S P E C I A L

F E A T U R E U p d a t e

Update in Pituitary 2010

Janet A. Schlechte
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242

This manuscript is based on an invited lecture entitled The Year in Pituitary, presented at the 91st Annual Meeting of The Endocrine Society in San Diego, California, on June 21, 2010. The purpose of the lecture was to highlight new or evolving issues in the management of pituitary disease. Papers selected were published in major journals between January 2009 and June 2010. Issues addressed include the safety of cabergoline in pregnancy, recurrence of hyperprolactinemia after dopamine agonist withdrawal, pegvisomant and hepatic dysfunction, and high-dose hydrocortisone as a predictor of mortality in patients with acromegaly. (J Clin Endocrinol Metab 96: 1 8, 2011)

Safety of Cabergoline in Pregnancy

Ono M, Miki N, Amano K, Kawamata T, Seki T, Makino R, Takano K, Izumi S, kada Y, Hori T 2010 Individualized high dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas. J Clin Endocrinol Metab 95:26722679. (1) Background lthough cabergoline is widely considered first-line treatment for hyperprolactinemia, an unresolved issue is fetal and maternal safety after drug exposure during pregnancy. Evidence from nearly 400 pregnancies suggests that cabergoline does not cause teratogenic effects (2), but concern persists as to whether cabergoline taken during early pregnancy results in a higher than normal risk for congenital malformations.

The mean cabergoline dose required was 3.1 mg/wk for women with macroadenomas and 1.8 mg/wk for those with microadenomas. Despite higher mean doses of cabergoline (2.2 mg/wk compared with 1.1 mg/wk in other studies), there was no increase in maternal adverse events. All of the pregnancies that occurred in patients with macroadenomas were uneventful. No visual disturbances or headaches were reported during the pregnancies, and repeat magnetic resonance imaging (MRI) exams were not required in any of the patients. After 6 to 24 months of cabergoline therapy, 52% of the microadenomas and 38% of the macroadenomas were no longer radiographically apparent. Lebbe M, Hubinont C, Bernard P, Maiter D 2010 Outcome of 100 pregnancies initiated under treatment with cabergoline in hyperprolactinaemic women. Clin Endocrinol 73:236 242. (3) Main findings In this retrospective analysis, Lebbe et al. (3) compared 100 pregnancies in 72 women treated with cabergoline at the time of conception with 163 controls matched for age and date of delivery. The mean fetal exposure dose to cabergoline was 3.6 4.7 mg. There were 84 deliveries resulting in 88 children. The incidence of spontaneous miscarriage (10%) and the neonatal malformation rate (3.4%) were similar to rates in the general population in Belgium. Thirty-one percent of the cabergoline-induced
Abbreviations: CI, Confidence interval; MRI, magnetic resonance imaging; RR, relative risk; SMR, standard mortality ratio.

Main findings In a prospective analysis of 85 women with prolactinomas in Japan (1), cabergoline normalized prolactin and restored regular menstrual cycles in all patients. Ninetyfour percent of the women achieved a pregnancy, and there were 83 live births, one stillbirth, and two abortions. The incidence of low birth weight infants (10%) and stillbirths (1.2%) was not significantly different from rates in the general Japanese population. In extended follow-up studies, none of the infants demonstrated abnormalities in linear growth or mental development.
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright 2011 by The Endocrine Society doi: 10.1210/jc.2010-2410 Received October 12, 2010. Accepted November 3, 2010.

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The Year in Pituitary 2009 2010

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pregnancies and 29% of the controls had complications including hypertension, gestational diabetes, and preterm labor. The cabergoline dose at conception, duration of treatment during pregnancy, and cumulative fetal exposure did not differ between pregnancies resulting in normal babies and those complicated by fetal or neonatal malformations. Long-term follow-up studies indicated that in utero exposure to cabergoline did not influence postnatal development of children observed up to 12 yr. An increase in tumor size was observed in 17 of 37 cases requiring reinstitution of cabergoline. Significance These studies bring to over 600 the number of pregnancies induced by cabergoline and indicate that cabergoline taken at the time of conception does not increase the risk of miscarriage or fetal malformation. Although the number of pregnancies is still smaller than reported for bromocriptine (over 6000), this is reassuring information that can be shared with women of childbearing age to allow for informed decisions in the treatment of hyperprolactinemia-induced infertility.

