Risk of gynecomastia and breast cancer associated with the use of 5-alpha reductase inhibitors for benign prostatic hyperplasia

Figures & data

Table 1 Characteristics of gynecomastia cohort (N=94,701)

Characteristics	n (%)
Age (years) at cohort entrya
40–49	16,160 (17.1)
50–59	28,751 (30.4)
60–69	30,626 (32.3)
70–79	16,109 (17.0)
80–89	2922 (3.1)
≥90	133 (0.1)
Year of cohort entry
<1995	46,056 (48.6)
1995–1999	26,533 (28.0)
2000–2004	13,957 (14.7)
2005–2009	6705 (7.1)
≥2010	1450 (1.5)
Length of follow-up (years)
<1	877 (0.9)
1–4	9947 (10.5)
5–9	21,383 (22.6)
10–14	28,417 (30.0)
≥15	34,077 (36.0)
BMI at cohort entry (kg/m^2)
<18.5	669 (0.7)
18.5–24.9	30,606 (32.3)
25–29.9	41,777 (44.1)
≥30	15,661 (16.5)
Unknown	5988 (6.3)
Smoking status at cohort entry
Nonsmoker	36,844 (38.9)
Smoker	15,968 (16.9)
Ex-smoker	15,556 (16.4)
Unknown	26,333 (27.8)
Comorbidities at cohort entry
Hypertension	17,658 (18.7)
Diabetes	4680 (4.9)
Hyperlipidemia	6248 (6.6)
Cardiovascular disease	14,734 (15.6)
Benign prostatic hyperplasia	5187 (5.5)
Cancer	1443 (1.5)
Hyperthyroid	403 (0.4)
Exposure on cohort entry date
Unexposed	94,688 (99.9)
5ARI	1 (0.0)
AB	12 (0.1)

Note:

a Cohort entry was defined as age ≥40 years and 3 years after the start of the patient’s electronic record.

Abbreviations: BMI, body mass index; 5ARI, 5-alpha reductase inhibitor; AB, alpha blocker.

Table 2 Cohort analysis: IRs and IRRs for gynecomastia by exposure

Characteristics	Nonexposed				5ARI (alone or in combination with AB)				AB only
	Cases	PY	IR (per 10,000 PY) (95% CI)	IRR (95% CI)	Cases	PY	IR (per 10,000 PY)	IRR (95% CI)	Cases	PY	IR (per 10,000 PY) (95% CI)	IRR (95% CI)
Age group (years)
40–59	117	320,462	3.7 (3.0–4.4)		13	4382	29.7 (15.8–50.7)		14	24,961	5.6 (3.1–9.4)
60–79	472	546,931	8.6 (7.9–9.4)		169	46,922	36.0 (30.8–41.9)		162	127,329	12.7 (10.8–14.8)
≥80	84	68,171	12.3 (9.8–15.3)		94	17,340	54.2 (43.8–66.3)		45	28,749	15.7 (11.4–20.9)
Calendar time
<1995	43	80,264	5.4 (3.9–7.2)		1	906	11.0 (0.1–61.4)		1	1326	7.5 (0.1–41.9)
1995–1999	127	268,265	4.7 (3.9–5.6)		15	6109	24.6 (13.7–40.5)		8	14,326	5.6 (2.4–11.0)
2000–2004	229	292,890	7.8 (6.8–8.9)		48	11,554	41.5 (30.6–55.1)		54	46,864	11.5 (8.7–15.0)
2005–2009	187	212,790	8.8 (7.6–10.1)		110	24,627	44.7 (36.7–53.8)		86	64,241	13.4 (10.7–16.5)
≥2010	87	81,354	10.7 (8.6–13.2)		102	25,450	40.1 (32.7–48.7)		72	54,282	13.3 (10.4–16.7)
Drugs known to be associated with gynecomastia
No	273	752,866	3.6 (3.2–4.1)		137	47,820	28.6 (24.1–33.9)		80	126,944	6.3 (5.0–7.8)
Yes	400	182,697	21.9 (19.8–24.1)		139	20,825	66.7 (56.1–78.8)		141	54,096	26.1 (21.9–30.7)
Total crude	673	935,563	7.2 (6.7–7.8)	1.0 (ref)	276	68,645	40.2 (35.6–45.2)	5.59 (4.86–6.43)	221	181,040	12.2 (10.7–13.9)	1.70 (1.46–1.98)
Adjusteda				1.0 (ref)				3.55 (3.05–4.14)				1.15 (0.98–1.34)

Note:

a Adjusted for age group, calendar time, and drugs known to be associated with gynecomastia.

