Summy 2

Theca Cells

LH stimulates androgen production

• upon binding to LH receptor, cholesterol goes through synthesis pathway (including progestin synthesis) and ends with testosterone

• lacks aromatase, cannot convert to estrogens as of yet

• testosterone then gets shuttled across blood vessels to get to granulosa cells

  • these hormones are v lipophilic, can cross v easily

LH

• maintains corpus luteum which will then release tons of E/P for conception

  • surge triggers ovulation

  • supports theca cells in the ovary

  • stimulates ovarian hormone production

FSH

stimulates growth of ovarian follicles and granulosa cell proliferation

Granulosa Cells

FSH stimulates aromatase expression

• these cells nurture the egg

• binding of FSH receptor stimulates aromatase production → testosterone can be converted to E

  • this serves as a T sink, huge concentration gradient

Ovarian Cycle → Follicular Phase

characterized by rising e and low p

• follicular growth stimulated by FSH → mature follicle produces e

  • primordial → primary → secondary → tertiary → Graafian follicle

    • consists of the egg/ovum, granulosa cells surrounding that, basement membrane around that, then theca cells

  • FSH initially high due to lack of e/p (no cl), but then drops as e rises

• no corpus luteum producing p just yet

Ovarian Cycle → Ovulation Phase

peak in GnRH and LH

• rising e stimulates GnRH which then stimulates LH surge

  • normally has a - feedback effect, but when concentration of e is high enough for a significant amount of time, it starts inducing + feedback

  • mediated by kispeptin

• LH surge causes ovulation → egg released

Ovarian Cycle → Luteal Phase

characterized by high e/p

• corpus luteum forms from post-ovulatory follicle → drives production of e/p

  • LH or hCG required for maintenance

  • maintains uterine tissue to prep for pregnancy

• LH/FSH fall due to - feedback from e/p

• if no pregnancy/no hCG (produced by embryo) → cl undergoes luteolysis → corpus albicans

  • p starts dropping

• at the end, lack of sex steroids removes - feedback and increases GnRH

  • LH/FSH start driving recruitment of new follicle for the next cycle

Uterine Cycle → Proliferative Phase

• e from follicular cells starts to stimulate endometrial lining proliferation until corpus luteum fully forms

• e also induced p receptor production in endometrium

Uterine Cycle → Secretory Phase

• p drops e receptor expression → dont want to be in proliferative phase anymore

• nutrients start to be secreted in preparation for embryo implantation

  • p also stimulates spiral artery growth and increases blood flow

Uterine Cycle → Menstrual Phase

• lack of hCG (would come from embryo, normally maintains cl) leads to loss of e/p

• lack of - feedback leads GnRH/FSH/LH to rise

  • recruiting new follicles

• p no longer able to maintain uterine lining

  • p is vasodilating → loss leads to massive vasoconstriction via spiral arteries → ischemia/tissue death → sloughing of the endometrium → bleeding

Estrogen on Cervix

• reduces viscosity of the cervical mucus → easier for sperm to enter

  • most viscous/permissive to sperm when ovulating

  • further increases quantity and pH (good environment for sperm)

Progesterone on Cervix

• increases mucus viscosity

• decrease pH

Where is estrogen proliferative?

both breast and uterus

Where is progesterone proliferative?

breast

alternatively protective in uterus

s/sx of menopause

• loss of protective effects → chd rates increase, osteo and bone fracture incidence rise

• hot flashes → vascular instability, issues with the brain

  • high fsh/lh mess with the hypothalamus which is where our temperature control lives

• urogenital system atrophy → can have painful intercourse

• sex drive decrease

• body mass increases while muscle density decreases

leydig cells

sertoli cells

FSH stimulates androgen binding protein synthesis + supports spermatogenesis

• binding to FSHR → androgen binding protein → high affinity for t

  • abg+t will get shuttled into lumen → increases t concentration → integral for spermatogenesis!

