Overview
This lecture covers the structure and hormonal development of the mammary gland, how milk composition changes over the postpartum weeks, the two neuroendocrine reflexes that drive milk production and ejection (prolactin and oxytocin), causes of lactation failure, the effect of stress on lactation, the contraceptive effect of breastfeeding, and the process of weaning. The reflex pathways (suckling stimulus to hormone release to breast action) are the throughline connecting most sections.
Mammary Gland Structure and Development
- Each breast has 15-20 lobes, each made up of smaller lobules.
- Each lobule contains hundreds of secretory units called alveoli. Alveoli are lined by secretory epithelial cells, surrounded by contractile myoepithelial cells, and have a rich capillary blood supply.
- Alveolar lumen drains into small tubules, which enter the duct system, which drains via lactiferous ducts to the nipple/areola.
- Secretory cell function: alveolar cells synthesise and secrete fluid, fat, protein and carbohydrate (mostly lactose).
- Protein: made on the rough ER, packaged into Golgi vesicles, released by exocytosis.
- Fat: made on the smooth ER, vesicles coalesce and are released by plasma membrane entrapment (bud off surrounded by membrane).
- Five developmental stages:
- Prepubertal: duct growth, limited branching.
- Puberty: duct branching, development of a layered epithelium (secretory and myoepithelial cells), fat deposition, cyclical growth/regression with the menstrual cycle.
- Pregnancy (lactogenesis): duct sprouting and branching, loss of adipose tissue, alveolar formation, but only little milk production at this stage.
- Lactation: full alveolar development, copious milk secretion.
- Hormonal drivers of development:
- Oestradiol: stimulates duct branching and fat deposition.
- Progesterone: stimulates alveolar development.
- Prolactin: stimulates milk production, but this effect is blocked by the high oestradiol and progesterone levels of pregnancy (which is why full milk production is held off until after birth).
- Hormone trends across the stages: oestradiol has a pubertal spike then rises through pregnancy, peaking late, before dropping sharply at parturition. Progesterone rises gradually through pregnancy then also drops sharply at parturition. Prolactin has a small pubertal peak, rises through pregnancy, dips at parturition, then rises again during lactation.
Milk Composition Over Time
- Milk production is possible from as early as 16 weeks of gestation, due to increasing prolactin and placental lactogen concentrations.
- Colostrum (week 1): rich in proteins, vitamins A, D, E and K, and immunoglobulins (antibodies); low in lactose and soluble fats.
- Transitional milk (from week 2 onward): a gradual change in which lactose and fat increase as protein declines.
- Mature milk: produced for months once established; production then becomes regulated by supply and demand.
Prolactin: The Milk Production Reflex
- Prolactin is required for milk production. It acts on secretory epithelial cells to promote synthesis of milk proteins.
- Prolactin secreted in response to the suckling stimulus promotes the milk production needed for the next feed.
- Suckling reflex pathway: nipple stimulation during suckling -> signal via dorsal horn/spinal cord and brainstem -> medial forebrain bundle -> inhibits tuberoinfundibular dopamine (TIDA) neurone activity in the hypothalamus -> reduced dopamine secretion -> because dopamine normally suppresses prolactin release, reduced dopamine facilitates prolactin release from the anterior pituitary -> increased blood prolactin -> acts on alveolar cells in the breast -> stimulates milk synthesis.
- Human data: plasma prolactin is near baseline (about 20-30 ng/ml) before nursing, rises sharply during nursing to peaks of roughly 175-300 ng/ml, then declines gradually over about 2-3 hours. A small early rise in let-down can occur even before nursing starts, during play with the infant, consistent with a conditioned component.
- Clinical: dopaminergic D2 agonists (bromocriptine, cabergoline) block prolactin secretion and will inhibit milk production.
Oxytocin: The Milk Ejection (Let-Down) Reflex
- Oxytocin triggers the milk ejection reflex (let-down) by causing myoepithelial cells to contract.
- Steroid hormone changes during pregnancy induce oxytocin receptors and increase breast responsiveness to oxytocin.
- The suckling stimulus causes pulsatile oxytocin secretion.
- Milk let-down can also occur as a conditioned reflex, triggered by playing with or thinking about the baby.
- Stress inhibits oxytocin secretion and milk let-down.
