Gynaecomastia in 786 adult men: clinical and biochemical findings

in European Journal of Endocrinology

Correspondence should be addressed to M G Mieritz; Email: m.mieritz@gmail.com

Objective

Gynaecomastia is a benign proliferation of glandular tissue of the breast; however, it is an important clinical observation because it can be the first symptom of an underlying disease. Some controversy exists concerning the clinical importance of an in-depth investigation of men who develop gynaecomastia. We hypothesise that a thorough work-up is required in adult men with gynaecomastia.

Design

All adult men (n = 818) referred to a secondary level andrological department at Rigshospitalet in Copenhagen, Denmark during a four-year period (2008–2011) under the diagnosis of gynaecomastia (ICD-10: N62) were included.

Methods

Thirty-two men who did not have gynaecomastia when examined were excluded; leaving 786 men for final analyses. They underwent an andrological examination, ultrasound of the testicles and analysis of endogenous serum hormones levels.

Results

In 43% of men with adult onset of gynaecomastia (≥18 years) an underlying, and often treatable, cause could be detected. In men younger at onset an underlying cause for gynaecomastia could be detected in merely 7.7%. The study is limited by the fact that we did not have access to investigate men who were referred directly by their GP to private clinics for plastic surgery or who sought cosmetic correction without consulting their GP first.

Conclusions

Our study demonstrates the importance of a thorough examination and provides a comprehensible examination strategy to disclose the underlying pathology leading to the development of gynaecomastia in adulthood.

Abstract

Objective

Gynaecomastia is a benign proliferation of glandular tissue of the breast; however, it is an important clinical observation because it can be the first symptom of an underlying disease. Some controversy exists concerning the clinical importance of an in-depth investigation of men who develop gynaecomastia. We hypothesise that a thorough work-up is required in adult men with gynaecomastia.

Design

All adult men (n = 818) referred to a secondary level andrological department at Rigshospitalet in Copenhagen, Denmark during a four-year period (2008–2011) under the diagnosis of gynaecomastia (ICD-10: N62) were included.

Methods

Thirty-two men who did not have gynaecomastia when examined were excluded; leaving 786 men for final analyses. They underwent an andrological examination, ultrasound of the testicles and analysis of endogenous serum hormones levels.

Results

In 43% of men with adult onset of gynaecomastia (≥18 years) an underlying, and often treatable, cause could be detected. In men younger at onset an underlying cause for gynaecomastia could be detected in merely 7.7%. The study is limited by the fact that we did not have access to investigate men who were referred directly by their GP to private clinics for plastic surgery or who sought cosmetic correction without consulting their GP first.

Conclusions

Our study demonstrates the importance of a thorough examination and provides a comprehensible examination strategy to disclose the underlying pathology leading to the development of gynaecomastia in adulthood.

Introduction

Breast development, gynaecomastia, in boys and men is a common condition (1). It is a benign proliferation of glandular tissue of the breast (2); however, it is an important clinical observation because it can be the first symptom of an underlying disease. Some controversy exists concerning the clinical importance of an in-depth investigation of adult men who develop gynaecomastia, but this study combined with earlier reports provides evidence for a comprehensive approach (3, 4, 5).

Changes in synthesis or bioavailability of sex steroids, often in favour of circulating oestrogens, have been proposed as a common cause of gynaecomastia (6). An altered sex steroid balance may result from a wide range of causes; e.g., testosterone deficiency, increased aromatase activity, changes in SHBG level or changes in sex steroid signalling as in partial androgen insensitivity syndrome (2, 7, 8). Accordingly, the use or misuse of medication (9), anabolic steroids, growth hormones, alcohol or cannabis (7, 10, 11, 12) have been reported to be a frequent causes of gynaecomastia, but often no underlying aetiology can be identified. Gynaecomastia has been reported to be ‘idiopathic’ in 61% of cases (13), leaving clinicians with few options to identify causal and/or treatable factors for most men. This is often the main argument for omitting a thorough work-up of men with palpable benign breast enlargement, but large retrospective and consecutive studies are lacking. We evaluated clinical and biochemical findings from a detailed suitable primary diagnostic work-up in a large consecutive cohort of adult men referred to our andrology outpatient clinic under the diagnosis of ‘Gynaecomastia’ (ICD-10: N62) during a four-year period (2008–2011).

Subjects and methods

Participants and clinical examination

All men (age ≥18 years) referred for evaluation of unilateral or bilateral gynaecomastia (ICD-10: N62) from 2008 to 2011, who underwent a structured work-up with clinical examination and blood sampling at the Department of Growth and Reproduction at Rigshospitalet, were included. In total 818 men were examined, however, the clinical examination showed that 32 men actually did not have gynaecomastia, thus leaving 786 patients for final analysis. If referrals included information on current or recent (<2 years) abuse of anabolic steroids (AAS), the men were not evaluated.

A detailed medical history was obtained, including information on self-reported onset of gynaecomastia – no preselection or differentiation between different symptoms of gynaecomastia at onset, e.g. soreness, protrusion of the nipple, was made. Gynaecomastia was defined as the presence of palpable glandular tissue. The physical examination included the evaluation of the presence of gynaecomastia (unilateral and/or bilateral) by palpation and determination of size of glandular tissue (largest diameter). The recording of unilateral or bilateral gynaecomastia was not specified for 265 men. Testis size was determined by palpation using an orchidometer, and testicular ultrasound examination was performed for volume measurement and to identify testicular tumours (14). All examinations were performed by trained andrologists.

