golf-inhibiting gynecomastia associated with atorvastatin therapy

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Golf-Inhibiting Gynecomastia Associated with Atorvastatin Therapy Kimberly B. Hammons, Pharm.D., Rebecca F. Edwards, Pharm.D., and William Y. Rice, III, M.D., M.S. Gynecomastia can have a significant emotional and social impact on men. Although numerous drug therapies may cause this condition, we found no documented cases of gynecomastia associated with atorvastatin. We describe the development of breast enlargement and tenderness in a 52-year-old Caucasian man 6 months after his simvastatin therapy had been switched to atorvastatin. His symptoms ultimately interfered with his ability to play golf and participate in other activities. These problems resolved after atorvastatin discontinuation and did not recur despite resumption of simvastatin therapy. The gynecomastia in this patient represented a possible adverse effect of atorvastatin according to the Naranjo adverse drug reaction probability scale. The mechanism may be atorvastatin’s theoretical suppression of adrenal or gonadal steroid production through effects on cholesterol synthesis. Based on this and other case reports, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) should be considered as a potential cause when evaluating otherwise unexplainable cases of gynecomastia in patients taking these drugs. Key Words: gynecomastia, atorvastatin, statins, adverse drug reactions. (Pharmacotherapy 2006;26(8):1165–1168) Gynecomastia is a common problem charac- terized either by an isolated, subareolar portion of tissue or by more distributed, general enlargement of the male breast. In most cases, the excess breast tissue occurs bilaterally. 1 Gynecomastia usually results from a shift in the delicate estrogen-androgen balance or from increased breast tissue sensitivity to normal estrogen levels. Although many patients with gynecomastia are relatively asymptomatic, some experience localized pain and tenderness. 1, 2 In addition to the physical changes, psycho- logical and social changes may occur when a man develops visibly notable breast tissue enlarge- ment. Men with gynecomastia are often concerned about potential malignancy. Although breast cancer in men is relatively rare, occurring at the rate of approximately 1500 cases/year in the United States, 3 sudden breast enlargement can be alarming. Men with breast enlargement may isolate themselves because of cosmetic embarrassment. In addition, concomitant pain and tenderness can adversely affect physical activities. We describe a man who developed late-onset gynecomastia after 6 months of atorvastatin therapy. His symptoms resolved when the drug was discontinued. Case Report A 52-year-old Caucasian man with a history of coronary artery disease, non–Q-wave myocardial infarction, hyperlipidemia, depression, gastro- esophageal reflux disease, benign prostatic hyperplasia, and chronic back pain came to the clinic for a follow-up visit. His chief complaint From the Moses Cone Health System, Greensboro, North Carolina (Dr. Hammons); the Section on General Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina (Drs. Edwards and Rice); and the School of Pharmacy, University of North Carolina, Winston-Salem, North Carolina (Dr. Edwards). Address reprint requests to Rebecca F. Edwards, Pharm.D., BCPS, Northwest Area Health Education Center, School of Medicine, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157.

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Page 1: Golf-Inhibiting Gynecomastia Associated with Atorvastatin Therapy

Golf-Inhibiting Gynecomastia Associated with Atorvastatin Therapy

Kimberly B. Hammons, Pharm.D., Rebecca F. Edwards, Pharm.D., and William Y. Rice, III, M.D., M.S.

Gynecomastia can have a significant emotional and social impact on men.Although numerous drug therapies may cause this condition, we found nodocumented cases of gynecomastia associated with atorvastatin. We describethe development of breast enlargement and tenderness in a 52-year-oldCaucasian man 6 months after his simvastatin therapy had been switched toatorvastatin. His symptoms ultimately interfered with his ability to play golfand participate in other activities. These problems resolved after atorvastatindiscontinuation and did not recur despite resumption of simvastatin therapy.The gynecomastia in this patient represented a possible adverse effect ofatorvastatin according to the Naranjo adverse drug reaction probability scale.The mechanism may be atorvastatin’s theoretical suppression of adrenal orgonadal steroid production through effects on cholesterol synthesis. Based onthis and other case reports, 3-hydroxy-3-methylglutaryl coenzyme A reductaseinhibitors (statins) should be considered as a potential cause when evaluatingotherwise unexplainable cases of gynecomastia in patients taking these drugs.Key Words: gynecomastia, atorvastatin, statins, adverse drug reactions.(Pharmacotherapy 2006;26(8):1165–1168)

