Hormonal control of growth and puberty

Growth requires

• net synthesis of proteins

• lengthening of the long bones

• increase in number and size of cells comprising soft tissue

Growth in humans

• continuous process

  • begins before birth

  • growth rates in children not steady

  • spurts of growth and development

• requires cooperation of several endocrine organs

growth rate

• not continuous

• factors responsible for promoting growth are not the same throughout growth period

• fetal growth

• promotes largely by hormones from placenta

• GH plays no role in fetal development

• postnatal growth

  • displayed during first two years of life

• pubertal growth

  • occurs during adolescence

normal growth rate depends on

• hormones

  • Children do not grow without adequate GH

  • Thyroid hormone, insulin and sex hormones at puberty play direct and permissive roles

  • Deficiency leads to abnormal growth and development

• genetic

  • potential adult size genetically determined at conception

• absence of stress

  • cortisol released from adrenals during stress is catabolic and inhibits growth

• adequate diet

  • require adequate protein, calorie intake, vitamins and minerals

  • obtained from food or manufactured in body

growth hormone

• produced by somatotrophs of anterior pituitary

  • release GH periodically throughout the day

  • peak secretion during sleep

• is anabolic hormones

• major targets are bone and skeletal muscle

  • stimulation of the epiphyseal plate leads to long bone growth

  • stimulation of skeletal muscles promotes increased muscle mass

• regulated by two hypothalamic hormones with antagonistic effects

  • growth hormone releasing hormone stimulated GH release (GHRH)

  • growth hormone inhibiting hormone inhibits GH release (GHIH)

Regulation of GH release

mechanism of GH action

• indirect actions

  • via insulin-like growth factors

  • acts on wide variety of cell types

• direct actions

  • more selective

  • involved in regulation of blood glucose and amino acid concentrations

  • cell division and differentiation

Insulin-like growth factor-1

• Produced by liver in response to GH stimulation

  • Mediates most of GH’s actions

• Synthesis affected by

  • Age

    • Increases at puberty – corresponds to increase in GH

  • Nutrition

    • Inadequate nutrition reduces production despite GH levels increasing

GH: indirect action long term effects

• Promotes growth indirectly

  • stimulates liver’s production of somatomedins

• Primary somatomedin is insulin-like growth factor (IGF-1) which

  • Acts directly on bone and soft tissues to bring about most growth promoting actions

  • Stimulates protein synthesis, cell division, and lengthening and thickening of bones

  • Stimulates uptake of sulphur into cartilage matrix

GH: direct action short term effects

• Increases fatty acid levels in blood

  • enhances breakdown of triglyceride fat stored in adipose tissue

• Increases blood glucose levels

  • decreases glucose uptake by muscles

• Stimulates stem cell division and differentiation in epithelial and connective tissue

Effects of GH on soft tissue

• Hyperplasia: Increases cell number

  • Stimulates cell division

  • Prevents apoptosis (cell death)

• Hypertrophy: Increases cell size

  • Promotes protein synthesis

  • Inhibits protein degradation

  • Increases uptake of amino acids by cells

  • Stimulates the cellular mechanisms responsible for protein synthesis

Effects of GH on bone

• stimulates osteoblast activity (formation of bone tissue)

• promotes proliferation of epiphyseal cartilage

  • promotes lengthening of bone if epiphyseal plate remains “open” ie cartilaginous

GH regulation

• Regulated by two hypothalamic hormones

  • Growth hormone-releasing hormone (GHRH)

  • Somatostatin

• GHRH

  • stimulates release of GH

  • secretion increases during exercise, fasting, and stress, and after ingestion of a protein-rich meal

• GH release is inhibited by hypothalamic hormone somatostatin

GH and diurnal rhythm

• GH levels low and constant during the day

• GH levels increase sharply after onset of deep sleep (5X daytime levels)

• GH levels then drop over the next few hours back to daytime levels

Factors affecting GH secretion

• Levels of GH are increased when energy demands are greater than available glucose reserves

  • Low blood glucose

  • Exercise

  • Stress

• GH increased under these conditions to

  • Conserve glucose for use by the brain

  • Make fatty acids available for use as an energy source for muscles

Factors affecting GH secretion

• Levels of GH are increased:

  • After a high protein meal

    • Amino acids used for protein synthesis

  • When blood fatty acids levels decline

    • Metabolises fat – releasing fatty acids – keeps blood levels constant

Factors affecting GH secretion

• Regulating levels of GH aimed at controlling levels of

  • Amino acids

  • Fatty acids

  • Glucose

Normal growth also requires

• Insulin

• thyroid hormone

• parathyroid hormone and calcitonin

• reproductive hormones

Insulin

• Produced by β-cells of the pancreas

• Decreases blood glucose levels when they get high

  • Promotes movement of glucose through the cell membranes

  • Stimulates the storage of both glucose and fats

  • Stimulates glycogen and protein synthesis

• Regulation of insulin is via negative feedback mechanisms

Thyroid hormone

• Consists of an amino acid core bound to either 3 (triiodothyroxine, T3) or 4 (thyroxine, T4) iodine atoms

• Both T3 and T4 are physiologically active but T3 activity is greater

• T4 is commonly converted to T3 in some target tissues

• Both T3 and T4 enter target cell nucleus

  • they bind with receptors that either activate or inhibit specific gene transcription

Effects of thyroid hormone

• Almost every cell in body contains thyroid hormone receptors

  • makes their effects widespread

• Three main categories of effects

  • Regulation of metabolic rate and thermoregulation

  • Promotion of growth and development

  • Synergism with sympathetic nervous system

Regulation of metabolic rate and thermoregulation

• Thyroid hormones set basal metabolic Promotion of growth and development (amount of energy required by body at rest) by

  • increasing rate of ATP consumption

  • increasing gluconeogenesis

  • initiating energy-requiring reactions in these same target cells

• Heat is generated

  • critical for core body temperature homeostasis

Promotion of growth and development

• Thyroid hormones are required for

  • normal bone growth

  • muscle growth

  • nervous system development

  • Reproductive capabilities

• Enhances protein synthesis and lipid breakdown

Synergism with sympathetic nervous system

• Increases in thyroid hormone levels act on target cells of sympathetic nervous system

  • increase (up-regulate) receptors for sympathetic neurotransmitters

  • affects regulation of blood pressure, heart rate, and other sympathetic activities

PTH and calcitonin

• Promotes the absorption of calcium salts (PTH) and deposition in bone (calcitonin)

• In the absence of adequate levels of PTH and calcitonin

  • Bones can still enlarge

  • Poorly mineralized , weak flexible

Reproductive hormones that effect growth

Testosterone

• anabolic

• stimulates bone growth

• stimulates growth in length

• increases muscle mass and weight

• Controlled by negative feedback mechanisms

Estrogen

• Not involved in growth stimulation

• Causes growth plates to close

• Stops growth in length

• Controlled by negative feedback mechanisms

Puberty

• Stage of physical maturation in which an individual becomes physiologically capable of sexual reproduction

• Onset varies among individuals

• May occur anytime from age 10 to 15

• Usually begins a year earlier in females than in males

• Lasts 3 – 5 years

Physical changes of puberty

• female secondary sex characteristics

• male secondary sex characteristics

Biological changes of puberty

• Neurosecretory factors and /or hormones

• Modulation of somatic growth

• Initiation of development of the sex glands

Major hormones of pubery

• GnRH

• LH and FSH

• Estrogen and progesterone

• testosterone

Physiology of puberty

• Activation of the hypothalamic-pituitary-gonadal axis

  • Induces ovarian and testicular sex hormone secretion

  • Responsible for the biological, morphological and psychological changes during puberty

• Sex steroid production

  • Appearance and maintenance of sexual characteristics

  • Capacity for reproduction

Hypothalamic-pituitary gonadal axis

• Major physiological function in both males and females

  • Development of primary and secondary sexual characteristics

  • Control of gametogenesis and reproduction

Hypothalamic-pituitary gonadal axis is active when?

• Active in males and females during three main periods of life

  • Midtrimester of the fetal period

  • Early in the neonatal period

  • From puberty throughout the reproductive years

Fetal period of Hypothalamic-pituitary gonadal axis

• Testosterone production is essential for sexual differentiation in males

• Elevated levels of FSH contributes to folliculogenesis in females

• Silenced towards term because of the negative feedback effects mediated by the placental hormones

Neonatal period of Hypothalamic-pituitary gonadal axis

• Increased activity due to decreased placental hormone levels at birth – disinhibits the hypothalamo-pituitary system

Puberty to adulthood period of Hypothalamic-pituitary gonadal axis

• Increased pulsatile release of GnRH occurs mostly at night in early puberty

• Required for FSH and LH secretion

• Later – pulsatile release of GnRH occurs throughout the 24 day

Initiation of puberty

• Factors unclear in humans

• Leptin - produced by adipocytes - thought to play a role in females

• Postulated that melatonin stimulates onset

  • Melatonin is anti-gonadotropic (inhibit effect of gonadotropic hormones)

  • Some evidence of reduced melatonin secretion at puberty in humans – particularly at night – when GnRH peaks

Male reproductive system

• Consists of: testes, duct system, accessory glands, and penis

• From testis, sperm travels within male reproductive duct system (epididymis, ductus deferens and urethra, before leaving the body via the penis)

• Accessory glands – seminal glands, the prostrate and the bulbourethral gland secrete fluids into the duct system.

