12266 Loss ofeteronygosity ora somatic mutation ofthe remaining normal [MENIN alll leads to tumorigenesis. About half of affected patients develop prolctinomas; acromegaly and Cushing’ syndrome are less ‘commonly encountered. is characterized by spotty skin pigmentation, smyxomas, and endocrine tumors inluding testicular, adrenal, and pituitary adenomas. Acromegaly occurs in about 20% ofthese patients ‘A subet of patients have mutations inthe Rla regulatory subunit of protein kinase A (PRKARIA). ‘McCune-Alright syndrome consists of polyostotic fibrous dys plsia, pigmented skin patches, and a variety of endocrine disorder including acromegaly, adrenal adenomas, and autonomous ovarian fanetion (Chap. 4260). Hormonal hypersecretion results from con- stitutive cyclic AMP production caused by inactivation ofthe GTPase activity of Gsa. The Gsa mutations occur postrygotcally, leading to a ‘mosaic pattern of mutant expression, Familial acromegaly isa rare disorder in which family members ‘may manifest either acromegaly or ggantiem, A subset of fais with 2 predisposition for familial pituitary tumors, especially acromegaly, have been found to harbor germline mutations in the AIP gene, which encodes the aryl hydrocarbon receptor interacting protein HYPERPROLACTINEMA tilogy - Hyperprolactinemia isthe mort common pituitary hormone Ihypersecretion syndrome in both men and women. PRL-secreting pituitary adenomas (prlactinomas) are the most common cause of PRL levels >200 ug/L (ee below). Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly caused by drugs pituitary stall compression, hypothyroidism, or renal alae (Table 403-5), Pregnancy and lactation are the important physiologic causes of | Ihyperprolactinemia,Sleep-asoiated hyperprolactinemia reverts o nor ‘mal rithin an hour of awakening Nipple stimulation and sexval orgasm ako may increase PRL Chest wallstimulation or trauma Gnluding chest surgery and herpes zoster) invoke the reflex suing ae with resultant Ihyperprolatinemia, Chronic renal flure elevates PRL. by decreasing peripheral clearance. Primary hypothyroidism is associated with mild Ihyperprolactinema, probably because of compensatory TRH secretion, Lesion ofthe hypothalamicpituitary region that disrupt hypotha- lamic dopamine synthesis, portal vestel delivery o actotrope responses ae associated with hyperprolactinemia. Thus, hypothalamic tumors ‘pts, infltrative disorders, and radation-induced damage cause ele. ‘vated PRL level, usually inthe range of 30-100 yg. Plurihormonal adenomas (including GH and ACTH tumors) may hypersecrete PRL dlisectly. Pituitary masses, including clinically nonfunctioning pituitary tumors, may compress the pituitary stalk to cause hyperpeoactinemia Drug-induced inhibition or disruption of dopaminergic receptor function isa common cause of hyperprolactinemia (Table 403-5). Thus, antipychotice and antidepresants are a relatively common cause of mild hyperprolactinemia. Most patents receiving risperidone have clevated prolactin levels, sometimes exceeding 200 ug/L Methyldopa Inhibits dopamine synthesis, and verapamil blocks dopamine release, leo leading to hyperprolactinemia, Hormonal agent that induce PRL Include estrogens and thyrotropin-eleasing hormone (TRH). Presentation and Diagnosis Amenorshea,galactorrhea and ineriity are the hallmarks of hypesprolactinemia in women. If hyperprolac tinemia develops before menarche, primary amenorrhea results, More commonly, hyperprolactinemia develops later in hfe and leads to oligomenorshea and ultimately to amenorthea, If hyperprlactinemia Js sustained, vertebral bone mineral density can be reduced compared ‘withage-matched controls, particularly when itis sesociated with pro- rounced hypoestrogenemia. Glactorthea i present in up to 80% of, Fhyperprolactinemic women. Although usually bilateral and spontane- ous it maybe unilateral or expressed only manually. Patients also may complain of decreased libid, weigh gain, and mild hirsutism In men with hyperprolactinemia, diminished libido, infertility, and visual los (om optic nerve compression) are the usual presenting symptoms. Gonadotropin suppression leads to reduced testosterone, etic uusjoqeray pue K60jounD0pu3 EINITETIE eriovocy or nvoenenocactinenia 1 Physiologic hypersecretion Pregnancy