Withdrawal of Cabergoline and Recurrence of Hyperprolactinemia

Kharlip J, Salvatori R, Yenokyan G, Wand G 2009 Recurrence of hyperprolactinemia after withdrawal of longterm cabergoline therapy. J Clin Endocrinol Metab 94: 2428 2436. (4) Background In a 2003 prospective analysis of 200 carefully selected patients and a stepwise withdrawal protocol, Colao et al. (5) reported that approximately 70% of patients with prolactin-secreting micro- and macroadenomas had remission of hyperprolactinemia 25 yr after withdrawal from cabergoline. The findings were striking because studies of unselected patients showed remission rates of only 10 20% after dopamine agonist withdrawal (6). In 2006, the Pituitary Society developed guidelines for dopamine agonist withdrawal designed for use in routine clinical settings. The guidelines specified a minimal duration of dopamine agonist therapy of 13 yr and suggested that a dopamine agonist be withdrawn in patients with normal prolactin and no evidence of tumor on MRI (7). Main findings Following the Pituitary Society guidelines, Kharlip et al. (4) examined rates of remission of hyperprolactinemia and clinical predictors of recurrence in 46 patients in a pitu-

itary center in Baltimore, Maryland. The patients had no history of surgery or radiation and were treated for 23 months before withdrawal of cabergoline for a median of 4.3 yr. Before drug withdrawal, all had normal prolactin, and none had tumor extension beyond the internal carotids, invasion of the sella floor, or proximity to the optic chiasm. Cabergoline was stopped if there was a substantial reduction in tumor size as judged by the treating endocrinologist. For microadenomas, any size reduction was acceptable; for macroadenomas, the lesion had to be intrasellar and less than 1 cm in maximal dimension. The estimated risk of recurrence of hyperprolactinemia was 54% at 1 yr and 63% at 18 months. The rate of recurrence was similar in microadenomas (52%) and macroadenomas (54%). In four patients with idiopathic hyperprolactinemia, the rate of recurrence was 75%. The median time to recurrence was 3 months, and 91% of recurrences occurred within 1 yr of cabergoline discontinuation. The median follow-up after withdrawal in patients who did not recur was 15 months (5 48 months). The rate of recurrence did not differ in those patients with less than 50% tumor size reduction or in those treated with higher doses of cabergoline before withdrawal. There was no evidence of tumor regrowth during follow-up. At the time of recurrence, 28% of the patients had galactorrhea, and 31% of the women and 22% of men had hypogonadism. The main predictors of recurrence were size of the tumor remnant and the prolactin nadir achieved at drug withdrawal. Each additional millimeter of size reduction from the original tumor size was associated with an 18% decrease in the risk of recurrence [95% confidence interval (CI), 335; P 0.17]. The frequency of recurrence was similar between patients who had visible tumor remnant and those who did not, and resolution of MRI findings was not associated with a lower recurrence rate. Dekkers O, Lagro J, Burman P, Jorgensen O, Romijn J, Pereira A 2010 Recurrence of hyperprolactinemia after withdrawal of dopamine agonists - meta analysis. J Clin Endocrinol Metab 95:4351. (8) Main findings This systematic review and meta-analysis (8) of 19 studies of dopamine agonist withdrawal reinforces the findings of Kharlip et al. (4). In this analysis, with a total of 743 patients, the pooled proportion of patients with normal prolactin after dopamine agonist withdrawal was 21%, and the likelihood of success was highest when cabergoline was used for 2 yr.

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Significance Despite the fact that the rates of remission are low and remission is short-lived, these analyses (4, 8) demonstrate that it is practical and safe to attempt dopamine agonist withdrawal in patients who have been treated for 2 yr if there is normalization of prolactin and evidence of tumor volume reduction. Although studies have shown no evidence of tumor regrowth, the high rates of recurrence, especially within the first year, and the hypogonadism that may accompany recurrence emphasize the importance of close follow-up when therapy is withdrawn.