Body height was measured using a calibrated wall-mounted Harpenden stadiometer (Holtain Ltc, Crymych, United Kingdom) and weight using a calibrated electronic scale (Bisco model PERS 200, Farum, Denmark) wearing light clothing.

Blood sampling

All men had blood samples taken and analysed for reproductive hormones, prolactin, thyroid hormones, liver enzymes, creatinine, sodium, potassium, human chorionic gonadotropin (hCG) and alpha foeto protein. If results were outside the reference levels, new blood samples were taken for repeated analysis of the variables.

Serum hormone analyses

Serum concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH) and sex hormone-binding globulin (SHBG) were measured by TR-IFMAs (Delfia, Perkin Elmer). Detection limits (LODs) and inter- and intra-assay coefficients of variation (CVs) were 0.05 IU/L, 2.7 and 2.1% for FSH, 0.05 IU/L, 1.94 and 3.0% for LH and 0.23 nmol/L, 7.51 and 5.1% for SHBG. Serum total testosterone (tT) was measured by radioimmunoassay using DPC Coat-A-Count RIA kits obtained from Diagnostic Products Corp. (Los Angeles, California, USA), with LOD 0.23 nmol/L and inter- and intra-assay CVs of 12.8 and 17%. The assay was compared against LC–MS/MS methodology with excellent performance at levels above 5 nmol/L (15). Estradiol (E2) was measured by radioimmunoassay (Pantex, Copenhagen, Denmark) with LOD of 18 pmol/L, inter-CV of 14.9 and intra-CV of 7.5. Until 2010, serum inhibin B was measured using double antibody enzyme immunometric assays (Oxford Bio-Innovation) with a LOD of 20 pg/mL and intra- and inter-assay CVs <16%. From 2010, inhibin B was measured using the Beckman Coulter Inhibin B genII assay, with a LOD of 3 pg/mL and intra- and inter-assay CVs <11%. The two methods were compared and agreement was observed. Free testosterone (cFT) (Vermeulen, Verdonck et al. 1999) and free estradiol (cFE2) were calculated (16), taking SHBG into account and assuming a fixed albumin at 43.8 g/L. Age-related reference ranges for these assays are based on healthy Danish men as previously published (17, 18, 19, 20).

Prolactin was measured on BRAHMS Kryptor (BRAHMS GmbH, Hennigsdorf, Germany) (LOD 25 mIU/L, with a day-to-day precision of 5–8%). Thyroid-stimulating hormone (LOD 0.014 mIU/L, day-to-day precision of 4–6%), thyroxine (T4) (LOD 5.4 nmol/L, day-to-day precision of 7%) and free T4 (LOD 0.3 pmol/L, day-to-day precision of 7%) were analysed on a Modular ANALYTIC-SP/ISE-E-module system (Roche Diagnostics), using the CFAS-specific Roche calibrators and the Roche Modular reagents for all assays.

Classification of causes of gynaecomastia

The diagnosis of an underlying Leydig cell insufficiency was based on the evaluation of testosterone and LH measurement and by the bivariate testosterone–LH plot (21). This setup also enables us to classify the men in primary, secondary or mixed deficiency. If the reason for testosterone deficiency was unclear, hCG, GnRH and/or Clomiphene tests were performed to support the diagnosis. If the response was insufficient on both pituitary/hypothalamic and gonadal levels, the testosterone deficiency was categorised as ‘mixed’.

Diagnosed underlying causes were grouped into sex-chromosomal and genetic disorder (Klinefelter syndrome, Kennedy syndrome or 47 and XYY), tumours (breast cancer, Leydig cell tumours, Sertoli cell tumours or germ cell tumours), other endocrine disorders (Cushing’s disease, hyperthyroidism, hyperprolactinaemia), liver insufficiency, medication due to comorbidities, AAS or cannabis, persistent pubertal gynaecomastia and ‘unexplained’ gynaecomastia. If more than one contributing factor was discovered, the treatable cause if existing was set as the main underlying cause.

Statistical analyses

Descriptive variables are displayed as medians and ranges (min–max). For men reporting that gynaecomastia had persisted since puberty, but who could not recall the exact age at onset, it was arbitrarily set to 16 years of age in the analyses. Comparisons of hormone levels between causal groups (with n ≥ 5) were performed on non-transformed data using the Mann–Whitney test using the ‘unexplained’ subgroup as the reference. Controlling for age was performed on selected groups and variables by logistic regression if median age was significantly different from the ‘unexplained’ subgroup. P values ≤0.05 were considered significant.

The diagnosis of an underlying pathology based on blood samples were only accepted if the pathological finding of the first blood sampling was confirmed by analysis of the second. However, as it was only a subset of analyses that were repeated, the primary blood samples were used for description in ‘Results’ section.

Ethical considerations

Ethical approval was not required as the analyses of patient records did not involve renewed contact with patients. The study was registered with and approved by the Danish Data Protection Agency (j.nr. 2012-41-0797).

Results

All underlying conditions were undiagnosed until referral for gynaecomastia and were identified due to the specific investigations.

Median age at examination was 35 years (18–91 years (median (range)) of the total 786 included men. Duration of gynaecomastia was 1.2 years (0.1–45.6), and age at onset was younger than 18 years in 196 (25%) of the men. In men with pubertal onset, the median size of glandular tissue was 4 cm (1–10), and 3 cm (1–10) in men with adult onset. Gynaecomastia was bilateral in 269 of 521 (52%) men, and unilateral in 252/521 (48%), left-sided in 141 and right-sided in 111.

