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28. Endocrine Disorder 부산백병원 산부인과 R4 서 영 진.

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Presentation on theme: "28. Endocrine Disorder 부산백병원 산부인과 R4 서 영 진."— Presentation transcript:

1 28. Endocrine Disorder 부산백병원 산부인과 R4 서 영 진

2 Hyperandrogenism Hirsutism : result of androgen excess
→ abnormalities of ovary, adrenal gland : increase expression of androgen effect Virilization : rare indicates marked elevations on androgen caused by an ovarian or adrenal neoplasm

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

4 Androgen effects in hair vary in relation to specific
regions of the body surface : no androgen dependence-lanugo, eyeblows, eyelashes : minimal sensitivity-limbs, trunk : sensitivity ↑- axilla, pubic region Result from both increased androgen production & skin sensitivity :skin sensitivity–depend on local activity of 5α-reductase : 5α-reductase - testosterone → dihyhrotestosterone in hair follicles

5 Hair: cyclic activity – growth (anagen)
involution (catagen) resting (telogen) : duration –according to body region, genetic factor age, hormonal effects Hirsutism: relative > absolute, designation

6 Hypertrichosis and Virilization
Hypertrichosis: androgen-independent terminal hair (nonsexual area: trunk, extremities) - AD congenital disorder metabolic disorder (anorexia nervosa, hyperthyroidism) medication (acetazoamide, cirticosteroid, cyclosporine, diazoxide, interferon, minoxidil..) Virilization: coarsening of the voice, increase muscle, clitoromegaly (width 3.4+1mm, length mm) feature of defeminization (loss of breast volume)

7 Focus on the age at onset & rate of progression
: rapid- more severe degree of hyperandrogenism (ex. ovaran or adrenal neoplasm, Cushing synd.) : anovulation- probability of hyperandrogenism Determining the extent of hirsutism : questions about shaving & use of depilatories : clinically mild, moderate, severe : scoring scale- adrogen-densitive hair in nine body scale of 0 to 4 → hirsutism > score 8

8

9 PCOS, congenital or adult onset adrenal hyperplasia,
DM, cardiovascular disease, drug use PEx: obesity, hypertension, galactorrhea, male-pattern baldness, acne, hyperpigmentation DDX :Cushing syndrome

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

11

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

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

14 Assessment of Hyperandrogenemia
Testosterone production ↑ ≠ total testosterone ↑ : because of depression of SHBG : moderate – normal range total testorterone : severe (virilization, neoplastic production of testosterone) - can be detected by measure of total testosterone : free testosterone level can be measured to assess increases in testosterone production

15 Free testosterone : standard technique- equilibrium dialysis but, expensive, complex, limited to settings : assessment of testosterone binding albiumin & SHBG AT = Ka [A] x FT AT- albumin-bound testosterone Ka – association constant of albumin for testosterone FT- free tetosterone A- albumin

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

17 Laboratory Evaluation
Bioavailable testosterone level (total testosterone, SHBG, and albumin level) Calculated free testosterone level Most clinical situations : total testosterone, DHEAS, 17-hydroxyprogesterone

18 Normal values for serum androgens
Testosterone (total) ng/dL Free testosterone (calculated) pg/mL Percent free testosterone % Bioavailable testosterone ng/dL SHBG nmol/L Albumin ,300-4,800 mg/dL Androstenedione ng/dL DHEAS μg/dL 17-OHP (follicular phase) ng/dL

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

20 Total testosterone > 200 ng/dL
: ovarian & adrenal tumor DHEAS > twice the upper limit : adrenal hyperplasia : upper limit 350 μg/dL (9.5 nmol/L) Virilization : total testosterone & DHEAS should be measured

21 Polycystic Ovary Syndrome(PCOS)
Most common cause of hyperandrogenism & hirsutism Stein-Leventhal syndrome : amenorrhea + bilat. Polycystic ovaries + obesity Principally oligomenorrhea or amenorrhea + clinical or laboratory evidence of hyperandrogenemia Diagnostic criteria : Major – chronic anovulation hyperandrogenemia clinical signs of hyperandrogenism other etiologies excluded

