Gynecomastia Evaluation and Management

1. GynecomastiaEvaluation and Management Dr Shahjada Selim Associate Professor Department of Endocrinology & Metabolism Bangabandhu Sheikh Mujib Medical University Faculty in Endocrinology, Texila American University, USA Website: http://shahjadaselim.com

2. Definition • Gynecomastia is an enlargement or swelling of breast tissue in males. It is most commonly caused by male estrogen levels that are too high or are out of balance with testosterone levels. • The presence of palpable breast tissue in males may be found in normal individuals, particularly in the newborn period, at puberty, and in the elderly

3. Epidemiology • Around 60% of all boys develop transient pubertal breast enlargement, and • 30–70% of adult men have palpable breast tissue, with the higher prevalence being seen in older men and those with concurrent medical illnesses

4. Etiopathogenesis Figure: Hormones Affecting Growth and Differentiation of Breast Tissue. • Estrogen and progesterone act in an integrative fashion to stimulate normal adult female breast development. Estrogen, acting through its receptor (ER), promotes ductal growth, while progesterone, acting through its receptor (PR), promotes alveolar development. • Although estrogens and progestogens are vital to mammary growth, but neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1.  • Prolactin is integral to breast development. Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone. • Estrogen effects on the breast might be the result of circulating estradiol levels or locally produced estrogens. Aromatase P450 catalyzes the conversion of the C19 steroids, androstenedione, testosterone, and 16−α−hydroxyandrostenedione to estrone, estradiol-17β, and estriol. As such, an overabundance of substrate or an increase in enzyme activity can increase estrogen concentrations and initiate the cascade to breast development in females and males.

5. Etiopathogenesis • Receptors for androgens, estrogens, progesterone, and prolactin are found in the male breast • It is believed that most cases of gynecomastia are caused by an imbalance of these two influences, with estrogen-induced stimulation predominating

6. Etiopathogenesis • Such an imbalance may occur with increased estrogen action on the breast, decreased androgen action, or a combination of the two • This may be due to an • Increase in circulating or tissue levels of estrogen, • Decrease in circulating or tissue levels of androgen, • Increased responsiveness of the breast to estrogen (e.g. increased numbers of estrogen receptors), • Decreased breast responsiveness to androgens (e.g. androgen Insensitivity due to receptor mutations or drugs)

7. Etiopathogenesis • More than one of these derangements may be present in a single patient • For example, the increased prevalence of gynecomastia in older men may be related to • Increased adiposity with age [adipose tissue is a major site of aromatization of androgens to estrogens ] • Decreased serum free testosterone due to aging [with decreased testosterone production as well as increased binding of testosterone to SHBG ] • Greater use of medications that may alter androgen or estrogen concentrations or action

9. Etiopathogenesis • Hyperprolactinemia may lead to gynecomastiathrough its effects on the hypothalamus to cause central hypogonadism • Prolactin has also been reported to - decrease androgen receptors -increase estrogen and progesterone receptors in breast cancer cells -if a similar effect were to occur in the male breast, gynecomastia might result

10. Types of Gynecomastia • Physiologic Gynecomastia • Pathologic Gynecomastia

11. Physiologic Gynecomastia Gynecomastia, breast development in males, can occur normally during three phases of life. • The first occurs shortly after birth in both males and females. This is partly caused by the high levels of estradiol and progesterone produced by the mother during pregnancy, which stimulates breast tissue in the newborn. Another mechanism is in part due to the increased conversion of steroid hormone precursors to sex steroids and a neonatal surge of gonadotropins. It can persist for several weeks after birth and can cause mild breast discharge called "witch's milk".

12. Physiologic Gynecomastia • Puberty marks the second situation in which gynecomastia can occur physiologically. In fact, up to 60% of boys have clinically detectable gynecomastia by age 14. Although it is mostly bilateral, it is often asymmetrical and can occur unilaterally. Pubertal gynecomastia usually resolves within 3 years of onset. • In early puberty, the pituitary gland releases gonadotropins at night and stimulates testicular production of testosterone during the very early morning hours. Estrogens, however, rise throughout the entire day.

13. Physiologic Gynecomastia • The third age range in which gynecomastia is frequently seen is during older age (>60 years). Although the exact mechanisms by which this can occur have not been fully elucidated, evidence suggests that it may result from increased peripheral aromatase activity secondary to the increase in total body fat, relatively elevated LH concentrations, and a decrease in serum testosterone concentrations associated with male aging. For instance, investigators have shown increased urinary estrogen levels in obese individuals, and have demonstrated aromatase expression in adipose tissue.

