madman
Super Moderator
Management of Gynecomastia and Male Benign Diseases (2022)
Manish M. Karamchandani, MD, Gabriel De La Cruz Ku, MD, Bradford L. Sokol, BS, Abhishek Chatterjee, MD MBA, Christopher Homsy, MD
GYNECOMASTIA
Definition
Gynecomastia is the benign enlargement of the male breast due to the increased proliferation of glandular tissue (ie, ductal hyperplasia).1,2 Gynecomastia should be differentiated from pseudogynecomastia (lipomastia), which is an enlargement of the male breast due to adipose tissue hypertrophy, without glandular involvement.1,2 Gynecomastia is thought to develop in response to a hormonal shift in the balance between estrogens and androgens that favors a relative increase in estrogens.1–3 The causes of the hormonal flux seen in gynecomastia are highly variable and may be physiologic or pathologic in nature.
Epidemiology
Physiologic gynecomastia is generally observed in 3 distinct age groups within the larger male population: neonates, adolescents, and older adults. Neonatal gynecomastia is thought to be the result of exposure to high concentrations of maternal estrogens and is observed in 60% to 90% of the newborn male population.2,4 Neonatal gynecomastia is typically self-limiting, resolving within 2 to 3 weeks after delivery.4 Pubertal gynecomastia is estimated to have a prevalence anywhere between 22% and 69% in adolescent boys with most cases occurring between ages 13 and 14 after the onset of testicular development.4–7 Lack of consistency regarding the size of palpable glandular tissue required for diagnosis may explain the wide range in reported prevalence among adolescents.2,8 Approximately 95% to 97% of pubertal gynecomastia cases will resolve without treatment within 18 months of initial discovery.1,4 Persistent pubertal gynecomastia accounts for approximately 25% of all cases of gynecomastia.9
Gynecomastia in older adults is highly prevalent and may affect as many as 36% to 57% of men in this age group.4,10–12 Unlike children and younger adults, gynecomastia in older adults is more associated with pathologic causes. Pathologic gynecomastia has been linked to numerous pathologic conditions including cirrhosis, malnutrition, drugs, hypogonadism, testicular tumors, hyperthyroidism, and chronic kidney disease.1,2 Approximately 58% of all cases of adult gynecomastia are idiopathic.2,9
Pathophysiology
The basic underlying mechanism responsible for the proliferation of glandular tissue in the breast is commonly thought to be an increase in the relative estrogen-to-androgen ratio, which may occur by either increased estrogen or decreased androgen availability to breast tissue.1,2 Androgens have an inhibitory effect on glandular development, whereas estrogens stimulate its growth. Factors that contribute to the overall estrogen/androgen environment in breast tissue include the initial production of testosterone and estrogen by the testes as well as the peripheral conversion of androgens to estrogens by the enzyme aromatase primarily in adipose tissue.1,2 Additionally, the serum concentration of sex hormone-binding globulin (SHBG) and the intactness of the androgen receptor pathways that lead to gene activation and transcription can alter the relative availability of estrogens and androgens under certain circumstances.1,2
*Gynecomastia as a result of pharmacologic intervention may comprise upward of 10% to 25% of all reported cases.15 Drugs strongly associated with gynecomastia including spironolactone, cimetidine, ketoconazole, human growth hormone, estrogens, human chorionic gonadotropin (hCG), antiandrogens, gonadotropin-releasing hormone agonists, 5-a reductase inhibitors.15 Other drugs that may also be associated with gynecomastia are risperidone, verapamil, nifedipine, omeprazole, alkylating agents, efavirenz, anabolic steroids, alcohol, marijuana, and opioids.9,15 All of these drugs are thought to either directly or indirectly affect the relative estrogen to androgen availability in breast tissue. Additionally, case reports of topical products containing lavender and tea tree oils may suggest an association of such products with the development of gynecomastia.16
*Pathologic conditions that may cause gynecomastia to include cirrhosis, malnutrition, hypogonadism (primary and secondary), Klinefelter syndrome, testicular tumors (Leydig and Sertoli cell varieties), hCG-secreting tumors, hyperthyroidism, and chronic kidney disease.1,2 More commonly, increased adipose tissue as seen in obesity and aging may upregulate the enzyme aromatase and contribute to the development of gynecomastia in these populations.1,2 It is important to keep in mind that most gynecomastia cases are idiopathic and may result from the interaction of multiple mechanisms.2,9
Workup and Diagnosis
The workup and diagnosis of gynecomastia can be challenging, with 25% to 58% of cases having no clear cause.1,2,9 As with other breast masses, workup begins with a thorough history elucidating when the growth was first detected, for how long, how fast it has grown, and associated symptoms such as pain, skin changes, nipple discharge, and weight gain or loss. It is also important to conduct a complete review of systems to detect causes such as endocrine, renal, or liver pathologic condition.17 The patient’s medications and nonprescription drug use (alcohol, tobacco, marijuana, testosterone, anabolic steroids, dietary supplements, and so forth) should also be reviewed.
