Gynecomastia and Premature Thelarche

DOI: 10.1542/pir.28-9-e572007;28;e57Pediatrics in Review

Stavros Diamantopoulos and Yong BaoGynecomastia and Premature Thelarche : A Guide for Practitioners

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Gynecomastia and PrematureThelarche:A Guide for PractitionersStavros Diamantopoulos,

MD,* Yong Bao, MD†

Author Disclosure

Drs Diamantopoulos

and Bao did not

disclose any financial

relationships relevant

to this article.

IntroductionGynecomastia is the presence of breast tissue in males. The term comes from the Greekword gyne (woman) and mastos (breast). Gynecomastia is common and often is a concernfor families, but it usually is a normal part of adolescent development. Pathologicgynecomastia does occur and can be related to a serious underlying problem. Anyabnormal breast development in males warrants evaluation.

Premature thelarche (thely�female, arche�beginning) is isolated breast development ingirls younger than 8 years of age. Premature thelarche usually is benign, but may signify amore complicated condition. Practitioners should know how to evaluate early breastdevelopment in girls.

Normal Breast Development and PhysiologyA mature mammary gland consists of 15 to 25 lactiferous ducts and lobes. Development ofthe breast tissue anlage is identical in the male and female fetus. Before puberty, the breastconsists of the same number of lactiferous ducts ending in small ductules lined withepithelial cells. It is not until puberty that mammary gland development progresses infemales, reaching completion during the first pregnancy. The mature terminal alveolarbuds formed in early pregnancy are called acini. The units of lactiferous ducts with theirlobules compose a lobe. Lobes are separated by dense connective tissue septa.

Several hormones influence breast development. Under estrogen stimulation, ductaland stromal components proliferate. Duct growth and division result in lobules thatconsist of alveolar buds clustering around a terminal duct. Lobules lie within a growingstroma of loose, hormone-sensitive connective tissue that supports the mammary gland.Progesterone promotes acinar differentiation of the ductal system. Prolactin has a trophiceffect on the alveolar buds, promoting acinar formation and the secretory differentiation ofthe mammary epithelium to support lactation. Receptors for luteinizing hormone (LH) /human chorionic gonadotropin (hCG) have been found in mammary tissue; it is believedthat these hormones also may affect breast development. Insulin and insulin-like growthfactor-1 also facilitate breast development. Androgens (testosterone and dihydrotestoster-one) limit breast development.

Significant decreases in estrogenic stimulation result in atrophic changes of the ductalsystem, characterized by fibrosis and hyalinization of the supporting connective tissue.Such atrophic changes occur physiologically after menopause.

Sex Hormone SynthesisTo understand how gynecomastia can develop, a review of androgen and estrogenbiosynthesis is necessary. Imbalance in the serum concentrations or in the synthesis ofandrogen or estrogen can lead to gynecomastia or premature thelarche.

The first step in the biosynthesis of androgen and estrogen is the uptake of cholesterolby mitochondria in the adrenals, ovaries, and testes (ie, the sex steroid-producing endo-crine glands). The testes make testosterone primarily. Testosterone is converted irrevers-ibly to the more biologically active androgen dihydrotestosterone in extragonadal tissues.The adrenal gland secretes dehydroepiandrosterone (DHEA) and androstenedione (Fig.1). Androstenedione can be aromatized to estrogen in peripheral tissues. Testosteroneproduced in the ovary is converted to estradiol by the enzyme aromatase. Some estradiol

*Fellow.†Assistant Professor, Division of Pediatric Endocrinology, Department of Pediatrics, Miller School of Medicine, University ofMiami, Miami, Fla.

Article endocrinology

Pediatrics in Review Vol.28 No.9 September 2007 e57



also is produced by this pathway in the testes and in otherextragonadal sites such as adipose tissue, skin, and liver.

Sex steroids circulate in the blood either free or boundto sex hormone-binding globulin (SHBG) and otherplasma proteins (Fig. 2). Because SHBG binds andro-gens with higher affinity than it binds estrogen, condi-tions that increase SHBG concentrations result in a rel-atively larger decrease in the free fraction of androgensthan in the fraction of estrogen.

Fetal and Neonatal Hormone SecretionThe fetus is exposed to high concentrations of estrogen,primarily estriol, produced by the mother and the pla-centa. On the first and second days after birth, testoster-

one secretion in boys and estradiolsecretion in girls surges due to neo-natal hypothalamic-pituitary-gon-adal axis activity. Gonadotropin se-cretion then declines, reaching anadir 10 days after birth, and sub-sequently increases again, reachinga peak at 2 months of age. By 6months of age, gonadotropin se-cretion drops to prepubertal levels.This “minipuberty of early infancy”is a physiologic process, often clin-ically apparent in both sexes, andcan be persistent, which may ex-plain the slight increase of breasttissue observed in some infants.

Because the fetal mammarygland is exposed to the hormonal

perturbations of pregnancy, neonatal galactorrhea(“witch’s milk”) frequently develops as a result of theacute decrease of estrogen and progesterone concentra-tions shortly after delivery. The sudden decrease in serumestrogen and progesterone may facilitate prolactin andoxytocin secretion by the neonatal pituitary.

