Digging within the Historical past of Endocrinology

In a earlier article I described my delight at seeing 13-lined Floor Squirrels for the primary time within the wild. These animals are a standard sight within the grasslands and prairies of north America. My first encounter with this species was 58 years earlier. Earlier than I joined him as a PhD pupil John Phillips (1933-1987) was again in Sheffield on his first lengthy depart from the College of Hong Kong the place he was Professor of Zoology, having been appointed three years earlier on the age of 29. In these days expat phrases have been such that after two years and 7 months ‘dwelling’ depart of 5 months was taken—a perfect association for these wishing to do analysis. I discovered him within the attic, used as an animal home. He was involved {that a} group of floor squirrels – stored collectively—was not thriving. I may see they have been being ate up commonplace rat lab pellets plus the standard combination of seeds, biscuit and so on given to hamsters. I instantly advised giving them extra protein since I had stored a associated species and knew that they ate bugs and different invertebrates along with the usually rodent food plan. The technician in cost  couldn’t consider I used to be proper however went off to gather a handful of mealworms which have been thrown into the ground cage. The bottom squirrels fell upon them and had quickly scoffed the lot. With the issue of feeding solved, John completed his work on them and returned to Hong Kong. I assumed that the work had been printed since in his report back to the Nuffield Basis in 1967, which funded his work in comparative endocrinology to the extent of pay, gear and consumables for a analysis unit in Hong Kong, he listed among the many publications one on the 13-lined Floor Squirrel which was in preparation for submission to the Journal of Endocrinology. Nonetheless, once I searched all his publications whereas researching this text I couldn’t discover it and solely this week have I discovered that the work was by no means printed and realised why it was by no means printed

Within the early many years of the twentieth century, endocrinology was in its infancy and there was nonetheless argument, relationship from the 1850s, of whether or not or not the adrenal glands are important for all times. The 13-lined Floor Squirrel (now Ictidomys tridecemlineatus however then included within the genus Citellus and later Spermophilus) achieved its fame as an oddity in comparative endocrinology as a result of it could persistently survive removing of the adrenal glands by advantage of the expansion of adrenocortical tissue within the ovary. Richard Arnold Groat (1915-1994) was a PhD pupil within the Division of Anatomy on the College of Wisconsin when he printed his findings in 1943 and 1944. Groat went on to work in quite a lot of medical colleges and in personal observe as a pathologist in North Carolina.

Groat confirmed that in frequent with quite a lot of different species, 13-lined Floor Squirrels solely survive after adrenalectomy if given 1% sodium chloride to drink. With that remedy the animals proceed to feed. Nonetheless, in contrast to in different species, Groat discovered that the salt water will be eliminated after a minimal of 15 days and that the bottom squirrels can stand up to a quick after 3-4 months. He then confirmed that adrenocortical-like tissue appeared within the ovaries after full removing of the adrenal glands strongly indicating that adrenal steroid hormones have been being produced by the ovary in portions enough for regular life.

I have no idea how Ian Chester Jones (1916-1996) heard of Groat’s work. There was no point out of it in his seminal monograph on the adrenal cortex which was printed in 1957. Nonetheless, he turned sufficiently to begin this work in 1961 at Harvard. He was once more working as a customer in Roy Orval Greep’s (1905-1997); he had spent a few years there within the Nineteen Fifties on a Fellowship of the Commonwealth Fund of New York (later to change into Harkness Fellowships). Ian Henderson, then a PhD pupil in Sheffield (1941-2019) was the second creator of the paper printed in 1963. They defined their curiosity in Groat’s work:

His [Groat’s] findings have all the time been open to the suspicion that they’re merely manifestations of adrenal rests which confirmed specific responsiveness on this species. However, his work might point out the capability of ovarian tissue to alter into a brand new kind which can be adrenocortical each in kind and performance. Ought to this be so, then a query of basic significance is raised. It might be, for instance, that the bottom squirrel shows, in intensified trend, a property that exists in mammals usually. For these causes, this paper presents a re-examination of the issue.

