Pulsatile Hormone
Refers to the rhythmic secretion of hormones in bursts or pulses rather than a constant steady release.
This pattern of hormone secretion is essential for maintaining normal physiological function and ensuring that target tissues/ organs respond appropriately to hormonal signals.
Example of pulsatile hormone:
- oxytocin (involved in the process of milk ejection - during breastfeeding)
- LH
- FSH
- insulin
- GnRH
- GH
- Cortisol
Oxytocin (OT)
Oxytocin in involved in a pulsatile hormone mechanism, particularly in the process of milk ejection during breastfeeding.
- Oxytocin is a hormone produced by the hypothalamus and released by the posterior pituitary gland
- plays a crucial role in various physiological processes- including childbirth and lactation
Pulsatile Release Mechanisms:
- during breastfeeding, the stimulation of the nipples by an infant suckling triggers a neural reflex which signals the hypothalamus to release oxytocin in a pulsatile manner from the posterior pituitary gland.
- these pulses of oxytocin causes smooth muscle cells surrounding the alveoli in the mammary glands to contract.
- this contraction forces milk from the alveoli into the ducts towards the nipples, facilitating milk ejection.
- milk ejection is triggered by synchronised bursts of OT neurons.
- in the absence of suckling oxytocin, neurons do not produce bursts - instead they spike at a low frequency due to random synaptic inputs
It’s important to note that milk is ejected from the other nipple which is not being suckled suggesting that the response to nipple stimulation is not located with the breast but rather somewhere else - brain.
Oxytocin network
- oxytocin cell’s axons projects to the posterior pituitary
- oxytocin cell’s dendrites form a bundle of network at the level of hypothalamus
- suckling leads to dendritic priming
What controls/ determines the bursts OT
OT bursts are controlled by:
Negative feedback loop
store depletion
When a baby suckles, it triggers the release of oxytocin in bursts. These bursts causes the milk to be ejected from the mammary glands. As the milk is released, the amount of oxytocin in the neurons gradually decreases because the hormone it being used in. This is store depletion and this can reduce the intensity of subsequent oxytocin burst as the baby continues to suckle for an extended period of time without a break.
At the same time, the body uses a negative feedback loop to regulate the process. Once enough oxytocin has been released and milk ejection has occurred, signals are sent back to the brain to reduce further oxytocin release which prevents an overload of hormone and ensues that milk release is not excessive.
In summary, as oxytocin stores get depleted during continuous suckling and as milk ejection reaches an appropriate level, the body naturally reduces further release of oxytocin through a negative feedback loop. This helps maintain balance and prevent overexertion of the system.
OT- is mediated fast positive feedback (effects of OT on its own dendrites) which produces bursts and is combined with slow negative feedback (depletion) which terminates bursts
And the pattern in which hormones are released are just as important as the amount of hormone released
Why pulsatility?
- Because hormone pattern needs to match to its target tissues:
For example:
- OT pulse match to breast tissue which are required for milk ejection
- pituitary luteinising hormone (LH) pulsatility is important for the release of sex steroids by ovaries
- gonadotropin releasing hormone (GnRH) pulse frequency determines the amount of LH released by the pituitary
Pulsatility refers to the overall pattern of burst-life hormone release - pulsatility refers to the intensity of hormone release
Pulse frequency refers to the quantified measure of how often these bursts occur
- a hormone can have high pulsatility with either a high/low pulse frequency
- Because hormone levels need to be tightly regulated with negative feedback look:
- hormone imbalance can result in serious health issues (infertility, growth hormone deficiency vs acromegaly, Cushing’s vs Addison’s, etc)
- so organisms have many negative feedback loops to regulate hormone levels
What is oscillation and what causes it:
- Oscillation refers any process that repeats itself at regular intervals - is the the the repetitive, cyclical fluctuation of any process
- Negative feedback loop causes oscillation
Hypothalamic-Pituitary- Gonadal (HPG) axis
- HPG axis is critical hormonal system which regulates reproductive function in both males and females = production of sperm and eggs, regulation of the menstrual cycle and control of puberty and sexual development.
