunits, an alpha subunit and either a beta A or beta B subunit, to form inhibin A and inhibin B, respectively In females, >>inhibin A is primarily produced by the dominant follicle and corpus luteum >>inhibin B is predominantly produced by small developing follicles. Serum inhibin A and B levels fluctuate during the menstrual cycle At menopause, with the depletion of ovarian follicles, serum inhibin A and B decrease to very low or undetectable levels.

Answer 13

Low levels of androgens (produced in the theca cells due to LH stimulation) encourage aromatisation. However, aromatisation (in the ovary) can only occur if FSH is present. Therefore, if a follicle lacks enough FSH receptors for the androgens to be aromatised to oestrogens, the testosterone is converted (by 5-alpha-reductase) to dihydrotestosterone (DHT). DHT inhibits aromatisation, cannot be aromatised, and inhibits FSH induction of LH receptor expression on the granulosa cells surrounding the antrums. Yes, LH receptors are also found on granulosa cells. LH acts on these receptors, stimulating the production of a small amount of progesterone to prepare the follicle for luteinisation (development of the corpus luteum, which occurs after ovulation). As a result, the non-dominant follicles disintegrate, a process known as atresia. This will also occur naturally in roughly 1,000 primary follicles each month.

Answer 14

LH increases the levels of prostaglandins in the follicular fluid, which causes smooth muscle contraction in the ovary, and LH increases the expression of proteolytic enzymes in the follicle, which helps to thin the follicular wall, allowing the oocyte to pop out. The LH surge lasts 48 hours.

Answer 15

Estrone (E1): The main oestrogen in PM women Converted from androgens in peripheral tissues Attempts to maintain oestrogenic effects in the absence of ovarian activity Oestradiol (E2): The most potent oestrogen produced by the ovaries in premenopausal women Maintains the menstrual cycle Estriol (E3): Weakest of all the oestrogens Produced by the placenta during pregnancy Maintains the uterus lining and supports foetal development

Answer 16

Oestogen levels No of oocytes decreases with age (atresia) --> decreased amount of inhibin released by the granulosa cells --> increased FSH --> increased activity of the aromatase enzyme --> fluctuating oestradiol levels !!!! Oestrogen levels only start to decrease about one year before menopause, as the small number of oocytes left can no longer make up for the effect that high FSH levels provide. Cycle become more irregular, with ovulation occurring less, not only because the number of oocytes has decreased but also because, with age, the quality of the oocytes also decreases. Decreased inhibin - less negative feedback on pituitary and hypothalamus - Increase in FSH - earlier follicle recruitment = shorter cycles

Answer 17

Initially high FSH/LH No more oocytes --> Levels of oestrogen decrease --> reduced negative feedback on the hypothalamus and pituitary gland --> 10-20-fold increase in the amount of FSH and a 3-fold increase in the amount of LH. After 3 years, FSH/LH reduces Levels decrease as pituitary gland cells and lose ability to respond to GnRH.

Answer 18

(1) LH is cleared from the body faster than FSH >> LH has a 20-minute half-life >> FSH, which has a 4-hour half-life (2) LH does not have an inhibin equivalent >> decreased inhibin increases FSH

Answer 19

Pre/ Post Vol: 5cm3/ 2cm3 Wt ??

Answer 20

Only stromal tissue and remnant steroidogenic tissue (from oocyte atresia) left in ovary --> respond to GnRH, FSH, and LH by releasing testosterone (but no E2) --> testosterone levels may rise within the first years postmenopause (this is not seen in every woman). Also at menopause there is less SHBG so more free circulating testosterone (and unbound oestrogen) Ultimately, testosterone levels post-menopause drop by 25%. But in a state of relative androgen excess --> can get hirsutism

Answer 21

25% ovaries, 25% adrenal gland 50% comes from peripheral conversion of androstenedione Post menopause as little to no androstenedione is produced by the ovaries--> Adrenal glands = predominate source of androstenedione and testosterone, which can be converted in the peripheries (most notably in adipose tissue) to estrone (E1)

Answer 22

Estrone (E1) premenopausal 30-200pg/mL, post-menopause 30-70pg/mL. Note: primarily produced peripherally by peripheral aromatisation of circulating androgens in adipocytes --- therefore later onset menopause in obese Oestradiol (E2) - more prominent decrease 20 times post-menopause.

