Gynecomastia

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Gynecomastia
Gynecomastia 001.jpg
A young adult male with significant gynecomastia
Pronunciation
SpecialtyEndocrinology, plastic surgery
Usual onsetAny age
DurationUsually up to 2 years but can be lifelong
CausesIncreased estrogen/androgen ratio (physiologic, medications, chronic kidney disease, obesity, cirrhosis, malnutrition, certain cancers)
Differential diagnosisLipomastia
TreatmentReassurance, aromatase inhibitors, SERMs, or surgery

Gynecomastia (also spelled Gynaecomastia)[a] is the abnormal non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogen and androgen.[4][5] Gynecomastia can cause significant psychological distress or unease.[6]

Gynecomastia can be normal in newborn babies due to exposure to estrogen from the mother, in adolescents going through puberty, and in older and obese men.[4] Most occurrences of gynecomastia do not require diagnostic tests.[4][5] Gynecomastia may be caused by abnormal hormone changes, any condition that leads to an increase in the ratio of estrogens/androgens such as liver disease, kidney failure, thyroid disease and some non-breast tumours. Alcohol and some drugs can also cause breast enlargement.[4][7] Other causes may include Klinefelter syndrome, metabolic dysfunction, or a natural decline in testosterone production.[4][6][8] This may occur even if the levels of estrogens and androgens are both appropriate, but the ratio is altered.[7]

Gynecomastia is the most common benign disorder of the male breast tissue and affects 35% of men, being most prevalent between the ages of 50 and 69.[5][9] It is normal for up to 70% of adolescent boys to develop gynecomastia.[6] Of these, 75% resolve within two years of onset without treatment.[10] If the condition does not resolve within 2 years, or if it causes embarrassment, pain or tenderness, treatment is warranted.[11][12] Medical treatment of gynecomastia that has persisted beyond two years is often ineffective. Gynecomastia is different from "pseudogynecomastia",[5][6] which is commonly present in men with obesity.[13][14]

Medications such as aromatase inhibitors have been found to be effective [15] and even in rare cases of gynecomastia from disorders such as aromatase excess syndrome or Peutz–Jeghers syndrome,[16] but surgical removal of the excess tissue can be needed to correct the condition.[17] In 2019, 24,123 male patients underwent the procedure in the US, accounting for a 19% increase since 2000.[18]

Definition[edit]

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogen and androgen.[4][5] Gynecomastia is different from "pseudogynecomastia",[5][6] which is defined as an excess of skin and adipose tissue in the male breasts without the development of true breast glandular tissue;[19][20] pseudogynecomastia is commonly present in men with obesity.[13][14]

Signs and symptoms[edit]

In gynecomastia there is typically enlargement of one or both breasts, symmetrically or asymmetrically, in a man. Soft, compressible, and mobile breast tissue is felt under the nipple and its surrounding skin in contrast to softer fatty tissue.[9][21] Dimpling of the skin and nipple retraction are not typical features of gynecomastia.[9] Milky discharge from the nipple is not a typical finding, but may be seen in a gynecomastic individual with a prolactin secreting tumor.[7] An increase in the diameter of the areola and asymmetry of the chest are other possible signs of gynecomastia.[22]

Men with gynecomastia may appear anxious or stressed due to concerns about its appearance and the possibility of having breast cancer.[23][24]

Causes[edit]

Gynecomastia is thought to be caused by an altered ratio of estrogens to androgens mediated by an increase in estrogen production, a decrease in androgen production, or a combination of these two factors.[7] Estrogen acts as a growth hormone to increase the size of male breast tissue.[7][23] The cause of gynecomastia is unknown in around 25% of cases.[21][24] Drugs are estimated to cause 10–25% of cases of gynecomastia.[25]

Linalool, which contains lavender, is found in the fragrance of cosmetic products and shampoos such as Pantene Pro-V.[26] Lavender and tea tree oil have been linked to gynecomastia and act as a endocrine disruptor with certain males.[27]

Certain health problems in men such as liver disease, kidney failure, or low testosterone can cause breast growth in men. Drugs and liver disease are the most common cause in adults.[28] Other medications known to cause gynecomastia include methadone; aldosterone antagonists (spironolactone and eplerenone); HIV medication; cancer chemotherapy; hormone treatment for prostate cancer; heartburn and ulcer medications; calcium channel blockers; antifungal medications such as ketoconazole; antibiotics such as metronidazole; tricyclic antidepressants such as amitriptyline; and herbals such as lavender, tea tree oil, and dong quai.[4] The insecticide phenothrin possesses antiandrogen activity and has been associated with gynecomastia.[29][30]

Physiologic[edit]

Gynecomastia of a boy going through puberty.

