PCOS & thyroid disorder

what is the HPO axis and hormone cycle

Hypothalamus releases H1 which moves to the ant. pit which rel H2 which goes to the target / terminal organ that rel H3

what are the hormone levels thru out the reproductive cycle

FSH - low spike b4 ovulation then reduces

E2 - high spike b4 ovulation and med spike after

LH - huge spike b4

PG - huge spike during ovulation otherwise very low

what are the warning signs of PCOS

excessive sweating

fatigue

unwanted hair growth

weight gain

infertility

altered mood

poor sleep

irregular periods

what is the NIH diagnostic criteria?

Hyper-androgenism

ovarian dysfunction

what are the symptoms of hyper-androgenism

hirsutism or alopecia

acne

adipose deposition

metabolic dysfunction

what are the symptoms of ovarian dysfunction

oligo or amenorrhea

follicular cyst development

impaired ovulation

infertility

why are contraceptions prescribed to women who are not pursuing pregnancy?

PCOS women exhibit irregular ovulation and risk of unwanted pregnancy is high

trt for infertility

weight loss

ovulation induction

\-SERM (clomiphene)

\-Aromatase inh (letrozole)

\-Gonadotropin (last resort)

what is the management of hyperandrogenism for women seeking fertility

delay drug trt until delivery

what is the management of hyperandrogenism for women not seeking fertility

Oral Contraceptives:

If no CI to OC - pills containing cyproterone, chlormadinone, Drospirenon, neutral progestin

moderate or severe hirsutism/unsatisfactory result then add cyproterone, finasteride or spirinolactone

If CI to OC - anti-androgens (spirinolactone) with secure contraception

trt for menstrual irregularities

oral contraceptive (low androgenic progestin drospirenone)

what are the benefits of Oral CPs

\-stabilize menstrual cycle

\-decr risk of endometrial cancer bcos of less hyperplasia

\-decr risk of ovarian cyst development

\-alters GnRH pulsating freq, decr ant pit responsiveness

\-sec mech include alteration of cervical mucus, endometrial receptivity, and tubal peristalsis

Which OCPs have the highest androgenic activity

norgestrel, levonorgestrel

Which OCPs have the mod to lower androgenic activity

norethindrone, norethindrone acetate (progestin only)

Which OCPs have the least androgenic activity

ethynodiol, norgestimate, gestodene, desogestrel

what is the risk for OCPs

Thrombosis (DVT and PE)

OC used in trt of Hyperandrogenism/Hirsutism

Estrogen–progestin combo ideally with a non-androgenic progestin (norgestimate, desogestrel, drospirenone \[e.g., Yaz\])

Controls hirsutism and acne, is effective treatment of oligomenorrhea and amenorrhea, and protects against unopposed estrogenic stimulation of the endometrium.

Potential adverse effects on insulin resistance and glucose tolerance, vascular reactivity, and coagulability are concerns

Spironolactone used in trt of Hyperandrogenism/Hirsutism

Possesses moderate antiandrogenic effects when administered in large doses (100–200 mg/day);

decreases adrenal androgen production and blocks androgen receptor; use with OC as risk for pregnancy (feminization of male infants) and breakthrough bleeding

Spironolactone and oral contraceptives appear to be synergistic

Eflornithibne (Vaniqa) used in trt of Hyperandrogenism/Hirsutism

Inhibits ornithine decarboxylase, leading to decreased rate of hair growth

Use of hair removal techniques is still required.

Do not wash skin for 8 hours after application.

Adverse effects include pruritus, burning/tingling skin, dry skin, and rash.

Pioglitazone (Actos) for the trt of insulin resistance

Insulin sensitizer that results in the reduction of androgen production by ovarian theca cells; this also results in a greater likelihood of ovulation

Improves blood glucose, Lowers plasminogen activator inhibitor 1 levels, Increases HDL-C

Doubles serum adiponectin levels

Concerns about use of TZD use during pregnancy, so not considered first line

Adverse effects include edema and weight gain

trt for acne

spironolactone

moa of spironolactone

aldosterone receptor antagonist (k+ sparing) for heart problems

testosterone antagonist to decr androgen effects on acne, hirsutism

what are the risks involved in spirinolactone

may cause birth defects, avoid in pregnancy or pt planning to be pregnant

moa of Eflornithine (Vaniqa)

inh ornithine decarboxylase red the rate of hair growth

warning ass with Eflornithine (Vaniqa)

preg cat C (used with caution)

trt for alopecia

\-5alpha reductase inh finasteride (propecia)

role of metformin in PCOS

\-decr hepatic glucose, fatty acid and cholesterol, impr glucose uptake

exhibit both AMPK dependent and independent mech. the lower insulin concn results in the red of androgen prod by ovarian theca cells with a 4 fold incr pot of ovulation

