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Received: 18 April 2018    Revised: 4 June 2018    Accepted: 13 June 2018

DOI: 10.1111/cen.13794

ORIGINAL ARTICLE

Statin medications and the risk of gynecomastia

Sean C. Skeldon1 | Bruce Carleton2 | James M. Brophy3 | Mohit Sodhi4 | 

Mahyar Etminan4

1
Department of Family and Community
Medicine, University of Toronto, Toronto, Summary
ON, Canada Objective: Case reports have suggested an increased risk of gynecomastia with
2
Division of Translational Therapeutics,
HMG-­CoA reductase inhibitors (ie, statins). A recent meta-­analysis also found that
Department of Pediatrics, Faculty of
Medicine, University of British Columbia, statins decrease circulating testosterone levels in men. We investigated whether
Vancouver, BC, Canada
­statin use was associated with an increased risk of gynecomastia.
3
Departments of Medicine and
Design: Case-­control study.
Epidemiology, Biostatistics and Occupational
Health, McGill University, Montreal, QC, Patients: A cohort of patients from a random sample of 9 053 240 US subjects from
Canada
the PharMetrics Plus™ health claims database from 2006 to 2016 was created.
4
Department of Ophthalmology and Visual
Sciences and Pharmacology, Faculty of Measurements: New cases of gynecomastia requiring at least two ICD-­9 codes were
Medicine, University of British Columbia, identified from the cohort and matched to 10 controls by follow-­up time and age
Vancouver, BC, Canada
using density-­based sampling. Rate ratios (RRs) for users of statins were computed
Correspondence: Mahyar Etminan, using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroid-
Ophthalmology and Visual Sciences, Faculty
of Medicine, Department of Anesthesia, ism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyper­
Pharmacology and Therapeutics, The prolactinemia and use of spironolactone, ketoconazole, H2 receptor antagonists (H2
University of British Columbia, The Eye
Care Center Room 323-2550 Willow Street, blockers), risperidone, testosterone and androgen deprivation therapy.
Vancouver BC, V5Z 3N9, Canada Results: Our cohort included 6147 cases of gynecomastia and 61 470 corresponding
­Email: etminanm@mail.ubc.ca
matched controls. The adjusted RR for current, recent and past statin use with re-
Funding information spect to gynecomastia was 1.19 (1.04-­1.36), 1.38 (1.15-­1.65) and 1.20 (1.03-­1.40),
Therapeutic Evaluation Unit of the British
Columbia Provincial Health Services respectively.
Authority. Conclusions: Statin use is associated with an increased risk of developing gyneco-
mastia. Clinicians should be cognizant of this effect and educate patients
accordingly.

KEYWORDS
case-control study, finasteride, gynecomastia, hydroxymethylglutaryl-CoA reductase
inhibitors

1 | I NTRO D U C TI O N Most commonly, gynecomastia is physiologic,3 with one-­third to

Gynecomastia is the benign proliferation of the glandular breast tis-
1
sue in men. It is characterized by subareolar breast enlargement and
occurs when there is an imbalance in the actions of oestrogen and
testosterone on breast tissue.1,2 Gynecomastia can create a psycho-
logical burden due to embarrassment, physical discomfort and a fear
of breast cancer. While half of men with gynecomastia are asymp-
1
tomatic, some men present with localized pain and/or tenderness.
two-­thirds of men over the age of 50 having some degree of gy-
necomastia on examination. 2 Nonphysiologic gynecomastia can
be the result of medical conditions such as primary or secondary
hypogonadism, Klinefelter’s syndrome, renal failure, alcoholic cir-
rhosis and hyperthyroidism. 10%-­25% of gynecomastia cases are
attributed to medications,4 including 21% of symptomatic cases.5
Medications commonly associated with gynecomastia include spi-
ronolactone, cimetidine, ketoconazole, antiandrogen therapies and

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© 2018 John Wiley & Sons Ltd Clinical Endocrinology. 2018;89:470–473.
SKELDON et al. |
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TA B L E   1   Characteristics of gynecomastia cases and matched approval was obtained from the University of British Columbia
controls Clinical Research Ethics Board.