Gynecomastia is a common problem charac-terized either by an isolated, subareolar portionof tissue or by more distributed, generalenlargement of the male breast. In most cases,the excess breast tissue occurs bilaterally.1

Gynecomastia usually results from a shift in thedelicate estrogen-androgen balance or fromincreased breast tissue sensitivity to normalestrogen levels. Although many patients withgynecomastia are relatively asymptomatic, someexperience localized pain and tenderness.1, 2

In addition to the physical changes, psycho-logical and social changes may occur when a mandevelops visibly notable breast tissue enlarge-

ment. Men with gynecomastia are oftenconcerned about potential malignancy. Althoughbreast cancer in men is relatively rare, occurringat the rate of approximately 1500 cases/year inthe United States,3 sudden breast enlargementcan be alarming. Men with breast enlargementmay isolate themselves because of cosmeticembarrassment. In addition, concomitant painand tenderness can adversely affect physicalactivities.

We describe a man who developed late-onsetgynecomastia after 6 months of atorvastatintherapy. His symptoms resolved when the drugwas discontinued.

Case Report

A 52-year-old Caucasian man with a history ofcoronary artery disease, non–Q-wave myocardialinfarction, hyperlipidemia, depression, gastro-esophageal reflux disease, benign prostatichyperplasia, and chronic back pain came to theclinic for a follow-up visit. His chief complaint

From the Moses Cone Health System, Greensboro, NorthCarolina (Dr. Hammons); the Section on General InternalMedicine, School of Medicine, Wake Forest University,Winston-Salem, North Carolina (Drs. Edwards and Rice);and the School of Pharmacy, University of North Carolina,Winston-Salem, North Carolina (Dr. Edwards).

Address reprint requests to Rebecca F. Edwards,Pharm.D., BCPS, Northwest Area Health Education Center,School of Medicine, Wake Forest University, Medical CenterBoulevard, Winston-Salem, NC 27157.

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PHARMACOTHERAPY Volume 26, Number 8, 20061166

was new-onset breast enlargement, tenderness,and soreness. He reported that the symptomshad gradually increased over the previous 6months and were interfering with his ability toplay golf and participate in other activities.

For the previous 2 years, his drug regimenconsisted of omeprazole 20 mg/day, amlodipine 5mg/day, aspirin 325 mg/day, zolpidem 10 mg atbedtime as needed, metaxalone 400 mg 2–3times/day, controlled-release oxycodone 20 mg 3times/day as needed for pain, rofecoxib 25mg/day, gabapentin 400 mg 3 times/day,doxazosin 8 mg/day, loratadine 5 mg–pseudo-ephedrine 120 mg twice/day as needed forallergic rhinitis, nitroglycerin 0.4 mg sublingualtablets as needed for chest pain, and atriamcinolone nasal inhaler. The patient hadpreviously taken simvastatin 40 mg/day for about6 months until this drug was switched toatorvastatin 40 mg/day. Atorvastatin wasincreased to 80 mg/day 3 months after thechange in therapy. The onset of gynecomastiasymptoms occurred approximately 6 monthsafter the start of atorvastatin therapy (3 mo afterthe dose escalation).

The patient denied any other prescription drugchanges or use of any herbal or over-the-counterproducts, alcohol, tobacco, or illicit drugs. Hisliver and renal function test results wereunremarkable. Thyroid screening 2 years earlierrevealed a thyroid-stimulating hormone level of1.105 mU/L (normal range 0.40–5.50 mU/L).Physical examination indicated that the patient’sleft breast was slightly larger than the right.