Pubertal onset gynaecomastia (<18 years, n = 196 (25%))

In men with onset of gynaecomastia younger than 18 years, the median age at onset was 14 years (8–18) and the duration at the time of examination was 10.2 years (0.41–45.6). In 7% (14/196) of the men an underlying cause of gynaecomastia could be identified. One was diagnosed with XYY Syndrome (karyotype 47, XYY), when he was referred for investigation of gynaecomastia at the age of 16 years; one had smoked cannabis at the time gynaecomastia developed; 12 (6%) had a current or recent use of anabolic steroids, but the majority 182 (93%) were without any detectable underlying condition despite the extensive investigation and thus classified as having ‘persistent pubertal gynaecomastia’.

Adult onset gynaecomastia (>18 years, n = 590 (75%))

Table 1 summarises the main underlying causes of gynaecomastia and the anthropometric characteristics of the adult patients.

Table 1

Anthropometric data on adult men (age ≥ 18 years at onset of gynaecomastia) arranged according to underlying diagnosis, displayed as medians (min–max). Due to lack of complete information on all participants, the exact number is listed in each section.

Age, (years)Height, (cm)Weight, (kg)BMI, (kg/m2)Age at onset of GNM, yearsDuration of GNM, yearsUnilateral GNM, n (%)GNM size, (cm)Mean testis size, mL
LeftRightPalpationUS
All men
Median (min–max)35 (18-91)180 (156-206)85 (46-712)26 (18-51)31 (8-91)1.2 (0.1-45.6)252 (48%)3.0 (0-10)3.0 (1-10)20 (4-43)13.0 (0.9-33.3)
n786739746736549549521259237726652
Adult onset, All
Median (min–max)42 (18-91)179 (156-201)85 (46-172)26 (18-51)41 (19-91)0.59 (0.1-36.7)231 (62%)3.0 (0-10)3.0 (1-8)20 (4-43)12.9 (0.85-33.3)
n590548555546405405374198181536483
Testosterone deficiency
Primary
Median (min–max)***62 (19-89)**177 (163-192)84 (56-162)*27 (18-44)***60 (23-88)0.67 (0.18-20.58)24 (60%)*4.0 (0-10)*4.0 (1-8)***10 (5-22.5)***4.6 (2.5-14.45)
n4743454343434020103429
Secondary
Median (min–max)**55 (22-79)**176 (164-196)**93 (60-172)***31 (20-51)**51 (26-79)*0.50 (0.21-10.0)8 (47%)*4.0 (2-8)*5.0 (2-8)20 (9-28)***11.0 (4.1-20.0)
n26252525212117982322
Mixed
Median (min–max)64** (58-66)175* (156-182)80 (46-98)23 (15-27)64** (58-65)0.56 (0.39-2.22)3 (60%)3.25 (3-4)5 (4-6)10.5*** (8-17.5)6.25** (2-11.5)
n66665552266
Chromosomal abnormalities
Klinefelter syndrome
Median (min–max)40 (26-55)185 (174-200)96 (78-111)26 (22-32)24 (23-43)6.63 (0.27-14.48)0 (0%)4.5 (2-7)5.5 (4-7)4 (4)2.05 (0.85-2.25)
n66664462233
Kennedy Syndrome
Median (min–max)511879928--0 (0%)--2517.7
n1111111
Testicular tumours
Leydig cell
Median (min–max)39 (36-42)180 (175-180)71 (70-77)20 (20-22)39 (38-40)1.0 (0.81-1.2)1 (50%)6.06.015 (12-20)7.7 (7.6-15.1)
n33332221133
Sertoli cell
Median (min–max)34 (32-36)191 (184-199)84 (77-91)22 (21-23)360.281 (100%)2.0-18.3 (17.5-19.0)11.6 (10.75-12.5)
n2222111122
Germ cell
Median (min–max)4117810229400.40 (0%)--1611
n111111111
Breast cancer
Median (min–max)73 (68-77)188 (185-191)94 (91-96)25 (25-50)4036.7*1 (50%)-5.019 (15-23)13 (8-18)
n2222112122
Endocrine disorder
Median (min–max)*46 (24-74)179 (169-201)81 (65-150)26 (18-44)* 47 (27-74)0.44 (0.18-11.1)10 (83%)2.0 (2-5)3.50 (3-4)*18.0 (9.0-32.5)14.0 (4.5-23.3)
n18171717121212521814
Liver insufficiency
Median (min–max)***54 (35-73)180 (169-187)92 (64-121)28 (21-36)**51 (33-73)0.57 (0.19-14.8)13 (76%)3.0 (1-6)3.0 (2-6)20.0 (8.0-30.0)12.8 (4.1-22.0)
n23191818151517791820
Kidney insufficiency
Median (min–max)781677326771.051 (100%)-3.0158.3
n1111111111
Medication
Median (min–max)***64 (21-91)**178 (156-195)88 (55-148)**27 (19-44)***62 (20-91)*0.7 (0.11-15.95)39 (60%)4.0 (1-10)3.00 (1-6)20 (8-36)13.0 (5.10-28.0)
n8579807973736535257767
Unexplained
Median (min–max)36 (18-77)180 (164-200)83 (52-129)*26 (18-38)34 (18-74)1.09 (0.14-32.8)102 (73%)3.0 (1-10)2.55 (1-10)21 (6-43)13.9 (3.9-33.3)
n2892702742692552551408086269247
Substance abuse
Steroid abuse
Median (min–max)*** 28 (21-50)179 (165-190)85 (57-140)*26 (19-45)***24 (19-46)*2.20 (0.21-19.8)25 (41%)3.0 (1-8)2.0 (1-7)20 (8-30)13.2 (4.6-31.5)
n7669706964646133327461
Cannabis abuse
Median (min–max)22 (19-27)192 (181-193)73 (68-82)21 (20-22)21 (19-26)0.39 (0.31-1.02)1 (50%)1.0 (1)2.0 (1-3)22 (20-23)14.6 (13.6-18.1)
n33333322233

excludes testosterone deficiency; *P < 0.05; **P < 0.01; *** P < 0.0005 compared with “unexplained” gynaecomastia (Mann-Whitney). GNM, gynaecomastia.