14. Physiologic Gynecomastia • Thus, like the gynecomastia of obesity, the gynecomastia of aging may partly result from increased aromatase activity, causing increased conversion of androgens to estrogens. Moreover, not only does total body fat increase with age, but there may be an increase in aromatase activity in the adipose tissue already present, increasing circulating estrogens even further. • SHBG increases with age in men. Since SHBG binds estrogen with less affinity than testosterone, the bioavailable estradiol to bioavailable testosterone ratio may increase in the obese older male. Lastly, elderly patients may take multiple medications associated with gynecomastia.

15. About 10–25% of cases are estimated to result from the use of medications, known as pathologic or nonphysiologic gynecomastia. • Medications known to cause gynecomastia include  good numbers Pathologic Gynecomastia

16. 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. Chronic disease

17. 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.  • Conditions that can cause malabsorption such as cystic fibrosis or ulcerative colitis may also produce gynecomastia. Chronic disease

18. Tumor • The testes may directly secrete too much estradiol from a Leydig-cell or Sertoli-cell tumor • They may also secrete estradiol indirectly through the stimulatory effects of a human chorionic gonadotropin (hCG)– • secreting tumor of gonadal or extragonadal germ-cell origin (also called eutopichCG production) or • a tumor derived from a nontrophoblastic tissue, such as a large-cell carcinoma of the lung or some gastric or renal-cell carcinomas (also called ectopic hCG production)

19. Adrenal tumor • An adrenal neoplasm may overproduce the weak androgen androstenedione and other androgen precursors such as dehydroepiandrosterone, which are converted into estrogens in peripheral tissues

20. AROMATASE ACTIVITY • An increase in aromatase activity has been reported in a number of patients with gynecomastia associated with a variety of disease processes, including • Thyrotoxicosis • Klinefelter syndrome, and • Adrenal and testicular tumors. • Aromatase activity increases both with age and with an increase in body fat

21. SHBG • Increase in the sex hormone–binding globulin concentration, which occurs with hyperthyroidism and some forms of liver disease, may be associated with greater binding of testosterone relative to estrogen, leading to a decrease in free testosterone relative to free estrogen

22. Summary of Causes of Gynecomastia sp

23. EVALUATION

24. A healthy man with long-standing stable gynecomastia and a negative history and physical examination generally does not need further evaluation • The presence of new-onset breast pain, tenderness, or enlargement suggests a more recent, ongoing process and should prompt further testing to detect underlying systemic or endocrine problems

25. A detailed history should be obtained, including • The duration/progression of the gynecomastia • The presence of breast pain or tenderness • Systemic disease (e.g. chronic liver or renal disease; hyperthyroidism; hypogonadism; prostate, testicular, or other cancer) • Recent weight gain or loss • Use of medication or recreational drugs • Exposure to other chemicals • Fertility and sexual function

26. Drugs Commonly Implicated to Gynecomastia A thorough medication history is particularly important and should include the use of nonprescription medications, anabolic steroids, and dietary supplements

27. FAMILY HISTORY • A family history of gynecomastia would suggest the possibility of an • Androgen resistance syndrome, • Familial aromatase excess, • Estrogen-producing Sertoli cell tumors [as may occur in Peutz-Jeghers syndrome or in the Carney complex]. • A family history of BRCA2-positive breast cancer significantly increases the lifetime risk of male breast cancer to 8–10%in carriers of the mutation

28. PHYSICAL EXAMINATION • The physical examination should note • Features of masculinization (voice, facial and body hair, skeletal muscle bulk), • Anthropometry • Tanner staging including -Testicular size and/or masses, -Penile size and development, • Signs of chronic liver or kidney disease, and evidence of hyperthyroidism • The breasts should be carefully examined to differentiate true gynecomastia with palpable glandular tissue from pseudogynecomastia, in which only adipose tissue can be felt

29. The patient lies flat on his back with his hands clasped beneath his head. Using the separated thumb and forefinger, the examiner slowly brings the fingers together from either side of the breast. In patients with true gynecomastia, a rubbery or firm mound of tissue that is concentric with the nipple–areolar complex is felt, whereas in patientswith pseudogynecomastia, no such disk of tissue is found.