Pegvisomant-Induced Liver Injury in Gilberts Syndrome

Berabeu I, Marazuela M, Lucas T, Loidi L, Alvarex-Escola C, Luque-Ramirez M, Fernandez-Rodriguez E, Paniagua A, Quintero C, Casanueva F 2010 Pegvisamontinduced liver injury is related to the UGT1A1*28 polymorphism of Gilberts syndrome. J Clin Endocrinol Metab 95:21472154. (9) Background Pegvisomant has been associated with hepatic dysfunction in patients with acromegaly, but the mechanism of the liver toxicity is not known. Gilberts syndrome is produced by a mutation in the gene UGT1A1*28 encoding bilirubin urine diphosphoglucuronate transferase, which conjugates bilirubin to glucuronic acid and can be associated with toxicity during treatment with drugs that are metabolized through glucuronidation reactions. The most common genotype in Gilberts syndrome in Caucasians is the UGT1A1*28 polymorphism, and the heterozygous carriers of this polymorphism have decreased hepatic glucuronidation activity without a high bilirubin. Based on liver injury in a patient with acromegaly and Gilberts syndrome, which developed during pegvisomant therapy, Bernabeu et al. (10) speculated that a decrease in hepatic glucuronidation activity related to the UGT1A1*28 variation might play a pathogenic role in pegvisomant-induced liver disease. Main findings This was a cross-sectional analysis conducted at four university hospitals in Spain (9). Thirty-six Caucasian patients with active acromegaly who were resistant to somatostatin analog therapy participated. Pegvisomant was initiated 1 month after the last dose of a somatostatin analog, and 28% of the patients developed abnormal liver function tests during therapy. The abnormalities were noted after 6 7 months of therapy with a mean dose of 15 5 mg/d and were more frequent in males

FIG. 1. All factor and stepwise multiple regression analysis of abnormal liver function studies in patients with Gilberts disease receiving pegvisomant. [Reprinted with permission from I. Bernabeu et al.: J Clin Endocrinol Metab 95:21472154, 2010 (10). 2010 The Endocrine Society.]

and younger patients. Ninety percent of those who developed abnormal liver function were UGT1A1*28 homozygotes or heterozygotes. The carriers of the UGT1A1*28 polymorphism had a higher incidence of liver function abnormalities (43%) than the uridine diphosphate-5glucuronyl transferase (UGT) wildtype (7%). The difference between the UGT1A1*28 carriers and wild-type persisted when adjusted in an all-factors multiple regression analysis for age, gender, alcohol consumption, and UGT1A1*28 polymorphism. Exploring the main determinants of liver function abnormalities using a step-wise method, the model identified only male gender and the UGT1A1*28 polymorphism as predictive variables for abnormalities in liver function (Fig. 1). Significance Little is known about the hepatic metabolism of pegvisomant, and it is not definitively established that UGTmediated glucuronidation is required. Although the small size of this study does not allow definitive pharmacogenetic conclusions, the results suggest that the UGT1A1*28 polymorphism directly, or through other genetic variations, could play a role in pegvisomant metabolism and hepatotoxicity. Because there are no identifiable predictors for liver injury during pegvisomant therapy, the authors recommend assessing the UGT1A1*28 polymorphism related to Gilberts syndrome in acromegalic patients who are candidates for pegvisomant therapy and close monitoring of liver function in UGT1A1*28 polymorphism carriers, particularly males, during pegvisomant therapy.

Schlechte

The Year in Pituitary 2009 2010

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Is Pegvisomant Therapy Associated with Tumor Growth?

