CLINICAL CASE SEMINAR
The Novel Use of Very High Doses of Cabergoline and a Combination of Testosterone and an Aromatase Inhibitor in the Treatment of a Giant Prolactinoma
MARY P. GILLAM, STEWART MIDDLER, DANIEL J. FREED, AND MARK E. MOLITCH
Division of Endocrinology, Metabolism, and Molecular Medicine (M.P.G., M.E.M.), Northwestern University, The Feinberg Medical School, Chicago, Illinois 60611; and Cedars-Sinai Medical Center (S.M.), University of California at Los Angeles School of Medicine, Los Angeles, California 90048
Despite the effectiveness of dopamine agonists in attenu- ating hyperprolactinemia and inducing tumor shrinkage, hy- pogonadism persists in up to 50% of cases of males with macroprolactinomas, even in individuals in whom PRL lev- els are normalized (5, 8, 9). Consequently, androgen replace- ment is required in many of these patients. In general, tes- tosterone replacement is straightforward; however, testosterone replacement in this case was associated with secondary elevations in PRL levels. Evidence for the causal relationship between testosterone replacement and a rise in PRL was suggested by the observation that PRL levels de- clined when testosterone was temporarily discontinued and rose again with its readministration. We postulate that the rise in PRL was a result of the aromatization of testosterone to estradiol, which in turn stimulated PRL synthesis and release. An accumulating body of evidence suggests that estrogen plays an integral role in the pathogenesis and pro- gression of lactotroph tumors (14). Specifically, estrogen ex- erts a stimulatory effect upon PRL secretion by disrupting the inhibitory influence of dopamine; chronic exposure to es- trogen functionally uncouples the anterior pituitary D2 re- ceptor from its G protein-coupled receptor (15). Estradiol in vitro stimulates PRL gene transcription and prevents the ability of dopamine agonists to inhibit PRL synthesis and secretion (16***8211;20). In vivo, large doses of estrogens have in- duced prolactinomas in rats and may induce them in humans as well (21***8211;23).
The frequency of testosterone-associated increases in PRL levels is unknown, because it has not been formally ad- dressed by any of the major trials evaluating dopamine ag- onist therapy in the treatment of males with macroprolacti- nomas who subsequently receive androgen replacement. In the only other report in the literature that describes this phenomenon, Prior et al. (24) reported a patient with a 6-cm invasive macroprolactinoma (initial PRL, 13,969 ***56319;***56320;g/liter) who responded to bromocriptine with a 63% reduction in PRL levels and the disappearance of his visual field defect. Testosterone replacement was followed by visual field de- terioration, increased tumor size, and return of PRL levels to baseline values. Indeed, this dramatic response is highly unusual. Testosterone replacement in the patient reported
here led to a more modest PRL rise. Nevertheless, the re- sponse was clinically significant because it required the in- troduction of a second agent (anastrazole) to ultimately at- tenuate this effect. A study that specifically analyzes PRL responses after testosterone replacement in hypogondal males with prolactinomas would be necessary to determine whether this response is a unique behavioral characteristic of rare prolactinomas or is one that is observed more commonly.
In the present case, the use of an aromatase inhibitor in conjunction with cabergoline facilitated testosterone replace- ment, because it prevented the secondary rise in PRL and, ultimately, the potential for tumor enlargement. The aro- matase inhibitor was specific for this effect, because discon- tinuation of anastrozole again led to rises in PRL levels. Interestingly, PRL levels reached their nadir during the pe- riod of aromatase inhibitor therapy. These levels were lower than at any other time point, including the period during which the patient was taking his maximum dose of caber- goline (21 mg/wk) without receiving testosterone. This sug- gests that further lowering of even relatively low levels of estradiol appears to have been beneficial. Consequently, the coadministration of very high doses of cabergoline with anastrozole may have permitted PRL levels to remain low for a duration sufficient to restore the normal pulsatility of GnRH. This in turn led to recovery of the endogenous go- nadal axis.
An alternative explanation for the recovery of endogenous testosterone production in this patient may relate to the powerful effect of estradiol deficiency on stimulation of GnRH neurons. Several recent studies have confirmed the observation that lack of estradiol serves as a more potent stimulator of gonadotropin secretion than testosterone de- ficiency on a molar basis, at both the hypothalamic and pituitary level (25***8211;29).
Short-term administration of aromatase inhibitors has not been associated with adverse effects upon protein or inter- mediary metabolism or a negative impact on body compo- sition, muscle strength, or measures of bone turnover in healthy eugonadal men (30). However, the long-term effects of aromatase inhibitors are uncertain. As observed in men afflicted with mutations in cytochrome p450 aromatase en- zyme or in the estrogen receptor ***56319;***56321; gene, chronic estrogen deficiency may have important clinical implications (31). In these individuals, estrogen deficiency has been associated with abnormal carbohydrate/lipid metabolism, abnormal skeletal development, disordered gonadotropin secretion, and infertility. Whether these effects would similarly de- velop in postpubertal males is not known.
In summary, this case illustrates several intriguing aspects of the management of a giant prolactinoma demonstrating relative dopamine agonist resistance, including 1) the step- wise reduction in PRL levels afforded by stepwise increases in cabergoline to very high doses; 2) the disproportionate degree of pituitary tumor shrinkage despite a dramatic low- ering of PRL levels; 3) the facilitation of testosterone replace- ment by an aromatase inhibitor; and 4) eventual recovery of endogenous gonadal function. Extraordinary pharmacolog- ical maneuvers may permit successful medical treatment of some patients with invasive macroprolactinomas.
The Journal of Clinical Endocrinology & Metabolism 87(10):4447***8211;4451 Printed in U.S.A. Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-0204