In childhood, sex steroid concentrations remain lowuntil the onset of puberty. In females, gonadotropinsstimulate the ovarian estradiol production responsiblefor the feminizing changes of puberty. In males, activa-tion of the gonadotropin axis stimulates testosteronesecretion. Sex steroid concentrations rise gradually untiladult concentrations are achieved at the end of puberty.Estradiol concentration reaches the adult range before

testosterone concentration does.The testes are responsible for morethan 95% of testosterone produc-tion and about 15% of estradiolproduction. Aromatization of an-drogens in extragonadal tissue isthe primary source of estrogen inmales.

GynecomastiaTrue gynecomastia is difficult todistinguish from other entities, es-pecially in obese individuals. Rareconditions that may mimic gyneco-mastia, such as neurofibromas, sar-comas, epithelial inclusion cysts,duct ectasia, and mastitis, oftencause unilateral breast enlarge-ment. Some of the conditions men-

Figure 1. Simplified sex steroid production pathway. Androgens may be converted toestrogens by the enzyme aromatase. DHEA�dehydroepiandrosterone, DHT�dihydro-testosterone, 17beta-HSD3�17-beta hydroxysteroid dehydrogenase III, 3beta-HSD�3-beta hydroxysteroid dehydrogenase.

Figure 2. Sex steroid production in endocrine glands, circulation in blood stream, andconversion in extraglandular tissues. T�testosterone, E2�estradiol, SHBG�sex hormone-binding globulin, DHT�dihydrotestosterone, DHEA�dehydroepiandrosterone,�4A�androstenedione, E�estrogen.

endocrinology gynecomastia

e58 Pediatrics in Review Vol.28 No.9 September 2007



tioned in this section affect girls as well as boys, in whichcase the breast enlargement technically represents pre-mature thelarche rather than gynecomastia.

EpidemiologyGynecomastia occurs primarily in three time periods:neonatal period/early infancy, adolescence, and old age.Up to 90% of neonates of both sexes may have palpablebreast tissue that even may increase slightly after birth. Inmale infants, we use the term gynecomastia to describethis condition; in females, we use the term thelarche.Breast enlargement usually resolves within the first fewmonths after birth but may persist for up to 12 months inmales and 18 to 24 months in females. After early in-fancy, prepubertal gynecomastia occurs rarely and war-rants careful evaluation.

In contrast, up to 60% of males may develop gyneco-mastia during adolescence. Peak incidence is observed inmid-puberty (13 to 14 years). Approximately 75% ofcases resolve within 2 years of appearance, but gynecom-astia may persist into adulthood. (1)

Pathogenesis and Conditions Associated WithGynecomastia

As noted previously, breast enlargement results from animbalance between androgenic and estrogenic stimula-tion. In most conditions, the estrogen effect is increased,but the androgen effect also may be decreased. Some-times, both estrogen increase and androgen decreasecontribute to the development of gynecomastia, witheither hormone having a predominant effect.

Neonatal Gynecomastia and ThelarcheFamily members eager to resolve breast development by“extracting the milk” may prolong or exacerbate physi-ologic neonatal gynecomastia because breast stimulationpromotes secretion of prolactin and oxytocin by thepituitary gland. Expressing milk from the neonatal breastalso may result in mastitis or galactocele formation.

Physiologic Pubertal GynecomastiaPhysiologic pubertal gynecomastia most likely is relatedto a lag in maturation of testosterone secretion, therebypermitting greater estrogen effect. Detection oftestosterone/estrogen imbalance requires a 24-hourevaluation because the estradiol-to-testosterone ratio in asingle blood sample is similar in boys who have and donot have gynecomastia. However, the 24-hour secretionpattern of testosterone and estradiol in boys who havebreast development indicates that the overall estradiol-to-testosterone ratio within 1 day is slightly higher. This

imbalance is considered transient, and the serumestradiol-to-testosterone ratio may be normal by thetime medical attention is sought. (1) Physiologic puber-tal gynecomastia usually presents at early to mid-puberty,with variable breast size and a peak incidence at 14 yearsof age.

Gynecomastia is a more common finding in obesemales and typically persists longer than does gynecomas-tia in nonobese males. Breast enlargement may be due toincreased aromatization of androstenedione to estroneby adipose tissue.

Idiopathic gynecomastia is a term used to describeabnormal breast development in males for which nopathologic cause has been identified after clinical andlaboratory investigation. Most cases develop in pubertyor adulthood, although idiopathic gynecomastia can oc-cur in prepubertal boys. By definition, idiopathic gyneco-mastia represents a benign condition, but it may persist,cause cosmetic and psychological problems, and requiretreatment.

Pathologic GynecomastiaHormonal causes of pathologic gynecomastia, listed inthe categories of increased estrogen or decreased andro-gen, are presented in Table 1. Male secondary hypogo-nadism may cause both decreased androgen and estrogenconcentrations and rarely causes gynecomastia. Severaldrug classes associated with gynecomastia are listed inTable 2. Many drugs have an estrogenic or antiandro-genic effect, but the underlying mechanisms remain un-known for other drugs.

