Breast Physiology: Normal and Abnormal Development and Function

陳怡仁 醫師 台北榮民總醫院 婦產部 國立陽明大學 講 師

Development and Function of Breast
• • • • • Embryology to Childhood Puberty Pregnancy Lactation Menopause

Anatomy

Anatomy
1.15-20 lobes 2.lobe:lobules, small branch, and larger ducts. 3.Radial fashion 4.Peripheral portions of lobes often overlap

Anatomy .

Mammary gland • Epithelial system of ducts • Lobuloalveolar secretory units • Mesenchymally derived fat pad .

The ducts contain one layer of epithelium and one layer of myoepithelial. • The ectoderm invaginates into the surrounding mesenchyme. • At term birth. • Mammary gland originates from milk streaks. .Embryology to Childhood Morphology • Breast formation beginning in the 6th weeks of fetal development. • During the later part of pregnancy this fetal epithelium further canalizes. bilateral ectodermal thickenings that extend from the axilla to the groin. the breasts has 6-10 ducts.

• At birth the withdrawal of maternal steroids results in secretion of neonatal prolactin (PRL) that stimulates newborn breast secretion. .Embryology to Childhood Hormones • The initial fetal stages of breast development are independent of sex steroid influence.

regardless of sex. may swell during pregnancy. The secretion dissipates within 34 weeks. • Witch’s milk: PRL stimulates newborn breast secretion (water. fat and debris) in 80-90% infants. • The accessory mammary tissue most located in the axilla.Embryology to Childhood Clinical correlates • Failure to completely regress result in accessory nipple (polythelia) and mammary tissue (polymastia). .

Embryology to Childhood Clinical correlates • Premature thelarche: breast development before the age of 8 years without concomitant signs of puberty. most commonly within the first 2 years of lifer. • Usually bilateral. • The second period may occur after 6 years .

Premature thelarche 14 months Tanner stage 3 13 months PRL: 100 ng/ml .

Embryology to Childhood Clinical correlates • Precocious puberty: Breast development before 8 years of age that is accompanied by other signs of puberty defines precocious puberty. cerebral infection. ovarian cyst or in primary hypothyroidism.( High level gonadotropins and estrogen) • Peripheral puberty: the effects of estrogen from food. hypothalamic hamartoma. • Central precocious puberty: due to premature GnRH. ( low levels of gonadotropins and high levels of estrogen) .

Hypothyrodism 5 years old A. Breast regression after treatment 3.5 year old Central precocious puberty . Tanner stage 2 B.

Puberty Morphology • Thelarche: the beginning of adult breast development ( white women 10 years) • Ductal growth phase: Club-shaped terminal end buds (TEBs) • Lobuloalveolar phase: TEBs form alveolar buds. the TDLU is termed a virginal lobule or lobule type 1 (Lob1) . 910 alveolar buds empty into terminal ductal lobular units (TDLUs) • In early puberty.

these buds are termed ductules or alveoli. . • Lobs during late teens but then decline after the mid twenties.Puberty Morphology • Under cyclic influence of ovarian hormones: some of the Lob1 will undergo further division and differentiate into a lobule type 2 (Lob 2). • In Lob 2 the alveolar buds become smaller but four times more numerous than Lob1.

maximum size of the lobules • Menstrual phase: Day 28-32 . only one epithelial type.Puberty menstrual cycle • Early follicular phase: Day 3-7. Minimum volume in 5-7 days. • Secretory phase: Day 21-27. • Follicular phase: Day 8-14. dense stroma. myoepiethelial and intermediate cell. progression of epithelial in to three cell type: luminal . • Ovulation: Increase alveoli volume and number.

Tanner stages of breast development .

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. Unopposed estrogen stimulation induce ductal growth. • Estrogen is the major hormonal influence on the breast at the onset of puberty. primarily stimulates ductal growth but also increases fat deposition.Puberty Estrogen Hormones • Estrogen window: The initial immaturity of hypothalamic-pituitary axis results in anovulatory cycles for the first 1 to 2 years after menses begin. • Estrogen a potent mamogen. • Estrogen receptors have been identified in both the epithelium and the stroma.

