Statin Medications and the Risk of Gynecomastia

Statin Medications and the Risk of Gynecomastia

Abstract and Introduction

Abstract

Objective: Case reports have suggested an increased risk of gynecomastia with HMG-CoA reductase inhibitors (ie, statins). A recent meta-analysis also found that statins decrease circulating testosterone levels in men. We investigated whether statin use was associated with an increased risk of gynecomastia.

Design: Case-control study.

Patients: A cohort of patients from a random sample of 9 053 240 US subjects from the PharMetrics Plus™ health claims database from 2006 to 2016 was created.

Measurements: New cases of gynecomastia requiring at least two ICD-9 codes were identified from the cohort and matched to 10 controls by follow-up time and age using density-based sampling. Rate ratios (RRs) for users of statins were computed using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H2 receptor antagonists (H2 blockers), risperidone, testosterone and androgen deprivation therapy.

Results: Our cohort included 6147 cases of gynecomastia and 61 470 corresponding matched controls. The adjusted RR for current, recent and past statin use with respect to gynecomastia was 1.19 (1.04–1.36), 1.38 (1.15–1.65) and 1.20 (1.03–1.40), respectively.

Conclusions: Statin use is associated with an increased risk of developing gynecomastia. Clinicians should be cognizant of this effect and educate patients accordingly.

Introduction

Gynecomastia is the benign proliferation of the glandular breast tissue in men.[1] 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 psychological burden due to embarrassment, physical discomfort and a fear of breast cancer. While half of men with gynecomastia are asymptomatic,[1] some men present with localized pain and/or tenderness. Most commonly, gynecomastia is physiologic,[3] with one-third to two-thirds of men over the age of 50 having some degree of gynecomastia on examination.[2] Nonphysiologic gynecomastia can be the result of medical conditions such as primary or secondary hypogonadism, Klinefelter’s syndrome, renal failure, alcoholic cirrhosis and hyperthyroidism. 10%–25% of gynecomastia cases are attributed to medications,[4] including 21% of symptomatic cases.[5]Medications commonly associated with gynecomastia include spironolactone, cimetidine, ketoconazole, antiandrogen therapies and 5-alpha reductase inhibitors.[4] Several case reports have also linked HMG-CoA reductase inhibitors, or statins, one of the most commonly prescribed drugs in the United States (USA),[6] to an increased risk of gynecomastia.[7–10] With over 15% of adults over the age of 20 reporting the use of statins, a significant number of men could be affected. Both the product monographs for rosuvastatin (Crestor)[11] and Pravastatin (Pravachol)[12] mention gynecomastia as rare adverse events; however, neither provide a magnitude of this risk. To our knowledge, the evidence supporting this association is limited to a collection of case reports and case series.[13] Thus, we examined the risk of gynecomastia in a large population-based cohort of men who had recently started statin therapy.

Material and Methods

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 database 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 approval was obtained from the University of British Columbia Clinical Research Ethics Board.

Case and Control Definition

Cases were defined as those newly diagnosed with gynecomastia, defined as the first diagnosis of gynecomastia (ICD-9 611.1). Each case had to have received a subsequent code for gynecomastia within 1 year of the first code with the first code deemed as the index date. For each case, ten male controls were identified from the database and matched to the case by follow-up time and age. Each control was allowed to become a future case and could have been selected more than once. As such, a control was allowed to be at risk of developing gynecomastia until that subject became a case, at which time they could no longer be a control. This method of control selection, also referred to as density-based sampling, has shown to generate an odds ratio which closely approximates a rate ratio (RR) derived from a Cox regression model in a cohort study.[16]

Exposure Definition and Statistical Analysis

We identified all statin prescriptions in the year prior to the index date including atorvastatin, rosuvastatin, pitavastatin, pravastatin, lovastatin, simvastatin and fluvastatin. We stratified statin use prior to the index date as current, recent or past use. Current use of a statin was defined as those who received at least one prescription from day 1 to 30 preceding the index date. Similarly, we categorized recent and past use as those who received a statin prescription between days 31–60 and days 61–365 prior to the index date, respectively. As a quality measure, we also studied finasteride, a drug widely recognized as increasing the risk of gynecomastia.[4] A conditional logistic regression model was constructed to compute adjusted rate ratios. In the model, we included the following covariates: alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H2 receptor antagonists (H2 blockers), risperidone, testosterone and androgen deprivation therapy. The reference group for this analysis were those not taking any statins.

Results

Our cohort included 6147 cases of gynecomastia and 61 470 corresponding matched controls. As expected more cases than controls had one of the conditions or medications associated with gynecomastia (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).

Table 1.  Characteristics of gynecomastia cases and matched controls
Cases Controls
N 6147 61 470
Age (years) 36.1 ± 19.7 36.1 ± 19.7
Follow–up (years) 3.1 ± 2.6 3.1 ± 2.6
Covariates (%)
   Alcoholic cirrhosis 1.25 0.20
   Hyperthyroidism 1.25 0.47
   Testicular cancer 0.28 0.08
   Klinefelter syndrome 0.15 0.01
   Obesity 11.05 5.22
   Hypogonadism 0.62 0.13
   Hyperprolactinaemia 0.03 0.00
   Ketoconazole 1.74 0.75
   Spironolactone 3.38 0.25
   H2 Blockers 1.07 0.58
   Androgen deprivation therapy 0.78 0.03
   Risperidone 1.20 0.61
   Testosterone 2.75 0.68
Table 2.  Crude and adjusted rate ratios of gynecomastia with use of statins and finasteride
Cases Controls Crude Adjusteda
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 (1–30) 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 (1–30) 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

aAdjusted for covariates in Table 1.

Discussion

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] atorvastatin[8]and rosuvastatin with gynecomastia.[9,10] In one report, the discontinuation of rosuvastatin led to significant 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 offending statin was discontinued and the patient was transitioned to an alternative statin.[8,10] In most cases the onset of gynecomastia after starting a statin was between 2–6 months.[8–10] 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 steroid 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 precursor 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 decrease in testosterone levels in men following statin use.[25] While it 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 unmeasured 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 associated with an increased risk of gynecomastia. Given the large number of men prescribed statins and the psychosocial distress, embarrassment 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 therapy for primary prevention of cardiovascular disease with their patients, 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 gynecomastia differs between individual statin medications.

MedScape, November 26, 2018

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