\-lactic acidosis may occur

what is the first line trt for most women with PCOS, particularly overweight or obese

metformin because of metabolic symptoms and insulin resistance

MOA of Clomiphene (clomid, serophene)

Induces ovulation by interfering with estrogen feeback to the brain leading to incr FSH release (pri- binds to receptors in ovaries, sec - direct effects on ovaries). induces rise in FSH and LH

(mst would ovulate only 50% conceive) - bcos anti-estrogenic effects can thin the endometrium

adverse effects of Clomiphene (clomid, serophene)

hot flashed, breast discomfort, ovarian hyperstimulation syndrome, abdominal distention/bloating

incr risk of multi-gestational preg due to incr antral follicles in pcos

CI of Clomiphene (clomid)

pregnancy and liver dx

moa of letrozole (Femara)

aromatase enz inh blocks the estrogen production causing less neg feedback on pit. FSJ rel cont leading to foliclular development and ovulation (promotes normal ovulation with longet t1/2)

incr ovulation by blocking estrogen production leading to incr in FSH release

CI of letrozole (Femara)

pregnancy

adverse effects for letrozole (Femara)

hot flashes, night sweats, insomnia, incr likelihood of multiple births

which med is used in cases where clomiphene and letrozole did not work

Gonadotropin - follicle stimulating hormone

(almost all pts with pcos will ovulate with FSH)

which meds have endometrium protections

\-oral combined contrac

\-metformin

\-progestin only CP

levonorgestrol IUD

what is the hypo-pituitary ovarian pathophys of PCOS

ovarian-induces incr in gonadotropin rel hormone resulting in abnormal incr in LH/FSH ratio with resulting incr in ovarian testosterone productiojn

what is the insulin resistance of the pathophys of pcos

incr in endogenous insulin levels caused by insulin resistance in muscle and adipose tissues results in excess androgen prod by the ovaries, causing incr testos prod

Excess insulin also decreases hepatic synthesis of sex hormone– binding globulin (SHBG), which normally binds free testosterone, resulting in increased hirsutism

clinical presentation of pcos

insulin resistance: acanthosis nigricans (broen discoloration in neck..)

\-overweight/obese

\-impaired glucose tolerance

\-nonalcoholic steatohepatitis

\-high risk of CAD, HTN tri

Abdominal obesity

symptoms typ begin around menarche

Diagnosis for PCOS

At least two of the following are present:

Oligoovulation or anovulation (oligomenorrhea or amenorrhea) less than 9 periods a yr

incr levels of circulating androgens (hyperandrogenemia) or clinic mani of androgen excess (hyperandrogenism)

Polycystic ovaries as defined by ovarian ultrasonography (transvaginal) - > 12, 2-9 mm diameter follicles in each ovary or increased ovarian volume (>10cm 3)

Rule other causes out

trt for infertility

weight loss

Letrozole

Clomiphene

trt for endometrial hyperplasia

oral contraceptive

Progestin challenge if > 3 months of amenorrhea; endometrial biopsy if > 1 yr of amenorrhea or if endometrial thickness on ultrasound is > 14 mm.

trt for hyperandrogenism/hirsutism

\-hair removal methods

\-OC

\-metformin

\-spirinolactone

\-eflornithine

trt for insulin resistance

\-metformin

\-pioglizaone (actos)

\-GLP1 analogue: weight loss

\-SGLT2 inh: weight loss

what is the hypothalamus pathway of thyroid secr

TSH is rel from the ant. pit which goes to the thyroid and rel T3 and T4

what is the min daily req of iron

150 ug/day

what is the wolff-Chaikoff effect

high iodine can transiently inh further iodine binding/uptake into thyroid follicle leading to transient hypothyroid symptoms