22 : Minor – insulin resistance
perimenarchal onset of hirsutism and obesity elevated LH-to-FSH ratio intermittent anovulation associated with hyperandrogenemia(free testosterone,DHEAS) Hirsutism : 70% of PCOS in U.S.A 10~20% in japan → difference in skin 5α-reductase activity Amenorrhea & oligomenorrhea Obesity : 50% in PCOS insulin resistance hyperglycemia (type 2 DM)

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

24 Pathology Macroscopically, : 2 ~5 times the normal ovary
: White, thickened cortex with multiple cyst Microscopically, : superficial cortex- fibrotic and hypercellular prominent blood vessel : smaller atretic follicles : luteinized stromal cells

25 Pathophysiology and Laboratory Finding
By abnormalities in 4 endocrinologically compartment 1) the ovaries 2) adrenal glands 3) the periphery (fat) 4) the hypothalamus-pituitary compartment

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

27 Testosterone level in PCOS
: no more than twice the upper normal (20-80 ng/dL) : ovarian hyperthecosis- >200 ng/dL Adrenal gland : hyperfunctioning CYP17 androgen-forming enzyme : DHEAS ↑ (50%) – hyeprresponsiveness to stimulation with ACTH

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

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

30 Insulin Resistance Insulin resistance & hyperinsulinemia
: ovarian dysfunction of PCOS : most common cause- obesity 1. Hyperinsulinemia is not a characteristic of hyperandrogenism in general but is uniquely associated with PCOS 2. in obese women with PCOS, 30-40% have glucose intolerance or DM, whereas ovulatory hyperandrogenic women have normal glucose tolerance and insulin  PCOS-obesity: synergistic

31 : reliable marker of insulin resistance in hirsute women
3. Suppression of ovarian steroidogenesis with long– acting GnRH analogs in women with PCOS does not change insulin levels or insulin resistance 4. Oophorectomy in patients with hyperthecosis accompanied by hyperinsulinemia and hyperandrogenemia does not change insulin resistance, despite a decrease in androgen levels Acanthosis nigricans : reliable marker of insulin resistance in hirsute women : thick, pigmented, velvety lesion- vulva, axilla, neck, breast, inner thigh

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

33 Screening strategies for diabetes and insulin resistance
Fasting glucose:insulin < 4.5 : insulin resistance 2 hr GTT : nonobese(10%), obese(40-50%) with PCOS - inpared glucose tolerance, type II DM testing women with PCOS for glucose intolerance is of value because their risk of cardiovascular disease correlates with this finding

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

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

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

37 Long-term Risks Chronic anovulation
: persistently elevated estrogen, unopposed by progesterone  increase the risk of endometrial carcinoma but, usually well-differentiated, stage I cure rates approaching 100% Prevention of endometrial cancer : endometrial biopsy should be considered in PCOS : influence factor:- abnormal bleeding, weight ↑, age

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

39 Treatment of Hyperandrogenism and PCOS
Depends on a aptient’s goals : hormonal contraception, ovulation induction, et al : ovulatory dysfuction  progestational interruption of unopposed estrogen effects on endometrium is required Interruption of hyperandrogenism & control of hirsutism : can be accomplished simutaneously : if patient desires pregnancy, control of hirsutism may not be possible

40 Weight Reduction The initial recommendation
: reduce insulin, SHBG, and androgen : restore ovulation with ovulation-induction agents Weight loss of as little as 5~7% : reduce bioavailable or calculated testosterone : restore ovulation & fertility in more than 75% women

41 Oral Contraceptives Combination OCs
: decrease adrenal & ovarian androgen production : reduce hair growth in 2/3 hirsute patients 1. progesterone component- LH ↓ androgen production ↓ 2. estrogen- increase hepatic production of SHBP free testosterone ↓ 3. circulating androgen ↓ 4. by inhibition of 5α-reductase - decrease conversion of testosterone to DHT in skin

