28. Endocrine 28. Endocrine DisorderDisorder

부산백병원 산부인과부산백병원 산부인과R4 R4 서 영 진서 영 진

HyperandrogenismHyperandrogenism Hirsutism : result of androgen excessHirsutism : result of androgen excess → → abnormalities of ovary, adrenal glandabnormalities of ovary, adrenal gland : increase expression of androgen effect : increase expression of androgen effect

Virilization : rareVirilization : rare indicates marked elevations on androgenindicates marked elevations on androgen caused by an ovarian or adrenal neoplasm caused by an ovarian or adrenal neoplasm

HirsutismHirsutism

Androgen ↑ : excessive growth of terminal hairAndrogen ↑ : excessive growth of terminal hair Pilosebaceous unitPilosebaceous unit : androgen-responsive area transforms : androgen-responsive area transforms vellus hair (fine, nonpigmented, short)vellus hair (fine, nonpigmented, short) → → terminal hair (coarse, stiff, pigmented, long) terminal hair (coarse, stiff, pigmented, long) Midline hair, sideburns, moustache, beard, chest,Midline hair, sideburns, moustache, beard, chest, intermammary hair, inner thigh, midline lower back,intermammary hair, inner thigh, midline lower back, intergluteal areaintergluteal area

Androgen effects in hair vary in relation to specific Androgen effects in hair vary in relation to specific regions of the body surfaceregions of the body surface : no androgen dependence-lanugo, eyeblows, eyelashes: no androgen dependence-lanugo, eyeblows, eyelashes : minimal sensitivity-limbs, trunk: minimal sensitivity-limbs, trunk : sensitivity ↑- axilla, pubic region: sensitivity ↑- axilla, pubic region

Result from both increased androgen production &Result from both increased androgen production & skin sensitivityskin sensitivity :skin sensitivity–depend on local activity of 5:skin sensitivity–depend on local activity of 5αα-reductase-reductase : 5: 5αα-reductase - testosterone → dihyhrotestosterone-reductase - testosterone → dihyhrotestosterone in hair folliclesin hair follicles

Hair: cyclic activity – growth (Hair: cyclic activity – growth (anagenanagen)) involution (involution (catagencatagen)) resting (resting (telogentelogen)) : duration –according to body region, genetic factor: duration –according to body region, genetic factor age, hormonal effectsage, hormonal effects

Hirsutism: relative > absolute, designationHirsutism: relative > absolute, designation

Hypertrichosis and VirilizationHypertrichosis and Virilization

Hypertrichosis: androgen-independent terminal hairHypertrichosis: androgen-independent terminal hair (nonsexual area: trunk, extremities)(nonsexual area: trunk, extremities) - AD congenital disorder- AD congenital disorder metabolic disorder (anorexia nervosa, hyperthyroidism) metabolic disorder (anorexia nervosa, hyperthyroidism) medication (acetazoamide, cirticosteroid, cyclosporine,medication (acetazoamide, cirticosteroid, cyclosporine, diazoxide, interferon, minoxidil..)diazoxide, interferon, minoxidil..)

Virilization: coarsening of the voice, increase muscle,Virilization: coarsening of the voice, increase muscle, clitoromegaly (width 3.4+1mm, length 5.1+1.4mm)clitoromegaly (width 3.4+1mm, length 5.1+1.4mm) feature of defeminization (loss of breast volume)feature of defeminization (loss of breast volume)

Focus on the age at onset & rate of progressionFocus on the age at onset & rate of progression : rapid- more severe degree of hyperandrogenism: rapid- more severe degree of hyperandrogenism (ex. ovaran or adrenal neoplasm, Cushing synd.)(ex. ovaran or adrenal neoplasm, Cushing synd.) : anovulation- probability of hyperandrogenism: anovulation- probability of hyperandrogenism

Determining the extent of hirsutismDetermining the extent of hirsutism : questions about shaving & use of depilatories: questions about shaving & use of depilatories : clinically mild, moderate, severe: clinically mild, moderate, severe : scoring scale- adrogen-densitive hair in nine body: scoring scale- adrogen-densitive hair in nine body scale of 0 to 4scale of 0 to 4 → → hirsutism > score 8 hirsutism > score 8

PCOS, congenital or adult onset adrenal hyperplasia,PCOS, congenital or adult onset adrenal hyperplasia, DM, cardiovascular disease, drug useDM, cardiovascular disease, drug use

PEx: obesity, hypertension, galactorrhea, PEx: obesity, hypertension, galactorrhea, male-pattern baldness, acne, hyperpigmentationmale-pattern baldness, acne, hyperpigmentation

DDX :Cushing syndromeDDX :Cushing syndrome

Role of AndrogenRole of Androgen

Androgen and their precusorsAndrogen and their precusors : produced by both the adrenal glands and the ovaries: produced by both the adrenal glands and the ovaries : response to ACTH and LH: response to ACTH and LH

Adrenal 17-KetosteroidsAdrenal 17-Ketosteroids : increases prepubertally: increases prepubertally : independent of pubertal maturation of H-P-O axis: independent of pubertal maturation of H-P-O axis : adrenal steroid secretion- : adrenal steroid secretion- adrenarcheadrenarche : in adrenal cortex (zona reticularis): in adrenal cortex (zona reticularis) : growth of pubic hair, axillary hair and production of: growth of pubic hair, axillary hair and production of sweat by the axillary pilosebaceous unitssweat by the axillary pilosebaceous units TestosteroneTestosterone : 1/2 – peripheral conversion of androstenedione: 1/2 – peripheral conversion of androstenedione 1/2 – direct glandular (ovary, adrenal) secretion1/2 – direct glandular (ovary, adrenal) secretion : 66~78%-binding sex hormone-binding globulin(SHBG): 66~78%-binding sex hormone-binding globulin(SHBG) bologically inactivebologically inactive 20~32%-asssociated albumin20~32%-asssociated albumin 1~2%-unbound or free1~2%-unbound or free

: increases SHBG - high estrogen (pregnancy, luteal: increases SHBG - high estrogen (pregnancy, luteal phase, use of estrogen)phase, use of estrogen) - thyroid hormone ↑, LC- thyroid hormone ↑, LC (→ reduced free testosterone)(→ reduced free testosterone) : decrease SHBG – free testosterone ↑: decrease SHBG – free testosterone ↑ - androgenic ds(PCOS, CAH, Cushing)- androgenic ds(PCOS, CAH, Cushing) medication, growth hormone, obesity,medication, growth hormone, obesity, hyperinsulinemia, pl]rolactinhyperinsulinemia, pl]rolactin

Assessment of HyperandrogenemiaAssessment of Hyperandrogenemia

Testosterone production ↑ ≠ total testosterone ↑Testosterone production ↑ ≠ total testosterone ↑ : because of depression of SHBG: because of depression of SHBG : moderate – normal range total testorterone: moderate – normal range total testorterone : severe (virilization,: severe (virilization, neoplastic production of testosterone)neoplastic production of testosterone) - can be detected by measure of total testosterone- can be detected by measure of total testosterone

: free testosterone level can be measured to assess: free testosterone level can be measured to assess increases in testosterone productionincreases in testosterone production

Free testosteroneFree testosterone : standard technique- equilibrium dialysis: standard technique- equilibrium dialysis but, expensive, complex, limited to settings but, expensive, complex, limited to settings

: assessment of testosterone binding albiumin & SHBG: assessment of testosterone binding albiumin & SHBG AT = KAT = Ka a [A] x FT[A] x FT

AT- albumin-bound testosteroneAT- albumin-bound testosterone KKa a – association constant of albumin for testosterone– association constant of albumin for testosterone

FT- free tetosterone FT- free tetosterone A- albuminA- albumin

The level of bioavailable testosteroneThe level of bioavailable testosterone : based on albumin, total testosterone, and SHBG: based on albumin, total testosterone, and SHBG Testosterone → DHT (dihydrotestosterone)Testosterone → DHT (dihydrotestosterone) : active metabolite: active metabolite : by 5: by 5αα-reductase -reductase · type I : skin· type I : skin · type II : liver, prostate, seminal vesicle, genital skin· type II : liver, prostate, seminal vesicle, genital skin -type II>type I(20-fold higher affinity for testosterone)-type II>type I(20-fold higher affinity for testosterone) the relative androgenicity of androgensthe relative androgenicity of androgens : DHT = 300: DHT = 300 testosterone = 100testosterone = 100 androstenedione = 10androstenedione = 10 DHEAS = 5 DHEAS = 5

Laboratory EvaluationLaboratory Evaluation

Bioavailable testosterone levelBioavailable testosterone level (total testosterone, SHBG, and albumin level)(total testosterone, SHBG, and albumin level) Calculated free testosterone levelCalculated free testosterone level

Most clinical situationsMost clinical situations : total testosterone, DHEAS, 17-hydroxyprogesterone: total testosterone, DHEAS, 17-hydroxyprogesterone

Normal values for serum androgensNormal values for serum androgens

Testosterone (total) 20-80 ng/dLTestosterone (total) 20-80 ng/dLFree testosterone (calculated) 0.6-6.8 pg/mLFree testosterone (calculated) 0.6-6.8 pg/mLPercent free testosterone 0.4-2.4 %Percent free testosterone 0.4-2.4 %Bioavailable testosterone 1.6-19.1 ng/dLBioavailable testosterone 1.6-19.1 ng/dLSHBG 18-114 nmol/LSHBG 18-114 nmol/LAlbumin 3,300-4,800 mg/dLAlbumin 3,300-4,800 mg/dLAndrostenedione 20-250 ng/dLAndrostenedione 20-250 ng/dLDHEAS 100-350 DHEAS 100-350 μμg/dLg/dL17-OHP (follicular phase) 30-00 ng/dL17-OHP (follicular phase) 30-00 ng/dL

Hirsutism + absent or abnormal menstrual periodHirsutism + absent or abnormal menstrual period : LH, FSH, prolactin, TSH: LH, FSH, prolactin, TSH Hypothyroidism & hyperprolactinemiaHypothyroidism & hyperprolactinemia : reduce SHBG → unbound testosterone↑: reduce SHBG → unbound testosterone↑ → → hirsutismhirsutism Cushing syndromeCushing syndrome : 24hr urinary cortisol: 24hr urinary cortisol overnight dexamethasone suppresion testovernight dexamethasone suppresion test - 1 mg dexamethasone at 11:00 PM- 1 mg dexamethasone at 11:00 PM blood cortisol checked at 8:00 AMblood cortisol checked at 8:00 AM > 2 > 2 μμg/dL → further workup g/dL → further workup

Total testosterone > 200 ng/dLTotal testosterone > 200 ng/dL : ovarian & adrenal tumor: ovarian & adrenal tumor

DHEAS > twice the upper limitDHEAS > twice the upper limit : adrenal hyperplasia: adrenal hyperplasia : upper limit 350 : upper limit 350 μμg/dL (9.5 nmol/L)g/dL (9.5 nmol/L)

VirilizationVirilization : total testosterone & DHEAS should be measured: total testosterone & DHEAS should be measured

