Gynecomastia

I have the following data from :

http://www.endotext.org/male/male14/male14.html

BREAST DEVELOPMENT

Early Fetal Life:

  • Epithelial cells <— derived from the epidermis of the area programmed to later become the areola
  • These epithelial cells —> proliferate into ducts, which connect to the nipple at the skin's surface.
  • With the decline in fetal prolactin, placental estrogen and progesterone at birth, the infantile breast regresses until puberty

Thelarche:

  • Initial appearance of the breast bud
  • Growth and division of the ducts occur
  • About 12 alveolar buds will cluster around a terminal duct
    • The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed.

HORMONAL REGULATION OF BREAST DEVELOPMENT

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ESTROGEN, GH AND IGF-1, PROGESTERONE, & PROLACTIN
  • Estrogens and progestogens are are ineffective in the absence of ant pituitary hormones.
    • They do not function without other mediators, such as GH and IGF-1.
    • Result of Estradiol
  • Progesterone interacts closely with pituitary hormones.
  • Maximal proliferation occurs during the luteal phase when progesterone reaches levels of 10-20 ng/mL (31- 62nmol) and estrogen levels are two to three times lower than in the follicular phase.
  • ER, PR and AR expression was observed in 100% (30/30) of gynecomastia cases.
  • Prolactin
    • Prolactin is secreted by the pituitary gland & mammary tissue epithelial cells & breast tumours.
    • Prolactin stimulates epithelial cell proliferation only in the presence of estrogen & progesterone.
  • LH and HCG receptors as well have been found in both male and female breast tissues, though its function remains to be determined.

ANDROGEN AND AROMATASE

Aromatase P450 catalyzes the conversion of the C19 steroids, androstenedione, testosterone, and 16-a-hydroxyandrostenedione to estrone, estradiol -17 β & estriol.

PHYSIOLOGIC GYNECOMASTIA

  • Shortly after birth
    • From high levels of estradiol and progesterone produced by the mother during pregnancy
    • Witch milk!
  • Puberty
  • Older age

PATHOLOGIC GYNECOMASTIA

INCREASED ESTROGEN

Any cause of estrogen excess from overproduction to peripheral aromatization of androgens.

  • Estrone in men
    • Testes —> 15% of estradiol and 5% of estrone
    • Extraglandular aromatization of testosterone and androstenedione to estradiol and estrone.
TUMORS
  • Testicular tumors
    • Mechanism:
      • Estrogen overproduction
      • Androgen overproduction with aromatization in the periphery to estrogens
      • Ectopic secretion of gonadotropins which stimulate otherwise normal Leydig cells.
    • Types:
      • Leydig cell tumours ( interstitial cell tumours )
        • Mostly benign but can be malignant
        • Produces Testosterone
      • Sertoli cell tumours
        • 10% malignant
        • Produces Estrogen
      • Ganulosa cell tumours
        • Produces Estrogen
      • Adrenal tumors
  • Germ cell tumours
    • Produces Estrogen and β-HCG
    • Seminomatous
    • Nonseminomatous
      • Embryonal carcinoma
      • Yolk sac carcinoma
      • Choriocarcinoma
      • Teratomas.

* High AFP and β-HCG
* High β-HCG ==> Analogue to LH ==> stimulate the Leydig cell LH receptor ==> gynecomastia
* High testicular estrogen ==> gynecomastia

  • Large cell carcinomas of the lung also can synthesize ectopic β-HCG.

Sertoli Cell tumors in boys with

  • Peutz-Jegher syndrome
    • Autosomal dominant
    • Pigmented macules on the lips
    • GI polyposis
    • Rapid growth
    • Advanced bone age
    • Hormonally active tumours
    • Increased aromatase overactivity
      • ==> gynecomastia
  • Carney complex
    • Autosomal dominant
    • Cardiac myxomas
    • Cutaneous pigmentation
    • Adrenal nodules
    • Hypercortisolism
    • Increased aromatase activity
  • Sex-cord tumors
  • Fibrolamellar hepatocellular carcinoma
    • Both —> ectopic aromatase activity ==> gynecomastia
  • Adrenal tumors
    • Secrete excess dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS) & androstenedione
      • —> aromatized peripherally to estradiol
Non-Tumour Causes OF Estrogen Excess
  • Familial elevation of extragonadal aromatase activity
  • Obesity
  • Hyperthyroidism
    • Increased aromatase activity
  • Displacement of Estrogens from SHBG ( Sex-Hormone Biding Globulin)
    • SHBG binds androgens more avidly than estrogen
    • Any condition or drug that can displace steroids from SHBG ==> even more easily displace estrogen==> higher circulating levels of estrogen.
  • Decreased Testosterone
    • Estrogen to Androgen ratio is important
      • High Estrogen —> suppress LH ==> decrease Testosterone ==> Gynecomastia