- it involves a series of interactions between the hypothalamus, the pituitary gland and the gonads (testes in makes and ovaries in females)
- Hypothalamus releases gonadotropin-releasing hormone (GnRH) in a pulsatile manner (the frequency and amplitude of these GnRH pulses are crucial from proper functioning of the HPG axis ).
- GnRH from the hypothalamus stimulates the anterior pituitary gland. In response to the GnRH, the pituitary release two key hormones:
- Luteinising hormone (LH):
In males = LH stimulates the Leydig cells in the testes to produce testosterone
In females = LH triggers ovulation and the formation of corpus luteum which produces progesterone
- Follicle-stimulating hormone (FSH)
In males = FSH promotes the production of sperm by acting on the Sertoli cells in the testes.
In females = FSH stimulates the growth and maturation of ovarian follicles which are necessary for ovulation and estrogen production
- Gonads are the primary reproductive organs that produce sex hormones and gametes (sperm in males and eggs in females).
— In males - testes produce testosterone which is essential for sperm production, development of male secondary sexual characteristics and maintenance of libido.
— In females- the ovaries produces estrogen and progesterone, estrogen is involved in the development of female secondary sexual characteristics, regulation of the menstrual cycle, and preparation for the uterus for pregnancy. Progesterone is crucial for maintaining pregnancy.
**Negative feedback loop*8
- the sex hormone (testosterone in males / estrogen and progesterone in females) exert negative feedback loop back onto the hypothalamus and the pituitary gland.
Mechanism:
- when the levels of these hormones rises ——> they inhibit the release of GnRH from the hypothalamus and LH/FSH from the anterior pituitary gland ——> this reduces the stimulation of the gonads ——> thereby decreasing the production of sex hormones.
This negative feedback loop helps maintain hormone levels within an optimal range - prevents either excessive or insufficient hormone production.
HPG axis is activated from puberty through adulthood and the it gradually declines with age - which is associated with decreased fertility and changes in sexual function.
And the pulsatile release of GnRH causes pulsatile release of LH and FSH and this pulsatility is essential for normal reproductive functions.
Where is GnRH pulse generator
- GnRH pulse generator is thought to be located in the basal hypothalamus specifically in the arcuate nucleus (ARC) and close to the preoptic area (POA)
- it is responsible for the rhythmic, pulsatile release of GnRH which is essential for regulation of LH and FSH secretion from the pituitary
Kisspeptin
Kisspeptin plays a crucial role in regulating the pulsatile release of GnRH and is a key component of reproductive hormonal axis.
- In context of the GnRH pulse generator, Kisspeptin is a vial neuropeptide that acts as a direct stimulator of GnRH secretion.
Kisspeptin:
- produced by neurons located in the arcuate nucleus (ArC) and AVPV of the hypothalamus — regions closely associated with the regulation of reproductive hormones
- Kisspeptin neurons in the ARC are especially important for the generation and regulation of the GnRH pulses.
- Kisspeptin acts by binding to the Kisspeptin receptors (KISS1R) which is also known ad GPR54 which is expressed on GnRH neurons. This interaction is crucial for the activation if GnRH neurons and the subsequent release of GnRH in a pulsatile manner.
- frequency and amplitude of GnRH pulses which is crucial for normal reproductive functions are influence by the Kisspeptin signalling.
Overall, Kisspeptin act as a gatekeeper of GnRH ensure that GnRH pulses are generated at the appropriate times and with proper intensity.
Kisspeptin is essential for:
- puberty
- menstrual cycle
- fertility
Kisspeptin neurons are sensitive to hormonal feedback, particularly sex steroids like estrogen and testosterone.
- testosterone exert negative feedback effects on Kisspeptin
- estrogen exert positive and negative feedback effects on Kisspeptin neurons depending on phases like the menstrual cycle, modulating GnRH pulse frequency according.
