madman
Super Moderator
An Approach to Gynecomastia in Primary Care Clinics (2022)
Kavya Bharathidasan, MD, Jordan Curl, BS, Vedesh Kumar Babu, MD, Shaili Felton, MD, and Kenneth Nugent, MD
Abstract
Gynecomastia is a more common finding in primary care clinics than is recognized. Because this finding can be easily overlooked, appropriate investigation and management often are missed. The workup of gynecomastia is highly individualized, based on the patient’s presentation and related factors. It should be guided by thorough history taking and physical examination. Unless the patient has associated symptoms, or there is suspicion of an underlying clinical disorder causing the gynecomastia, the patient need not be investigated further. A breast ultrasound is not routinely recommended. Gynecomastia is a benign finding that will spontaneously regress in most patients; however, patients who are concerned with their physical appearance can be treated either medically or surgically. Patients who have had gynecomastia for more than 1 year tend to have fibrosis, which may be more difficult to treat. Management of gynecomastia is highly patient-centered, following a detailed discussion about treatment goals, and should be started early. Gynecomastia is not considered a premalignant condition; routine screening is not cost-effective, and imaging studies should be pursued only if physical examination findings suggest malignancy.
Gynecomastia is a more common finding in primary care clinics than is recognized. Approximately 40% to 55% of men have gynecomastia on autopsy.1 Because this finding can be easily overlooked, appropriate workup and management often are missed. According to the American Society of Andrology and European Academy of Andrology guidelines for the management of gynecomastia published in 2019, 45% to 50% of cases are caused by an underlying pathology when properly investigated.2 Based on age at onset, gynecomastia can be loosely divided into infantile, prepubertal, adult-onset, and senile. In this article, we focus on breast swelling in the adult and geriatric populations, when a case of gynecomastia requires more workup, which laboratory tests and imaging studies should be ordered, and who should be treated. For this discussion, we classify patients with gynecomastia into three broad categories: patient A, with no medication history or pertinent medical history other than concern over his breast swelling; patient B, who has an underlying medical disorder and has noticed a new onset increase in breast size; and patient C, who presents for a well visit with no complaints or medical history of gynecomastia and was incidentally found to have enlarged breasts on examination.
*Epidemiology
*Etiology
The pathophysiological basis for gynecomastia usually involves a hormonal imbalance, resulting in either excess estrogens or a deficiency of androgens. Estrogens promote the proliferation of breast tissue, whereas androgens counteract this process. It is important to note that gynecomastia can occur even in males with normal testosterone levels when there are excess estrogens. Endogenous causes include disease states affecting the metabolism of estrogens, increased sensitivity of the breast tissue to circulating estrogens, decreased sensitivity to androgens, impaired production/release of androgens, increased binding of testosterone to sex hormone–binding globulin, and/or increased peripheral aromatization of androgens into estradiol. Hyperprolactinemia is a commonly observed cause of gynecomastia.5,7 High prolactin levels suppress gonadotropic-releasing hormone, which leads to central hypogonadism and alters the androgen: estrogen ratio. Adolescent gynecomastia is a normal physiological phenomenon during puberty in which surges of luteinizing hormone, follicle-stimulating hormone, growth hormone, and insulin-like growth factor 1 cause an initial increase in estrogen levels followed by an increase in testosterone levels. As androgen levels rise and the testosterone: estrogen ratio is restored, there is spontaneous regression of breast hyperplasia associated with virilization.2 Senile gynecomastia results from the physiologic decline in androgens and increase in aromatase activity with increasing age.8 Exogenous causes can be dietary or medication-related through similar mechanisms as endogenous causes acting either directly or indirectly (Table). Drug-induced gynecomastia accounts for 10% to 25% of all cases of gynecomastia.9 Treatment with gonadotropic-releasing hormone antagonists in androgen deprivation therapy, such as with leuprolide in the management of prostate cancer, is associated with hypogonadism and subsequently can cause breast enlargement. Not all patients with true gynecomastia have an attributable cause because roughly 25% of cases are idiopathic.10,11
Breast enlargement can be unilateral or bilateral and asymptomatic or painful. The time of onset and changes since onset should be reviewed carefully during history taking. Rarely, pubertal gynecomastia can persist into adulthood and is called essential gynecomastia.9
*Diagnosis
After gynecomastia is suspected, the first step is to differentiate true gynecomastia from pseudogynecomastia (lipomastia or adipomastia) (Fig. 1). On physical examination, the two can be distinguished by palpating the retro-areolar area between the examining index finger and thumb in a pincer grasp to identify the consistency of the breast tissue. If it is smooth and resembles the consistency of adipose tissue, then these findings are consistent with pseudogynecomastia. Glandular tissue is more suggestive of true gynecomastia and is characterized as a soft discoidal lesion below the nipple, usually 2 to 4 cm in diameter.10 Other important physical findings include tenderness, discharge, mobility, and skin changes over the swelling. A fixed hard mass with irregular borders, bloody discharge, ulceration or skin changes (peau d’orange), a retracted nipple, and associated lymphadenopathy are highly suspicious for malignancy. Galactorrhea can occur in patients with gynecomastia secondary to hyperprolactinemia.