Age at onset of gynaecomastia was 42 years (18–91) in the group of men with adult onset of gynaecomastia and the duration at the time of examination was 0.6 years (range 0.1–36.7). Misuse of anabolic steroids (n = 76) or cannabis (n = 3) was reported in 79 men and considered as the basic cause for their development of gynaecomastia. In the remaining 511 men, testicular problems were the main cause for gynaecomastia in 91 men (17.8%); some degree of testosterone deficiency was detected in 79 men (15.4%), 6 men were diagnosed with Klinefelter syndrome (1.2%) and 6 with testicular tumours (1.2%). Concomitant or recent use of medication known to be associated with the development of gynaecomastia for various comorbidities was the second most frequent cause (n = 85, 16.6%), whereas the other reasons highlighted in Table 1 were all less frequent.

Among the 511 men, the reason remained ‘unexplained’ in 289 (57%). The palpable gynaecomastia in these men were additionally confirmed by ultrasound examination in 65 (23%) of these. Figure 1 summarises the distribution of causes of adult onset gynaecomastia excluding men who used anabolic steroids or cannabis.

Figure 1
Figure 1

Pie chart showing the distribution of underlying causes of gynaecomastia with adult debut in men with no substance abuse.

Citation: European Journal of Endocrinology 176, 5; 10.1530/EJE-16-0643

Testosterone deficiency

Men with testosterone deficiency had smaller testicles than the ‘unexplained’ group (P < 0.01), assessed by palpation and US (Table 1). Testis size was the smallest in men with primary testosterone deficiency. Men with testosterone deficiency were shorter than men in the unexplained group. However, for those with primary and secondary testosterone deficiency, the difference was no longer significant when controlled for age or BMI in a logistic regression model. Patients with primary and mixed testosterone deficiency, including Klinefelter patients, had elevated gonadotrophins and SHBG, reduced levels of tT, cFT and inhibin B (Table 2). Furthermore, in these men, tT/LH, cFT/LH and inhibin B/FSH were reduced, whereas cFE2/cFT was elevated (Table 3).

Table 2

Hormone levels in adult men (age min. 18 years at onset of gynaecomastia) arranged according to underlying diagnosis, displayed as medians (min–max). Due to lack of complete information on all participants, the exact number is listed in each section.

FSH, IU/LLH, IU/LT, nmol/LcFT, pmol/LE2, pmol/LcFE2, pmol/LSHBG, nmol/LInhibin B, pg/mL
All men
Median (min–max)3.7 (0.01–117)3.9 (0.0–80.0)14 (0–209)280 (0–8315)67 (1–1771)1.57 (0.02–28.51)34 (3–244)168 (1–584)
n765776777774775772774756
Adult onset, All
Median (min–max)4.0 (0.0–117.0)4.2 (0.0–80.0)14 (0–136)259 (0–5587)68 (1–1771)1.55 (0.02–28.51)37 (5–244)162 (1–584)
n574585586584585583584569
Testosterone deficiency
Primary
Median (min–max)***33.8 (2.3–117)***16.5 (6.01–80)***9 (0–22)***120 (4–255)57 (1–1771)(**)1.11(0.02–19.41)***55 (17–141)***1 (1–221)
n4146474746464741
Secondary
Median (min–max)3.2 (0.9–21.5)***2.2 (0.6–17.7)***5 (0–17)***112 (0–255)68 (1–279)1.68 (0.03–7.00)31 (13–62)**110 (1–300)
n2626262526252525
Mixed
Median (min–max)(**)15.4 (2.7–25.5)**7.9 (3.8–10.8)***9 (2–10)***110 (26–163)47 (1–98)*0.88 (0.02–1.79)(*)54 (34–98)**22 (1–229)
n66666666
Chromosomal abnormalities
Klinefelter syndrome
Median (min–max)***26.0 (18.4–44.9)***19.2 (13.1–28.6)***3 (2–7)***72 (21–118)63 (1–119)1.69 (0.03–3.51)30.0 (12–77)***1 (1)
n56666666
Kennedy syndrome
Median (min–max)2.43.9213511062.1550190
n11111111
Testicular tumours
Leydig cell
Median (min–max)1.6 (1.1–2.1)3.6 (2.6–3.9)14 (10–14)292 (213–375)159 (94–175)4.20 (2.73–4.50)27 (20–29)222 (123–321)
n23333332
Sertoli cell
Median (min–max)4.55.2 (3.8–6.5)13 (9–17)258 (208–308)47 (46–48)1.18 (1.07–1.28)32 (23–41)209
n12222221
Germ cell
Median (min–max)*1.0*1.092141002.8721145
n11111111
Breast cancer
Median (min–max)9.6 (5.6–13.7)5.2 (4.7–5.6)16 (14–18)*180 (176–185)63 (47–79)1.01 (0.82–1.21)*74 (66–82)143 (116–169)
n22222222
†Endocrine disorders
Median (min–max)*5.2 (2.0–42.0)5.3 (1.3–29.0)15 (2–39)195** (42–274)62 (1–1096)1.2 (0.03–23.50)44 (11–244)165 (1–346)
n1818181818181817
Liver insufficiency
Median (min–max)(***)7.3 (0.0–48.5)**5.8 (0.0–34.8)15 (6–28)(***)231 (119–387)**95 (34–766)1.80 (0.67–28.51)**53 (5–197)(***)122 (1–339)
n2323232323232323
Kidney insufficiency
Median (min–max)6.24133461.715
n111111
Medication
Median (min–max)(***)5.7 (1.5–50.1)**4.9 (1.8–35.3)(*)14 (5–40)(***)224 (84–556)(*)78 (1–1001)1.57 (0.03–17.68)***47 (13–122)(*)161 (1–364)
n8484848484848482
Unexplained
Median (min–max)3.5 (0.2–42.2)3.8 (0.2–13.6)15 (6–41)298 (131–1603)67 (1–203)1.56 (0.03–7.55)36 (5–93)181 (1–584)
n286288288287288287287274
Substance abuse
Steroid abuse
Median (min–max)***2.2 (0.0–10.9)***3.1 (0.0–6.8)15 (0–136)306 (0–5487)59 (1–376)1.531 (0.02–13.73)***27 (6–83)187 (34–382)
n7474747474747474
Cannabis abuse
Median (min–max)2.3 (1.9–3.0)3.5 (3.0–6.1)26 (26–27)552 (396–584)74 (73–75)1.77 (1.38–1.77)36 (35–57)215 (176–220)
n33333333