• External genitalia – scrotum that enclose the testes, urethra and penis

Hormones and male reproductive function

• GnRH

  • Produced by the hypothalamus

  • Stimulates the release of LH and FSH by anterior pituitary

• LH and FSH act on separate components of the testes

Seminiferous tubule

• sertol/nurse cells are important

• leydig cells are important aka interstitial cells #

Hormones and male reproductive function

• LH

  • Acts on interstitial (Leydig) cells

  • Regulates testosterone secretion

  • Interstitial cell-stimulating hormone (ICSH) – alternate name in males

• FSH

  • Acts on seminiferous tubules – specifically Sertoli cells

  • Enhances spermatogenesis

Brain-testicular axis

• Hormonal regulation of spermatogenesis and testicular androgen production involves interactions between

  • Hypothalamus

  • Anterior Pituitary

  • Testes

• Relationship called brain-testicular-axis

Hormones involved in brain-testicular axis

• Testosterone

  • main hormone involved in regulation of spermatogenesis and male reproductive physiology

  • regulated by multi-tiered negative feedback loop

• Brain-testicular-axis

  • regulates hormones involved in testosterone production and testicular function

• First-tier control – Gonadotropin-releasing hormone (GnRH), secreted by hypothalamus

• Second-tier control – anterior pituitary detects GnRH; stimulates secretion of gonadotropins

• Third-tier control – in testes: LH, FSH, stimulates secretion of inhibin, androgen binding protein, testosterone

Brain-testicular axis: FSH

• FSH stimulates spermatogenesis indirectly

• Stimulates Sertoli cells to release androgen-binding protein (ABP)

• ABP binds to and concentrates testosterone in spermatogenic cells

• ABP-testosterone complex stimulates spermatogenesis

• FSH directly makes Sertoli cells receptive to stimulatory effect of testosterone

• androgen = male hormone

Brain-testicular axis: LH

• LH binds to interstitial cells

• Stimulates them to secrete testosterone

• Locally testosterone is the final trigger for spermatogenesis

• Testosterone entering the blood-stream exerts a number of effects at other body sites

Brain-testicular axis: Inhibin

• Inhibin – peptide hormone secreted by the Sertoli cells

• High sperm count – increases inhibin release

• Inhibits anterior pituitary release of FSH

• Increased levels of inhibin decreases spermatogenesis

• Sperm count < 20 million/ml – inhibin secretion declines steeply

Brain-testicular axis: Testosterone

• Testosterone: negatively inhibits LH in TWO ways

• Acts on the hypothalamus

  • inhibits GnRH

  • Indirectly decreases LH and FSH secretion by the anterior pituitary

• Acts directly on the anterior pituitary

  • Reduces response of LH secretory cells to GnRH

• Exerts a greater inhibitory effect on LH than FSH

Three sets of hormones that balance amount of testosterone and sperm produced

• GnRH – indirectly stimulates testes via effects on LH and FSH release

• Gonadotropins (LH and FSH) – directly stimulate the testes

• Testosterone and inhibin – exert negative feedback controls on the hypothalamus and anterior pituitary

• In absence of GnRH and gonadotropins

  • testes atrophy

  • sperm and testosterone production ceases

Testosterone

• synthesised from cholesterol

• ~98% circulated in blood

• bound to one of two transport proteins – protected from metabolism in liver

  • Sex hormone binding globulin (SHBG) [~44%]

  • Serum Albumin (~54%)

• Exerts it effect by activating specific genes

Testosterone: effects on reproductive organs

• Targets accessory reproductive organs – causes them to grow and assume adult size and function

  • Ducts

  • Glands

  • Penis

• In adult males – normal plasma levels of testosterone maintains these organs

• When testosterone is deficient or absent

  • All accessory organs atrophy

  • Semen volume decline

  • Erection and ejaculation impaired

  • Sterility and impotence

  • Treated with testosterone replacement therapy

Testosterone and male 2nd sex characteristics

• Appearance of pubic, axillary and facial hair

• Enhanced hair growth on the chest and other body areas (in some men)