How does TH fnx as steroidal hormone and bind to nuclear hormone receptors

T3 attached to thyroid binding proteins enters the cytoplasm where T3 binds to the molecules activating the cell by displacing the corepressor and attaching the coactivator all in all making the cell active

differences betwn T3 and T4

T3 has a higher affinity for the receptor but with a short t1/2 of 1 day and is produced less and more free while T4 is more bound to plasma with a longer t1/2 of 7 days and only converted to T3 when needed

what are the major fnxs of TH

reg growth development during fetal stage and childhood

reg metabolism in the heart, kidney, skeletal, liver, and thermogenesis in all organ system

regulate energy expenditure

what deficiency can be caused in fetal development from hypothy

cretinism (preventable by suff iodine in the diet)

what deficiency can be caused in adult from hypothy

myxedema coma

caused by altered mental status, decr pressure shock, cerebral anoxia, and effusions low na

what does the test say to indicate hyper or hypo thyriodism

Hypo: all is low except TSH

Hyper: all is high except TSH

comparison of HPT axis in dysfunction

Graves (high levels): no TSH but high levels of T3 and 4 with stimulating autobody

Hashimotos (low levels): High TSH but no T3 and 4 due to destruction if cells with destructive autoantibidy

symptoms of graves dx

Arrythmias, agitation nervousness, sweating, heat intolerance, thinning har, expophthalmosis

what is thyroid storm

sudden, acute exacerbation of hyperthyroidism which is life threatening

symp include palpitations, heart failure, hyperthermia

trt for thyroid storm

CV symptoms: propranolol, diltiazem if BB ciontraindicated

TH production: potassium iodide or PTU to decr TH syn

sewuester excess TH with bile acid seq (cholestyramine) and facilitate fecal excetion or plasmaphoresis

common signs hyperthyroid dx

Flushed, Moist Skin, Thinning of hair, Proptosis, lid lag, Pretibial myxedema, Palmar erythema, Brisk DTR’s, Goiter, Tremo

common symptoms of hyperthyroid dx

Weakness, fatigue, Nervousness, Muscle aches, Weight Loss, Heat Intolerance, Palpitations, Amenorrhea, Diarrhea

hyperthyr trt

to decr TH syn and or inhibit TH rel:

Thalidomides

Uptake inhibitors

radioactive iodine

surgical resection

causes of hyperthyroid

graves dx, toxic uninodular goiter, multinodular goiter, drugs, tumor, thyroiditis

example of drug induced hyperthyroidism

Iodine-containing contrast dyes

Amiodarone

Iodinated glycerol

Alpha-Interferon

Alemtuzumab (anti-CD52)

Thyroid Hormones (T3, T4

trt for hyperthy

Thioamides

Beta Blockers

uptake inhibitors

radioactive iodine

surgical resection

what are the adv of surgery for hyperthy

definitive

TOC-malignancy, respiratory or swallowing difficulties

Existence of CI’s to RAI/Thioamides

Non-compliant pt

what are the disadv of surgery

risk if hypothy

surgery risks

other surgery risks

cosmetic conseq

must safequard against thyroid storm

Drugs under Thiamides with comparisons

propylthiouracil (PTU) - preferred in 1st trimester, lactation, and thyroid storm

Methimazole (Tapazole) - longer T1/2, better compliance, lower isk of hepatotox, no bitter taste. Generally considered the thioamide of choice. Does not block T4-T3 conversion. minimal protein binding.

trt comparison between MMI and PTU

MMI: 1st line agent in HTR in children and adults

PTU: preferable in 1st trimester, life threatening thyrotoxicosis, toxic rxn to MMI, not candidate for RAI or surgery and req anti-thyr

what are the risks of using antithyroid drugs during pregnancy

aplasia cutis

esophageal atresia (cannot breath thru the nose)

choanal atresia

moa of thioamides

inh organification and coupling of TH leading to decr syn

inh thyroid peroxidase enzyme (TPO).

PTU inh T4 --> T3 conversion May normalize TSH levels over time Precursor to surgical removal of thyroid

Adverse effects of thioamides

N/V/D, bitter taste

hypothyrodism, hepatitis

goiter, maculo-papular rash, fever, arthralgia (severe), agranulocytosis hepatotox, pancreatitis, ANCA-positive vasculitis

pt info: report fever, sore throat, flu-like symptoms

moa of Beta Blockers

\-manages sympathetic-mediated symptoms

\-inh peripheral T4 conversion

(propranolol and nadolol)