excludes testosterone deficiency; *P < 0.05; **P < 0.01; ***P < 0.0005 compared with “unexplained” gynaecomastia (Mann-Whitney). P-values in parenthesis were no longer significant after adjusting for age in a logistic regression model.

Table 3

Hormone ratios in adult men (age min 18 years at onset of gynaecomastia) arranged according to underlying diagnosis, displayed as medians (min–max). Due to lack of complete information on all participants, the exact number is listed in each section.

E2/T, pmol/nmol100*cFE2/cFTInhibin B/FSH, pg/mL/IU/LtT/LH, nmol/IUcFT/LH, pmol/IU
All
Median (min – max)4.6 (0.1–8500)0.60 (0.0–967)48.02 (0.01–18800)3.8 (0.0–20854)74 (0–821582)
n774772754775773
Adult onset, All
Median (min – max)4.7 (0.1–8500)0.60 (0.0–967)43.28 (0.01–16300)3.5 (0.0–13601)66 (0–548681)
n585583567585583
Testosterone deficiency
Primary
Median (min – max)***8.7 (0.2–131)***1.20 (0.0–19.8)***0.05 (0.01–29.88)***0.5 (0.0–1.8)***7 (0–23)
n4646404646
Secondary
Median (min – max)***10.8 (0.6–2500)***1.39 (0.1–372.5)44.75 (0.12–305)***2.29 (0.0–7.9)***40 (0–143)
n2625252625
Mixed
Median (min – max)5.2 (0.5–9.7)0.80 (0.1–1.38)1.23(**) (0.05–83.88)***1.0 (0.3–2.4)***14 (4–42)
n66666
Chromosomal abnormalities
Klinefelter syndrome
Median (min – max)26.5** (0.2–56.1)3.37** (0.00–8.60)***0.04 (0.02–0.05)***0.2 (0.1–0.3)***4 (1–6)
n66566
Kennedy syndrome
Median (min – max)5.00.6080.505.590
n11111
Testicular tumours
Leydig cell
Median (min – max)12.9 (6.5–16.2)1.54 (0.70–2.00)175.6 (59.4–291.8)3.8 (3.5–4.1)82 (76–106)
n33233
Sertoli cell
Median (min – max)4.0 (2.8–5.2)0.50 (0.40–0.60)46.552.9 (1.38–4.42)57 (32–80)
n22122
Germ cell
Median (min – max)11.41.34145.0*9.1221
n11111
Breast cancer
Median (min – max)4.0 (3.4–4.6)0.60 (0.50–0.70)19.40 (8.47–30.34)3.0 (3.0–3.1)35 (33–37)
n22222
Endocrine disorders (excl testosterone deficiency)
Median (min – max)4.5 (0.5–107.8)0.60 (0.10–14.6)34.46 (0.03–111.7)(**)2.5 (0.7–12.0)***37 (5–209)
n1818171818
Liver insufficiency
Median (min – max)(*)6.3 (2.2–74.4)**0.86 (0.30–7.60)(***)16.22 (0.02–10400)(**)2.8 (0.7–1029)(***)40 (7.06–37415)
n2323232323
Kidney insufficiency
Median (min – max)12.21.280.622
n1111
Medication
Median (min – max)(**)5.5 (0.1–54.9)(***)0.70 (0.00–7.40)(***)34.16 (0.02–161.98)***2.9 (0.5–9.6)***50 (5–218)
n8484828484
Unexplained
Median (min – max)4.3 (0.1–17.6)0.50 (0.00–2.20)51.47 (0.02–676.5)4.0 (0.9–206.7)79 (12.12–8017)
n288287284288287
Substance abuse
Steroid abuse
Median (min – max)4.50 (0.3–8500)0.50 (0.00–967)***89.03 (5.32–16300)(*)4.6 (1.0–13601)(**)99 (22.30–548681)
n7474747474
Cannabis abuse
Median (min – max)2.9 (2.9–2.9)0.30 (0.30–0.40)97.35 (58.7–116.2)7.4 (4.2–8.8)157 (65.4–192.0)
n33333

P < 0.05; **P < 0.01; ***P < 0.0005 compared with “unexplained” gynaecomastia (Mann-Whitney). P-values in parenthesis were no longer significant after adjusting for age in a logistic regression model.

