Module 1: The endocrine system

The posterior pituitary gland secretes two main neurohormones: oxytocin and
anti-diuretic hormone (vasopressin). Structurally these peptides are closely related,
but functionally they play quite distinct roles in the body. Anti-diuretic hormone is
involved in fluid balance and will be examined more in the renal system module.
Oxytocin is well known as the hormone of labour and lactation, but also involved in
trust and social bonding.

Learning objectives

By the end of this unit, you should be able to:

Describe the synthesis and secretion of the two main posterior pituitary
neurohormones.

Explain how oxytocin acts during labour and lactation.

Describe a positive feedback loop.

Posterior pituitary neurohormones

A typical example of a
neurohormone is oxytocin.
Oxytocin is a peptide hormone
with 9 amino acid residues. It is
produced by neurons located in
the hypothalamus. These
neurons release oxytocin at their
nerve terminals in the posterior
pituitary gland. Oxytocin then
circulates to have effects on
distant target tissues, such as smooth muscle cells in the mammary gland during
lactation (milk let down), or the smooth muscle cells in the uterus (labour).

Image: 'Oxytocin happiness love hormone structural chemical formula' by eshana_blue, Adobe Stock.

Recall that the anatomical arrangement between the hypothalamus and posterior
pituitary gland involves a neural connection. The hypothalamic neurons that
produce oxytocin are located in the PVN and SON and have axons that extend down
the infundibulum into the posterior pituitary gland, where oxytocin is released into
systemic circulation (see figure below). Remember that oxytocin is stored in
vessicles in the nerve terminals in the posterior pituitary and released in response to
action potentials in the PVN and SON neurons.

Image source: The Hypothalamus and Posterior Pituitary Gland. Access for free at
https://openstax.org/books/anatomy-and-physiology/pages/1-introduction, modified.

Besides oxytocin, there is another posterior pituitary hormone, antidiuretic hormone

(ADH). It is also produced in the hypothalamic PVN and SON neurons - although in
general, not in the same neurons as oxytocin. For example, there are approximately
3,000 neurons in the human SON, and only about 3% of them co-localise (produce
both) oxytocin and antidiuretic hormone. ADH acts to promote water reabsorption in
the distal tubules of the kidney and we will investigate ADH further in the Renal
System module. Interestingly, ADH has another name, vasopressin - because it also
causes constriction of blood vessels to increase blood pressure.

Oxytocin - Physiological actions

Oxytocin (OT) is best known for its role in labour and lactation. In these "peripheral
reproductive roles" (discussed more below), oxytocin acts as a neurohormone.
However, oxytocin has many other biological roles, particularly within the brain -
where oxytocin acts as a neurotransmitter or neuromodulator. Oxytocin affects
social behaviours and appears important for social memory, bonding and trust,
sexual and maternal behaviour. Indeed, some of these effects indeed help facilitate
the more classical reproductive roles. In males, OT also has reproductive roles in
spermatogenesis, sperm transport and orgasm - although these roles remain to be
fully elucidated.

Oxytocin causes contractility of smooth muscle

A key target cells for oxytocin is smooth muscle. Oxytocin stimulates contraction of
smooth muscle by binding to OT-receptors and by inducing an increase in
cytoplasmic calcium.

Refresher ➢ Cross-bridges in smooth muscle

Recall that the formation of cross-bridges in smooth muscle (unlike skeletal

and cardiac muscle) occurs when myosin light-chain kinase (MLCK)
phosphorylates (introduces a phosphate group into a molecule or compound)
myosin, allowing binding of myosin to actin. MLCK is activated by the
presence of Ca2+, as a result of release from the SR and influx via the voltage-
gated Ca channels. Contraction continues to occur whilst MLCK is active.

This is covered in more detail in our Cell Physiology course: 'Tissue Biology
(CELLS2x)' - Module 1: Muscle tissue (link opens in a new tab).

Oxytocin binds to OT receptors on surface of smooth muscle cells (see figure

below). The signal transduction pathway, downstream of the receptor, involves
activation of Gq proteins that signal via phospholipase C to Inositol Phosphate 3
(IP3) and Diacylglycerol (DAG). IP3 moves through the cytoplasm and binds to IP3
receptors on the sarcoplasmic reticulum. The receptors act as Ca2+ channels,
allowing movement of Ca2+ into the cytoplasm. At the same time, signalling results
in Ca2+ influx via L-Type Ca channels. Overall, an increase in cytoplasmic Ca2+
occurs; resulting in muscle contraction.