*‌ Primary hypogonadism
*‌ Reduction in serum testosterone ==> increased LH ==> increases testicular estradiol production
* ==> increased estrogen to androgen ratio
* Klinefelter's syndrome
* XXY karyotype
* Primary testicular failure

  • Any acquired testicular disease resulting in primary hypogonadism
    • Viral
    • Bacterial orchitis
    • Trauma
    • Radiation
  • Kallmann's syndrome
    • Congenital secondary hypogonadism
      • Anosmia
  • Reifenstein's syndrome
    • Androgen resistant
    • Complete and partial testicular feminization
    • Degrees of pseudohermaphroditism
  • Kennedy Syndrome
    • Neurodegenerative disease
    • Decreased effective testosterone
    • Defective androgen receptor
Other
  • End stage renal disease
    • Reduced testosterone
  • Liver disease (cirrhosis)
    • Estrogen overproduction
  • Thyrotoxicosis
    • Elevated estrogen
  • Spinal Cord disorder
  • HIV
  • Drugs
    • Possible Mechanisms:
      • Intrinsic estrogen-like properties
      • Drugs
      • Recreational use of marijuana, heroin, methadone and amphetamines

Stimulate estrogen synthesis

Supply aromatizable estrogen precursors

Direct Testicular Damage

Block testosterone synthesis

Block androgen action

Displace estrogen from SHBG

Estrogen vaginal cream

Gonadotropins

Exogenous androgen

Busulfan

Ketoconazole

Flutamide

Spironolactone

Estrogen-containing embalming cream

Growth Hormone

Androgen precursors (ie androstenedione and DHEA)

Nitrosurea

Spironolactone

Bicalutamide

Ethanol

Delousing powder

Vincristine

Metronidazole

Finasteride

Digitalis

Ethanol

Etomidate

Cyproterone

Clomiphene

Zanoterone

Marijuana

Cimetidine

Ranitidine

Spironolactone

MALE BREAST CANCER

Male breast cancer is rare and comprises only 0.2 percent of all male cancers. Despite this low figure, men with gynecomastia , especially elderly, worry about breast cancer and often seek medical advice, making this sort of consultation rather common in primary health care (34). Male breast cancer, though uncommon, has been associated with gynecomastia and necessitates inclusion in the differential diagnosis. Men with Klinefelter’s syndrome have a 20- to 50-fold increased risk of breast cancer. Other risks include hyperestrogenic conditions like obesity, alcohol, exogenous estrogen exposure and testicular disorders. It is unclear if these are specific risks for breast cancer are linked to the stimulatory process responsible for gynecomastia (31).High ambient temperature, exhaust emissions, family history, radiation to chest and liver damage are also risk factors for male breast cancer (20).

PATIENT EVALUATION

HISTORY AND PHYSICAL EXAMINATION

At presentation, all patients require a thorough history and physical exam. Particular attention should be given to medications, drug and alcohol abuse, as well as other chemical exposures. Symptoms of underlying systemic illness, such as hyperthyroidism, liver disease, or renal failure should be sought. Furthermore, the clinician must recall neoplasm as a possible etiology and should establish the duration and timing of breast development. Obviously, rapid breast growth that has occurred recently is more concerning than chronic gynecomastia. Additionally, the clinician should inquire about fertility, erectile dysfunction and libido to rule out hypogonadism, either primary or secondary, as a potential cause.

In our experience, the breast examination is best performed with the patient supine and with the examiner palpating from the periphery to the areola. The glandular mass should be measured in diameter. Gynecomastia is diagnosed by finding subareolar breast tissue of 2 cm in diameter or greater. Malignancy is suspected if an immobile firm mass is found on physical examination. Skin dimpling, nipple retraction or discharge, and axillary lymphadenopathy further support malignancy as a possible diagnosis. Tenderness may be present in patients with gynecomastia of less than 6 months duration, but it is unusual in patients with breast cancer.

A thorough testicular exam is essential. Bilaterally small testes imply testicular failure, while asymmetric testes or a testicular mass suggest the possibility of neoplasm. Visual field impairment may suggest pituitary disease. Physical findings of underlying systemic conditions such as thyrotoxicosis, HIV disease, liver, or kidney failure should also be assessed. As obesity is often associated with gynecomastia, body mass index should be documented (34).