Table 1. Causes of AbnormalBreast Development in MalesIncreased Estrogen

● Estrogen-secreting tumors● Tumors secreting human chorionic gonadotropin● Increased aromatase activity● Exogenous estrogen● Liver dysfunction● Hyperthyroidism● Congenital adrenal hyperplasia

Decreased Androgen

● Primary gonadal dysfunction● Defects in testosterone biosynthesis● Androgen insensitivity





NeoplasiaTESTICULAR TUMORS. Testicular tumors such as germ

cell, Sertoli cell, and Leydig cell tumors account for 1.5%of childhood neoplasias and may be associated withgynecomastia. Germ cell tumors are the most commontesticular neoplasms, with two peaks of occurrence: onein the first 2 years after birth and one after 14 years of age.Germ cell tumors may secrete hCG, resulting in in-creased secretion of both testosterone and estradiol bythe testis, with the increase in estradiol secretion out ofproportion to that of testosterone. Risk factors for germcell tumors are cryptorchidism and gonadal dysgenesis(usually associated with ambiguous genitalia). Germ celltumors typically develop within the testis but also mayappear in the central nervous system (CNS), mediasti-num, retroperitoneum, and sacrococcygeal area.

Gynecomastia may be present in 10% to 15% of pa-tients who have Sertoli and Leydig cell tumors, withgynecomastia appearing before a testicular mass is palpa-ble. Leydig or Sertoli cell tumors are extremely rare inchildhood and may increase the production of estrogen.Precocious puberty is common in Leydig but rare inSertoli cell tumors. Sertoli cell tumors usually present inthe first postnatal year and typically are benign. However,Sertoli cell tumors can present after 5 years of age, atwhich time they are associated with more malignantbehavior. Sertoli cell tumors may be seen in associationwith Peutz-Jeghers syndrome (characterized by mucosallentigines, hamartomatous gastrointestinal polyps, andnongastrointestinal tumors). Leydig cell tumors have apeak incidence in children during middle childhood (5 to6 years); unlike adult cases, they rarely metastasize inchildren.

LIVER TUMORS. Hepatoblastoma occurs almost ex-clusively in the first 3 years after birth. This tumor maysecrete hCG, which rarely can induce breast enlarge-ment. Hepatoblastoma that produces hCG usuallycauses signs of precocious puberty in females. Hepato-cellular carcinoma may cause breast enlargement by in-creased aromatization of androgen precursors to estra-diol.

ADRENAL TUMORS. Adrenal tumors associated withbreast enlargement typically produce large amounts ofDHEA and dehydroepiandrosterone sulfate (DHEAS)because the tumors are relatively deficient in 3-beta-hydroxysteroid dehydrogenase. These androgen precur-sors are aromatized into estrogen, whose increased con-centrations may induce gynecomastia. Although rare,adrenal tumors also may produce estrogen directly. Ad-T

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renal tumors generally cause virilization in girls, butbreast enlargement also may occur in combination withother signs of precocious puberty. In general, adrenaltumors that cause feminization are malignant.

HypogonadismPrimary hypogonadism, also known as hypergonado-tropic hypogonadism, is due to gonadal dysfunction.Primary hypogonadism is characterized by testicular dys-function and abnormally elevated serum concentrationsof gonadotropins (follicle-stimulating hormone [FSH]and LH). The increased serum concentrations of LHstimulate production of estradiol by Leydig cells withinthe testis, leading to gynecomastia.

The most common diagnosis associated with hyper-gonadotropic hypogonadism is Klinefelter syndrome, acondition that occurs in about 1 of every 600 newbornmales. Salient features in adolescents include eunuchoidbody habitus, testicular atrophy, gynecomastia, and be-havioral problems. Gynecomastia in boys caused byKlinefelter syndrome may be associated with an increasedrisk of breast cancer, unlike other causes of gynecomastia.

Other causes of hypergonadotropic hypogonadisminclude testicular damage from orchitis (most commonlymumps orchitis), trauma, chemotherapy, radiation, renalfailure, myotonic dystrophy, spinal cord injury, or abnor-malities of testicular determination. The latter categoryincludes a group of conditions such as 46,XY gonadaldysgenesis, 45X/46,XY gonadal dysgenesis, and 46,XXmaleness.

Secondary hypogonadism is associated with condi-tions that disrupt gonadotropin-releasing hormone pro-duction by the hypothalamus or the production of LHand FSH by the pituitary. Gynecomastia is extremelyunusual in secondary hypogonadism because both tes-tosterone and estradiol secretion is low. However, tes-tosterone production may be subnormal compared withthat of estradiol, thereby causing an abnormal estrogen-to-androgen ratio. Three conditions that may lead tosecondary hypogonadism with gynecomastia are cranio-pharyngioma resection, prolactin-secreting pituitary ad-enoma, and hyperprolactinemia of any cause. Althoughthe peak incidence of craniopharyngioma is 5 to 9 yearsof age, obesity and hypopituitarism in adolescent boysmay develop years after craniopharyngioma resection,leading to gynecomastia. Prolactin-secreting pituitaryadenomas and hyperprolactinemia of any cause may sup-press gonadotropin production, leading to secondaryhypogonadism and gynecomastia. Milky nipple dis-charge (galactorrhea) may be an associated sign of hyper-prolactinemia.

