Endocrine Disorders

Chapter 25. Endocrine disorders



I. Hyperandrogenism




A. Hirsuitism




  • The presence of hair in androgen-dependent sites in which hair does not normally
    appear in women


  • cf. Hypertrichosis


    • Androgen-independent growth of hair that is prominent in nonsexual areas such as
      the trunk and extremities.

    • ex) AD congenital disorder, metabolic disorder (Anorexia nervosa, hyperthyroidism,
      porphyria cutanea tarda), Medication (phenytoin, minoxidil, cyclosporine, diazoxide)


  • cf. Virilization


    • Male-pattern baldness, coarsening of the voice, decreased in breast size, increase in
      muscle mass.

    • Loss of female body contour (obesity, particularly of the upper segment,
      waist-to-hip ratio), enlargement of the clitoris.


1. Role of Androgens.



  • Figure 25-1

  • Testosterone : most important circulating androgen



    • 50 % : peripheral conversion of secreted androstenedione
    • 50 % : direct glandular secretion



    • Circulating testosterone (85%) : bound to sex hormone-binding globuline (SHBG)

      ---> biologically inactive.


    • SHBG

      ↑ : pregnancy, luteal phase, estrogen therapy, increased thyroid hormone level,
      liver cirrhosis

      ↓ : androgen, androgenic medication (Progestational agent, Danazol),
      androgenic disorder (PCOS, Cushing's syndrome), Glucocorticoid, Growth
      hormone, Prolactin, insulin, obesity.



    • Relative androgenicity of androgen :
      Dihydrotestosterone, 300 , Testosterone, 100 , Androstenedione, 10 , DHEAS, 5



2. Laboratory evaluation.




  • Initial lab. testing for the assessment of hirsuitism

    --> Total testosterone, DHEAS, 17-OH-progesterone



  • Table 25.1
  • Testosterone level in the male range ( > 200ng/dl )
    -> marker of neoplasm (ovary, adrenal)



  • DHEAS ; moderate elevation - PCOS

    > 700 ug/dl ( 20 nmol/L ) --> adrenal or ovarian tumor



  • 17-HP : 200 ~ 800 ng/dl --> ACTH test

    800 ng/dl ↑ --> 21-hydroxylase def.


B. Polycystic Ovarian Syndrome



  • Symptoms :



    1. Oligomenorhea to Amenorrhea
    2. Infertility
    3. Hirsuitism
    4. Obesity
    5. Hyperandrogenism & chronic anovulation and exclude secondary causes such as
      neoplasm, hyperprolactinemia, and adult-onset congenital adrenal hyperplasia.


1. Pathology



  • Macroscopically, white thickened cortex with multiple cysts that are typically less
    than 1cm in diameter.
  • Microscopically,



    1. Superficial cortex is fibrotic & hypocellular and may contain prominent blood
      vessels
    2. Increased number of follicles with luteinized interna.
    3. Stroma : luteinized stromal cells.


2. Pathophysiology & Lab. findings




  • Dysregulation of the cytochrome P-450c17, the androgen-forming enzyme in both
    the adrenals and the ovaries, may be the central pathogenetic mechanism underlying
    hyperandrogenism in PCOS



  • Peripheral compartment : skin, adipose tissue




    1. The presence of 5-a-reductase in the skin largely determines the presence or
      absence of hirsuitism
    2. Aromatase and 17-b-HSD activities are increased in fat cells and peripheral
      aromatization is increased with body weight.
    3. The metabolism of estrogens, by way of reduced 2-hydroxylation and
      17-a-oxidation, is decreased.
    4. Whereas E2 is at a follicular phase level in PCOS patients, E1 levels are
      increased as a result of peripheral aromatization of androstenedione
    5. Chronic hyperestrogenic state results with reversal of the E1:E2 ratio.



  • Hypothalamic - pituitary compartment




    1. GnRH pulse frequency --> LH pulse frequency ↑
    2. LH pulse frequency --> LH↑,LH/FSH ratio ↑
    3. FSH : not increased with LH (because of the synergistic negative feedback of
      chronically elevated estrogen levels and normal follicular inhibin.)
    4. Elevated prolactin level : abnormal estrogen feedback to the pituitary gland.