Polycystic Ovary Syndrome(PCOS)Polycystic Ovary Syndrome(PCOS)

Most common cause of hyperandrogenism & hirsutismMost common cause of hyperandrogenism & hirsutism Stein-Leventhal syndromeStein-Leventhal syndrome : amenorrhea + bilat. Polycystic ovaries + obesity: amenorrhea + bilat. Polycystic ovaries + obesity Principally oligomenorrhea or amenorrheaPrincipally oligomenorrhea or amenorrhea + clinical or laboratory evidence of hyperandrogenemia+ clinical or laboratory evidence of hyperandrogenemia Diagnostic criteriaDiagnostic criteria : Major – chronic anovulation: Major – chronic anovulation hyperandrogenemiahyperandrogenemia clinical signs of hyperandrogenismclinical signs of hyperandrogenism other etiologies excludedother etiologies excluded

: Minor – insulin resistance: Minor – insulin resistance perimenarchal onset of hirsutism and obesityperimenarchal onset of hirsutism and obesity elevated LH-to-FSH ratioelevated LH-to-FSH ratio intermittent anovulation associated withintermittent anovulation associated with hyperandrogenemia(free testosterone,DHEAS)hyperandrogenemia(free testosterone,DHEAS)

Hirsutism : 70% of PCOS in U.S.AHirsutism : 70% of PCOS in U.S.A 10~20% in japan10~20% in japan → → difference in skin 5difference in skin 5αα-reductase activity-reductase activity Amenorrhea & oligomenorrheaAmenorrhea & oligomenorrhea Obesity : 50% in PCOSObesity : 50% in PCOS insulin resistanceinsulin resistance hyperglycemia (type 2 DM)hyperglycemia (type 2 DM)

Abnormal lipoproteinsAbnormal lipoproteins : total cholesterol. TG, LDL↑: total cholesterol. TG, LDL↑ : HDL, apoprotein A-I ↓: HDL, apoprotein A-I ↓ Other findingOther finding : impaired fibrinolysis: impaired fibrinolysis HypertensionHypertension atherosclerosis & cardiovascular diseaseatherosclerosis & cardiovascular disease MI MI

PathologyPathology

Macroscopically,Macroscopically, : 2 ~5 times the normal ovary: 2 ~5 times the normal ovary : White, thickened cortex with multiple cyst: White, thickened cortex with multiple cyst

Microscopically,Microscopically, : superficial cortex- fibrotic and hypercellular: superficial cortex- fibrotic and hypercellular prominent blood vessel prominent blood vessel : smaller atretic follicles: smaller atretic follicles : luteinized stromal cells: luteinized stromal cells

Pathophysiology and Laboratory FindingPathophysiology and Laboratory Finding

By abnormalities in 4 endocrinologically compartmentBy abnormalities in 4 endocrinologically compartment 1) the ovaries1) the ovaries 2) adrenal glands2) adrenal glands 3) the periphery (fat)3) the periphery (fat) 4) the hypothalamus-pituitary compartment 4) the hypothalamus-pituitary compartment

The ovariesThe ovaries : most consistent contributor of androgen: most consistent contributor of androgen : dysregulation of CYP17(androgen-forming enzyme): dysregulation of CYP17(androgen-forming enzyme) : this hormone relates to ovarian androgenic activity: this hormone relates to ovarian androgenic activity 1. total & free testosterone level correlate directly1. total & free testosterone level correlate directly with LH levelswith LH levels 2. more sensitive to gonadotropic stimulation, as a2. more sensitive to gonadotropic stimulation, as a result of CYP17 dysregulationresult of CYP17 dysregulation 3. GnRH agonist- suppresses testosterone and3. GnRH agonist- suppresses testosterone and androstenedione levelsandrostenedione levels 4. large dose of GnRH agonist are required for andro- 4. large dose of GnRH agonist are required for andro- gen suppression than endogenous gonadotropin-gen suppression than endogenous gonadotropin- induced estrogen suppression induced estrogen suppression

Testosterone level in PCOSTestosterone level in PCOS : no more than twice the upper normal (20-80 ng/dL): no more than twice the upper normal (20-80 ng/dL) : ovarian hyperthecosis- >200 ng/dL: ovarian hyperthecosis- >200 ng/dL

Adrenal glandAdrenal gland : hyperfunctioning CYP17 androgen-forming enzyme: hyperfunctioning CYP17 androgen-forming enzyme : DHEAS ↑ (50%) – hyeprresponsiveness to stimulation: DHEAS ↑ (50%) – hyeprresponsiveness to stimulation with ACTHwith ACTH

Peripheral compartment (skin & adipose tissue)Peripheral compartment (skin & adipose tissue) 1. 51. 5αα-reductase in skin determines the presence or -reductase in skin determines the presence or absence of hirsutismabsence of hirsutism 2. fat cell: aromatase & 172. fat cell: aromatase & 17ββ-HSD activity ↑-HSD activity ↑ 3. with obesity, estrogen metabolism ↓3. with obesity, estrogen metabolism ↓ 4. E1 level ↑ : result of peripheral aromatization of4. E1 level ↑ : result of peripheral aromatization of androstenedioneandrostenedione 5. E1 : E2 ratio ↑5. E1 : E2 ratio ↑

Hypothalamic-pituitary compartmentHypothalamic-pituitary compartment 1. LH pulse frequency ↑: the frequent observation of1. LH pulse frequency ↑: the frequent observation of elevated LH & LH:FSH ratioelevated LH & LH:FSH ratio 2. FSH : not increased with LH2. FSH : not increased with LH result from the combination of increased result from the combination of increased gonadotropin pulse frequency and synergisticgonadotropin pulse frequency and synergistic negative feedback of elevated estrogen andnegative feedback of elevated estrogen and normal ovarynormal ovary 3. prolactin ↑ : abnormal estrogen feedback to the 3. prolactin ↑ : abnormal estrogen feedback to the pituitary gland pituitary gland

Insulin ResistanceInsulin Resistance

Insulin resistance & hyperinsulinemiaInsulin resistance & hyperinsulinemia : ovarian dysfunction of PCOS: ovarian dysfunction of PCOS : most common cause- obesity: most common cause- obesity

1. Hyperinsulinemia is not a characteristic of 1. Hyperinsulinemia is not a characteristic of hyperandrogenism in general but is uniquely hyperandrogenism in general but is uniquely associated with PCOSassociated with PCOS 2. in obese women with PCOS, 30-40% have glucose2. in obese women with PCOS, 30-40% have glucose intolerance or DM, whereas ovulatory hyperandrogenic intolerance or DM, whereas ovulatory hyperandrogenic women have normal glucose tolerance and insulin women have normal glucose tolerance and insulin PCOS-obesity: synergisticPCOS-obesity: synergistic

3. Suppression of ovarian steroidogenesis with long–3. Suppression of ovarian steroidogenesis with long– acting GnRH analogs in women with PCOS does not acting GnRH analogs in women with PCOS does not change insulin levels or insulin resistance change insulin levels or insulin resistance 4. Oophorectomy in patients with hyperthecosis 4. Oophorectomy in patients with hyperthecosis accompanied by hyperinsulinemia and accompanied by hyperinsulinemia and hyperandrogenemia does not change insulin hyperandrogenemia does not change insulin resistance, despite a decrease in androgen levelsresistance, despite a decrease in androgen levels

Acanthosis nigricansAcanthosis nigricans : reliable marker of insulin resistance in hirsute women: reliable marker of insulin resistance in hirsute women : thick, pigmented, velvety lesion- vulva, axilla, neck,: thick, pigmented, velvety lesion- vulva, axilla, neck, breast, inner thighbreast, inner thigh

Acanthosis nigricansAcanthosis nigricans : reliable marker of insulin resistance in hirsute women: reliable marker of insulin resistance in hirsute women : thick, pigmented, velvety lesion- vulva, axilla, neck,: thick, pigmented, velvety lesion- vulva, axilla, neck, breast, inner thighbreast, inner thigh : testosterone >150 ng/dL: testosterone >150 ng/dL fasting insulin > 25 fasting insulin > 25 μμIU/mLIU/mL Max insulin response to glucose load(75g)>300 Max insulin response to glucose load(75g)>300 μμIU/mL IU/mL

Screening strategies for diabetes and insulin Screening strategies for diabetes and insulin resistanceresistance

Fasting glucose:insulin < 4.5 : insulin resistanceFasting glucose:insulin < 4.5 : insulin resistance 2 hr GTT : nonobese(10%), obese(40-50%) with PCOS2 hr GTT : nonobese(10%), obese(40-50%) with PCOS - inpared glucose tolerance, type II DM- inpared glucose tolerance, type II DM

testing women with PCOS for glucose intolerance is oftesting women with PCOS for glucose intolerance is of value because their risk of cardiovascular disease correlates value because their risk of cardiovascular disease correlates

with this findingwith this finding

InterventionsInterventions

In obese, insulin–resistant women, caloric restriction thatIn obese, insulin–resistant women, caloric restriction that results in weight reduction will reduce the severity of results in weight reduction will reduce the severity of insulin resistance (a 40% decrease in insulin level with a insulin resistance (a 40% decrease in insulin level with a 10–kg weight loss)10–kg weight loss) Insulin resistance/hyperinsulinemia has been Insulin resistance/hyperinsulinemia has been recognized as a cluster syndrome now called the recognized as a cluster syndrome now called the metabolic syndromemetabolic syndrome or or dysmetabolic syndrome Xdysmetabolic syndrome X

Female waist >35 inchesFemale waist >35 inches Triglycerides >150 mg/dLTriglycerides >150 mg/dL HDL cholesterol <50 mg/dLHDL cholesterol <50 mg/dL Blood pressure >130/85 mm HgBlood pressure >130/85 mm Hg Fasting glucose: 110–125 mg/dLFasting glucose: 110–125 mg/dL 2–hour GTT (75 g): 140–199 mg/dL2–hour GTT (75 g): 140–199 mg/dL

Ultrasonographic studiesUltrasonographic studies

Most important findingMost important finding : bilateral increase in number if microcyst (0.5~0.8cm): bilateral increase in number if microcyst (0.5~0.8cm) : more than five microcyst in any imaging plane in: more than five microcyst in any imaging plane in each ovaryeach ovary : but, neither sufficiently sensitive nor specific finding: but, neither sufficiently sensitive nor specific finding

Long-term RisksLong-term Risks

Chronic anovulationChronic anovulation : persistently elevated estrogen, unopposed by: persistently elevated estrogen, unopposed by progesteroneprogesterone increase the risk of endometrial carcinomaincrease the risk of endometrial carcinoma but, usually well-differentiated, stage Ibut, usually well-differentiated, stage I cure rates approaching 100%cure rates approaching 100%

Prevention of endometrial cancer Prevention of endometrial cancer : endometrial biopsy should be considered in PCOS: endometrial biopsy should be considered in PCOS : influence factor:- abnormal bleeding, weight ↑, age: influence factor:- abnormal bleeding, weight ↑, age