Both male and female newborns may show breast development at birth or in the first weeks of life.[31] During pregnancy, the placenta converts the androgenic hormones dehydroepiandrosterone (DHEA) and DHEA sulfate to the estrogenic hormones estrone and estradiol, respectively; after these estrogens are produced by the placenta, they are transferred into the baby's circulation, thereby leading to temporary gynecomastia in the baby.[23][32] In some infants neonatal milk (also known as "witch's milk") can leak from the nipples.[21] The temporary gynecomastia seen in newborn babies usually resolves after two or three weeks.[23]

Gynecomastia in adolescents usually starts between the ages of 10 and 12 and commonly goes away after 18 months.[23]

Declining testosterone levels and an increase in the level of subcutaneous fatty tissue seen as part of the normal aging process can lead to gynecomastia in older men. This is also known as senile gynecomastia.[23] Increased fatty tissue in these men leads to increased conversion of androgenic hormones such as testosterone to estrogens.[23]

When the human body is deprived of adequate nutrition, testosterone levels drop, while the adrenal glands continue to produce estrogens, thereby causing a hormonal imbalance.[23] Gynecomastia can also occur once normal nutrition is restarted (this is known as refeeding gynecomastia).[23]

Non-physiologic[edit]

Medicines[edit]

An exceptional case of extreme gynecomastia in a 63-year-old man, treated with the nonsteroidal antiandrogen flutamide for prostate cancer. (a) With flutamide; (b) after discontinuation of flutamide.[33] More than 90% of cases of gynecomastia with nonsteroidal antiandrogens including flutamide are mild to moderate.[34][35]

About 10–25% of cases are estimated to result from the use of medications, known as nonphysiologic gynecomastia.[17][24] Medications known to cause gynecomastia include cimetidine, ketoconazole, gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, 5α-reductase inhibitors such as finasteride and dutasteride, certain estrogens used for prostate cancer, and antiandrogens such as bicalutamide, flutamide, and spironolactone.[7][17][36][37]

Medications that are probably associated with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine; risperidone, olanzapine, anabolic steroids,[17][38] alcohol, opioids, efavirenz, alkylating agents, and omeprazole.[17][29] Certain components of personal skin care products such as lavender essential oil[39] or tea tree oil and certain dietary supplements such as dong quai and Tribulus terrestris have been associated with gynecomastia.[24]

Chronic disease[edit]

People with kidney failure are often malnourished, which may contribute to gynecomastia development. Dialysis may attenuate malnutrition of kidney failure. Additionally, many kidney failure patients experience a hormonal imbalance due to the suppression of testosterone production and testicular damage from high levels of urea also known as uremia-associated hypogonadism.[24][40]

In individuals with liver failure or cirrhosis, the liver's ability to properly metabolize hormones such as estrogen may be impaired. Additionally, those with alcoholic liver disease are further put at risk for development of gynecomastia; ethanol may directly disrupt the synthesis of testosterone and the presence of phytoestrogens in alcoholic drinks may also contribute to a higher estrogen to testosterone ratio.[24] Conditions that can cause malabsorption such as cystic fibrosis or ulcerative colitis may also produce gynecomastia.[24]

A small proportion of male gynecomastia cases may be seen with rare inherited disorders such as spinal and bulbar muscular atrophy and the very rare aromatase excess syndrome.[41][42]

Tumors[edit]