Physical examination is performed with the patient both in a seated, upright position, and in the supine position.18 Breast tissue should be examined in a consistent, methodical fashion using the thumb and forefinger, ensuring that all areas of the breast are palpated. It is important to note the laterality, texture of tissue, location, tenderness, and if there are any palpable lymph nodes. Gynecomastia should be bilateral, glandular (rubbery), located underneath the nipple-areolar complex (NAC), nontender, and without associated discharge or palpable lymph nodes.17,18 If the patient presents in the early, growth phase of gynecomastia they may report tenderness. Additionally, some patients may also present with unilateral or asymmetric gynecomastia.11 In comparison, male breast cancer will commonly be unilateral and can be firm, tender, located away from the NAC, and associated with discharge or nipple retraction.1 The remainder of the physical examination should be tailored to the patient’s history, potentially consisting of a thyroid examination, assessing for liver and kidney disease, secondary sexual development, and any testicular mass or enlargement because these positive findings can help establish the cause remainder of the physical examination should be tailored to the patient’s history, potentially consisting of a thyroid examination, assessing for liver and kidney disease, secondary sexual development, and any testicular mass or enlargement because these positive findings can help establish the cause.
Laboratory evaluation should be guided by the history and physical examination findings. Thyroid, renal, and hepatic function tests should be obtained, as should serum levels of testosterone, prolactin, follicle-stimulating hormone, and luteinizing hormone.17,19,20 Although not a common cause of gynecomastia, hyperprolactinemia can be evaluated with serum prolactin.21 If there is a concern for malignancy-associated gynecomastia, serum levels of estrogen, hCG, dehydroepiandrosterone, and urinary 17-ketosteroids should also be obtained. Karyotype testing can also be performed if there is a concern for Klinefelter syndrome.19
*Contrary to the workup of female breast masses, routine mammography and breast ultrasonography is not recommended unless there is suspicion of breast cancer or unilateral breast enlargement is present, in which case it is appropriate to perform mammography and ultrasound, and if positive, core needle biopsy (CNB).17,22–24 If there is a concern for a distant tumor or malignancy as the cause, then testicular ultrasound, and abdominal and/or chest computed tomography (CT) should be obtained.
Medical Treatment
Medical management of gynecomastia should be centered around the physical examination, imaging/biopsy, and laboratory findings. Underlying conditions such as malignancy or endocrine disorders should be addressed first because the resolution of the condition can reduce the amount of glandular tissue. Offending medications and drugs should be discontinued when possible. For idiopathic and pubertal cases, selective estrogen receptor modulator (SERM) therapy with raloxifene and tamoxifen can be effective.18,25 SERM therapy can also be trialed in patients who have refractory gynecomastia in which the underlying cause has been treated. Aromatase inhibitor therapy can also be useful in the treatment of true gynecomastia. Anastrozole has been found to be effective in pubertal gynecomastia18; however, in adults, it has been found to have little to no effect.26 Testosterone has been reported to be successful in cases of hypogonadism27; however, it may increase gynecomastia rather than decrease the amount of tissue, particularly if the patient is eugonadal.
In situations where the offending medication cannot be discontinued, such as with androgen deprivation therapy for prostate cancer, treatment with tamoxifen or raloxifene together with radiation has been found to significantly reduce gynecomastia.28,29
Most cases of gynecomastia are benign and self-limiting; however, if gynecomastia has been present for greater than 12 months, it is unlikely that it will resolve with discontinuation of offending medications or with medical treatment because the glandular tissue has likely developed irreversible fibrosis and hyalinization.17 In these scenarios, surgical excision by an experienced plastic surgeon is the most effective treatment. It is important to note that gynecomastia itself is a benign condition and does not need treatment unless there are aesthetic and psychological reasons for pursuing treatment.
