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Physiological Breast Development and Involution

At birth, (the breasts are identical in males and females): demonstrating only the presence of major ducts;
and the Nipple is represented by a small mammary pit.

During infancy, a proliferation of mesenchyme transforms; (evaginates) the mammary pit into  a nipple.

The Male breast and the immature Female breast ;( pre-pubertal); are similar to each other:-

The Nipple is small; but the areola is fully formed. The breast tissues don’t extend beyond the margins of
the areola and formed from few ducts embedded in fibrous Stroma.

Normal Development and Physiology of the Breast:--

The breast remains undeveloped in the female until puberty.

Pre-pubertal: the breast is composed primarily of dense fibrous Stroma and scattered few ducts lined with
epithelium ;). At the terminal ends of mammary ducts; there are poorly-developed but potentially
secretory acini.

(Menarche: onset of menstrual cycles.) Thelarche: refers to onset of breast enlargement and maturation.

At puberty ;( as measured by breast development and the growth of pubic hair), begins between the
ages of 8 – 12 years. The process of Female breast maturation is initiated by low-amplitude pulses of
pituitary gonadotropins, which raise serum estradiol concentrations.

(The maturation of Female Breast is under the control of pituitary hormones; estrogen, progesterone,
adrenal hormones, and the trophic effects of insulin; growth; and thyroid hormone.)

Hormonal Control of Breast Maturation and Function:-

The hypothalamic neuro-trophic hormones are responsible for regulation of the secretion of the hormones
that affect maturation and function of the breast tissues; as well as onset of menstrual cycle.

In the female neonate, circulating estrogen and progesterone levels decrease after birth and remain low
throughout childhood because of the sensitivity of the hypothalamic-pituitary axis to negative feedback
from these hormones.

With the onset of puberty, there is a decrease in the sensitivity of the hypothalamic-pituitary axis to
negative feedback and an increase in its sensitivity to positive feedback from estrogen.

This Physiological Insult  will initiate increased release of Gonadotropin releasing hormone (GnRH) from
the hypothalamus; which in turn  stimulate release of the pituitary gonadotropins; luteinizing
hormone;(LH) and follicle-stimulating hormone; (FSH); that ultimately  regulate the release of estrogen
and progesterone from the ovaries.
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Estrogen and progesterone; will initiate establishment of the menstrual cycle ;( menarche); and
maturation of Breast tissues.

Positive and negative feedback effects of circulating estrogen and progesterone regulate the secretion of
LH, FSH, and GnRH.

The hormone-dependent maturation of the Female breast:-

The exact timing of breast maturation; and the coordinated development of both breast buds may vary
from the average in individual girls. (Asymmetric growth is the rule rather than the exception)

Breast maturation; entails increased deposition of fat, proliferation of connective tissue Stroma; the
formation of new ducts by branching and elongation, and at the terminal ducts; there are solid masses of
lobular epithelial cells (the future breast lobules.)

Nipple-Areola Complex; the areola pigment becomes darker; (rosy hue); and the nipple assumes an
elevated configuration

Estrogen initiates ductal development; increase vascularity and fat deposition, whereas progesterone is
responsible for development and differentiation of Lobular epithelium; the TDLU.

Within the mammary gland; there are a number of paracrine regulatory factors, some stimulatory and
some inhibitory, which influence cell division and differentiation; these are insulin-like growth factors,

epidermal growth factor and transforming growth factor .

The post-pubertal; (Adolescent) mature; (resting) breast:--

It contains fat, Fibrous Stroma, lactiferous ducts, and lobular epithelial units. The size of the resting post-
pubertal breast depends upon the fat content.

Generally; the Inactive-(Resting) post-pubertal Breast; consists primarily of ductal epithelium; the lobular
epithelium is sparse and the breasts remain incompletely developed until first pregnancy occurs.
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Adolescent Breast; (Post-pubertal)-Resting- Proliferation and branching of new duct with

appearance of lobular epithelial units. However the lobular epithelium is sparse and consists
primarily of ductal epithelium

Pre-pubertal gynecomastia: - refers to symmetrical enlargement and projection of the breast bud in a
young girl before age of 6-8 years, unaccompanied by the other changes of puberty. This process, which
may be unilateral; is physiological; not neoplastic and is not an indication for biopsy.

Precocious Puberty; is a pathological condition; characterized by bilateral enlargement of the breast with
other signs of puberty before age of 8 years; due to functioning adrenal or ovarian tumors.

Cyclic changes in the Breast ;( with phases of menstrual cycle):-

During phases of the menstrual cycle; the glandular epithelium and lobular Stroma undergo cyclic
stimulation; and the dominant process is hypertrophy rather than hyperplasia.

At the time of ovulation-(Mid-Cycle), estrogen stimulation the ductal and alveolar epithelium increases
in height; and duct Lumina become more prominent, with accumulation of some secretions. This leads to 
increase in the size and density of the breasts; (the Breasts may be felt granular or nodular.)

In the late luteal- (premenstrual) phase, there is intra-lobular fluid accumulation of and edema; which
may produce pain and breast engorgement.

With the onset of menstruation, the breast engorgement subsides and epithelial hypertrophy decreases.