Buhk J, Jung S, Psychogios M, Goricke S, Hartz S, SchulzHeis, S, Klingebiel R, Forsting M, Bruckmann H, Dorfler A, Jordan M, Buchfelder M, Knauth M 2010 Tumor volume of growth hormone-secreting pituitary adenomas during treatment with pegvisamont. J Clin Endocrinol Metab 95:552558. (11) Background Pegvisomant functions as a GH receptor antagonist by blocking GH receptor dimerization. Because the drug blocks the effect of GH rather than suppressing GH secretion, there has been concern that therapy may stimulate tumor growth as a consequence of a defective feedback mechanism regulating GH secretion. A few reports have noted an increase in tumor volume during pegvisomant therapy, but follow-up has not been systematic and few studies have extended beyond 12 months (12). Main findings Applying a highly standardized MRI protocol in five neuroradiological centers in Germany, Buhk et al. (11) prospectively assessed the effects of pegvisomant therapy on tumor volume. Patients were recruited from an open-label, prospective, observational multicenter registry (ACROSTUDY). The doses of pegvisomant ranged between 5 and 30 mg. Three-dimensional tumor volume assessment was performed by a single double-blinded observer, and volumetric analyses were performed at baseline, 6, 12, and 24 months. Sixty-one patients pretreated with somatostatin analogs (most with long-acting octreotide) participated. About one third had received radiotherapy, and 87% had previous surgical treatment. In three patients who had acromegaly for 1.3 to 10.8 yr, there was a significant increase in tumor volume that necessitated discontinuation of the drug. IGF-I values were normal in one patient and slightly elevated in the other two. All increases in tumor volume were observed during the first 12 months of the study, and the changes from baseline to 1 yr were 710, 1.4 2.0, and 0.11.8 cc in the affected subjects, respectively. Despite these radiographic increases in tumor volume, no patient had clinical impairment secondary to the size change. All of the subjects who demonstrated an increase in tumor volume had received long-acting octreotide before starting pegvisomant with drug-free intervals of 2 months. No significant volume changes were observed between the 12- and 24-month follow-up visits, and the 4.9% increase in tumor volume is similar to that observed in patients undergoing other medical therapy for acromegaly (13). Patients who had undergone radiation did not show

a significant decrease in tumor volume during the first years of pegvisomant treatment, and increases in tumor size appeared to be unrelated to IGF-I levels. Significance These data suggest that pegvisomant is a safe treatment option during the initial 2 yr of therapy in acromegalic patients with residual pituitary tumor. Because the patients who developed an increase in tumor volume had received long-acting octreotide treatment before pegvisomant was begun, it is possible that the tumor volume increase is due to medication crossover during the first month of enrollment as has been previously reported (14). Although sophisticated volumetric measurements will not be necessary or available in the routine clinical setting, it remains important to perform regular and standardized sella MRI exams to screen for potential tumor growth.

Should Patients Who Develop GH Deficiency after Treatment for Acromegaly Be Treated with GH?
Miller K, Wexler T, Fazepi P, Gunnell L, Graham G, Beauregard C, Hemphill L, Nachtigall L, Loeffler J, Swearingen B, Biller B, Klibanski A 2010 GH deficiency after treatment of acromegaly: A randomized, placebocontrolled study of GH replacement. J Clin Endocrinol Metab 95:567577. (15) Background It is well established that GH deficiency that develops as a consequence of nonfunctioning tumors is associated with abnormalities in body composition and cardiovascular risk markers and that GH replacement reverses these abnormalities (16). It is also clear that as many as 70% of acromegalic patients treated with surgery and/or radiation may develop GH deficiency (17), but little is known about the effects of GH replacement in these individuals. Main findings This is a randomized, placebo-controlled trial designed to determine the effect of GH on body composition, cardiovascular risk markers, and quality of life in 13 males and 17 females with GH deficiency after therapy for acromegaly (15). Dual-energy x-ray absorptiometry and cross-sectional computed tomography were used to assess body composition, and bioelectric impedance analysis was used to assess total body water. In the GH-treated group, there was a significant decrease in total body fat mass (1.6 kg) compared with the placebo group (0.7 kg) (P 0.04). There was also a significant decrease in total abdominal fat in study subjects

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with cured acromegaly, in particular those with elevated cardiovascular risk.