Hyperestrogenic stateHyperestrogenic state : breast cancer, ovarian cancer ↑ (2-3 fold): breast cancer, ovarian cancer ↑ (2-3 fold) : the risk is greater in nonobase women, : the risk is greater in nonobase women, not taking oral contraceptivesnot taking oral contraceptives

Treatment of Hyperandrogenism and PCOSTreatment of Hyperandrogenism and PCOS

Depends on a aptient’s goalsDepends on a aptient’s goals : hormonal contraception, ovulation induction, et al: hormonal contraception, ovulation induction, et al : ovulatory dysfuction: ovulatory dysfuction progestational interruption of unopposed estrogenprogestational interruption of unopposed estrogen effects on endometrium is requiredeffects on endometrium is required

Interruption of hyperandrogenism & control of hirsutismInterruption of hyperandrogenism & control of hirsutism : can be accomplished simutaneously: can be accomplished simutaneously : if patient desires pregnancy, control of hirsutism may: if patient desires pregnancy, control of hirsutism may not be possiblenot be possible

Weight ReductionWeight Reduction

The initial recommendationThe initial recommendation : reduce insulin, SHBG, and androgen: reduce insulin, SHBG, and androgen : restore ovulation with ovulation-induction agents: restore ovulation with ovulation-induction agents

Weight loss of as little as 5~7%Weight loss of as little as 5~7% : reduce bioavailable or calculated testosterone: reduce bioavailable or calculated testosterone : restore ovulation & fertility in more than 75% women: restore ovulation & fertility in more than 75% women

Oral ContraceptivesOral Contraceptives

Combination OCsCombination OCs : decrease adrenal & ovarian androgen production: decrease adrenal & ovarian androgen production : reduce hair growth in 2/3 hirsute patients: reduce hair growth in 2/3 hirsute patients

1. progesterone component- LH ↓1. progesterone component- LH ↓ androgen production ↓androgen production ↓ 2. estrogen- increase hepatic production of SHBP2. estrogen- increase hepatic production of SHBP free testosterone ↓free testosterone ↓ 3. circulating androgen ↓3. circulating androgen ↓ 4. by inhibition of 54. by inhibition of 5αα-reductase-reductase - decrease conversion of testosterone to DHT in skin- decrease conversion of testosterone to DHT in skin

When use OCS, a balance must be maintained When use OCS, a balance must be maintained

between the decrease in free testosterone levels and the intrbetween the decrease in free testosterone levels and the intr

insic androgenicity of the progestininsic androgenicity of the progestin : progestin (: progestin (norgesterol, norethindrone, norethindrone acetatenorgesterol, norethindrone, norethindrone acetate)) - androgenic activity ↑- androgenic activity ↑ - new progestin (- new progestin (desogestrel, gestodene, desogestrel, gestodene,

norgestimate, grospirenonenorgestimate, grospirenone) )

Medroxyprogesterone AcetateMedroxyprogesterone Acetate

Directly affects the hypothalamic-pituitary axis by Directly affects the hypothalamic-pituitary axis by decreasing GnRH production and release ofdecreasing GnRH production and release of gonadotropingonadotropin reduce testosterone & estrogen production in ovaryreduce testosterone & estrogen production in ovary Oral: 20~40 mg dailyOral: 20~40 mg daily IM: 150 mg every 6 weeks to 3 monthsIM: 150 mg every 6 weeks to 3 months Side effects: amenorrhea, bone density ↓, depression,Side effects: amenorrhea, bone density ↓, depression, headache, hepatic dysfunction, Wt. gainheadache, hepatic dysfunction, Wt. gain

Gonadotropin-releasing Hormone AgonistGonadotropin-releasing Hormone Agonist

Allow the differentiation of androgen produced byAllow the differentiation of androgen produced by adrenal sources from that of ovarian sourcesadrenal sources from that of ovarian sources GnRH agonist : suppress ovarian steroidsGnRH agonist : suppress ovarian steroids Leuprolide acetateLeuprolide acetate IM every 28 days IM every 28 days : decrease hirsutism & hair diameter: decrease hirsutism & hair diameter + OCs or estrogen replacement+ OCs or estrogen replacement : prevent bone loss, menopause side effect: prevent bone loss, menopause side effect

GlucocorticoidsGlucocorticoids

Dexamethasone Dexamethasone : treat adrenal or mixed adrenal and: treat adrenal or mixed adrenal and ovarian hyperandrogenismovarian hyperandrogenism 0.25 mg nightly or every other nightly0.25 mg nightly or every other nightly : suppress DHEAS (<400 : suppress DHEAS (<400 μμg/dL)g/dL) 40 times the glucocorticoid effect of cortisol40 times the glucocorticoid effect of cortisol : if daily over 0.5 mg, adrenal suppression &: if daily over 0.5 mg, adrenal suppression & Cushing syndromeCushing syndrome : maintain morning cortisol level (>2 : maintain morning cortisol level (>2 μμg/dL)g/dL) Reduce hair growth rate & acneReduce hair growth rate & acne

KetoconazoleKetoconazole

Inhibits the key steroidogenic cytochromesInhibits the key steroidogenic cytochromes 200 mg/day : reduce androstenedione200 mg/day : reduce androstenedione testosteronetestosterone calculated free testosteronecalculated free testosterone

SpironolactoneSpironolactone

Effective K sparing diuretics for treatment of HTNEffective K sparing diuretics for treatment of HTN Antagonist of aldosteroneAntagonist of aldosterone : competitively binds to aldosterone receptors in the: competitively binds to aldosterone receptors in the distal tubular region of the kidneydistal tubular region of the kidney 1. competitive inhibition of DHT at intracellular receptor1. competitive inhibition of DHT at intracellular receptor 2. testosterone biosynthesis ↓ by a decrease in the CYP2. testosterone biosynthesis ↓ by a decrease in the CYP 3. androgen catabolism ↑3. androgen catabolism ↑ 4. inhibition of skin 54. inhibition of skin 5αα-reductase activity -reductase activity

Using at least 100 mg daily for 6 monthsUsing at least 100 mg daily for 6 months : most common dosage- 50~100 mg twice daily: most common dosage- 50~100 mg twice daily : reduce sexual hair, hair diameter, hair volume: reduce sexual hair, hair diameter, hair volume

Side effectSide effect : menstrual irregularity (metrorrhagia): menstrual irregularity (metrorrhagia) : mastodynia, urticardia, scalp hair loss: mastodynia, urticardia, scalp hair loss

Not recommendedNot recommended : renal insufficiency, hyperkalemia: renal insufficiency, hyperkalemia : check K, Cr level: check K, Cr level

Cyproterone AcetateCyproterone Acetate

Synthetic progestinSynthetic progestin : antiandrogenic properties: antiandrogenic properties : competitive inhibition of testosterone, DHT at the: competitive inhibition of testosterone, DHT at the level of androgen receptorlevel of androgen receptor : hepatic enzyme ↑- androgen clearance ↑: hepatic enzyme ↑- androgen clearance ↑

+ + ethinyl estradiolethinyl estradiol : reduce testosterone, androstenedione: reduce testosterone, androstenedione suppress gonadotropinsuppress gonadotropin increase SHBG increase SHBG

Reverse sequential regimensReverse sequential regimens : cyproterone acetate 100 mg/day on days 5 to 10: cyproterone acetate 100 mg/day on days 5 to 10 ethinyl estradiol 30-50 mg/day on days 5 to 26ethinyl estradiol 30-50 mg/day on days 5 to 26

Side effectSide effect : fatigue, Wt. gain, libido ↓, nausea, headache,: fatigue, Wt. gain, libido ↓, nausea, headache, irregular bleeding irregular bleeding

FlutamideFlutamide

Nonsteroidal antiandrogenNonsteroidal antiandrogen : used in prostate cancer: used in prostate cancer : inhibition of nuclear binding of androgen on tissues: inhibition of nuclear binding of androgen on tissues : weak inhibitor of tetosterone biosynthesis: weak inhibitor of tetosterone biosynthesis

+ low dose OCs+ low dose OCs : improvement hirsutism: improvement hirsutism : androstenedione, DHT, LH FSH ↓: androstenedione, DHT, LH FSH ↓ : side effect- dry skin, hot flush, appetite ↑, dizziness,: side effect- dry skin, hot flush, appetite ↑, dizziness, libido ↓libido ↓

+ + ethinyl-drospirenone, metforminethinyl-drospirenone, metformin : reduce excess total and abdominal fat: reduce excess total and abdominal fat : dysadipocytokinemia in young women with: dysadipocytokinemia in young women with hyperinsulinemic PCOS hyperinsulinemic PCOS

CimetidineCimetidine

Histamine H2 receptor antagonistHistamine H2 receptor antagonist : weak ability to occupy androgen receptor: weak ability to occupy androgen receptor : inhibit DHT binding at the level of the hair follicle: inhibit DHT binding at the level of the hair follicle

FinasterideFinasteride

Inhibitor of type 2 5Inhibitor of type 2 5αα-reductase -reductase 5 mg daily5 mg daily

Ovarian Wedge ResectionOvarian Wedge Resection

Transient reduce androstenedion levelTransient reduce androstenedion level prolonged minmal decrease in testosteroneprolonged minmal decrease in testosterone 85%: maintenance of ovulatory cycle85%: maintenance of ovulatory cycle

Laparoscopic ElectrocauteryLaparoscopic Electrocautery

Severe PCOS whose condition is resistant to Severe PCOS whose condition is resistant to clomiphene citrateclomiphene citrate Coagulation each microcystCoagulation each microcyst Risk: adhesionRisk: adhesion

Physical Methods of hair RemovalPhysical Methods of hair Removal

Depilatory, shaving, plunking, bleachingDepilatory, shaving, plunking, bleaching Electorolysis: permanentElectorolysis: permanent destroy hair folliclesdestroy hair follicles Laser hair removalLaser hair removal

Insulin SensitizersInsulin Sensitizers

Metformin (glucophage)Metformin (glucophage) : inhibit hepatic glucose production &: inhibit hepatic glucose production & enhance peripheral glucose uptakeenhance peripheral glucose uptake : 500 mg three times daily: 500 mg three times daily → → improve ovulation (+ clomiphene citrate) improve ovulation (+ clomiphene citrate)

Cushing SyndromeCushing Syndrome

Adrenal cortex : three steroid hormoneAdrenal cortex : three steroid hormone glucocorticoidglucocorticoid mineralocorticoidmineralocorticoid sex steroid (androgen, estrogen precursors)sex steroid (androgen, estrogen precursors) Glucocrticoid ↑Glucocrticoid ↑ : nitrogen wasting & catabolic sate: nitrogen wasting & catabolic sate → →muscle weakness, osteoporosis, skin atrophy,muscle weakness, osteoporosis, skin atrophy, nonhealing ulceration, ecchymosesnonhealing ulceration, ecchymoses : immune resistance ↓: immune resistance ↓ → →bacterial or fungal infectionbacterial or fungal infection : guconeogenesis and antagonism to insulin action: guconeogenesis and antagonism to insulin action → →glucose intolerance glucose intolerance