Surgical Management
The most effective treatment of gynecomastia is surgery. However, as stated above, before consideration of any surgery, it is necessary that every patient has a complete medical and physical evaluation, hormone levels, review of medications and supplements, ultrasound, and ruling out any other systemic diseases.21,30
Surgical treatment is typically reserved for patients with long-lasting gynecomastia without spontaneous regression or refractory to medical treatment, usually after 6 months to 1 year of observation since the initial presentation in adults, and up to 2 years in pubertal patients.30–32 Surgery is routinely performed on an outpatient basis. Several surgical techniques and combinations have been described that depend on the grade of gynecomastia.33 The Simon classification is the most used, followed by the Rohrich classification.32,34 The Simon classification places emphasis on the degree of enlargement and presence of excess skin, whereas the Rohrich classification places emphasis on the degree of enlargement and ptosis while also differentiating on the type of tissue present. (Tables 1 and 2)
Surgical procedures
The major principle of gynecomastia surgery is restoring the chest shape with minimal scar.35 Although there are many surgical techniques described in the literature, the most commonly used technique is the skin-sparing mastectomy.36
*Outcomes and complications
OTHER BENIGN BREAST DISEASE
Breast Cysts
Breast cysts are fluid-filled sacs within the breast and occur very rarely in men.
Lipomas
Lipomas are benign tumors of mature white fat cells contained within a fibrous capsule and are the most common neoplasm of the male breast.62–64
Pseudoangiomatous Stromal Hyperplasia
Pseudoangiomatous stromal hyperplasia (PASH) is another benign condition that can be seen in men. PASH is a proliferation of mesenchymal breast tissue, specifically stromal myofibroblasts, due to hormonal stimulation.68
Breast Infections
Infections of the breast are yet another condition that can affect men. Types of infections can include cellulitis, breast abscess, and skin abscess overlying the breast.
Seromas
A seroma is a subcutaneous collection of fluid comprising a mixture of plasma, lymph, and inflammatory exudate and is a common complication associated with many surgical procedures.87,88
Manish M. Karamchandani, MD, Gabriel De La Cruz Ku, MD, Bradford L. Sokol, BS, Abhishek Chatterjee, MD MBA, Christopher Homsy, MD
GYNECOMASTIA
Definition
Gynecomastia is the benign enlargement of the male breast due to the increased proliferation of glandular tissue (ie, ductal hyperplasia).1,2 Gynecomastia should be differentiated from pseudogynecomastia (lipomastia), which is an enlargement of the male breast due to adipose tissue hypertrophy, without glandular involvement.1,2 Gynecomastia is thought to develop in response to a hormonal shift in the balance between estrogens and androgens that favors a relative increase in estrogens.1–3 The causes of the hormonal flux seen in gynecomastia are highly variable and may be physiologic or pathologic in nature.
Epidemiology
Physiologic gynecomastia is generally observed in 3 distinct age groups within the larger male population: neonates, adolescents, and older adults. Neonatal gynecomastia is thought to be the result of exposure to high concentrations of maternal estrogens and is observed in 60% to 90% of the newborn male population.2,4 Neonatal gynecomastia is typically self-limiting, resolving within 2 to 3 weeks after delivery.4 Pubertal gynecomastia is estimated to have a prevalence anywhere between 22% and 69% in adolescent boys with most cases occurring between ages 13 and 14 after the onset of testicular development.4–7 Lack of consistency regarding the size of palpable glandular tissue required for diagnosis may explain the wide range in reported prevalence among adolescents.2,8 Approximately 95% to 97% of pubertal gynecomastia cases will resolve without treatment within 18 months of initial discovery.1,4 Persistent pubertal gynecomastia accounts for approximately 25% of all cases of gynecomastia.9
Gynecomastia in older adults is highly prevalent and may affect as many as 36% to 57% of men in this age group.4,10–12 Unlike children and younger adults, gynecomastia in older adults is more associated with pathologic causes. Pathologic gynecomastia has been linked to numerous pathologic conditions including cirrhosis, malnutrition, drugs, hypogonadism, testicular tumors, hyperthyroidism, and chronic kidney disease.1,2 Approximately 58% of all cases of adult gynecomastia are idiopathic.2,9
Pathophysiology
