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Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in male patients with cancer
Article first published online: 23 JUL 2007
Copyright © 2007 American Cancer Society
Volume 110, Issue 6, pages 1173–1177, 15 September 2007
How to Cite
Dev, R., Del Fabbro, E. and Bruera, E. (2007), Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in male patients with cancer. Cancer, 110: 1173–1177. doi: 10.1002/cncr.22924
- Issue published online: 31 AUG 2007
- Article first published online: 23 JUL 2007
- Manuscript Accepted: 1 MAY 2007
- Manuscript Revised: 25 APR 2007
- Manuscript Received: 12 MAR 2007
- National Institutes of Health Grant. Grant Numbers: # R01NR010162-01A1, #R01CA122292,01
- cancer cachexia;
- megestrol acetate;
- adrenal insufficiency;
Patients with advanced cancer may develop cachexia, which is often treated with megestrol acetate (MA). In addition to thromboembolic disease, MA may cause symptomatic suppression of the hypothalamic pituitary adrenal axis. In male patients with cancer, treatment with MA may also suppress the gonadal axis, resulting in symptomatic androgen deficiency. Three cases are presented to highlight the symptomatic burden of adrenal insufficiency and hypogonadism. Clinicians need an increased awareness of the complication of adrenal insufficiency secondary to MA treatment and a low threshold to test for adrenal and gonadal dysfunction in symptomatic male patients with advanced cancer. Cancer 2007. © 2007 American Cancer Society.
Patients with cancer often develop cachexia, which is characterized by a number of physical symptoms such as anorexia, chronic nausea, early satiety, and fatigue. Currently, megestrol acetate (MA) is frequently used as a palliative agent to treat cancer cachexia, and 2 recent systematic reviews have concluded that MA improves appetite and results in weight gain in cancer patients.1, 2 However, the authors of a third systematic review expressed doubts as to whether a small gain in weight translated into a significant clinical benefit, particularly in view of the risk of severe side effects.3 In addition to thromboembolic disease, treatment with MA can result in symptomatic adrenal insufficiency.4 After reviewing the English literature, we identified 1 case report of a patient with cystic fibrosis receiving MA with suppression of both the adrenal and gonadal axis.5 Our case series identifies 3 symptomatic cancer patients who were being treated with MA who had abnormalities in both their adrenal and gonadal axis.
A 20-year-old white male with a history of osteosarcoma originating in the left femur with metastases to the lungs and liver presented with fever, intermittent abdominal pain, lower extremity edema, melena, and feeling “low.” He was previously treated with preoperative chemotherapy followed by limb salvage surgery that was complicated by the development of chronic osteomylitis. After recovering from surgery, the patient received radiation therapy and additional chemotherapy, including methotrexate, gemcitabine, doxorubicin, and, most recently, ifosfamide 1 week before presentation. His medical history was significant for venous thrombosis and his medications included MA (at a dose of 600 mg/daily), fluconazole, trimethoprim-sulfamethoxazole, and morphine. On physical examination, his vital signs were notable for a heart rate of 129 beats per minute. He appeared thin and pale; his oral examination revealed thrush. Abdominal examination of the patient was notable for a large right-sided mass, and the examination of his extremities revealed 2+ pitting edema as well as a small area of erythema located at his limb salvage surgical site. At the time of admission, a complete blood cell count revealed low hemoglobin (7.8 g/dL), decreased platelets (49 k/uL), and a normal level of white blood cells. Also notable on initial laboratory testing was hyponatremia (132 mmol/L) and hypoalbuminemia (2.4 g/dL). The patient was immediately hospitalized, received a transfusion of packed red blood cells, and was treated for presumed infection with broad-spectrum intravenous antibiotics. On admission, MA was continued without stress dose glucocorticoids. During hospitalization, palliative care consultants ordered morning serum cortisol (2.5 μg/dL [normal, 4.3–22.4 g/dL]) as well as serum total testosterone (24 ng/dL [normal, 241–827 ng/dL]). In addition, serum adrenocorticotropic hormone (ACTH) was low at 5 pg/mL (normal, 7–50 pg/mL) and an adrenocorticotropin stimulation test revealed inadequate adrenal response consistent with adrenal insufficiency. MA was replaced with hydrocortisone (at a dose of 300 mg/daily) and his clinical condition slowly improved. The septic workups initiated at the time of admission, including cultures of the blood, throat, and urine, were negative. He was eventually discharged home on hydrocortisone taper and broad-spectrum antibiotics. During an outpatient follow-up visit he was doing well, and his subsequent laboratory testing revealed normal morning testosterone levels.