LABORATORY EVALUATION

All patients who present with gynecomastia should have serum testosterone, estradiol, LH and HCG measured (Fig 2). Further testing should be tailored according to the history, physical examination and the results of these initial tests. An elevated HCG or a markedly elevated serum estradiol suggests neoplasm and a testicular ultrasound is warranted to identify a testicular tumor, keeping in mind, however, other non-testicular tumors can also secrete HCG. A low testosterone level, with an elevated LH and normal to high estrogen level indicates primary hypogonadism. If the history suggests Klinefelter's Syndrome, then a karyotype should be performed for definitive diagnosis. Low testosterone, low LH and normal estradiol levels imply secondary hypogonadism, and hypothalamic or pituitary causes should be sought. If testosterone, LH and estradiol levels are all elevated, then the diagnosis of androgen resistance should be entertained. Liver, kidney and thyroid function should be assessed if the physical examination suggests liver failure, kidney failure, or hyperthyroidism, respectively. Furthermore, if examination of breast tissue suggests malignancy, a biopsy should be performed. This is of particular importance in patients with Klinefelter's syndrome, who have an increased risk of breast cancer. On the other hand, if the examination finding is compatible with breast abscess, then fine needle aspiration for microscopy, acid-fast bacilli and culture is warranted (37).

Figure 2. Algorithm for investigation of gynecomastia

TREATMENT

Treatment of the underlying endocrinologic or systemic disease that has caused gynecomastia is mandatory. Testicular tumors, such as Leydig cell, Sertoli cell or granulosa cell tumors should be surgically removed. In addition to surgery, germ cell tumors are further managed with chemotherapy involving cisplatin, bleomycin and either vinblastine or etoposide (24, 59). Should underlying thyrotoxicosis, renal or hepatic failure be discovered, appropriate therapy should be initiated. Medications that cause gynecomastia should also be discontinued whenever possible based on their role in management of the underlying condition. The improvement should be apparent within 1 month after discontinuation of the culprit drug (10). Of course, if a breast biopsy indicates malignancy, then mastectomy should be performed.

If no pathologic abnormality is detected, then appropriate treatment is close observation. A careful breast exam should be done initially every 3 months until the gynecomastia regresses or stabilizes, after which a breast exam can be performed yearly. It is important to remember that most cases of pubertal gynecomastia may resolve spontaneously within one to two years, around 20% of patients have residual gynecomastia by the age of 20 (67) . An Information sheet about gynecomastia is available for those patients who are interested to know more about their conditions (30).

MEDICAL TREATMENT

If the gynecomastia is severe, does not resolve, and does not have a treatable underlying cause, some medical therapies may be attempted. There are 3 classes of medical treatment for gynecomastia: androgens (testosterone, dihydrotestosterone, danazol), anti-estrogens (clomiphene citrate, tamoxifen) and aromatase inhibitors such as testolactone.

Testosterone treatment of hypogonadal men with gynecomastia often fails to produce breast regression once gynecomastia is established. Unfortunately, testosterone treatment may actually produce the side effect of gynecomastia by being aromatized to estradiol. Thus, although testosterone is used to treat hypogonadism, its use to specifically counteract gynecomastia is limited (72). Dihydrotestosterone, a non-aromatizable androgen, has been used in patients with prolonged pubertal gynecomastia with good response rates (38). Since dihydrotestosterone is given either intramuscularly or percutaneously, this may restrict its usefulness. Danazol, a weak androgen that inhibits gonadotropin secretion, resulting in decreased serum testosterone levels, has been studied in a prospective placebo-controlled trial, whereby gynecomastia resolved in 23 percent of the patients, as opposed to 12 percent of the patients on placebo (35). The dose used for gynecomastia is 200 mg orally twice daily. Unfortunately, undesirable side effects including edema, acne, and cramps have limited its use (45).