3. Insulin Resistance




  • Most common cause of insulin resistance & compensatory hyperinsulinemia
    : obesity



  • Acanthosis nigricans



    • Marker for insulin resistance in hirsute women
    • Thickened, pigmented, velvety skin lesion -- vulva, axilla, nape of the neck, below
      the breast, inner thigh



  • Hair-AN syndrome




    • Hyperandrogenism, insulin resistance, acanthosis nigricans
    • High testosterone level ( > 1.5ng/ml )
    • Fasting insulin level (> 25 ug/ml), maximal serum insulin responses to glucose load

      (> 300ug/ml)



4. Radiologic studies



  • USG -- Ovarian size is increased. Bilaterally increased number of microcysts
    measuring 0.5 ~ 0.8 cm with generally more than five microcysts in each ovary


5. Long-term risks




  • Coronary artery disease.
  • Persistently elevated estrogen levels, uninterrupted by progesterone --> increased the
    risk of endometrial cancer.
  • Breast cancer.



C. Treatment of Hyperandrogenism & PCOS




  • Treatment depends on a patient's goals.
  • 1st line of treatment : Weight loss

  • Table 25.2


1. Oral Contraceptives



  • Benefits




    • Progestine components suppresses LH. --> ovarian androgen production↓

    • Estrogen -> SHBG production↑ -> free testosterone concentration↓
    • Circulating androgen level↓
    • Decrease conversion of testosterone to dihydrotestosterone in the skin
      by inhibition of 5-a-reductase.
    • Adrenal androgen secretion is reduced.


2. Medroxyprogesterone acetate : directly affects the hypothalamic pituitary axis.



  • Side effects : amenorrhea, headache, fluid retention, weight gain, hepatic dysfunction,
    depression.


3. GnRH agonists




  • Leuprolide acetate IM (every 28days)
  • Suppress ovarian steroids to castrate levels in patient with PCOS


4. Glucocorticoids



  • Dexamethasone 0.25mg nightly or every other night --> suppress DHEAS
    concentrations to < 400 ng/ml


5. Ketoconazole



  • Inhibit the key steroidogenic cytochromes


6. Spironolactone



  • Mechanism of action



    • Competitive inhibition at the intracellular receptor level for dihydrotestosterone
      (DHT)
    • Suppression of testosterone biosynthesis by a decrease in the P-450 system
    • Increase in androgen catabolism (with increased peripheral conversion of
      testosterone to E2)
    • Inhibition of skin 5-a-reductase activity



  • Side effect : menstrual irregularity (metrorrhagia), urticaria, mastodynia, scalp hair
    loss, nausea, fatigue



  • Contra Indication : renal insufficiency, hyperkalemia


7. Cyproterone acetate



  • Synthetic progestin derived from 17-HP with potent antiandrogenic properties.
  • Competitive inhibition of testosterone and dihydrotestosterone at the level of
    androgen receptors.
  • Induce hepatic enzyme --> increase the metabolic clearance rate of plasma
    androgens
  • Side effects : fatigue, weight gain, decreased libido, irregular bleeding, nausea,
    headaches.


8. Flutamide



  • Nonsteroidal antiandrogen, weak inhibitor of testosterone biosynthesis
  • Side effects : dry skin, hot flashes, increased appetite, headache, fatigue, nausea,
    dizziness, decreased libido, breast tenderness


9. Cimetidine : weak antiandrogenic effect.



10. Finasteride : specific inhibitor of 5-a-reductase enzyme activity



11. Ovarian wedge resection (bilateral)




  • Transient reduction in androstenedione levels & prolonged minimal decrease in
    plasma testosterone


12. Laparoscopic electrocautery




  • Five to eight points in each ovary were cauterized for 5 ~ 6 sec. with 300 - 400 W.

    --> 90% ovulation & 70% conception rate


13. Physical methods of Hair removal




    a. Depilatory creams

    b. Shaving, waxing

    c. Bleaching

    d. Electrolysis



D. Cushing's Syndrome




  • Three classes of steroid hormone



    a. Glucocorticoids



      ↑ --> muscle weakness, osteoporosis, atrophy of the skin with striae, nonhealing
      ulceration, ecchymoses, reduced immune resistance, glucose intolerance



    b. Mineralocorticoid



      ↑ --> arterial hypertension, hypokalemic alkalosis.

      fluid retension -> pedal edema



    c. Sex steroid ( androgen and estrogen precursors)