Answer 23

Levels of androstenedione and testosterone remain constant post-menopause. DHEA produced by the adrenal glands slowly decrease, and by the age of 70-80, have dropped 74% from peak levels (peak levels are seen between the ages 20 and 30).

Answer 24

Glycoprotein produced by the liver Increased by Hyperthyroidism Pregnancy Oestrogen administration. Decreased by Androgens Progestins Growth hormone Insulin Weight gain Corticoids Menopause A decrease in SHBG will result in higher numbers of unbound oestrogen and testosterone

Answer 25

African American and Latina women start menopause 2 years earlier than white women. A Nigerian study found the average age of menopause to be the opposite, 2 years higher than that of white women. Asian and Caucasian women start menopause at a similar age, but Thai women have lower median age (49.5 years). India reports an average age of menopause up to 5 years earlier.

Answer 26

Smoking: 1-2 years earlier, perimenopause shorter >> polycyclic aromatic hydrocarbons toxic to ovarian follicles >> Drug metabolism increased in smokers so circulating oestrogen may be reduced. >> Smoking also has anti-oestrogenic effects. Malnourished / veggie Lower SES

Answer 27

Increased parity Prior use of oral contraceptives - debatable Alcohol

Answer 28

Lipophilic - stimulate receptors inside cells rather than on the surface. There are two types of oestrogen receptors (ER) - in the nucleus of cells: ER alpha ER beta

Answer 29

HIGHER OESTROGEN Increased FSH --> increasing aromatisation of androstenedione and testosterone. Decreased levels of Sex Hormone-binding Globulin, increasing the amount of free/ biologically active oestrogen. Obesity and increased adipose tissue increase peripheral aromatisation of androstenedione and testosterone. LOWER PROG Less ovulation --> corpus luteum not being formed, which is the primary source of progesterone.

Answer 30

Thermoregulatory centre in the brain innervated by neurokinin-kisspeptin-dynorphin neurones (KNDY) During menopause these neurones swell and activate the thermoregulatory centre -> hot flush This can be antagonised with NK3 receptor antagonists and oestrogen Paper "During menopause, lack of oestradiol (E2) negative feedback results in increased expression of KISS1 and TAC3 mRNA but decreased expression of PDYN mRNA. Consequently, KNDy neurones become hypertrophied, as seen by increased size of nuclei/nucleoli and increased Nissl substance. KNDy neurones project to the hypothalamic thermoregulatory centre (the median POA and adjacent MnPO). During menopause, the increase in NKB signalling and overstimulation of KNDy neurons increases activity in the thermoregulatory centre which then becomes hypersensitive to external cues from peripheral sensors, leading to activation of heat dissipation effectors. "

Answer 31

MOA: non-hormonal selective neurokinin 3 (NK3) receptor antagonist. >> blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron, which is postulated to restore the balance in KNDy neuronal activity in the thermoregulatory centre of the hypothalamus. Indication: Moderate to severe vasomotor symptoms associated with menopause Dose: 45 mg once daily.

Answer 32

Trabecular > Cortical Trabecular bone = spongy-looking porous interior of bones, usually vertebrae and the end of long bones) Cortical bone = strong compact bone found near the outer layer of long bones, makes up 80% of skeleton ERα and β are seen in cortical bone but ERβ is seen more in trabecular bone The most important actions of E2 are through ERα receptors

Answer 33

RANKL and Osteoprotegerin (OPG) regulate bone remodelling (produced by osteoblasts) Lining cells (a type of osteoblast that has stopped making new bone) respond to hormones and cytokines by releasing RANKL. RANKL binds to osteoclasts, which then proliferate and secrete acid and proteases, which create a pit in the bone (Howship’s lacunae). Osteoblasts come along and deposit collagen to be mineralised, but they also release OPG, which inhibits osteoclasts from destroying any more bone. Oestrogen --> encourages the release of OPG Menopause --> less oestrogen --> less OPG --> less osteoclasts inhibited from destroying bone.