Figure 2 illustrates testosterone and LH levels as well as hormone ratios depicted on a reference curve. Some men with clinical signs of testosterone deficiency had serum levels of tT that were within the normal reference level, although in the lower range. However, these men were characterised by an abnormal tT/LH and/or cFT/LH ratio; this mismatch is clearly seen in Fig. 2D and E. In two individuals only one of these ratios were abnormal (one with high E2/tT and cFE2/cFT and one with empty sella but no available ratios due to lack of SHBG).

Figure 2
Figure 2

(A, B and C) Testosterone (tT), free testosterone (cFT) and LH according to age in men with primary (red), secondary (green) and mixed (red/green) testosterone deficiency and Klinefelter syndrome (blue) compared to mean and ±2 s.d. of a normal material of healthy Danish men. (D and E) Ratios of testosterone (tT) and free testosterone (cFT) according to LH in men with primary (red), secondary (green) and mixed (red/green) testosterone deficiency and Klinefelter syndrome (blue). 95% of healthy Danish adult men are on the left side of the black line.

Citation: European Journal of Endocrinology 176, 5; 10.1530/EJE-16-0643

Testicular tumours

The ultrasound examinations showed testicular tumours in six men, and none of these tumours were detected by palpation alone. Two men with Sertoli cell, three men with Leydig cell tumours, and one man with a germ cell tumour. Patients with Leydig cell tumours tended to have lower levels of FSH and elevated E2, cFE2, E2/tT and cFE2/cFT compared to controls, whereas reproductive hormones did not differ in men with Sertoli cell tumours compared to controls; however, the levels of FSH and LH tended to be higher and tT/LH and cFT/LH ratios tended to be lower. Only one man was diagnosed with a malignant germ cell tumour (seminoma), and he presented with low gonadotrophins, high E2/tT ratio and cFE2/cFT, but did not have detectable elevation of hCG.

Medication-induced gynaecomastia

Use of medication was mainly reported in older men (64 years (21–91 years), n = 85) suffering from comorbidities and use of drugs is known to be associated with gynaecomastia. Table 4 summarises the medications taken by the men in this group. These 85 men had lower levels of tT (P = 0.018) and cFT (P < 0.0005) and elevated FSH (P < 0.0005), LH (P < 0.0005), E2 (P = 0.036), SHBG (P < 0.0005) and inhibin B (P = 0.014) compared with the ‘unexplained’. However, when adjusted for age in a logistic regression model, only the difference in LH, SHBG, tT/LH and cFT remained significant.

Table 4

Medication used by men categorized with medication as underlying cause of gynaecomastia (n = 85). 16 men had more than a single drug proposed to cause gynaecomastia. 50% of men using Simvastatin also used other medication able to cause gynaecomastia.

Medicinal groupDrugn
Cardiovascular agentsSpironolacton19
Digoxin6
Enalapril5
Amlodipin4
Verapamil2
Unknown ACE inhibitor1
5-alpha reductase inhibitorsDutasterid4
Finasterid4
OpioidsMorphine6
Tramadol5
Buprenorphin2
Metadon3
Oxycodon1
Anti-psychoticsRisperidon2
Chlorprotixen2
Anti-depressantsNortriptylin1
Sertralin1
Olansapin1
NeurolepticsUnknown1
Anti-retroviralUnknown3
StatinsSimvastatin10
Atorvastatin5
Rosuvastatin2
AntacidsOmeprazole2
Pantoprazole2
Lansoprazole1
Esomeprazol1
Unknown proton pump inhibitor1
Immunosuppressant agentsMethotrexate1
Glukokorticoids1
Ciclosporin1
Prednisolone1
Natural remedy‘Saw palmetto’1

Other causes

In 23 men (median age 45 years (35–73)), the biochemical evaluation revealed parenchymal liver problems (elevated alanine transferase and lactate dehydrogenase) as the only discernible explanation for gynaecomastia. They had highly elevated SHBG, E2 and LH, whereas cFT and inhibin B were low. E2/tT and cFE2/cFT were elevated and tT/LH, cFT/LH and inhibin B/FSH were lowered (all P < 0.01). When controlling for age, the difference in LH, SHBG and cFE2/cFT remained significant.

One man was diagnosed with renal insufficiency (elevated creatinine and carbamide). His tT, cFT and SHBG were low, hence, altering the ratios of E2/tT (high), tT/LH (low) and cFT/LH (low).

Eighteen men were diagnosed with endocrine disorders (hyperthyroidism (n = 10, having high (normal) testosterone, SHBG and elevated E2/tT and especially E2/cFT), hyperprolactinaemia (n = 7, having secondary testosterone deficiency) and Cushing’s disease (n = 1, having elevated androstendion and besides gynaecomastia also a Cushingoid appearance).

The palpation of the breast tissue of three men raised suspicion of unilateral breast cancer as their breast tissues were hard and irregular. Further evaluation including biopsy confirmed the suspicion in two of these men aged 77 and 69 years (0.4% of men with no AAS). The hormonal testing of these men was normal. The oldest of the two men with breast cancer actually also had bilateral gynaecomastia, that had lasted for several years until a recent additional unilateral breast development made him seek his GP for this.