42 : progestin (norgesterol, norethindrone, norethindrone acetate)
When use OCS, a balance must be maintained between the decrease in free testosterone levels and the intrinsic androgenicity of the progestin : progestin (norgesterol, norethindrone, norethindrone acetate) - androgenic activity ↑ - new progestin (desogestrel, gestodene, norgestimate, grospirenone)

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

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

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

46 Ketoconazole Inhibits the key steroidogenic cytochromes
200 mg/day : reduce androstenedione testosterone calculated free testosterone

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

48 Using at least 100 mg daily for 6 months
: most common dosage- 50~100 mg twice daily : reduce sexual hair, hair diameter, hair volume Side effect : menstrual irregularity (metrorrhagia) : mastodynia, urticardia, scalp hair loss Not recommended : renal insufficiency, hyperkalemia : check K, Cr level

49 Cyproterone Acetate Synthetic progestin : antiandrogenic properties
: competitive inhibition of testosterone, DHT at the level of androgen receptor : hepatic enzyme ↑- androgen clearance ↑ + ethinyl estradiol : reduce testosterone, androstenedione suppress gonadotropin increase SHBG

50 Reverse sequential regimens
: cyproterone acetate 100 mg/day on days 5 to 10 ethinyl estradiol mg/day on days 5 to 26 Side effect : fatigue, Wt. gain, libido ↓, nausea, headache, irregular bleeding

51 Flutamide Nonsteroidal antiandrogen : used in prostate cancer
: inhibition of nuclear binding of androgen on tissues : weak inhibitor of tetosterone biosynthesis + low dose OCs : improvement hirsutism : androstenedione, DHT, LH FSH ↓ : side effect- dry skin, hot flush, appetite ↑, dizziness, libido ↓

52 Cimetidine + ethinyl-drospirenone, metformin
: reduce excess total and abdominal fat : dysadipocytokinemia in young women with hyperinsulinemic PCOS Cimetidine Histamine H2 receptor antagonist : weak ability to occupy androgen receptor : inhibit DHT binding at the level of the hair follicle

53 Ovarian Wedge Resection
Finasteride Inhibitor of type 2 5α-reductase 5 mg daily Ovarian Wedge Resection Transient reduce androstenedion level prolonged minmal decrease in testosterone 85%: maintenance of ovulatory cycle

54 Laparoscopic Electrocautery
Severe PCOS whose condition is resistant to clomiphene citrate Coagulation each microcyst Risk: adhesion Physical Methods of hair Removal Depilatory, shaving, plunking, bleaching Electorolysis: permanent destroy hair follicles Laser hair removal

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

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

57 Symptoms : weight gain, central & over clavicle fat redistribution (neck, trunk, abdomen, cheeks) : cortisol excess- insomnia, mood disturbance, overt phycosis, depression Sex steroid precursor overproduction - hyperandrogenism (hirsutism, acne, oligomenorrhea, amenorrhea, thinning scalp hair) Mineralocortocoid overproduction - arterial HTN, hypokalemic alkalosis → fluid retention may cause pedal edema

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

59 Cause Category Cause Relative incidence
ACTH-dependent Cushing syndrome % Ectopic ACTH-secreting tumor % Ectopic CRH-secreting tumor % ACTH-independent Adrenal cancer % Adrenal adenoma % Micronodular adrenal hyperplasia rare Iatrogenis/factitious common

60 ACTH-dependent : result from ACTH secreted by pituitary adenomas or from an ectopic source : hallmark- normal or high ACTH with increased cortisol Pituitary adenoma : microadenomas (<10mm) : resistant to the feedback effect of cortisol Ectopic ACTH syndrome : 1/2- small-cell carcinoma in lung : bronchial & thymic carcinomas, pancreas carcinoid tumor, thyroid medullary cercinomas