Answer 34

Osteoblasts: RANKL (stimulate monocytes to form OC) OPG - suppresses OC Osteoclasts Collagenase (digest collagen) HCI (dissolves hydroxyapatite into CaPO4 - calc into blood)

Answer 35

Looks at 10 year risk of fracture Considers numerous risk factors: age, sex, height, weight, personal and family fracture hx, smoking, glucocorticoid use, RA, EtOH Low risk = reassure + lifestyle advice Intermediate risk = DEXA High risk = offer bone protection Reassess every 2 years or if risk factors change

Answer 36

(1) Ca + Vit D supplements (2) Bisphosphonates Tx + prevent osteoporosis Aledronate, Risedronate Bisphosphonate is incorporated with hydroxyapatite in bone to increase bone mass Skeletal half-life of bisphosphonates is around 10 years so long term benefit even if stopped Zoledronate is once yearly IV but expensive PO must be swallowed whole and sit upright for 30 mins as can cause oesophageal irritation Rare risks are osteonecrosis of the jaw, AF and femur fractures (3) Desunomab 60mg S/C every 6/12 - monoclonal Ab which reduced osteoclast activity RANKL secreted by osteoblasts to cause bone resorption-->Desunomab binds to RANKL and inhibits bone resorption Effect wears off immediately after stopping usage Strontium osteoblast replication -> reduce bone absorption

Answer 37

Premeno Mostly subcutaneous white adipose tissue (lower body, hips, and thighs) Postmeno Increased visceral fat and decreased amounts of subcutaneous fat When oestrogen binds to ER alpha on types of adipose tissue, these are the following effects: Increased accumulation of subcutaneous fat Hyperplasia of subcutaneous fat, rather than hypertrophy, which is what is associated with obesity Insulin sensitivity Anti-inflammatory effects on visceral fat After menopause, there are lower levels of oestrogen and, as a result, lower levels of ER alpha ---> Hypoxia and fibrosis of subcutaneous fat Hypertrophy and fibrosis of visceral fat, which is pro-inflammatory Insulin resistance

Answer 38

Oestrogen >>regulates glucose transport >>increases aerobic glycolysis >>increases ATP generation >> provides an antioxidant effect Post menopause, low oestrogen levels >> lower brain glucose levels. The brain uses fat from the myelin around nerves as its alternate fuel source. The breakdown of the myelin leaves debris behind, leading to inflammation. An increase in oxidative stress also increases the amount of reactive oxygen species formed, whose effects would normally be dampened by oestrogen’s antioxidant ability. Brain function is affected in many areas, including the following: The brain stem (insomnia) The amygdala, the emotional centre of the brain (mood swings) The hippocampus, where memories are stored (memory loss)

Answer 39

Increases HDL cholesterol Decreases LDL cholesterol Vasodilator properties Promotes blood clot formation SO: overall cardio-protective, increased levels can = increase coagulation = increased risk of VTE

Answer 40

high-density lipoprotein (HDL) low-density lipoprotein (LDL) Lipoprotein = outer layer (phospholipids/apoproteins) and inner core (cholesterol/triglycerides). Process 1. Very-Low Density Lipoprotein (VLDL) made liver to transport cholesterol and triglycerides to body tissues. 2. After losing a certain amount of its content, it becomes intermediate-density lipoprotein (IDL), which returns to the liver, where it becomes HDL or is converted by hepatic lipases to LDL. LDL can do one of three things: 60% is returned to the liver, and its contents are recycled 40% stays in the blood to transport cholesterol to body tissues LDL in the blood may be deposited in the damaged endothelium of blood vessels, leading to atherosclerosis HDL has the opposite function of LDL. It collects cholesterol from body tissues and returns it to the liver. It reduces atherosclerosis and, therefore, clot formation by removing cholesterol that has built up in the endothelium of blood vessel walls.