Cases Controls

N 6147 61 470 2.2 | Case and control definition

Age (years) 36.1 ± 19.7 36.1 ± 19.7
Cases were defined as those newly diagnosed with gynecomastia,
Follow-­up (years) 3.1 ± 2.6 3.1 ± 2.6
defined as the first diagnosis of gynecomastia (ICD-­9 611.1). Each
Covariates (%) case had to have received a subsequent code for gynecomastia
Alcoholic cirrhosis 1.25 0.20 within 1 year of the first code with the first code deemed as the
Hyperthyroidism 1.25 0.47 index date. For each case, ten male controls were identified from
Testicular cancer 0.28 0.08 the database and matched to the case by follow-­up time and age.
Klinefelter syndrome 0.15 0.01 Each control was allowed to become a future case and could have
Obesity 11.05 5.22 been selected more than once. As such, a control was allowed to
Hypogonadism 0.62 0.13 be at risk of developing gynecomastia until that subject became a
case, at which time they could no longer be a control. This method
Hyperprolactinaemia 0.03 0.00
of control selection, also referred to as density-­b ased sampling,
Ketoconazole 1.74 0.75
has shown to generate an odds ratio which closely approximates
Spironolactone 3.38 0.25
a rate ratio (RR) derived from a Cox regression model in a cohort
H2 Blockers 1.07 0.58
study.16
Androgen deprivation therapy 0.78 0.03
Risperidone 1.20 0.61
Testosterone 2.75 0.68 2.3 | Exposure definition and statistical analysis
We identified all statin prescriptions in the year prior to the index
date including atorvastatin, rosuvastatin, pitavastatin, pravasta-
5-­alpha reductase inhibitors.4 Several case reports have also linked tin, lovastatin, simvastatin and fluvastatin. We stratified statin
HMG-­CoA reductase inhibitors, or statins, one of the most com- use prior to the index date as current, recent or past use. Current
monly prescribed drugs in the United States (USA),6 to an increased use of a statin was defined as those who received at least one
risk of gynecomastia.7-10 With over 15% of adults over the age of 20 prescription from day 1 to 30 preceding the index date. Similarly,
reporting the use of statins, a significant number of men could be we categorized recent and past use as those who received a sta-
affected. Both the product monographs for rosuvastatin (Crestor)11 tin prescription between days 31-­6 0 and days 61-­365 prior to the
and Pravastatin (Pravachol)12 mention gynecomastia as rare adverse index date, respectively. As a quality measure, we also studied fin-
events; however, neither provide a magnitude of this risk. To our asteride, a drug widely recognized as increasing the risk of gyneco-
knowledge, the evidence supporting this association is limited to a mastia.4 A conditional logistic regression model was constructed
13
collection of case reports and case series. Thus, we examined the to compute adjusted rate ratios. In the model, we included the fol-
risk of gynecomastia in a large population-­based cohort of men who lowing covariates: alcoholic cirrhosis, hyperthyroidism, testicular
had recently started statin therapy. cancer, Klinefelter syndrome, obesity, hypogonadism, hyperpro-
lactinemia and use of spironolactone, ketoconazole, H2 receptor
antagonists (H2 blockers), risperidone, testosterone and androgen
2 |  M ATE R I A L A N D M E TH O DS deprivation therapy. The reference group for this analysis were
those not taking any statins.

2.1 | Data sources and study design

The data for this study have been previously published.14 In brief,
we used a random sample of PharMetrics Plus (QUINTILES IMS,
Parsippany, NJ, USA), a large health claims database in the US which
captures health records for over 150 million US residents. The da-
tabase captures physician visits through international classification
of diseases, ninth and tenth editions (ICD-­9 and 10). All outpatient
prescription drugs are captured, which includes information on drug
name, dose quantity dispensed and days supply. The database has
shown to have a good representation of all geographic areas of the
United States.15 Our study used a case-­control design including a
random sample of 9 053 240 subjects from 2006 to 2016. Ethics
3 | R E S U LT S
Our cohort included 6147 cases of gynecomastia and 61 470 cor-
responding matched controls. As expected more cases than controls
had one of the conditions or medications associated with gyneco-
mastia (Table 1). The adjusted RR was 1.19 (95% CI 1.04-­1.36) for
statin use 0-­30 days prior to the index date, 1.38 (95% CI 1.15-­1.65)
for statin use 31-­60 days prior to the index date and 1.20 (95% CI
1.03-­1.40) 61-­365 days prior to the index date (Table 2). The RR for
current use of finasteride was 3.42 (95% CI: 2.36-­4.94). The RR was
similar for recent use and past use of finasteride (Table 2).
472      | SKELDON et al.

TA B L E   2   Crude and adjusted rate ratios of gynecomastia with use of statins and finasteride

Crude Adjusteda

Cases Controls Rate ratio 95% CI Rate ratio 95% CI

Number of subjects 6147 61 470

No use of statin (%) 87.83 90.79 1 Ref 1 Ref
Any use of statin (%) 12.17 9.21 1.46 1.33-­1.61 1.23 1.12-­1.36
Current use (1-­3 0) 5.42 4.26 1.42 1.26-­1.61 1.19 1.04-­1.36
Recent use (31-­60) 2.80 1.90 1.66 1.40-­1.97 1.38 1.15-­1.65
Past use (61-­365) 3.95 3.05 1.45 1.25-­1.67 1.20 1.03-­1.40
No use of finasteride (%) 98.19 99.50 1 Ref 1 Ref
Any Use of finasteride (%) 1.81 0.50 3.83 3.06-­4.79 3.61 2.83-­4.60
Current use (1-­3 0) 0.73 0.22 3.54 2.51-­4.98 3.42 2.36-­4.94
Recent use (31-­60) 0.46 0.10 5.00 3.18-­7.86 4.47 2.73-­7.33
Past use (61-­365) 0.62 0.18 3.56 2.46-­5.16 3.38 2.27-­5.03
a
Adjusted for covariates in Table 1.

