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FEEDBACK REGULATION OF HORMONE SECRETION

A key principle of homeostasis is that physiological systems can be modulated via feedback loops.  Maintenance of a relatively constant internal environment relies on negative feedback loops to keep a controlled variable within the normal physiological range and return that variable to the physiological set point.  (In contrast, positive feedback loops accelerate changes in the internal environment and maximise departure from any physiological set point.)

The synthesis and/or secretion of hormones can be regulated by:

• Direct feedback loops

• First order feedback loops

• Second order feedback loops

• Third order feedback loops

Each of the above differ in the number of control points: points in the feedback loop at which negative feedback can suppress further hormone synthesis and/or secretion.  Direct feedback loops and first order feedback loops are both characterised by only one control point, whereas second order feedback loops are defined by having two control points and third order feedback loops have three control points.  For vertebrate taxa (including but not limited to mammals), the vast majority of endocrine axes are regulated through second or third order feedback loops:

For a direct feedback loop, a physiological stimulus directly stimulates an endocrine gland to synthesise / secrete hormones into the circulatory system.  When that hormone exerts its action of the target cells / organ, the compensatory physiological response (or responses) exerted by that target organ decreases the incoming physiological stimulus and this is the one and only control point within that direct feedback loop.  Direct feedback loops are rare in mammals, the only true example being atrial natriuretic peptide (ANP).  When the atria of the mammalian heart are stretched (due to an increase in plasma volume), the atrial cardiomyoctes are stimulated to synthesise and secrete more ANP.  This short half-life peptide hormone acts on the kidneys to increase the loss of sodium (latin = natrium) ions in the urine (i.e. natriuresis).  Because water is also lost from the body with these sodium ions, there is a decrease in plasma volume that lessens the stretch of the cardiac atria, lowering the stimulus to further synthesis and secretion of ANP, hence a direct feedback loop.

Second and third order feedback loops are elaborations of a first order feedback loop in which one or twoendocrine glands, respectively, are introducedbetween the integrator and the ultimate effector / target organ.  Theseriesof interactingendocrine glandsare referred to as anendocrine axis.

In a second order feedback loop, the change in the controlled variable is detected by the sensor which relays a signal to the integrator via a sensory neurone.  As in a first order feedback loop, where the incoming signal deviates from the physiological set point, the integrator then sends a signal (usually via a connecting neurone) not to the ultimate effector / target organ but, in this case, to an intermediary endocrine gland.  That gland exerts its actions on the distant effector cells in the target organ not via neurones but via hormones secreted into a circulatory system – blood / lymph / haemolymph.  When the effector / target organ acts, negative feedback is exerted at two control points: as in first order feedback loops, the compensatory response lowers the stimulus to the sensor (decreasing the sensory drive to the endocrine axis) but in addition, the effector / target organ exerts negative feedback on the endocrine gland to suppress further hormone synthesis / secretion.

In a third order feedback loop, as in first and second order feedback loops, the change in the controlled variable is detected by the sensor which relays a signal to the integrator via a sensory neurone.  As just seen for a second order feedback loop, where the incoming signal deviates from that associated with the physiological set point, the integrator sends a signal to an intermediary endocrine gland to modulate the synthesis and / or secretion of the first hormone in this physiological sequence.  Hormone 1 from endocrine gland 1 is then carried by a circulatory system to a second intermediary endocrine gland.  The action of hormone 1 stimulates the synthesis and / or secretion of hormone 2 by endocrine gland 2, and it is that second hormone which acts on the effector cells in the final target organ.  When the effector / target organ acts, negative feedback can be exerted at three control points: the compensatory response lowers the stimulus to the sensor (decreasing the sensory drive to the endocrine axis) in addition to which the effector / target organ exerts negative feedback on both of the endocrine glands to suppress further synthesis / secretion of hormones 1 and 2.