During Pregnancy:--

There is dramatic increase in circulating ovarian and placental estrogens and progestins.
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Formation of new Lobules and Acini ;( Adenosis of pregnancy); There is proliferation and branching of
minor terminal ducts; new Acini bud-off these minor ducts.

Proliferation of the glandular epithelium ;( ductal and lobular); i.e. Proliferation of the TDLU.

Differentiation of Lobular Acini--the acini now display a lumen surrounded by the epithelial secretory cells.

There is relative diminution in the volume of the fibrous Stroma and adipose tissue.

The Stroma is infiltrated with lymphocytes, plasma cells and these cells are the source of the antibody
component of the milk secreted in the first few days after delivery ;( colostrum).

The Areola enlarged; and its pigmentation is enhanced. The accessory areolar glands (Montgomery’s
glands) become prominent and appear as small elevations on the surface of the areola; and they secrete
oily substance which serves in lubrication of the nipple during suckling and lactation.

In the last days of pregnancy, the breast acini secrete colostrum, a yellow, sticky, serous fluid rich in
antibodies, which is then replaced by true secretion of milk.
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After Delivery (during Lactation):--

There is a sudden loss of placental hormones, (progesterone, and estrogen level decreased); permitting
full expression of the lactogenic action of prolactin.

Persistent high levels of prolactin; is the principal trigger for milk formation; (alongside the permissive
actions of glucocorticoids, insulin, and thyroxine).

Prolactin Hormone up-regulates hormone receptors and stimulates acinar epithelial development.
Prolactin stimulates the synthesis of milk fats and proteins.

Enlargement of the breasts occurs via hypertrophy of (acinar); alveolar epithelium and accumulation of
secretory products in the Lumina of the minor ducts and acini.

Breast during Lactation; hypertrophy of (acinar); alveolar epithelium and accumulation of secretory
products in the Lumina of the minor ducts and acini.

There are two lactogenic hormones:

(a)--Prolactin which is secreted by the lactotrophs in the anterior pituitary.

(b)--human placental lactogen (hpL) which is produced by the maternal placenta.

The secretion placental lactogen reaches a peak during the final weeks of pregnancy and this prepares
the breast for milk production; (stimulates acinar epithelium development); and at this stage there is
no significant secretion of milk because the high levels of estrogen and progesterone in maternal blood
have an inhibitory effect on milk production.
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Soon after childbirth, hpL disappears from the maternal circulation, the levels of estrogen and
progesterone sharply decreased in maternal blood; permitting full expression of the lactogenic action
of prolactin hormone.

Milk Production and Release:-

Milk production and release are controlled by neuro-hormonal reflex arcs that originate in nerve endings of
the nipple-areola complex.

Stimulation of the nipple; (infant suckling); appears to be the physiologic signal for continued pituitary
secretion of prolactin and acute release of oxytocin.

Maintenance of lactation requires regular stimulation of these neural reflexes, which results in;  release
of Oxytocin from posterior pituitary; which in turn mediates;  the secretion of prolactin.; prolactin
secretion  stimulates the synthesis of milk fats and proteins.

(Oxytocin is a polypeptide which is synthesized in the hypothalamus and stored in the posterior pituitary
(neuro-hypophysis).

The milk expulsion is caused by contraction of the Myo-epithelial cells that surround the mammary ducts
and terminal ductules; in response to the pituitary peptide oxytocin. Contraction of the Myo-epithelial
cells, will results in compression of alveoli and expulsion of milk into the lactiferous sinuses.

The normal, healthy, well-nourished lactating woman forms about 1 litre of milk/day.

With cessation of Breast Feeding; there is a fall in the prolactin level and no stimulus for release of
oxytocin; dormant milk causes increased pressure within the ducts and alveoli, which results in atrophy of
the epithelium; so the breast then returns to a resting state and to the cyclic menstrual changes.

After Weaning; decrease in breast size is due to atrophy of glandular and ductal epithelium.

Artificial suppression of lactation by the administration of estrogen or by administering dopaminergic

agents such as (bromocriptine); which have an inhibitory effect on the synthesis and release of prolactin.

After Menopause; (Breast Involution):--

Menopause is defined by cessation of menstrual flow for at least 1 year; usually occurs between the ages
of 40 - 55 years, with a median age of 51 years; due to natural steep decrease in the secretion of estrogen
and progesterone by the ovaries.

There will be involution; and progressive decrease in the amount of glandular tissue in the breast,
(decrease of the mammary ducts and the lobular glandular epithelial elements) of the resting breast;
which is replaced by increased fat deposition. So; there is consequent reduction in breast tissue density;
which renders the breast tissue more amenable to mammographic examination.
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There is atrophy of Cooper Ligaments ;( the breasts become pendulous due to loss of supportive
elements); and the connective tissue Stroma; becomes less cellular.

In some women, marked fatty deposition of the breast; and in others, the breasts shrink considerably.

At Menopause; there will be progressive decrease and involution of the ductal and lobular glandular
epithelial elements which is replaced by increased fat deposition. There is atrophy of Cooper Ligaments
and the connective tissue Stroma; becomes less cellular.

Under the influence of Hormone replacement therapy (HRT); there is persistence of lobular glandular
epithelium, hyperplasia of the ductal epithelium, and even cyst formation.

HRT can lead to increased breast density, which may lower the sensitivity of mammography.