Download Megestrol Acetate–Induced Adrenal Insufficiency

Pharmacy Report
Megestrol Acetate–Induced Adrenal Insufficiency
Sowmya Nanjappa, MD, Christy Thai, PharmD, Sweta Shah, MD, and Matthew Snyder, PharmD
Summary: A man aged 65 years with metastatic renal cell carcinoma presented for evaluation after a recent
fall. A thorough workup of the case was performed and secondary adrenal insufficiency induced by the administration of megestrol acetate was determined to be the cause. Adrenal insufficiency is a serious disorder that is
a potential adverse event of megestrol acetate, a medication used to help patients with cancer cachexia increase
their appetite and gain weight. This association is not well recognized in clinical practice, so this case highlights
the importance of distinguishing possible endocrine complications induced by the long-term administration or
sudden discontinuation of megestrol acetate.
Introduction
Adrenal insufficiency is a serious complication that is
a potential adverse event of megestrol acetate, a medication used to help patients with cancer cachexia increase their appetite and gain weight.1,2 However, this
association is not well recognized in clinical practice.3
Case Report
A man aged 65 years with hypertension and stage 4
clear cell renal cell carcinoma (RCC) with metastases
to the brain, lungs, bones, and pancreas was admitted for evaluation after a recent fall. His past surgical
history was significant for left nephrectomy and adrenalectomy nearly 20 years ago. After his RCC did not
respond to sunitinib and pazopanib treatment, his chemotherapy regimen was changed about 1 month ago to
twice daily oral axitinib (5 mg). During his admission,
he was hypotensive and his mental status was altered.
Vitals were blood pressure of 71/49 mm Hg, respiratory rate of 18 breaths/minute, heart rate of
101 beats/minute, temperature of 98.8 °F, and oxygen
saturation of 96% on room air. Findings on physical examination were unremarkable, except for tenderness
and swelling in his left lower extremities secondary to
the recent fall. Findings on complete blood count with
a differential and comprehensive metabolic panel were
all within normal limits. Findings following a workup
for sepsis and brain imaging were negative.
After ruling out potential causes, including infecFrom the Departments of Internal Medicine (SN), Pharmacy (CT,
MS), H. Lee Moffitt Cancer Center & Research Institute, and University of South Florida Morsani College of Medicine (SS), Tampa,
Florida.
Submitted February 26, 2016; accepted March 4, 2016.
Address correspondence to Sowmya Nanjappa, MD, Moffitt
Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
E-mail: [email protected]
No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced
in this article.
April 2016, Vol. 23, No. 2
tion, brain metastases, dehydration, electrolyte imbalances, and hypothyroidism, a workup for adrenal
insufficiency was performed because hypotension
persisted while his mental status improved. A morning serum cortisol level was below 1.0 µg/dL. A cosyntropin stimulation test revealed serum cortisol
levels of 5.9 and 8.9 µg/dL at 30 and 60 minutes, respectively, with a pretest plasma adrenocorticotropic
hormone (ACTH) level below 5 pg/mL, indicating secondary adrenal insufficiency.
A review of the patient’s medication list unveiled
no agents commonly known to induce adrenal insufficiency with one exception. He had recently been
treated with daily megestrol acetate (oral suspension
625 mg) for about 4 weeks prior to his current admission, and this dose had been continued for the
initial portion of this hospitalization. We suspected
that this agent might be the likely culprit, so it was
discontinued.
Oral hydrocortisone 20 mg every morning/10 mg
every evening was initiated for adrenal insufficiency, and his blood pressure significantly improved.
Steroids were discontinued prior to a follow-up appointment 3 months following discharge. Repeat serum cortisol level and ACTH value were 20 µg/dL
and 68 pg/mL, respectively; these results confirmed
resolution of the adrenal insufficiency secondary to
megestrol acetate.
Discussion
Adrenal insufficiency is a serious, potentially
life-threatening condition that stems from primary adrenal failure or secondary adrenal disease owing to an
impaired hypothalamic–pituitary–adrenal (HPA) axis.1
The disorder can chronically cause fatigue, anorexia,
weakness, abdominal pain, and hypotension, whereas
the acute syndrome may induce hypotensive crisis, fever, clouded sensorium, and myopathy.1 Those affected
typically require stress-dose steroids for surgical proCancer Control 167
cedures or severe illness and glucocorticoid replacement on a long-term basis.
