03 - Growth Hormone and Prolactin

growth hormone (GH)

anterior pituitary peptide hormone that acts directly on tissues

• synthesized and secreted by somatotropes, which make up 1/3 of pituitary cells

• exists in multiple molecular forms

  • 10% monomeric (20kDa)

  • 90% dimeric inactive form (22kDa)

• 50% of hormone is bound to protein in plasma

  • unusual for peptide hormone → binds to protein like a steroid

• short half-life of 6-20 minutes

• synthesis stimulated by GHRH from hypothalamus

• requires thyroid hormone for formation of normal amounts

  • absence of TH leads to cretinism, which includes short stature

stimulators of GH secretion

• GHRH → acts on pituitary to release GH 

  • acts on liver to make IGF-1

  • acts on adipose tissue to make free fatty acids

• ghrelin (from stomach)

• stress

• amino acids (arginine)

• traumatic and psychogenic stress

inhibitors of GH secretion

• somatostatin → acts on pituitary to inhibit GH release

• IGF-1 → made from liver, negative feedback on GH

  • inhibits GHRH and increases somatostatin

• free fatty acids → made by adipose tissue, negative feedback on GH

IGF-1

secreted by the liver when stimulated by GH

• negative feedback regulator of GH secretion on hypothalamus

• long half-life due to binding proteins

GH pulsatile secretion

released in episodic peaks

• largest release in early hours of sleep

• diurnal rhythm → sleep/wake release

• secretion persists throughout life

GH secretion in lifetime

GH secretion persists throughout life but decreases after age of 40

• GH levels higher in children, with peak period during puberty

• secretion increases in neonatal period as growth becomes dependent on GH and IGF-1

  • remains throughout childhood but peaks during puberty

• TH enhances GH and IGF-1 secretion to support bone growth and maturation

• adults produce GH for metabolism, but levels fall during senescence

• between ages 20 and 40, secretions slows down with associated TH decrease

GH acttions

• growth → long bones for stature development

  • 30% growth potential

• metabolic → IGFs to increase lean body mass

  • lipolysis of adipose tissue

  • increase in muscle mass

target tissue response to GH

• bone metabolism → increase bone mass by endochondral bone formation

  • increase osteoclast differentiation and activity

  • increase osteoblast activity

• linear growth → promotes epiphyseal growth

• adipose tissue → increase lypolysis and decrease lipogenesis

  • inhibit lipoprotein lipase (LPL)

  • stimulate hormone-sensitive lipase (HSL)

• muscle → increase metabolically active tissue and energy expenditure

  • increase amino acid transport

  • increase nitrogen retention

physiological effect of GH on stature

GH stimulates growth of epiphyseal plates and promotes long bone growth

• stimulates increases in length and width

• initiates proliferation of epiphyseal cartilage progenitor cells

• requires presence of thyroid hormone to sustain growth

• largely mediated by release of IGF-1

  • GH targets liver and releases IGF-1 in response

  • stimulates osteoblast activity for bone elongation

• other factors like nutrition may modulate release of IGF-1

GH abnormalities

• pituitary dwarfism → childhood lack of GH

  • often associated with other pituitary hormone losses

  • pure GH loss will not prevent normal reproduction

  • 3-4 feet in stature

• Laron dwarfism → lack of response to GH due to receptor issue

• gigantism → overproduction of GH in childhood

• acromegaly → adult overproduction of GH

  • thickening of facial bone

GH genetic potential

GH is a faciliator of genetic expression of growth

• not primary determinant of growth

• affects approximately ±30% of genetic potential

fed vs fasting states of GH and IGF-1

• anabolic → fed state with excess calories over immediate needs

  • increase IGF → increased organ size and function, linear growth, increased lean body mass

• catabolic → fasting state with fewer calories than needed

  • decreased adiposity

prolactin (PRL)

secreted by lactotropes in anterior pituitary, and acts directly on mammary gland

• exists in both males and females

• metabolic

• plays major role in pregnancy and post-partum lactation

lactotrope in anterior pituitary

secretes prolactin

• not part of endocrine axis

• normally under inhibitory influence of hypothalamus

  • if pituitary stalk is compromised, secretion of PRL is increased

• control of PRL involves neuro-endocrine feedback loop

  • suckling → neural signal → inhibits hypothalamic dopamine → increased prolactin release

lactation

final maturation of breast during pregnancy from exposure to prolactin, hGHv, hCS (hPL), and sex steroids

• estrogen stimulates PRL to nearly 10x normal, but blocks metabolic process

• immediately after pregnancy → lactation

  • requires rapid sex steroid withdrawal

  • elevated PRL basal and pulsatile levels

• maintenance of lactation requires pulsatile release of pRL

• major hormone:

  • PRL → synthesis and secretion of milk

  • oxytocin → ejection of milk from mammary gland

development of breasts

occurs mostly during pubertal development

• continues with each menstrual cycle into early 20s

  • estrogen → development of ductal tissue

  • progesterone → development of alveoli

• full maturation requires exposure to hormone mileu of pregnancy

• last stages of epithelial cell arrangement with basement membrane and tight junctions occurs after loss of pregnancy with delivery of placenta

  • with increase of prolactin and withdrawal of sex hormones

• breast size is mostly a mater of fat depots in tissue

initiation of lactation

• first need prolonged exposure to hormones of pregnancy to establish final maturation of breasts

  • large increase of prolactin levels

• need rapid withdrawal of sex steroids as occurs with delivery of placenta

  • small increase of prolactin levels

• must initiate nursing immediately to maintain exposure to high levels of prolactin during baseline, which is necessary to establish lactation

maintenance of lactation

production of milk in mature mammary gland. depends on continued stimulation by prolactin

• also requires glucocorticoids and insulin

• initiation of lactation requires PRL release with nursing

• maintenance of lactation requires continuous secretion of PRL associated with suckling

• high estrogen and progesterone inhibit lactation by interfering with PRL

• milk production occurs in stages:

  • colostrum → first 4-5 days

  • transition milk → 5-10 days

  • mature milk → by 14 days

control of PRL secretion

positive feedback for PRL secretion

• sucking causes release of PRL and milk synthesis 

  • release diminishes with time post-partum, but milk synthesis is sustained

  • promotes synthesis of milk for next feeding, not current feeding

• normally under tonic inhibition by hypophysiotropic hormone dopamine (PIH)

• TRH increases PRL

• estradiol increases PRL, but blocks metabolic effects of PRL on breast

• open loop → no feedback control by products to alter pituitary stimulation

• continued secretion throughout life in males and females

prolactin actions

• trophic action on breasts → sex steroid interaction during pregnancy

• milk synthesis → initiation and maintenance of lactation

• delay in menstrual cyclicity during breast feeding is due to PRL

  • may act at level of hypothalamus to slow GnRH pulse generator

  • decreased levels of LH and loss of LH surve

prolactinoma

pathological levels of PRL leads to reproductive problems

• gynecomastia

• hypothalamus

  • inhibits GnRH

  • infertility in women → amenorrhea

  • erectile dysfunction in men