Chapter 25 Endocrine disorders(2)

부산백병원산부인과

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 s

triae, nonhealing ulceration and recuced immune resistance, glucose intolerance and central obesity

Overproduction of sex steroid precursors Some degree of masculinization in women (hirsutism, acne, oligo

menorrhea or amenorrhea) Some degree of feminization in men (gynecomastia and impotenc

e)

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 c

onvenient Cure rate following surgical removal of adrenal adenomas ; appro

aches 100%

Treatment of cushing’s disease(1)

Transshenoidal resection ; TOC Cure rate ; 80% with microadenomas, less than 50% with macroad

enomas

Medical therapy Mitotane ; induce medical adrenalectomy during or after pituitary ra

diation 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 pituita

ry or adrenal origin

Treatment of cushing’s disease(2)

Nelson’s syndrome ACTH-secreting pituitary adenoma that develops after bilateral adr

enalectomy for cushing’s ds Complicate 10-50% of bilateral adrenalectomy Caused by macroadenoma that produce sellar pressure symptom

s 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 bloo

dstream

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 mas

culinized 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 havin

g a child with CAH ; controversial 20mg/kg in three divided doses administered as soon as preg

nancy 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 s

urgical repair

Prolactin disorders

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

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, br

east 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 an

d hyperprolactinemia without adenoma Estrogen replacement or Ocs in pts with irregular menses or ame

norrhea ; prevent osteopenia In absence of symptoms, repeat imaging in 12 mon to assess fur

ther growth of the microadenoma

Pituitary diorders-microadenoma(2)

Medical treatment Ergot alkaloid ; ↑ dopamine levels ↓ PRL levels Bromocriptine ; ↓PRL synthesis, DNA synthesis , cell multiplicati

on 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 do

se 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 t

umor 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 discontinuati

on of bromocriptine therapy, long-term therapy is required Normalized PRL or resumption of mense ; should not be t

aken as absolute proof of tumor response to treatment Surgical intervention ; tumors that are unresponsive to br

omocriptine or that cause persistent visual field loss Common recurrence of hyperprolactinemia and tumor growth

Metabolic dysfunctiondrug-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 advis

able PRL measurement ; no value Bromocriptine ; to resolve sx &visual field deficits in sym

ptomatic pts to allow completion pregnancy before initiation of definitive therapy

Breast feeding ; not c/Ix in presence of micro- or macroadenoma