61 ACTH-independent cause
: most common- iatrogenic or factitious : corticosteroid- variety of diseases with an inflammatory component

62 Diagnostic Workup for Cushing Syndrome
Screening : 24hr urinary free cortisol - normal range (30~80 μg/day) : overnight dexamethasone suppression test - previous night 11:00 PM 1 mg dexamethasone next day 8:00 AM cortisol

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

64 Differentiation of Cushing syndrome
: high-dose dexamethasone suppression test : used to differentiate from other cause : 2 mg every 6 hours for 2 days : suppresses ACTH in most Cushing syndrome (Cushing’s disease) : no effect- ectopic or adrenal Cushing syndrome

65 Differentiation of ectopic ACTH syndrome
: high plasma ACTH - >4.5 pmol/L or >20 pg/mL - ectopic ACTH production from adrenal gland : low plasma ACTH - <1.1 pmol/L or <5 pg/ml - adrenal Cushing syndrome

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

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68 Laboratory Diagnosis of Cushing Syndrome
Dagnosis hr urinary cortisol DEX low-dose DEX high-dose ACTH ACTH-dependent Cushing synd (60%) ↑ ↑ ↓ normal Pituitary adenoma Basophilic hyperplasia Nodular adrenal hyperplasia Cyclic Cushing synd Ectopic ACTH (15%) ↑ ↑ ↑ ↑ Ectopic CRH(rare) ↑ ↑ ↑↓ ↑ ACTH-independent Adrenal neoplasia ↑ ↑ ↑ ↓ Adenoma (10%) carcinoma (15%) 1’ adrenocorticorid nodular dysplasia(<1%) Pseudo-Cushing synd ↑ ↑ ↓ normal (alcohol-relate,<1%) Exogenous glucocorticoids/ ↑↓ ↓ ↓ ↓ factitious (not cortisol)

69 Treatment of ACTH-independent Form of Cushing Syndrome
Exclude iatrogenic or factitious etiology Usually, adrenal cancers (tumors are relatively inefficient in steroid synthesis) : >6cm- detected by CT or MRI : large, irregular image : unilateral adrenalectomy is preferable in malignancy, complete resection is impossible : postoperative chemotherapy (mitotane)

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

71 Treatment of Cushing Disease
Treatment of choice : transsphenoidal resection : cure rate- 80% (microadenomas) 50% (macroadenomas) Radiation therapy : 4,200~4,500 cGy : total improvement- 15~25% of adults 80% of chilren

72 Medical therapy : mitotane after pituitary radiation : maintain cortisol levels while a patient awaits the full effect of radiation : adrenal enzyme inhibitors - aminoglutethimide, ametyrapone, trilostanes, etomidate : ketoconazole - inhibits adrenal steroid biosynthesis - 600~800 mg/day for 3 months to 1 year

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

74 Congenital Adrenal Hyperplasia
Autosomal recessive disorder Failure to synthesize the fully functional enzyme 1.a relative decrease in cortisol enzyme 2.a compensatory increase in ACTH level 3. hyperplasia of the zona reticularis of adrenal certex 4. an accumulation of the precursors of the affected enzyme in bloodstream

75 21-Hydroxylase Deficiency
>90% of adrenal hyperplasia Salt wasting-severe form : congenital manifestation during the first 2 weeks of life : hypovolemic salt-wasting crisis, hyponatremia, hyperkalemia, acidosis With or without salt-wasting & new born adrenal crisis : genital virilization (clitoromegaly, labioscrotal fusion, abnormal urethral course)

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

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

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79 Nonclassic Adult-onset Congenital adernal hyperplasia
Nonclassic type of 21-hyoroxlase deficiency : partial deficiency in 21-hydroxylation : late-onset, milder hyperandrogenemia : result from mutation both alleles for 21-hydroxylase Symptoms of AOAH present during of after puberty 1. Those with ovulatory abnormalities and features consistent with PCOS (39%) 2. Those with hirsutism alone without oligomenorrhea (39%) 3. Those with elevated circulating androgens but without symptoms (cryptic) (22%)

