Hyperpituitarism Treatment & Management
- Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD more...
Prolactinoma is the only pituitary adenoma for which long-term medical management is fully satisfactory. Unless the patient presents with an acute threat to vision, hydrocephalus, cerebrospinal fluid leak, or other surgical emergency, medical management with dopamine agonists should be attempted before surgical treatment is considered. Dopamine agonists are potent suppressors of PRL secretion and promptly lower serum PRL levels, abolish galactorrhea, and restore normal gonadal function in most patients with hyperprolactinemia of any cause. Dopamine agonists can also inhibit tumor cell replication in 60-80% of prolactinomas. In small tumors, dopamine agonists cause tumor shrinkage, while the results vary in larger tumors. Successful long-term use of these drugs can obviate the need for pituitary surgery.
The treatment of choice for patients with Cushing disease is transsphenoidal microsurgery. Medical therapy for Cushing disease is adjunctive only. The goal is to inhibit the enzymes responsible for cortisol synthesis with adrenal enzyme inhibitors, such as metyrapone, aminoglutethimide, and ketoconazole. Metyrapone and aminoglutethimide have been the standard therapy, and, when the 2 agents are used in combination, adverse effects may be decreased. Ketoconazole, a broad-spectrum antimycotic drug, inhibits adrenal steroid biosynthesis at several sites, including side chain cleavage and 11B-hydroxylation. Occasionally, patients with ACTH-secreting tumors respond to bromocriptine.
Somatostatin analogs are highly effective therapies for patients with GH excess. Octreotide suppresses circulating GH levels to less than 2.5 µg/L in 65% of patients with acromegaly and normalizes IGF-I levels in 70% of patients. Long-term studies of patients older than 14 years confirm that the effects of octreotide remain well sustained over time. Octreotide also shrinks tumors, but the effect is generally modest.
A continuous subcutaneous infusion of octreotide in a pubertal boy with pituitary gigantism consistently suppressed GH production. New long-acting formulations, including long-acting octreotide and lanreotide, have been reported to consistently suppress GH and IGF-I in patients with acromegaly with once monthly or biweekly intramuscular depot injections. The author has had success in using the sustained-release formulation in a female adolescent with MAS-related GH excess and can provide details upon inquiry.
Dopamine agonists bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion, although the precise mechanism of action remains unclear. PRL levels are often adequately suppressed; however, GH levels and IGF-I levels are rarely normalized with this treatment modality. Fewer than 20% of patients achieve GH levels less than 5 ng/mL and fewer than 10% achieve normalization of circulating IGF-I levels. Tumor shrinkage occurs in a minority of patients. A dopamine agonist is generally used as adjuvant medical treatment for GH excess. Its effectiveness may be additive to that of octreotide. Long-acting formulations are available, but data on long-term control of GH and IGF-I with these agents are not available.
A novel hepatic GH receptor antagonist recently has been approved by the Food and Drug Administration (FDA). Pegvisomant (Sensus Corporation, Austin, Tex) effectively suppresses circulating GH and IGF-I levels in patients with acromegaly due to pituitary tumors, as well as ectopic GHRH hypersecretion. IGF-I levels are normalized in as many as 90% of patients treated daily with this drug for 3 months.
Long-term studies are underway. The ACROSTUDY database provides an opportunity to assess the long-term safety of pegvisomant in the treatment of acromegaly. The main safety focus of this long-term follow up is on the potential risk of increased pituitary tumor size, potential for increased liver enzymes, and effects of pegvisomant at the injection site. There are 33 patients in the cohort younger than 18 years. Overall, it seems a selection bias may exist towards more severely affected patients, most subjects were enrolled in Europe, where pegvisomant is registered for patients in whom every other therapeutic intervention failed to control their acromegaly. In the future, additional data on more patients for longer duration will provide further information about the treatment of this rare condition.
Pediatric experience, although scant, has been published and agrees with the efficacy and adverse event profile reported with adult patients.
Transsphenoidal surgery is the treatment of choice for Cushing disease in children. Initial remission rates of 70-98% of patients and long-term success rates of 50-98% have been reported.
The preferred primary treatment for the patient with acromegaly is surgery, with a surgical cure rate at 10 years approaching 83% in the largest reported series. Such surgery should be performed at large centers with documented experience, including published outcome and adverse event profiles.
For prolactinomas, surgery has good outcome with a long-term (10-year) surgical cure rate approaching 82% in the largest reported series with very low morbidity and no mortality.
Irradiation is reserved for the few patients who are intolerant of medication. Irradiation of the pituitary gland in children is not recommended, because it can lead to panhypopituitarism, optic nerve and optic chiasm injury, delayed radiation injury of the brain, increased risk of a second brain tumor, and epilation.
