22/3 Flashcards
When to stop CHC age
50 - switch to PO method
When to check FSH
Woman > 50 with amenorrhea on POP/IMP/LNG-IUS and wants to stop contraception . >30.
COCP for HMB
Qlaira (oestradiol valerate/ dienogest)
Need 9 day starting window
BMI and contraception
BMI no other RF OR Hx of bariatric surgery
CHC: >=35 UKMEC 3 ; >=30-34 UKMEC 2
Rest 1
BMI plus other RFs
(BMI anything 30+)
CHC and DMPA: 3
Rest of PO methods: 2
Cu-IUD: 1
If obese and DMPA - inject deltoid
Patch less effective >90kg
Hx of bariatric surgery - non oral CHC more effective
BMI for LNG - EC
BMI >26 or wt >70 for double dose
In-hospital insertion for IUD and cardiac disease:
Fontan’s circulation
Eisenmenger’s physiology
Tachycardia
Pre-existing bradycardia
Contraception and cardiac drug interactions
Bosentan (ERA – endothelial receptor antagonist) – decreases prog and eostro levels in contra
Progesterone’s by VTE risk
In 10,000
6
Levongestrel
Norethisterone
Norigestimate
8
Etonogestewl
Noewlgestromin
10
Desogestrel
Drosper
Gestrodene
UKMEC and breastfeeding
Not including IUDs
Not including IUDs
0 to <6 weeks
CHC 4
DMPA 2
Rest 1
6weeks to <6 months
CHC 2
Rest 1
> =6 months
All 1
UKMEC and PP non-breastfeeding
Not including IUDs
Not including IUDs
0 to <3 weeks
Other VTE RF: CHC 4, DMPA 2, Rest 1
No other VTE RF: CHC 3, DMPA 2, Rest 1
3-6 weeks
Other VTE RF: CHC 3, DMPA 2, Rest 1
No other VTE RF: CHC 2, Rest 1
> =6 weeks
All 1
PP and IUDS (breast and non breastfeeding)
Within 48hours UKMEC 1
48 hours - <4 weeks UKMEC 3
>=4 weeks UKMEC 1
PP sepsis UKMEC 4
Early pregnancy USS
When and how to measure
Best achieved between 8-13+6/40 using CRL
More accurate than MSD
Horizontal plane
Beyond 14/40,
» if no prior early pregnancy scan, use HC +/- FL to calculate gestation
» if prior scan, generally FL, AC, BPD and HC are collected to assess fetal growth
BPD (biparietal diameter - skull)
HC (head circumference)
AC (abdominal circumference)
FL (femur length)
Gestational sac
When is it seen from / what does it measure
What does it look like
How fast does it double
Earliest seen from 4.5/52 from LMP, measuring 4mm
Signs
Eccentrically placed within endometrium,
Well circumscribed/round
Evidence of trophoblastic change
Double ring sign
Peripheral vascularity
Once 3-4mm, trophoblastic borders echo bright
Usually doubles in size ever 2-3 days
EP USS landmarks
Yolk Sac
Usually first landmark seen within GS
Seen from when GS reaches 8mm around 5/40
Fetal Pole
Visible by 6/40
Initially a thickened area on outer side of YS
First visible when 1-2mm length, grows roughly 1mm/day
Cranial/caudal ends not clear until rhomboencephalon visible around 53 days
Fetal cardiac activity
Visible from ~6/40 / CRL 5mm
Twins
When splitting occurs to give DCDA, MCDA, MCMA
USS features of DCDA, MCDA twins
1 in 80 spontaneous pregnancies
Days 1-3 (Morula): Dichorionic, diamniotic (70% of twins are dichorionic). All are DIZYGOUS
Days 4-8 (Blastocyst): Monochorionic, diamniotic (30% twins are monochorionic)
Days 8-13 (Implantation): Monochorionic, monoamniotic (1% of twin pregnancies)
Dichorionic diamniotic twins
Two placental masses and thick membrane between amniotic sacs
Chorionic tissue seen between the layers of membranes = LAMBDA SIGN
Monochorionic, diamniotic twins
Shared placental mass but separate amniotic sacs
Thin membrane between each and no chorionic tissue between these = T SIGN
MCT = molly catherine tom
Risk of miscarriage based on gestation on uss
Overall 10 to 30%
reduces depending on stage of pregnancy reached:
12% once GS seen
7% if FH seen
3% if FH persists to 8 to 12/40
Mat age and miscarriage
Advancing maternal age (due to increasing risk of aneuploidy)
<35 = 10%
33-39 = 25%
Age 40-44 = 50%
>45 = >90%
Most common trisomy causing miscarriage
Trisomy 16
Complete molar
Empty ovum plus 1/2 sperm
46XX or 46XY
1 in 5000-2000 pregnancies
Ultrasound appearances:
No evidence of fetal tissue
5-7 weeks: polypoid mass
>8 weeks: cystic appearances of villous tissue, no gestation sac/fetus
>13 weeks: ‘bunch of grapes’ appearance
Complete molar management - why avoid oxytocin
Surgical management
Avoid using oxytocin infusion before procedure completed
Oxytocin use associated with risk of tissue embolization
Use instead: misoprostol and ergometrine in this
Pre op: Prostaglandins or physical dilators ok
Complete molar vs partial molar follow up
Complete:
If HCG negative within 6 weeks –> FU for 6/12
If HCG still positive by 6 weeks –> FU for 6/12 following normalisation of HCG
Partial:
Concluded once HCG returned to normal on two samples, 4 weeks apart
Partial molar
Normal ovum, 2 sperm
Karyotype 69 XXX/XXY/XYY
1 in 700 pregnancies
Ultrasound appearance:
Fetus or fetal tissue usually present (with or without cardiac activity)
Enlarged placental tissue out of proportion to the gestation
Areas of abnormal and enlarged chorionic villi with central cavitation/cystic spaces
HSA1
Clauses for Abortion – Routine Abortion Care
A – Risk to life of woman
B – Risk of grave permanent injury to woman
C – Pregnancy not exceeded 24/40; injury to physical or mental health of woman
D – Pregnancy not exceeded 24/40; injury to the physical or mental health of existing children of the woman
E – Fetal Abnormality
HSA2
Clauses for Abortion – Emergency Abortion Care
The form must be completed by one practitioner certifying their opinion, formed in good faith, that the circumstances in which abortion can be performed in an emergency existed, i.e. the abortion is immediately necessary
1 – to save the life of the pregnant woman
2 – to prevent grave permanent injury to the physical or mental health of the pregnant woman
Misoprostol
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
Medical abortion regimen if CI to mife <12/40
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)
Post surgical abx prophylaxis
Oral doxycycline 100mg BD for 3-7 days
Rectal metronidazole 1g for one dose
Amoxicillin 500mg TDS 5 days
STOP – Complications – Uterine Atony
RF
Management
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