HyperthyroidismGynecomastia is common in boys who have thyrotoxico-sis, due primarily to increased production of andro-stenedione, which is aromatized to estrogen.

Aromatase ExcessIncreased aromatase activity has been described in somecases of familial gynecomastia. (2) In these families,gynecomastia generally appears in the prepubertal years.Transmission usually is autosomal dominant, and theincrease in serum estrone may be greater than that ofestradiol in affected patients.

Defects in Testosterone BiosynthesisPatients who have 17-beta-hydroxysteroid dehydroge-nase III (also termed 17-ketoreductase) deficiency have adefect in the conversion of androstenedione to testoster-one. Affected individuals typically develop gynecomastiain adolescence due to high serum LH concentrations, aswell as to high concentrations of androstenedione that isaromatized to estrogen.

Abnormalities of End Organ Responsiveness toAndrogen

Children afflicted with partial androgen insensitivity typ-ically have ambiguous genitalia at birth and gynecomas-tia at puberty. Some who have subtle abnormalities ofandrogen receptor function may present with gynecom-astia and normal-appearing male genitalia but experienceinfertility later in life.

Congenital Adrenal Hyperplasia (CAH)Poorly controlled CAH due to 21-hydroxylase deficiencyis a rare cause of gynecomastia. Breast development isdue to increased aromatizable androstenedione. Otherrare forms of CAH associated with gynecomastia include11-beta-hydroxylase deficiency and 3-beta-hydroxy-steroid dehydrogenase deficiency. Deficiency of 11-beta-hydroxylase typically is characterized by virilization andvariable hypertension. Deficiency of 3-beta-hydroxy-steroiddehydrogenase,characterizedby impairedsteroid-ogenesis of glucocorticoids, mineralocorticoids, and sexsteroids, may present with salt wasting and ambiguousgenitalia. As with adrenal tumors, CAH can affect girls.Virilization is the prominent feature, and breast enlarge-ment may occur with other signs of precocious puberty.





Environmental Estrogen ExposureNumerous drugs (Table 2), anabolic steroids, and mari-juana can cause breast enlargement in both sexes, as canestrogen exposure from cosmetics or food. Environmen-tal estrogen exposure is discussed in detail in the the-larche section.

Systemic DiseaseLiver cirrhosis can cause gynecomastia through impairedcatabolism of estrogens. Renal failure also is associatedwith gynecomastia, probably from testicular damage andabnormal elevation of serum LH concentrations. (1)

Refeeding gynecomastia also occurs. Proposed mech-anisms for patients developing gynecomastia while re-covering from prolonged starvation are a transient de-crease in estrogen catabolism or recovery from ahypogonadic state with an abnormal ratio of estradiol totestosterone production, similar to the situation ob-served in puberty.

History and Physical ExaminationTable 3 lists the specific information that should besought when taking a history during the evaluation ofgynecomastia.

A physical examination is important to confirm thepresence of gynecomastia and to investigate other relatedconditions that may be present. The breasts are observedfirst, with the male patient wearing no clothes on theupper part of the body and sitting upright with his handshanging loosely on his sides. (Some males prefer to weara gown, especially if they have gynecomastia.) The breastand nipple shape and contour are noted with the patientlying down and putting his hands behind his neck. Theexaminer should palpate gently from the center of thenipple to the periphery to ascertain the margins of breastdevelopment and then measure breast diameter. A breastdiameter greater than 4 cm defines macrogynecomastia,which warrants a more detailed investigation because thesize of the breast tissue is a function of both the magni-

Table 3. Elements of a History for Evaluation of GynecomastiaQuestion Rationale

Presenting ComplaintAge at Onset of Puberty

-Early (before 9 years of age) Consider tumors that produce androgen and estrogen-Normal Physiologic gynecomastia more likely-Late Consider gonadal dysfunction, abnormalities of testosterone

biosynthesis or actionAge of Onset of Gynecomastia

-Before puberty Consider causes of prepubertal gynecomastia such as steroid-secreting tumors

-During puberty Physiologic gynecomastia more likely-After puberty Physiologic gynecomastia less likely; consider abnormalities

such as gonadal dysfunction, tumors, drugsProgression Rapid progression is not typical of physiologic gynecomastiaTenderness, pain Suggestive of true gynecomastia (versus fatty

pseudogynecomastia)Nipple discharge

-Milky Consider increased prolactin secretion-Serosanguineous/sebaceous Consider local conditions

Past Medical HistorySurgery for cryptorchidism or hypospadias Consider testicular dysfunctionPsychosocial functioning and learning problems Consider substance abuse (alcohol, marijuana), Klinefelter

syndromeRecovery from chronic illness or weight loss Consider refeeding gynecomastiaDrug Use Drugs causing gynecomastiaFamily HistoryFamily history of gynecomastia or abnormal sexual

developmentHormonal abnormality more likely

Social HistoryParticipation in competitive sports (adolescents) Anabolic steroid useOther cases among peers (household or school) Estrogen in food and cosmeticsAdoption history Refeeding gynecomastia





tude and duration of the estrogen-to-androgen imbal-ance. Although typically described as a “coiled rope,” thetexture of glandular tissue may vary from a discrete elasticdisc under the nipple to a diffuse mass indistinguishablefrom adipose tissue. Asymmetric or unilateral breast de-velopment is common and does not predict underlyingdisease. Applying soft pressure from the periphery of thebreast toward the nipple may induce the nipple to dis-charge any underlying fluid.