The basic underlying mechanism responsible for the proliferation of glandular tissue in the breast is commonly thought to be an increase in the relative estrogen-to-androgen ratio, which may occur by either increased estrogen or decreased androgen availability to breast tissue.1,2 Androgens have an inhibitory effect on glandular development, whereas estrogens stimulate its growth. Factors that contribute to the overall estrogen/androgen environment in breast tissue include the initial production of testosterone and estrogen by the testes as well as the peripheral conversion of androgens to estrogens by the enzyme aromatase primarily in adipose tissue.1,2 Additionally, the serum concentration of sex hormone-binding globulin (SHBG) and the intactness of the androgen receptor pathways that lead to gene activation and transcription can alter the relative availability of estrogens and androgens under certain circumstances.1,2
*Gynecomastia as a result of pharmacologic intervention may comprise upward of 10% to 25% of all reported cases.15 Drugs strongly associated with gynecomastia including spironolactone, cimetidine, ketoconazole, human growth hormone, estrogens, human chorionic gonadotropin (hCG), antiandrogens, gonadotropin-releasing hormone agonists, 5-a reductase inhibitors.15 Other drugs that may also be associated with gynecomastia are risperidone, verapamil, nifedipine, omeprazole, alkylating agents, efavirenz, anabolic steroids, alcohol, marijuana, and opioids.9,15 All of these drugs are thought to either directly or indirectly affect the relative estrogen to androgen availability in breast tissue. Additionally, case reports of topical products containing lavender and tea tree oils may suggest an association of such products with the development of gynecomastia.16
*Pathologic conditions that may cause gynecomastia to include cirrhosis, malnutrition, hypogonadism (primary and secondary), Klinefelter syndrome, testicular tumors (Leydig and Sertoli cell varieties), hCG-secreting tumors, hyperthyroidism, and chronic kidney disease.1,2 More commonly, increased adipose tissue as seen in obesity and aging may upregulate the enzyme aromatase and contribute to the development of gynecomastia in these populations.1,2 It is important to keep in mind that most gynecomastia cases are idiopathic and may result from the interaction of multiple mechanisms.2,9
Workup and Diagnosis
The workup and diagnosis of gynecomastia can be challenging, with 25% to 58% of cases having no clear cause.1,2,9 As with other breast masses, workup begins with a thorough history elucidating when the growth was first detected, for how long, how fast it has grown, and associated symptoms such as pain, skin changes, nipple discharge, and weight gain or loss. It is also important to conduct a complete review of systems to detect causes such as endocrine, renal, or liver pathologic condition.17 The patient’s medications and nonprescription drug use (alcohol, tobacco, marijuana, testosterone, anabolic steroids, dietary supplements, and so forth) should also be reviewed.
Physical examination is performed with the patient both in a seated, upright position, and in the supine position.18 Breast tissue should be examined in a consistent, methodical fashion using the thumb and forefinger, ensuring that all areas of the breast are palpated. It is important to note the laterality, texture of tissue, location, tenderness, and if there are any palpable lymph nodes. Gynecomastia should be bilateral, glandular (rubbery), located underneath the nipple-areolar complex (NAC), nontender, and without associated discharge or palpable lymph nodes.17,18 If the patient presents in the early, growth phase of gynecomastia they may report tenderness. Additionally, some patients may also present with unilateral or asymmetric gynecomastia.11 In comparison, male breast cancer will commonly be unilateral and can be firm, tender, located away from the NAC, and associated with discharge or nipple retraction.1 The remainder of the physical examination should be tailored to the patient’s history, potentially consisting of a thyroid examination, assessing for liver and kidney disease, secondary sexual development, and any testicular mass or enlargement because these positive findings can help establish the cause remainder of the physical examination should be tailored to the patient’s history, potentially consisting of a thyroid examination, assessing for liver and kidney disease, secondary sexual development, and any testicular mass or enlargement because these positive findings can help establish the cause.