A 63-year-old white male with a history of nonsmall cell lung cancer presented to the palliative medicine clinic reporting decreased appetite, profound fatigue, and lightheadedness on standing. He was previously treated with neoadjuvant chemotherapy comprised of carboplatin and paclitaxel, and subsequently underwent pneumonectomy of his left lung. After recovering from surgery, he received further chemotherapy with docetaxel plus imexon and pemetrexed. Despite treatment, his disease metastasized to his liver and the upper pole of his right kidney, sparing the adrenal glands. His past medical history was notable for tobacco abuse and renal vein thrombosis, and his current medications included MA (at a dose of 400 mg/daily) and enoxaprin. On physical examination, his vital signs were normal and he appeared well. The initial laboratory evaluation including a complete blood cell count was within normal limits with the exception of decreased hemoglobin (10.8 g/dL). On subsequent laboratory testing, the patient was noted to have diminished morning serum cortisol (1.9 μg/dL) and decreased total serum testosterone (31 ng/dL). Thyroid-stimulating hormone and serum albumin levels were normal. Secondary to his history of thromboembolic disease, low serum cortisol, and diminished testosterone, MA was tapered while he was supplemented with dexamethasone (at a dose of 4 mg/daily) and topical testosterone (at a dose of 5 g/daily). On the follow-up outpatient visit, he was noted to have profound improvement in symptoms of fatigue and no further episodes of lightheadedness.
A 71-year-old white male with a history of metastatic carcinoma of unknown primary involving the left humerus presented to the palliative medicine clinic reporting diaphoresis, nocturia, fatigue, dyspnea with exertion, and increased drowsiness. The patient was previously treated with radiation therapy and chemotherapy with paclitaxel, carboplatin, and, most recently, capecitabine. His medical history was significant for hypothyroidism, mild renal insufficiency, depression, and benign prostatic hypertrophy. His medications included long-acting oxycodone for pain, MA (at a dose of 800 mg/daily), escitalopram oxalate, levothyroxine, and fludrocortisone. On physical examination, the patient appeared well, with the exception of faint skin erythema on his left upper extremity. His initial laboratory testing revealed critically low morning serum cortisol (1.4 μg/dL), decreased morning total testosterone (31 ng/dL), and a diminished thyroid-stimulating hormone level at 0.03 mIU (normal, 0.4–4.5 mIU). His levothyroxine dosage was decreased and MA was discontinued. In addition, treatment with dexamethasone (at a dose of 1 mg/daily) and methylphenidate was initiated. On a follow-up visit in the palliative medicine clinic, he noted significant improvement of his symptoms and he was subsequently tapered off dexamethasone. On repeat laboratory testing, androgen deficiency was confirmed. After discussing the risks and benefits of therapy, the patient was prescribed a transdermal testosterone patch (5 g/daily).
MA has been shown to stimulate appetite in patients with anorexia and cancer cachexia in several placebo-controlled trials.6–9 However, its use has the potential for undesired side effects including thromboembolism, adrenocortical suppression, hyperglycemia, hypertension, alopecia, gynecomastia, and impotence. Adrenal insufficiency may be an unrecognized complication because patients can present with nonspecific symptoms including fatigue, joint pain, anorexia, and gastrointestinal abnormalities, and during periods of increased stress they may manifest additional symptoms including cardiovascular instability and hypoglycemia.10 In addition to adrenal suppression, MA can result in low testosterone,11, 12 which is linked with symptoms of fatigue, decreased libido, sleep disturbance, and poor concentration. Other effects of long-term androgen deficiency include low bone mineral density, reduced muscle mass, mild anemia, and increased body fat. Low testosterone in cancer patients has also been associated with mood disturbances13 and decreased appetite.14 Our case series raises questions as to whether the inherent glucocorticoid activity of MA provides adequate physiologic supplementation to prevent the symptoms of adrenal insufficiency and whether the treatment of anorexia with MA inadvertently results in symptomatic androgen deficiency in male patients with cancer.
A progesterone analog, MA stimulates appetite by an unknown mechanism. MA at doses of > 160 mg/day can inhibit ACTH, resulting in adrenal insufficiency10 at the hypothalamic-pituitary level.15–17 However, MA does have inherent glucocorticoid properties and binds to glucocorticoid receptors with approximately half the binding affinity of dexamethasone and twice the affinity of cortisol.18
A review of the literature reveals case reports of MA use resulting in symptomatic adrenal insufficiency in patients with cancer.19, 20 Children with cancer may have increased susceptibility for symptomatic adrenal suppression when being treated with MA for symptoms of cachexia.21 During periods of acute illness, patients receiving MA are recommended to receive empiric therapy with stress doses of corticosteroids.16, 22 When discontinuing chronic MA therapy, the manufacturer directs physicians to consider glucocorticoid supplementation in patients with symptoms of adrenal insufficiency in the stressed or nonstressed state. It may be difficult to determine the degree of stress in a patient with advanced cancer. Future research may be needed to address the question of whether glucocorticoid supplementation or MA taper is safer than abrupt discontinuation of chronic therapy in patients with advanced disease and children with cancer.