In fashionable phrases, there may be one other attainable rationalization: a inhabitants of pluripotent stem cells or partially differentiated cells within the ovary stimulated by ACTH from the pituitary to divide and differentiate into cells typical of the adrenal cortex fairly than of the ovary, the ovary and adrenal cortex being of comparable embryonic derivation. With the unfavorable suggestions between concentrations of adrenal steroid hormones and ACTH secretion, the concentrations of ACTH within the blood would have been sky excessive within the adrenalectomized animals.

Basically Chester Jones & Henderson confirmed Groat’s findings. As with Groat, they have been unable to seek out adrenal rests—small remoted clumps of adrenocortical tissue outwith the adrenal gland—within the regular adrenal. These happen in numerous places together with the ovary and testis in mammals.

The implication of the observations could be that with the obvious absence of adrenal rests, the ovary of the intact floor squirrel wouldn’t be producing adrenal steroid hormones. Nonetheless, Gavin Vinson (1939-2021) then additionally working with Chester Jones in Sheffield discovered that ovarian tissue may convert progesterone to the adrenal steroid hormones, corticosterone. In his paper of 1965 he wrote (references omitted):

It’s significantly fascinating that the ovary has the capability to transform progesterone to corticosterone. Whereas this could be ascribed to adrenal rests, Groat (1943, 1944) and Chester Jones & Henderson (1963) have been unable to seek out adrenocortical tissue within the ovaries and adnexia of regular floor squirrels. One other risk is that ovarian cells, probably the interstitium, of the bottom squirrel are in a position to produce each intercourse and adrenocortical steroids. A lovely speculation is that, because the ovary shares a standard embryological origin with the adrenal cortex, all through the vertebrates each tissues are in a position (to a better or lesser diploma) to fabricate each oestrogens and corticosteroids.

Whereas there may be present molecular proof in opposition to the latter within the latter rationalization in mammals, I think the reason probably lies in a small inhabitants of partially differentiated adrenocortical cells within the ovary of the bottom squirrel, i.e. cryptic and extensively unfold adrenal rests with the potential to develop into clumps of adrenocortical tissue.

William George Henry Seliger (1922-2016), A James Blair and Harland Winfield Mossman (1898-1991) adopted up Groat’s work in 1966; they have been in the identical division as Groat within the College of Wisconsin and I think Groat might have been Mossman’s pupil. They confirmed that the cells attribute of the adrenal cortex which seem within the ovary are in shut relationship to the epithelial remnants of the rete ovarii and the medullary cords. An identical cells have been discovered across the efferent ductules of the testis in adrenalectomized males. Histochemical exams indicated the cells have been equivalent to regular adrenocortical cells. In vitro, the areas of the ovary with the adrenal-like cells transformed progesterone to adrenal steroid hormones recognized as corticosterone and desoxycorticosterone (11-deoxycorticosterone)* the mixture offering each glucocorticoid and mineralocorticoid exercise. Affirmation of the important position of the ovaries and testes in adrenalectomized floor squirrels was obtained:

Female and male animals adrenalectomized a 12 months earlier than and maintained on faucet water died inside 4 days when the gonads and adnexa have been eliminated. Male animals adrenalectomized a 12 months earlier than and maintained on faucet water survived actively for 2 weeks when the testicles have been eliminated, supplied that the efferent ductules and surrounding adrenal cortex-like cells have been left in place. These animals died inside 4 days after the adnexa have been eliminated.

To return to the paper by Phillips and Chester Jones that was by no means printed, the chronology means that the work they have been doing in September/October 1965 produced outcomes indistinguishable from these printed by Seliger, Blair and Mossman in 1966. Briefly, that they had been scooped.

Because the Nineteen Sixties there was little so as to add to the story. It will appear that cells with the potential  to change into adrenal cortical cells will be retained throughout embryonic improvement within the ovaries and testes within the floor squirrel. In that respect there may be nothing new—adrenal tissue has been discovered after adrenalectomy in comparable places of mesodermal origin in different mammals. Within the rat a report from the Twenties indicated an incidence of 19%. Equally, some human sufferers present accent adrenal tissue after adrenalectomy. Nonetheless, what makes the 13-lined Floor Squirrel particular is the extent and consistency of formation of adrenocortical tissue within the ovary and testis. The discovering in 1967 of comparable buildings within the ovary after adrenalectomy of the Northern or 5-striped Palm Squirrel (Funambulus pennantii) by Seth and Prasad of the College of Delhi, means that sciurid rodents might all present the phenomenon.