Examination of the genitalia is important for docu-menting pubertal stage and detecting testicular tumors.In boys younger than 9 years, testicular volume greaterthan 3 mL (using a Prader orchidometer) or testicularlength more than 2.5 cm (excluding the epididymis)indicates precocious puberty. The presence of pubertalsigns in a boy younger than 9 years suggests an underly-ing malignancy or a CNS lesion until proven otherwise.Both testes should be palpated and transilluminated fortumors. Patients who have gonadal dysfunction (ie,Klinefelter syndrome) may have small, firm testes afterpuberty.

Physiologic gynecomastia usually appears when malesare at Sexual Maturity Rating stages 2 to 3 for pubic hairand genitalia. The presence of gynecomastia associatedwith a discrepancy between testicular size (smaller thanexpected) and pubic hair development should alert theclinician to the possibility of hypogonadism because pu-bic hair development may be stimulated by adrenal ste-roids, creating the impression that pubertal progressionis appropriate when it is not.

The general examination provides useful informationsuch as growth and nutritional status, body habitus, liversize and texture, presence of abdominal masses, andpresence of any physical stigmata suggestive of syn-dromic conditions. A bulky, tall phenotype frequently isseen in adolescents who have physiologic gynecomastia.Presence of eunuchoid body habitus is suggestive ofKlinefelter syndrome.

Abnormal neurologic, visual field, or funduscopicfindings together with small testes may indicate pituitaryor other CNS disease that may be causing hypogonado-trophic hypogonadism.

Patients who have findings suggestive of physiologicgynecomastia should be reassured but followed regu-larly. Follow-up is important to monitor pubertal pro-gression and breast development, whether or not labo-ratory investigations are performed. A full physicalexamination with particular attention paid to the featuresoutlined previously should be undertaken at everyfollow-up visit.

Specialist Referral and Laboratory EvaluationFor those patients who appear to have pathologic gy-necomastia, additional evaluation is necessary, includingconsultation with a pediatric endocrinologist. Candi-dates for specialist referral and laboratory evaluation in-clude:

• Patients who have history or physical examinationfindings suggestive of underlying pathologic conditions.

• All patients who have gynecomastia and presentbetween 3 months of age and before puberty, unlessgynecomastia was present from birth. Onset of gyneco-mastia at a late stage of puberty also may require evalua-tion.

• Patients who have macrogynecomastia (�4 cm) orwho experience rapid increase in breast size becauseeither condition may indicate persistent estrogen andandrogen imbalance due to an underlying pathologiccondition rather than to a transient physiologic imbal-ance.

Patients who have galactorrhea should be evaluatedfor conditions that cause hyperprolactinemia. Otherforms of nipple discharge (purulent, serous, sanguine-ous, brownish) suggest local disease or skin conditionsthat may require referral to a surgeon or a dermatologist.Although extremely rare, breast carcinomas and ductalpapillomas do occur in males and may manifest withbloody discharge.

Other reasons for referral to a specialist include paren-tal request, physician unease, and risk of patient noncom-pliance with follow-up.

Laboratory TestingLaboratory investigations can precede specialist referral,but normal laboratory results do not necessarily excludeunderlying pathologic conditions and do not obviate theneed for continued follow-up. The initial laboratoryinvestigation may include determining 8 AM fasting se-rum concentrations of LH, FSH, testosterone, estradiol,beta-hCG, DHEAS, and liver enzymes. A guide forinterpreting these tests is presented in Figure 3.

Imaging studies for gynecomastia generally are notuseful.

ManagementThe key role of the primary care pediatrician is to deter-mine which cases represent physiologic gynecomastiaand which are suspicious for pathologic gynecomastiaand require specialist referral. For patients who havepathologic gynecomastia, specialists usually managetreatment. For physiologic gynecomastia, clinicians orspecialists usually reassure patients and follow them





closely. There are various approaches to the managementof marked idiopathic gynecomastia.

Pharmacologic treatment can decrease estrogen effecteither by blocking estrogen receptors or by inhibitingaromatase activity. Two possible categories of drugs havebeen considered for the treatment of pathologic gyneco-mastia: 1) specific estrogen receptor modulators (alsoknown as antiestrogens) such as tamoxifen, raloxifene,and clomiphene citrate, and 2) aromatase inhibitors suchas testolactone, anastrozole, and letrozole. Current dataare insufficient to demonstrate the effectiveness of eitherclass of drugs. Some reports on tamoxifen and raloxifenehave shown improvement in up to 91% of patients, (3)but no double-blind, placebo-controlled trials in this agegroup support these findings. The effectiveness of anas-trozole was investigated recently in a double-blind,placebo-controlled study of 80 adolescent boys who hadgynecomastia. The criterion for improvement was agreater than 50% reduction of breast volume. No benefitof anastrozole over placebo was demonstrated. (4) Sur-gery is an option to reduce breast size, but some expertsadvocate a trial of tamoxifen before considering surgery.

