Gynecomastia

Introduction

Gynecomastia is a benign enlargement of the male breast (usually bilateral but sometimes unilateral) resulting from a proliferation of the glandular component of the breast. It is defined clinically by the presence of a rubbery or firm mass extending concentrically from the nipples.

Gynecomastia can develop in males of any age or weight, but often arises around puberty as breast development is affected by hormonal changes. An accumulation of excess fat, and not breast gland tissue, is sometimes seen in obese men – this is not true gynecomastia and is sometimes called pseudogynecomastia.

Associated Anatomy

Male breast development occurs in an analogous fashion to female breast development. At puberty in the female, complex hormonal interplay occurs resulting in growth and maturation of the adult female breast.

In early fetal life, epithelial cells, derived from the epidermis of the area programmed to become the areola, proliferate into ducts, which connect to the nipple at the skin’s surface. The blind ends of these ducts bud to form alveolar structures in later gestation. With the decline in fetal prolactin and placental estrogen and progesterone at birth, the infantile breast regresses until puberty.

During thelarche in females, the initial clinical appearance of the breast bud and growth and division of the ducts occur, giving rise to club-shaped terminal end buds, which then form alveolar buds. Approximately a dozen alveolar buds will cluster around a terminal duct, forming the type 1 lobule. The type 1 lobule will mature into types 2 and 3 lobules, called ductules. The number of alveolar buds increases to as many as 50 in type 2 and 80 in type 3 lobules. The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed.

Causes

Common known causes of gynecomastia include physiological hormonal changes, use of medications and pathological entities such as cirrhosis, hyperthyroidism, testicular tumors and hypogonadism. Less common causes include androgen insensitivity syndrome, Kallmann syndrome, defects of testosterone pathway and tumors.

Differential Diagnosis

Differential diagnosis should be made for following conditions:

• Breast Cancer
• Dermoid Cyst
• Hypogonadism
• Lymphangioma
• Pseudogynecomastia in obese

Drugs

Androgens:

Androgens are group of drug that suppress pituitary release of gonadotropic hormones. These agents are used to inhibit the effects of estrogen linked with gynecomastia in men. Following drugs are used:

Testosterone (Androderm, AndroGel, Axiron, Testim)

Testosterone is the predominant male sex hormone used for replacement therapy in male hypogonadism.

Danazol

Danazol is a synthetic steroid analog with strong antigonadotropic activity (it inhibits LH and FSH) and weak androgenic action.

Selective Estrogen Receptor Modulators:

Selective estrogen receptor modulators inhibit estrogen effects.

Clomiphene (Clomid, Serophene)

Clomiphene stimulates the release of pituitary gonadotropins.

Tamoxifen

Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases deoxyribonucleic acid (DNA) synthesis and inhibits estrogen effects.

Epidemiology

Gynecomastia is the most common reason for male breast evaluation. The condition is common in infancy and adolescence, as well as in middle-aged to older adult males. One estimate is that 60-90% of infants have transient gynecomastia due to the high estrogen state of pregnancy.

The next peak of occurrence is during puberty, with a prevalence ranging from 4-69%. Some reports have shown a transient increase in estradiol concentration at the onset of puberty in boys who develop gynecomastia. Pubertal gynecomastia usually has an onset in boys aged 10-12 years. It generally regresses within 18 months, and persistence is uncommon in men older than 17 years. The third peak occurs in older men, with a prevalence of 24-65%

 

Natural Progression

Gynecomastia can appear as a rubbery or firm mass that starts from underneath the nipple and then spreads outwards over the breast area. It usually affects both breasts but often in different amounts so there is asymmetry, or it may only affect one breast. Sometimes the growing tissue can be painful or tender, and if this occurs then you should be examined by a doctor. Gynecomastia can also result in significant psychological and social stress, leading to anxiety and embarrassment.

 

Pathophysiology

Gynecomastia is a result of enlargement of glandular breast tissue and adipose tissue. The hormone estrogen is responsible for the growth of glandular tissue, as well as the suppression of testosterone secretion. Estrogen suppresses luteinizing hormone, the hormone that is responsible for testicular secretion of testosterone. This process of hormonal imbalance leads to gynecomastia.

Pubertal gynecomastia is thought to be caused by a faster rise in estradiol than the rise of testosterone, causing an imbalance that normally regresses with time as testosterone increases.

Medical conditions such as tumors of the adrenal, pituitary, and testes can cause increases in estrogen and decrease testosterone. These imbalances lead to hormonal imbalances resulting in gynecomastia in some males.

 

Possible Complications

Other than the associated risk of breast cancer, gynecomastia does not cause any long-term complications.