• Deepening of the voice as the larynx enlarges

• Skin thickens and becomes oilier

Testosterone and somatic effects

• Thickening and strengthening of the bones

• Skeletal muscle increases in size and mass

• Epiphyseal plate closure occurs late in puberty due to increased estrogen levels (bone growth stops)

Testosterone and metabolic effects

• Anabolic

• Stimulates hematopoiesis (production of blood cells)

• Enhances basal metabolic rate

Testosterone and neural effects

• Responsible for libido in males

• Masculinizes the brain (e.g. differences in male and female brain areas in response to sexual arousal)

• Promotes aggressiveness

Hormones and the female reproductive cycle

• Regulatory pattern more complicated than in males

• Interplay of secretions from pituitary and gonads control the female reproductive cycle

  • Coordinates both the ovarian and uterine cycle

  • Infertility results if cycles not coordinated

Female reproductive cycle (leptin)

• Onset of puberty linked to adiposity

• Adipose tissue produces leptin – which acts on the hypothalamus

• Leptin stimulates the hypothalamus to secrete GnRH

• Low blood levels of lipids and leptin delays puberty

Female reproductive cycle

• GnRH stimulates the anterior pituitary to produce LH and FSH

• LH and FSH stimulate the ovaries to produce estrogen and progesterone

• Hormones interact to produce the cyclic events occurring in the ovaries

Female reproductive cycle (ovary)

Ovary has TWO related endocrine units

• Estrogen-secreting follicle during the first half of the cycle

  • Follicular Phase

• Corpus luteum which secretes both progesterone and estrogen during the second half of the cycle

  • Luteal Phase

Phases of the ovarian cycle

• Follicular Phase

  • Development of the follicle

  • Secretion of estrogen from follicle

• Ovulation

  • Occurs at mid-cycle

  • Ejection of egg from ovary

• Luteal Phase

  • Secretion of estrogens and progesterone from the corpus luteum (previously the follicle) after ovulation

Early follicular phase

• Early in the follicular phase

  • Estrogen levels are low

  • GnRH pulse is low

  • FSH secretion > LH secretion by anterior pituitary

  • Estrogens released by developing follicles inhibits LH secretion

• As secondary follicles develop

  • FSH levels decline due to negative feedback effects of inhibin and estrogen

• Follicular development and maturation continue

  • Supported by combination of estrogens, FSH and LH

Late follicular phase

• As tertiary follicles begin forming

  • Concentration of estrogens rises sharply

  • GnRH pulse frequency increases and stimulates LH secretion

• At roughly day 10 of the cycle – effect of estrogen on LH changes from inhibition to stimulation

• High estrogen levels ↑ gonadotrope sensitivity to GnRH

Ovulation

• At about day 14

  • Estrogen levels peak

  • Gonadotropes are at maximum sensitivity

  • GnRH pulse frequency is high

• Result

  • Massive release of LH from anterior pituitary gland

• Sudden surge of LH triggers

  • Rupture of the follicular wall

  • Ovulation

Luteal phase

• High LH levels that trigger ovulation

  • Formation of the corpus luteum

  • Corpus luteum secretes progesterone, estrogen and inhibin

• As progesterone and estrogen levels rise

  • Negatively feeds back on anterior pituitary and hypothalamus

  • GnRH pulse frequency declines to very low levels and stimulates LH secretion more than FSH secretion

  • LH (low levels) maintains the structure and secretory function of the corpus luteum

• Progesterone - Main hormone of the luteal phase

• Primary function - Prepare the uterus for pregnancy

• Progesterone levels remains high for a week

• If pregnancy does not occur - Corpus luteum begins to degenerate 12 days after ovulation

Estrogen and reproductive organs

• Promote oogenesis and follicle growth in the ovary

• Exert anabolic effects on the female reproductive tract – grow larger and become functional – to support pregnancy

  • Uterine tubes

  • Uterus

  • vagina

• Enhanced motility of the uterus and uterine tubes

• Vaginal mucosa thickens – and external genitalia mature

Estrogen and 2nd sexual characteristics

• Growth of breasts

• Increased deposit of subcutaneous fat (hips and breasts)

• Widening of pelvis

• DHEA (adrenal androgen) and not estrogen causes growth of axillary and pubic hair

Estrogen and growth

• Not involved in stimulating growth

• Adrenal androgen DHEA causes female growth spurt

• Stops growth in length by causing growth plates to close