Lower Serum Androstenedione Levels in Pre-Rheumatoid Arthritis versus Normal Control Women: Correlations with Lower Serum Cortisol Levels

Figure 2

An inductive categorical schema of adrenal cortical and ovarian tropic (ACTH, LH, and FSH) and trophic (steroidogenic cell mass or competency) influences on cortisol, adrenal androgen (AA), and sex hormone production, in relation to AA status in females. Negative feedback control of the hypothalamic-pituitary-adrenal (HPA) and ovarian (HPG) axes is illustrated. Solid lines indicate stimulation and dashed lines indicate inhibition, within the respective systems. Direct and indirect interactions between the respective HPA and HPG axes are not illustrated. The HPA axis can inhibit the HPG axis at multiple levels and estrogen may stimulate the HPA axis [17]. The enlarged ovary model portrays tropic (LH, FSH) and trophic mechanisms operating in polycystic ovarian syndrome (PCOS), rather than a normally large gland. The adrenal cortex and ovary are derived from a common embryonic anlage. It is not known if trophic influences can cause an “enlarged adrenal organ syndrome,” analogous to PCOS. Regarding low adrenal and low ovarian gland sizes, defined syndromes are also not documented, but individual variation and diminishing size occur in natural aging. Cortisol is synthesized mainly in the zona fasciculata (ZF, white area), which has the largest mass of the adrenal cortex (circa 70%). The AAs, DHEA and androstenedione, are mainly produced in the zona reticularis (ZR, darker grey area), which has the smallest mass (circa 10%). In females, the AAs are the major source of androgenic compounds. The mineralocorticoids are synthesized in the outermost zona glomerulosa (ZG, light gray area), which has a medium mass (circa 20%) of the adrenal cortex. Cortisol and AA production are stimulated by ACTH secretion in a pulsatile pattern under regulation of the hypothalamic-pituitary (H-P) axis. Cortisol, in turn, inhibits the H-P in a negative feedback manner. It directly suppresses hypothalamic corticotropin releasing hormone (CRH) and its action on the pituitary secretion of ACTH. Insufficiency of cortisol leads to less inhibition of the CRH-ACTH axis and to increased ACTH. In normal aging, cortisol levels are fully maintained in the setting of decreased AA production and associated decreased ZR mass. The overall size of the adrenal cortex is stable in aging, but the outer cortical zones (ZG and ZF) are relatively increased in size to the diminished ZR [18]. The ovarian AA steroids are androstenedione mainly and testosterone (T), which lack negative feedback inhibition at the H-P levels, a function accomplished by estrogen (E).