      ♀ --> hirsuitism, acne, oligomenorrhea, amenorrhea, thinning of scalp hair

      ♂ --> gynecomastia, impotence



  • Laboratory findings : CBC - granulocytosis, lymphocyte↓, eosinophil↓

    urine - calcium secretion↑


1. Causes




  • Table 25.3

  • Pituitary ACTH-secreting adenomas or Cushing's disease are the most common cause
    of Cushing's syndrome.
  • Ectopic ACTH syndrome is most often caused by malignant tumors

    ex) Small-cell carcinoma of the lung, bronchial & thymic carcinoma, Carcinoid tumor
    of the pancreas, medullary carcinoma of the thyroid

  • The hallmark of ACTH-dependent forms of Cushing's syndrome

    ; presence of normal or high plasma ACTH concentrations with increased cortisol
    levels.

    ; adrenal glands -- hyperplastic bilaterally
  • The most common cause of ACTH-independent Cushing's syndrome is exogenous or
    iatrogenic (superphysiologic therapy with cortical steroids) or factitious (self-induced)

  • Figure 25.2

  • Table 25.4


2. Treatment of Cushing syndrome : surgical removal of a neoplasm


3. Treatment of Ectopic ACTH/CRH-producing neoplasm




    a. Surgical therapy : Trans-spheroidal resection


    b. Radiation therapy ; high-voltage external pituitary radiation


    c. Medical therapy



    • Adrenal enzyme inhibitors : mitotane, aminoglutethimide, metyrapone, trilostane,
      etomidate.
    • Ketoconazole : inhibit adrenal steroid biosynthesis at the side arm cleavage &
      11-β-hydroxylation steps.


◎ Nelson's SD.



  • an ACTH-secreting pituitary adenoma (macroadenoma) that develops after bilateral
    adrenalectomy for Cushings disease.
  • Symptoms ; sellar pressure symptom. of headaches, visual-field disturbances,
    ophalmoplegia, severe hyperpigmentation (melanocyte stimulating hormone activity)
  • Treatment ; surgical removal or radiation


E. Congenital Adrenal hyperplasia




  • AR.
  • Definition of 21-hydroxylase : 90 ~ 95 % of all cases of CAH


1. Laboratory testing




  • Basal follicular 17-HP, 200 ng/ml --> excludes the disorder
  • Basal 17-HP > 500 ng/ml --> establishes the diagnosis
  • 200 < 17-HP < 500 : requires ACTH stimulating testing
  • In the ACTH stimulation test, plasma levels of 17-HP are checked 1 hour following
    intravenous administration of a bolus of 0.25mg ACTH 1-24
  • 17-HP levels after ACTH stimulation in adult-onset adrenal hyperplasia are
    generally > 1000 ng/dl.


2. Clinical Presentation




  • PCOS (39%)
  • Hirsuitism alone without amenorrhea (39%)
  • Cryptic(22%) -- Hyperandrogenism but no hyperandrogenic symptom


3. Genetics




  • 21-hydroxylase gene is located on the short arm of chromosome 6 in the midst of
    the HLA region
  • 21-hydroxylase gene is now termed CYP 21,
  • Its homologue is the pseudogene cyp21p
  • The CYP21 gene & the CYP21p pseudogene alternate with two genes called C4b &
    C4a, both of which code for the fourth component(C4) of serum complement


4. 11-β hydroxylase def.




  • 11-deoxycortisol levels are higher than 25ng/ml 60min. after ACTH 1-24 stimulation
  • Classic pattern

    a. Diagnosed at a younger age.

    b. Virilization, hypertension with related cardiomyopathy

    c. Retinopathy.


5. 3-β hydroxysteroid dehydrogenase def.



6. Treatment of adult-onset adrenal hyperplasia




  • Dexamethasone - evening administration is more effective with a dosage of
    0.25 - 0.5mg.