The dilemma of managing idiopathic excessive breast

development is whether to treat acondition early in its development,when it may resolve without inter-vention, or to defer treatment andrisk the chance that treatment willbe less effective if eventual breastdevelopment is much greater. Theauthors believe that reassuranceand close follow-up are the main-stays of management until moredata are available regarding the ef-fectiveness of pharmacologic inter-vention.

Premature ThelarcheBreast development in females isconsidered premature if it occursbefore 8 years of age. Prematurethelarche is defined as isolatedbreast development without evi-dence of sexual hair development,estrogenization of vaginal mucosa,acceleration of linear growth, rapidbone maturation, adult body odor,or behavioral changes typical of pu-berty. Although some experts ad-vocate using the lower age limit of7 years for Caucasian girls, this de-

cision should be made by a pediatric endocrinologist inindividual cases. The lower age limit for African-American and Mexican-American girls is younger thanfor Caucasian girls by approximately 1 year. Therefore,the 7-year criterion might be more appropriate for thesegroups.

Isolated premature thelarche usually is considered todiffer from central precocious puberty, which is the early(before 8 years of age) maturation of the hypothalamic-pituitary-gonadal axis with development of two or moresexual characteristics. However, it has been suggestedthat premature thelarche may represent one end of acontinuum from isolated breast development to centralprecocious puberty. (5)

Premature thelarche typically occurs during the first 2years after birth, and breast size may fluctuate cyclically.Premature thelarche usually does not progress to preco-cious puberty and typically resolves during childhood,but may last until puberty. By definition, prematurethelarche does not affect the time of pubertal onset. (6)

Exaggerated thelarche describes a variant of isolatedbreast development. Although there is no axillary orpubic hair, there may be some acceleration of growth

Figure 3. Interpretation of laboratory tests recommended for initial investigation ofgynecomastia. LH�luteinizing hormone, FSH�follicle-stimulating hormone,T�testosterone, nl�normal, E2�estradiol, beta-hCG�beta human chorionic gonadotro-pin, DHEAS�dehydroepiandrosterone sulfate





velocity and bone maturation at the time of breast devel-opment. Limited numbers of patients who have exagger-ated thelarche have been studied; the mean age at pre-sentation in one study was 3.7 (1.9 to 6.9) years. Theauthors also noted that persistent thelarche until pubertywas more common than noted before, with possibleprogression to central precocious puberty and early men-struation. (5)

As mentioned, breast development present from birthalmost always is physiologic, and the tissue should de-crease gradually and resolve within the first 2 postnatalyears. Key features of premature thelarche and preco-cious puberty are presented in Table 4.

Pathophysiology and CausesIsolated premature thelarche and exaggerated thelarchemay be due to partial activation of the hypothalamic-pituitary-gonadal axis, principally by FSH secretion, or tofailure of follicular involution with or without ovariancyst formation. In the latter case, estrogen secretion maybe sufficient to cause menstrual bleeding.

A less common cause is gonadotropin-independentestrogen production, as seen in McCune-Albright syn-drome and rare ovarian or adrenal tumors (althoughthese conditions usually present with precocious pu-berty). McCune-Albright syndrome generally presentswith the classic triad of gonadotropin-independent pre-cocious puberty, cafe au lait macules, and polyostoticfibrous dysplasia. Activating GNAS1 mutations with mo-saic distribution are the underlying cause of precociouspuberty. GNAS1 is a subunit of the G-protein coupledreceptors involved in intracellular signal transduction ofseveral hormones. The presence of such mutations in theovaries results in estrogen production without gonado-

tropin stimulation. The mosaic distribution may accountfor differences in manifestations of McCune-Albrightsyndrome. Such mutations also have been identified infemales who have premature or exaggerated thelarchewithout having other features of this syndrome. Otherrare conditions that may present with thelarche due togonadotropin-independent estrogen production includehepatocellular carcinoma, adrenal tumors, and CAH.

Premature thelarche may result from exposure toexogenous estrogen, including estrogen-containing cos-metic and hair products. One study reported an associa-tion between an increase in the incidence of prematurethelarche and estrogen concentrations in poultry, (7)although this finding has not been confirmed. Infantformulas containing soy also may be associated withthelarche, but insufficient evidence is available to recom-mend avoidance of specific foods. An outbreak of cases ofthelarche in female students and gynecomastia in malestudents at a school in Italy has been reported. (8)Although this event might suggest a common exposure,no cause has been established.

