BERKELEY, CA (UroToday.com) - Pituitary apoplexy can occur after administration of gonadotropin-releasing hormone agonist (GnRHa) for treatment in patients with prostate cancer. Patients may present with sudden headache, visual deficits, altered mental status, and nausea. Although rare, it is generally thought to be due to hemorrhage or infarction in a previously silent pituitary tumor. Often there is a delay in its diagnosis. Since GnRHa therapy results in symptoms of hypogonadism, the expected complaints of feeling poorly with ill-defined fatigue and behavior changes can be attributed to the GnRHa therapy. In the case of GnRHa induced pituitary apoplexy, these symptoms are actually resulting from adrenal insufficiency and panhypopituitarism.

A previously unrecognized adenoma is present in 64% to 86% of cases^1-3. In autopsy series, clinically silent pituitary adenomas are found in 6-23% of the adult population⁴ and apoplexy occurs in up to 17% of patients with known pituitary adenomas^1-5. The prevalence of clinically silent microadenomas increases to 30% in the elderly⁵ placing a significant proportion of individuals at risk for apoplexy.

Dynamic pituitary testing with hypothalamic releasing hormones, including GnRH alone or in combination with TRH, has been linked with pituitary apoplexy. A review by Otsuka et al in 1998, showed 22 of the 29 reported cases of pituitary apoplexy following dynamic pituitary function testing involved GnRH administration⁶. Macroadenomas were present in all reported cases. In the majority (70%) of cases, symptoms of apoplexy appeared within 60 minutes after administration and by 72 hours in all cases. There are 7 reported cases of pituitary apoplexy following administration of GnRHa for the treatment of prostate cancer^7-13. All patients had pituitary macro-adenomas that were previously unrecognized. Most of the adenomas were confirmed to be gonadotroph adenomas and apoplexy was reported within less than 4 hours in all but one.

These patients were treated with goserelin injection, triptorelin, or luperolide. The exact mechanism by which GnRHa precipitates pituitary apoplexy in patients with adenomas remains unclear. A synthetic GnRHa is 100-fold more potent than the naturally occurring gonadotropin releasing hormone (GnRH). By binding to GnRH receptors on pituitary gonadotropin-producing cells, GnRHa analogs cause LH and FSH levels to increase dramatically during the first week with a transient rise in serum testosterone¹⁴. There is down regulation with chronic use resulting is a decrease in serum LH with resultant hypogonadism¹⁵. In contrast to gonadotroph desensitization in normal subjects with chronic administration, there appears to be a persistent agonist effect on LH secretion in patients with LH secreting pituitary tumors^16-17.

GnRHa may induce growth of the pituitary tumor and compress surrounding vessels resulting in necrosis and hemorrhage. It may also increase the metabolic activity of tumor or may precipitate a direct vascular event leading to hemorrhage^18-19.

Pituitary apoplexy as a side-effect of GnRHa is rare. In patients treated for prostate cancer with GnRHa, 6 of 7 reported cases developed signs of apoplexy within a few hours of initial treatment. Clinicians using GnRHa need to be aware of this complication, which may necessitate immediate neurosurgery to preserve sight and administration of stress doses of hydrocortisone to avoid death from acute adrenal insufficiency. We therefore recommend that patients inform their physicians immediately if headache, visual disturbances, or symptoms of adrenal insufficiency occur within 24 hours after GnRHa administration.

References:
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2. Randeva HS, Schoebel J, Byrne J, Esiri M, Adams CB, Wass JA. Classical pituitary apoplexy: Clinical features, management and outcome. Clin Endocrinology. 1999;51:181–188.
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4. Kovacs K, Horvath E. Pathology of pituitary tumors. Endocrinol Metab Clin North Am. 1987;16:529–551.
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6. Otsuka F, Kageyama J, Ogura T, Makino H. Pituitary apoplexy induced by a combined anterior pituitary test: Case report and literature review. Endocrine Journal. 1998;45:393–398.
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8. Chanson P, Schaison G. Pituitary apoplexy caused by GnRH-agonist treatment revealing gonadotroph adenoma. J Clin Endocrinol Metab. 1995;80:2267–2268.
9. Morsi A, Jamal S, Silverberg JD. Pituitary apoplexy after leuprolide administration for carcinoma of the prostate. Clin Endocrinol. 1996;44:121–124.
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11. Eaton HJ, Phillips PJ, Hanieh A, Cooper J, Bolt J, Torpy DJ. Rapid onset of pituitary apoplexy after goserelin implant for prostate cancer: need for heightened awareness. Internal Medicine Journal. 2001;31:313-4.
12. Hernandez Morin N, Huet D, Hautecouverture M. Two cases of non-functional gonadotroph adenoma pituitary apoplexy following GnRH-agonist treatment revealing gonadotroph adenoma and pseudopituitary apoplexy after GnRH administration. Annales d Endocrinologie. 2003;64:227-31.
13. Hands KE, Alvarez A, Bruder J, Gonadotropin Releasing Hormone Agonist Induced Pituitary Apoplexy in the Treatment of Prostate Cancer: Case Report and Review of the Literature, Endocrine Practice, 2007
14. Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. New England Journal of Medicine. 1991;324:93-103.
15. Bhasin S. Regulation of body composition by androgens. Journal of Endocrinological Investigation. 2003;26:814-22.
16. Roman SH, Goldstein M, Kourides IA, Comite F, Bardin CW, Krieger DT. The Luteinizing Hormone-Releasing Hormone (LHRH) Agonist [D-Trp6 –Pro9 –Net]LHRH Increased Rather than Lowered LH and α-Subunit Levels in a Patient with an LH-Secreting Pituitary Tumor. J Clin Endocrinol and Metab. 1984;58(2):313-319.
17. Klibanski A, Jameson JL, Biller BMK, et al. Gonadotropin and α-Subunit Responses to Chronic Gonadotropin-Releasing Hormone Analog Administration in Patients with Glycoprotein Hormone-Secreting Pituitary Tumors. J Clin Endocrinol and Metab. 1989;68(1):81-86.
18. Waxman J, Man A, Hendry WF, et al. Importance of early tumor exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br Med J. 1985;291:1387.
19. Sassolas G, Lejeune H, Trouillas J, et al. Gonadotropin-Releasing Hormone Agonists are Unsuccessful in Reducing Tumoral Gonadotropin Secretion in Two Patients with Gonadotropin-Secreting Pituitary Adenomas. J Clin Endocrinol and Metab. 1988;67(1):180-185.

Written by
Kathleen E. Hands, MD - Clinical Assistant Professor of Medicine/Diabetes - University of Texas Health Science Center at San Antonio - Staff Endocrinologist, Texas Diabetes Institute, as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Gonadotropin-Releasing Hormone Agonist-Induced Pituitary Apoplexy in Treatment of Prostate Cancer: Case Report and Review of Literature - Abstract

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