80 Genetic of 21-hydoxylase deficiency
1. The 21–hydroxylase gene is located on the short arm of chromosome 6, in the midst of the HLA region. 2. The 21–hydroxylase gene is now termed CYP21. Its homologue is the pseudogene CYP21P . 3. Because CYP21P is a pseudogene, the lack of transcription renders it nonfunctional. The CYP21 is the active gene. 4. The CYP21 gene and the CYP21P pseudogene alternate with two genes called C4B and C4A, both of which encode for the fourth component (C4) of serum complement . 5. The close linkage between the 21–hydroxylase genes and HLA alleles has allowed the study of 21–hydroxylase inheritance patterns in families through blood HLA typing

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

82 11β-Hydoxylase Deficiency
5~8% of CAH, or 1 in 100,000 birth Common symptom: hypertension Two isoenzyme: CYP11-B1 & CYP11-B2 middle of long arm of chromosome 8 - synthesis of cortisol and aldosterone Diagnosis : 11-deoxycortisol > 25 ng/mL 60 min after ACTH stimulation 1/3: Lt. ventricular hypertrophy death is reported from cerebrovascular accident

83 3β-Hydoxysteroid Dehydrogenase Deficiency
Both the adrenal glands & ovaries Transforming Δ-5 steroid into the Δ-4 compounds Marked elevation of DHEA & DHEAS of mildly elevated testosterone & androstenedione → screening protocol using exogenous ACTH stimulation

84 Treatment of Adult-onset Congenital Adranal Hyperplasia
Dexamethasone: suppress the H-P axis evening 0.25~0.5 mg, most effective : maintain cortisol level ( > 2 μg/dL) progestin for endometrial regulation clomiphene citrate or gonaditropin for ovulation induction progestin & androgen for control hirsutism

85 Androgen-secreting Ovarian and Adrenal Tumors
Hirsutism, vorolization, rapidly progressing signs of androgen excess Determination if levels of testosterone & DHEAS : testosterone- 2.5 times the upper normal or 200 ng/dL → ovarian androgen-secreting tumor : DHEAS > 800 μg/dL → adrenal tumor Evaluation : first, USG in ovarian neoplasm : Duplex Doppler : CT, MRI, selective venous catheterization

86 Adrogen-producing Ovarian Neoplasms
Granulosa cell tumors : 1~2% (postmenopausal > premenopausal women) : usually associated with estrogen production : TAH c BSO : malinancy potential- 60~90% depend on stage, tumor size, histologic atypia Thecomas : rare, older age, seriod-type (luteinized thecomas) : rare malinant, rare bilateral : simple oophorectomy

87 Sclerosing stromal tumor
: benign, <30 years : a few case, estrogenic or androgenic manifestations Sertoli-Leidig cell tumors : previously, androblastoma, arrhenoblastoma : 11% of solid ovarian tumors : contain Sertoi cells, Leydig cells, fibroblasts : most common virilizing tumor in reproductive age but, musculinization- 1/3 : bilateral 1.5%, 80%- stage IA : Tx: USO TAH c BSO + adjuvant Tx (in advanced stage)

88 Pure sertoli cell tumors
: usuallly unilateral : if premenopausal with stage I → USO : maliganat tumors are rapidly fatal Gynandroblastoma : benign, well differentiated, testicular elements : Tx- USO or unolateral oophorectomy

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

90 Steroid Cell Tumors Composed entirely of steroid-secreting cells
Virilization or hirsutism : 3/4 of Leydig cell tumors

91 Stromal Hyperplasia and Stromal Hyperthecosis
: nonneoplastic proliferation of ovarian stromal cell : 60~80 years : associated with hyperandrogenism, endometrial carcinoma, obesity, HTN, glucose intolerance Stromal hyperthecosis : presence of luteinized stromal cell at distance from the follicles : order age- mild, reproductive age- severe