Xenoestrogens are chemical substances that bind tothe estrogen receptor. A wide variety of chemicals, suchas organochlorines, polychlorinated bisphenyls, para-bens, bisphenol A, and phthalates, as well as syntheticestrogen diethylstilbestrol and other substances, haveestrogenic properties. Some xenoestrogens are used inpesticides, cosmetics, and packaging material. However,only limited data suggest a relationship between their useand the onset of thelarche or gynecomastia.

Exposure to estrogen-containing cosmetics, especiallycertain hair products, is more common in African-American families and may cause early sexual develop-ment. (9) Caregiver use of estrogen-containing creams

Table 4. Key Features of Premature Thelarche and Precocious PubertyFeature Premature Thelarche Precocious PubertyIncidence peak (range) 6 mo to 2 y (<8 y) 5 to 8 y (<8 y)Breast

Sexual Maturity Rating stage Usually 2, early 3 2 through 5Size fluctuation In 80% No

Pubic hair No At least one present plus breastdevelopment

Axillary hair NoApocrine odor NoMenses No* YesLinear growth acceleration No* YesAdvanced bone age No* YesOutcome Considered benign May be associated with short stature,

early onset of puberty

*May be present in exaggerated thelarche.





may result in breast development in children. Althoughdata on absorption and systemic effects of such prod-ucts are lacking, it is important to exclude this possi-bility when evaluating prepubertal children presentingwith breast development. A list of hormone-containing cosmetics may be found on the Internet atwww.environmentaloncology.org/publications/careproducts.htm. Such cosmetics should not be used inchildren.

Other mechanisms that may play a role in inducingthelarche include increased sensitivity of breast receptorsto estrogen and increased aromatization of adrenal pre-cursors.

Epidemiology and CourseA population-based study in Minnesota found an inci-dence of 20.8 cases of premature thelarche per 100,000patient-years, with 60% of cases presenting in the first 2years after birth and a less pronounced incidence peak atages 5 to 7 years. (6) A more recent study found aprevalence of 2.1% among 3-year-old African-Americanand 0.7% among Caucasian girls. (10) However, thestudy did not specify how many children also had otherpubertal signs. Although age of onset does not strictlypredict course, breast enlargement before 2 years of ageis considered suggestive of premature thelarche, with abenign course and resolution in 44% to 66% of cases. (6)

In contrast, later onset may predictpersistence or exaggerated the-larche variant.

Breast development may be uni-lateral in up to 50% of patients.Time of resolution may range from6 months to 6 years. (6) One studyobserved progression to precociouspuberty in 14 of 100 females whopresented with isolated breast de-velopment. (11) Although it is un-clear whether these patients hadtrue central precocious puberty or ahigh risk for developing precociouspuberty, this study does indicatethat close follow-up of childrenwho experience premature the-larche is essential.

EvaluationPremature thelarche must be dis-tinguished from true precociouspuberty. Features of true preco-cious puberty include breast devel-

opment and estrogenization of the vaginal mucosa andlabia minora associated with adult body odor, pubic andaxillary hair development, acceleration of linear growth,and rapid bone maturation. When the patient presentswith two or more signs of precocious puberty, prematurethelarche is excluded.

When breast development is the only pubertal signpresent, the history and physical examination may pro-vide clues for environmental estrogen exposure or thepresence of McCune-Albright features. If isolated breastdevelopment is observed, the previous pattern of growthshould be evaluated. The breast should be examined andsize determined (see “Physical examination” in the pre-vious section on gynecomastia). Gentle retraction of thelabia is important to determine if the mucosa has areddish prepubertal appearance or a pinker, more estro-genized look. Serial measurements of breast size can beused to monitor changes over time.

If clues for environmental estrogen exposure orMcCune-Albright features are not present, the mostuseful clinical tool is examination of growth velocity.A bone age radiograph should be obtained if acceleratedgrowth velocity is present or if previous growth measure-ments are unavailable and breast development is substan-tial or increasing. An algorithm for evaluating femalespresenting with early breast development is provided inFigure 4. Follow-up is essential to establish the diagnosis

Figure 4. Algorithm for evaluation of females presenting with early breast development.BA�bone age. *See text for indications to measure BA.





of premature thelarche. A normal growth velocity, theabsence of additional pubertal features, and lack of sig-nificant progression of breast development support thediagnosis of premature thelarche.

Laboratory Investigation and Referral to aSpecialist

The primary care practitioner should consider referral toa pediatric endocrinologist when the diagnosis of prema-ture thelarche is uncertain and central precocious pu-berty is suspected. Radiographic determination of boneage estimates the extent of estrogenic stimulation be-cause estrogen promotes bone maturation, and an ad-vanced bone age suggests significant estrogen effect.Although studies have shown that patients who experi-ence premature thelarche may have higher serum con-centrations of FSH and estradiol as well as more matureovarian morphology, as shown by ultrasonography, base-line values of FSH and estradiol usually are not helpfulbecause they may be normal even in patients who havetrue precocious puberty. The specialist may order a go-nadotropin stimulation test and pelvic ultrasonographyto rule out central precocious puberty or ovarian neo-plasms.

