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 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)

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

cause Six recognized noniatrogenic causes(table 25.3)

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%

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

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

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

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

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)

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

Prolactin disorders

Prolactin secretion 199 amino acid within human prolactin with MW 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

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

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)

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

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

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)

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

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

Metabolic dysfunction drug-induced hyperprolactinemia

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