92 : virilization, obesity, hyperinsulinemia, HTN
: with HAIR-AN syndrome - hyperandrogenism, insulin resistance and acanthosis nigricans : ovarian androgen ↑(testosterone,DTH,androstenedione) : Tx - wedge resection but, in severe case, only transient - bilateral oophorectomy GnRH agonist

93 Virilization during Pregnancy
Frequently. luteomas of pregnancy : maternal & fetal musculinization : usually regresses postpartum : 30%- maternal virilization 65%- virilized female newborn Krukenberg tumor, mucinous cystic tumor, Brenner tumor, serous cystadenoma, ecdodermal sinus tumor, dermoid cyst

94 Virilizing Adrenal Neoplasm
Most common: adrenal carcinoma - DHEAS ↑, hypercortisolism - often large and detectable on abd. examination Less commonly, testosterone-secreting adenomas - normal or moderately elevated DHEAS Pure virilizing adrenal neoplasm - 90% benign, - peak age: 20~40 years (pure testosterone-secreting adenomas: menopause) - unilateral

95 Prolactin Disorder A product of the anterior pituitary (1933)
Be found in nearly every vertebrate species Primary function : initiation and maintenance of lactation : roles for reproductive system

96 Prolactin secretion

97 199 amino acids Molecular weight: 23,000 daltons Human growth hormone, placental lactogen : lactogenic activity : but, 16% & 13% amino acid sequence homology with prolactin Chromosome 6 encodes prolactin 5 exons & 4 introns Three fomrs : monomer- little (50%) dimer- big multimeric- big-big : proportion- physiologic, pathologic, and hormonal stimulation do not require glycosylation for primary activities

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

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

100

101

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

103

104 Physical Signs Amenorrhea without galactorrhea (15%)
: the cessation of normal ovulatory process resulting from elevated prolactin level, via hypothalamic mediation, on GnRH pulsatile release Isolated galactorrhea : within normal range of prolactin (50%) : because of prior episode of hyperprolactinemia or other factor, sensitivity of breast to the lactotrophic stimulus by normal prolactin levels

105 Both galactorrhea & amenorrhea
: 2/3- hyperprolactinemia (1/3 pituitary adenoma) Delayed puberty : check prolactin & TSH levels !!! : pituitary abnormalities (craniopharyngioma, adenoma) multiple endocrine neoplasia type-I (MEN-I) (gastrinoma, insulinoma, parathyroid hyperplasia, pituitary neoplasia)

106

107 Imaging Techniques Larger microadenomas & macroadenoma
: prolactin > 100 ng/mL Smaller aicroadenomas & suprasellar tumors : prolactin < 100 ng/mL

108

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

110

111 90% of untreated women, microadenoma do not
enlarge over a 4- to 6-year period Prolactin level correlate with tumor size, but, both elevation & reduction may occur without any change in tumor size If prolactin increase significantly or CNS Sx., repeat imaging

112 Hypothalamic Disorders
Dopamine : arcuate nucleus → median eminence → hypophyseal portal system → anterior pituitary Disrupt dopamine pathway : disrupt dopamine release → hyperprolactinemia

113 Pituitary Disorder (Microadenoma)
25% of autopsy series of U.S. population 40% stain positively for prolactin Clinically significant tumor: 14/100,000 individuals 1/3 of hyperprolactineima: radiologic lesion microadenoma (< 1cm) Generally benign course, gradually regress spontaneously

114 Monoclonal in origin : genetic mutation→ release stem cell growth inhibition → autonomous ant. pituitary hormone production Rarely progress to macroadenoma : only 7% Chronic headache, visual disturbance, extraocular muscle palsies