The query stays of whether or not the flexibility to kind new adrenocortical tissue has any purposeful significance. In different phrases, has the retention of mesodermal remnants able to forming adrenocortical cells been topic to optimistic pure choice in some mammals—or are they merely vestiges that solely assume a physiological significance below laboratory and medical circumstances that by no means happen in regular life?

A attainable clue to some purposeful position of adrenocortical cells within the ovary comes from the rabbit. In 1974 Hiroshi Mori and Keishi Matsumoto reported:

Adrenocortex-like cells have been persistently discovered within the mesovarium or within the hilus of the ovary of rabbits lower than three months outdated. The adrenocortex-like cells occurred often within the type of nodules amongst or close to the mesonephric tubules. However they generally appeared inside the rete ovarii both in direct contact with the epithelial cells or scattered within the stroma.

Histochemical research indicated they have been adrenocortical cells. Furthermore, ovarian plus mesovarium tissue in vitro was in a position to convert progesterone to corticosterone. These research, now 50 years outdated, increase one other query: what’s the position of adrenocortical hormones within the ovary of younger rabbits?

If one thing comparable obtains within the ovary of different mammals in adolescence, is is then attainable that the squirrels have had purposeful adrenocortical cells within the ovary and/or testis earlier in life and that adrenalectomy merely stimulates the remaining inhabitants of dormant stem cells? Has anyone had a glance?

*Whereas the strategies used to establish steroid hormones within the Nineteen Sixties don’t fulfill fashionable standards, there is no such thing as a cause to suspect they weren’t as said by the varied authors of the time.

Chester Jones I, Henderson IW. 1963. The ovary of the 13-lined Floor Squirrel (Citellus tridecemlineatus Mitchell) after adrenalectomy. Journal of Endocrinology 26, 265-262 doi:10.1677/joe.0.0260265

Groat RA. 1943). Adrenocortical-like tissue within the ovaries of adrenalectomized floor squirrel (Citellus tridecemlineatus). Endocrinology 32, 488-492 doi:10.1210/endo-32-6-488

Groat RA. 1944. Formation and development of adrenocortical-like tissue within the ovaries of adrenalectomized floor squirrel. Anatomical Document 89, 33-41 doi:10.1002/ar.1090890104

MacFarland WE. 1945. The important necessity of adrenal cortical tissue in a mammal and the consequences of proliferation of cortical cells from dormant coelomic mesothelium. Anatomical Document 93, 233-249 doi:10.1002/ar.1090930303

Mori H, Matsumoto Okay. 1974. Fixed prevalence of adrenocortical tissue within the juvenile rabbit ovary. American Journal of Anatomy 141, 73-89 doi:10.1002/aja.1001410105

Seliger W, Blair AJ, Mossman HW. 1966. Differentiation of adrenal cortex-like tissue on the hilum of the gonads in response to adrenalectomy. American Journal of Anatomy 118, 615-629 doi:10.1002/aja.1001180217

Seth P, Prasad MRN. 1967. Impact of bilateral adrenalectomy on the ovary of the 5 striped Indian palm squirrel, Funambulus pennanti (Wroughton). Common and Comparative Endocrinology 8. 157-162. doi:10.1016/0016-6480(67)90124-4

Vinson GP. 1965. Steroid manufacturing in vitro by the ovaries and adrenal glands of the thirteen-lined floor squirrel (Citellus tridecemlineatus Mitchell). Jourbnal of Endocrinology 32, 401-402 doi:10.1677/joe.0.0320401

Wilson JB, Zopey M, Augustine J, Schaffer R, Chiang M, Friedman TC. 2021. Excessive prevalence of adrenal remnant tissue in sufferers present process bilateral adrenalectomy for Cushing’s illness. Hormones and Metabolic Analysis 53, 161-168 doi: 10.1055/a-1253-2854

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