SymptomsSymptoms : weight gain, central & over clavicle fat redistribution : weight gain, central & over clavicle fat redistribution (neck, trunk, abdomen, cheeks)(neck, trunk, abdomen, cheeks) : cortisol excess- insomnia, mood disturbance, overt : cortisol excess- insomnia, mood disturbance, overt phycosis, depressionphycosis, depression

Sex steroid precursor overproductionSex steroid precursor overproduction - hyperandrogenism (hirsutism, acne, oligomenorrhea,- hyperandrogenism (hirsutism, acne, oligomenorrhea, amenorrhea, thinning scalp hair)amenorrhea, thinning scalp hair)

Mineralocortocoid overproductionMineralocortocoid overproduction - arterial HTN, hypokalemic alkalosis- arterial HTN, hypokalemic alkalosis → → fluid retention may cause pedal edema fluid retention may cause pedal edema

Laboratory finding associated with hypercortisolismLaboratory finding associated with hypercortisolism : granulocytosis, lymphocytes ↓, urinary Ca ↑: granulocytosis, lymphocytes ↓, urinary Ca ↑

CauseCause

Category Cause Relative inCategory Cause Relative incidencecidence

ACTH-dependentACTH-dependent Cushing syndrome 60% Cushing syndrome 60% Ectopic ACTH-secreting tumor 15%Ectopic ACTH-secreting tumor 15% Ectopic CRH-secreting tumor 10%Ectopic CRH-secreting tumor 10%

ACTH-independentACTH-independent Adrenal cancer 15% Adrenal cancer 15% Adrenal adenoma 10%Adrenal adenoma 10% Micronodular adrenal hyperplasia rare Micronodular adrenal hyperplasia rare Iatrogenis/factitious commonIatrogenis/factitious common

ACTH-dependent ACTH-dependent : result from ACTH secreted by pituitary adenomas or: result from ACTH secreted by pituitary adenomas or from an ectopic sourcefrom an ectopic source : hallmark- normal or high ACTH with increased cortisol: hallmark- normal or high ACTH with increased cortisol

Pituitary adenomaPituitary adenoma : microadenomas (<10mm): microadenomas (<10mm) : resistant to the feedback effect of cortisol: resistant to the feedback effect of cortisol

Ectopic ACTH syndromeEctopic ACTH syndrome : 1/2- small-cell carcinoma in lung: 1/2- small-cell carcinoma in lung : bronchial & thymic carcinomas, pancreas carcinoid: bronchial & thymic carcinomas, pancreas carcinoid tumor, thyroid medullary cercinomastumor, thyroid medullary cercinomas

ACTH-independent causeACTH-independent cause

: most common- iatrogenic or factitious: most common- iatrogenic or factitious

: corticosteroid- variety of diseases with an: corticosteroid- variety of diseases with an

inflammatory componentinflammatory component

Diagnostic Workup for Cushing Diagnostic Workup for Cushing SyndromeSyndrome

ScreeningScreening : 24hr urinary free cortisol: 24hr urinary free cortisol - normal range (30~80 - normal range (30~80 μμg/day)g/day) : overnight : overnight dexamethasonedexamethasone suppression test suppression test - previous night 11:00 PM 1 mg - previous night 11:00 PM 1 mg dexamethasonedexamethasone next day 8:00 AM cortisolnext day 8:00 AM cortisol

Confirmation if diagnosisConfirmation if diagnosis : 2-day, low-dose : 2-day, low-dose dexamethasone dexamethasone suppression testsuppression test - 0.5 mg every 6 hours for 2 days- 0.5 mg every 6 hours for 2 days - Cushing syndrome is ruled out- Cushing syndrome is ruled out urinary 17-hydroxycorticosteroid < 3 mg/24hrurinary 17-hydroxycorticosteroid < 3 mg/24hr plasma cortisol < 4plasma cortisol < 4μμg/dayg/day urinary free cortisol < 25 urinary free cortisol < 25 μμg/24 hrg/24 hr

Differentiation of Cushing syndromeDifferentiation of Cushing syndrome : high-dose : high-dose dexamethasone dexamethasone suppression testsuppression test : used to differentiate from other cause: used to differentiate from other cause : 2 mg every 6 hours for 2 days: 2 mg every 6 hours for 2 days

: suppresses ACTH in most Cushing syndrome: suppresses ACTH in most Cushing syndrome (Cushing’s disease) (Cushing’s disease) : no effect- ectopic or adrenal Cushing syndrome: no effect- ectopic or adrenal Cushing syndrome

Differentiation of ectopic ACTH syndromeDifferentiation of ectopic ACTH syndrome : high plasma ACTH: high plasma ACTH - >4.5 pmol/L or >20 pg/mL- >4.5 pmol/L or >20 pg/mL - ectopic ACTH production from adrenal gland- ectopic ACTH production from adrenal gland

: low plasma ACTH: low plasma ACTH - <1.1 pmol/L or <5 pg/ml- <1.1 pmol/L or <5 pg/ml - adrenal Cushing syndrome- adrenal Cushing syndrome

ACTH-independent and –dependentACTH-independent and –dependent : ACTH-independent: ACTH-independent - adrenal scan or MRI- adrenal scan or MRI prepared for adrenal surgeryprepared for adrenal surgery : ACTH-dependent: ACTH-dependent - CRH test- CRH test - CRH ( 1- CRH ( 1μμg/kg IV over 1 min)g/kg IV over 1 min) simultaneous sampling 3~5 minutes later ofsimultaneous sampling 3~5 minutes later of both the inf. petrosal sinuses/peripheral vein ratioboth the inf. petrosal sinuses/peripheral vein ratio - 95% of Cushing syndrome > 2 ratio- 95% of Cushing syndrome > 2 ratio - if not, indicate ectopic ACTH secretion- if not, indicate ectopic ACTH secretion → → check chest & abdominal CTcheck chest & abdominal CT

Laboratory Diagnosis of Cushing SyndromeLaboratory Diagnosis of Cushing Syndrome

Dagnosis 24hr urinary cortisol DEX low-dose DEX high-dose ACTHDagnosis 24hr urinary cortisol DEX low-dose DEX high-dose ACTHACTH-dependent ACTH-dependent Cushing synd (60%) ↑ ↑ ↓ normalCushing synd (60%) ↑ ↑ ↓ normal Pituitary adenomaPituitary adenoma Basophilic hyperplasiaBasophilic hyperplasia Nodular adrenal hyperplasiaNodular adrenal hyperplasia Cyclic Cushing syndCyclic Cushing syndEctopic ACTH (15%) ↑ ↑ ↑ ↑Ectopic ACTH (15%) ↑ ↑ ↑ ↑Ectopic CRH(rare) ↑ ↑ ↑↓ ↑Ectopic CRH(rare) ↑ ↑ ↑↓ ↑

ACTH-independentACTH-independent Adrenal neoplasia ↑ ↑ ↑ ↓Adrenal neoplasia ↑ ↑ ↑ ↓ Adenoma (10%)Adenoma (10%) carcinoma (15%)carcinoma (15%) 1’ adrenocorticorid 1’ adrenocorticorid nodular dysplasia(<1%)nodular dysplasia(<1%)Pseudo-Cushing synd ↑ ↑ ↓ normalPseudo-Cushing synd ↑ ↑ ↓ normal (alcohol-relate,<1%)(alcohol-relate,<1%)Exogenous glucocorticoids/ ↑↓ ↓ ↓ ↓Exogenous glucocorticoids/ ↑↓ ↓ ↓ ↓ factitious (not cortisol) factitious (not cortisol)

Treatment of ACTH-independent Form Treatment of ACTH-independent Form ofofCushing SyndromeCushing Syndrome Exclude iatrogenic or factitious etiologyExclude iatrogenic or factitious etiology

Usually, adrenal cancersUsually, adrenal cancers (tumors are relatively inefficient in steroid synthesis)(tumors are relatively inefficient in steroid synthesis) : >6cm- detected by CT or MRI: >6cm- detected by CT or MRI : large, irregular image: large, irregular image : unilateral adrenalectomy is preferable: unilateral adrenalectomy is preferable in malignancy, complete resection is impossiblein malignancy, complete resection is impossible : postoperative chemotherapy (: postoperative chemotherapy (mitotanemitotane))

Adrenal adenomas (<3cm)Adrenal adenomas (<3cm) : usually unilateral: usually unilateral : children, adolescents, young adults: children, adolescents, young adults : contain numerous small (>3mm) nodule: contain numerous small (>3mm) nodule : identified by CT or MRI: identified by CT or MRI : treatment of choice: treatment of choice - surgical removal unilaterally- surgical removal unilaterally cure rate- 100% cure rate- 100% - after surgery. cortisol replacement needed- after surgery. cortisol replacement needed because H-P-A axis is suppressed by autonomous because H-P-A axis is suppressed by autonomous cortisol production cortisol production

Treatment of Cushing DiseaseTreatment of Cushing Disease

Treatment of choiceTreatment of choice : transsphenoidal resection: transsphenoidal resection : cure rate- 80% (microadenomas) : cure rate- 80% (microadenomas) 50% (macroadenomas)50% (macroadenomas)

Radiation therapyRadiation therapy : 4,200~4,500 cGy : 4,200~4,500 cGy : total improvement- 15~25% of adults: total improvement- 15~25% of adults 80% of chilren80% of chilren

Medical therapyMedical therapy : : mitotane mitotane after pituitary radiationafter pituitary radiation : maintain cortisol levels while a patient awaits the full: maintain cortisol levels while a patient awaits the full effect of radiationeffect of radiation

: adrenal enzyme inhibitors: adrenal enzyme inhibitors - - aminoglutethimide, ametyrapone, trilostanes,aminoglutethimide, ametyrapone, trilostanes, etomidateetomidate

: : ketoconazoleketoconazole - inhibits adrenal steroid biosynthesis- inhibits adrenal steroid biosynthesis - 600~800 mg/day for 3 months to 1 year- 600~800 mg/day for 3 months to 1 year

Nelson syndromeNelson syndrome : adenomatous progression of ACTH-secreting cells: adenomatous progression of ACTH-secreting cells in patient with Cushing syndrome treated by bilatealin patient with Cushing syndrome treated by bilateal adrenalectomyadrenalectomy : 10~50% of bilateral adrenalectomy cases: 10~50% of bilateral adrenalectomy cases : sellar pressure symptoms: sellar pressure symptoms - headache, visual disturbance, ophthalmoplegia- headache, visual disturbance, ophthalmoplegia : high ACTH level- severe hyperpigmentation: high ACTH level- severe hyperpigmentation : treatment- surgery + radiation: treatment- surgery + radiation

Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

Autosomal recessive disorderAutosomal recessive disorder

Failure to synthesize the fully functional enzymeFailure to synthesize the fully functional enzyme 1.a relative decrease in cortisol enzyme1.a relative decrease in cortisol enzyme 2.a compensatory increase in ACTH level2.a compensatory increase in ACTH level 3. hyperplasia of the zona reticularis of adrenal certex3. hyperplasia of the zona reticularis of adrenal certex 4. an accumulation of the precursors of the affected4. an accumulation of the precursors of the affected enzyme in bloodstreamenzyme in bloodstream