THE HYPOTHALAMO-PITUITARY COMPLEX: EMBRYOLOGY AND ANATOMY

As noted above, for vertebrate species, hormone synthesis and / or secretion are usually regulated through second or third order feedback loops.  In the third order feedback loops, the roles of “endocrine gland 1” and “endocrine gland 2” are commonly filled by the hypothalamus and by the pituitary gland, respectively, with the downstream effector cells / target organ also being an endocrine gland.  Examples of endocrine axes which include the hypothalamus and pituitary gland upstream of a third endocrine gland include:

• the hypothalamo-pituitary adrenal (HPA) axis;

• the hypothalamo-pituitary gonadal (HPG) axes (specifically the hypothalamo-pituitary ovarian and the hypothalamo-pituitary testicular axes in females and males, respectively);

• the hypothalamo-pituitary thyroid (HPT) axis.

The hypothalamus, part of the diencephalon, is a collection of specialist neurones that form clusters (hypothalamic nuclei) just below / underneath the thalamus (hence hypothalamus).  The hypothalamus is physically connected to the pituitary gland via a narrow pituitary stalk: the infundibulum.

In mammals, the pituitary gland has two major lobes, each with different embryonic origins:

• the posterior pituitary lobe, or neurohypophysis, is formed by an outgrowth of neural tissue down from the hypothalamus;

• the anterior pituitary lobe, or adenohypophysis, is instead formed by a growth of glandular epithelial tissue up from the roof of the buccal cavity (mouth).

In the same way that the hypothalamus contains different neurones in discrete hypothalamic nuclei, the endocrine cells of the anterior pituitary / adenohypophysis are organised in distinct populations which produce different hormones: the corticotropes, the gonadotropes, the lactotropes, the somatotropes and the thyrotropes.  (The functions of each of these anterior pituitary cell populations is defined below).

The differing embryonic origins dictate how the hypothalamus communicates with cells in the posterior lobe / neurohypophysis and in the anterior lobe / adenohypophysis.  For the posterior lobe, magnocellular neurones with cell bodies in the hypothalamus (specifically in the supraoptic, ventromedial and paraventricular nuclei of the hypothalamus) have axons which span from the hypothalamus down into the posterior pituitary along the the hypothalamo-hypophyseal tract.  Hence, neurohypophyseal hormones are transcribed and translated in the hypothalamus and then transported along axons from the hypothalamus to be secreted from the posterior pituitary gland:  

In contrast, due to their distinct embryonic origin from the roof of the buccal cavity, the cells of the anterior lobe of the pituitary gland / adenohypophysis are connected to the hypothalamus through the hypothalamo-hypophyseal portal circulation which starts with capillaries in the median eminence of the hypothalamus (in the third ventricle of the brain) and ends with capillaries that drain into the adenohypophysis.  Hence, peptide hormones and neurotransmitters secreted from the hypothalamic parvicellular neurones at the median eminence are transported directly to the anterior pituitary cells via this portal circulation: 

THE HYPOTHALAMO-PITUITARY COMPLEX: CELLS AND HORMONES

The hypothalamus responds to endocrine (hormonal) and / or neural stimuli by synthesising and secreting 6 hypophysiotropic hormones (of which 5 are peptide hormones and one, dopamine, is a neurotransmitter):

 The term “hypophysiotropic” indicates that these 6 hormones act on the anterior pituitary gland (adenohypophysis) and are tropic.  A tropic hormone is one which influences / directs a downstream organ (usually another endocrine gland) and a hypophysiotropic hormone is normally the first hormone in an endocrine axis of two or three hormones.  The hypophysiotropic hormones secreted from the hypothalamus are as depicted above and as tabulated below:  

Those hypothalamic hormones termed releasing hormones (i.e. TRH, CRH, GHRH and GnRH) stimulate both the synthesis (transcription, translation and post-translational modifications) and secretion of peptide / protein / glycoprotein hormones from the relevant target cells in the anterior pituitary gland.  In contrast, two of the hypothalamic hormones (dopamine and GHIH / somatostatin) inhibit adenohypophyseal hormone synthesis / secretion.  GHIH / somatostatin acts as an antagonistic partner to GHRH such that the balance between GHRH and GHIH determines the net effect on growth hormone (GH) synthesis / secretion from the anterior pituitary somatotrope cells.  Synthesis and secretion of prolactin (PRL) from the lactotrope cells is unique in that no releasing hormone has ever been identified for PRL.  Instead, it appears that PRL secretion is under dominant negative control exerted by the neurotransmitter dopamine acting specifically on D₂-receptors for DA.  Hence, it is decreased suppression (rather than stimulation) of lactotrope function by DA that increases PRL secretion for lactation.  (N.B. Although DA suppresses PRL, it still qualifies as a hypophysiotropic hormone: it still influences the function of a downstream gland, even if that influence is inhibitory rather than stimulatory.)