low dose if they have HF

Adv for Beta Blocker

used as adjunctive cause of symptomatic control quickly

effective for preparation of surgery/RAI

Disadvantage of Beta Blocker

does not alter the underlying thyroid dx

contraindications include; asthma, COPD, CHF

what is the management of hyperthyroid in preg

all thioamines cross the placenta

methimazole is preferred in 2nd and 3rd trimester

PTU is preferred in 1st trimester due to higher plasma protein binding

adv in drug therapy

noninvasive

minimize chances of hypothy

use in pts with CIs to surgery/RAI

disadv of drug therapy

not definitive trt

possible medication side effects

req longterm complinace

moa of iodine uptake inh

inh sodium-iodine transporter

used mainly for drug interaction induced hyper like amiodarone

perchlorate is not used due to aplastic anemia

Meds under iodides

SSKI - better palability

Lugols’s solution

Thyro-Block

Potassium iodide: Iosat, thyrosafe, Thyro Shield

moa of radioactive iodine (Iodides)

lugols solution: block thyroid hormone secr. inh organification and peripheral T4 conversion. Decr gland size/vascularity

rapidly absorbed and concn in thyroid follicle with t1/2 of 5 days

good to use before surgery but bad for radioactive iodides RAI. DO not use with toxic goitre/ HOT nodule

adverse effects of radioactive iodine

destroys thyroid parenchyma leading to epithelial swelling, necrosis, follicle disruption, edema, leukocyte infiltration

allergic rxn, metallic taste, escape phenomenon

Avoid in pregnancy and lactation risk for fetal thyroid destruction

adv of radioactive iodine

prompt effectiveness

effective adjunct for surgery

Definitive

Alternative for non-surgical candidate

For patients who fail or experience ADR to drug therapy

For patients in which disease recurrence would complicate other diseases

Non-compliant pt

disadv of radioactive iodine

risk for hypo

CI in pregnancy, lactation, nodular goiter or adenomas; prior to RAI

concern in children

possible radiation thyroiditis

must safeguard against thyroid storm

which meds inh peripheral T4 to T3 conversion

\-contrast media: ipodate and iohexol

\-beta-adrenergic antagonist: propranolol; TH incr the expression of B-AR, leads to resembling non-spe SNS stimulation

\-corticosteroids: inh 5-deiodinase, decr T3 production

\-Tyrosine kinase inh: sunitinib causes hypo as expected ADR

\-lithium: inh coupling of iodotyrosine to decr T4 prod and rel

Pt monitoring for thyroid hormone replacement

\-evaluation of the clinincal response, assessment of pt compliance, and drug interactions/ADRs, adjustment of dosage as need

monitor at 3-6 week intervals early on and then annually once a euthyroid state is established

what pre treatment is needed prior to RAI

Thioamides to prevent thyroid storm

DO not use Iodide

what pre trt is used prior surgery

iodide to reduce size

can you have hyperthy post partum

yes, because there is rel of stored thyroid hormones

trt by symptom

Trt of choice for Graves’ dx

Thiamides 18-24 mnths; once stopped remission can happen

trt of choice for graves’ ophthalmopathy

Teprotumunab (tepezza) - An IGF-1R blocker; fully human monocloncal antibody

trt of choice for Toxic Nodular Goiter

RAI therapy

surgery

avoid Iodides

trt of choice for Thyroiditis

sel limited and inflammatory

trt symptomatically with NSAID or steroid and BB as needed

look for subseq transient hypothy

trt of choice for neonatal thyrotoxicosis

\
trt with thioamides and/or Beta Blocker

prevalence in preg and mothers with hx of graves’ dx

trt of choice of iodine-induced HTR dx

due to excessive iodine ingestion (Jod-Basedow)

D/C source of iodine

usually self-limited

trt of choice for thyrotoxicosis factitia

Due to excessive thyroid hormone admin. Getting thyroid replacement but are not really hyperthyroid

D/C or decr dose of throid hormone

trt of choice for pituitary adenoma

rare casue and req neurosurgical resection

trt of choice for subclinical hyperthy

no trt unless TSH < 0.1

concerns for CVD, angina, arrhythmias, osteoporosis, and symptomatic HTR

trt of choice for Thyroid storm

medical emergency

supportive therapy; fluids fever and nutrition

trt precipitating avent

high dose of PTU (bcos of T4-T3 conversion)

iodide therapy

Beta blocker therapt

IV glucocorticoids

what are follicles

they are the functional units of the thyroid gland. They are the sites where key thyroid elements function: thyroglobulin, tyrosine, iodine, thryroxien (T4) and Triiodotyrosine (T3)

what is the normal thyroid hormone synthesis

1. iodine trapping
2. organification
3. coupling
4. Release

what are primary causes of hypothy

hashimotos, latrogenic (RAI, surgery, x-ray), drugs

iodine def, enzyme defects, thyroid hyperplasia, goitrogens