21-Hydroxylase Deficiency21-Hydroxylase Deficiency

>90% of adrenal hyperplasia>90% of adrenal hyperplasia

Salt wasting-severe formSalt wasting-severe form : congenital manifestation during the first 2 weeks of life: congenital manifestation during the first 2 weeks of life : hypovolemic salt-wasting crisis, hyponatremia,: hypovolemic salt-wasting crisis, hyponatremia, hyperkalemia, acidosishyperkalemia, acidosis With or without salt-wasting & new born adrenal crisisWith or without salt-wasting & new born adrenal crisis : genital virilization (clitoromegaly, labioscrotal fusion,: genital virilization (clitoromegaly, labioscrotal fusion, abnormal urethral course)abnormal urethral course)

In simple virilizing CAHIn simple virilizing CAH : diagnosed as virilized newborn girls or as rapid: diagnosed as virilized newborn girls or as rapid growing masculinized boys at 3 to 7 years 0f agegrowing masculinized boys at 3 to 7 years 0f age : diagnosis is based on basal level of: diagnosis is based on basal level of 21-hydroxylase ↔17-hydroxyprogesterone (17-OHP)21-hydroxylase ↔17-hydroxyprogesterone (17-OHP) 1. Basal follicular phase 17–OHP less than 200 ng/dL 1. Basal follicular phase 17–OHP less than 200 ng/dL virtually excludes the disorder; no further testing is virtually excludes the disorder; no further testing is requiredrequired 2. Basal 17–OHP greater than 500 ng/dL establishes the 2. Basal 17–OHP greater than 500 ng/dL establishes the diagnosis; there is no need for further testing diagnosis; there is no need for further testing 3. Basal 17–OHP greater than 200 ng/dL and less than 3. Basal 17–OHP greater than 200 ng/dL and less than 500 ng/dL requires ACTH stimulation testing500 ng/dL requires ACTH stimulation testing

4. In the ACTH stimulation test, plasma levels of 17–OHP4. In the ACTH stimulation test, plasma levels of 17–OHP are checked 1 hr following intravenous administrationare checked 1 hr following intravenous administration of a bolus of 0.25 mg ACTH 1–24 (of a bolus of 0.25 mg ACTH 1–24 (cosyntropincosyntropin [ [CortrosynCortrosyn]]).). 17–OHP levels after ACTH stimulation in adult–onset 17–OHP levels after ACTH stimulation in adult–onset adrenal hyperplasia are generally greater than adrenal hyperplasia are generally greater than 1,000 ng/dL.1,000 ng/dL. 5. Individuals who are heterozygous (carriers) for both5. Individuals who are heterozygous (carriers) for both adult–onset adrenal hyperplasia and CAH reveal adult–onset adrenal hyperplasia and CAH reveal stimulated 17–OHP values less than 1,000 ng/dL. stimulated 17–OHP values less than 1,000 ng/dL. In many cases, an overlap with the values seen in the In many cases, an overlap with the values seen in the normal population is observednormal population is observed

Nonclassic Adult-onset Nonclassic Adult-onset Congenital adernal hyperplasia Congenital adernal hyperplasia Nonclassic type of 21-hyoroxlase deficiencyNonclassic type of 21-hyoroxlase deficiency : partial deficiency in 21-hydroxylation: partial deficiency in 21-hydroxylation : late-onset, milder hyperandrogenemia: late-onset, milder hyperandrogenemia : result from mutation both alleles for 21-hydroxylase: result from mutation both alleles for 21-hydroxylase Symptoms of AOAH present during of after pubertySymptoms of AOAH present during of after puberty

1. 1. Those with ovulatory abnormalities and features Those with ovulatory abnormalities and features consistent with PCOS (39%)consistent with PCOS (39%) 2. Those with hirsutism alone without oligomenorrhea 2. Those with hirsutism alone without oligomenorrhea (39%)(39%) 3. Those with elevated circulating androgens but without3. Those with elevated circulating androgens but without symptoms (cryptic) (22%)symptoms (cryptic) (22%)

Genetic of 21-hydoxylase deficiencyGenetic of 21-hydoxylase deficiency

1. The 21–hydroxylase gene is located on the short arm1. The 21–hydroxylase gene is located on the short arm of chromosome 6, in the midst of the HLA region.of chromosome 6, in the midst of the HLA region. 2. The 21–hydroxylase gene is now termed 2. The 21–hydroxylase gene is now termed CYP21.CYP21. Its Its homologue is the pseudogene homologue is the pseudogene CYP21PCYP21P . . 3. Because 3. Because CYP21PCYP21P is a pseudogene, the lack of is a pseudogene, the lack of transcription renders it nonfunctional. The transcription renders it nonfunctional. The CYP21CYP21 is the is the active gene.active gene. 4. The 4. The CYP21CYP21 gene and the gene and the CYP21PCYP21P pseudogene alternate pseudogene alternate with two genes called with two genes called C4BC4B and and C4AC4A, both of which , both of which encode for the fourth component (encode for the fourth component (C4C4) of serum ) of serum complement .complement . 5. The close linkage between the 21–hydroxylase genes5. The close linkage between the 21–hydroxylase genes and and HLAHLA alleles has allowed the study of 21–hydroxylase alleles has allowed the study of 21–hydroxylase inheritance patterns in families through blood inheritance patterns in families through blood HLAHLA typing typing

Prenatal diagnosis and treatmentPrenatal diagnosis and treatment

Women with CAH or AOAHWomen with CAH or AOAH : high frequency of mutation in 21-hydroxylase: high frequency of mutation in 21-hydroxylase In families at risk for CAH, one partner expresses the In families at risk for CAH, one partner expresses the CAH or AOAHCAH or AOAH : first trimester- chorionic villus sampling: first trimester- chorionic villus sampling : in involvement, : in involvement, dexmethasonedexmethasone treatment treatment (20 mg/kg tid, no later than 9 weeks)(20 mg/kg tid, no later than 9 weeks) DexamethasoneDexamethasone cross placenta & suppress ACTH cross placenta & suppress ACTH effectively reduces genital ambiguity in genetic femaleeffectively reduces genital ambiguity in genetic female (but, 2/3 still require surgical repair of genitalia)(but, 2/3 still require surgical repair of genitalia)

1111ββ-Hydoxylase Deficiency-Hydoxylase Deficiency

5~8% of CAH, or 1 in 100,000 birth5~8% of CAH, or 1 in 100,000 birth Common symptom: hypertensionCommon symptom: hypertension Two isoenzyme: CYP11-B1 & CYP11-B2Two isoenzyme: CYP11-B1 & CYP11-B2 middle of long arm of chromosome 8 middle of long arm of chromosome 8 - synthesis of cortisol and aldosterone- synthesis of cortisol and aldosterone DiagnosisDiagnosis : 11-deoxycortisol > 25 ng/mL 60 min : 11-deoxycortisol > 25 ng/mL 60 min after ACTH stimulationafter ACTH stimulation 1/3: Lt. ventricular hypertrophy1/3: Lt. ventricular hypertrophy death is reported from cerebrovascular accidentdeath is reported from cerebrovascular accident

33ββ-Hydoxysteroid Dehydrogenase -Hydoxysteroid Dehydrogenase DeficiencyDeficiency Both the adrenal glands & ovariesBoth the adrenal glands & ovaries Transforming Transforming ΔΔ-5 steroid into the -5 steroid into the ΔΔ-4 compounds-4 compounds

Marked elevation of DHEA & DHEAS of mildly elevatedMarked elevation of DHEA & DHEAS of mildly elevated testosterone & androstenedionetestosterone & androstenedione → → screening protocol using exogenous ACTH stimulationscreening protocol using exogenous ACTH stimulation

Treatment of Adult-onset Treatment of Adult-onset Congenital Adranal HyperplasiaCongenital Adranal Hyperplasia Dexamethasone: suppress the H-P axisDexamethasone: suppress the H-P axis evening 0.25~0.5 mg, most effectiveevening 0.25~0.5 mg, most effective : maintain cortisol level ( > 2 : maintain cortisol level ( > 2 μμg/dL)g/dL)

progestin for endometrial regulationprogestin for endometrial regulation clomiphene citrate or gonaditropin for ovulation inductionclomiphene citrate or gonaditropin for ovulation induction progestin & androgen for control hirsutismprogestin & androgen for control hirsutism

Androgen-secreting Androgen-secreting Ovarian and Adrenal TumorsOvarian and Adrenal Tumors

Hirsutism, vorolization, rapidly progressing signs ofHirsutism, vorolization, rapidly progressing signs of androgen excessandrogen excess Determination if levels of testosterone & DHEASDetermination if levels of testosterone & DHEAS : testosterone- 2.5 times the upper normal or 200 ng/dL: testosterone- 2.5 times the upper normal or 200 ng/dL → → ovarian androgen-secreting tumorovarian androgen-secreting tumor : DHEAS > 800 : DHEAS > 800 μμg/dLg/dL → → adrenal tumoradrenal tumor EvaluationEvaluation : first, USG in ovarian neoplasm: first, USG in ovarian neoplasm : Duplex Doppler: Duplex Doppler : CT, MRI, selective venous catheterization: CT, MRI, selective venous catheterization

Adrogen-producing Ovarian NeoplasmsAdrogen-producing Ovarian Neoplasms

Granulosa cell tumorsGranulosa cell tumors : 1~2% (postmenopausal > premenopausal women): 1~2% (postmenopausal > premenopausal women) : usually associated with estrogen production: usually associated with estrogen production : TAH c BSO: TAH c BSO : malinancy potential- 60~90%: malinancy potential- 60~90% depend on stage, tumor size, histologic atypiadepend on stage, tumor size, histologic atypia

ThecomasThecomas : rare, older age, seriod-type (luteinized thecomas): rare, older age, seriod-type (luteinized thecomas) : rare malinant, rare bilateral: rare malinant, rare bilateral : simple oophorectomy: simple oophorectomy

Sclerosing stromal tumorSclerosing stromal tumor : benign, <30 years: benign, <30 years : a few case, estrogenic or androgenic manifestations: a few case, estrogenic or androgenic manifestations

Sertoli-Leidig cell tumorsSertoli-Leidig cell tumors : previously, androblastoma, arrhenoblastoma: previously, androblastoma, arrhenoblastoma : 11% of solid ovarian tumors: 11% of solid ovarian tumors : contain Sertoi cells, Leydig cells, fibroblasts: contain Sertoi cells, Leydig cells, fibroblasts : most common virilizing tumor in reproductive age: most common virilizing tumor in reproductive age but, musculinization- 1/3but, musculinization- 1/3 : bilateral 1.5%, 80%- stage IA: bilateral 1.5%, 80%- stage IA : Tx: USO: Tx: USO TAH c BSO + adjuvant Tx (in advanced stage)TAH c BSO + adjuvant Tx (in advanced stage)

Pure sertoli cell tumorsPure sertoli cell tumors : usuallly unilateral: usuallly unilateral : if premenopausal with stage I: if premenopausal with stage I → → USOUSO : maliganat tumors are rapidly fatal: maliganat tumors are rapidly fatal