MA also has profound effects on testosterone, reducing levels to near castration levels in elderly men11 and in patients with advanced prostatic cancer.12 Although to our knowledge the mechanism of androgen suppression is unknown, MA has been shown to reduce serum luteinizing hormone levels in patients with prostate23 and breast cancer.24 In addition, in healthy elderly men, MA was shown to increase prolactin levels by 150%,17 which can result in androgen deficiency. In male patients with advanced cancer, other medications, including glucocorticoids25 and chronic opioids,26 may also contribute to the increased frequency of androgen deficiency.13
The first patient in the current study presented with fever and nonspecific symptoms, raising concern for possible underlying infection and sepsis. During admission, clinicians were unaware of the risk of endocrine abnormalities associated with MA use such as adrenal insufficiency and low testosterone. In view of his history of venous thrombosis, MA was discontinued and adrenal insufficiency was treated with hydrocortisone. Although the patient's septic workup was negative, an underlying infectious etiology could not be definitively excluded. However, because symptoms of adrenal insufficiency can overlap with that of sepsis, clinicians need a low threshold to evaluate the adrenal axis when patients being treated with MA are hospitalized or exposed to increased stress. In addition to adrenal insufficiency, the patient had low testosterone, which may have contributed to his symptom burden. After discontinuing MA, his total testosterone level returned to within normal limits.
The second patient in our study presented to the palliative outpatient clinic with nonspecific symptoms of poor appetite, fatigue, and lightheadedness. His laboratory tests revealed critically low morning cortisol and testosterone levels. Because a morning cortisol level < 4 μg is specific for an impaired hypothalamic pituitary axis,27, 28 further testing with low-dose adrenocorticotropin was not pursued. In addition to adrenal and gonadal axis suppression, the patient had a history of thromboembolic disease, making it difficult to justify continuation of MA. His symptoms resolved with glucorticoid supplementation. Other possible causes of androgen deficiency in our second patient include an unrecognized side effect of past chemotherapy as well as his history of advanced cancer.
The third patient in the current study presented to our ambulatory palliative clinic with multiple nonspecific symptoms. His evaluation revealed several abnormalities in the hypothalamic pituitary axis, including abnormal thyroid function, critically low morning serum cortisol, and diminished morning total testosterone. After his levothyroxine dose was adjusted and MA was replaced with dexamethasone, his symptoms improved. Several confounding factors including preexisting thyroid deficiency and concurrent treatment with fludrocortisones make it difficult to determine the impact of MA on the hypothalamic pituitary axis, and whether his symptom improvement was secondary to discontinuation of MA versus treatment with glucocorticoids is unclear. In addition, despite being tapered off glucocorticoids, his morning total testosterone remained low, and he was offered transdermal testosterone replacement therapy.
Physicians need to be conscious of the inherent glucocorticoid activity of MA and to have a heightened awareness of the complication of adrenal insufficiency. After treatment of adrenal insufficiency, follow-up cortisol levels, which we acknowledge are lacking in our case series, should be checked to confirm the recovery of the adrenal axis. In addition, patients with cancer receiving MA who present with symptoms of abnormal mood, anorexia, decreased libido, fatigue, or insomnia need their morning testosterone levels measured. The symptomatic impact of androgen suppression secondary to MA needs to be better characterized and research into the utility of monitoring the hypothalamic pituitary axis before and during therapy with MA may be needed. It may be argued that all symptomatic male cancer patients receiving MA, glucocorticoids, or opioids need to be screened for hypogonadism, because testosterone replacement may play an important role in symptom management. To our knowledge, clinical trials addressing the benefits of androgen replacement in hypogonadic men with advanced cancer are currently lacking. However, in a recent open-label study, hypogonadic noncancer patients receiving chronic opioid therapy benefited symptomatically from testosterone supplementation,29 and the Endocrine Society guidelines suggests considering short-term testosterone replacement in men with androgen deficiency receiving high-dose glucocorticoids.30
In conclusion, the hypothalamic pituitary adrenal and gonadal axis in conjunction with the pineal gland regulates our thirst, hunger, libido, mood, and energy level. The hypothalamic pituitary axis is not protected by the blood/brain barrier and is exposed to multiple therapeutic agents that are utilized in patients with advanced cancer. In the palliative patient population, medications such as MA, glucocorticoids, and opioids are often used for symptom control but have the potential to suppress the axis. Future research on the symptomatic benefits of the physiologic supplementation of hydrocortisone and testosterone in patients with advanced cancer with adrenal insufficiency and hypogonadism is needed.