- Pathway: nipple stimulation during suckling -> dorsal horn/spinal cord -> brainstem -> medial forebrain bundle -> hypothalamo-hypophyseal tract; increased firing after nipple or reproductive tract stimulation stimulates oxytocin neurons in the paraventricular and supraoptic nuclei of the hypothalamus -> oxytocin released from the posterior pituitary -> increased blood oxytocin -> acts on myoepithelial cells in the breast -> stimulates milk ejection/let-down.
- Rabbit data: bursts of neuronal firing occur during suckling and during nipple grooming. Plasma oxytocin rises from near 0 to a peak of around 260 pmol/l during/after suckling, with smaller secondary peaks aligning with nipple-grooming events, before declining.
Lactation Failure
- Definition: inadequate milk production and/or a failure of milk ejection.
- Inadequate production is usually due to insufficient prolactin secretion, caused by postpartum hypopituitarism, obesity, or D2 receptor agonists (e.g. those used to treat hyperprolactinaemia or prolactinoma).
- Can be treated with D2 receptor antagonists.
- Oxytocin or oxytocin receptor agonists are not widely used to treat lactation failure.
- Reliable indicators of adequate milk supply: nappy output (poo frequency under 5 weeks of age, and wet nappies) and weight gain.
- NOT reliable indicators of low milk supply: short feeds, small breasts, being unable to pump, softer breasts, no longer feeling the let-down reflex, stopping leaking, wakeful babies who won’t settle, a baby that will still take a bottle, and frequent feeds.
Stress and Lactation
- Acute stress (e.g. an unwelcome visitor) inhibits oxytocin secretion and milk let-down. In one study, suckling-associated oxytocin pulses were frequent and high under control conditions, reduced to a single pulse when the mother performed mental calculation, and reduced to a single, smaller pulse under noise distraction.
- Chronic stress (e.g. depression, overwork) is linked to poor lactation in some women.
- It is unclear whether chronic stress acts directly on milk production, or acts secondarily via impaired let-down reducing subsequent production.
Contraceptive Effects of Lactation
- Breastfeeding is a natural form of contraception and an important regulator of birth spacing in many societies.
- The length of postpartum infertility is variable and depends on the frequency and duration of the suckling stimulus; it can be reliable until the first sign of menstruation returns.
- Suckling stimulates prolactin but inhibits GnRH. The mechanism is uncertain; proposed explanations include:
- Hyperprolactinaemia, though only 5-10% of GnRH neurons carry prolactin receptors, limiting a direct action.
- Endogenous opioids: suckling releases opioids such as endorphins, which inhibit GnRH neurons.
- Negative energy balance: low body fat can itself lead to infertility.
- Human data comparing women with suppressed ovulation versus ovulation after supplementary infant food was introduced: sucking episodes per day and sucking duration were similar between groups before supplementary food, then declined faster in the ovulation group afterwards. Plasma prolactin started high (roughly 1000-1700 mU/l) in both groups, declined after supplementary food was introduced, and dropped further/faster in the ovulation group, falling below a threshold associated with return of ovulation.
Weaning and Cessation of Lactation
- Reduced suckling stimulation reduces milk synthesis.
- Distension and engorgement of the mammary gland causes rupture of alveolar walls, compression of blood vessels, and hypoxia.
- This is followed by resorption of secreted material, collapse of alveoli, and an increase in fat deposition; the process may take 2-3 months.
- Pharmacological blockade of milk production is possible using dopaminergic agonists.
Self-test
- Define an alveolus and describe its cellular components.
- Describe the roles of oestradiol, progesterone and prolactin in mammary gland development.
- List the five developmental stages of the mammary gland, with one structural feature of each.
- Describe how protein and fat are each secreted by mammary alveolar cells, naming the organelles involved.
- Distinguish colostrum, transitional milk and mature milk in terms of composition and timing.
- Describe the steps of the suckling-induced prolactin reflex, from nipple stimulation to milk synthesis.
- Explain why a reduction in dopamine secretion increases prolactin release.
- Predict the effect of a dopaminergic D2 agonist such as bromocriptine on lactation, and explain why.
- Describe the steps of the oxytocin-mediated milk ejection (let-down) reflex.
- Explain what is meant by a conditioned let-down reflex, and describe how stress affects milk let-down.
- Distinguish inadequate milk production from failure of milk ejection as causes of lactation failure, and give a cause of each.