Abbreviations: IR, incidence rate; IRR, incidence rate ratio; 5ARI, 5-alpha reductase inhibitor; AB, alpha blocker; PY, person-years; CI, confidence interval; ref, reference.

Table 3 Gynecomastia-nested case–control analysis: characteristics by case/control status

Characteristics	Gynecomastia cases, n=1142, n (%)	Controls, n=4164, n (%)	Univariate OR (95% CI)
Age (years) at index date
40–49	17 (1.5)	67 (1.6)	a
50–59	124 (10.9)	479 (11.5)	a
60–69	386 (33.8)	1423 (34.2)	a
70–79	397 (34.8)	1457 (35.0)	a
80–89	203 (17.8)	698 (16.8)	a
≥90	15 (1.3)	40 (1.0)	a
Mean ± SD	70.5±9.4	70.2±9.4	a
Index year
<1995	45 (3.9)	172 (4.1)	a
1995–1999	147 (12.9)	546 (13.1)	a
2000–2004	324 (28.4)	1209 (29.0)	a
2005–2009	374 (32.8)	1358 (32.6)	a
≥2010	252 (22.1)	879 (21.1)	a
Length of record before index date (years)
Mean ± SD	12.6±5.4	12.4±5.4	a
BMI (kg/m^2)
<18.5	16 (1.4)	42 (1.0)	1.29 (0.71–2.32)
18.5–24.9	374 (32.8)	1263 (30.3)	1.0 (ref)
25–29.9	452 (39.6)	1843 (44.3)	0.84 (0.72–0.98)
≥30	261 (22.9)	812 (19.5)	1.10 (0.92–1.33)
Unknown	39 (3.4)	204 (4.9)	0.65 (0.45–0.94)
Mean ± SD	27.2±5.2	27.0±4.3
Smoking status
Nonsmoker	438 (38.4)	1654 (39.7)	1.0 (ref)
Smoker	108 (9.5)	522 (12.4)	0.78 (0.62–0.99)
Ex-smoker	540 (47.3)	1740 (41.8)	1.18 (1.02–1.38)
Unknown	56 (4.9)	248 (6.0)	0.82 (0.58–1.15)
Comorbidities
Hypertension	464 (40.6)	1572 (37.8)	1.13 (0.98–1.29)
Diabetes	136 (11.9)	481 (11.6)	1.03 (0.84–1.26)
Hyperlipidemia	269 (23.6)	772 (18.5)	1.38 (1.17–1.63)
Cardiovascular disease	517 (45.3)	1386 (33.3)	1.71 (1.49–1.97)
Benign prostatic hyperplasia	555 (48.6)	1785 (42.9)	1.27 (1.10–1.46)
Orchitis	66 (5.8)	214 (5.1)	1.15 (0.86–1.53)
Alcohol-related disorders	56 (4.9)	159 (3.8)	1.32 (0.96–1.81)
Cancer >2 years before index date	55 (4.8)	131 (3.2)	1.56 (1.12–2.16)
Hyperthyroid	10 (0.9)	29 (0.7)	1.26 (0.61–2.62)
Drugs associated with gynecomastia prescribed within 60 days of index date	658 (57.6)	1567 (37.6)	2.35 (2.05–2.70)

Note:

a Matching variable.

Abbreviations: OR, odds ratio; CI, confidence interval; BMI, body mass index; ref, reference.

Table 4 Case–control analysis: 5ARI and AB exposure among gynecomastia cases and matched controls