F. Androgen-secreting Ovarian & Adrenal Tumors




  • In prepubertal girls, virilizing tumors may cause signs of heterosexual precocious
    puberty in addition to hirsuitism, acne, and virilization


  • Markedly elevated testosterone level (2.5times the upper normal range or over
    200ug/dl) : typical of an ovarian tumor


  • DHEAS level > 8ug/ml --> typical of an adrenal tumor


  • Evaluation ; Vaginal & abdominal ultrasound, CT scanning. MRI, Selective venous
    catheterization, nuclear medicine scanning of the abdomen and pelvis after injection
    with Np-59





G. Androgen-Producing Ovarian Neoplasm



1. Granulosa cell tumor



  • Associated with estrogen production
  • Most common functioning tumors in children & lead to isosexual precocious


2. Thecoma



  • Rarely malignant, rarely bilateral


3. Sclerosing stromal tumor ; 30 yrs old↓



4. Sertoli-leydig cell tumor


  • Most common virilizing tumors in women of reproductive age.


5. Pure sertoli cell tumor



6. Gynandroblastoma



7. Sex cord tumors with annular tubulesSCTAT)



  • Associated with Peutz-Jeghers syndrome (GI polyposis, mucocutaneous melanin
    pigmentation)
  • SCTAT with P-J SD ; bilateral, benign
  • SCTAT without P-j SD : unilateral ,malignant




H. Stromal hyperplasia & Stromal HyperThecosis



1. Stromal hyperplasia



  • Nonneoplastic proliferation of ovarian stromal cells.
  • 60 ~ 80 years of age.
  • Hyperandrogenism, endometrial cancer, obesity, hypertension, glucose intolerance


2. Stromal hyperthecosis




  • Presence of luteinized stromal cells at a distance from the follicle
  • Virilization, obesity, hypertension, hyperinsulinemia, glucose intolerance
  • Treatment - Wedge resection, bilateral oophorectomy, GnRH agonist



I. Virilization during pregnancy



  1. Luteomas of pregnancy - associated with maternal & fetal masculinization
  2. Krukenberg tumor.
  3. Mucinous cystic tumor
  4. Brenner tumor
  5. Serous cystadenoma
  6. Endodermal sinus tumor
  7. Dermoid cyst



    II. Prolactin Disorders




    • Product of anterior pituitary
    • Primary function - initiation & maintenance of lactation
    • Significant role within & beyond the reproductive system


    A. Prolactin secretion



    • 199 amino acids. MW 23,000 daltons

    • 3 forms i) " little "; monomer


      ii) " big " ; dimer

      iii) " big-big"; multimer

      : proportion vary with physiologic, pathologic, hormonal situation


    • "little" prolactin ; 50%↑


    • Bioactivity & immunoreactivity - influenced by glycosylation

      glycosylated form - predominant

      most potent biologic form ; 23000 dalton MW nonglycosylated form


    • Secretion is primarily under inhibitory control by dopamine

      c.f.) metoclopramide ; dopamine antagonists --> abolishes the pulsatility of prolactin
      release and increase serum prolactin level.



    • Table 25.5


    B. Hyperprolactinemia



    1. Evaluation




    • Normal range ; 5-27 ng/ml during menstrual cycle

      (sample should not be drawn soon after the patient awakes or after procedure)



    • Secreted in pulsatile fashion

      * frequency ; 14 pulse/ 24 hrs - late follicular phase

      9 pulse/ 24 hrs - late luteal phase



    • Diurnal variation

      ; lowest level- midmorning after the patient awakes

      ; levels rise 1 hr after the onset of sleep

      ; peak- between 5^7 AM



    • Elevated level should always be rechecked !

      ; at midmorning, not after stress, venipuncture, breast stimulation, physical exam

      -> increase PRL levels



    • Physical signs



      • Amenorrhea without galactorrhea ; a/w hyperprolactinemia in 15 %


      • Elevated prolactin related to the following gonadal & hypothalamic-pituitary effects


        i) Reduction in granulosa cell number and FSH binding

        ii) Inhibition of granulosa cell 17 β estradiol production by interfering with
        FSH action

        iii) Inadequate luteinization and reduced progesterone

        iv) Suppression of prolactin on GnRH pulsatile release



      • Isolated galactorrhea ; prolactin levels are within normal range in 50%

        (earlier transient episode of hyperprolactinemia --> triggering persistent
        galactorrhea)



      • 1/3 of galactorrhea have normal menses.



      • Hyperprolactinemia (66%) occurs in the absence of galactorrhea - may result
        from inadequate estrogenic or progestational priming of the breast



      • In patient with both galactorrhea & amenorrhea


        . 2/3 : hyperprolactinemia

        . 1/3 : pituitary adenoma.



    • Imaging Technique.