 

Possible Treatment

Generally, no treatment is required for physiologic gynecomastia. Pubertal gynecomastia resolves spontaneously within several weeks to 3 years in approximately 90% of patients. Breasts greater than 4 cm in diameter may not completely regress.

Identifying and managing an underlying primary disorder often alleviates breast enlargement.  If hypogonadism (primary or secondary) is the cause of gynecomastia, parenteral or transdermal testosterone replacement therapy is instituted. However, testosterone does have the potential to exacerbate gynecomastia through the aromatization of the exogenous hormone into estradiol.

For patients with idiopathic gynecomastia or with residual gynecomastia after treatment of the primary cause, medical or surgical treatment may be considered.

A major factor that should influence the initial choice of therapy for gynecomastia is the condition’s duration. It is unlikely that any medical therapy will result in significant regression in the late fibrotic stage (a duration of 12mo or longer) of gynecomastia. As a result, medical therapies, if used, should be tried early in the condition’s course.

Pharmacologic Therapy

With the administration of clomiphene, an antiestrogen, approximately 50% of patients achieve partial reduction in breast size, and approximately 20% of patients note complete resolution. Adverse effects, while rare, include visual problems, rash, and nausea.

Tamoxifen, an estrogen antagonist, is effective for recent-onset and tender gynecomastia.  Up to 80% of patients report partial to complete resolution. Nausea and epigastric discomfort are the main adverse effects. 

Other drugs used, albeit less frequently, include danazol.  Danazol, a synthetic derivative of testosterone, inhibits pituitary secretion of LH and follicle-stimulating hormone (FSH), which decreases estrogen synthesis from the testicles.

Breast Surgery

Reduction mammoplasty is considered for patients with macromastia or long-standing gynecomastia or in persons in whom medical therapy has failed. It is also considered for cosmetic reasons (and for accompanying psychosocial reasons). 

More extensive plastic surgery may be required in patients with marked gynecomastia or who have developed excessive sagging of the breast tissue due to weight loss. If surgery is necessary for patients with pseudogynecomastia, liposuction may be warranted.

A retrospective study by Zavlin et al found the prevalence of gynecomastia surgery complications in pediatric and adult patients to be low, with 30-day surgical complication rates of 3.9% and 1.9%, respectively, and 30-day medical complication rates of 0.0% and 0.3%, respectively. The investigators also found that the mean operative time for pediatric patients (111.3 minutes) was almost double that for adults (56.7 minutes). 

A Chinese study indicated that endoscopic subcutaneous mastectomy, without skin excision, could be an effective treatment for gynecomastia. In a report on the procedure’s use in 65 patients (125 breasts) with gynecomastia, grade IIB or III, the authors stated that only a few operative complications occurred, including 2 cases of partial nipple necrosis and 1 case of subcutaneous hydrops. They also reported that postsurgical chest contour was satisfactory in all patients and that no recurrences were seen during the 3- to 36-month follow-up period.

Complications of surgery include sloughing of tissue due to a compromised blood supply, contour irregularity, hematoma or seroma formation, and permanent numbness in the nipple-areolar area.

 

Primary Prevention

There are no established methods for the primary prevention of gynecomastia.

 

Prognosis

In approximately 90% of cases, pubertal gynecomastia resolves within a period of months to several years. However, macromastia seldom resolves completely and often requires surgery.

Gynecomastia that occurs secondary to an underlying, treatable cause (eg, drug-induced gynecomastia) usually responds to treatment or removal of the primary cause. Men with Klinefelter syndrome have a 10- to 20-fold increased risk for breast cancer.

Research has indicated that the psychological effects of gynecomastia can include depression, anxiety, disordered eating, body dissatisfaction, and reduced self-esteem. 

A study by Sir et al suggested that gynecomastia can impinge on male sexual function. The study, which included 47 patients and 30 healthy controls, found that, as evaluated with the International Index of Erectile Function (IIEF), scores for erectile function, orgasmic function, and intercourse satisfaction were significantly lower in patients with gynecomastia than in the control group. However, the gynecomastia patients had a significantly higher mean IIEF desire score than did the controls. The study also found that hormone profiles (serum free triiodothyronine [T3], free thyroxine [T4], thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH], prolactin, estradiol, total testosterone, free testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate [DHEA-SO₄]) for the gynecomastia patients were similar to those of the controls, with the exception of FSH and free T3, which were significantly lower.

 

Secondary Prevention

There are no established methods for the secondary prevention of gynecomastia.

