Review
A brief history of adrenal research: Steroidogenesis – The soul of the adrenal

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Abstract

The adrenal is a small gland that escaped anatomic notice until the 16th century, and whose essential role in physiology was not established until the mid 19th century. Early studies were confounded by failure to distinguish the effects of the cortex from those of the medulla, but advances in steroid chemistry permitted the isolation, characterization and synthesis of many steroids by the mid 20th century. Knowledge of steroid structures, radiolabeled steroid conversions, and the identification of accumulated urinary steroids in diseases of steroidogenesis permitted a generally correct description of the steroidogenic pathways, but one confounded by the failure to distinguish species-specific differences. The advent of cloning technologies and molecular genetics rapidly corrected and clarified the understanding of steroidogenic processes. Our laboratory in San Francisco was one of several contributing to this effort, focusing on human steroidogenic enzymes, the genetic disorders in their biosynthesis and the transcriptional and post-translational mechanisms regulating enzyme activity.

Highlights

► The adrenal glands were first clearly described anatomically in 1563. ► In 1856, Brown-Sequard first showed that the adrenals were essential for life. ► Organic chemistry permitted the isolation, and synthesis of many steroids. ► Identifying all the steroidogenic enzymes required molecular genetic technologies. ► Despite these advances, the adrenal cortex remains a very active area of research.

Section snippets

Introduction to the Keith Parker Memorial Lecture

It was indeed an honor to give the second Keith Parker Memorial Lecture at the biennial Adrenal Cortex Conference. Keith was a friend and a creative, ground-breaking scientist who was taken from us far too soon. We all miss him deeply. Following his discovery of the transcription factor SF1 (steroidogenic factor 1), much of Keith’s career concerned adrenal development in rodent systems, while mine has concerned human steroidogenesis, but we were both focussed on the adrenal. Below I shall

Anatomists: discovery of the adrenal

Whereas it is self-evident that the adrenal has always been with us, early anatomists apparently failed to note its presence. In the context of describing animal sacrifices, Leviticus 3:4 and 4:9 both refer to “…the two kidneys, and the fat that is on them, which is by the flanks…” (King James translation) and in a different context Claudius Galen (ca. 130–201) only described ‘loose flesh’ atop the left kidney (Leoutsakos and Leoutsakos, 2008). Thus it seems that the ancients could not

Physiologists: adrenal function

The linkage of earlier anatomy with clinical observation in the mid 19th century began the modern era of adrenal research. Thomas Addison (1793–1860) first described tuberculosis of the adrenal in 1849 (Addison, 1849) and then wrote his famous, detailed monograph “On the Constitutional and Local Effects of Disease of the Suprarenal Capsule” in 1855 (Pearce, 2004). In studies of (autopsied) patients with anemia, he found bilateral adrenal pathological changes that appeared to be independent of

Chemists: adrenal hormones

The general organic chemistry of polycyclic compounds received much attention in the early 20th century. Heinrich Wieland and Adolph Windaus received the 1927 and 1928 Nobel prizes in chemistry for their work on bile acids and the structure of cholesterol, but their structures were incorrect, featuring four-ring structures with two 5-carbon rings (Wieland, 1928, Windaus, 1928); the correct cyclopentanophenanthrene structure was then determined by Rosenheim and King in 1932 (reviewed in

Clinical investigators: adrenal hyperplasias

The effectiveness of cortisone in Addison’s disease and its increased availability quickly permitted its trial in other clinical settings. Wilkins was first to report its successful use in CAH (Wilkins et al., 1950, Wilkins et al., 1951); Bartter published similar results as an abstract (Bartter et al., 1950) and then as a full paper (Bartter et al., 1951). This opened a vigorous era of clinical investigation of the pathways of steroidogenesis in a variety of inherited adrenal and gonadal

Steroidogenic enzymes: proteins, cDNAs and genes

An understanding of steroidogenic processes required identification of the responsible steroidogenic enzymes. The discovery of cytochrome P450 enzymes was central to the understanding of steroidogenesis (for reviews and personal reflections, see Cooper, 1973, Estabrook, 2003, Omura, 2011). Early studies noted that steroid 21-hydroxylation by bovine adrenal microsomes was inhibited by carbon monoxide and reversible by light, but the responsible protein was not identified (Ryan and Engel, 1956,

Future directions

While the above tour through the adrenal cortex might suggest to the young investigator that everything of interest in the adrenal has been done, that is far from the truth. As illustrated by the outstanding science presented at the 15th Adrenal Cortex Conference, the following areas, in no particular order, require further investigation. (1) The precise molecular itinerary of a cholesterol molecule as it enters the mitochondrion and the mechanism of StAR’s action remain unclear. (2)

Acknowledgements

The author wishes to acknowledge the dozens of fellows, students and collaborators with whom he has studied steroidogenesis since the early 1980s. One, Prof. Synthia H. Mellon, deserves special mention (Fig. 7). It was reading Sindy’s 1978 Ph.D. thesis (with Seymour Lieberman, who had studied with Reichstein) that catalyzed my departure from pituitary polypeptides and into the world of steroidogenesis, and launched both a successful career and a loving marriage.

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