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Chapter 25 Endocrine disorders(2)

Chapter 25 Endocrine disorders(2). 부산백병원 산부인과 R2 강영미. Cushing ’ s syndrome. Adrenal cortex ; three classes of steroid hormones Glucocorticoids, mineralocorticoids and sex hormones. Hyperfunction of adrenal gland(1). Increased glucocorticoids action

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Chapter 25 Endocrine disorders(2)

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  1. Chapter 25 Endocrine disorders(2) 부산백병원 산부인과 R2 강영미

  2. Cushing’s syndrome • Adrenal cortex ; three classes of steroid hormones • Glucocorticoids, mineralocorticoids and sex hormones

  3. Hyperfunction of adrenal gland(1) • Increased glucocorticoids action • Results in nitrogen wasting and catabolic state • Cause muscle weakness, osteoporosis, atrophy of the skin with striae, nonhealing ulceration and recuced immune resistance, glucose intolerance and central obesity • Overproduction of sex steroid precursors • Some degree of masculinization in women (hirsutism, acne, oligomenorrhea or amenorrhea) • Some degree of feminization in men (gynecomastia and impotence)

  4. Hyperfunction of adrenal gland(2) • Overproduction of mineralocorticoids • Arterial hypertension, and hypokalemic alkalosis and pedal edema

  5. cause • Six recognized noniatrogenic causes(table 25.3)

  6. Treatment of ACTH-independent forms of cushing’s syndrome • Adrenal cancer • Mitotane after surgery ; benefit in preventing or delaying recurrent disease • Surgical removal of neoplasm ; TOC • Unilateral well-circumscribed adenoma ; flank approach is most convenient • Cure rate following surgical removal of adrenal adenomas ; approaches 100%

  7. Treatment of cushing’s disease(1) • Transshenoidal resection ; TOC • Cure rate ; 80% with microadenomas, less than 50% with macroadenomas • Medical therapy • Mitotane ; induce medical adrenalectomy during or after pituitary radiation • To prepare severely ill patient for surgery and to maintain normal cortisol levels while patient awaits full effect of radiation • Ketoconazole ; inhibits adrenal steroid biosynthesis at the side arm cleavage and 11b-hydroxylation steps • Effective for long-term control of hypercortisolism of either pituitary or adrenal origin

  8. Treatment of cushing’s disease(2) • Nelson’s syndrome • ACTH-secreting pituitary adenoma that develops after bilateral adrenalectomy for cushing’s ds • Complicate 10-50% of bilateral adrenalectomy • Caused by macroadenoma that produce sellar pressure symptoms of headache, visual field distrubances and opthalmoplegia • Treatment ; surgical removal or radiation

  9. Congenital adrenal hyperplasia • CAH ; AR disoreders • Following effects • Relative decrease in cortisol production • Compensatory increase in ACTH levels • Hyperplasia of the zona reticularis of the adrenal cortex • Accumulation of the precursors of the affected enzyme in the bloodstream

  10. 21-hydroxylase deficiency • Responsible for over 90% of all cases of CAH • Diagnosed earlier in affected women than in men • ∵ causes genital virilization • Diagnosed as virilized newborn females or as rapidly growing masculinized boys at 3 to 7 yrs of age • Basal follicular phase 17-OHP<200ng/dl ; exclude disorders • No further testing is required • Basal 17-OHP>500ng/dl ; confirm • No need for further testing • Basal 17-OHP >200 and <500ng/dl ; ACTH stimulation testing

  11. Nonclassic congenital adrenal hyperplasia • Partial deficiency in 21-hydroxylation • Late onset, mild hyperandrogenemia • No or mild clinical symptoms or signs • Three phenotypic varieties ; PCOS(39%), hirsutism alone without oligomenorrhea(39%) and cryptic(22%, hyperandrogenism but no hyperandrogenic symptoms)

  12. Prenatal diagnosis and treatment • 21-hydroxylase gene ; located on short arm of chr 6, in the midest of the HLA region, termed CYP21 • In families at risk for CAH ; first-trimester prenatal screening –CYP21gene using PCR • Dexamethasone treatment for all pregnant women at risk of having a child with CAH ; controversial • 20mg/kg in three divided doses administered as soon as pregnancy is recognized and no later than 9 weeks of gestation • Cross placenta and suppresses ACTH in the fetus • If female fetus, therapy is continued • Effectively reduces genital ambiguity but 2/3 pts still requires surgical repair