      • Prolactin level with adenoma : usually 100ng/ml ↑
      • Drug-induced or physiologic etiology : scanning may not be necessary.
      • Cone-down view : screening technique.
      • CT / MRI
      • For patient who desire fertility, MRI is indicated to differentiate microadenoma
        from macroadenoma.



    2. Hypothalamic disorder.




    • Dopamine - produced in the arcuate nucleus

      - inhibit prolactin release
    • Lesions that disrupt dopamine release -> result in hyperprolactinemia
    • Lesion that disrupt dopamine release : suprasellar area, pituitary gland, infundibular
      stalk, adjacent bone, brain, cranial nerve, dura, leptomeninges, nasopharynx, vessels


    3. Pituitary Disorders.




    • Microadenoma



      • < 1cm, benign
      • Over 1/3 of hyperprolactinemia : radiologic abnormality consistent with adenoma
        remainder : simple hyperplasia.
      • Hypothesis for the formation of adenoma :
        reduction in dopamine concentration in hypophyseal portal system
        vascular isolation of tumor
      • Microadenoma rarely progress to macroadenoma.
      • Should be advised to notify of chronic headache, visual disturbance, extraocular
        muscle palsy.
      • Formal visual field testing : unnecessary.
      • Treatment


        1. Expectant Mx : if do not desire fertility




        • Hyperprolactinemia induced estrogen deficiency --> osteopenia.
          estrogen replacement or OC are indicated to amenorrhea or irregular menses.
        • Drug-induced hyperprolactinemia : expectantly with attention to the risk of
          osteoporosis
        • Repeat imaging in 6 ~ 12 months that there has been no further growth
          (5% of tumors show on increase in size.)



        1. Medical Tx.




        • Ergot alkaloid ; mainstay of therapy ' bromocriptine' - increase dopamine level
        • Excretion ; biliary tree (caution to liver disease)
        • Adverse effect ; nausea, headache, hypotension, dizziness, fatigue, drowsiness,
          nasal congestion, constipation
        • Oral or vag. Bromocriptine, pergolide, cabergoline, methergoline, CV205-502
        • Repeat MRI at 6^12 months after prolactin levels are normal.
          : Normal prolactin levels and resumption of menses should not be considered
          proof of tumor response to treatment.
        • Discontinuation of bromocriptine therapy after 2 to 3 yrs - because some
          adenomas undergo hemorrhagic necrosis & cease to function
        • Further MRI ; only to evaluate new symptoms.


    • Macroadenoma




      • Symptoms ; severe headache, visual change, Diabetes Insipidus, blindness
      • Follow Up ; after prolactin level has reached normal range, MRI within 6 months,
        then yearly for several years, (prolactin ; 6 months)


      • Medical treatment



        • Bromocriptine : best initial & long-term treatment option.


          1/2 : 50% reduction in size. after 6months of Tx.

          1/4 : 33% reduction


        • Tumor regrowth occurs in over 60% after discontinuation

          ∴ long-term treatment is the rule



      • Surgical treatment



        • Indication Unresponsive to bromocriptine

          Persistent visual field loss



      • Recurrence of hyperprolactinemia & tumor growth - not uncommon
      • Recurrent hyperprolactinemia - periodic MRI scan


    4. Use of Estrogen in Hyperprolactinemia



    • In rodent, rapid prolactinoma occurs with high dose estrogen
    • In human, estrogen administration : no evidence of growth of pituitary adenoma
      or progression of idiopathic hyperprolactinemia to adenoma


    5. Pituitary adenoma in Pregnancy



    • Microadenoma : rarely create complication during pregnancy
    • Monitoring : serial gross visual field exam, fundoscopic exam, if symptom (+), MRI

      * prolactin level : no value.
    • Macroadenoma : monitoring as microadenoma with monthly Goldman perimetry visual
      field testing.
    • Bromocriptine : to resolve symptom & visual field deficiency temporarily to allow
      completion of pregnancy before definitive therapy
    • Breast feeding : is not contraindication in the presence of prolactinoma.



    III. Thyroid disorder.



    • 10 times more common in women than men
    • 1% of females : overt hypothyroidsm.