• Progesterone is essential for lobuloalveolar growth.Puberty Hormones • Insulin-like growth factor-I (IGF-I) synergizes with estrogen to increase elongation and growth at the TEB. • Progesterone does not appear to be essential in early ductal growth. estrogen and glucocorticoids in addition to progesterone. GH. . • However. are necessary for full lobuloalveolar development. PRL.

. approximately 5 days after the progesterone peak. • Apoptosis peaks just before menses.Puberty Progesterone Hormones • A peak in mitosis within 24 hours of the progesterone peak and estimated peaks of breast volume. • Brest fullness and tenderness occur premenstrually. epithelial volume and surface temperature within 2 to 4 days after the progesterone peak.

Reduction mammoplasty is treatment option. Final breast size may be asymmetric. Usually no hormonal imbalances. skin striae. periareolar hair. • Juvenile hypertrophy: postpubertal continuation of epithelial and stromal growth that results in breasts that can weigh 3 to 8 kg. .Puberty Clinical correlates • Normal variants: development may be initially unilateral.

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• Etiology: Altered rations of androgen to estrogens increase peripheral aromatization of androgen • Other cause: Marijuana. • 70% of pubertal boys but rarely exceeds the Tanner B2 (elevation of the breast and papilla as a small mound) • Resolved with several months to 2 years. LH receptor deficiency. .Puberty Clinical correlates • Gynecomastia :adolescent male at age 13-14. • Pain in 25% cases. testosterone deficiency.

9-year-old boy with right sided gynecomastia .

Tanner stage 5 Hypospadias 16 years old Partial androgen resistance After complete mastectomy .

. DM. several genetic abnormalities. hyperprolactinemia.Puberty Failure of estrogen production • Insufficient development of the ductal system • Primary ovarian failure • Hypogonadotropism: Turner syndrome. Cushing’s syndrome. brain tumor. isolated gonadotropin insufficiency. hypothyroidism.

(fat-derived estrogens cause an earlier differentiation of the breast.Puberty correlation with breast cancer • Positive correlation between tallness in pubertal girls (age 7-5) and risk of future breast cancer. decrease malignant potential.) . ( high serum IGF levels) • Overweight children seem to have a decreased risk of breast cancer.

Congenital adrenal hyperplasia Congential adreanl hyperplaisa 10-year-old boy Genetic female .

Turner syndorme 15-year-old (XO) 19-year-old XO/XX after estrogen treatment .

the number of Lob 3 significantly increase. • If the first term pregnancy occurs before the 30 y/o. . • This proliferation leads to formation more differenced forms of lobules ( Lob3 and 4) • Lob 3 can have 10 times the alveoli per lobules compared with Lob 1.Pregnancy Morphology • First phase: occurs during early pregnancy. proliferation of distal duct to more lobule and more alveoli within each lobule.

• During the last trimester the epithelial cells are filled with fat droplets.Pregnancy Morphology • Phase 2: midpoint of pregnancy • Differentiation of the lobular units into secretory units • Cell proliferation are minimized and the alveoli differentiate into acini. the acini distend with colostrum. • The increase in breast size during this period is secondary to distention of acini and increased vascularity. .

• Estrogen increase during gestation parallels that of PRL. Estrogen is believed to be a direct and indirect modulator of PRL secretion. initiation of lactogenesis is inhibited by the presence of progesterone.Pregnancy Hormones • PRL: play a continued role in lobuloalveolar differentiation. ( progesterone can stimulate the production of PRL transcription inhibitor) . • PRL increases beginning at 8 weeks and continues to rise throughout gestation and postpartum. • During pregnancy.

• Lob1 of the nulliparuous woman would seem to be a prime target for carcinogen.Pregnancy Clinical correlates • Gravid hypertrophy is the rapid enlargement of the breast during pregnancy. It may appear during a second pregnancy. • Early parity has a protective effect against breast. • Postmenopauseal women who were parous ultimately had the same percentage of Lob 1 as the nulliparous women. but the proliferative index of Lob 1 in nulliparous women was higher than that parous women. .

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. • The second half of gestation: final maturation of the gland into the secretory organ of lactation.Lactation Morphology • The first half of pregnancy: significant ductal and lobuloalveolar proliferation and formation of Lob 3 and some Lob 4 . The ability to synthesize and secrete the milk is termed lactogenesis.