Answer 41

High levels of HDL Low levels of LDL Positive effect of oestrogen >> Suppresses hepatic lipase enzyme --> less IDL to LDL --> more IDL to HDL. >> Antioxidant effects: inhibits oxidation of LDL that is deposited in the endothelium --> reduced atherosclerosis >> Vasodilatory effects by increasing endothelial production of nitrous oxide.

Answer 42

Increases the synthesis and activity of matrix metalloproteinases, which are produced by inflammatory cells and break down the protective fibrous cap of the atherosclerotic plaque, exposing the underlying thrombogenic collagen. It is important to reduce the risk factors for atherosclerosis before menopause because when the time comes, and exogenous oestrogen is needed, the risk might outweigh the benefit if there are pre-existing plaques.

Answer 43

1. Damage to BV endothelium (increase in adhesion molecules) 2. LDL enters tunica intima. 3. Inflammatory reaction begins - endothelium releases ROS, which oxidises LDL into Ox-LDL, worsening the inflammatory process. 4. Damaged endothelium releases cytokines to attract monocytes. 5. Monocytes enter the tunica intima, differentiate into macrophages, and engulf the Ox-LDL. >> If a macrophage takes up too much Ox-LDL it becomes a foam cell 6. Platelets arrive and release growth factors--> smooth muscle proliferation and migration from the tunica media to form a fibrous cap over the foam cells 7. If fibrous cap breaks --> very thrombogenic surface is exposed to platelets / clotting factors --> thrombus/embolism. Role of HDL Binds to specific scavenger receptors on the surface of the macrophages --> remove cholesterol and prevent macrophage apoptosis. >> but problem if HDL cannot enter the tunica intima i.e. too many foam cells, which form a fat streak - fat streak is thrombogenic.

Answer 44

Oral oestrogen is metabolised by the liver. Oestrogen metabolism in the liver can impact the hepatic synthesis of proteins --> increases clotting factors

Answer 45

Hypergonadotropic hypogonadism and amenorrhoea < 40 Prev = 1% Pathophysiology (1) lack of follicles (2) follicles present but non-functional --> oestrogen decreased, FSH increased (more than 30IU/L on two blood samples taken 4-6 weeks apart). Causes: Causes: Turner syndrome: causes increased atresia of primordial follicles during the gestational period. Fragile X syndrome Galactosemia: galactose metabolites are toxic to the ovaries. FSH receptor mutations Ovarian toxins: mumps, cytomegalovirus, or tuberculosis may cause oophoritis; chemotherapy. Congenital adrenal hyperplasia Mutations affecting the binding of FSH and LH to receptors.

Answer 46

Turners Pregnancy Hormonal contraception Thyroid pathology Stress Pituitary prolactinoma – prolactin prevents the release of GnRH Pituitary failure – radiotherapy or Sheehan’s syndrome Polycystic ovarian syndrome Asherman’s syndrome

Answer 47

First line – HRT (oestrogen and progesterone with a uterus, just oestrogen without a uterus) Do not offer SSRI or clonidine for VM symptoms alone Isoflavones or black cohosh – some evidence they help with VM symptoms

Answer 48

Oestrogen receptors (a and b) are present in the vagina, the vestibule of the vulva, urethra, trigone of the bladder, and on autonomic and sensory neurons in the vagina and vulva. Only oestrogen-b receptors can be detected in postmenopausal women Hypoestrogenic environment of urogenital tract tissue = changes in the thickness of the vaginal epithelium and lamina propria, atrophy of smooth muscles, reduction of vaginal-area blood flow, and loss of tissue elasticity (decreased concentration of collagen, elastin, and hyaluronic acid) Diminution of glycogen concentration in vaginal cells results in an alteration in the vaginal microbiome (fewer lactobacilli) and an increase of vaginal pH