  • also makes a t sink → less t in the sertoli cell, more in the lumen

• note that e is also important for the synthesis of enzymes that will produce t

• can also produce inhibins which participate in negative feedback loop

male external genitalia development

• SRY gene is present on y chromosome → initiates testis development

  • if sry not present or malfunctioning → lack of testes → no t → no dht → female external genitalia despite xy chromosomal sex

• testes wil then start producing anti-mullerian hormone AMH and t

  • AMH inhibits mullerian ducts and causes them to disappear

    • this blocks the development of the uterus, fallopian tubes, and upper third of the vagina

  • the preserved wolffian tubes become the epididymis, vas deferens, and prostate

• once t enters systemic circulation, it reaches the skin around the genitalia and activates androgen receptors

  • these cells have 5alpha r and produce dht → powerfully contribute to further development

  • dht will help develop the rest of the penis and scrotum

• Define pubarche, adrenarche and

hormonal contraception

• manipulating the menstrual cycle

  • mimicking luteal phase so body thinks youre alr pregnant and it doesnt have to do anything

    • also target LH spike to prevent or delay ovulation

emergency contraception

block or delay LH surge/ovulation

infertility

• inability to conceive after 12 months of trying (<35) or 6 months of trying (>35)

  • goal is to normalize and induce ovulation → synch up cycle with introduction of sperm

estrogen positive feedback

if e concentration is high for a prolonged period of time, it activates kispeptin and results in + feedback which will trigger ovulation

estrogen ses

• breast tenderness/enlargement → stimulates breast tissue growth

• headache

• fluid retention/bloating

• nausea

• cv complications → clots, stroke, heart attack

  • increases clotting factor production from liver

• endometrial hyperplasia

• cancer

progestin ses

• menstrual irregularities

• acne

• tiredness

• vaginal dryness/atrophy

• vte

• breast cancer

• mood changes

• lower bmd → increased risk with implant

Combined Oral Contraceptives

1. low levels of e/p provide negative feedback onto lh/fsh → prevent follicle development, no rupture no pregnancy

2. p also thickens cervical mucus → prevents sperm from entering cervix

3. p also also thins the uterine lining → endometrium too thin for successful implantation

when would patch be preferable?

• patch skips first pass metab → prevents increase in liver proteins

  • beneficial for older pts who may be more sensitive to changes in drug elimination and such

ella moa

• agonism at the hypothalamus → blocks/delays LH surge via - feedback

• antagonism at the ovary → blocks follicle rupture/ovulation

mifepristone

PR antagonism

• used for medication abortion

• lack of p to help maintain endometrium for embyro and all the other good stuff → expulsion within hours

misoprostol

prostaglandin analog

• promotes contraction of uterus → results in expulsion of fetus

clomipheme

SERM for infertility

• er antagonist at the hypothalamus → blocks negative feedback effect → GnRH pulse frequency increases → increased FSH/LH → FOLLICLE STIMULATIONN

  • works to stimulate multiple follicles at once

  • also blocks e in the uterus, thins endometrial lining → honestly problematic for pregnancy, as fertilization may occur but implantation may not

• er agonist in the ovaries → increases FSH-mediated stimulation of LH receptors

letrozole

aromatase inhibitor for infertility

• blocks estrogen production from testosterone, reducing negative feedback effect → increased LH → FOLLICLE STIMULATIONNN

pk changes in pregnant pts

• increased Vd, increased fluid volume, greater clearance, increased liver protein production

  • they clear drugs mega fast!!!! and the properties of those drugs will change within them as well

• can also have decreased gastric emptying and small intestinal motility → overall decreased drug absorption

how to treat ed

block cGMP or decrease ca → net vasodilation

preeclampsia

new onset htn with proteinuria or end organ damage w/wo proteinuria

• related to the failure to remodel the spiral arteries into/out of the placenta

  • fetus cant get all of the nutrients that it needs

  • poor development of feto-placental vasculature

• timing usually occurs after 20 weeks

preeclampsia ppx

ASA 81-162mg at NIGHT starting ~12 weeks until delivery

• ideally start prior to 16 weeks, but can initiate before 28 weeks

preeclampsia diagnosis

• proteinuria with SBP >140 or DBP >90, confirm twice

  • if no proteinuria, requires some sign of end organ damage

preeclampsia with severe features diagnosis

• proteinuria w/ SBP >160 or DBP >110 OR SBP >140 or DBP >90 with one of the following features of end organ damage

  • new onset cerebral or visual changes

  • platelets <100k

  • lfts 2x nl

  • pulmonary edema

  • scr >1.1 → pregnant pts have LOW scr bc they clear so well, normally within 0.4-0.5

how old do we want baby to be for delivery

• try to get baby to term ~37 week but hopefully 39 weeks → better brain development, baby adjusts better to ex-utero