GynandroblastomaGynandroblastoma : benign, well differentiated, testicular elements: benign, well differentiated, testicular elements : Tx- USO or unolateral oophorectomy: Tx- USO or unolateral oophorectomy

Sex cord tumors with annular tubules (Sex cord tumors with annular tubules (SCTATsSCTATs)) : associated with Peutz-jeghers syndrome: associated with Peutz-jeghers syndrome (G-I polyposis, mucocutaneous melanin pigmentation)(G-I polyposis, mucocutaneous melanin pigmentation) : mophology- between granulosa cell tumor and: mophology- between granulosa cell tumor and Sertoli cell tumorSertoli cell tumor : with Peutz-jeghers syndrome: with Peutz-jeghers syndrome - bilateral & benign- bilateral & benign without Peutz-jeghers syndromewithout Peutz-jeghers syndrome - almost always unilateral & mailgnant- almost always unilateral & mailgnant

Steroid Cell TumorsSteroid Cell Tumors

Composed entirely of steroid-secreting cells Composed entirely of steroid-secreting cells Virilization or hirsutismVirilization or hirsutism : 3/4 of Leydig cell tumors: 3/4 of Leydig cell tumors

Stromal Hyperplasia andStromal Hyperplasia and Stromal Hyperthecosis Stromal Hyperthecosis Stromal hyperplasiaStromal hyperplasia : nonneoplastic proliferation of ovarian stromal cell: nonneoplastic proliferation of ovarian stromal cell : 60~80 years: 60~80 years : associated with hyperandrogenism, endometrial: associated with hyperandrogenism, endometrial carcinoma, obesity, HTN, glucose intolerancecarcinoma, obesity, HTN, glucose intolerance

Stromal hyperthecosisStromal hyperthecosis : presence of luteinized stromal cell at distance from: presence of luteinized stromal cell at distance from the folliclesthe follicles : order age- mild, reproductive age- severe: order age- mild, reproductive age- severe

: virilization, obesity, hyperinsulinemia, HTN: virilization, obesity, hyperinsulinemia, HTN : with : with HAIR-AN syndromeHAIR-AN syndrome - - hhyperyperaandrogenism,ndrogenism, i insulinnsulin r resistance andesistance and aacanthosis canthosis nnigricans igricans : ovarian androgen ↑(testosterone,DTH,androstenedione): ovarian androgen ↑(testosterone,DTH,androstenedione)

: Tx: Tx - wedge resection- wedge resection but, in severe case, only transientbut, in severe case, only transient - bilateral oophorectomy- bilateral oophorectomy GnRH agonistGnRH agonist

Virilization during PregnancyVirilization during Pregnancy

Frequently. luteomas of pregnancyFrequently. luteomas of pregnancy : maternal & fetal musculinization: maternal & fetal musculinization : usually regresses postpartum: usually regresses postpartum : 30%- maternal virilization: 30%- maternal virilization 65%- virilized female newborn65%- virilized female newborn

Krukenberg tumor, mucinous cystic tumor, BrennerKrukenberg tumor, mucinous cystic tumor, Brenner tumor, serous cystadenoma, ecdodermal sinus tumor, tumor, serous cystadenoma, ecdodermal sinus tumor, dermoid cyst dermoid cyst

Virilizing Adrenal NeoplasmVirilizing Adrenal Neoplasm

Most common: adrenal carcinomaMost common: adrenal carcinoma - DHEAS ↑, hypercortisolism- DHEAS ↑, hypercortisolism - often large and detectable on abd. examination- often large and detectable on abd. examination Less commonly, testosterone-secreting adenomas Less commonly, testosterone-secreting adenomas - normal or moderately elevated DHEAS- normal or moderately elevated DHEAS

Pure virilizing adrenal neoplasmPure virilizing adrenal neoplasm - 90% benign,- 90% benign, - peak age: 20~40 years- peak age: 20~40 years (pure testosterone-secreting adenomas: menopause)(pure testosterone-secreting adenomas: menopause) - unilateral- unilateral

Prolactin DisorderProlactin Disorder

A product of the anterior pituitary (1933)A product of the anterior pituitary (1933) Be found in nearly every vertebrate speciesBe found in nearly every vertebrate species Primary function Primary function

: initiation and maintenance of lactation: initiation and maintenance of lactation

: roles for reproductive system: roles for reproductive system

Prolactin secretionProlactin secretion

199 amino acids199 amino acids Molecular weight: 23,000 daltonsMolecular weight: 23,000 daltons Human growth hormone, placental lactogenHuman growth hormone, placental lactogen : lactogenic activity: lactogenic activity : but, 16% & 13% amino acid sequence homology with: but, 16% & 13% amino acid sequence homology with prolactinprolactin Chromosome 6 encodes prolactinChromosome 6 encodes prolactin 5 exons & 4 introns5 exons & 4 introns Three fomrs : monomer-Three fomrs : monomer- little little (50%)(50%) dimer- dimer- bigbig multimeric- multimeric- big-bigbig-big : proportion- physiologic, pathologic,: proportion- physiologic, pathologic, and hormonal stimulationand hormonal stimulation

do not require glycosylation for primary activitiesdo not require glycosylation for primary activities

Inhibitory control mediated by dopamineInhibitory control mediated by dopamine : by the tuberoinfundibular dopaminergic neuron into: by the tuberoinfundibular dopaminergic neuron into the poral hypophyseal vesselthe poral hypophyseal vessel : dopamine receptor- on pituitary lactotrophs: dopamine receptor- on pituitary lactotrophs TRH: releasing factorTRH: releasing factor GABA, neurohormone & transmitter: inhibitory factors GABA, neurohormone & transmitter: inhibitory factors

HyperprolactinemiaHyperprolactinemia

Physiologic disturbance, pharmacologic agents,Physiologic disturbance, pharmacologic agents, compromised renal functioncompromised renal function Acute stress, painful stimuliAcute stress, painful stimuli Most common: pharmacologic causeMost common: pharmacologic cause (antipsychotics, antidopaminergic agents)(antipsychotics, antidopaminergic agents)

EvaluationEvaluation

5~27 ng/mL throughout the normal menstrual cycle5~27 ng/mL throughout the normal menstrual cycle Pulsatile secretion: 14 pulse/24 hrs (late follicular phase)Pulsatile secretion: 14 pulse/24 hrs (late follicular phase) ↓ ↓ 9 pulse/24hrs (late luteal phase)9 pulse/24hrs (late luteal phase) Diurnal variationDiurnal variation : lowest- midmorning (← sample preferably): lowest- midmorning (← sample preferably) : rise 1 hour after onset of sleep and continue to rise: rise 1 hour after onset of sleep and continue to rise until peak values (5~7AM)until peak values (5~7AM) Sample should not be obtainedSample should not be obtained : after awakes, procedure, stressful event, breast stimuli,: after awakes, procedure, stressful event, breast stimuli, previous venipuncture, PEx, previous venipuncture, PEx,

Physical SignsPhysical Signs

Amenorrhea without galactorrhea (15%)Amenorrhea without galactorrhea (15%) : the cessation of normal ovulatory process resulting: the cessation of normal ovulatory process resulting from elevated prolactin level, via hypothalamicfrom elevated prolactin level, via hypothalamic mediation, on GnRH pulsatile releasemediation, on GnRH pulsatile release

Isolated galactorrheaIsolated galactorrhea : within normal range of prolactin (50%): within normal range of prolactin (50%) : because of prior episode of hyperprolactinemia or: because of prior episode of hyperprolactinemia or other factor, sensitivity of breast to the lactotrophicother factor, sensitivity of breast to the lactotrophic stimulus by normal prolactin levels stimulus by normal prolactin levels

Both galactorrhea & amenorrheaBoth galactorrhea & amenorrhea : 2/3- hyperprolactinemia: 2/3- hyperprolactinemia (1/3 pituitary adenoma)(1/3 pituitary adenoma)

Delayed pubertyDelayed puberty : check prolactin & TSH levels !!!: check prolactin & TSH levels !!! : pituitary abnormalities (craniopharyngioma, adenoma): pituitary abnormalities (craniopharyngioma, adenoma) multiple endocrine neoplasia type-I (MEN-I)multiple endocrine neoplasia type-I (MEN-I) ((gastrinoma, insulinoma, parathyroid hyperplasia, pituitary neoplasiagastrinoma, insulinoma, parathyroid hyperplasia, pituitary neoplasia ))

Imaging TechniquesImaging Techniques

Larger microadenomas & macroadenomaLarger microadenomas & macroadenoma : prolactin > 100 ng/mL: prolactin > 100 ng/mL Smaller aicroadenomas & suprasellar tumorsSmaller aicroadenomas & suprasellar tumors : prolactin < 100 ng/mL: prolactin < 100 ng/mL

MRI of sella & pituitary gland with enhancementMRI of sella & pituitary gland with enhancement : provide best anatomical detail: provide best anatomical detail : differentiate microadenoma from macroadenoma: differentiate microadenoma from macroadenoma : identify other potenial sellar or suprasellar masses: identify other potenial sellar or suprasellar masses

90% of untreated women, microadenoma do not 90% of untreated women, microadenoma do not enlarge over a 4- to 6-year periodenlarge over a 4- to 6-year period Prolactin level correlate with tumor size,Prolactin level correlate with tumor size, but, both elevation & reduction may occur withoutbut, both elevation & reduction may occur without any change in tumor sizeany change in tumor size If prolactin increase significantly or CNS Sx.,If prolactin increase significantly or CNS Sx., repeat imagingrepeat imaging

Hypothalamic DisordersHypothalamic Disorders

DopamineDopamine : arcuate nucleus: arcuate nucleus → → median eminencemedian eminence → → hypophyseal portal systemhypophyseal portal system → → anterior pituitaryanterior pituitary Disrupt dopamine pathwayDisrupt dopamine pathway : disrupt dopamine release: disrupt dopamine release → → hyperprolactinemiahyperprolactinemia

Pituitary Disorder (Microadenoma)Pituitary Disorder (Microadenoma)

25% of autopsy series of U.S. population25% of autopsy series of U.S. population 40% stain positively for prolactin40% stain positively for prolactin Clinically significant tumor: 14/100,000 individualsClinically significant tumor: 14/100,000 individuals

1/3 of hyperprolactineima: radiologic lesion1/3 of hyperprolactineima: radiologic lesion microadenoma (< 1cm)microadenoma (< 1cm)

Generally benign course,Generally benign course, gradually regress spontaneouslygradually regress spontaneously

Monoclonal in originMonoclonal in origin : genetic mutation→ release stem cell growth inhibition: genetic mutation→ release stem cell growth inhibition → → autonomous ant. pituitary hormone productionautonomous ant. pituitary hormone production

Rarely progress to macroadenomaRarely progress to macroadenoma : only 7%: only 7%

Chronic headache, visual disturbance, Chronic headache, visual disturbance, extraocular muscle palsiesextraocular muscle palsies

[Expectant management][Expectant management] In women, do not desire fertilityIn women, do not desire fertility menstrual function intactmenstrual function intact