Answer 49

-Non-hormonal vaginal lubricants and moisturizers Topical oestrogen changes parabasal cells to superficial cells --> pH and vaginal blood flow Parabasal cells can be seen on microscopy Cells from the basal layer of the vaginal epithelium (indicate thin and atrophic epithelium) Typically small cells with a large nucleus:cytoplasm ratio intravaginal dehydroepiandrosterone (DHEA) increases blood estrogen concentration

Answer 50

St John’s Wort Anti-depressant effects Many drug interactions Black Cohosh Oestrogen-like effects and possible neurotransmitter activity Interacts with anti-hypertensives Associated with severe liver failure Isoflavones Phytoestrogens (soya, nuts, lentils, rice) Evening Primrose Oil For cyclical breast tenderness Reduces hot flushes/sweats Drug interactions – tamoxifen, anticonvulsants, anti-coagulants, asthmatics

Answer 51

All oral oestrogens are converted into E1 and E2 (E1>E2) All oral methods metabolised in the liver 30% activity lost through 1st pass metabolism All other methods, e.g. topical, transdermal, miss first pass metabolism

Answer 52

Oestrogen: Patch eg Evorel patch Tablets eg Oral oestradiol 1mg Progesterone: micronised progesterone (Utrogestan 200mg orally for 12 days a month) Or Provera 10mg orally for 12 days a month Or Norethisterone 5mg orally for 12 days a month Or Mirena IUS Or Combi: Femoston 1/10 1mg oestradiol + 10mg dydrogesterone (different pills in packet in cycle)

Answer 53

Can use oestrogen only Oral oestrogen preparations: Three tablet types available Conjugated equine estrogens (E1) Estradiol 17β (E2) Estradiol valerate (E2) Higher doses required to ensure adequate conversion into E1 for therapeutic benefit Conjugated equine estrogens may have a higher prothrombotic risk compared to estradiol.

Answer 54

All estradiol 17β Avoid 1st pass metabolism Can measure serum oestrodiol levels Less effect on clotting Reduces triglycerides More suitable for Liver disease, gallstones, VTE risk, diabetes, triglyceridaemia Enzyme inducing drugs Malabsorption Migraines Oestrogen implant needs oestrogen monitoring as can cause tachyphylaxis (recurrence of menopausal sx) Good for women with B/L oophorectomy who need higher doses of oestrogen

Answer 55

When progestogenic side effects occur can change to different, preferably less androgenic preparation Can also use mirena for local rather than systemic effects Structurally related to testosterone and more androgenic Norethisterone and levogestrel/norgestrel Structurally related to progesterone and less androgenic Dydrogesterone and medroxyprogesterone acetate Drospiernone – spironolactone derivative with anti-mineralocorticoid and anti-androgenic activity Oral micronized progesterone (e.g. utrogestan) – very similar to progestogen Without any andirogenic/glucocorticoid activity Anti-mineralocorticoid activity = can reduce BP = good for CV effects/HTN/VTE/CVA

Answer 56

Combined HRT = Breast cancer C/I Not in 1st year but risk increases with time// Reduces when HRT stopped bigger risk if BMI/Smoker/EtOH Background risk 13 per 1000 Oestrogen only 16 per 1000 Sequential HRT 20 per 1000 Continuous HRT 23 per 1000

Answer 57

Oral HRT only Double risk of VTE but absolute risk remains small VTE more likely in 1st year of use Conjugated equine oestrogen + MPA carry the highest risk of VTE Transdermal preps do not increase VTE risk

Answer 58

Breast Cancer Do not use systemic HRT Only used in exceptional circumstances Consider SSRI (but not if using tamoxifen) Do not offer herbal remedies

Answer 59

If not starting tx, review at 6 to 12 months Review at 3/12 if starting or changing HRT Review yearly thereafter if stable Seek support if bleeding for >3/12 Stopping can be gradual or immediate Sx last for 2-5 years so consider using for 3-5 years Discontinuation recommended after 5 years or after 60 At each F/U appt check BP, BMI, review risks vs benefits and breast cancer screening