• may delivery as early as 34 weeks when necessary

serious adverse effects of chc → ACHES

• Abdominal pain → ectopic pregnancy

• Chest pain → PE

• Headache → stroke

• Eye problems → thrombosis of retinal blood vessels

• Severe leg pain → DVT

missed dose of chc

• if you miss more than 4-5 days, just use backup for a week

  • for pop, missing just one dose also can require backup for a week

when to resume chc after ella

• if resuming hormonal contraception, wait 5 days

  • if pt has missed more than or equal to 3 days of bc, can start the day of

  • USE BACK UP CONTRACEPTION FOR 12 DAYS TOTALL

  • during the 5 days you dont have the coc on board, need it

  • then when you have the coc, need to do another 7 before full effect

when to resume bc after plan b

can resume same day

how to know if pt not pregnant

• ≤7 days after the start of normal menses

• No sexual intercourse since last menses

• Correct and consistent use of reliable contraception

• ≤7 days after pregnancy loss or induced abortion

• <4 weeks postpartum

• <6 months postpartum, amenorrheic, and exclusively breastfeeding or ≥85% of feeds are breastfeeds

medication abortion within first trimester

• for use within first 10 weeks

• mifepristone + misoprostol

  • mif first then miso after a day → thin that lining to prevent implantation, then increase expulsion

• misoprostol alone

Medication Abortion in the 2nd Trimester

meds off label to induce labor

procedural abortion in first trimester

• manual vacuum aspiration

• electrical vacuum aspiration

• dilation and crettage

procedural abortion in second trimester

dilation and evacuation

how to follow up for abortion

• medical abortion requires follow up after 7-14 days to confirm abortion

  • can do serum hcg before treatment then repeat on day 8

  • ultrasound at clinic on day 8

  • home pregnancy test after 4 weeks

when to start bc after medication abortion

• can start on day of mif administration

  • pill, patch, ring, dmpa, implant

• can start after 5-9 days of mif administration

  • iud

diagnostic labs for menopause

high fsh, low e

when is MHT risk benefit ratio positive

for pts <60 within 10 years of menopause

when is MHT risk benefit ratio negative

for pts >60 or 10-20 years after menopause onset\

• higher risk of coronary heart disease, stroke, vte, dementia

thyroid hormone and bone homeostasis

th important for linear growth of bone → affect both oc and ob

• high th → osteo/high bone turnover

• low th → brittle bone/low turnover

th hormone synthesis

1. Iodide Uptake → na/i symporter shuttles charged iodide into lumen of follicular cell

2. Oxidation → charged iodide converted into iodine via thyroid peroxidase TPO living on apical membrane

3. Iodide Attachment → thyroglobin has tons of tyrosine residues on it, TPO also attaches iodine to the tyrosine

   1. one iodine → monoiodotyrosine aka MIT

   2. two iodines → dioiodotyrosine aka DIT

4. Coupling → TPO couples up the mits and dits

   1. mit + dit = t3

   2. dit + dit = t4

   3. atp, thyroid hormone still attached to thyroglobin → not yet free to act!

5. Movement Back into Cell → thyroglobin gets endocytosed

6. TH Release → TH gets cleaved off of thyroglobin via proteases

7. TH Secretion → just go free

   1. in circulation, th is 99% bound to thyroxin binding globulin → TBG

   2. so only like 1% is biologically active lol

th binding

• binds to thyroid hormone receptor in the nucleus

• forms heterodimer with retinoid x receptor → act as a transcription factor

• affect metabolism, growth/development, cv/neuro function, etc

hypothyroidism s/sx

• weight gain

• extreme tiredness

• cold intolerance

• muscle cramps

• severe constipation

• memory issues

• delayed deep tendon reflexes

hyperthyroidism s/sx

• arrythmias

• unexplained sweating

• weight loss

• termor

• brisk deep tendon reflexes

• hypertension

• diarrhea

graves dx

autoimmune disorder, autoantibodies to TSH receptor bind and stimulate TH production

• definitive diagnosis with +TRab test

  • but bc the abs dont respond to - feedback, will also see low TSH + high TH

• s/sx

  • goiter → enlargement of thyroid gland as continuous stimulation induces hypertrophy of tissue

  • pretibial myxedema → thick red skin on feet area

    • fibroblast lead to dermal thickening

  • thyroid eye disease → fibroblasts/inflammation causes swelling and expansion of tissue behind the eyes

    • bulging eyes

    • smoking big risk factor

thyroid storm

• acute, life-threatening presentation

• s/sx

  • acute onset

  • hyperthermia

  • severe tachy

  • heart failure

• can progress quickly to delirium, coma, and death

• precipitating events → major physiologic stressors !