Laboratory evaluation should be guided by the history and physical examination findings. Thyroid, renal, and hepatic function tests should be obtained, as should serum levels of testosterone, prolactin, follicle-stimulating hormone, and luteinizing hormone.17,19,20 Although not a common cause of gynecomastia, hyperprolactinemia can be evaluated with serum prolactin.21 If there is a concern for malignancy-associated gynecomastia, serum levels of estrogen, hCG, dehydroepiandrosterone, and urinary 17-ketosteroids should also be obtained. Karyotype testing can also be performed if there is a concern for Klinefelter syndrome.19
*Contrary to the workup of female breast masses, routine mammography and breast ultrasonography is not recommended unless there is suspicion of breast cancer or unilateral breast enlargement is present, in which case it is appropriate to perform mammography and ultrasound, and if positive, core needle biopsy (CNB).17,22–24 If there is a concern for a distant tumor or malignancy as the cause, then testicular ultrasound, and abdominal and/or chest computed tomography (CT) should be obtained.
Medical Treatment
Medical management of gynecomastia should be centered around the physical examination, imaging/biopsy, and laboratory findings. Underlying conditions such as malignancy or endocrine disorders should be addressed first because the resolution of the condition can reduce the amount of glandular tissue. Offending medications and drugs should be discontinued when possible. For idiopathic and pubertal cases, selective estrogen receptor modulator (SERM) therapy with raloxifene and tamoxifen can be effective.18,25 SERM therapy can also be trialed in patients who have refractory gynecomastia in which the underlying cause has been treated. Aromatase inhibitor therapy can also be useful in the treatment of true gynecomastia. Anastrozole has been found to be effective in pubertal gynecomastia18; however, in adults, it has been found to have little to no effect.26 Testosterone has been reported to be successful in cases of hypogonadism27; however, it may increase gynecomastia rather than decrease the amount of tissue, particularly if the patient is eugonadal.
In situations where the offending medication cannot be discontinued, such as with androgen deprivation therapy for prostate cancer, treatment with tamoxifen or raloxifene together with radiation has been found to significantly reduce gynecomastia.28,29
Most cases of gynecomastia are benign and self-limiting; however, if gynecomastia has been present for greater than 12 months, it is unlikely that it will resolve with discontinuation of offending medications or with medical treatment because the glandular tissue has likely developed irreversible fibrosis and hyalinization.17 In these scenarios, surgical excision by an experienced plastic surgeon is the most effective treatment. It is important to note that gynecomastia itself is a benign condition and does not need treatment unless there are aesthetic and psychological reasons for pursuing treatment.
Surgical Management
The most effective treatment of gynecomastia is surgery. However, as stated above, before consideration of any surgery, it is necessary that every patient has a complete medical and physical evaluation, hormone levels, review of medications and supplements, ultrasound, and ruling out any other systemic diseases.21,30
Surgical treatment is typically reserved for patients with long-lasting gynecomastia without spontaneous regression or refractory to medical treatment, usually after 6 months to 1 year of observation since the initial presentation in adults, and up to 2 years in pubertal patients.30–32 Surgery is routinely performed on an outpatient basis. Several surgical techniques and combinations have been described that depend on the grade of gynecomastia.33 The Simon classification is the most used, followed by the Rohrich classification.32,34 The Simon classification places emphasis on the degree of enlargement and presence of excess skin, whereas the Rohrich classification places emphasis on the degree of enlargement and ptosis while also differentiating on the type of tissue present. (Tables 1 and 2)
Surgical procedures
The major principle of gynecomastia surgery is restoring the chest shape with minimal scar.35 Although there are many surgical techniques described in the literature, the most commonly used technique is the skin-sparing mastectomy.36
*Outcomes and complications
OTHER BENIGN BREAST DISEASE
Breast Cysts
Breast cysts are fluid-filled sacs within the breast and occur very rarely in men.
Lipomas
Lipomas are benign tumors of mature white fat cells contained within a fibrous capsule and are the most common neoplasm of the male breast.62–64
Pseudoangiomatous Stromal Hyperplasia
Pseudoangiomatous stromal hyperplasia (PASH) is another benign condition that can be seen in men. PASH is a proliferation of mesenchymal breast tissue, specifically stromal myofibroblasts, due to hormonal stimulation.68
Breast Infections
Infections of the breast are yet another condition that can affect men. Types of infections can include cellulitis, breast abscess, and skin abscess overlying the breast.
Seromas
A seroma is a subcutaneous collection of fluid comprising a mixture of plasma, lymph, and inflammatory exudate and is a common complication associated with many surgical procedures.87,88