  13. Prolactin disorders

  14. Prolactin secretion • 199 amino acid within human prolactin with MW 23000 daltons • Three forms ; monomer, dimer and multimeric species called little, big, and big-big prolactin • Little prolactin(MW 23000daltons) ; more than 50% • Most potent biologic form ; 23000dalton nonglycosylated form of prolactin • Under inhibitory control mediated by dopamine • Dopamine ; primary prolactin-inhibiting factor • GABA & other neuropeptides ; prolactin inhibiting factor

  15. Hyperprolactinemia-evaluation • Plasma levels ; 5-27ng/ml throughout normal mens cycles • Secreted in pulsatile fashion with pulse frequency ranging from 14/24hrs(late follicular phase) to 9/24hrs(luteal phase) • Diurnal variation ; lowest levels occurring in midmorning, rise 1 hr after onset of sleep and continue to rise until peak values reached between 5-7AM • Should not drawn soon after patient awakes or after procedures • Preferably is drawn midmorning and not after stress, venipuncture, breast exam • Prolactin and TSH ; basic evaluation in infertile women

  16. Hyperprolactinemia-physical signs • Amenorrhea without galactorrhea(ovulation cessation) ; related following gonadal and hypothalamic-pituitary effects • ↓ in granulosa cell number and FSH binding , inhibition of granulosa cell 17 b-estradiol production by interfering with FSH action, inadequate luteinizaion and reduced progesterone and suppressive effects of prolactin on GnRH pulsatile release which may mediate most of the anovulatory effects • Isolated galactorrhea ; within normal range in nearly 50% of such patients • Amenorrhea and galactorrhea • 2/3 ; have hyperprolactinemia • (1/3 ; have pituitary adenoma)

  17. Hyperprolactinemia-imaging techniques • In patients with larger micro- and macroadenomas ; higher than 100ng/ml • Levels lower than 100ng/ml ; smaller microadenomas and other suprasellar tumors • Over 90% of untreated women, microadenomas not enlarge over 4 to 6 yrs period • PRL correlate with tumor size but both ↓& ↑ in PRL may occur without any change in tumor size • F/U PRL ↑ or central nervous system symptoms(+) → repeat scanning

  18. Pituitary disorders-microadenoma(1) • Microadenoma • Monoclonal in origin • Generally be reassured of benign course • Rarley progress to macroadenoma(7%) • Expectant management • In women who no not desire fertility, used for microadenomas and hyperprolactinemia without adenoma • Estrogen replacement or Ocs in pts with irregular menses or amenorrhea ; prevent osteopenia • In absence of symptoms, repeat imaging in 12 mon to assess further growth of the microadenoma

  19. Pituitary diorders-microadenoma(2) • Medical treatment • Ergot alkaloid ; ↑ dopamine levels ↓ PRL levels • Bromocriptine ; ↓PRL synthesis, DNA synthesis , cell multiplication and tumor growth • Result in normal PRL or return of ovulatory menses in 80-90% of patients • Excreted via biliary tree, caution in liver ds • Regimen ; one-half tablet every evening(1.25mg) for 1 week, one-half tablet morning and evening (1.25mg) during second week, one-half tablet in the morning(1.25mg) and full tablet every evening(2.5mg) during third week and one tablet every morning and early evening during the fourth week and thereafter(2.5mg twice a day)

  20. Pituitary disorders-microadenoma(3) • Medical treatment • Pharmacokinetics ; peak serum levels occur 3 hrs after an oral dose with a nadir at 7 hrs, little detectable bromocriptine in serum by 11 to 14 hrs, ∴ required twice-a-day administration • Adverse effect ; nausea, headaches, hypotension, dizziness, fatigue, and drowsiness, constipation, psychotic reaction • Cabergoline, another ergot alkaloid • Very long half-life, given orally once per week • As effective as bromocriptine in lowering PRL and in reducing tumor size

  21. Pituitary adenoma-macroadenoma • Bromocriptine ; best initial and potentially long-term treatment option but TSS may be required • ↓in PRL and size • ∵ tumor regrowth occurs in over 60% of cases after discontinuation of bromocriptine therapy, long-term therapy is required • Normalized PRL or resumption of mense ; should not be taken as absolute proof of tumor response to treatment • Surgical intervention ; tumors that are unresponsive to bromocriptine or that cause persistent visual field loss • Common recurrence of hyperprolactinemia and tumor growth

  22. Metabolic dysfunctiondrug-induced hyperprolactinemia

  23. Monitoring pituitary adenomas during pregnancy • Rarely create cx during pregnancy • Monitoring c serial gross visual field exam & fundoscopic exam • Persistent sx(headaches, visual field deficits) ; MRI advisable • PRL measurement ; no value • Bromocriptine ; to resolve sx &visual field deficits in symptomatic pts to allow completion pregnancy before initiation of definitive therapy • Breast feeding ; not c/Ix in presence of micro- or macroadenoma

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