  • infection

  • trauma

  • radioactive iodine tx

  • surgery

hashimotos

antibodies to endogenous thyroid proteins are produced, damaging thyroid gland

• antigen-presenting cells (dendritic cells, macrophages) pick up thyroid protein

  • t/b cells get activated and inflammatory mediators wreak havoc

  • b lymphocytes, t cells, macrophages infiltrate the thyroid and damage follicular cells

• risk factors: women, smokers, age >50

• diagnose with +TPO abs

  • drop in TH, but TSH high to try and increase production

amiodarone induced hypothyroidism

amiodarone looks similar to iodine, saturates the thyroid and prevent further iodide uptake

myxedema coma

• life threatening, acute situation requiring immediate intervention

• altered mental status leading to coma, cv collapse, respiratory failure, hypothermia

when is lio preferred

issue with deiodinases, myxedema coma

how long to use thioamides

• requires 12-18 months of treatment and observation before we can decide to trial off

  • can stop when pt is euthyroid, graves spontaneously reverses itself

thioamde ses

• maculopapular pruritic rash

• agranylocytosis

• dose dependent liver issues

ptu

• risk of severe hepatitis

• used in first trimester of pregnancy → more strongly protein bound, more likely to stay in maternal circulation

• also has effects in periphery → blocks t4 to t3 conversion

  • preferred in thyroid storm

levo dosing regular pt

• calculate ibw

• dose 1.6 mcg/kg/day

• start off with full dose

levo dosing for older/prolonger hypothyroidism

50 mcg/day and titrate up by 12.5-25 mcgs every 4-6 weeks

levo dosing for pt with cv disease

12.5-25 mcg/day and titrate slowly every 4-6 weeks

thioamide monitoring

• tfts (t3/t4) q2-6weeks until euthyroid

  • then q4-6 weeks/2-3 months

• tsh is unreliable to monitor early on → takes months to regain normal levels

• get baseline lfts

PTH

defend against hypocalcemia → acts via cAMP (Gs) and PLC (Gq) to stimulate activity of PTHR

• regulated by calcium and vitamin d

PTH in kidneys

• stimulation of ca reabsorption

  • increase na/k/2cl in tal → more k in cell, more leakage into lumen, encourages ca reabsorption paracellularly

  • increases ca channel expression on apical side of distal tubule

• vit d synthesis increases via stimulation of 1 alpha hydroxylase → increase absorption of ca from intestines

• removes phos/bicarb transporter from apical surface of proximal tubule → phos/bicarb loss in urine!

  • 10-15% of ca is complexed with phos, getting rid of it allows kidneys to increase free ca concentration

  • stopping ca from complexing with these two increases free concentrations in blood

pth in bone

stimulates bone resorption

• receptor binding stimulates m-csf release → stimulates differentiation of new ocs from stem cells in bone marrow

  • macrophage colony stimulating factor

• formation of competent oc also starts expressing/releasing RANK

  • so its able to activate other ocs and stimulate resorption

vit d receptor

• activation increases ca receptor synthesis → leads to PTH suppression

  • with the same concentration, cell can be stimulated more easily

• activation also suppresses PTH gene activation + decreases proliferation/differentiation of stem cells

  • block differentiation into mature parathyroid gland cell

osteoclasts

c for chew, break down and resorb bone

• have RANK receptors and alpha/beta integrins

  • rank ligand is a cytokine, can be membrane-bound or secreted by oc/ob/activated lymphocytes

  • binding to RANK receptors induces maturation and activation

• when the integrins bind to bone, they activate a signaling cascade and form a resorption pit

  • proton pump expression increases

  • expression of lysosomes containing proteolytic enzymes increases

    • work to demineralize bone and break down osteoid (protein bit of bone)

• after the pit forms, integrins are released and oc can move on to another section of bone

osteoblasts

• hey lay down in the lacuna pit and synthesize osteoid (protein part of bone)

  • osteoids are where mineralization occurs → pump out ca phosphate

• once the lacuna gets filled, this new rebuilt bone is stronger than what was intially there

• release osteoprotegrins as well → protect bone by acting as RANK receptor decoys

  • bind and sequester rank ligand to prevent activation

sclerostin

• secreted by oc

  • oc → increased activity/lifespan, differentiation

  • ob → decreased activity, increased apoptosis/decreased life span

    • also inhibits osteoprotegrin production

• intermittent/bolus PTH inhibits sclerostin release

  • which is how it has anabolic effects

sex steroids and bone

• estrogens and androgens increase bone formation

  • increase ob differentiation and decrease oc differentiation

• e also works on lymphocytes to decrease rankl expression

vit d effects

increases ca/phos reabsorption in intestines and kidneys

blocks PTH synthesis and release, as well as inhibit parathyroid growth → both normally work to increase resorption

calcitonin

prevent hypercalcemia

• synthesized and released by parafollicular cells found inbetween thyroid follicles in response to high ca