115 [Expectant management]
In women, do not desire fertility menstrual function intact Hyperprolactinemia-induced estrogen deficiency : develop osteopenia : therefore, estrogen replacement or contraceptives In absence of symptoms, imaging may be repeated in 12 months to assess further growth of the microadenoma

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

117 - adverse effect: nausea, headache, hypotension,
dizziness, fatigue, drowsiness, vomiting, constipation, nasal congestion ‘hallucination, delusion, mood change’ - regimen: increased gradually 1 wks mg every evening 2 wks mg every morning & evening 3 wks mg morning, 2.5 mg evening 4 wks- 2.5 mg every morning & evening

118 Cabergoline - long half life, twice per week - slow elimination by pituitary tumor, high affinity binding to dopamine receptor entensive enterohepatic recirculation - fewer adverse effect Pergolide or methergoline Discontinuation of medication : successful to maintain normal prolactinlevel : recerrence rate- macroadenoma > microadenoma

119 Pituitary Disorder (Macroadenoma)
> 1cm Bromocriptine & transsphenoidal surgery Symptom : severe headache, visual field change, DI, blindness [Medical Treatment] Bromocriptine: decrease prolactin & tumor size Discontinuation: tumor regrowth, so long-term Tx Repeat MRI & prolactin every 6 months [Surgical Intervention] Unresponsive to medical treatment

120 Monitoring Pituitary Adenomas During Pregnancy
Rarely complications during pregnancy but, recommended visual field Ex. & fundoscopy If, persistent headache, visual deficit : MRI scanning While taking bromocriptine, become pregnant : discontinuation medication : but, not teratogenecity in animals data do not suggest it is harmful to fetus in human Breastfeeding: not contraindicated in microadenoma or macroadenoma

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

122 Thyroglobulin : major protein formed in the thyroid gland : iodine content- 0.1~1.1% by weight : 33% of iodine- form of T3 & T4 (remainder- MIT,DIT) : storage capacity- keep euthyroid state for 2 months T3 : primary physiologically functional thyroid hormone : T4>T3 40~100 times but, T4- slow turnover, lower binding affinity T3- high turnover, higher binding affinity

123 Thyroid hormone : increased oxygen consumption heat production metabolism of fat, protein, and carbohydrate → balance fuel efficiency carburetor function in an engine

124 Iodide Metabolism Iodine : 150~300 mg/day
: indigested in the form of iodized salt : dietary iodine insufficient region - goitrous hypothyroidism among adult inadequate fetal thyroxine ( endemic goiter, cretinism)

125 Risk Factors for Autoimmune Thyroid Disorders
Environmental factor : pollutants, Ab to Yersinia enterocolitica Immunoglobulin produced against the thyroid are polyclonal, and the multiple combination of various Ab present

126 Evaluation- Thyroid Function
T3RU % x T4 total = free T4 index : T3,T4- binding protein TBG : resin uptake- compete with TBG for T3 binding : high T3 resin uptake - reduced TBG receptor →high T4 index→ hyperthyroidism TSH : best way to screen for thyroid dysfunction

127 Immunologic Abnormalities

128 Antithyroglobulin Ab (anti-Tg)
: hashimoto thyroiditis, Graves ds., acute thyroiditis, nontoxic goiter, thyroid cancer Antithyroid peroxidase Ab (anti-TPO) : antimocrosomal Ab : hashimoto thyroiditis, Graves ds., postpartum thyroiditis : histology- lymphocyte thyroiditis TSH receptor Ab (THSR-Ab or TRAb)

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

130 Hashimoto Thyroiditis
Chronic lymphocytic thyroiditis Hyper-or hypothyroidism, euthyroid goiter, diffuse goiter High level antimicrosomal & antithyroglobulin Ab Histology : cellular hyperplasia, follicular cell disruption infiltration of lymphocyte, monocyte, plasma cell : interstitial cell- fibrosis, lymphocyte infiltration