More than one underlying cause

Twelve percent of the men with adult onset of gynaecomastia had more than one underlying cause of breast development – predominantly with primary testosterone deficiency or medication as main treatable cause.

Discussion

In this prospective study, we report frequent findings of underlying pathologies in men evaluated because of gynaecomastia. Using a standardised and simple diagnostic procedure, we detected pathological findings in 43% of men with no prior misuse of steroids. These causes included testosterone deficiency, use of medication, hyperthyroidism, hyperprolactinaemia, Klinefelter syndrome and testicular tumours. This emphasises that adult onset gynaecomastia may be a clinical sign of an underlying disease in a significant proportion of men.

The men we diagnosed with an underlying reason for their gynaecomastia had no prior knowledge of these reasons. Although not reported here in detail, the patients generally had not primarily complained of any other symptoms (e.g. fatigue, affected memory, decreasing muscle strength etc. were only unmasked after a detailed questioning). In some men, potentially serious conditions such as testicular tumours, hyperthyroidism and hyperprolactinaemia were diagnosed because of a primary complaint of gynaecomastia. Other publications have also described gynaecomastia as the first symptom of underlying diseases (22, 23, 24), but despite this, it is not always a common practice to refer men with gynaecomastia for an andrological examination before referring them to cosmetic surgery (25). Due to the large number of men with hitherto unknown testicular problems, it seems appropriate to suggest that men with gynaecomastia should undergo a thorough andrological examination, including examination of the testicles.

Our study has several strengths. It was based on a large consecutively referred group of patients, the hormone assessments were done in a single certified laboratory, and the standardised work-up was performed by doctors who were trained andrologists and certified in testicular ultrasound. All men were investigated because they sought medical care because of the gynaecomastia that in most men were recently developed. We did not systematically record whether the gynaecomastia was associated with tenderness, but the clinical impression is that it was the case in approximately 50%. The largest limitation of this study lies in the risk of selection bias. Our clinic belongs to a tertiary centre, and although we have our local catchment area from which general practitioners (GPs) refer men for a primary diagnostic work-up, we do not have any information about how many men these GP’s actually saw due to breast development and did not refer to us. However, the patients had not had any systematic biochemical screening performed prior to referral, and thus, selection bias because of biochemistry seems low – except for the fact that many GPs in our experience tend to measure prolactin prior to referring patients. Thus, men with increased prolactin levels might have been referred elsewhere primarily and may be underrepresented in our study. Similarly, men who were in antiandrogen or other androgen deprivation treatment, because of prostate cancer, were not referred for investigation. Another limitation is that we did not have access to investigate men who were referred directly by their GP to private clinics of plastic surgery or who sought cosmetic correction without consulting their GP first. This may be the case for many men who have had used anabolic steroids when their gynaecomastia developed, and these men are usually not offered investigation of an underlying cause. We classified gynaecomastia as caused by medication if gynaecomastia was a known side effect of the drug. Some drugs are associated with a high risk of development and other drugs a lower risk; we could not determine to which degree the drugs actually were the cause as we did not follow the men classified by gynaecomastia caused by medication after our initial screening to test if changes in medication changed the presence of gynaecomastia. Secondly, there are certainly groups of drugs that could not be replaced. Assuming that the drugs considered being causal in reality was unrelated to gynaecomastia, these men should be added to the group of men with unexplained gynaecomastia. Thus, the number of men in other groups would remain the same. The distinction between gynaecomastia and lipomastia can be difficult in very obese individuals – and as we did not routinely use ultrasound imaging to support the diagnosis, it is possible that men with breast enlargement due to fat tissue alone have been misdiagnosed as having gynaecomastia. It can be speculated that such men will tend to end up by being classified as ‘unexplained’; however, the BMI of that group did not differ much from the other classification groups.

We did not perform follow-up on the men in this study as our main function was diagnostic. Only men diagnosed with testosterone deficiency were treated in our department. Men with other conditions were referred on to other departments for treatment.

Our results highlight the usefulness of a thorough patient history including information of time of onset of gynaecomastia. To which degree gynaecomastia in puberty needs a diagnostic work-up is controversial, but this study indicates that even if pubertal gynaecomastia persists, it is most often not because of underlying pathology. In adult men with gynaecomastia since puberty, an underlying illness is less likely and inquiring about substance abuse and examination of testis size may suffice. Extremely small testicles could indicate Klinefelter syndrome and should lead to a more detailed investigation. Men with adult onset of gynaecomastia concomitant with ASS do most likely not need a thorough work-up – the endocrine profile will be disturbed and may be difficult to interpret if the abuse is ongoing or recent. The association between AAS and the development of gynaecomastia is well known (26, 27, 28, 29) and men who reported using anabolic steroids at referral were not offered further investigation. This was also the case for men in anti-androgenic treatment due to prostate cancer as this is also known to cause gynaecomastia (30). The mechanism behind breast development in men with abuse of cannabis is thought to be the similarity in the chemical structure between E2 and cannabinol (the major active component in marihuana), rather than changes in hormone levels (10). However, the group of men with cannabis abuse in our study is too small to conclude on.

A thorough diagnostic work-up ought to be done only on those with adult onset gynaecomastia provided that they are not in androgen deprivation therapy or are abusing AAS. AAS abuse does not exclude other underlying pathology but renders analysis of hormones levels virtually impossible. Exclusion of a testicular tumour may be sufficient. In our study, almost 10% of the patients presented with more than one obvious explanation, with testicular insufficiency and use of medication the most common combination. Thus, identification of one obvious cause for gynaecomastia such as medication should not preclude a detailed investigation.