Endocrinologists fill a critical role in the diagnosis, preoperative, perioperative, and postoperative management of all pediatric patients with pituitary adenomas.
The experience of the neurosurgeon is critical for the outcome of transsphenoidal adenomectomy. In addition, the referring physician should obtain the published outcome and adverse event profiles for the surgeon and her or his institution. Such information should be discussed with the patient and patient's family prior to referral to another institution.
Kasum M, Oreskovic S, Zec I, Jezek D, Tomic V, Gall V, et al. Macroprolactinemia: new insights in hyperprolactinemia. Biochem Med (Zagreb). 2012. 22(2):171-9. [Medline].
Lonser RR, Ksendzovsky A, Wind JJ, Vortmeyer AO, Oldfield EH. Prospective evaluation of the characteristics and incidence of adenoma-associated dural invasion in Cushing disease. J Neurosurg. 2012 Feb. 116(2):272-9. [Medline].
van der Lely AJ, Biller BM, Brue T, et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012 May. 97(5):1589-97. [Medline].
Devoe DJ, Miller WL, Conte FA, et al. Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 1997. 82:3196-202. [Medline].
Avramides A, Karapiperis A, Triantafyllidou E, et al. TSH-secreting pituitary macroadenoma in an 11-year-old girl. Acta Paediatr. 1992. 81:1058-1060. [Medline].
Benveniste RJ, King WA, Walsh J, et al. Repeated transsphenoidal surgery to treat recurrent or residual pituitary adenoma. J Neurosurg. 2005. 102:1004-1012. [Medline].
Booth GL, Redelmeier DA, Grosman H, et al. Improved diagnostic accuracy of inferior petrosal sinus sampling over imaging for localizing pituitary pathology in patients with Cushing's disease. J Clin Endocrinol Metab. 1998 Jul. 83(7):2291-5. [Medline].
Ciccarelli A, Daly AF, Beckers A. The epidemiology of prolactinomas. Pituitary. 2005. 8:3-6. [Medline].
Colao A, Loche S, Cappabianca P. Pituitary adenomas in children and adolescents. Clinical presentation, diagnosis, and therapeutic strategies. The Endocrinologist. 2000. 10:314-27.
Colao A, Lombardi G. Growth-hormone and prolactin excess. Lancet. 1998 Oct 31. 352(9138):1455-61. [Medline].
Cozzi R, Attanasio R, Barausse M, et al. Cabergoline in acromegaly: a renewed role for dopamine agonist treatment?. Eur J Endocrinol. 1998 Nov. 139(5):516-21. [Medline].
[Guideline] Cozzi R, Baldelli R, Colao A, Lasio G, Zini M, Attanasio R. AME Position Statement on clinical management of acromegaly. J Endocrinol Invest. 2009. 32(6 Suppl):2-25. [Medline].
de Boer L, Hoogerbrugge CM, van Doorn J, et al. Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid-labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos syndrome. J Pediatr Endocrinol Metab. 2004. 17:615-627. [Medline].
De Menis E, Visentin A, Billeci D, et al. Pituitary adenomas in childhood and adolescence. Clinical analysis of 10 cases. J Endocrinol Invest. 2001. 24:92-97. [Medline].
Dhillon KS, Cohan P, Kelly DF, et al. Treatment of hyperthyroidism associated with thyrotropin-secreting pituitary adenomas with iopanoic acid. J Clin Endocrinol Metab. 2004. 89:708-711. [Medline]. [Full Text].
Duncan E, Wass JA. Investigation protocol: acromegaly and its investigation. Clin Endocrinol (Oxf). 1999 Mar. 50(3):285-93. [Medline].
Eugster EA, Pescovitz OH. Gigantism. J Clin Endocrinol Metab. 1999 Dec. 84(12):4379-84. [Medline].
Gillam MP, Fideleff H, Boquete HR, Molitch ME. Prolactin excess: treatment and toxicity. Pediatr Endocrinol Rev. 2004. 2:108-114. [Medline].
Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. 2000 Feb. 85(2):526-9. [Medline].
Gsponer J, De Tribolet N, Deruaz JP, et al. Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore). 1999. 78:236-269. [Medline].
Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. 1990 Dec. 71(6):1427-33. [Medline].
Herman-Bonert VS, Zib K, Scarlett JA, Melmed S. Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab. 2000 Aug. 85(8):2958-61. [Medline]. [Full Text].
Howell DL, Wasilewski K, Mazewski CM, et al. The use of high-dose daily cabergoline in an adolescent patient with macroprolactinoma. J Pediatr Hematol Oncol. 2005. 27:326-329. [Medline].