Testicular tumors such as Leydig cell tumors or Sertoli cell tumors[43] (such as in Peutz–Jeghers syndrome)[10] or hCG-secreting choriocarcinoma[29] may result in gynecomastia. Other tumors such as adrenal tumors, pituitary gland tumors (such as a prolactinoma), or lung cancer, can produce hormones that alter the male–female hormone balance and cause gynecomastia.[21]

Individuals with prostate cancer who are treated with androgen deprivation therapy may experience gynecomastia.[44]

Pathophysiology[edit]

Pathology: A large glandular mass of male breast tissue, surgically removed
Microscopic image showing gynecomastoid hyperplasia, the cellular changes seen in gynecomastia H&E stain

The causes of common gynecomastia remain uncertain, but are thought to result from an imbalance between the actions of estrogen and androgens at the breast tissue.[8][17] Breast prominence can result from enlargement of glandular breast tissue, chest adipose tissue (fat) and skin, and is typically a combination.[29] As in females, estrogen stimulates the growth of breast tissue in males.[7] In addition to directly stimulating male breast tissue growth, estrogens indirectly decrease secretion of testosterone by suppressing luteinizing hormone secretion, resulting in decreased testicular secretion of testosterone.[7] Furthermore, estrogens can increase blood levels of the protein sex hormone-binding globulin (SHBG), which binds free testosterone (the active form) leading to decreased action of testosterone in male breast tissue.[7]

Primary hypogonadism (indicating an intrinsic problem with the testes in males) leads to decreased testosterone synthesis and increased conversion of testosterone to estradiol potentially leading to a gynecomastic appearance.[23] Klinefelter syndrome is a notable example of a disorder that causes hypogonadism and gynecomastia, and has a higher risk of breast cancer in males (20–50 times higher than males without the disorder).[45] Central hypogonadism (indicating a problem with the brain) leads to decreased production and release of luteinizing hormone (LH, a stimulatory signal for endogenous steroid hormone synthesis) which leads to decreased production of testosterone and estradiol in the testes.[23]

Individuals who have cirrhosis or chronic liver disease may develop gynecomastia for several reasons. Cirrhotics tend to have increased secretion of the androgenic hormone androstenedione from the adrenal glands, increased conversion of this hormone into various types of estrogen,[7] and increased levels of SHBG, which leads to decreased blood levels of free testosterone.[23] Around 10–40% of individuals with Graves' disease (a common form of hyperthyroidism) experience gynecomastia.[23] Increased conversion of testosterone to estrogen by increased aromatase activity,[7] increased levels of SHBG and increased production of testosterone and estradiol by the testes due to elevated levels of LH cause the gynecomastia. Proper treatment of the hyperthyroidism can lead to the resolution of the gynecomastia.[23]

Medications are known to cause gynecomastia through several different mechanisms. These mechanisms include increasing estrogen levels, mimicking estrogen, decreasing levels of testosterone or other androgens, blocking androgen receptors, increasing prolactin levels, or through unidentified means.[23] High levels of prolactin in the blood (which may occur as a result of certain tumors or as a side effect of certain medications) has been associated with gynecomastia.[23] A high level of prolactin in the blood can inhibit the release of gonadotropin-releasing hormone and therefore cause central hypogonadism.[7][23] Receptors for prolactin and other hormones including insulin-like growth factor 1, insulin-like growth factor 2, luteinizing hormone, progesterone, and human chorionic gonadotropin have been found in male breast tissue, but the impact of these various hormones on gynecomastia development is not well understood.[7]

Diagnosis[edit]

To diagnose gynecomastia, a thorough history and physical examination are obtained by a physician. Important aspects of the physical examination include evaluation of the male breast tissue with palpation to evaluate for breast cancer and pseudogynecomastia (male breast tissue enlargement solely due to excess fatty tissue), evaluation of penile size and development, evaluation of testicular development and an assessment for masses that raise suspicion for testicular cancer, and proper development of secondary sex characteristics such as the amount and distribution of pubic and underarm hair.[7] Gynecomastia usually presents with bilateral involvement of the breast tissue but may occur unilaterally as well.[24]