    A. Thyroids Hormones



    • Iodide : actively transported into the thyroid follicular cell


      --> Thyroid peroxide TPO) oxidizes iodide near the cell-colloid surface &
      incorporates it into tyrosyl residues within the thyroglobulin molecule

      --> result in the formation of monoiodotyrosine (MIT) & diiodotyrosine (DIT)

      --> Triiodothyronine (T3) & Thyroxine (T4) formed by secondary coupling of MIT & DIT catalyzed by TPO



    • TPO : membrane-bound, heme-containing oligomer, localized in rER, Golgi vesicle &
      follicular cell surface


    • Thyroid antimicrosomal antibodies found in patients with autoimmune thyroid disease
      are directed against the TPO enzyme


    • Thyroid-stimulating hormone (TSH)

      : regulates thyroidal iodine metabolism by activation of adenylate cyclase

      --> facilitates endocytosis, digestion of thyroglobulin-containing colloid & release
      of thyroid hormones T4, T3, rT3


    • Thyroid hormones - effects on cells include increased oxygen consumption, heat
      production, increased metabolism of fat, proteins & carbohydrate


    1. Iodide Metabolism




    • Daily allowance : 150 ~ 300 g/day
    • Sufficiency of iodine : a/w development of autoimmune thyroid disorder.


    2. Factors affecting Thyroid function




    • Iodide
    • Pollutants (plasticizers, polychlorinated bipheols & coal processing pollutants)
    • Ab to Yersinia enterocolitica.
    • Female hormonal milieu & its potential effects on immune surveillance


    B. Evaluation



    1. Thyroid Function.



    • ↑TBG conditions : pregnancy, oral pill, ERT, hepatitis, genetic abnormality of TBG,
      --> require measuring T3RU for clarification.
    • FTI ( Free T4 Index ) : % free T4 ( T3RU ) × T4 total
    • TSH measurement : best single screen for thyroid dysfunction.


    2. Immunologic Abnormalities



    • Antithyroglobuliin Ab.

      : noncomplement-fixing IgG polyclonal antibodies, (+) in Hashimoto's thyroiditis, Graves' Dz, acute thyroiditis, nontoxic goiter, thyroid cancer, normal women.


    • Antimicrosomal antibody-direct against TPO

      : (+) in Hashimoto's thyroiditis, Graves' disease & postpartum thyroiditis
      ,cytotoxic, complement fixing Ig G Ab


    • Atibody to T3 & T4.

      : (+) in Hashimoto's thyroiditis & Graves' Dz. who have antithyroglobulin Antibody



    • Antibody to TSH receptor



    1. TSAb. (Thyroid-stimulating Ab) or PSI (Thyroid stimulating Ig)

      : monoclonal or limited polyclonal --> mimic TSH action


    2. TBII (TSH-binding Inhibitor Ig)

      block TSH binding

      block both pre-& postreceptor process

      TGI (Thyroid Growth-promoting Ig)

      : stimulate growth, but not hormone release.

      c.f antagonist : TGI-blocking Ab. - inhibiting TSH-mediated growth response


    C. Autoimmune Thyroid Disease.




    • Hypothyroidism > hyperthyroidism
    • F>M
    • Other autoimmune conditions a/w Graves' Dz.

      : Hashimoto's thyroiditis, Addison's Dz, ovarian failure, RA, Sjoren's SD, IDDM,
      vitiligo, pernicious anemia, MG, ITP...


    1. Hashimoto's thyroiditis



    • Chronic lymphocytic thyroiditis
    • Present as hyperthyroidism, hypothyroidism, euthyroid goiter, or diffuse goiter.
    • High levels of anti-microsomal & antithyroglobulin Ab (+)
    • The composition of various Ab (TBII, TGI etc.) result in varied physical finding
    • Autoantibody

      • TBII : causing the atophic form & congenital hypothyroidism in some neonates.
      • TGI : causing the goitrous variety



    • 3 Classic types of autoimmune injury

      • complement-mediated cytotoxicity
      • stimulation or blockade of hormone receptor


    1) Clinical Characteristics & Dx.




    • Mostly, relatively asymptomatic with painless goiter & hypothyroidism


    • Symptom : Cold intolerance, constipation, carotene deposition in the periorbital
      region, carpal tunnel syndrome, dry skin, fatigue, hair loss, lethargy, wt.gain.
      c.f Hashitoxicosis (<-- represent a variant of Graves' Dz.) - in 4~8%



    • Diagnosis

      ↑ TSH level during routine screening

      ↑ serum antithyroglobulin & antimicrosomal Ab

      ↑ ESR


    2) Treatment




    • Symptomatic hypothyroidism --> T4 replacement
    • Pregnant women with↑ TSH level --> L-thyroxine.