GH, Body Composition, and Physical Performance in Recreational Athletes

Meinhardt U, Nelson A, Hansen J, Birzniece V, Clifford D, Leung K, Graham K, Ho K 2010 The Effects of Growth Hormone on Body Composition and Physical Performance in Recreational Athletes Ann Intern Med 152:568 577. (20) Background Despite the lack of evidence that GH enhances athletic performance, athletes frequently use GH and androgenic anabolic steroids based on observations that GH improves body composition and that testosterone enhances the effect of GH (21). Main findings This was an 8-wk randomized trial followed by a 6-wk washout performed in 96 healthy recreational athletes between the ages of 18 and 40 yr in Australia (20). The study was designed to assess the effect of GH alone or in combination with testosterone on body composition and performance. Women received GH or placebo, men received GH and testosterone, GH and placebo testosterone, testosterone and placebo GH, or double placebo. Fat mass and lean body mass were measured using dualenergy x-ray absorptiometry, and extracellular water was measured by bromide dilution. Physical tests included maximum O2 consumption, dead lift, jump height, and sprint capacity, which is a measure of anaerobic work capacity. At baseline, body cell mass correlated with all measures of physical performance. There were three main findings: GH and testosterone reduced fat mass, increased lean body mass, and increased body cell mass, and the effects were greater when the two treatments were combined. GH led to significant improvements in sprint capacity, and this effect nearly doubled when GH was administered with testosterone. The combination of GH and testosterone had no effect on aerobic capacity or other measures of strength or power, and the effect disappeared 6 wk after discontinuation of therapy. Changes in body cell mass did not correlate with improvement in sprint capacity, except when GH was coadministered with testosterone. Significance This is the first demonstration of a change in physical performance with GH, but the athletic significance of the

FIG. 2. Effect of GH on total body and abdominal fat. [Adapted with permission from K. K. Miller et al.: J Clin Endocrinol Metab 95:567 577, 2010 (17). 2010 The Endocrine Society.]

receiving GH compared with placebo (11.6 vs. 1.4%; P 0.04) (Fig. 2). Visceral adipose tissue in the GH-treated group decreased by 15% compared with placebo (P 0.01), and fat-free mass increased by 1.5 kg in the GH group compared with 0.1 kg in the placebo group without a change in total body water (P 0.02). Mean high-sensitivity C-reactive protein levels fell from 2.9 to 2.1 mg/liter after GH administration (P 0.05), but administration of GH did not result in a significant change in carotid intimal medial thickness, lipid profiles, fibrinogen, glucose, hemoglobin A1C, or insulin sensitivity. Quality of life as measured by the Adult Growth Hormone Deficiency Assessment improved with GH (P 0.05), and side effects were minimal. Significance These findings suggest that patients with cured acromegaly who develop GH deficiency might benefit from GH replacement, and the improvement in body composition seen with GH could have important clinical consequences because visceral adiposity is associated with an increase in coronary heart disease and inflammatory cardiac risk markers. These conclusions, however, need to be tempered by the observations of Norrman et al. (18) who demonstrated an increase in vascular events after 2 yr of GH replacement in adults with GH deficiency previously treated for acromegaly. Although the improvement in body composition and high-sensitivity C-reactive protein in the treated acromegalic subjects is comparable to the results in randomized trials of GH in adults with nonfunctioning pituitary tumors, the findings may not be generalizable because cardiovascular disease, hypertension, and valve regurgitation are more common in acromegalic subjects (19). Additional studies will be necessary to examine the safety and advisability of giving GH to patients

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The Year in Pituitary 2009 2010

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improvement in sprint capacity remains to be established. Further work is needed to address whether GH given for longer periods of time at higher doses will improve aerobic performance, strength, or power, and it will be important to investigate the biochemical mechanism(s) that may underlay the apparent GH facilitation of anaerobic capacity.

with diverticula throughout the colon, the authors surmise that diverticula in acromegaly may develop due to disturbed matrix regulation caused by excess GH and IGF-I.