STOP - complications - AFE
Triad
Pathophys
Management
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
RPOC management
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
Anti-D and abortion
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
cells
Primordial germ
Primary
Secondary
Tertiary/ antral
Graafian
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.
What type of hormone are gonadotrophs (LH/FSH)
Peptide
Water-soluble
Where is GNRH produced from
arcuate nucleus of the hypothalamus
Graafian follicle –> dominant follicle process
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)
What is inhibin
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.
Process of atresia of follicles
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.
Physiology of ovulation
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.
Types of oestrogens
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
Perimenopause pathophysiology
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
AMH and menopause
Post menopause pathophysiology
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.
Why is there more FSH than LH in menopause
(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
Weight and vol of pre and post menopausal ovary
Pre/ Post
Vol: 5cm3/ 2cm3
Wt ??
What happens to testosterone menopause (early vs late)
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
Where does testosterone come from in a woman
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)
E1 and E2 levels during menopause
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.
Types of progesterone and menopause
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).
SHBG
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
Ethnic differences in menopause
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.
Early menopause risk factors
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
Later menopause RFs
Increased parity
Prior use of oral contraceptives - debatable
Alcohol
Properties of steroid hormones oestrogen and progesterone
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
What does it mean by excess unopposed oestrogen in perimenopause
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.
Thermoregulatory centre and menopause
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. “
fezolinetant
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.
Which type of bone is most effected by menopause?
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
Bone remodelling normal and menopausal
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.
Chemicals produced by osteoblasts vs osteoclasts
Osteoblasts:
RANKL (stimulate monocytes to form OC)
OPG - suppresses OC
Osteoclasts
Collagenase (digest collagen)
HCI (dissolves hydroxyapatite into CaPO4 - calc into blood)
Fracture risk
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
Bone treatment: non-hormonal options
(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
Changes to the distribution of adipose tissue in menopause
interaction between fat and oestrogen (and affect of menopause on this)
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
Pathophysiology brain fog
Oestrogen
»regulates glucose transport
»increases aerobic glycolysis
»increases ATP generation
» provides an antioxidant effect
Post menopause, low oestrogen levels»_space; 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)
CV effect of oestrogen
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
hat are HDL and LDL
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.
Why are women protected from CVD before menopause?
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.
Oestrogen’s negative effects on atherosclerosis
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.
Atherosclerosis process
- Damage to BV endothelium (increase in adhesion molecules)
- LDL enters tunica intima.
- Inflammatory reaction begins - endothelium releases ROS, which oxidises LDL into Ox-LDL, worsening the inflammatory process.
- Damaged endothelium releases cytokines to attract monocytes.
- Monocytes enter the tunica intima, differentiate into macrophages, and engulf the Ox-LDL.»_space; If a macrophage takes up too much Ox-LDL it becomes a foam cell
- Platelets arrive and release growth factors–> smooth muscle proliferation and migration from the tunica media to form a fibrous cap over the foam cells
- 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.
Effect of exogenous oestogen on clotting factors
Oral oestrogen is metabolised by the liver.
Oestrogen metabolism in the liver can impact the hepatic synthesis of proteins –> increases clotting factors
POI
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.
Causes of secondary amenorrhoea
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
Menopause vasomotor symptoms - treatment
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
genitourinary syndrome of menopause (GSM)- pathophysiology
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
genitourinary syndrome of menopause (GSM)- treatment
-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
Menopause: herbal options
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
HRT - oral oestrogens
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
Combined sequential HRT
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)
HRT no uterus
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.
HRT
Patches/gels/implant OESTROGEN
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
SE from Progesterone component of HRT
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
HRT and breast ca
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
VTE risk and HRT
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
Breast cancer and menopause management
Breast Cancer
Do not use systemic HRT
Only used in exceptional circumstances
Consider SSRI (but not if using tamoxifen)
Do not offer herbal remedies
HRT FU
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
