1 내분비 내과 case review Nonfunctioning pituitary tumor 내분비 대사 내과 R3 하상진

2 Sella mass

3 Pituitary adenoma

4 Pituitary tumor

5 Introduction  Gonadotroph adenomas are the most common pituitary macroadenomas but are the hardest to recognize for three reasons: 1.They secrete inefficiently 2.They secrete variably 3.Their secretory products usually do not cause a recognizable clinical syndrome  Gonadotroph adenomas, like other pituitary adenomas, appear to be true clonal neoplasms.  The factors that promote the formation of nonfunctioning pituitary adenomas are not well understood. The pituitary tumor transforming gene is overexpressed in most nonfunctioning adenomas. It also appears to play a role in tumor invasiveness since expression is increased in tumors that invade the sphenoid bone.

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7 Clinical presentation

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10 Dignosis

11 Work-up seqeunce 1.Recognition that a patient's visual abnormality or other neurologic symptom could represent an intrasellar lesion. 2.Confirming the presence of an intrasellar lesion by an imaging procedure. 3.Detecting secretory abnormalities of gonadotropins and their subunits that are characteristic of a gonadotroph adenoma.

12  Nonfunctioning pituitary tumor 1. “Endocrine inactive pituitary tumor” “Nonfunctioning & gondotropin-producing pituitary tumor” 2. Pituitary tumor with no hormone hypersecretion & related symptoms 3. Positive for intact gonadotropins and/or their subunits by immunocytochemistry 4. DDx from craniopharyngiomas, meningiomas, arachnoid cysts, granulomatous diseases, gliomas, metastatic tumors, and chordomas.

13 preoperative diagnosis of pituitary adenomas 1) use of serum markers, and 2) gonadotropin responses to TRH.  Demonstration of elevated serum levels of glycoprotein hormones and/or free subunit levels, typically alpha-subunit and FSH-beta may suggest the presence of a pituitary adenoma, indicating the utility of such tumor markers  Patients with clinically nonfunctioning tumors may demonstrate unique gonadotropin responses following hypothalamic peptide administration in up to 40% of patients, administration of TRH results in stimulation of serum levels of gonadotropins and/or free subunits. These data suggest that TRH receptors, not found in normal gonadotroph membranes, are expressed on neoplastic gonadotroph cells.

14 Imaging procedure  Magnetic resonance imaging (MRI) 1.superior resolution and its ability to demonstrate the optic chiasm. 2.able to detect blood, thereby permitting recognition of hemorrhage into the pituitary and distinction of an aneurysm from other intrasellar lesions.  CT scanning advantage of demonstrating calcium, which may be helpful in making the diagnosis of a craniopharyngioma

15 Hormonal abnormalities  pituitary adenoma of gonadotroph or thyrotroph cell origin should be suspected if 1.The serum prolactin concentration is less than 100 ng/mL 2.The patient does not appear acromegalic and the serum concentration of insulin-like growth factor-1 (IGF-1) is not elevated. 3.The patient does not have Cushing's syndrome or supranormal urine cortisol excretion

16  Men 1.Supranormal basal serum FSH concentration in a man who has an intrasellar mass lesion 2.Supranormal basal serum concentration of the free alpha subunit of glycoprotein hormones or supranormal responses of intact FSH and LH or LH beta subunit to thyrotropin releasing hormone responsiveness was not seen in growth hormone or prolactin secreting pituitary adenomas. 3.Supranormal serum LH accompanied by a supranormal serum testosterone concentration, whether or not accompanied by an elevated FSH level, is strong evidence that the lesion is one of the unusual gonadotroph adenomas that secretes intact LH [22,27]. testosterone22,27

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18  Women  Basis of the FSH and LH values alone; complicated as below cases  In a woman over 50 years of age who has an intrasellar mass and elevated gonadotropins, distinguishing between an adenoma and normal postmenopausal gonadotroph cells as the source  In a woman under 50 years of age who has an intrasellar mass and elevated serum gonadotropins, distinguishing between an adenoma and premature ovarian failure as the source of the gonadotropins  a few combinations of basal FSH, LH, and free alpha subunit values 1.Markedly supranormal FSH level + subnormal LH concentration; 2.Serum free alpha subunit concentration that is supranormal when intact FSH and LH are not, or is supranormal out of proportion to the FSH and LH

19  Markedly elevated serum estradiol concentration and an FSH concentration that is not suppressed, associated with endometrial hyperplasia and polycystic ovaries by ultrasound, in a woman of premenopausal age who presents with amenorrhea or oligomenorrhea  gonadotroph adenoma secreting FSH constantly and causing ovarian hyperstimulation estradiol

20  Confirmation that an intrasellar mass in a woman is a gonadotroph adenoma achieved by an increase in the FSH or LH or, more frequently, the LH beta subunit response to TRH.