Exposure	Gynecomastia cases, n=1142, n (%)	Controls, n=4164, n (%)	Crude OR (95% CI)	Adj ORa (95% CI)
Nonexposed	661 (57.9)	2855 (68.6)	1.0 (ref)	1.0 (ref)
5ARI (only or in combination with AB)	272 (23.8)	394 (9.5)	3.26 (2.69–3.97)	3.31 (2.66–4.10)
Finasteride	198 (17.3)	322 (7.7)	2.87 (2.32–3.54)	2.92 (2.31–3.68)
Dutasteride	74 (6.5)	72 (1.7)	5.42 (3.74–7.85)	5.40 (3.64–8.00)
AB only	209 (18.3)	915 (22.0)	1.04 (0.87–1.25)	1.01 (0.82–1.23)
Number of prescriptions
Nonexposed	661 (57.9)	2855 (68.6)	1.0 (ref)	1.0 (ref)
5ARI (only or in combination with AB)
1 prescription	8 (0.7)	14 (0.3)	2.72 (1.12–6.60)	2.33 (0.94–5.79)
2–9 prescriptions	82 (7.2)	92 (2.2)	4.14 (3.01–5.69)	4.27 (3.03–6.01)
10–19 prescriptions	73 (6.4)	90 (2.2)	3.72 (2.66–5.21)	3.82 (2.67–5.47)
20–29 prescriptions	46 (4.0)	48 (1.2)	4.44 (2.89–6.82)	4.60 (2.92–7.26)
≥30 prescriptions	63 (5.5)	150 (3.6)	1.95 (1.41–2.70)	1.89 (1.33–2.69)
AB only
1 prescription	9 (0.8)	47 (1.1)	0.91 (0.44–1.88)	0.93 (0.45–1.95)
2–9 prescriptions	54 (4.7)	192 (4.6)	1.23 (0.89–1.69)	1.20 (0.86–1.68)
10–19 prescriptions	40 (3.5)	175 (4.2)	1.04 (0.73–1.50)	1.04 (0.71–1.53)
20–29 prescriptions	39 (3.4)	118 (2.8)	1.50 (1.03–2.19)	1.37 (0.93–2.03)
≥30 prescriptions	67 (5.9)	383 (9.2)	0.80 (0.61–1.07)	0.77 (0.57–1.03)
Exposure timing
Nonexposed	661 (57.9)	2855 (68.6)	1.0 (ref)	1.0 (ref)
5ARI (only or in combination with AB)
Current	240 (21.0)	368 (8.8)	3.09 (2.53–3.79)	3.14 (2.51–3.92)
Recent	23 (2.0)	19 (0.5)	5.49 (2.93–10.30)	6.64 (3.39–12.98)
Past	9 (0.8)	7 (0.2)	5.12 (1.89–13.88)	3.83 (1.34–10.91)
AB only
Current	185 (16.2)	796 (19.1)	1.06 (0.87–1.28)	1.02 (0.83–1.26)
Recent	11 (1.0)	79 (1.9)	0.62 (0.33–1.19)	0.59 (0.30–1.16)
Past	13 (1.1)	40 (1.0)	1.53 (0.81–2.89)	1.45 (0.75–2.78)

Notes:

a Adjusted for body mass index, smoking status, hypertension, hyperlipidemia, cardiovascular disease, cancer, alcohol-related disorders, benign prostatic hyperplasia, and drugs known to be associated with gynecomastia prescribed within 60 days prior to the index date, conditional on the matching factors.

Abbreviations: 5ARI, 5-alpha reductase inhibitor; AB, alpha blocker; adj OR, adjusted odds ratio; ref, reference; CI, confidence interval.

Table 5 Gynecomastia case–control analysis: 5ARI and AB exposure among gynecomastia cases and matched controls, stratified by use of drugs known to be associated with gynecomastia

Exposure	Gynecomastia cases, n=1142, n (%)	Controls, n=4164, n (%)	Crude OR (95% CI)	Adj ORa (95% CI)
Nonexposed
No gyn drugs	269 (23.6)	1849 (44.4)	1.0 (ref)	1.0 (ref)
Gyn drugs	392 (34.3)	1006 (24.2)	2.93 (2.44–3.52)	2.79 (2.32–3.36)
5ARI (only or in combination with AB)
No gyn drugs	136 (11.9)	212 (5.1)	5.35 (4.08–7.01)	5.32 (4.00–7.08)
Gyn drugs	136 (11.9)	182 (4.4)	6.31 (4.77–8.35)	5.85 (4.36–7.84)
AB only
No gyn drugs	79 (6.9)	536 (12.9)	1.09 (0.82–1.44)	1.07 (0.80–1.43)
Gyn drugs	130 (11.4)	379 (9.1)	2.85 (2.21–3.68)	2.66 (2.04–3.47)

Notes: Gyn drugs: drugs known to be associated with gynecomastia development.

a Adjusted for body mass index, smoking status, hypertension, hyperlipidemia, cardiovascular disease, cancer, alcohol-related disorders, and benign prostatic hyperplasia, conditional on the matching factors.

Abbreviations: 5ARI, 5-alpha reductase inhibitor; AB, alpha blocker; adj OR, adjusted odds ratio; ref, reference; CI, confidence interval.