The patient’s weight was 101.8 kg, which was a5-kg increase since his previous visit (6 moearlier). A mammogram performed 10 days afterthe atorvastatin was discontinued revealed anabnormally increased amount of fibroglandulartissue bilaterally. No masses, microcalcifications,or architectural distortions were identified, rulingout consideration of malignancy.

Approximately 2 months after the atorvastatinwas discontinued, the patient’s breast tendernesswas much improved, and further diagnostictesting was no longer indicated. In addition, hisweight had decreased by 4 kg to 97.7 kg. At thattime, simvastatin 40 mg/day was restarted, andthe gynecomastia resolved completely.

Discussion

Gynecomastia is most common in puberty andin advanced age, when hormone levels arechanging or declining. During puberty, symptoms

tend to resolve in 1–2 years with stabilization ofhormone production.2 Gynecomastia in oldermen (> 65 yrs) is often a result of primarytesticular failure, or secondary testicular failuredue to hypogonadism. It is associated withKlinefelter’s syndrome, a genetic disorder inwhich males have more than one X chromosomepaired with a single Y chromosome. Gynecomastiaalso develops in men with renal failure, hepaticdisease (particularly alcoholic cirrhosis), orhyperthyroidism. In most patients, the conditionresolves when the underlying disease is treated,renal or hepatic function improves, or thyroidfunction returns to normal.2

Obesity can also lead to development of gyneco-mastia, through alteration of the estradiol:testos-terone ratio. In obese patients, sex hormone–binding globulin levels decrease, which initiallyincreases free testosterone levels and, later,estradiol levels.4 In a study of 214 hospitalizedmen, gynecomastia was correlated linearly withbody mass index.5 As many as 80% of men witha body mass index greater than 25 kg/m2

experienced signs and symptoms of gyneco-mastia. Another concern regarding obese patientsis the difficulty in distinguishing betweenpseudogynecomastia, which is breast enlargementdue to adipose tissue, and true gynecomastia,which results from glandular tissue changes.6

Gynecomastia is caused by drug therapy in10–15% of cases.6 Drugs that increase estrogenproduction or augment estrogenic activity play aclear, obvious role. Other drugs may hindertestosterone synthesis or effect. In most cases,however, the mechanism of development of drug-induced gynecomastia is unknown.7 Numerousdrugs have been associated with this disorder,such as chemotherapeutic alkylating agents,calcium channel blockers, phenytoin, digitalisglycosides, histamine2-receptor blockers,neuroleptics, ketoconazole, eplerenone, andspironolactone.4, 7 Several drugs of abuse havealso been implicated, such as marijuana, heroin,and anabolic steroids.1, 4 Although drug-inducedgynecomastia is not always fully reversible, someimprovement is usually seen after the drug isdiscontinued.2

The 3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitors (statins) could theoreticallysuppress adrenal or gonadal steroid productionthrough their effects on cholesterol synthesis.8–10

This suppression may result in gynecomastia dueto a higher estradiol:testosterone ratio. Clinicalstudies evaluating effects of various statins onbasal and reserve steroid levels have been

Page 3: Golf-Inhibiting Gynecomastia Associated with Atorvastatin Therapy

ATORVASTATIN-ASSOCIATED GYNECOMASTIA Hammons et al 1167

conflicting. For example, lovastatin, atorvastatin,and simvastatin do not seem to damage adrenalreserve or decrease basal plasma cortisolconcentrations.8, 10–12 Lovastatin also has notdemonstrated reduced testosterone levels.10

In contrast, atorvastatin, simvastatin, andfluvastatin studies have reported small decreasesin total testosterone concentration.9, 11 A study of83 men randomized to receive simvastatin 80mg/day or placebo found a median 13.6% drop intotal testosterone level after 12 weeks oftherapy.12 No evidence showed a compensatoryincrease in gonadotropin. In addition, althoughtotal, free, and bioavailable basal testosteroneconcentrations all decreased with simvastatincompared with placebo, only the change inbioavailable basal testosterone concentration(-10.2% vs 1.4%) was statistically significant.