30. Attention should be paid to • The symmetry and smoothness of the glandular tissue; • Unusual firmness • Finding suggestive of breast carcinoma • Asymmetry • Eccentric location (not centered beneath the areola) • Fixation to the skin or chest wall, • Nipple retraction, • Bleeding or nipple discharge, ulceration, or • Associatedlymphadenopathy In all this condition biopsy is indicated.

31. LABORATORY EVALUATION • Routine biochemical testing should evaluate • thyroid, liver, and kidney function • serum testosterone (total and/or bioavailable), estradiol, LH, FSH, prolactin, and -hCG

32. Flow Chart: Evaluation of Gynecomastia

33. Treatment

34. Asymptomatic men with long-standing breast enlargement do not require treatment; reassurance is often all that is required.

35. In those with symptoms (pain, tenderness, embarrassment or excessive worry), treatment is guided by • the cause • the patient’s goals • relief of discomfort • restoration of normal appearance • reassurance regarding cancer • treatment of an underlying illness

36. In men with an identifiable underlying disorder (e.g. hyperthyroidism, testicular tumor), treatment of that disorder will often ameliorate the breast enlargement and symptoms, at least partially. • Similarly, if the gynecomastiais believed to be due to a medication or recreational drug, withdrawal of that agent should lead to at least some improvement over a period of a few months.

37. If the breast enlargement has been present for more than 1 yr, complete regression is less likely, due to the predominance of dense fibrous tissue

38. Teenage boys with pubertal gynecomastiacan usually be observed, with the expectation that the gynecomastia will spontaneously resolve over 1–2 yr in most cases. • Gynecomastia related to dialysis or refeeding is also generally self-limited, and reassurance may be sufficient treatment

39. In some men with hypogonadism of short duration, testosterone replacement may lead to the resolution or improvement of associated gynecomastia. • However, because testosterone can be aromatized to estradiol, it may worsen the breast enlargement in some cases, and the patient should be warned of this possibility

40. Antiestrogens have been increasingly used in recent years to decrease the stimulatory effect of estrogens on the male breast. • Tamoxifen and raloxifene, which block the estrogen receptor, and aromatase inhibitors such as anastrozolehave all been used with varying degrees of success in the treatment of gynecomastia.

41. Neither tamoxifen nor raloxifenehas been associated with significant side effects in the majority of patients. • Tamoxifen has been used in doses of 10–20 mg/d • Raloxifene at a dose of 60 mg/d for 3–9 months.

42. Anastrozole was successfully used to reduce the estrogen excess and breast enlargement in a patient with • Familial aromatase excess, • Patient with a feminizing Sertoli cell tumor • Hypogonadal men with gynecomastia induced by testosterone therapy. • It should be noted that none of these drugs have been approved by USFDA for the treatment of gynecomastia.

43. For men with gynecomastia due to androgen deprivation therapy for prostate cancer, prophylactic radiation therapy directed at the breast has been somewhat successful in preventing new-onset gynecomastia . • Tamoxifenhas also been used successfully in this situationand appears to be superior to both radiotherapy and anastrozole . • Daily administration of tamoxifen was shown to be more efficacious than weekly dosing.

44. Surgery to remove the breast tissue has been widely used in the treatment of gynecomastia. • It should probably be performed by highly experienced surgeons to achieve the best cosmetic result. • Excision with or without liposuction has been successfully used. • Surgical treatment of pubertal gynecomastia should generally be postponed until the completion of puberty to minimize the possibility of postoperative regrowth of breast tissue.

45. Algorithm of Management of Gynecomastia

46. Controversy

47. Some authors have recommended performing mammography and/or breast ultrasound in all cases • In agreement with others to use these imaging tools only when there are physical findings that raise a suspicion of breast cancer or a BRCA-2 mutation is suspected or known to be present.

48. Although the sensitivity and specificity of mammography are both greater than 90% in the diagnosis of male breast cancer, the much higher prevalence of gynecomastia compared with breast cancer leads to a positive predictive value of only 55%

49. For breast sonography, the positive predictive value was reported as only 17% . • Therefore universal application of imaging seems unlikely to be cost effective • In one study of male breast mammography, all of the men diagnosed with breast cancer also had physical findings that were suspicious for malignancy

50. Some authors have felt that the routine laboratory evaluation of all men with gynecomastia to detect underlying disease is also not cost-effective and suggesting more selective laboratory testing, guided by the individual patient’s medical history and examination