131

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

133

134 Treatment : thyroxine (levothyroxine) replacement - does not reduce gland size but, prevents further growth : monitor TSH at least 6 weeks : 0.025~0.075 mg gd Hypothyrodism : decreased fertility resulting from ovulatory difficulties & spontaneous abortion : amenorrhea, anovulation → replacement therapy reverse these defects

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

136 Clinical characteristics
: triad- exophthalmos, goiter, hyperthyroidism : frequent bowel movement, heat intolerance, irritability, nervousness, palpitation, tachycardia, tremor, Wt. loss, lower extremity swelling : PEx.- lid leg, nontender thyroid enlargement, thick skin cervical venous bruit : severe- acropathy, chemosis, dermopathy, clubbing, conjunctivitis, pretibial myxedema, vision loss

137 Diagnosis : check T4, T3, and TSH : useful in evaluating medical Tx, prognosis, and anticipating neonatal thyrotoxicosis : smoking- independent risk factor

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

139 <Thyroid-stimulating receptor Ab in Graves disease>
: TSHR-Ab or TBII : parallels the degree of hyperthyroidism : measurement of TSHR-Ab - useful marker of disease severity - predictive of subsequent outcome

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

141 : Methimazole - 10 mg every 8 to 24 hours - nonpregnant women → if pregnant: skin lesion, aplasia cutis congenita - but, longer dosing interval & lower cost : iodine - congenital goiter : lithium - Ebstein’s anomaly

142 Surgery : subtotal thyroidectomy : most rapid & consistent method for euthyroid state : children, young women, pregnant, coexistent thyroid nodule → potential candidates for thyroidectomy : postoperative complication - hypoparathyroidism, recurrent laryngeal nerve palsy, anesthetic & surgical risk, hypothyroidism, failure to relieve thyrotoxicosis β- Blocker : propranolol- hypersensitive to other medical therapy

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

144 Hyperthyroidism in GTD and Hyperemesis Gravidarum
Because weak TSH-like activity of hCG, high hCG may be associated with biochemical and clinical hyperthyroidism Removal of GTD or resolution of hCG : regress symptom

145 Thyroid Function in Pregnancy
High level of hCG at the end of 1st trimester : thyrotropic effects of TSH : TSH level may show transient depression So, replacement thyroid hormone : fetal or infant neurodevelopmental outcome ↑

146 Reproductive Effects of Hyperthyroidism
High level of TSAb in Graves ds. : fetal-neonatal hyperthyroidism (2~10%) Severe thyrotoxicosis : Wt. loss, irregular menstruation, amenorrhea : increased spontaneous abortion : increased congenital anomalies → treated with methimazole

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

148 Postpartum Thyroid Dysfunction
Symptom appear 1 to 8 months postpartum Be confused with postpartum depression Diagnostic criteria 1) no Hx. of thyroid disorder before or during pregnancy 2) documented abnormal TSH level during the first year postpartum 3) absence of positive TSH-receptor Ab titer (Graves ds.) or toxic nodule

149 Incidence: 5% : 25% of these women- permanent hypothyroid Histologically, : lymphocytic infiltration & inflammation : antimicrosomal Ab Familial Hx. or autoimmune ds. Hx. : risk ↑ Clinical characteristics : often begin with transient hyperthyroid phase : type I DM- risk 3 times : previous postpartum thyroiditis- 70% recurrence TSH, T4,T3, T3 resin uptake, antimicrosomal Ab titer

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

151 Antithyroid Antibodies and Disorder of Reproduction
Increased risk of spontaneous abortion Serve as peripheral markers of abnormal T-cell function and implicate an immune component as the cause of reproductive failure

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

153 Gonadal Dysgenesis and Down Syndrome
Gonadal dysgenesis (ex. Turner syndrome) : high prevalence of autoimmune thyroid disorders : 50%- anti-TPO & anti-TG autoantibodies : subclinical or clinical hypothyroidism Down syndrome : autoimmune thyroid disorder ↑ : most common- Hashimoto thyroiditis 50% of patients over 40 ages


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