    2. Reproductive effects of Hypothyroidism.



    • Hypothyroidism : a/w↓ fertility resulting from ovulatory difficulties and not
      spontaneous abortion.
    • Menorrhagia, amenorrhea, anovulation, luteal phase defect
    • Replacement therapy - reverse the hyperprolactinemia & correct ovulatory defect


    3. Graves' Disease




    • Heritable specific defect by suppressor T cell


      --> development of helper T cell

      --> react to thyroid antigen

      --> induce B-cell mediated response



    • HLA class II antigen DR, DP, DQ, DS


    1) Clinical Characteristics & Dx.




    • Classical triad : Exophthalmos, goiter, & hyperthyroidism


    • a/w symptom :↑bowel movement, heat intolerance, irritability, nervousness,
      palpitation, tachycardia, tremor, wt.loss, lower external swelling.


    • P/E : lidlag, nontender thyroid enlargement, onycholysis, palmar erythema, proptosis,
      staring gaze, thick skin...

      if. severe cases : acropachy, chemosis, clubbing, dermopathy, exophalmus with
      ophthalmoplegia, follicular conjunctivitis, pretibial myxedema, vision loss.


    • Diagnosis

      T3 ↑, but T4 levels - mostly normal

      TSH↓

      Antimicrosomal Ab (+)

      TSAb : useful in evaluating medical treatment, prognosis & potential fetal
      complication..


    2) Treatment




    • Medication --> potentially harmful effects on the fetus, special attention must be
      given to the case of contraception & the potential for pregnancy.


    (1) 131I Ablation




    • Effective care in about 80% of cases
    • Most commonly utilized definitive Tx. in nonpregnant women
    • Postablative hypothyroidism : 50% within 1st year.


    (2) Antithyroid Drugs.




    • PTU & Methimazole
    • Low doses : block the secondary coupling Rx. that form T3 & T4 from DIT &
      MIT.
    • Higher doses --> block iodination of tyrosyl residues in thyroglobulin.
    • 30% --> remission.


    1. PTU (100mg, every 8 ~ 24hr)

      - block the intrathyroid synthesis of T3 & the pph conversion of T4 to T3.

      - not cross placenta.

      - drug of choice in pregnancy.



    2. Methimazole (10mg, every 8 ~ 24hr)


      - not drug of choice in pregnancy , d/t not block pph conversion & cross
      placenta.


    3. Iodide & Lithium.

      - reduce thyroid hormone release & inhibit the organification of iodine.


      (3) Surgery




      • Subtotal thyroidectomy
      • Ix.

        1. Medical Tx failed

        2. Hypersensitive to medical Tx.



      • Risk

        1. Hypoparathyroidism

        2. Recurrent laryngeal n. paralysis

        3. Hypothyroidism.


      (4) β-blocker.



      4. Reproductive Effects of Hyperthyroidism




      • Most women. : ovulatory & fertile
      • Severe thyrotoxicosis : wt. loss, irregular mens, amenorrhea, ↑spontaneous abortion,
        ↑congenital anomalies.


      5. Postpartum Thyroid Dysfunction.



      • Often difficult to diagnose, Sx. appear 1 ~ 8 months postpartum.
      • Incidence : 5 % -> 25% permanent hypothyroid
      • Histo : lymphocytic infiltration & inflammation.
      • Antimicrosomal Ab (+)


      1) Clinical Characteristics & Dx.



      • Symptom : Depression, fatigue, palpitation, at 6 ~ 12 wks. postpartum.

        c.f. postpartum thyroid dysfunction should be considered in all women with
        postpartum psychosis.


      • Diagnosis

        (-) of thyroid tenderness, pain, fever, ↑ESR, leucocytosis

        TSH, T4, T, T3RU, antimicrosomal Ab titer.


      2) Treatment



      • mostly hypothyroid phase and require 6 ~ 12 months of T4 replacement if they are
        symptomatic.

        (c.f.. 10 ~ 30% --> permanent hypothyroidism)



      • rarely hyperthyroid phase : not routinely use of anti-thyroid medication, but
        propranolol for symptomatic relief.