The workup of gynecomastia is highly individualized based on the patient’s presentation and related factors. It should be guided by thorough history taking and physical examination. Unless the patient has pain or associated symptoms or there is suspicion of underlying disease causing the gynecomastia, the patient need not be investigated further. Although obesity increases the incidence of pseudogynecomastia because of excess adipose deposition, high circulating levels of leptin also promote aromatization of androgens to estrogens, causing true gynecomastia.11
With patient A, if he is obese, then lifestyle changes and weight reduction can be tried before a workup is started. Otherwise, the treating physician can reassure the patient and follow up biannually to monitor regression. The psychological component of gynecomastia should be addressed during the encounter because patients often are embarrassed about their body image and fear developing breast cancer in the future.11 For patients B and C, a thorough review of medications is essential before investigating for underlying medical conditions. The most prescribed medications in primary care clinics that can cause gynecomastia are cimetidine, spironolactone, ketoconazole, and phenytoin (Table). The most common drugs known to cause gynecomastia in nearly 40% to 70% of patients are testosterone-lowering medications, such as bicalutamide, flutamide, or nilutamide, used to treat prostate cancer.9
A thorough dietary history should be obtained along with a history of over-the-counter supplement use. Increased consumption of soy (greater than 300 mg/day) has been associated with gynecomastia because of phytoestrogens; other herbal remedies such as ginseng and dong quai also can cause gynecomastia.11,12 Environmental estrogens from paints and cleaning supplies and consumption of excess poultry treated with diethylstilbestrol have been described to cause gynecomastia.10 Fifty percent of bodybuilders taking high-dose anabolic steroids develop gynecomastia as a result of peripheral aromatization.13 Use of anabolic steroids, marijuana, heroin, or amphetamines can lead to irreversible gynecomastia.11
If no potential offending agent is identified, then the next step is to screen for hyperthyroidism (thyroid function tests), chronic liver disease (liver enzymes), end-stage renal disease (kidney function tests), and testicular tumors (by tumor markers such as β-human chorionic gonadotropin and α-fetoprotein for germ cell tumors). Feminizing or estrogen-producing tumors can present with breast enlargement and proliferation. If a mass cannot be found on examination, then a testicular ultrasound can be ordered to screen for tumors that are too small to be palpated. Approximately 7% to 11% of men with testicular tumors develop gynecomastia before a mass is physically palpable.14 Sudden, painful gynecomastia can be a helpful clue in the diagnosis of recurrent testicular cancer.9 An abdominal CT scan or pituitary magnetic resonance image can detect adrenal or pituitary tumors if clinically suspected.