Image source: Oxytocin signal transduction in smooth muscle cells. Kenneth-Lopez Loo, UQ.

Oxytocin during labour

In labour, oxytocin causes increased contractility of the myometrium - the smooth

muscle in the uterus.

Image source: 'Myometrium'. By macrovector, Adobe Stock, cropped

The uterus has three layers, which comprise the uterine wall:

the endometrium - inner epithelial cell layer, with mucous membrane.

the myometrium - middle layer, mainly smooth muscle.

the perimetrium - outer visceral layer.

During pregnancy, the myometrium increases greatly in size, about a 20-fold

increase. This is due to an increase in cell number (hyperplasia) and mainly an
increase in cell size (hypertrophy). In particular, as the fetus grows there is
stretched-induced hypertrophy.

Oxytocin receptors are expressed on the myometrial cells. In non-pregnant women,

OT receptor expression in the myometrium is low, but during pregnancy, there is a
marked upregulation of OT receptor expression - particularly towards "term" - the
end of pregnancy. This upregulation of receptors, together with the increase in the
size of the myometrium, prepares the uterus for the major contractile events of
labour.

Oxytocin - positive feedback loop

During labour, oxytocin is released in large quantities from the posterior pituitary
gland. Recall that neurohormone release only occurs in response to action potentials
in the neurons that produce the neurohormone. During labour, the mechanism that
causes oxytocin release is a positive feedback loop. This can be seen in the
schematic below.

In the early stages of labour, there is myometrial contractility that is not driven by
the neurohormone oxytocin, but rather by other hormones - prostaglandins and
placental corticotrophic releasing hormone. These early contractions push the baby
down the uterus towards the cervix. Within the cervix there are mechanoreceptors
which detect stretch, and these become activated. From the receptors, there is
neuronal replay of the nerve impulses via the spinal cord up into the brain, and
eventually to the oxytocin neurons in the hypothalamus. The stretch signals
activate, that is, cause action potentials, of the oxytocin neurons in the PVN and
SON. This causes release of oxytocin at the nerve terminal in the posterior pituitary
gland and release of large quantities of oxytocin into systemic circulation.

Image source: 'Positive Feedback Loop'. Access for free at https://openstax.org/books/anatomy-and-

physiology/pages/1-introduction

Oxytocin causes a marked increase in myometrial contractility. The stronger

contractions further push the baby down the birth canal, causing more
mechanoreceptor activation in the cervix, and conesequently more oxytocin release
and increased contractility - i.e. a positive feedback effect. The cycle ends with
birth.

Oxytocin during lactation

A similar oxytocin positive feedback loop also occurs during lactation. In breast
feeding, oxytocin causes contraction of the myoepithelial cells in the mammary
gland. OT receptors are expressed on these smooth muscle epithelial cells and their
contraction causes the movement of milk fluid in the alveoli, out into the lactiferous
duct, and to the baby via the nipple. Note, oxytocin causes contractility, and this
process in breast feeding is milk ejection or milk 'let-down'. Oxytocin does not
cause the production of milk per se, as this occurs in the epithelial cells - which are
under the control of the hormone prolactin

The figure below illustrates the positive feedback oxytocin response in suckling
induced milk let down. Sucking via mechanoreceptor stimulation of the nipple
(aerola) induces neuronal sensory signals to the hypothalamic oxytocin neurons,
which release oxytocin into circulation, and result in myoepthelial cell contraction in
the mammary gland. Such contraction causes milk ejection from the mammary
gland, out the nipple, as baby sucks. Baby receives milk and sucks more, causing
further oxytocin release. This positive feedback loop ends when baby stops sucking
- is satiated.

Image source: 'Milk let-down reflex'. Access for free at https://openstax.org/books/anatomy-and-

physiology/pages/1-introduction, modified.

Remember that the hypothalamus is an integrator centre, receiving many

neuronal inputs. In lactation oxytocin release and therefore milk let down can
be adversely affected by fear and anxiety. It is therefore important that
nursing mothers have quiet, stress-free environments to nurse their babies.

Also, some mothers can experience milk let-down without the sucking
stimulus, and sensory inputs, such as baby crying, sight and smell, all can
result in activation of the hypothalamic oxytocin neurons, increased plasma
concentrations of oxytocin and milk let-down.