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