Although management of the disorder is relatively straightforward, making an accurate and timely
diagnosis often proves to be challenging in the oncology setting. Patients with cancer frequently experience these symptoms, sometimes as a result of disease
progression, surgery, radiation, chemotherapy, or a
combination of all of these. Oftentimes, cachexia seen
over time with adrenal insufficiency can mimic wasting characteristic of metastatic disease.4 Paraneoplastic
syndromes and malnutrition may cause severe electrolyte abnormalities, clouding, or covering up of the
evidence of the role of adrenal insufficiency in such irregularities.4
In addition to causing adrenal insufficiency–associated symptoms, such as fatigue, weakness, myopathy, and pain, chemotherapy and immunotherapy
agents can directly give rise to the disorder.5-7 The tyrosine kinase inhibitors sunitinib and imatinib and, more
frequently, the checkpoint-blocking immunotherapies
ipilimumab, nivolumab, and pembrolizumab have
been reported to cause adrenal insufficiency.5-7 Given
the limited data available, it will be interesting to see
whether the effects of these agents on adrenal function
extend to other members of their respective classes as
their use continues to increase.
Medications commonly used as supportive care
can also induce adrenal insufficiency.1,7-10 The detrimental impacts of the long-term administration and
abrupt discontinuation of steroids on adrenal function
are well known.1 Use of glucocorticoids is also common in patients with cancer, and these agents play a
critical role in the treatment of various hematological
malignancies, immune-related adverse events,7,8 the relief of symptoms secondary to brain metastases,9 and
pain management.10
Similarly, megestrol acetate, which is a synthetic
progestin with antiestrogenic properties, is often used
to help patients with cancer cachexia increase their appetite and gain weight.2 Secondary to its inherent glucocorticoid-like effect,2 the agent is thought to cause
suppression of the HPA axis at the hypothalamus
through negative feedback, thus resulting in low levels
of serum cortisol and plasma ACTH.11,12
Although stimulating the appetite through the
use of megestrol acetate was useful in a patient like
ours, megestrol acetate has been associated with
thrombosis, hyperglycemia, hypertension, osteoporosis, hypogonadism, and adrenal insufficiency.3 Its
clinical benefit is often outweighed by these potential adverse events, many of which are already at a
heightened risk of occurring in this patient population (eg, thrombosis). Several questions regarding
the length of time needed for megestrol acetate–induced adrenal suppression and subsequent restora168 Cancer Control
tion of HPA axis function after discontinuation of
the drug are still unknown.
Leinung et al13 conducted a trial that initiated 80
mg megestrol acetate 3 times a day in study patients
with normal cortisol and ACTH levels prior to therapy.
After 1 month, both values significantly decreased,
and study participants also displayed a significantly
decreased response to cosyntropin stimulation.13 An
interventional trial found that 6 of 7 study patients
with adrenal suppression recovered normal function
within 2 weeks, with the remaining patient doing so
in 6 weeks (NCT00575029). However, general data are
lacking, so definitive timeframes are uncertain. Nevertheless, our case describes a patient who developed
treatment-related adrenal insufficiency after 1 month
of therapy, but successfully recovered in 3 months after
the medication was discontinued.
Although adrenal insufficiency is a reported potential adverse event of megestrol acetate, it is not well
recognized in clinical practice.3 Adrenal suppression
can stem from abrupt discontinuation of the agent.
However, as in our case, megestrol acetate has been
found to cause this effect in patients actively taking the
agent, thus complicating the diagnosis.2,14,15
Postulated mechanisms for the latter scenario
include a dual agonist–antagonist action (binding to
the glucocorticoid receptor while simultaneously preventing endogenous glucocorticoids from doing so), a
greater tendency to suppress the HPA axis rather than
induce glucocorticoid-like effects, and concurrent
acute stress or illness in a patient whose HPA axis is
already suppressed.11,15 Retrospectively, the patient
was not taking any other medication likely to cause
such an effect.
The origin of our patient’s adrenal insufficiency
was also clouded by numerous factors, including prior
left adrenalectomy, tyrosine kinase inhibitor use, and
metastatic RCC. This case of megestrol-induced adrenal insufficiency was only discovered after extensive
workup and elimination of other possible causes.
Conclusions
Although obtaining and analyzing a patient’s medication history may be challenging, thorough and
accurate assessment of previous and current medication use is a necessity that proved to be pivotal in
this case. Given the potentially severe complications
of adrenal insufficiency, this report underscores the
importance of recognizing possible endocrine complications induced by the long-term administration
or sudden discontinuation of megestrol acetate. However, further study is still needed to draw definitive
conclusions on the effects of megestrol acetate on adrenal function.
Acknowledgment: We thank the patient for his
cooperation throughout the duration of the case.
April 2016, Vol. 23, No. 2
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