Lactation Chest wall simulation Sleep Sess 1 Hypothalami-pitultary stalk damage Tumor Canlopharngima Spas pltitary mass eningioma Dysgerminema Mota Emp sla Lymphooytihypophysis asenema vith sta Compression Granulomat fattest Iraaten Trauma utara secton Supraclir surge 1. Plutary hypersecretion Prolactroma eramesaly Iv. Systemic disorders Chronic eal fare Hypothynosm rae Pseocyss Eplepcsazwes LV. Drug-induced hypersecretion Dopamine receptr backers ‘ple antipsychotics esperidone Phenethaznes horpromazhe,perphenazine Butyrophenones haloperidol Thoranthenes Metoclpramide Doamine sythess inhibitors aNethyidopa Catecholamine depletars Reserpine Opiates H,atapensts CGmetidine, aniiine Inipraies ‘Amipyne amexapine Serotonin eupate hits Flucitine Cau channe bockers Veropamt Estrogens Tryrtopinleeng hormane ete hiperobcinema 200 yy snes neiyindcabe aa peacnscetng ity lea Pyle sane, pethradin uy ced typoImpotence, and oligospermia, True galactorthes is uncommon in men ‘with hyperprolactinemia If the disorder is long-standing, secondary. tffets of hypogonadism are evident, including ceteopena, reduced ‘mule mass, and decreased beard growth. “The diagnosis ofiiopathic hyperpolactinemis is made by excla- son of known causes of hyperprolactinemia i the setting of «normal pituitary MRL Some of these patents may harbor small microadeno- ‘nas below visble MRI sensitivity (-2 mi). cauacronnuea Galacrrhea he inappropriate dicharge of mikcotsining Bi fom the bret considered abnormal persistslongerthan6monthsafer Chldbth or dacontnuaton of bens feting Popurtum glctorrhea Ssocated with amenorhen ia eliiing dirder aly sociated ‘rth edeatey crated PRL evel Galactica yon ontane- Dy, ort may Bechtel by nipple presr noth mens women, fatten may vay in color and constency(ransparent, milky, of Soy) and arte eer unity o bist: Mommogrephy trad isindated for bloody dchares tical fom a singe ipo, which maybe caused y bres cancer. Galactose tmoly soc! with hyperolcinemia cad by any ofthe cond fons listed in Table 40-5 Acme is aneciated with atrreain Shout one third of paints Tree ofgalctorfhen sal inva ‘managing the undying diode (eg replacing, fer bypthyroiin, discontinuing medication, testing prlatinoms). labora aventgton Bas fasting morning PRL vee (normally £20 yg) shouldbe measored to anes hyperscretion Both false postive and false-negative results may be encountered: Inpatients ‘ath masked elvted PRL eves (©1000 g/L, eprted tests may Berallowered besa of assay aria sample ition equied to meanre these high sales actualy Fall elerated values may be cased by agregtd forms of celting PRL. which ar sally Biology active macropolacinema).Hypotyredsm shoo be ‘cided by measuring TSH and, levee ‘Treatment of hyperprolactinemia depends onthe cause of elevated PAL levels. Regardless of the etiology, however, treatment should be aimed at normalizing PRL levels to alleviate suppressive effects ‘on gonadal function, halt galactorrhea, and preserve bone mineral ‘density. Dopamine agonists are elective for mast causes of hyper- prolactinemia (see the treatment section for prolactinoma, below) Fegardles ofthe underiying cause if the patients taking a medication known to cause hyperprolac- tineria, the drug should be withdrawn, if possible. For psychiatric patients who require neuroleptic agents, supervised dose titration Or the addition of a dopamine agonist can help restore normopro- lactinemia and alleviate reproductive symptoms. However, dopa mine agonists may worsen the underlying psychiatric condition, especially at high doses. Hyperprolactineria usualy resolves after adequate thyroid hormone replacement in hypothyroid patients or ater renal transplantation in patients undergoing dialyss Resection Of hypothalamic or selar mass lesions can reverse hyperpeolac- tineria caused by stalk compression and reduced dopamine tone, Granulomatous infiltrates occasionally respond to glucocorticoid administration. Inpatients with reversible hypothalamic damage, ro treatment may be warranted. In up to 308% of patents with hyper- prolactinemia usually without a vile pituitary microadenoma-— the condition may resolve spontaneously. PROLACTINONA [logy and Prevalence Tumors arising from lacttrope cells account for about half ofall functioning pituitary tumors, witha population