Hyperprolactinemia-induced estrogen deficiencyHyperprolactinemia-induced estrogen deficiency : develop osteopenia: develop osteopenia : therefore, estrogen replacement or contraceptives: therefore, estrogen replacement or contraceptives

In absence of symptoms,In absence of symptoms, imaging may be repeated in 12 months to assessimaging may be repeated in 12 months to assess further growth of the microadenomafurther growth of the microadenoma

[Medical Treatment][Medical Treatment] Ergot alkaloids: mainstay of therapyErgot alkaloids: mainstay of therapy BromocriptineBromocriptine - strong dopamine agonist- strong dopamine agonist decrease prolactin leveldecrease prolactin level decrease lesion size within 1~2 weeksdecrease lesion size within 1~2 weeks - decrease prolactin synthesis, DNA synthesis, cell- decrease prolactin synthesis, DNA synthesis, cell multiplication, and overall size of prolactinomamultiplication, and overall size of prolactinoma - result in normal prolactin level or return of ovulatory- result in normal prolactin level or return of ovulatory menses in 80~90% of patientsmenses in 80~90% of patients - excreted via the biliary tree, caution in the liver ds.- excreted via the biliary tree, caution in the liver ds. patientspatients

- adverse effect: nausea, headache, hypotension,- adverse effect: nausea, headache, hypotension,

dizziness, fatigue, drowsiness, dizziness, fatigue, drowsiness, vomiting,vomiting,

constipation, nasal congestionconstipation, nasal congestion

‘ ‘hallucination, delusion, mood hallucination, delusion, mood change’change’

- regimen: increased gradually- regimen: increased gradually

1 wks- 1.25 mg every evening1 wks- 1.25 mg every evening

2 wks- 1.25 mg every morning & evening2 wks- 1.25 mg every morning & evening

3 wks- 1.25 mg morning, 2.5 mg evening3 wks- 1.25 mg morning, 2.5 mg evening

4 wks- 2.5 mg every morning & evening4 wks- 2.5 mg every morning & evening

CabergolineCabergoline - long half life, twice per week- long half life, twice per week - slow elimination by pituitary tumor,- slow elimination by pituitary tumor, high affinity binding to dopamine receptorhigh affinity binding to dopamine receptor entensive enterohepatic recirculation entensive enterohepatic recirculation - fewer adverse effect- fewer adverse effect

Pergolide Pergolide or or methergolinemethergoline

Discontinuation of medication Discontinuation of medication : successful to maintain normal prolactinlevel: successful to maintain normal prolactinlevel : recerrence rate- macroadenoma > microadenoma: recerrence rate- macroadenoma > microadenoma

Pituitary Disorder (Macroadenoma)Pituitary Disorder (Macroadenoma)

> 1cm> 1cm BromocriptineBromocriptine & transsphenoidal surgery & transsphenoidal surgery SymptomSymptom : severe headache, visual field change, DI, blindness: severe headache, visual field change, DI, blindness

[Medical Treatment][Medical Treatment] BromocriptineBromocriptine: decrease prolactin & tumor size: decrease prolactin & tumor size Discontinuation: tumor regrowth, so long-term TxDiscontinuation: tumor regrowth, so long-term Tx Repeat MRI & prolactin every 6 monthsRepeat MRI & prolactin every 6 months[Surgical Intervention][Surgical Intervention] Unresponsive to medical treatment Unresponsive to medical treatment

Monitoring Pituitary Adenomas Monitoring Pituitary Adenomas During PregnancyDuring Pregnancy

Rarely complications during pregnancyRarely complications during pregnancy but, recommended visual field Ex. & fundoscopybut, recommended visual field Ex. & fundoscopy If, persistent headache, visual deficitIf, persistent headache, visual deficit : MRI scanning: MRI scanning While taking While taking bromocriptine,bromocriptine, become pregnant become pregnant : discontinuation medication: discontinuation medication : but, not teratogenecity in animals: but, not teratogenecity in animals data do not suggest it is harmful to fetus in humandata do not suggest it is harmful to fetus in human Breastfeeding: not contraindicated in microadenoma orBreastfeeding: not contraindicated in microadenoma or macroadenomamacroadenoma

Thyroid DisorderThyroid Disorder

10 times more: women > men10 times more: women > men 1% of female in U.S.A1% of female in U.S.A Iodide (critical component of thyronines) Iodide (critical component of thyronines) → → triiodothyronine (T3) & thyroxine (T4)triiodothyronine (T3) & thyroxine (T4) Thyroid follicular cell: synthesis hormonesThyroid follicular cell: synthesis hormones - sodium-iodide symporter (NIS)- sodium-iodide symporter (NIS) - TSH: uptake stimulation with Na-K ATPase- TSH: uptake stimulation with Na-K ATPase - thyroid peroxidase (TPO): MIT,DIT formation within- thyroid peroxidase (TPO): MIT,DIT formation within thyroglobulinthyroglobulin : secondary forms T3, T4 : secondary forms T3, T4

ThyroglobulinThyroglobulin : major protein formed in the thyroid gland: major protein formed in the thyroid gland : iodine content- 0.1~1.1% by weight: iodine content- 0.1~1.1% by weight : 33% of iodine- form of T3 & T4: 33% of iodine- form of T3 & T4 (remainder- MIT,DIT)(remainder- MIT,DIT) : storage capacity- keep euthyroid state for 2 months: storage capacity- keep euthyroid state for 2 months

T3T3 : primary physiologically functional thyroid hormone: primary physiologically functional thyroid hormone : T4>T3 40~100 times: T4>T3 40~100 times but, T4- slow turnover, lower binding affinity but, T4- slow turnover, lower binding affinity T3- high turnover, higher binding affinityT3- high turnover, higher binding affinity

Thyroid hormoneThyroid hormone

: increased oxygen consumption: increased oxygen consumption

heat productionheat production

metabolism of fat, protein, and carbohydratemetabolism of fat, protein, and carbohydrate

→ → balance fuel efficiencybalance fuel efficiency

carburetor function in an enginecarburetor function in an engine

Iodide MetabolismIodide Metabolism

IodineIodine : 150~300 mg/day: 150~300 mg/day : indigested in the form of iodized salt: indigested in the form of iodized salt

: dietary iodine insufficient region: dietary iodine insufficient region - goitrous hypothyroidism among adult- goitrous hypothyroidism among adult inadequate fetal thyroxine ( endemic goiter, cretinism)inadequate fetal thyroxine ( endemic goiter, cretinism)

Risk Factors Risk Factors for Autoimmune Thyroid Disordersfor Autoimmune Thyroid Disorders

Environmental factorEnvironmental factor : pollutants, Ab to : pollutants, Ab to Yersinia enterocoliticaYersinia enterocolitica

Immunoglobulin produced against the thyroid are Immunoglobulin produced against the thyroid are polyclonal, and the multiple combination of various polyclonal, and the multiple combination of various Ab presentAb present

Evaluation- Thyroid FunctionEvaluation- Thyroid Function

T3RU % x T4 total = free T4 indexT3RU % x T4 total = free T4 index

: T3,T4- binding protein TBG: T3,T4- binding protein TBG

: resin uptake- compete with TBG for T3 binding: resin uptake- compete with TBG for T3 binding

: high T3 resin uptake: high T3 resin uptake

- reduced TBG receptor- reduced TBG receptor

→ →high T4 index→ hyperthyroidismhigh T4 index→ hyperthyroidism TSHTSH

: best way to screen for thyroid dysfunction: best way to screen for thyroid dysfunction

Immunologic AbnormalitiesImmunologic Abnormalities

Antithyroglobulin Ab (anti-Tg)Antithyroglobulin Ab (anti-Tg) : hashimoto thyroiditis, Graves ds., acute thyroiditis,: hashimoto thyroiditis, Graves ds., acute thyroiditis, nontoxic goiter, thyroid cancernontoxic goiter, thyroid cancer

Antithyroid peroxidase Ab (anti-TPO)Antithyroid peroxidase Ab (anti-TPO) : antimocrosomal Ab: antimocrosomal Ab : hashimoto thyroiditis, Graves ds., postpartum thyroiditis: hashimoto thyroiditis, Graves ds., postpartum thyroiditis : histology- lymphocyte thyroiditis: histology- lymphocyte thyroiditis

TSH receptor Ab (THSR-Ab or TRAb)TSH receptor Ab (THSR-Ab or TRAb)

Autoimmune Thyroid DiseaseAutoimmune Thyroid Disease

Most common thyroid diseaseMost common thyroid disease : autoimmune thyroid disorder: autoimmune thyroid disorder combined effects of multiple Ab productioncombined effects of multiple Ab production Transplacental transmission of immunoglobulinTransplacental transmission of immunoglobulin : autoimmune disorder: autoimmune disorder : Hashimoto thyroiditis, Addison ds., ovarian failure,: Hashimoto thyroiditis, Addison ds., ovarian failure, RA, Sjogren synd., DM I, vitiligo, MG, ITPRA, Sjogren synd., DM I, vitiligo, MG, ITP Assessment of thyroid functionAssessment of thyroid function : infertile & pregnant women, AF, hyperemesis, DM I,: infertile & pregnant women, AF, hyperemesis, DM I, Hx. of postpartum thyroiditis, et al. Hx. of postpartum thyroiditis, et al.

Hashimoto ThyroiditisHashimoto Thyroiditis

Chronic lymphocytic thyroiditisChronic lymphocytic thyroiditis Hyper-or hypothyroidism, euthyroid goiter, diffuse goiterHyper-or hypothyroidism, euthyroid goiter, diffuse goiter High level antimicrosomal & antithyroglobulin AbHigh level antimicrosomal & antithyroglobulin Ab

HistologyHistology : cellular hyperplasia, follicular cell disruption: cellular hyperplasia, follicular cell disruption infiltration of lymphocyte, monocyte, plasma cellinfiltration of lymphocyte, monocyte, plasma cell : interstitial cell- fibrosis, lymphocyte infiltration: interstitial cell- fibrosis, lymphocyte infiltration

Clinical characteristics Clinical characteristics : relatively asymptomatic with painless goiter and : relatively asymptomatic with painless goiter and hypothyroidismhypothyroidism : hypothyroidism- cold intolerance, constipation, fatigue,: hypothyroidism- cold intolerance, constipation, fatigue, carpal tunnel synd., dry skin, hair loss,carpal tunnel synd., dry skin, hair loss, lethargy, Wt. loss lethargy, Wt. loss : hyperthyroidism- 4~8%: hyperthyroidism- 4~8% similar symptoms with Graves ds.similar symptoms with Graves ds. DiagnosisDiagnosis : elevated TSH, antithyroglobulin & antomicrosomal Ab: elevated TSH, antithyroglobulin & antomicrosomal Ab : ESR ↑ - depend on the course of disease: ESR ↑ - depend on the course of disease

TreatmentTreatment : thyroxine (: thyroxine (levothyroxinelevothyroxine) replacement) replacement - does not reduce gland size- does not reduce gland size but, prevents further growthbut, prevents further growth : monitor TSH at least 6 weeks: monitor TSH at least 6 weeks : 0.025~0.075 mg gd: 0.025~0.075 mg gd