The names and functions of the anterior pituitary hormones synthesised and secreted in response to the hypothalamic hypophysiotropic hormones are as tabulated below: 

Through their tropic actions, most of the anterior pituitary hormones play intermediary roles between the hypothalamus and the downstream target organs (many of which are endocrine glands).  Specifically, in mammals:

• PRL acts on the mammary glands (breasts) to stimulate lactation;

• TSH indirectly increases the basal metabolic rate (BMR) – by stimulating the synthesis of the thyroid hormones, thyroxine and triiodothyronine, from thyroglobulin in the thyroid follicles;

• ACTH indirectly elevates the plasma glucose concentration and triggers cell differentiation – by stimulating the synthesis of the glucocorticoid steroid, cortisol.  (In addition, ACTH can also promote the development of secondary sexual characteristics – by stimulating the synthesis of the adrenal androgen, dehydroepiandrosterone [DHEA] in the adrenal cortex);

• GH stimulates growth and development indirectly (via hepatic insulin-like growth factors [IGF’s]) and through direct actions (e.g. on bone);

• FSH promotes the formation of second sexual characteristics in females – by stimulating the growth of ovarian follicles and then stimulating them to synthesise estradiol (via actions on granulosa cells).  In males, FSH indirectly promotes spermatogenesis – by stimulating the Sertoli cells of the testis that line the seminiferous tubules;

• LH indirectly regulates female sexual receptivity (estrus / ‘heat’) in mammals – by acting on ovarian theca and granulosa cells to stimulate estradiol synthesis and to release the mature germ cells (oocytes) at ovulation.  In addition, LH is necessary to stimulate progesterone synthesis (for pregnancy) by the post-ovulatory ovarian corpus luteum and to promote fertility in males – by stimulating testis Leydig cells to synthesise testosterone.

Within each of the major endocrine axes, there are negative feedback loops to control the synthesis and / or secretion of tropic hormones.  In long loop negative feedback, the end organ hormone (e.g. thyroxine, cortisol, estradiol, progesterone or testosterone) exerts negative feedback to suppress the relevant hypothalamic hormone (e.g. TRH, CRH or GnRH, respectively) and the corresponding anterior pituitary hormones (e.g. TSH, ACTH or FSH and LH, respectively).  In short loop negative feedback, the feedback loop runs from the anterior pituitary to the hypothalamus (e.g. ACTH suppresses further synthesis and secretion of CRH): 

DIURNAL / CIRCADIAN RHYTHYMS

The feedback loops that regulate hormone secretion culminate in some hormones exhibiting a diurnal / circadian rhythm over a 24 hour period.  For example, in mammals which are active during the daylight hours (e.g. humans), the plasma concentration of the adrenal glucocorticoid steroid, cortisol, is highest on waking (between 9 and 11 AM) and then falls to a nadir in the late evening / early night (around 11 PM).  This circadian pattern helps to elevate plasma glucose levels when those mammals need to be at their most active (late morning and through the afternoon) but ensure that the plasma glucose levels are lowest when the animal is preparing for sleep:

In nocturnal mammals, the diurnal pattern is shifted by 12 hours ensuring plasma glucose levels are increased by cortisol when the animals are at their most active.  The pattern can also be disrupted, in humans, by shift work when people are required to be alert at a time when plasma glucose concentrations are low and their physiological organ systems are anticipating sleep.

