Integrated endocrinology :Concepts

Integrated endocrinology

We can regard the endocrine system as having the following physiological missions

Regulation of sodium and water balance: preservation of the volume/pressure reservoir required for tissue perfusion

Regulation of calcium balance: preservation of extracellular fluid concentrations required for membrane integrity, intracellular signaling, hemostasis,etc., and preservation of skeletal integrity

Regulation of energy balance: preserving, accessing, and interconverting metabolic fuels to meet

cellular energy demands

Coordination of processes for coping with a hostile environment

Coordination of growth and development

Coordination of processes associated with reproduction and lactation

It is clear that at least some aspect of virtually every physiological system lies within the realm of endocrine control

No single hormone or endocrine gland can accomplish any of these missions alone, and virtually every hormone participates in fulfilling multiple missions

Consequently, it is to understand not only how hormones act but also how they interact.

                Control of hormone action

Negative feedback

The essence of negative feedback control of hormone secretion is that some consequence of secretion blocks or dampens further secretion

 Hypothalamic input to the negative feedback system allows for episodic override and adjustment of the set point in response to environmental inputs

Positive feedback

 In positive feedback systems, the consequences of hormone secretion feed back is to reinforce the drive for secretion rather than dampen it.

Rather than maintaining matters stable and unchanging, positive feedback creates instability and leads to explosive changes . Consequently, positive feedback is rare in biology

Eg: During parturition

      Coagulation

      Generation of action potential

Concepts of  Specificity

Because of “internal secretion” of hormones into the blood, hormones are widely disseminated throughout the body and have access to virtually all cells. However, only certain cells respond to any particular hormone. These “target” cells differ from all other cells in the respect that they express receptors for that hormone.

The information delivered to the target cell is present in the structure and three-dimensional conformation of the hormone and is sufficient only to activate the receptor.

 It appears that activation of one particular receptor is an all-or-none phenomenon, with gradations in response resulting from gradations in the numbers of receptors that are activated in each cell.

 The receptor, by virtue of the biochemical changes it triggers in transducing the signal, initiates a particular biochemical change or group of changes. The signals generated in the target cell are determined by the signal-transducing component of the receptor.

In many cases, there is more than a single class of receptors for a particular hormone, and each class usually activates a different biochemical pathway.

The nature of the final response elicited in a target cell is not determined by the intracellular signal generated by the receptor but, rather, by the effective machinery expressed in the cell as a consequence of its  differentiated state

For example,

Receptors for the parathyroid hormone are present in the basal membranes of cells of both the proximal and distal portions of the nephron . Binding of the hormone initiates the same signaling cascade in both cell types,but the proximal tubules respond by decreasing phosphate reabsorption from the glomerular filtrate and increasing hydroxylation of vitamin D, while the distal cells respond by increasing reabsorption of calcium

CONCEPTS RELATED TO TARGET CELL RESPONSIVENESS

Responsiveness of target cells to stimulation by their hormones is not constant but may vary widely in different physiological states and is often adjusted by the actions of other hormones or local paracrine or autocrine agents as well as the primary hormone

Factors that govern the magnitude of the response to a hormone.

1)  Concentration of the hormone

        which in turn is determined by

a)      The rate of hormone secretion

b)      The rate of delivery by the circulation to the target cell surface, which is slower if the hormone circulates bound to plasma proteins than if it is unbound

c)       The rate at which the hormone is degraded or excreted

2) Number of competent target cells that express functional receptors

3) The sensitivity of each target cell to hormonal stimulation is not constant and depends on

a)      The number of functional receptors that are expressed

b)      The affinity of the receptor for the hormone

c)       The status of postreceptor amplification mechanisms

d)      The status and abundance of effector molecules

The sensitivity to a hormone of target organ is often defined as the concentration needed to produce a half-maximal response

Target organ sensitivity is not constant and is often adjusted in accordance with physiological circumstances.

Can be done by:

a)      Changing the number of receptors expressed.

b)      On the cellular level, upregulation or downregulation of effector molecules such as enzymes, ion channels

c)       On the tissue/organ level aggregate of the contributions of all of the respond-ing cells, so that the magnitude of the response to a particular concentration of hormone is a function of the number of available cells as well as the competence of each cell.

Factors that govern the duration of the response to a hormone.

1)  The duration of hormone availability, which is determined by

a)      The duration of secretion

b)      The rate of hormone clearance from the blood, usually described as its half-life

2)  Whether the response results from

a)      A rapidly reversible covalent change, i.e., phosphorylation or dephosphorylation of key enzyme

b)      Or genomic events involving synthesis of proteins and the half-lives of the proteins