Table 6 Breast cancer: characteristics of cases and controls

Characteristics	Breast cancer cases, n=48, n (%)	Controls, n=478, n (%)	Univariate OR (95% CI)
Age (years) at index date
40–49	1 (2.1)	10 (2.1)	a
50–59	4 (8.3)	42 (8.8)	a
60–69	8 (16.7)	88 (18.4)	a
70–79	20 (41.7)	198 (41.4)	a
80–89	15 (31.3)	140 (29.3)	a
Mean ± SD	73.2±9.9	73.1±9.9	a
Index year
<1995	1 (2.1)	10 (2.1)	a
1995–1999	8 (16.7)	80 (16.7)	a
2000–2004	13 (27.1)	128 (26.8)	a
2005–2009	14 (29.2)	140 (29.3)	a
≥2010	12 (25.0)	120 (25.1)	a
Length of record before index date (years)
Mean ± SD	11.2±5.9	11.3±5.8	a
BMI (kg/m^2)
<18.5	1 (2.1)	9 (1.9)	1.02 (0.12–8.56)
18.5–24.9	15 (31.3)	145 (30.3)	1.0 (ref)
25–29.9	25 (52.1)	219 (45.8)	1.10 (0.56–2.16)
≥30	7 (14.6)	85 (17.8)	0.81 (0.31–2.08)
Unknown	0 (0.0)	20 (4.2)	b
Smoking status
Nonsmoker	18 (37.5)	192 (40.2)	1.0 (ref)
Smoker	5 (10.4)	59 (12.3)	0.91 (0.32–2.56)
Ex-smoker	3 (6.3)	32 (6.7)	1.25 (0.62–2.49)
Unknown	22 (45.8)	195 (40.8)	0.95 (0.25–3.57)
Comorbidities
Hypertension	16 (33.3)	174 (36.4)	0.86 (0.44–1.68)
Diabetes	3 (6.3)	66 (13.8)	0.42 (0.13–1.39)
Hyperlipidemia	6 (12.5)	83 (17.4)	0.65 (0.26–1.66)
Cardiovascular disease	16 (33.3)	165 (34.5)	0.95 (0.49–1.82)
Benign prostatic hyperplasia	22 (45.8)	211 (44.1)	1.09 (0.57–2.09)
Gynecomastia (diagnosed more than 2 years before index date)	3 (6.3)	4 (0.8)	b
Alcohol-related disorders	1 (2.1)	16 (3.4)	0.60 (0.08–4.84)
Prostate surgery	8 (16.7)	33 (6.9)	3.07 (1.23–7.63)

Notes:

a Matching variable.

b Too few cases or controls.

Abbreviations: OR, odds ratio; BMI, body mass index; CI, confidence interval; SD, standard deviation; ref, reference.

Table 7 Breast cancer case–control study: 5ARI and AB exposure among breast cancer cases and matched controls

Exposure	Breast cancer cases, n=48, n (%)	Controls, n=478, n (%)	Crude OR (95% CI)	Adj ORa (95% CI)
Ever prescribed
Nonexposed	27 (56.3)	278 (58.2)	1.0 (ref)	1.0 (ref)
5ARI (alone or in combination with AB)	10 (20.8)	58 (12.1)	1.86 (0.79–4.37)	1.52 (0.61–3.80)
AB only	11 (22.9)	142 (29.7)	0.82 (0.37–1.82)	0.71 (0.31–1.62)
Combination ever prescribed
Nonexposed	27 (56.3)	278 (58.2)	1.0 (ref)	1.0 (ref)
5ARI only	2 (4.2)	15 (3.1)	b	b
5ARI and AB	8 (16.7)	43 (9.0)	1.97 (0.79–4.89)	1.65 (0.63–4.34)
AB only	11 (22.9)	142 (29.7)	0.82 (0.37–1.82)	0.71 (0.31–1.62)
Number of prescriptions
Nonexposed	27 (56.3)	278 (58.2)	1.0 (ref)	1.0 (ref)
5ARI (alone or in combination with AB), ;<10 prescriptions	6 (12.5)	22 (4.6)	2.89 (1.03–8.12)	2.27 (0.76–6.77)
5ARI (alone or in combination with AB), ≥10 prescriptions	4 (8.3)	36 (7.5)	b	b
AB only, <10 prescriptions	2 (4.1)	53 (11.1)	b	b
AB only, ≥10 prescriptions	9 (18.8)	89 (18.6)	1.07 (0.45–2.55)	0.99 (0.41–2.39)

Notes:

a Adjusted for gynecomastia (diagnosed >2 years before index date) and prostate surgery, conditional on the matching factors.

b Too few cases or controls.

Abbreviations: 5ARI, 5-alpha reductase inhibitor; AB, alpha blockers; adj OR, adjusted odds ratio; CI, confidence interval; SD, standard deviation; ref, reference.