A hormonal workup can be performed if the preliminary laboratory values are inconclusive. Hypogonadism should be ruled out by testing for serum levels of morning testosterone, morning luteinizing hormone, follicle-stimulating hormone, and estradiol. Other tests of slightly lesser significance include sex hormone–binding globulin and prolactin. Hyperprolactinemia has been identified in some patients with gynecomastia, but most patients with elevated prolactin do not tend to develop enlarged breasts. High prolactin levels can inhibit luteinizing hormone and follicle-stimulating hormone, which in turn causes hypogonadism leading to gynecomastia.9
Occasionally, the patient has preexisting conditions, such as Klinefelter syndrome, which alerts the clinician to this possible diagnosis. The human immunodeficiency virus also has been associated with gynecomastia. Although it is unclear whether antiretroviral drugs contribute to the pathogenesis, hypogonadism caused by the disease process is a plausible explanation.9 Evans et al describe a direct mammotropic effect of antiretroviral drugs on breast tissue.15
A breast ultrasound is not routinely recommended and does not influence the course of management unless the patient presents with symptoms or signs suspicious of malignancy. Ultrasonography usually reveals a hypoechoic irregular mass without associated axillary adenopathy (Fig. 2).16 Mammography and fine-needle aspiration cytology/biopsy can help diagnose breast cancer but are not essential for every patient who presents with gynecomastia. Normal histological findings show dilated ducts with periductal fibrosis, stromal hyalinization, and increased subareolar fat. If the breast enlargement is associated with pain and tenderness, then hyperplasia of the ductal epithelium with infiltration by inflammatory cells may occur.17 Patients who have had gynecomastia for more than 1 year tend to have more fibrous tissue, which may be difficult to treat with medical management.
*Treatment
*Gynecomastia and Breast Cancer
Most patients with gynecomastia will not develop breast cancer in their lifetimes. Conditions associated with a higher risk include Klinefelter syndrome; a history of cryptorchidism, orchitis, or orchiectomy; a family history of breast cancer, particularly with BRCA1/BRCA2 mutations; and previous radiation exposure. Men who have a BRCA2 gene mutation are at an 8% to 10% increased risk of developing male breast cancer.22 Sub-Saharan Africans and Ashkenazi Jews also have a slightly higher risk than the general population.23 Patients with Klinefelter syndrome have a 10- to 30-fold increased risk of developing breast cancer.10,11
Conclusions
Public awareness and clinical research on gynecomastia and male breast cancer have increased significantly during the past several decades. The number of yearly breast reduction surgeries performed for gynecomastia has increased by 29% from 2000 to 2014.28 A sense of uneasiness or hesitancy seems to prevail in the primary care physician’s practice when he or she encounters a patient with gynecomastia, however. Given the number of underlying conditions that could present as gynecomastia, it is essential to investigate when appropriate to avoid missing significant diagnoses, such as testicular cancer. It also is the responsibility of the primary care physician to openly discuss concerns regarding body image and possible psychosocial stressors and presently available treatment modalities to the patient.
Kavya Bharathidasan, MD, Jordan Curl, BS, Vedesh Kumar Babu, MD, Shaili Felton, MD, and Kenneth Nugent, MD
Abstract
Gynecomastia is a more common finding in primary care clinics than is recognized. Because this finding can be easily overlooked, appropriate investigation and management often are missed. The workup of gynecomastia is highly individualized, based on the patient’s presentation and related factors. It should be guided by thorough history taking and physical examination. Unless the patient has associated symptoms, or there is suspicion of an underlying clinical disorder causing the gynecomastia, the patient need not be investigated further. A breast ultrasound is not routinely recommended. Gynecomastia is a benign finding that will spontaneously regress in most patients; however, patients who are concerned with their physical appearance can be treated either medically or surgically. Patients who have had gynecomastia for more than 1 year tend to have fibrosis, which may be more difficult to treat. Management of gynecomastia is highly patient-centered, following a detailed discussion about treatment goals, and should be started early. Gynecomastia is not considered a premalignant condition; routine screening is not cost-effective, and imaging studies should be pursued only if physical examination findings suggest malignancy.
Gynecomastia is a more common finding in primary care clinics than is recognized. Approximately 40% to 55% of men have gynecomastia on autopsy.1 Because this finding can be easily overlooked, appropriate workup and management often are missed. According to the American Society of Andrology and European Academy of Andrology guidelines for the management of gynecomastia published in 2019, 45% to 50% of cases are caused by an underlying pathology when properly investigated.2 Based on age at onset, gynecomastia can be loosely divided into infantile, prepubertal, adult-onset, and senile. In this article, we focus on breast swelling in the adult and geriatric populations, when a case of gynecomastia requires more workup, which laboratory tests and imaging studies should be ordered, and who should be treated. For this discussion, we classify patients with gynecomastia into three broad categories: patient A, with no medication history or pertinent medical history other than concern over his breast swelling; patient B, who has an underlying medical disorder and has noticed a new onset increase in breast size; and patient C, who presents for a well visit with no complaints or medical history of gynecomastia and was incidentally found to have enlarged breasts on examination.