A review of the medications or illegal substances an individual takes may reveal the cause of gynecomastia.[24] Recommended laboratory investigations to find the underlying cause of gynecomastia include tests for aspartate transaminase and alanine transaminase to rule out liver disease, serum creatinine to determine if kidney damage is present, and thyroid-stimulating hormone levels to evaluate for hyperthyroidism. If these initial laboratory tests fail to uncover the cause of gynecomastia, then additional tests to evaluate for an underlying hormonal balance due to hypogonadism or a testicular tumor should be checked including total and free levels of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, serum beta human chorionic gonadotropin (β-hCG), and prolactin.[24]

High levels of prolactin are uncommon in people with gynecomastia.[24] If β-hCG levels are abnormally high, then ultrasound of the testicles should be performed to check for signs of a hormone-secreting testicular tumor.[24] Markers of testicular, adrenal, or other tumors such as urinary 17-ketosteroid or serum dehydroepiandrosterone may also be checked if there is evidence of hormonal imbalance on physical examination. If this evaluation does not reveal the cause of gynecomastia, then it is considered to be idiopathic gynecomastia (of unclear cause).[24]

Differential diagnosis[edit]

Other causes of male breast enlargement such as mastitis,[24][46] breast cancer, pseudogynecomastia, lipoma, sebaceous cyst, dermoid cyst, hematoma, metastasis, ductal ectasia, fat necrosis, or a hamartoma are typically excluded before making the diagnosis.[24] Another condition that may be confused with gynecomastia is enlargement of the pectoralis muscles.[citation needed]

Imaging[edit]

Mammography is the method of choice for radiologic examination of male breast tissue in the diagnosis of gynecomastia when breast cancer is suspected on physical examination.[7][9] However, since breast cancer is a rare cause of breast tissue enlargement in men, mammography is rarely needed.[7] If mammography is performed and does not reveal findings suggestive of breast cancer, further imaging is not typically necessary.[9] If a tumor of the adrenal glands or the testes is thought to be responsible for the gynecomastia, ultrasound examination of these structures may be performed.[7]

Histology[edit]

Early histological features expected to be seen on examination of gynecomastic tissue attained by fine-needle aspiration biopsy include the following: proliferation and lengthening of the ducts, an increase in connective tissue, an increase in inflammation, and swelling surrounding the ducts, and an increase in fibroblasts in the connective tissue.[23] Chronic gynecomastia may show different histological features such as increased connective tissue fibrosis, an increase in the number of ducts, less inflammation than in the acute stage of gynecomastia, increased subareolar fat, and hyalinization of the stroma.[22][23] When surgery is performed, the gland is routinely sent to the lab to confirm the presence of gynecomastia and to check for tumors under a microscope. The utility of pathologic examination of breast tissue removed from male adolescent gynecomastia patients has recently been questioned due to the rarity of breast cancer in this population.[47]

Classification[edit]

The spectrum of gynecomastia severity has been categorized into a grading system:[48]

  • Grade I: Minor enlargement, no skin excess
  • Grade II: Moderate enlargement, no skin excess
  • Grade III: Moderate enlargement, skin excess
  • Grade IV: Marked enlargement, skin excess

Treatment[edit]

Mild cases of gynecomastia in adolescence may be treated with advice on lifestyle habits such as proper diet and exercise with reassurance. In more severe cases, medical treatment may be offered including medication or surgical intervention.[23]

Medication[edit]

Gynecomastia can respond well to medical treatment although it is usually only effective when done within the first two years after the start of male breast enlargement.[7] Selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, and clomifene may be beneficial in the treatment of gynecomastia but are not approved by the Food and Drug Administration for use in gynecomastia.[7][17][49] Clomifene seems to be less effective than tamoxifen or raloxifene.[49] Tamoxifen may be used to treat gynecomastia in adults and of the medical treatments used, tamoxifen is the most effective.[50][51] Recent studies have shown that treatment with tamoxifen may represent a safe and effective mode of treatment in cases of cosmetically disturbing or painful gynecomastia.[17][52] Aromatase inhibitors (AIs) such as anastrozole have been used off-label for cases of gynecomastia occurring during puberty but are less effective than SERMs.[16][49]