prevalence of ~10/100,000 in men and ~30/100,000 in women. Mixed tumors that secrete combinations of GH and PRL, ACTH and PRL, and rarely TSH and PRL are also seen. These plurihormonal tumors are urvaly recognized by immunohistochemistry, sometimes without spparent clinical manifestations from the production of addtional 267 hormones. Micrasdenomas are classified af 1 cm in diameter and may be locally invasive and impinge on adjacent structures. The female-to-male ratio for microprolactinomas is 201, Whereas the sex ratio is near 1:1 for macroadenomas. Tumor size generally correlates directly with PRL concentrations values >250 tig/Luslly are associated with macroadenomas. Men tend to present ‘with large tumors than women, posibly because the features of male Fhypogonadism ace less readily evident. PRL levels remain stable in ‘most patients, reflecting the slow growth of these tumors. About 5% of ‘icroadenomas progres inthe lng term to macroadenomas. Presentation and Diagnosis Women usually present with amenorshea, inferlity, and galactorchea Ifthe tumor extends ouside the sell, ‘visual field defector other mass effects may be seen. Men often pes ent with impotence, lose of libido, iferlity, or signs of central nervous system (CNS) compresion, including headaches and visual defects, ‘Assuming that physiologic and medication-induced causes of hyperp rolactinemia are excluded (Table 403), the diagnosis of prolactinoma Islikelywitha PRL level>200 ug/L. PRL levels <100 g/L maybe caused bby microadenomas, other sellar lesions that decrease dopamine inhibi tion, or neoplastic causes of hyperprolatinemia For this reason, an [MRI shouldbe performed in all patients with hyperprolactinemia. Its Important to remember that hyperprolactinemia caused secondarily by the mase effects of nonlactotrope lesions i als corected by treatment with dopamine agonist despite fallure to shrink the underlying mats. Consequently, PRL suppression by dopamine agonists doesnot neces sarily indicate thatthe underlying lesion ia proactinoms, Because microadenomas rarely progress to become macroadeno. ‘mas, no treatment may be needed if patientsare asymptomatic and fertility is not desired; these patients should be monitored by regu: lar sell PRL measurements and MAL scans For symptomatic micto- adenomas, therapeutic goals include control of hyperprolactinemia, eduction of tumor size, restoration of menses and fertity, and resolution of galactorthea. Dopamine agonist doses should be titrated to achieve maximal PRL suppression and restoration of reproductive function (Fic. 403-3). A normalized PRL level does not fensute reduced tumor size. However, tumor shrinkage usually is ‘ot seen in those who do not respond with lowered PRL levels. For ‘macroadenomas, formal visual field testing should be performed before initiating dopamine agonists. MRI and visual fields should be assessed at 6 to 12-month intervals unt the mass shrinks and annually thereafter until maximum size reduction has occurred, eoicat (ral dopamine agonists (cabergoline and bromocriptine) are the ‘mainstay of therapy for patients with micro- or macroprolactinomas. Dopamine agonists suppress PRL secretion and synthesis as well as lactotrope cell proliferation. In patients with microadenomas who hhave achieved normoprolactinemia and significant reduction of, tumor mass, the dopamine agonist may be withdrawn after 2 years. These patients should be monitored carefully for evidence of pro- lactinoma recurrence. About 20% of patients (especially males) are resistant to dopaminergic treatment; these adenomas may exhibit decreased D, dopamine receptor numbers ora postreceptor defect. ©, receptor gene mutations inthe pituitary have not been reported sawoupurs souny Keynug souawy (PTT STEEL TS Cabergoline An exgoline derivative, cabergoline is a long-acting dopamine agonist with high D, receptor arity. The drug effectively suppresses PRL for >14 days after a single ofal dose and induces prolactinoma shrinkage in most patients. Cabergoline (05-10 mg twice weekly) achieves normoprolactinemia. and resumption of ‘normal gonadal function in ~80% of patients with microadenomas; sgalactorchea improves or resolves in 90% of patients. Cabergoine Formalizes PRL and shrinks ~70% of mactoprolactinomas, Mass