21  only about 35 percent of these tumors secrete enough gonadotropins to raise the serum levels [25].25

22  Distinguishing gonadotroph adenomas from primary hypogonadism  Long-standing primary hypogonadism can cause gonadotroph cell hypertrophy and therefore overall pituitary enlargement [29], and in this way, as well as in elevated gonadotropin concentrations, is similar to gonadotroph adenomas.29  Primary hypogonadism differs from gonadotroph adenomas in several ways: 1.The degree of pituitary enlargement is much less 2.Both LH and FSH are elevated 3.Neither intact gonadotropins nor their subunits respond to TRH

23  Abnormal secretion of other pituitary hormones  In rare cases, however, concomitant secretion of TSH and prolactin has been reported.  ( A serum prolactin concentration that is elevated, but under 100 ng/mL, is not necessarily indicative of concomitant secretion by the adenoma; it more often reflects increased secretion by normal lactotroph cells that are less than normally inhibited because of stalk compression by the adenoma.)  Deficient secretion of other pituitary hormones often occurs due to the mass effect of the typically large gonadotroph adenomas and should always be investigated.

24 Pituitary incidentaloma

25 Treatment

26 Management diagram

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28 Endoscopic Pituitary Surgery

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32 Postop management  Immediate postoperative management  In the few days after surgery, the patient may develop diabetes insipidus, SIADH, or both.  increased manipulation of pituitary & its stalk during surgery  major cause is inappropriate ADH release from the injured posterior pituitary gland ( relative adrenal insufficiecny 도 기여함 )  fall in the plasma sodium concentration is most severe on the sixth to seventh postoperative day.  Patients with polyuria due to diabetes insipidus :Tx with aqueous vasopressin. Desmopressin (dDAVP), which is longer-acting, should be avoided at this time, because it might cause hyponatremia if the diabetes insipidus suddenly remits, particularly if it is then followed by the SIADH. vasopressin Desmopressin  dDAVP should be used if diabetes insipidus lasts for more than four to five days or is present at the time of discharge from the hospital. Maintenance hydrocortisone replacement should also be prescribed at discharge.hydrocortisone

33  Short-term postoperative management  Four to six weeks after discharge from the hospital, the patient should be evaluated for the amount of residual adenoma, visual function (by acuity and visual fields), and hormonal function of the nonadenomatous pituitary.  This evaluation should include measurements of: 1.Serum thyroxine. 2.Early morning serum cortisol 48 hours after discontinuation of hydrocortisone. If the serum cortisol value is 18 µg/dL (497 nmol/L), the patient has normal adrenal function; if it is between 4 and 17 µg/dL (110 and 469 nmol/L), a test of corticotropin (ACTH) reserve, such as a metyrapone test, should be performed. Serum testosterone in a man or serum estradiol in a premenopausal woman. hydrocortisonecorticotropinmetyraponetestosteroneestradiol 3.24-hour urine volume if the patient has significant nocturia. A water deprivation test should be performed if the urine output is above 3 L/day; values above 6 L/day are almost always due to diabetes insipidus.  Any hormonal deficiencies that are identified should be treated.

34  Long-term postoperative management  Long-term monitoring should include testing every six to 12 months initially 1.To detect growth of residual adenoma tissue and the adequacy of hormonal replacement. 2.Vision should also be periodically evaluated 3.Evaluation for tumor regrowth should include measurement of whatever serum marker was elevated before surgery and an MRI  if there is no regrowth after a year or two, the interval between scans can be lengthened.  Early detection permits appropriate use of radiation therapy to minimize the need for repeat surgery.

35 1.Residual adenoma tissue may regrow. The frequency varies and may depend on the nature of the adenoma. In one group of 65 patients considered at low risk for recurrence after transsphenoidal surgery (no pituitary invasion and presumed complete surgical excision), 21 (32 percent) had evidence of tumor regrowth during a mean follow-up period of 76 months 2.In contrast, in a report of 91 patients with nonfunctioning pituitary macroadenomas who underwent surgery without radiotherapy, tumor regrowth was seen in only 10 percent of patients, with a mean time to tumor regrowth of approximately six years.  If MRI six months after transsphenoidal surgery shows little adenoma tissue or tissue not in a location of clinical significance, we recommend observation only by MRI, initially yearly. Clin Endocrinol (Oxf) 1999; 51:281. J Clin Endocrinol Metab 2006; 91:1796.