Mature milk secretion begins 30-40 hours postpartum and averages 1-2 ml/g of breast tissue per day. . • Lactogenesis II: initiation of significant milk secretion at or just after parturition.Lactation Lactogenesis • Lactogenesis I: synthesis of unique milk components. an immature milk product. Mature milk is composed of fat and protein suspended in a lactose solution. The alveoli distend with colostrum. This initial product is colostrum (nutritional and passive immunity for he baby. Lob 4 formed in this stage. Begins between 15-20 weeks. The rate of lactation remains constant of the first 6 months of lactation.

It is triggered by physical distortion of the luminal epithelial cells or by accumulation of apoptosis-inducing factors in the milk. with a decrease in the number of alveoli per lobule. • There two phases of post lactational involution. including destruction of basement membranes and alveolar structure and . the breast involutes and returns to a state resembling that of pregnancy. . • The 2nd phase is characterized by a active tissue remodeling.Lactation Weaning • After weaning occurs. • The lobules decrease in size. • The first phase is reversible.

is able to initiate lactogenesis II. PRL. • The hormone is secreted in increasing amounts throughout pregnancy and peaks before delivery. in the background of dissipating progesterone. . in concert with glucocorticoids. • Neural stimuli for sucking enhance the release of PRL.Lactation Hormones • PRL is the principal hormone of the synthesis of milk proteins and the maintenance of lactation. • After birth. • Glucocorticoids work along the PRL to differentiate mammary epithelium and stimulate milk synthesis and secretion.

resulting in an expulsion of milk into the lactiferous sinuses.Lactation Hormones • Oxytocin is responsible fore release of stored milk. . • Oxytocin stimulates contraction of the myoepithelial cells surrounding the acini and small ducts. commonly referred to as milk let-down. • Ocytocin is secreted from the posterior pituitary by a sensory stimulation from the nipple areola complex.

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retained placenta. • Delay of lactogenesis II more than 72 hours postpartum. .Lactation Clinical correlates • Delayed onset of lactation: lack of infant suckling. unscheduled cesarean delivery or vaginal delivery with prolonged stage 2 labor and obesity.

Have women with smaller breast inadequate milk production ? • Women with smaller-capacity breasts achieved lactational success by increasing the frequency of feeding and the degree of breast emptying with each feeding. • Women with larger –capacity breasts have more flexibility in scheduling their feedings and can go longer at night without compromising their synthesis capabilities. .

.s syndrome ( infarction of the pituitary gland with ensuing insufficiency of PRL and other hormones) • Metoclopramide and oral TRH may increase the secretion of PRL and improve lactation .Lactation Clinical correlates • Lactational failure may be the first sign of Sheehan.

sexual intercourse . . Cushing’s syndrome. • Galactorrhea may be associated with adrenal insufficiency. surgery. • MRI should be obtained to exclude a pituitary tumor. • PRL < 100 ng/ml and no evidence of a pituitary tumor. • Pituitary tumors. sleep or drug can inhibit PRF release leading to an increase PRL. renal failure. • Amenorrhea is associated with galactorrhea. no treatment is needed. acromegaly. • Stress from exercise. or lung tumor.Galactorrhea • Inappropriate secretion of milky fluid in the absence of pregnancy or breastfeeding for more than 6 months. hypothyroidism (TRH) and hypothalamic lesions may cause galactorrhea.

• Climacteric phase from age 45 to 55 has a moderate decrease in glandular epithelium.Menopause Morphology • Increased number of Lob 1 and a decline in Lob 2 and 3. • The end of the fifth decade mostly Lob 1. • Glandular epithelium undergoes apoptosis. the interlobular stomal tissue regresses. and there is replacement by fat. .

testosterone and dehydroepiandrosterone become predominant. . • In nulliparous women these Lob1 cells have a higher proliferative index than that of parous women.Menopause Clinical correlates • Estrogen and progesterone have declined. The more highly proliferative cells in nulliparous women add to their risk. androstenedione . • All postmenopausal women are more susceptible to interaction with carcinogens. and ovarian androgens.

hormonal and clinical correlates of the various stages of development. puberty. infancy and childhood. lactation and menopause. .Summary • The morphologic. including that of the embryo. pregnancy.

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