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Issue 142 Winter 2021

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‘For endocrine evolution is not an evolution of hormones but an evolution of uses to which they are put.’


This perceptive comment was made by Peter Medawar in 1953 (Symposia of the Society for Experimental Biology VII: Evolution 320–338), and is the first published statement to this effect, though it was quickly adopted or assumed by others. It is somewhat irritating, since Medawar was a Nobel Prize-winning immunologist, not at endocrinologist at all, yet his statement was stunningly accurate, guided perhaps by Peter Krohn and Ian Chester Jones, from whom he sought advice.


There’s a remarkable parallel here with the classical concept of skeletal evolution, as interpreted from comparative anatomy. Here, the identity of the skeletal elements that, for example, make up the limbs of coelacanths, amphibia, reptiles, birds and terrestrial or flying mammals has been well understood by generations of undergraduates.


There are many other examples, like the way in which the swim bladder was adapted on land to become an air-breathing lung. Indeed, fins that have become limbs and swim bladders that have become lungs are present in some species today, like lungfish, that are subject to variable availability of their ponds and lakes.


This illustrates the redesignation of structures to different functions as the environment or mode of life changes. It’s the product of the essential compromise between the ‘maximum parsimony’ and ‘no-redundancy’ concepts that perhaps might once have prevailed in evolutionary thought, before the baggage of unexpressed or otherwise redundant DNA in every nucleus was known.


But how fascinating that the same has occurred in hormones!


Perhaps most striking is the number of uses to which prolactin has been put – osmoregulation in fish, water-seeking behaviour in certain amphibia, pigeon crop secretion and contributing to lactation in mammals – a truncated list for sure.


What of the steroid hormones? Of the steroid-mediated processes that show widest variation in the vertebrates, reproduction ranks high in the list. The steroid hormones are thought (generally) to be essentially identical across the vertebrates, and the same groups of steroids, oestrogens and progestagens are present throughout. Indeed, it is this area that led Medawar to his near-aphorism.


It’s in the evolution of corticosteroids that things may seem muddy. Once upon a time, I thought that the first evolutionary appearance of zonation in the mammalian adrenal cortex nicely coincided with the separate production of glucocorticoids and mineralocorticoids, because it’s only in mammals that they have distinct functions. It’s too neat: the mineralocorticoid-secreting glomerulosa, the glucocorticoid-secreting fasciculata (and the general glory hole of the reticularis making androgen, sulphoconjugating, and xenobiotic-metabolising) was never as clear as that.


Somehow or other it’s mostly the term ‘glucocorticoid’ that has misled us all. If we understood the essential functions of glucocorticoids, we might begin to understand why mammals appear to require a whole specialised cell type, with its own trophic factor, to make them. From the start it never was thought to be just about carbohydrate metabolism. But the range of functions in which glucocorticoids appear to have a role is huge, and finding a unified physiological and evolutionary explanation for a single control system is elusive.


Even if the actions of mineralocorticoids and glucocorticoids were neat, separated, discontinuous, how could that be explained by the promiscuity with which each binds to the other’s receptor (MR and GR) which, moreover, bind to the same response elements in the promoters of target genes?


Recent studies by Bridgham et al. (Science 2006 312 97) on the evolution of corticosteroid receptors show very nicely that MR and GR binding affinities for aldosterone and cortisol are discriminatory even in teleosts, in which aldosterone isn’t generally secreted at all. We should look at fish physiology to speculate how the uses to which the corticosteroids are put have evolved.


Marine teleosts, you might think, don’t actually need aldosterone. They have no trouble getting enough sodium, their problem is getting rid of it. So they excrete sodium across the gills (and kidneys), a process stimulated by, well, a ‘glucocorticoid’ – cortisol in fact. Those that live in fresh water have the opposite problem, vanishingly low availability of sodium, so they have a highly effective kidney that (with the gills) resorbs sodium aided, yes, by cortisol again. Associated with this, they must eliminate relatively vast volumes of water, perhaps also facilitated by cortisol.


Here we come across a concept more familiar to a mammalian endocrinologist, for the elimination of a water load, and indeed shifting of water between body compartments, is an important ‘glucocorticoid’ function in mammals. But we are like neither marine nor fresh water teleosts. We terrestrial vertebrates are somewhere in between. Perhaps we’re more like euryhaline or estuarine fish, or fish whose watery habitats dry out occasionally. We too have the potential to be subjected to big changes in the availability of water, and of sodium.


So perhaps our ancestors didn’t crawl out of the sea at all. They came out of an estuary, or were left high and dry by capricious tides. But they were fully prepared, or ‘preadapted’, being equipped with limbs, lungs, a ‘glucocorticoid’ and a balanced set of MR and GR.


The rest is history.




Read more about the author, Gavin Vinson, in his obituary

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