- List the reliable indicators of adequate milk supply, and give two commonly assumed but unreliable indicators.
- Describe three proposed mechanisms by which suckling inhibits GnRH secretion during lactation.
- Describe the physiological changes that occur in the breast during weaning.
- A stressed, postpartum woman is feeding frequently but reports her milk “isn’t coming”. Using the relevant reflex pathway, explain how stress could produce this despite adequate feeding frequency.
Answers
Reveal answers
- An alveolus is a secretory unit within a lobule, lined by secretory epithelial cells that produce milk, surrounded by contractile myoepithelial cells, with a rich capillary blood supply; its lumen drains into a small tubule.
- Oestradiol stimulates branching of ducts and fat deposition; progesterone stimulates alveolar development; prolactin stimulates milk production, but this effect is blocked by high oestradiol and progesterone during pregnancy.
- Prepubertal (duct growth, limited branching); puberty (duct branching, layered epithelium, fat deposition, cyclical change); early/late pregnancy, i.e. lactogenesis (duct sprouting/branching, loss of adipose tissue, alveolar formation, little milk production); lactation (full alveolar development, copious milk secretion).
- Protein is synthesised on the rough endoplasmic reticulum, packaged by the Golgi apparatus into vesicles, and released by exocytosis. Fat is synthesised on the smooth endoplasmic reticulum; vesicles coalesce and are released via plasma membrane entrapment.
- Colostrum (week 1) is rich in protein, vitamins A/D/E/K and immunoglobulins, but low in lactose and soluble fats. Transitional milk (from week 2) shows lactose and fat rising as protein declines. Mature milk is the stable composition produced for months once established, regulated by supply and demand.
- Nipple stimulation during suckling signals via the dorsal horn/spinal cord and brainstem to the medial forebrain bundle, which inhibits TIDA neurone activity in the hypothalamus, reducing dopamine secretion; this facilitates prolactin release from the anterior pituitary, increasing blood prolactin, which acts on alveolar cells to stimulate milk synthesis.
- Dopamine normally tonically inhibits prolactin secretion from the anterior pituitary, so a reduction in dopamine removes this inhibition and allows prolactin release to increase.
- It would inhibit lactation, because D2 agonists block prolactin secretion, and prolactin is required for milk production.
- Nipple stimulation during suckling signals via the dorsal horn/spinal cord, brainstem and medial forebrain bundle to the hypothalamo-hypophyseal tract, stimulating oxytocin neurons in the paraventricular and supraoptic nuclei; oxytocin is released from the posterior pituitary, increasing blood oxytocin, which acts on myoepithelial cells to cause contraction and milk ejection.
- A conditioned let-down reflex is one triggered by cues associated with the baby (e.g. playing with or thinking about the infant) rather than by direct nipple stimulation. Stress inhibits oxytocin secretion and suppresses let-down, as shown by suckling-associated oxytocin pulses being reduced or abolished by acute distraction/stress (mental calculation, noise).
- Inadequate milk production is usually due to insufficient prolactin secretion (e.g. from postpartum hypopituitarism, obesity, or D2 receptor agonists). Failure of milk ejection is due to inadequate oxytocin action (e.g. from stress inhibiting oxytocin secretion).
- Reliable indicators: nappy output (poo frequency under 5 weeks, wet nappies) and weight gain. Unreliable indicators include, for example, short feeds and small breasts (also acceptable: inability to pump, softer breasts, no longer feeling let-down, stopping leaking, wakeful babies, baby taking a bottle, frequent feeds).
- (1) Hyperprolactinaemia, though only 5-10% of GnRH neurons have prolactin receptors; (2) endogenous opioids released by suckling (e.g. endorphins) inhibiting GnRH neurons; (3) negative energy balance, where low body fat leads to infertility.
- Reduced suckling reduces milk synthesis; distension/engorgement causes rupture of alveolar walls, compression of blood vessels and hypoxia; this is followed by resorption of secreted material, collapse of alveoli and increased fat deposition, taking 2-3 months.
- Stress inhibits oxytocin secretion, and oxytocin is required for the myoepithelial cell contraction that drives milk ejection (let-down). Even with adequate suckling-driven prolactin secretion maintaining milk synthesis, impaired oxytocin release means the milk already made cannot be effectively ejected, so the mother perceives that milk “isn’t coming”.