High Doses of Hydrocortisone as a Predictor of Mortality in Acromegaly

Sherlock M, Reulen C, Alonso A, et al. 2009 ACTH deficiency, higher doses of hydrocortisone replacement and radiotherapy are independent predictors of mortality in patients with acromegaly. J Clin Endocrinol Metab 94: 4216 4223. (25) Background Several retrospective studies have demonstrated increased mortality in patients with acromegaly with standard mortality ratios (SMRs) of 1.33.0 (26, 27). Potential factors associated with the increased mortality include elevated GH and IGF-I, radiotherapy, and hypopituitarism. The fact that typical, widely used doses of hydrocortisone (30 mg/d) are substantially higher than physiological cortisol production rates (28) and the observation by Filipsson et al. (29) that GH-deficient adults with ACTH deficiency treated with a daily hydrocortisone equivalent greater than 25 mg had higher total cholesterol, triglycerides, waist circumference, and hemoglobin A1C levels than GH-deficient subjects taking no hydrocortisone suggest another cause for the increased mortality. Main findings Using a large United Kingdom database incorporating 501 well-characterized patients with acromegaly with a median duration of follow-up of 14 yr, Sherlock et al. (25) assessed the influence of prior radiotherapy, hypopituitarism, and replacement therapy on mortality. All-cause mortality was elevated with a SMR of 1.7 (1.4 2.0) (P 0.001). There were significant increases in cardiovascular, respiratory, and cerebrovascular deaths but no increase in deaths due to cancer. Compared with the general population, prior radiotherapy [2.1 (1.72.6); P 0.006], ACTH deficiency [2.5 (1.9 3.2); P 0.0005], and gonadotropin deficiency [2.1 (1.6 2.7); P 0.37] were all associated with an elevated SMR. When adjusted for sex, age, period of follow-up, and radiotherapy, only ACTH deficiency was associated with significantly increased mortality (Table 1). Supraphysiological doses of hydrocortisone were also associated with an increasing SMR [2.8 (2.2 3.7); P 0.00001]. After adjustment for age, sex, length of followup, and radiotherapy, there was a significant increase in the relative risk (RR) of mortality in patients receiving hydrocortisone equivalents between 25 and 30 mg and for

Acromegaly and Colonic Diverticula

Wassenaar M, Cazemier N, Biermasz N, Pereira A, Roelfsema F, Smit J, Hommes D, Felt-Bersma R, Romijn J 2010 Acromegaly is associated with an increased prevalence of colonic diverticulitis. J Clin Endocrinol Metab 95:20732079. (22) Background The presence of colonic diverticula in patients with Marfans syndrome and the similarity of cardiac valve and aortic root abnormalities in patients with acromegaly and Marfans syndrome (23, 24) led Wassenaar et al. (22) to examine whether elevated GH in acromegaly could predispose to colonic diverticula. Main findings Reports of screening colonoscopies were reviewed in 107 patients with cured or biochemically controlled acromegaly and 214 age- and sex-matched nonacromegalic controls (22). The mean duration of remission of acromegaly was 9.8 yr, and the estimated duration of active disease was 9.7 yr. Colonic diverticula were present in 37% of patients with acromegaly compared with 19% of controls (P 0.002). Dolichocolon (34%) and adenomatous polyps (34%) were also more frequent in acromegalics compared with controls (P 0.002). Diverticula in the acromegalics were detected at a younger age than in controls (58 vs. 72 yr). The only factor that predisposed to development of diverticula was duration of disease, which was almost twice as long in the patients with diverticula (14.3 3.1 vs. 8.7 0.9 yr) (P 0.001). The association with duration of active disease was stronger when adjusted for previous IGF-I excess. The highest tertile of disease duration adjusted for pretreatment GH and IGF-I was associated with a 4-fold increased risk for diverticula. Significance This case-control study (22) is the first to demonstrate an association with colonic diverticula and suggests that, in addition to the effect of GH and IGF-I on collagen in joints and cardiac valves, there may be an irreversible effect of GH on collagen in the colon. Because connective tissue disorders like Marfans syndrome are associated

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TABLE 1. Effect of pituitary axis deficiency on mortality adjusted for radiotherapy, follow-up time, sex, attained age, and calendar year
RR ACTH Normal Deficient TSH Normal Deficient Gonadotropins Normal Deficient 1 1.7 1 1.0 1 1.2 95% CI P value

cortisone may be different in patients with controlled vs. active acromegaly.

Acknowledgments
Address all correspondence and requests for reprints to: Janet A. Schlechte, M.D., Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242. E-mail: janet-schlechte@uiowa.edu. Disclosure Summary: The author has no financial or other relationships with any proprietary entity producing health care goods or services consumed by or used on patients.

1.2, 2.5 0.7, 1.4 0.8, 1.8

0.004 0.829 0.433

Reprinted with permission from M. Sherlock et al.: J Clin Endocrinol Metab 94:4216 4223, 2009 (29). The Endocrine Society.

