Gynecomastia

Gynecomastia
Other names: Gynaecomastia
A young adult male with gynecomastia
Pronunciation
  • /ˌɡaɪnɪkoʊˈmæstiə, ˌdʒaɪ-, -kə-/ or /ɡaɪˈniːkəˌmæstiə, -koʊ-/ [1][2]
SpecialtyEndocrinology, plastic surgery
SymptomsEnlargement of one or both breasts[3]
Usual onsetAny age[3]
DurationMonths to years[3]
CausesPhysiologic, obesity, liver disease, kidney failure, certain cancers, thyroid disease, medications, recreationally drugs, malnutrition[3]
Differential diagnosisPseudogynaecomastia, breast cancer, dermoid cyst[4][3]
TreatmentReassurance, addressing the underlying cause, medications, surgery[5]
MedicationTamoxifen, clomiphene[3]
FrequencyCommon[4]

Gynecomastia is the non-cancerous enlargement of one or both breasts in men.[3][6] Some only use the term when enlargement is due to glandular tissue and use the term pseudogynaecomastia when enlargement is the result of excessive fat tissue.[5][6] Occasionally tenderness may be present.[4] The condition can result in psychological distress.[6]

Gynecomastia can be normal in newborns due to exposure to estrogen from the mother, during puberty, and in older men.[3] These cases do not generally require further investigations.[5] It can also be associated with obesity, liver disease, kidney failure, certain cancers, thyroid disease, certain medications and recreational drugs, Klinefelter syndrome, and malnutrition.[3] The underlying mechanism often involves increased estrogen or decreased androgen levels.[4]

Cases that occur in puberty generally resolve within two years and require only simple reassurance.[5][7] The condition also commonly resolves if the underlying cause is addressed.[5] Medications such as tamoxifens or clomiphene are effective when used early.[3] In long standing cases surgery, such as liposuction or surgical excision, is the only effective option.[5]

Gynecomastia affects about 35% of men and is most common between the ages of 50 and 69.[5] It is present in up to 90% of newborns and 60% of boys during puberty.[6] It is the most common reason males seek medical care for a breast issue.[8] Description of the condition date from 2nd century by Galen.[8]

Definition

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. It is different to "pseudogynaecomastia" which is due to excessive fat tissue.[9][5]

Signs and symptoms

In gynecomastia there is 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.[10][11] Dimpling of the skin and nipple retraction are not typical features of gynecomastia.[10] Milky discharge from the nipple is not a typical finding, but may be seen in a gynecomastic individual with a prolactin secreting tumor.[4] An increase in the diameter of the areola and asymmetry of the chest are other possible signs of gynecomastia.[12]

Men with gynecomastia may appear anxious or stressed due to concerns about its appearance and the possibility of having breast cancer.[13][14]

Causes

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.[4] Estrogen acts as a growth hormone to increase the size of male breast tissue.[4][13] The cause of gynecomastia is unknown in around 25% of cases.[11][14] Drugs are estimated to cause 10–25% of cases of gynecomastia.[15]

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.[16] 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.[9] The insecticide phenothrin possesses antiandrogen activity and has been associated with gynecomastia.[17][18]

Physiologic

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.[19] 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.[13][20] In some infants neonatal milk (also known as "witch's milk") can leak from the nipples.[11] The temporary gynecomastia seen in newborn babies usually resolves after two or three weeks.[13]

Gynecomastia in adolescents usually starts between the ages of 10 and 12 and commonly goes away after 18 months.[13]

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.[13] Increased fatty tissue in these men leads to increased conversion of androgenic hormones such as testosterone to estrogens.[13]

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.[13] Gynecomastia can also occur once normal nutrition is restarted (this is known as refeeding gynecomastia).[13]

Non-physiologic

Medicines

A 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.[21] More than 90% of cases of gynecomastia with nonsteroidal antiandrogens including flutamide are mild to moderate.[22][23]

About 10–25% of cases are estimated to result from the use of medications, known as nonphysiologic gynecomastia.[24][14] 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.[4][24][25][26]

Medications that are probably associated with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine; risperidone, olanzapine, anabolic steroids,[24][27] alcohol, opioids, efavirenz, alkylating agents, and omeprazole.[24][28] Certain components of personal skin care products such as lavender essential oil[29] or tea tree oil and certain dietary supplements such as dong quai and Tribulus terrestris have been associated with gynecomastia.[14]