• increases cAMP → inhibits oc, reduces phos/ca/na reabsorption

PTRhP

Defend against hypocalcemia

• parathyroid hormone related peptide → same effects as PTH but not a real hormone

  • but cant activate 1 alpha hydroxy and stimulate vit d production

  • basically PTH receptor needs prolonged stimulation in order to do that, but PTHrP only binds transiently

• V important developmentally

phosphatonins

prevent hyperphosphatemia

• synthesized in obs and osteocytes

• regulate phos in kidney → phosphaturesis

  • remove na/p cotransporter from apical membrane in proximal tubule

  • inhibits 1 alpha h → drops vit d synth and thus drops phos reabsorption in intestine

hypercalcemia s/sx

• kidney stones → kidney cant reabsorb all the ca, complexes in collecting ducts and causes damage → CKD

• osteoporosis → decreases calcification of bone

• peptic ulcer, pancreatitis → dk why

• cns effects → alterered neuronal excitability

• hr drops, conduction slows → premature ventricular contractions, arrythmias, afib, asystole

hypocalcemia s/sx

• generally stem from the effect on excitable cells

  extracellular ca essential for function of k leak channel → no ca, muscles/nerves are hyper-excitable

  • burning prickling feeling due to nerve hypersensitivity

  • muscle spasms → threshold for firing way too low

    • cramps, tetany

  • long qt

  • seizures

where are the main fracture risks

• fragility fractures → bone unable to handle normal load

  • femur and vertebrae are esp susceptible

    • femur hold torso/head load → handles the most force

    • vertebrae → tons of trabecular bone, strength is often compromised and we see compression fractures

preventing osteo

• physical activity, weight-bearing activity

• fall prevention strats → get rid of tripping hazards, etc

• ca/vitd supplementation

bisphos

• look like phos and intercolate with bone (bind to hydroxyapatite crystals) → upon liberation via ocs, they kill them !

  • once the ocs die, the bisphos can reintegrate with bone and have v long duration of effect

bisphos ses

• po → esophageal and gastric irritation

  • ci with gi dx

• iv → flu like symptoms

• onj → increased bone turnover in jaw + introduction of agent interfering with bone turnover → bad

  • have to do all dental work before starting!!!

• atypical femoral fracture!! → Persistent thigh pain or groin pain, associated with long term bisphos use

serms for osteo

• estrogens increase ob differentiation and decrease oc differentiation

  • e also works on lymphocytes to decrease rankl expression → decrease oc activity this way too

denosumab

rank ligand inhibitor

• mimics osteoprotegrins structurally

• work to directly decrease differentiation/maturation/activity of ocs

• administered q6mos

• have to use bisphos to maintain bone after you complete the one year course

• pt must have normal ca or you must plan to replete during tpx

  • also have onj risk

• given q6 months

romosozumab

sclerostin inhibitor

• blocks rank ligand

  • decreases oc differentiation

  • increase opg

  • decrease ob apoptosis

• net effect is increased bone formation and decreased bone resorption

• given sq monthly, limit to 1 year use

• have to follow with bisphos after two years

• ses

  • mi/stroke/cv death

  • avoid within 1 year of acs

pth analogs

stimulate ob activity, anabolic

1. Stimulating osteoblast function and increasing bone formation

2. increasing gastrointestinal calcium absorption

3. increasing renal tubular reabsorption of calcium

• require maintenance therapy with bisphos

• may only use for two years → anabolic window

• ses

  • hypercalcemia, hypercalciuria

  • CI in children with open growth plates → will close too early !

  • administer while sitting bc it can cause dizziness/lightheadedness

bmd screening

q1-2 years for women 65+

osteo non-modifiable risk factors

• age >65

• female sex

• ethnicity

• prior fractures

• early menopause

osteo modifiable risk factors

• smoker

• low body weight

• low ca/vit d

• physical inactivity

• diet

osteo risk stratification → high risk

• prior hx of fracture, t < -2.5

  • bisphos or denosu

osteo risk stratification → very high risk

• recent fracture within 12 months, fracturs while on therapy, t < -3

  • start with anabolic

bisphos renal cutoffs

• renal impairment <30

  • avoid alen/zole when crcl <35

  • avoid iba/rise when crcl <30

ibandronate

only has efficacy for vertebral fractures

bisphos drug holiday

• PO can consider after 5 years or 6-10 years for pt with high fracture risk

• IV can consider after 3 years or 6 years for pt with high fracture risk