A few cases of gynecomastia caused by the rare disorders aromatase excess syndrome and Peutz–Jeghers syndrome have responded to treatment with AIs such as anastrozole.[16] Androgens/anabolic steroids may be effective for gynecomastia.[49] Testosterone itself may not be suitable to treat gynecomastia as it can be aromatized into estradiol, but nonaromatizable androgens like topical androstanolone (dihydrotestosterone) can be useful.[49]

Surgery[edit]

Male with asymmetrical gynecomastia, before and after excision of the gland and liposuction of the waist

If chronic gynecomastia does not respond to medical treatment surgical removal of glandular breast tissue is usually required.[17] The American Board of Cosmetic Surgery reports surgery is the "most effective known treatment for gynecomastia."[53] Surgical approaches to the treatment of gynecomastia include subcutaneous mastectomy, liposuction-assisted mastectomy, laser-assisted liposuction, and laser-lipolysis without liposuction. Complications of mastectomy may include hematoma, surgical wound infection, breast asymmetry, changes in sensation in the breast, necrosis of the areola or nipple, seroma, noticeable or painful scars, and contour deformities.[48] In 2019, 24,123 male patients underwent surgical treatment for gynecomastia in the US, accounting for a 19% increase since 2000. Thirty-five percent of those patients were between the ages of 20 and 29, and 60% were younger than age 29 at the time of the operation. At an average surgeon's fee of $4,123, gynecomastia surgery was also the 11th most costly male cosmetic surgery of 2019.[54]

Others[edit]

Radiation therapy and tamoxifen have been shown to help prevent gynecomastia and breast pain from developing in prostate cancer patients who will be receiving androgen deprivation therapy. The efficacy of these treatments is limited once gynecomastia has occurred and are therefore most effective when used prophylactically.[55]

In the United States, many insurance companies deny coverage for surgery for gynecomastia treatment or male breast reduction on the basis that it is a cosmetic procedure.[56][57][58][59]

Prognosis[edit]

Gynecomastia is not physically harmful, but in some cases it may be an indicator of other more serious underlying conditions, such as testicular cancer.[7] The glandular tissue typically grows under the influence of hormonal stimulation and is often tender or painful. Furthermore, gynecomastia frequently presents social and psychological difficulties such as low self-esteem or shame for the sufferer.[47][48] Weight loss can alter the condition in cases triggered by obesity, but losing weight will not reduce the glandular component and patients cannot target areas for weight loss. Massive weight loss can result in sagging chest tissue known as chest ptosis.[citation needed]

Epidemiology[edit]

Gynecomastia is the most common benign disorder of the male breast tissue and affects 35 percent of men, being most prevalent between the ages of 50 and 69.[5][9]

New cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years old.[48] Newborn gynecomastia occurs in about 60–90 percent of male babies and most cases resolve on their own.[23][24] During adolescence, around 50 to 70 percent of males are estimated to exhibit signs of gynecomastia.[7] Gynecomastia in older men is estimated to be present in 24–65 percent of men between the ages of fifty and eighty. Estimates on asymptomatic gynecomastia is about up to 70% in men aged 50 to 69 years.[23][60]

The prevalence of gynecomastia in men may have increased in recent years, but the epidemiology of the disorder is not fully understood.[29] The use of anabolic steroids and exposure to chemicals that mimic estrogen in cosmetic products, organochlorine pesticides, and industrial chemicals have been suggested as possible factors driving this increase.[29][59] According to the American Society of Plastic Surgeons, breast reduction surgeries to correct gynecomastia are becoming increasingly common. In 2006, there were 14,000 procedures of this type performed in the United States alone.[59]

Society and culture[edit]

Gynecomastia can result in psychological distress for those with the condition. Common slang or derogatory terms for gynecomastia include man tits, man boobs or moobs.[61] Support groups exist to help improve the self-esteem of affected people.[62]

In 2019, a 12-person Philadelphia jury awarded $8 billion in punitive damages to plaintiffs tied to the use of Risperidone. Risperidone is an atypical antipsychotic that was originally approved to treat psychosis, but its use in children, including those with autism, ADHD, and schizophrenic diagnoses, has grown over the last two decades.[63]