36 RADIATION 1.Preventing regrowth of a pituitary adenoma of residual adenoma tissue that poses a significant neurologic risk. 2.When administered for adenoma regrowth, conventional radiation therapy results in ten year control rates, defined as lack of progression clinically and radiologically, of approximately 80 %. 3.Not employed as primary therapy for gonadotroph and other clinically nonfunctioning pituitary adenomas, because its effects occur too slowly to be appropriate when a patient has visual impairment. 4.primary therapy in selected patients whose adenomas are sufficiently large to threaten the optic chiasm but are not causing visual impairment or other neurologic symptoms

37  Conventional radiation therapy  supervoltage radiation, administered in 23 to 25 daily doses of 2 Gy each.  Side effects of conventional radiation therapy can occur both during therapy and up to 10 years later.  complication during treatment 1.nausea, lethargy; remit within one to two months 2.loss of taste and smell & loss of hair at the radiation portals ;remit within six months.  most common late complication ; loss of function in the nonadenomatous pituitary ;~50 % likelihood that at least one pituitary hormone that was normal prior to radiation will be subnormal within the ensuing five years [16].16  Neurologic complications are less common but more serious. 1.Optic neuropathy 2.malignant neoplasms  Anecdotes also suggest increased risk of cerebrovascular disease, but there is little documentation.

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39  Stereotactic radiation  Source of the radiation. 1.Photons administered by a linear accelerator 2.Gamma radiation from a (60)Co source ("gamma knife") 3.Proton beam therapy  Fractionated doses. (fractionated stereotactic radiotherapy, stereotactic conformal radiotherapy, or intensity-modulated radio therapy) administered from a linear accelerator or from a proton source in 1.8 Gy fractions for a total dose of 45 to 50 Gy.  Single fraction dose ( stereotactic "radiosurgery“, gamma "knife“) 1.administering a single dose of 10 to 27 Gy from a linear accelerator, a (60)Co source, or by proton beam. (60)Co emits gamma radiation, 2.should be employed only for adenomas that are confined to the sella and are a certain minimum distance from the optic chiasm.

40  Several series have now reported the results of fractionated radiotherapy using a linear accelerator or proton beam for a median duration of observation of 40 months or more. The following results were observed: 1.Adenoma size : reduced or stable in 90 to 100 % of the patients. 2.No neurologic damage attributable to the radiation was observed in the two studies in which radiation was delivered by linear accelerator, but in another report of 68 patients, radiation-induced ophthalmopathy occurred in two patients. In the study of proton beam treatment, temporal lobe necrosis occurred in one patient and new visual deficiencies in three. 3.Pituitary hormonal deficiencies : one third of the subjects in the three studies during the median observation period of 40 or more months.

41  Two reports describe the results of single-dose radiation in patients with pituitary adenomas.  One report is a review of 35 studies that involved 1621 patients (452 with clinically nonfunctioning adenomas) treated with single- dose radiation from a linear accelerator, gamma source, or proton beam, in which the median period of observation was 40 months in about half. #adenoma size controlled : 90 percent; #new hypopituitarism varied widely among individual neuropathy (~ 1%); other cranial neuropathies( ~ 1.3%) ; parenchymal brain damage, especially in the hypothalamus and temporal lobe(~ 0.8 %)

42  In a subsequent report from a single center, 100 patients with clinically nonfunctioning adenomas were treated with single-dose radiation from a gamma source and followed for a median of 45 months. #Adenoma volume decreased or remained stable (~ 92%) #new hypopituitarism developed (~ 20% overall & 25 % in those followed for >2 new neurological deficits occurred.  Overall, single-dose radiation also appears to give good results, but not clearly superior to those previously reported with conventional radiation.  Stereotactic radiotherapy has also been utilized for other pituitary tumors

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47 DRUG THERAPY  The extraordinary success of dopamine agonists in reducing the size of, as well as secretion by, lactotroph adenomas has prompted attempts to find a pharmacologic treatment for gonadotroph adenomasdopamine  To date, however, no drug has been found that consistently and substantially reduces the size of gonadotroph adenomas 1.Dopamine agonists 2.Octreotide 3.GnRH superactive agonist analogs 4.GnRH antagonist