References
1. Ono M, Miki N, Amano K, Kawamata T, Seki T, Makino R, Takano K, Izumi S, Okada Y, Hori T 2010 Individualized high dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas. J Clin Endocrinol Metab 95: 26722679 2. Colao A, Abs R, Ba rcena DG, Chanson P, Paulus W, Kleinberg DL 2008 Pregnancy outcomes following cabergoline treatment: extended results from a 12 year observational study. Clin Endocrinol (Oxf) 68:66 71 3. Lebbe M, Hubinont C, Bernard P, Maiter D 2010 Outcome of 100 pregnancies initiated under treatment with cabergoline in hyperprolactinaemic women. Clin Endocrinol (Oxf) 73:236 242 4. Kharlip J, Salvatori R, Yenokyan G, Wand GS 2009 Recurrence of hyperprolactinemia after withdrawal of long-term cabergoline therapy. J Clin Endocrinol Metab 94:2428 2436 5. Colao A, Di Sarno A, Cappabianca P, Di Somma C, Pivonello R, Lombardi G 2003 Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 349: 20232033 6. Biswas M, Smith J, Jadon D, McEwan P, Rees DA, Evans LM, Scanlon MF, Davies JS 2005 Long-term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas. Clin Endocrinol (Oxf) 63:26 31 7. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R, Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J, Scanlon M, Sobrinho LG, Wass JA, Giustina A 2006 Guidelines of The Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf) 65:265273 8. Dekkers OM, Lagro J, Burman P, Jrgensen JO, Romijn JA, Pereira AM 2010 Recurrence of hyperprolactinemia after withdrawal of dopamine agonistsmeta-analysis. J Clin Endocrinol Metab 95:4351 9. Bernabeu I, Marazuela M, Lucas T, Loidi L, Alvarez-Escola C, Luque-Ramrez M, Fernandez-Rodriguez E, Paniagua AE, Quinteiro C, Casanueva FF 2010 Pegvisomant-induced liver injury is related to the UGT1A1*28 polymorphism of Gilberts syndrome. J Clin Endocrinol Metab 95:21472154 10. Bernabeu I, Cameselle-Teijeiro J, Casanueva FF, Marazuela M 2009 Pegvisomant-induced cholestatic hepatitis with jaundice in a patient with Gilberts syndrome. Eur J Endocrinol 160:869 872 11. Buhk JH, Jung S, Psychogios MN, Go ricke S, Hartz S, Schulz-Heise S, Klingebiel R, Forsting M, Bru ckmann H, Do rfler A, Jordan M, Buchfelder M, Knauth M 2010 Tumor volume of growth hormonesecreting pituitary adenomas during treatment with pegvisomant. J Clin Endocrinol Metab 95:552558 12. Jimenez C, Burman P, Abs R, Clemmons DR, Drake WM, Hutson KR, Messig M, Thorner MO, Trainer PJ, Gagel RF 2008 Follow-up of pituitary tumor volume in patients with acromegaly treated with pegvisomant in clinical trials. Eur J Endocrinol 159:517523

those receiving more than 30 mg/d (Table 2). The main cause of death in the high-dose hydrocortisone groups was cardiovascular disease. Significance This is the first study to show an increase in mortality in patients with ACTH deficiency on higher doses of hydrocortisone and highlights the deleterious effects of glucocorticoid excess (25). Larger studies will be necessary to assess optimum replacement doses and to determine how the risk(s) associated with glucocorticoid overreplacement compare(s) with the risks of elevated GH and IGF-I in increasing mortality. Irrespective of dose, another issue is the fact that standard glucocorticoid replacement therapy does not mimic the normal circadian rhythm of cortisol secretion, and sustained glucocorticoid exposure likely has different effects than cyclical therapy on steroid responsive enzymes and occupancy of the glucocorticoid receptor (30). Although this study was not designed to determine the effect of GH on mortality in patients taking hydrocortisone, the interaction(s) of the GH/IGF-I system with 11-hydroxysteroid dehydrogenase-1 (31) raises the possibility that therapeutic requirements for hydro-

TABLE 2. Effect of increasing dose of hydrocortisone (HC) on mortality in patients with acromegaly compared to the general population, standardized for sex, attained age, and calendar period
HC daily (mg) None 0 HC 20 20 HC 25 25 HC 30 HC 30 RR 1 1.3 1.4 1.6 2.9 95% CI 0.7, 2.6 0.6, 3.3 1.1, 2.4 1.4, 5.9 P value 0.439 0.429 0.014 0.003

Adapted with permission from M. Sherlock et al.: J Clin Endocrinol Metab 94:4216 4223, 2009 (29). The Endocrine Society.

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