Chronic disease

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.[14][30]

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.[14] Conditions that can cause malabsorption such as cystic fibrosis or ulcerative colitis may also produce gynecomastia.[14]

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.[31][32]

Tumors

Testicular tumors such as Leydig cell tumors or Sertoli cell tumors[33] (such as in Peutz–Jeghers syndrome)[7] or hCG-secreting choriocarcinoma[28] 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.[11]

Individuals with prostate cancer who are treated with androgen deprivation therapy may experience gynecomastia.[34]

Pathophysiology

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.[35][24] Breast prominence can result from enlargement of glandular breast tissue, chest adipose tissue (fat) and skin, and is typically a combination.[28] As in females, estrogen stimulates the growth of breast tissue in males.[4] 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.[4] 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.[4]

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.[13] 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).[36] 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.[13]

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,[4] and increased levels of SHBG, which leads to decreased blood levels of free testosterone.[13] Around 10–40% of individuals with Graves' disease (a common form of hyperthyroidism) experience gynecomastia.[13] Increased conversion of testosterone to estrogen by increased aromatase activity,[4] 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.[13]

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.[13] 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.[13] A high level of prolactin in the blood can inhibit the release of gonadotropin-releasing hormone and therefore cause central hypogonadism.[4][13] 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.[4]

Diagnosis

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.[4] Gynecomastia usually presents with bilateral involvement of the breast tissue but may occur unilaterally as well.[14]

A review of the medications or illegal substances an individual takes may reveal the cause of gynecomastia.[14] 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.[14]

High levels of prolactin are uncommon in people with gynecomastia.[14] 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.[14] 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).[14]

Imaging

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.[4][10] However, since breast cancer is a rare cause of breast tissue enlargement in men, mammography is rarely needed.[4] If mammography is performed and does not reveal findings suggestive of breast cancer, further imaging is not typically necessary.[10] 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.[4]

Histology

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.[13] 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.[12][13] 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.[37]

Classification

The spectrum of gynecomastia severity has been categorized into a grading system:[38]

  • 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

Differential diagnosis

Other causes of male breast enlargement such as mastitis,[14][39] breast cancer, pseudogynecomastia, lipoma, sebaceous cyst, dermoid cyst, hematoma, metastasis, ductal ectasia, fat necrosis, or a hamartoma are typically excluded before making the diagnosis.[14] Another condition that may be confused with gynecomastia is enlargement of the pectoralis muscles.

Treatment

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 tried including surgical intervention.[13]

Medication

Medical treatment of gynecomastia is most effective when done within the first two years after the start of male breast enlargement.[4] 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.[4][24][40] Clomifene seems to be less effective than tamoxifen or raloxifene.[40] Tamoxifen may be used for painful gynecomastia in adults.[24] Aromatase inhibitors (AIs) such as anastrozole have been used off-label for cases of gynecomastia occurring during puberty but are less effective than SERMs.[41][40]

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.[41] Androgens/anabolic steroids may be effective for gynecomastia.[40] 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.[40]

Surgery

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

If chronic gynecomastia is untreated, surgical removal of glandular breast tissue is usually required.[24] 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.[38]

Others

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.[42]

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.[43][44][45][46]

Prognosis

Gynecomastia is not physically harmful, but in some cases it may be an indicator of other more serious underlying conditions, such as testicular cancer.[4] 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.[37][38] 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.

Epidemiology

Gynecomastia is the most common benign disorder of the male breast tissue and affects 35 percent of men, being most common between the ages of 50 and 69.[10][5]

New cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years old.[38] Newborn gynecomastia occurs in about 60–90 percent of male babies and most cases resolve on their own.[13][14] During adolescence, around 50 to 70 percent of males are estimated to exhibit signs of gynecomastia.[4] 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.[13][47]

The prevalence of gynecomastia in men may have increased in recent years, but the epidemiology of the disorder is not fully understood.[28] 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.[28][46] 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.[46]

History

Description of the condition date from 2nd century by Galen.[8]

Word origin

The term comes from the Greek γυνή gyné (stem gynaik-) meaning "female" and μαστός mastós meaning "breast".[48]

Society and culture

Gynecomastia can result in psychological distress. Common slang or derogatory terms for gynecomastia include man boobs or moobs.[49] Support groups exist to help improve the self-esteem of affected people.[50]

In 2019, a 12-person Philadelphia jury awarded $8 billion in punitive damages to plaintiffs tied to the use of risperidone. Risperidone is a medication used to treat children who are aggressive or excessively irritable. Risperidone 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.[51] Risperidone has been linked to gynecomastia.