This circadian / diurnal pattern very much relies on the lag in negative feedback and in endocrine stimulation between CRH, ACTH and cortisol.  When the plasma concentration of cortisol peaks, this exerts long loop negative feedback on CRH and ACTH.  As the secretion of these hypothalamic and anterior pituitary hormones fall, so does the concentration of cortisol in the plasma.  At the night time nadir in cortisol concentrations, there is minimal negative feedback, and so the levels of CRH and ACTH are able to increase at night, driving further synthesis of cortisol, levels of which rise again until they reach the morning peak.  In mammals (including humans) subject to chronic stress, there is less negative feedback of cortisol at the level of the hypothalamus and anterior pituitary.  As a consequence, the circadian pattern in cortisol is lost and the concentration of cortisol remains high throughout the day and night (which explains the disruption to sleep cycles associated with stress).

NEUROENDOCRINE REFLEXES

In neuroendocrine cells, instead of neurones releasing neurotransmitters into a synapse or neuromuscular junction, those neurones release small peptide hormones (3-44 amino acids) into either the local or the systemic circulation.  With the exception of the dopaminergic neurones that control prolactin secretion from the lactotropes, all of the hypothalamic neurones discussed above are neuroendocrine cells: they secrete tropic peptide hormones into the hypothalamo-hypophyseal portal circulation to control the endocrine activity of cells in the anterior pituitary / adenohypophysis.

Turning to the posterior pituitary / neurohypophysis, in mammals, vasopressin (AVP or LVP) and oxytocin (OT) are two closely related nonapeptide hormones with “lariat” structures stabilised by a covalent disulphide bond between cysteine residues at peptide positions 1 and 6:

(The above structures are for the human hormones.  While human “arginine vasopressin” [AVP] has an arginine residue at peptide position 8, this is replaced by an alternative basic amino-acid, lysine, in porcine vasopressin [LVP].  Moreover, in fishes, amphibians and birds, the physiological functions of AVP and of OT are performed by a single peptide –vasotocin– from which AVP / LVP and OT diverged following duplication of the ancestral gene encoding vasotocin.)

The primary physiological role for OT is to induce the contraction of smooth muscles in the uterus (myometrium) and in the mammary gland.  This contractile action is achieved through the OT receptor: a GPCR which couples, via G_q, to phospholipase C such that OT triggers an elevation of the intracellular calcium (Ca²⁺) concentration via the inositol trisphosphate (IP₃) second messenger pathway.  AVP has two major roles acting both as an anti-diuretic hormone (by facilitating water resorption in the distal nephrons and collecting ducts of the kidneys) and as a vasopressor (inducing the contraction of vascular smooth muscle cells to increase vascular resistance and hence raise blood pressure).

As noted above, these neuropeptide hormones are transcribed and translated in the cell bodies of magnocellular neurones located in the supraoptic, ventromedial and / or paraventricular nuclei (SON, VMN and PVN, respectively) of the hypothalamus.  While still in the hypothalamus, both AVP and OT are packaged into secretory vesicles before being transported along the cytoskeleton along the axons from the cell bodies in the hypothalamus along to the axonal terminals in the posterior pituitary gland / neurohypophysis.  The secretion of the neurohypophyseal hormones can be regulated by neuroendocrine reflexes.  In the Fergusson reflex, sensory inputs from the distended cervix can trigger increased secretion of OT that stimulates myometrial contractions which further distend the cervix.  This positive feedback spiral is crucial for the safe birth of an infant in a eutherian (placental) mammal, minimising the time that the infant spends in the birth canal.  Likewise, in the suckling or milk ejection reflex, stretching of the nipple and surrounding areola sends a sensory input to increase secretion of OT that stimulates contraction of the lobulo-alveolar ducts in the mammary gland, promoting increased milk ejection for the infant.

A third example of a neuroendocrine reflex is seen not in the pituitary gland, but in the medulla of the adrenal gland.  When an animal is frightened, this increases stimulation of the adrenal medulla by the sympathetic branch of the autonomic nervous system.  As a consequence, the chromaffin cells of the adrenal medulla increase synthesis and secretion of the catecholamine hormone, adrenaline.  This neuroendocrine reflex is pivotal in the “fight or flight” response, with adrenaline increasing the mobilisation of glucose stores, increasing cardiac output (by increasing heart rate) and suppressing any non-vital physiological processes.