KNDy neurons
—-> KNDy neurons in the ARC form a pulse generator that drives LH pulses by controlling the secretion of GnRH
- KNDy neurons refers to specific population of neurons that co-express 3 key neuropeptides:
1. Kisspeptin
2. Neurokinin B (NKB)
3. Dynorphin
-together these are key regulators of GnRH pulse generation which goes on to regulate LH
KNDy ensure the proper timing and frequency of LH pulses which is essential for normal reproductive function in both males and females
- Synchronous pulses in KNDy network match LH pulses
- stimulation of KNDy neurons triggers LH pulses
- Inhibition of KNDy neurons down-regulates LH pulses
Pulse generation in KNDy network results from the interaction between fast positive feedback and slow negative feedback.
—-> The model demonstrates the role of basal firing rates and Dynorphin - mediated negative feedback:
- With Dynorphin, changing the basal activity the pulse frequency changes - so when we increase the basal firing rate of the KNDy neurons which increases the overall basal activity also increases the frequency of the pulses.
- By removing Dynorphin there is a slow negative feedback sets the pulse time scale: the network stop oscillating and was set at either high or low state of activity
—-> Pulse generation and surge generation are mediated by distinct KiSS population
In summary:
GnRH pulse generation is produced by fast positive feedback (NKB) and slow negative feedback (Dynorphin)
Pulse frequency encodes the amount of hormone released at the pituitary (LH) and gonads (estradiol/ testosterone)
Gonadal steroids in turn modulate the pulse generator frequency
KNDy neurons
KNDy neurons in the ARC form a pulse generator that drives LH pulses
Pulsatility of Stress - HPA (hypothalamic- pituitary- adrenal) axis
HPA axis governs the pulsatile release of stress hormone particularly cortisol.
- Hypothalamus release corticotropin - releasing hormone (CRH) and vasopressin
- Pituitary gland- in response to CRH in secrets adrenocorticotropic hormone (ACTH)
- Adrenal glands- ACTH stimulates the adrenal gland to produce abdominal release cortisol which is the primary stress hormone
Cortisol pulsatility:
- cortisol is released in a pulsatile manner and its level fluctuates throughout the day following a circadian rhythm
- cortisol levels are usually at its peak early in the morning, shortly after waking- this peak helps the body to wake up and prepare for the day by mobilising energy stores
- cortisol levels gradually declines throughout the day - this decline is crucial for allowing the body to rest and recover during sleep.
- in addition to circadian rhythm cortisol also has a ultradian rhythm which refers to smaller, regular pulses of cortisol releases which occurs roughly every 1-2 hours throughout the day- these pulses ensues that cortisol is available to responded to immediate demands and maintain homeostasis.
Regulation by the HPA axis:
-CRH pulsatility drive the pulsatile release of ACHT from the anterior pituitary - the pulsatile release of CRH is influenced by the body’s internal clock located within the SCN of they hypothalamus.
- ACHT pulsatility acts on the adrenal cortex promoting the pulsatile secretion of cortisol
- feedback mechanisms:
- cortisol exerts negative feedback on both hypothalamus and the pituitary which Renaults the release of CRH and ACHT- this feedback loop helps modulate the pulsatility and amplitude of cortisol release.
Acute response to stress:
Acute stressor - when an acute stressor is encountered (like an immediate physical/ emotional challenge) the HPA axis is rapidly increases the frequency and amplitude of CRH, ATCH and cortisol pulses. This leads to a spike of cortisol levels, preparing the body to deal with stress by increasing blood sugar level enhancing alertness and suppressing non-essential functions like digestion.
Once the stress is resolved, cortisol levels return to the normal pulsatile pattern. However, if the stressor is persistent or chronic, this can lead to prolonged elevated cortisol levels disturbing the normal pulsatility and leading to potential health issues.
Chronic stress can disturb the normal pulsatile pattern of cortisol release. For example it might lead to a sustained increase in cortisol levels with reduced or flattened pulses, which can contribute to arrange of health problems, such as immune suppression, metabolic syndrome, depression, and anxiety.
Prolong exposure to high cortisol levels can eventually lead to HP axis fatigue where the body becomes less responsive to stress potentially resulting in inadequate cortisol production and blunted stress response.
Delayed negative feedback produces oscillations