In Murray v. Janssen Pharmaceuticals, Murray was a Risperidone user who was prescribed the medication at age 9 and developed male breasts. A jury decided in Murray's favor in November 2015 and awarded him $1.75 million. The $1.75 million jury verdict represented damages for "disfigurement and mental anguish," though it was later reduced to $680,000.[64] In the second portion of the bifurcated trial, the plaintiffs sought to prove that the companies knew and deliberately disregarded evidence that Risperidone could lead to gynecomastia in young males, and nonetheless promoted the medication off-label and released the medication into the open market for prescription and use by patients without disclosing the side effects.[64] The jury found for the plaintiffs in the second portion of the trial and awarded $8 billion in punitive damages. The amount was later reduced to $6.8 million by Judge Kenneth Powell Jr.[65]

Etymology[edit]

The term comes from the Greek γυνή gyné (stem gynaik-) meaning "female" and μαστός mastós meaning "breast".[3]

See also[edit]

References[edit]

Explanatory notes

  1. ^ The term comes from the Greek γυνή gyné (stem gynaik-) meaning "female" and μαστός mastós meaning "breast".[3]

Citations

  1. ^ "Gynaecomastia | Definition of Gynaecomastia by Oxford Dictionary on Lexico.com". Lexico Dictionaries | English. OxfordDictionaries.com. Retrieved 17 November 2020.
  2. ^ "Definition of Gynecomastia". www.merriam-webster.com. Retrieved 17 November 2020.
  3. ^ a b Iuanow, Elaine; Kettler, Mark; Slanetz, Priscilla J. (March 2011). "Spectrum of Disease in the Male Breast". American Journal of Roentgenology. 196 (3): W247–W259. doi:10.2214/AJR.09.3994. PMID 21343472.
  4. ^ a b c d e f g "Breast enlargement in males: MedlinePlus Medical Encyclopedia". medlineplus.gov. 2018. Retrieved 25 November 2020.. Updated by Brent Wisse (10 November 2018)
  5. ^ a b c d e f g Thiruchelvam, Paul; Walker, Jonathan Neil; Rose, Katy; Lewis, Jacqueline; Al-Mufti, Ragheed (22 September 2016). "Gynaecomastia". BMJ. 354: i4833. doi:10.1136/bmj.i4833. PMID 27659195. S2CID 220098795.
  6. ^ a b c d e Niewoehner, CB; Schorer, AE (March 2008). "Gynaecomastia and breast cancer in men". British Medical Journal. 336 (7646): 709–713. doi:10.1136/bmj.39511.493391.BE. PMC 2276281. PMID 18369226.
  7. ^ a b c d e f g h i j k l m n o p q r s t u Narula, Harmeet S.; Carlson, Harold E. (November 2014). "Gynaecomastia—pathophysiology, diagnosis and treatment". Nature Reviews Endocrinology. 10 (11): 684–698. doi:10.1038/nrendo.2014.139. PMID 25112235. S2CID 40159424.
  8. ^ a b Johnson RE, Murad MH (November 2009). "Gynecomastia: pathophysiology, evaluation, and management". Mayo Clinic Proceedings. 84 (11): 1010–1015. doi:10.4065/84.11.1010. PMC 2770912. PMID 19880691.
  9. ^ a b c d e f Chau, A; Jafarian, N; Rosa, M (February 2016). "Male Breast: Clinical and Imaging Evaluations of Benign and Malignant Entities with Histologic Correlation". The American Journal of Medicine (Review). 129 (8): 776–91. doi:10.1016/j.amjmed.2016.01.009. PMID 26844632.
  10. ^ a b Shulman, D. I.; Francis, G. L.; Palmert, M. R.; Eugster, E. A.; Lawson Wilkins Pediatric Endocrine Society Drug and Therapeutics, Committee. (1 April 2008). "Use of Aromatase Inhibitors in Children and Adolescents With Disorders of Growth and Adolescent Development". Pediatrics. 121 (4): e975–e983. doi:10.1542/peds.2007-2081. PMID 18381525. S2CID 39852740.