Investigators have reported a 64 percent response rate with 100 mg/day of clomiphene citrate, a weak estrogen and moderate antiestrogen (41). Lower doses of clomiphene have shown varied results, indicating that higher doses may need to be administered, if clomiphene is to be attempted. Tamoxifen, also an antiestrogen, has been studied in 2 randomized, double-blind studies in which a statistically significant regression in breast size was achieved, although complete regression was not documented (1). One study compared tamoxifen with danazol in the treatment of gynecomastia. Although patients taking tamoxifen had a greater response with complete resolution in 78 percent of patients treated with tamoxifen, as compared to only a 40 percent response in the danazol-treated group, the relapse rate was higher for the tamoxifen group (70). Although complete breast regression may not be achieved and a chance of recurrence exists with therapy, tamoxifen, due to relatively lower side effect profile, may be a more reasonable choice when compared to the other therapies. If used, tamoxifen should be given at a dose of 10 mg twice a day for at least 3 months (45). Responders usually improve with reduced pain within 1 month. Another anti-estrogen, raloxifene has also been used in the treatment of pubertal gynecomastia but its efficacy needs to be evaluated in randomized prospective studies (39 ) .

An aromatase inhibitor, testolactone, has also been studied in an uncontrolled trial with promising effects (77). Further studies must be performed on this drug before any recommendations can be established on its usefulness in the treatment of gynecomastia. Newer aromatase inhibitors such as anastrozole and letrozole may have therapeutic potential (47, 60), but recent randomized, double-blind, placebo-controlled trials have not confirmed its efficacy. In a study involving patients receiving bicalutamide therapy for prostate cancer, only t amoxifen, but not anastrozole, significantly reduced the incidence of gynecomastia/breast pain when used prophylactically and therapeutically(7, 63). In another study with pubertal gynecomastia, no significant difference was demonstrated between the anastrozole and placebo groups in patients suffering from pubertal gynecomastia (58).

From various series, some patients with gynecomastia show no significant improvement after medical treatment . This may be related to the stage of disease at which medical treatment is initiated. It has been suggested that patient with long history of gynecomastia, in which the breast tissue becomes fibrotic, tend to be resistant to medical treatment (67, 34).

SURGICAL TREATMENT

When medical therapy is ineffective, particularly in cases of longstanding gynecomastia, or when the gynecomastia interferes with the patient's activities of daily living, or when there is suspicion of malignancy of breast, then surgical therapy is appropriate. This includes removal of glandular tissue coupled with liposuction, if needed, preferably with individualized approach (27). Nowadays, minimally invasive surgery is available and it may be associated with few complications and prompt recovery (33). Of note if malignancy is suspected, histological examination is mandatory (34). Uses of delicate cosmetic surgical techniques are warranted to prevent unsightly scarring.

PREVENTION OF GYNECOMASTIA IN MEN WITH PROSTATE CANCER

Because androgen deprivation is one of the commonly used treatment modalities for advanced prostate cancer, its possible role in the development of gynecomastia is of particular concern to clinicians. Tamoxifen has been demonstrated its efficacy in preventing gynecomastia in patients receiving bicalutamide (Casodex) for prostate cancer in randomized controlled trial (57). Boccardo et al showed 10% patients in the tamoxifen group (20 mg daily dose) developed gynecomastia, whereas 51% in the anastrozole group and 73% in placebo group had gynecomastia over a period of 48 weeks (7). Fradet et al showed tamoxifen reduced the incidence of gynecomastia in patients with prostate cancer receiving bicalutamide in dose dependent manner (22). Likewise, it has been shown that low dose tamoxifen (20 mg/week) is inferior to the daily regimen (20mg/day) in terms of the prevention and treatment of gynecomastia(5). Current data suggests tamoxifen 20mg per day is the optimum dose required for prophylaxis of gynecomastia in patients with prostate cancer receiving androgen deprivation therapy (5, 22). Low dose prophylactic irradiation has been variably reported to reduce the rate of gynecomastia in men receiving estrogens or antiandrogens for prostate cancer (15, 55, 74).

SUMMARY

In summary, gynecomastia is a relatively common disorder. The causes of its development range vastly from benign physiologic processes to rare neoplasms. Thus, in order to properly diagnose the etiology of the gynecomastia, the clinician must understand the hormonal factors involved in breast development. Parallel to female breast development, estrogen, along with GH and IGF-1 is required for breast growth in males. Since a balance exists between estrogen and androgens in males, any disease state or medication that can increase circulating estrogen or decrease circulating androgen, causing an elevation in the estrogen to androgen ratio, can induce gynecomastia. Due to the diversity of possibly etiologies, including neoplasm, performing a careful history and physical is imperative. Once gynecomastia has been diagnosed, treatment of the underlying cause is warranted. If no underlying cause is discovered, then close observation is appropriate. If the gynecomastia is severe, however, medical therapy can be attempted and if ineffective, glandular tissue can be removed surgically.