Joshi SM, Hewitt RJ, Storr HL, et al. Cushing's disease in children and adolescents: 20 years of experience in a single neurosurgical center. Neurosurgery. 2005. 57:281-285. [Medline].
Kanter AS, Diallo AO, Jane JA Jr, et al. Single-center experience with pediatric Cushing's disease. J Neurosurg. 2005. 103:413-420. [Medline].
Kunwar S, Wilson CB. Pediatric pituitary adenomas. J Clin Endocrinol Metab. 1999 Dec. 84(12):4385-9. [Medline].
Lafferty AR, Chrousos GP. Pituitary tumors in children and adolescents. J Clin Endocrinol Metab. 1999 Dec. 84(12):4317-23. [Medline].
Lonser RR, Wind JJ, Nieman LK, Weil RJ, DeVroom HL, Oldfield EH. Outcome of surgical treatment of 200 children with Cushing's disease. J Clin Endocrinol Metab. 2013 Mar. 98(3):892-901. [Medline].
Mindermann T, Wilson CB. Pediatric pituitary adenomas. Neurosurgery. 1995 Feb. 36(2):259-68; discussion 269. [Medline].
Newman CB. Medical therapy for acromegaly. Endocrinol Metab Clin North Am. 1999 Mar. 28(1):171-90. [Medline].
Ng LL, Chasalow FI, Escobar O, Blethen SL. Growth hormone isoforms in a girl with gigantism. J Pediatr Endocrinol Metab. 1999. 126:99-106. [Medline].
Oliveira Mda C, Abech DD, Barbosa-Coutinho LM, Ferreira NP. Macroprolactinoma at 6 years of age: diagnostic difficulties. [Portuguese]. Arq Neuropsiquiatr. 1992. 50:397-401. [Medline].
Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug. 83(8):2730-4. [Medline].
Orth DN. Cushing's syndrome. N Engl J Med. 1995 Mar 23. 332(12):791-803. [Medline].
Pandey P, Ojha BK, Mahapatra AK. Pediatric pituitary adenoma: a series of 42 patients. J Clin Neurosci. 2005. 12:124-127. [Medline].
Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol. 2005. 153:195-201. [Medline].
Saito E, Correll CU, Gallelli K, et al. A prospective study of hyperprolactinemia in children and adolescents treated with atypical antipsychotic agents. J Child Adolesc Psychopharmacol. 2004. 14:350-358. [Medline].
Sakazume S, Obata K, Takahashi E, et al. Bromocriptine treatment of prolactinoma restores growth hormone secretion and causes catch-up growth in a prepubertal child. Eur J Pediatr. 2004. 163:472-474. [Medline].
Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clin North Am. 1987. 16:765-792. [Medline].
Sotos JF. Overgrowth. Hormonal Causes. Clin Pediatr (Phila). 1996 Nov. 35(11):579-90. [Medline].
Stevens JR, Kymissis PI, Baker AJ. Elevated prolactin levels in male youths treated with risperidone and quetiapine. J Child Adolesc Psychopharmacol. 2005. 15:893-900. [Medline].
[Guideline] Stewart PM, Petersenn S. Rationale for treatment and therapeutic options in Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009. 23 Suppl 1:S15-22. [Medline].
Storr HL, Afshar F, Matson M, et al. Factors influencing cure by transsphenoidal selective adenomectomy in paediatric Cushing's disease. Eur J Endocrinol. 2005. 152:825-833. [Medline].
Tamura T, Tanaka R, Korii K, Okazaki H. Pediatric pituitary adenoma. Endocr J. 2000. 47:S95-S99. [Medline].
Thorner MO, Vance ML, Laws ER. The anterior pituitary. In: Wison JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa:. WB Saunders. 1998:249-340.
Trainer PJ, Drake WM, Katznelson L, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000 Apr 20. 342(16):1171-7. [Medline].
van Haelst MM, Hoogeboom JJ, Baujat G, et al. Familial gigantism caused by an NSD1 mutation. Am J Med Genet A. 2005. 139:40-44. [Medline].
van Haute FR, Taboada GF, Corrêa LL, Lima GA, Fontes R, Riello AP, et al. Prevalence of sleep apnea and metabolic abnormalities in patients with acromegaly and analysis of cephalometric parameters by magnetic resonance imaging. Eur J Endocrinol. 2008. 158:459-65. [Medline].
Yang MH, Chuang H, Jung SM, et al. Pituitary apoplexy due to prolactinoma in a Taiwanese boy: patient report and review of the literature. J Pediatr Endocrinol Metab. 2003. 16:1301-1305. [Medline].
Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am. 1998 Mar. 27(1):109-26. [Medline].