*Epidemiology
*Etiology
The pathophysiological basis for gynecomastia usually involves a hormonal imbalance, resulting in either excess estrogens or a deficiency of androgens. Estrogens promote the proliferation of breast tissue, whereas androgens counteract this process. It is important to note that gynecomastia can occur even in males with normal testosterone levels when there are excess estrogens. Endogenous causes include disease states affecting the metabolism of estrogens, increased sensitivity of the breast tissue to circulating estrogens, decreased sensitivity to androgens, impaired production/release of androgens, increased binding of testosterone to sex hormone–binding globulin, and/or increased peripheral aromatization of androgens into estradiol. Hyperprolactinemia is a commonly observed cause of gynecomastia.5,7 High prolactin levels suppress gonadotropic-releasing hormone, which leads to central hypogonadism and alters the androgen: estrogen ratio. Adolescent gynecomastia is a normal physiological phenomenon during puberty in which surges of luteinizing hormone, follicle-stimulating hormone, growth hormone, and insulin-like growth factor 1 cause an initial increase in estrogen levels followed by an increase in testosterone levels. As androgen levels rise and the testosterone: estrogen ratio is restored, there is spontaneous regression of breast hyperplasia associated with virilization.2 Senile gynecomastia results from the physiologic decline in androgens and increase in aromatase activity with increasing age.8 Exogenous causes can be dietary or medication-related through similar mechanisms as endogenous causes acting either directly or indirectly (Table). Drug-induced gynecomastia accounts for 10% to 25% of all cases of gynecomastia.9 Treatment with gonadotropic-releasing hormone antagonists in androgen deprivation therapy, such as with leuprolide in the management of prostate cancer, is associated with hypogonadism and subsequently can cause breast enlargement. Not all patients with true gynecomastia have an attributable cause because roughly 25% of cases are idiopathic.10,11
Breast enlargement can be unilateral or bilateral and asymptomatic or painful. The time of onset and changes since onset should be reviewed carefully during history taking. Rarely, pubertal gynecomastia can persist into adulthood and is called essential gynecomastia.9
*Diagnosis
After gynecomastia is suspected, the first step is to differentiate true gynecomastia from pseudogynecomastia (lipomastia or adipomastia) (Fig. 1). On physical examination, the two can be distinguished by palpating the retro-areolar area between the examining index finger and thumb in a pincer grasp to identify the consistency of the breast tissue. If it is smooth and resembles the consistency of adipose tissue, then these findings are consistent with pseudogynecomastia. Glandular tissue is more suggestive of true gynecomastia and is characterized as a soft discoidal lesion below the nipple, usually 2 to 4 cm in diameter.10 Other important physical findings include tenderness, discharge, mobility, and skin changes over the swelling. A fixed hard mass with irregular borders, bloody discharge, ulceration or skin changes (peau d’orange), a retracted nipple, and associated lymphadenopathy are highly suspicious for malignancy. Galactorrhea can occur in patients with gynecomastia secondary to hyperprolactinemia.
The workup of gynecomastia is highly individualized based on the patient’s presentation and related factors. It should be guided by thorough history taking and physical examination. Unless the patient has pain or associated symptoms or there is suspicion of underlying disease causing the gynecomastia, the patient need not be investigated further. Although obesity increases the incidence of pseudogynecomastia because of excess adipose deposition, high circulating levels of leptin also promote aromatization of androgens to estrogens, causing true gynecomastia.11
With patient A, if he is obese, then lifestyle changes and weight reduction can be tried before a workup is started. Otherwise, the treating physician can reassure the patient and follow up biannually to monitor regression. The psychological component of gynecomastia should be addressed during the encounter because patients often are embarrassed about their body image and fear developing breast cancer in the future.11 For patients B and C, a thorough review of medications is essential before investigating for underlying medical conditions. The most prescribed medications in primary care clinics that can cause gynecomastia are cimetidine, spironolactone, ketoconazole, and phenytoin (Table). The most common drugs known to cause gynecomastia in nearly 40% to 70% of patients are testosterone-lowering medications, such as bicalutamide, flutamide, or nilutamide, used to treat prostate cancer.9
A thorough dietary history should be obtained along with a history of over-the-counter supplement use. Increased consumption of soy (greater than 300 mg/day) has been associated with gynecomastia because of phytoestrogens; other herbal remedies such as ginseng and dong quai also can cause gynecomastia.11,12 Environmental estrogens from paints and cleaning supplies and consumption of excess poultry treated with diethylstilbestrol have been described to cause gynecomastia.10 Fifty percent of bodybuilders taking high-dose anabolic steroids develop gynecomastia as a result of peripheral aromatization.13 Use of anabolic steroids, marijuana, heroin, or amphetamines can lead to irreversible gynecomastia.11
If no potential offending agent is identified, then the next step is to screen for hyperthyroidism (thyroid function tests), chronic liver disease (liver enzymes), end-stage renal disease (kidney function tests), and testicular tumors (by tumor markers such as β-human chorionic gonadotropin and α-fetoprotein for germ cell tumors). Feminizing or estrogen-producing tumors can present with breast enlargement and proliferation. If a mass cannot be found on examination, then a testicular ultrasound can be ordered to screen for tumors that are too small to be palpated. Approximately 7% to 11% of men with testicular tumors develop gynecomastia before a mass is physically palpable.14 Sudden, painful gynecomastia can be a helpful clue in the diagnosis of recurrent testicular cancer.9 An abdominal CT scan or pituitary magnetic resonance image can detect adrenal or pituitary tumors if clinically suspected.