The men with testosterone deficiency had low levels of tT, cFT or testosterone–LH levels outside the reference level in the bivariate plot indicating Leydig cell impairment. Their E2 levels were not increased as such; however, the E2/T balance tended to a shift toward oestrogen. These findings support that the balance between androgens and estrogens is an important factor in the development of gynaecomastia, with estradiol promoting breast development and testosterone inhibiting the development of glandular tissue (1). Thus, even men with testosterone in the low-normal range may benefit from testosterone substitution.

In a large proportion of men, medications for comorbidities were the only factor identifiable as causing gynaecomastia. The classification of the medicine, in Table 4 as cause of gynaecomastia, is based on available knowledge (31, 32, 33). For many drugs, the exact mechanisms for inducing gynaecomastia remain unknown (9, 34). Nevertheless, it is important to consider the choice of medication and the possibility to change the current treatment to avoid breast development. In cases where medication cannot be substituted, therapy of e.g. testosterone deficiency could be initiated.

We detected breast cancer in two men. We did, however, only see men referred under the diagnosis of ‘gynaecomastia’ as men referred under the diagnosis of ‘breast cancer’ are primarily seen by breast cancer surgeons. A recent study described a 10-fold higher risk of breast cancer in men who have had gynaecomastia (35). The mechanism is unknown, but it is speculated that the altered sex hormone balance, in favour of increased oestradiol/testosterone, could cause abnormal stimulation of the breast tissue (36). Alternatively, it might be due to the simple fact that the breast cancer was regarded as gynaecomastia before further examination (37).

In conclusion, we detected endocrinological diseases, including testosterone deficiency, thyrotoxicosis, Cushing’s disease, hyperprolactinaemia and testicular cancer among our patients referred with gynaecomastia. More than one likely reason for gynaecomastia was also a frequent finding. Thus, identification of one obvious cause for gynaecomastia such as medication should not preclude a detailed investigation. This stresses the importance of a thorough examination to disclose any underlying pathology leading to the development of gynaecomastia in adulthood. Even in older men, where the usefulness has been questioned (38) and gynaecomastia has been suggested to be a normal physiological change (39), we often detected a treatable underlying cause. The age of men in whom we detected an underlying cause for gynaecomastia was substantially higher than those in whom the reason remained unexplained. Based on our experience, we propose that the examination procedure can be done in structured and simple setup as illustrated in Fig. 3.

Figure 3
Figure 3

Flow chart displaying a comprehensible clinical and biochemical work-up of adult men presenting with breast development.

Citation: European Journal of Endocrinology 176, 5; 10.1530/EJE-16-0643

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Funding

Support from the Research Fund of Rigshospitalet was given to M G M (grant no. 9595-33563), A J U (grant no. 9615.05.8.87) and N J (grant no. R42-A1326).

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  • View in gallery

    Pie chart showing the distribution of underlying causes of gynaecomastia with adult debut in men with no substance abuse.

  • View in gallery

    (A, B and C) Testosterone (tT), free testosterone (cFT) and LH according to age in men with primary (red), secondary (green) and mixed (red/green) testosterone deficiency and Klinefelter syndrome (blue) compared to mean and ±2 s.d. of a normal material of healthy Danish men. (D and E) Ratios of testosterone (tT) and free testosterone (cFT) according to LH in men with primary (red), secondary (green) and mixed (red/green) testosterone deficiency and Klinefelter syndrome (blue). 95% of healthy Danish adult men are on the left side of the black line.

  • View in gallery

    Flow chart displaying a comprehensible clinical and biochemical work-up of adult men presenting with breast development.

  • 1

    BraunsteinGD.Gynecomastia. New England Journal of Medicine1993328490495. (doi:10.1056/NEJM199302183280708)

  • 2

    BraunsteinGD.Clinical practice. Gynecomastia. New England Journal of Medicine200735712291237. (doi:10.1056/NEJMcp070677)

  • 3

    ChanWBYeungVTChowCCSoWYCockramCS.Gynaecomastia as a presenting feature of thyrotoxicosis. Postgraduate Medical Journal199975229231. (doi:10.1136/pgmj.75.882.229)

    • Search Google Scholar
    • Export Citation
  • 4

    AhmedMKanjiABegumT.Gynaecomastia: an unusual presenting symptom of bladder cancer.BMJ Case Reports2015. (doi:10.1136/bcr-2015-210649)

  • 5

    KimIYoungRHScullyRE.Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature. American Journal of Surgical Pathology19859177192. (doi:10.1097/00000478-198503000-00002)

    • Search Google Scholar
    • Export Citation
  • 6

    RussoJRussoIH.Development of the human breast. Maturitas200449215. (doi:10.1016/j.maturitas.2004.04.011)

  • 7

    MieritzMGRakêtLLHagenCPNielsenJETalmanM-LMPetersenJHSommerSHMainKMJørgensenNJuulA.A longitudinal study of growth, sex steroids, and IGF-1 in boys with physiological gynecomastia. Journal of Clinical Endocrinology and Metabolism201510037523759. (doi:10.1210/jc.2015-2836)

    • Search Google Scholar
    • Export Citation
  • 8

    HellmannPChristiansenPJohannsenTHMainKMDunoMJuulA.Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia. Archives of Disease in Childhood201297403409. (doi:10.1136/archdischild-2011-300584)

    • Search Google Scholar
    • Export Citation
  • 9

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