In a study of 24 patients with type 2 diabetesmellitus who received atorvastatin 20 mg/day for3 months, testosterone levels in the 16 malepatients decreased from 3.55 to 3.24 ng/ml.13

The free testosterone index also decreasedslightly, but the differences were not statisticallysignificant. Current product information foratorvastatin and several other statins recom-mends they be combined only cautiously withdrugs such as ketoconazole, cimetidine, andspironolactone, which decrease levels ofendogenous steroid hormones.8–10, 14

In a MEDLINE search, we found no documentedcase reports of gynecomastia related specificallyto atorvastatin therapy. Postmarketing reportshave described gynecomastia associated withother statins, including simvastatin andlovastatin.15, 16 The Adverse Drug ReactionsAdvisory Committee in Australia reported 11cases of gynecomastia that occurred 2–10 monthsafter the start of simvastatin therapy.15 A Swedishsource (translated into English only in abstractform)16 cited 45 cases of gynecomastia associatedwith lovastatin listed in the World HealthOrganization Adverse Drug Reaction Registry.

Considering these published findings, wefound it intriguing that our patient’s gynecomastiaresolved after simvastatin therapy was restarted.Hypothetically, atorvastatin and rosuvastatin,particularly at higher doses, may have a moreprofound impact on steroidogenesis than otherstatins because of more potent lipid-loweringeffects.

Rare cases of gynecomastia have been asso-ciated with other drugs in our patient’s regimen,such as omeprazole, amlodipine, gabapentin, anddoxazosin. Reports indicate that gynecomastia is

likely to develop within 1–3 months after thestart of therapy.17–20 Our patient had taken all ofthese drugs for at least 2 years before the onset ofhis symptoms. Perhaps his gynecomastiaresulted from an additive effect of these drugscombined with atorvastatin. After atorvastatinwas discontinued, his symptoms resolved eventhough he continued taking omeprazole,amlodipine, and gabapentin, seemingly ruling outindependent or combined effects of these threedrugs alone. He had stopped taking doxazosinseveral months before the onset of his symptoms.

Using the Naranjo adverse drug reactionprobability scale,21 a score of 3 was calculated forthe event, indicating a possible adverse drugreaction. The score was derived as follows: 2points for the adverse event occurring afteradministration of the drug, 1 point for improve-ment in the adverse reaction when the drug wasstopped, and 1 point for confirmation of theadverse event by objective evidence (mammogram);1 point was subtracted from the total scorebecause other potential causes of gynecomastiaexisted, such as some of his other drugs andobesity. However, our patient’s symptomsresolved completely despite continuation of theseother drugs.

Patients with obesity and other diseasesassociated with gynecomastia may also be moresusceptible to statin-associated gynecomastia.For example, in a cross-sectional study of 108male patients who underwent renal or cardiactransplantation, 83.3% of those with radiologicallyconfirmed gynecomastia had taken a statin for atleast 3 months in the preceding 2 years versusonly 39.6% in the control group.22

Conclusion

Our report describes a possible case ofatorvastatin-induced gynecomastia after 6months of therapy with the drug. For at least 2years before symptom onset, the patient had beentaking four other drugs rarely associated withgynecomastia. More research is needed toexamine this unusual but possible adverse effectof statin therapy, including any potentialdifferences within the statin class. Clinicians areencouraged to consider statins as a potentialcause when evaluating cases of gynecomastia inpatients taking these drugs.

Acknowledgment

We wish to thank Laura Reynolds for her editorialassistance.

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PHARMACOTHERAPY Volume 26, Number 8, 20061168

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