OutcomeIsolated premature thelarche is considered a benign con-dition that has no effect on the age of puberty onset,menses, final height, or fertility. Although menarcheappeared to occur earlier in one study, (12) menarche inthese females was consistent with the timing of maternalmenarche. The theoretical risk of increased breast cancerdue to prolonged estrogenic stimulation has not beensupported by studies.

Other Breast DisordersOther rare conditions that may mimic breast develop-ment in both sexes usually present with unilateral breastenlargement and include congenital breast anomalies,neurofibromas, sarcomas, epithelial inclusion cysts, ductectasia, and mastitis. Among the congenital breast anom-alies are accessory nipples (polythelia) or breasts (poly-mastia), lack of nipple development (athelia) or absenceof breast development (amastia), and inverted nipples.Marked breast asymmetry, juvenile hyperplasia, and tu-berous breasts are other breast anomalies. Neoplasms areextremely rare. In pubertal females, the most commonbreast tumor is benign fibroadenoma. Mastitis in neo-nates may be severe and require treatment with intrave-nous antibiotics.

SummaryGynecomastia in males and premature thelarche in fe-males are common conditions in the pediatric popula-tion. Although gynecomastia and premature thelarcherepresent benign physiologic conditions in most cases, itis important to recognize and treat those patients whomay have underlying pathologic conditions. Clues tounderlying disease include age of onset, extent and pro-gression, presence of accompanying signs of pubertaldevelopment, and use of drugs. If clues to underlyingconditions are identified, referral to a specialist is war-ranted.

ACKNOWLEDGMENTS. The authors would like tothank Dr Gary Berkovitz, Professor, Chief of the Divi-sion of Pediatric Endocrinology, Miller School of Med-icine, University of Miami, for his help and guidance inediting the manuscript. We also wish to thank Dr Milt-iades Douvoyannis, Department of Pediatrics, Universityof Iowa, for providing help in bibliographic research andhelpful discussions from the point of the general pedia-trician.

References1. Mahoney CP. Adolescent gynecomastia. Differential diagno-sis and management. Pediatr Clin North Am. 1990;37:1389–14042. Berkovitz GD, Guerami A, Brown TR, MacDonald PC, MigeonCJ. Familial gynecomastia with increased extraglandular aromatiza-tion of plasma carbon19-steroids. J Clin Invest. 1985;75:1763–17693. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Benefi-cial effects of raloxifene and tamoxifen in the treatment of pubertalgynecomastia. J Pediatr. 2004;145:71–764. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy ofanastrozole for the treatment of pubertal gynecomastia: a random-ized, double-blind, placebo-controlled trial. J Clin EndocrinolMetab. 2004;89:4428–44335. Stanhope R, Brook CC. Thelarche variant: a new syndrome ofprecocious sexual maturation? Acta Endocrinol (Copenh). 1990;123:481–4866. Van Winter JT, Noller KL, Zimmerman D. Natural history ofpremature thelarche in Olmsted County, Minnesota, 1940 to1984. J Pediatr. 1990;116:278–2807. Saenz de Rodriguez CA, Bongiovanni AM, Conde de BorregoL. An epidemic of precocious development in Puerto Rican chil-dren. J Pediatr. 1985;107:393–3968. Nizzoli G, Del Corno G, Fara GM, Chiumello G. Gynaecom-astia and premature thelarche in a schoolchildren population ofnorthern Italy. Acta Endocrinol Suppl (Copenh). 1986;279:227–2319. Tiwary CM, Ward JA. Use of hair products containing hormoneor placenta by US military personnel. J Pediatr Endocrinol Metab.2003;16:1025–103210. Herman-Giddens ME, Slora EJ, Wasserman RC. Secondary





sexual characteristics and menses in young girls seen in officepractice: a study from the Pediatr Res in Office Settings network.Pediatrics. 1997;99:505–51211. Pasquino AM, Pucarelli I, Passeri F. Progression of prematurethelarche to central precocious puberty. J Pediatr. 1995;126:11–1412. Salardi S, Cacciari E, Mainetti B, Mazzanti L, Pirazzoli P.Outcome of premature thelarche: relation to puberty and finalheight. Arch Dis Child. 1998;79:173–174

Suggested ReadingBraunstein GD. Gynecomastia. N Engl J Med. 1993;328:490–495

Braunstein GD. Prevention and treatment of gynecomastia. UpToDate Online. 2007;15.1. Available at: www.uptodate.com

Herskovitz E, Leiberman E. Gynecomastia: a review. The Endocri-nologist. 2002;12:321–332

Ilicki A, Prager Lewin R, Kauli R, Kaufman H, Schachter A, LaronZ. Premature thelarche–natural history and sex hormone secre-tion in 68 girls. Acta Paediatr Scand. 1984;73:756–762

Lazala C, Saenger P. Pubertal gynecomastia. J Pediatr EndocrinolMetab. 2002;15:553–560

Stanhope R. Premature thelarche: clinical follow-up and indicationfor treatment. J Pediatr Endocrinol Metab. 2000;13(suppl 1):827–830





DOI: 10.1542/pir.28-9-e572007;28;e57Pediatrics in Review

Stavros Diamantopoulos and Yong BaoGynecomastia and Premature Thelarche : A Guide for Practitioners

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