  11. ^ "Gynecomastia: Surgery, treatment, causes, and symptoms". www.medicalnewstoday.com. 11 January 2018. Retrieved 16 April 2021.
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  13. ^ a b Z. Hochberg (1 January 2007). Practical Algorithms in Pediatric Endocrinology. Karger Medical and Scientific Publishers. pp. 21–. ISBN 978-3-8055-8220-9.
  14. ^ a b Seth Thaller; Mimis Cohen (28 February 2013). Cosmetic Surgery After Massive Weight Loss. JP Medical Ltd. pp. 133–. ISBN 978-1-907816-28-4.
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  16. ^ a b c Wit, Jan M.; Hero, Matti; Nunez, Susan B. (March 2012). "Aromatase inhibitors in pediatrics". Nature Reviews Endocrinology. 8 (3): 135–147. doi:10.1038/nrendo.2011.161. PMID 22024975. S2CID 21710403.
  17. ^ a b c d e f g h i Deepinder F, Braunstein GD (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. PMID 22862307. S2CID 22938364.
  18. ^ https://www.plasticsurgery.org/documents/News/Statistics/2019/plastic-surgery-statistics-full-report-2019.pdf[full citation needed]
  19. ^ Mark Dennis; William Talbot Bowen; Lucy Cho (31 August 2016). Mechanisms of Clinical Signs - EPub3. Elsevier Health Sciences. pp. 599–. ISBN 978-0-7295-8561-3.
  20. ^ William T. O'Donohue; Lorraine T. Benuto; Lauren Woodward Tolle (8 July 2014). Handbook of Adolescent Health Psychology. Springer Science & Business Media. pp. 246–. ISBN 978-1-4614-6633-8.
  21. ^ a b c d Devalia HL, Layer GT (April 2009). "Current concepts in gynaecomastia". Surgeon. 7 (2): 114–19. doi:10.1016/s1479-666x(09)80026-7. PMID 19408804.
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  23. ^ a b c d e f g h i j k l m n o p q r s t u v Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B (19 March 2014). "Gynecomastia: Clinical evaluation and management". Indian J Endocrinol Metab. 18 (2): 150–58. doi:10.4103/2230-8210.129104. PMC 3987263. PMID 24741509.
  24. ^ a b c d e f g h i j k l m n o p Dickson, G (1 April 2012). "Gynecomastia". American Family Physician. 85 (7): 716–22. PMID 22534349.
  25. ^ Deepinder, Fnu; Braunstein, Glenn D (September 2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. PMID 22862307. S2CID 22938364.
  26. ^ fragrance https://www.womensvoices.org/2013/02/28/is-your-favorite-company-holding-out-on-you/pantene_label/[full citation needed]
  27. ^ https://www.nih.gov/news-events/news-releases/lavender-tea-tree-oils-may-cause-breast-growth-boys
  28. ^ Ghosh, Amit (2010). Mayo Clinic internal medicine board review (9th ed.). [Rochester, MN.]: Mayo Clinic Scientific Press. p. 209. ISBN 978-0-19-975569-1.
  29. ^ a b c d e f Barros, Alfredo Carlos Simões Dornellas de; Sampaio, Marcelo de Castro Moura (2012). "Gynecomastia: physiopathology, evaluation and treatment". Sao Paulo Medical Journal. 130 (3): 187–197. doi:10.1590/s1516-31802012000300009. PMID 22790552.
  30. ^ Brody, Steven A.; Loriaux, D. Lynn (October 2003). "Epidemic of Gynecomastia among Haitian Refugees: Exposure to an Environmental Antiandrogen". Endocrine Practice. 9 (5): 370–375. doi:10.4158/EP.9.5.370. PMID 14583418.
  31. ^ Fleisher, Gary (2010). Textbook of pediatric emergency medicine (6th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health. p. 731. ISBN 978-1-60547-159-4.
  32. ^ Melmed, Shlomo (2011). Williams Textbook of Endocrinology: Expert Consult. pp. Chapter 19. ISBN 978-1-4377-3600-7.
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