4 |  D I S CU S S I O N decrease in testosterone levels in men following statin use.25 While it

Our study demonstrates that past use of statins is associated with
an increased risk of gynecomastia in men. The validity of our results
was supported by finding an increased risk with finasteride, a 5-­
alpha reductase inhibitor used for the treatment of benign prostatic
hyperplasia that is widely associated with this adverse event. These
results provide credence to previously published case reports, which
linked pravastatin,7 atorvastatin8 and rosuvastatin with gynecomas-
tia.9,10 In one report, the discontinuation of rosuvastatin led to signif-
icant improvement in the degree of gynecomastia.9 The patient was
then started on lovastatin without evidence of recurrence. Similarly,
two other reports noted resolution of gynecomastia after the of-
fending statin was discontinued and the patient was transitioned to
an alternative statin.8,10 In most cases the onset of gynecomastia
8-10
after starting a statin was between 2-­6 months. A study of the
Italian spontaneous adverse drug reaction reporting database found
8 cases of gynecomastia with a statin as the suspected offending
drug, with four cases each involving rosuvastatin or atorvastastin.17
In seven of the eight cases, the gynecomastia improved or resolved
with the withdrawal of the statin. Postmarketing surveillance has
also linked simvastatin and lovastatin to gynecomastia.18,19
While the exact mechanism that statins could induce gynecomastia
is not clear, there is a body of evidence that statins can impact sex ste-
roid hormone levels. The pathways in which medications are believed
to lead to gynecomastia are either through oestrogen excess, androgen
deficiency, or an altered oestrogen to testosterone ratio.3 Statins act
by inhibiting HMG-­CoA reductase, which is the rate-­limiting enzyme
in the cholesterol biosynthesis pathway. Cholesterol is an obligate pre-
cursor of sex hormones, and as such, statins may reduce the availability
of cholesterol for androgen synthesis. Initially, studies were mixed on
whether there was a correlation between statin use and a reduction in
circulating androgen levels.20-24 Recently, a meta-­analysis of placebo-­
controlled randomized trials of statins found that there was a significant
is unclear whether lower testosterone levels from statins lead to sexual
dysfunction or lower libido,24,26 it remains plausible that in some men it
could result in gynecomastia.
Some limitations of our study merit emphasis. As with any study
using large population-­based administrative data sets, we did not
have access to individualized patient records and could not assess
medication adherence or the use of nonprescription medications,
supplements or illicit drugs (such as anabolic steroids or marijuana)
that may have influenced the risk of gynecomastia. We could also
not determine whether cases of gynecomastia were symptomatic
or not. It is also possible that our findings partially reflect unmea-
sured confounders or intergroup differences in the baseline risk of
gynecomastia. Due to sample size limitations, we were also unable
to differentiate between different statin medications. Previous case
reports suggested that the risk of gynecomastia may be higher with
more potent statins such as rosuvastatin or atorvastatin.8-10
In conclusion, using a case-control design from a sample of over
nine million subjects, we found that past use of statins was associ-
ated with an increased risk of gynecomastia. Given the large number
of men prescribed statins and the psychosocial distress, embarrass-
ment and physical discomfort that gynecomastia can cause,1,3 it is
important that clinicians are aware of this potential adverse event
and inform patients and monitor for it. While discussing statin ther-
apy for primary prevention of cardiovascular disease with their pa-
tients, physicians should include gynecomastia as a potential risk
when balancing the benefits that statins may offer. 27 Future studies
should confirm these results and investigate whether the risk of gy-
necomastia differs between individual statin medications.
AC K N OW L E D G E M E N T S
The study was funded by the Therapeutic Evaluation Unit of the
British Columbia Provincial Health Services Authority.
SKELDON et al.
CONFLICT OF INTEREST
The authors report no conflict of interest.
ORCID
Mahyar Etminan  http://orcid.org/0000-0003-4628-6270
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How to cite this article: Skeldon SC, Carleton B, Brophy J,
Sodhi M, Etminan M. Statin medications and the risk of
gynecomastia. Clin Endocrinol (Oxf). 2018;89:470–473.
https://doi.org/10.1111/cen.13794