In Murray v. Janssen Pharmaceuticals, Murray was a Risperdal user who was prescribed the drug 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.[52] In the second portion of the bifurcated trial, the plaintiffs sought to prove that the companies knew and deliberately disregarded evidence that Risperdal could lead to gynecomastia in young males, and nonetheless promoted the drug off-label and released the drug into the open market for prescription and use by patients without disclosing the side effects.[52] 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.[53]

See also

References

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  2. ↑ "Definition of Gynecomastia". www.merriam-webster.com. Archived from the original on 9 March 2021. Retrieved 17 November 2020.
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  5. 1 2 3 4 5 6 7 8 9 Thiruchelvam, Paul; Walker, Jonathan Neil; Rose, Katy; Lewis, Jacqueline; Al-Mufti, Ragheed (22 September 2016). "Gynaecomastia". British Medical Journal. 354: i4833. doi:10.1136/bmj.i4833. ISSN 1756-1833. PMID 27659195. S2CID 220098795. Archived from the original on 1 March 2021. Retrieved 29 November 2020.
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  13. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 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.
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  15. ↑ Deepinder, Fnu; Braunstein, Glenn D (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. ISSN 1474-0338. PMID 22862307. S2CID 22938364.
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  17. ↑ Barros, Alfredo Carlos Simões Dornellas de; Sampaio, Marcelo de Castro Moura (2012). "Gynecomastia: physiopathology, evaluation and treatment". São Paulo Medical Journal. 130 (3): 187–197. doi:10.1590/S1516-31802012000300009. ISSN 1516-3180. PMID 22790552. Reinforcing the evidence suggesting that there is a relationship between chemicals and GM, it is worthwhile mentioning the epidemic onset observed among Haitian refugees in 1981 about four months after arrival in United States detention centers.22 After analyzing all identifiable environmental exposures, it was then found that phenothrin, a multi-insecticide contained in sprays that they had used was the causative agent.23 It is now widely known that phenothrin has antiandrogenic activity.
  18. ↑ Steven A. Brody MD; D. Lynn Loriaux MD (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. ISSN 1530-891X. PMID 14583418.
  19. ↑ 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.
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  22. ↑ Gillatt, David (2006). "Antiandrogen treatments in locally advanced prostate cancer: are they all the same?". Journal of Cancer Research and Clinical Oncology. 132 (S1): 17–26. doi:10.1007/s00432-006-0133-5. ISSN 0171-5216. PMID 16845534. S2CID 23888640. Unlike CPA, nonsteroidal antiandrogens appear to be better tolerated than castration, allowing patients to maintain sexual activity, physical ability, and bone mineral density, but these agents have a higher incidence of gynecomastia and breast pain (mild to moderate in > 90% of cases).
  23. ↑ Goldspiel BR, Kohler DR (1990). "Flutamide: An Antiandrogen for Advanced Prostate Cancer". Ann Pharmacother. 24 (6): 616–623. doi:10.1177/106002809002400612. PMID 2193461. S2CID 26125621. [...] They [in patients treated with flutamide] observed mild gynecomastia in 30 patients (57%), moderate gynecomastia in 19 (36%), and massive gynecomastia in four patients (8%). Complaints of nipple and areolar tenderness were noted in 50/53 patients (94%%)." Airhart et al. reported that 42% of patients receiving flutamide 750 mg/d or 1500 mg/d developed gynecomastia within 12 weeks of starting treatment with an apparent direct correlation between the dose of flutamide administered and the severity of gynecomastia. In another study, two of five evaluable patients developed moderate gynecomastia with mild tenderness at four and eight weeks after starting flutamide 750 mg/d. Patients with pre-existing gynecomastia as a result of previous endocrine therapy with estrogens sustained no worsening of their gynecomastia and may have improved symptomatically." Keating et al.
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  25. ↑ Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF (April 2014). "Aldosterone antagonists for preventing the progression of chronic kidney disease". Cochrane Database of Systematic Reviews. 4 (4): CD007004. doi:10.1002/14651858.CD007004.pub3. PMID 24782282.
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