A hormonal workup can be performed if the preliminary laboratory values are inconclusive. Hypogonadism should be ruled out by testing for serum levels of morning testosterone, morning luteinizing hormone, follicle-stimulating hormone, and estradiol. Other tests of slightly lesser significance include sex hormone–binding globulin and prolactin. Hyperprolactinemia has been identified in some patients with gynecomastia, but most patients with elevated prolactin do not tend to develop enlarged breasts. High prolactin levels can inhibit luteinizing hormone and follicle-stimulating hormone, which in turn causes hypogonadism leading to gynecomastia.9
Occasionally, the patient has preexisting conditions, such as Klinefelter syndrome, which alerts the clinician to this possible diagnosis. The human immunodeficiency virus also has been associated with gynecomastia. Although it is unclear whether antiretroviral drugs contribute to the pathogenesis, hypogonadism caused by the disease process is a plausible explanation.9 Evans et al describe a direct mammotropic effect of antiretroviral drugs on breast tissue.15
A breast ultrasound is not routinely recommended and does not influence the course of management unless the patient presents with symptoms or signs suspicious of malignancy. Ultrasonography usually reveals a hypoechoic irregular mass without associated axillary adenopathy (Fig. 2).16 Mammography and fine-needle aspiration cytology/biopsy can help diagnose breast cancer but are not essential for every patient who presents with gynecomastia. Normal histological findings show dilated ducts with periductal fibrosis, stromal hyalinization, and increased subareolar fat. If the breast enlargement is associated with pain and tenderness, then hyperplasia of the ductal epithelium with infiltration by inflammatory cells may occur.17 Patients who have had gynecomastia for more than 1 year tend to have more fibrous tissue, which may be difficult to treat with medical management.
*Treatment
*Gynecomastia and Breast Cancer
Most patients with gynecomastia will not develop breast cancer in their lifetimes. Conditions associated with a higher risk include Klinefelter syndrome; a history of cryptorchidism, orchitis, or orchiectomy; a family history of breast cancer, particularly with BRCA1/BRCA2 mutations; and previous radiation exposure. Men who have a BRCA2 gene mutation are at an 8% to 10% increased risk of developing male breast cancer.22 Sub-Saharan Africans and Ashkenazi Jews also have a slightly higher risk than the general population.23 Patients with Klinefelter syndrome have a 10- to 30-fold increased risk of developing breast cancer.10,11
Conclusions
Public awareness and clinical research on gynecomastia and male breast cancer have increased significantly during the past several decades. The number of yearly breast reduction surgeries performed for gynecomastia has increased by 29% from 2000 to 2014.28 A sense of uneasiness or hesitancy seems to prevail in the primary care physician’s practice when he or she encounters a patient with gynecomastia, however. Given the number of underlying conditions that could present as gynecomastia, it is essential to investigate when appropriate to avoid missing significant diagnoses, such as testicular cancer. It also is the responsibility of the primary care physician to openly discuss concerns regarding body image and possible psychosocial stressors and presently available treatment modalities to the patient.