 

Risk factors

Common Risk Factors:

• Idiopathic
• Drugs
• Spironolactone
• Cimetidine
• Recombinant human growth hormone
• Estrogens
• Human chorionic gonadotropin
• Anti-androgens
• Gonadotropin releasing hormone (GNRH) agonists
• 5-alpha reductase inhibitors
• Ketoconazole
• Cirrhosis
• Hypogonadism
• Testicular neoplasms
• Hyperthyroidism
• Chronic kidney disease

Less Common Risk Factors:

• Feminizing adrenal tumors
• Ectopic hCG excretion
• Familial prepubertal gynecomastia

 

Signs or Symptoms

Common symptoms include:

• Breast pain
• Breast enlargement

Less common symptoms of gynecomastia include:

• Abdominal distention secondary to ascites
• jaundice
• Persistent nausea
• oliguria
• fluid retention
• fatigue
• weight loss
• tremors
• Decreased sleep
• Decrease appetite
• Decrease concentration
• Decreased libido

 

Studies

Active Not Recruiting

Number of studies: 0

Completed

Number of studies: 7

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Enrolling by Invitation

Number of studies: 0

Not Yet Recruiting

Number of studies: 0

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Recruiting

Number of studies: 0

Results Available

Number of studies: 9

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Results Not available

Number of studies: 9

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Suspended

Number of studies: 0

Terminated

Number of studies: 0

Withdrawn

Number of studies: 1

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Types

Three types of gynecomastia, florid, fibrous and intermediate, have been identified. The type seen is usually related to the length of the condition. Florid gynecomastia is usually seen in early stages of the condition, four months or less. This type is characterized by an increase in ductal tissue and vascularity. Fibrous gynecomastia is seen after a year duration and is noted to have more stromal fibrosis and few ducts. After one year, intermediate gynecomastia is present which is thought to be a progression from florid to fibrous.

 

Typical Test

Physical examination

Doctors should follow next recommendations when performing physical examination of patient with gynecomastia:

Perform a thorough examination of the breasts, noting their size and consistency. In addition, determine the presence of any nipple discharge or axillary lymphadenopathy.

Differentiate between true gynecomastia and pseudogynecomastia. These 2 entities may be distinguished by having the patient lie on his back with his hands behind his head. The examiner then places a thumb on each side of the breast and slowly brings the thumbs together. In true gynecomastia, a ridge of glandular tissue will be felt that is symmetrical to the nipple-areolar complex. With pseudogynecomastia, the fingers will not meet until they reach the nipple.

Also note the following in gynecomastia:

• Glandular tissue – Gynecomastia can be detected when the size of the glandular tissue exceeds 0.5 cm in diameter
• Testicles – Examine the testicles, noting their size and consistency; carefully look for nodules or asymmetry
• Feminization – Note signs of feminization, including typical body hair distribution and eunuchoid habitus
• Stigmata – Check for any stigmata of chronic liver disease, thyroid disease, or renal disease

Note that hematoma, lipoma, male sexual dysfunction, and neurofibroma can be included in the differential diagnosis of gynecomastia.

Laboratory findings

Asymptomatic gynecomastia which is discovered on physical examination has a very low diagnostic yield and usually normal blood hormone levels.

Gynecomastia which is tender and of recent onset should have, following lab work up:

• Alpha-fetoprotein (AFP)
• Blood urea nitrogen (BUN)
• Creatinine (Cr)
• Dehydroepiandrosterone-sulfate (DHEA-S)
• Estradiol
• Erythrocyte sedimentation rate (ESR)
• Human chorionic gonadotropin (HCG)
• Liver function tests (LFTs)
• Prolactin
• Testosterone
• Thyroid stimulating hormone (TSH)

Imaging studies

Order a mammogram if 1 or more features of breast cancer are apparent upon clinical examination. This can be followed by fine-needle aspiration or breast biopsy, as the case merits. 

Obtain a testicular ultrasonogram if the serum estradiol level is elevated and the clinical examination findings suggest the possibility of a testicular neoplasm.

Breast imaging, through mammography or ultrasonography, may be controversial, because gynecomastia is much more common than male breast cancer. The positive predictive value of imaging in males is 55% using mammography and 17% using ultrasonography. However, a study by Telegrafo et al in which ultrasonography was used to diagnosis and classify gynecomastia found the same results as when mammography was used, suggesting that ultrasonography can be employed as a primary imaging modality for determining the presence of gynecomastia and categorizing its shape. 

Histologic findings

Characteristic findings include proliferation of ductules and stroma (consisting of connective-tissue elements such as fibroblasts, collagen, and myofibroblasts) and occasional acini. Gynecomastia of short duration consists of a prominent ductular component with loose stroma. Long-standing gynecomastia consists of dense stroma with few ductules.

References:

https://www.wikidoc.org/index.php/Gynecomastia
https://www.ncbi.nlm.nih.gov/books/NBK279105/
https://www.ncbi.nlm.nih.gov/books/NBK430812/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770912/
https://emedicine.medscape.com/article/120858-overview
https://clinicaltrials.gov/