HypothyrodismHypothyrodism : decreased fertility resulting from ovulatory difficulties: decreased fertility resulting from ovulatory difficulties & spontaneous abortion& spontaneous abortion : amenorrhea, anovulation: amenorrhea, anovulation → → replacement therapy reverse these defectsreplacement therapy reverse these defects

Graves DiseaseGraves Disease

Suppressor T lymphocyteSuppressor T lymphocyte → → develop helper T-cell populationdevelop helper T-cell population → → that react to multiple epitopes of thyrotropin receptorthat react to multiple epitopes of thyrotropin receptor → → B-cell-mediated responseB-cell-mediated response → → feature of Graves diseasefeature of Graves disease TSAb (thyroid-stimulating Ab)TSAb (thyroid-stimulating Ab) : 90% of Graves ds.: 90% of Graves ds. HLA II AgHLA II Ag : upregulated by chronic stimulation of TSH receptor: upregulated by chronic stimulation of TSH receptor → → reduction in the iodinating capacity of thyroid tissuereduction in the iodinating capacity of thyroid tissue Use of Use of interferon-interferon-αα

Clinical characteristicsClinical characteristics : triad- exophthalmos, goiter, hyperthyroidism: triad- exophthalmos, goiter, hyperthyroidism : frequent bowel movement, heat intolerance, irritability,: frequent bowel movement, heat intolerance, irritability, nervousness, palpitation, tachycardia, tremor, Wt. loss,nervousness, palpitation, tachycardia, tremor, Wt. loss, lower extremity swellinglower extremity swelling

: PEx.- lid leg, nontender thyroid enlargement, thick skin: PEx.- lid leg, nontender thyroid enlargement, thick skin cervical venous bruitcervical venous bruit

: severe- acropathy, chemosis, dermopathy, clubbing,: severe- acropathy, chemosis, dermopathy, clubbing, conjunctivitis, pretibial myxedema, vision lossconjunctivitis, pretibial myxedema, vision loss

DiagnosisDiagnosis : check : check T4, T3T4, T3, and , and TSHTSH : useful in evaluating medical Tx, prognosis, and: useful in evaluating medical Tx, prognosis, and anticipating neonatal thyrotoxicosisanticipating neonatal thyrotoxicosis : smoking- independent risk factor: smoking- independent risk factor

TreatmentTreatment

Iodine-131 AblationIodine-131 Ablation : single dose of radioactive iodine-131: single dose of radioactive iodine-131 : effective cure on about 80%: effective cure on about 80% : nonpregnant women: nonpregnant women : miscarriage rate ↑: miscarriage rate ↑ but, no reported increase in the rate of stillbirths, but, no reported increase in the rate of stillbirths, preterm labor, low birth weight, congenital malformationpreterm labor, low birth weight, congenital malformation or deathor death : postablative hypothyroidism in 50%: postablative hypothyroidism in 50% replacement replacement levothyroxinelevothyroxine

<Thyroid-stimulating receptor Ab in Graves disease><Thyroid-stimulating receptor Ab in Graves disease> : TSHR-Ab or TBII: TSHR-Ab or TBII : parallels the degree of hyperthyroidism: parallels the degree of hyperthyroidism

: measurement of TSHR-Ab: measurement of TSHR-Ab - useful marker of disease severity- useful marker of disease severity - predictive of subsequent outcome- predictive of subsequent outcome

Antithyroid DrugsAntithyroid Drugs : : Propylthiouracil (PTU)Propylthiouracil (PTU) - 100mg tid over 1 months - 100mg tid over 1 months high dose- control of thyrotoxic symptomhigh dose- control of thyrotoxic symptom - blocks intrathyroid synthesis of T3- blocks intrathyroid synthesis of T3 peripheral conversion of T4 to T3peripheral conversion of T4 to T3 - not cross placenta !!!- not cross placenta !!! - S/E: appetite, emotional change, insomnia, tremor,- S/E: appetite, emotional change, insomnia, tremor, pruritus, granulocytosis, et al.pruritus, granulocytosis, et al.

: : MethimazoleMethimazole - 10 mg every 8 to 24 hours- 10 mg every 8 to 24 hours - nonpregnant women - nonpregnant women → → if pregnant: skin lesion, aplasia cutis congenitaif pregnant: skin lesion, aplasia cutis congenita - but, longer dosing interval & lower cost- but, longer dosing interval & lower cost

: : iodineiodine - congenital goiter- congenital goiter : : lithiumlithium - Ebstein’s anomaly- Ebstein’s anomaly

SurgerySurgery : subtotal thyroidectomy: subtotal thyroidectomy : most rapid & consistent method for euthyroid state: most rapid & consistent method for euthyroid state : children, young women, pregnant, coexistent thyroid: children, young women, pregnant, coexistent thyroid nodule → potential candidates for thyroidectomynodule → potential candidates for thyroidectomy

: postoperative complication: postoperative complication - hypoparathyroidism, recurrent laryngeal nerve palsy,- hypoparathyroidism, recurrent laryngeal nerve palsy, anesthetic & surgical risk, hypothyroidism, failure to anesthetic & surgical risk, hypothyroidism, failure to relieve thyrotoxicosisrelieve thyrotoxicosis

ββ- Blocker- Blocker : : propranololpropranolol- hypersensitive to other medical therapy- hypersensitive to other medical therapy

Thyroid StormThyroid Storm

In severe hypothyroidismIn severe hypothyroidism : physiologic stress: physiologic stress - childbirth, systemic infection, surgery- childbirth, systemic infection, surgery : symptom: symptom - diarrhea, vomiting, fever, dehydration, mental status- diarrhea, vomiting, fever, dehydration, mental status : treatment: treatment - - ββ-blocker, glucocorticoid, PTU, iodide -blocker, glucocorticoid, PTU, iodide

Hyperthyroidism in GTD andHyperthyroidism in GTD andHyperemesis GravidarumHyperemesis Gravidarum Because weak TSH-like activity of hCG,Because weak TSH-like activity of hCG, high hCG may be associated with biochemical andhigh hCG may be associated with biochemical and clinical hyperthyroidismclinical hyperthyroidism

Removal of GTD or resolution of hCGRemoval of GTD or resolution of hCG : regress symptom: regress symptom

Thyroid Function in PregnancyThyroid Function in Pregnancy

High level of hCG at the end of 1High level of hCG at the end of 1stst trimester trimester : thyrotropic effects of TSH: thyrotropic effects of TSH : TSH level may show transient depression: TSH level may show transient depression

So, replacement thyroid hormone So, replacement thyroid hormone : fetal or infant neurodevelopmental outcome ↑ : fetal or infant neurodevelopmental outcome ↑

Reproductive Effects of Reproductive Effects of HyperthyroidismHyperthyroidism

High level of TSAb in Graves ds.High level of TSAb in Graves ds. : fetal-neonatal hyperthyroidism (2~10%): fetal-neonatal hyperthyroidism (2~10%)

Severe thyrotoxicosisSevere thyrotoxicosis : Wt. loss, irregular menstruation, amenorrhea: Wt. loss, irregular menstruation, amenorrhea : increased spontaneous abortion: increased spontaneous abortion : increased congenital anomalies: increased congenital anomalies → → treated with treated with methimazolemethimazole

Risk of exposing a fetus to TAHR-AbRisk of exposing a fetus to TAHR-Ab : fetal-neonatal hyperthyroidism- 2~10%: fetal-neonatal hyperthyroidism- 2~10% : transplacental passage of TSHR-Ab: transplacental passage of TSHR-Ab - 16% neonatal mortality- 16% neonatal mortality FDIU, stillbirth, skeletal anomalyFDIU, stillbirth, skeletal anomaly

Postpartum Thyroid Dysfunction Postpartum Thyroid Dysfunction

Symptom appear 1 to 8 months postpartumSymptom appear 1 to 8 months postpartum Be confused with postpartum depressionBe confused with postpartum depression

Diagnostic criteriaDiagnostic criteria 1) no Hx. of thyroid disorder before or during pregnancy1) no Hx. of thyroid disorder before or during pregnancy 2) documented abnormal TSH level during the first year 2) documented abnormal TSH level during the first year postpartumpostpartum 3) absence of positive TSH-receptor Ab titer (Graves ds.)3) absence of positive TSH-receptor Ab titer (Graves ds.) or toxic noduleor toxic nodule

Incidence: 5%Incidence: 5% : 25% of these women- permanent hypothyroid : 25% of these women- permanent hypothyroid Histologically,Histologically, : lymphocytic infiltration & inflammation: lymphocytic infiltration & inflammation : antimicrosomal Ab: antimicrosomal Ab Familial Hx. or autoimmune ds. Hx.Familial Hx. or autoimmune ds. Hx. : risk ↑: risk ↑

Clinical characteristics Clinical characteristics : often begin with transient hyperthyroid phase: often begin with transient hyperthyroid phase : type I DM- risk 3 times: type I DM- risk 3 times : previous postpartum thyroiditis- 70% recurrence: previous postpartum thyroiditis- 70% recurrence TSH, T4,T3, T3 resin uptake, antimicrosomal Ab titer TSH, T4,T3, T3 resin uptake, antimicrosomal Ab titer

TreatmentTreatment : T4 replacement: T4 replacement : 10~30% permanent hypothyroidism: 10~30% permanent hypothyroidism : TSH follow up for discontinuation of replacement Tx.: TSH follow up for discontinuation of replacement Tx.

Antithyroid Antibodies and Antithyroid Antibodies and Disorder of ReproductionDisorder of Reproduction Increased risk of spontaneous abortionIncreased risk of spontaneous abortion

Serve as peripheral markers of abnormal T-cell Serve as peripheral markers of abnormal T-cell functionfunction

and implicate an immune component as the cause and implicate an immune component as the cause of of

reproductive failurereproductive failure

Thyroid NudulesThyroid Nudules

Common finding on PEx.Common finding on PEx. Demonstrated by USG (>50%)Demonstrated by USG (>50%) Clinical and laboratory evaluationClinical and laboratory evaluation : DDx. functional or malignant: DDx. functional or malignant If notfunctional “cold” noduleIf notfunctional “cold” nodule : FNA for R/O malignancy: FNA for R/O malignancy : 2~20%- malignant: 2~20%- malignant → → surgical biopsysurgical biopsy

Gonadal Dysgenesis and Down SyndromeGonadal Dysgenesis and Down Syndrome

Gonadal dysgenesis (ex. Turner syndrome)Gonadal dysgenesis (ex. Turner syndrome) : high prevalence of autoimmune thyroid disorders: high prevalence of autoimmune thyroid disorders : 50%- anti-TPO & anti-TG autoantibodies: 50%- anti-TPO & anti-TG autoantibodies : subclinical or clinical hypothyroidism: subclinical or clinical hypothyroidism

Down syndromeDown syndrome : autoimmune thyroid disorder ↑: autoimmune thyroid disorder ↑ : most common- Hashimoto thyroiditis: most common- Hashimoto thyroiditis 50% of patients over 40 ages50% of patients over 40 ages