Biological Effects of Cortisol

Abstract

Cortisol is an essential steroid hormone, synthesized from cholesterol and released from the adrenal gland. Cortisol is mostly known for its implication in physiological changes associated with stressful circumstances. It has as main function to regulate our response to stress, via activation of the hypothalamic–pituitary–adrenal axis (HPA-axis). However, this hormone has a variety of effects on different functions throughout the body in normal circumstances or at its basal levels. Cortisol act on tissues and cells of the liver, muscle, adipose tissues, pancreas, testis, and ovaries. Moreso, it is also implicated in the regulation of various processes such as energy regulation, glucose metabolism, immune function, feeding, circadian rhythms, as well as behavioral processes. The body continuously monitors the cortisol levels to maintain steady levels (homeostasis). In this chapter, we attempt to describe the biological effects of cortisol on the various organs of the body in humans and other animal species, with emphasis on the action mechanism implicated at level of the cells of the main target tissues or organs.

1. Introduction

Cortisol is a steroid hormone from the glucocorticoid family, produced in the adrenal glands [1, 2]. The secretion and release of cortisol is orchestrated by the hypothalamic-pituitary–adrenal (HPA) axis, one of the major neuro-endocrine systems of the organism. Briefly, the hypothalamic corticotropin releasing hormone CRH acts on the pituitary to cause release of ACTH, and ACTH then stimulates the adrenal gland (zona fasciculata and zona reticularis) to release glucocorticoids among which cortisol [3, 4]. The prominent glucocorticoid synthesized following the activation of the HPA axis in most mammals is cortisol; however in rodents and birds, corticosterone is the principal glucocorticoid secreted [5]. At optimal levels, cortisol works along with the other hormones of the body to maintain homeostasis. The secretion of cortisol follows a circadian rhythm; it is also essential for the survival of several living organisms [6]. Cortisol is a ubiquitous hormone, as it acts on almost every tissue and organs in the body (Figure 1), regulates numerous physiological processes including gluconeogenesis, protein catabolism, immune response, water balance, lipolysis, cardio-vascular function, reproduction, and skeletal growth [8]. Beyond these functions, in most living organisms, cortisol has a vital function: It is the key hormone involved in stress response; It is implicated in the physiological changes observed during an adaptive response (behavioral, cognitive, and physiological) necessary to deal with the upcoming actual stressor or stressful circumstances.

Figure 1.

The main biological effects of cortisol (Modified from Johnston III et al [7]).

Along with other glucocorticoids (GCs), cortisol is known to display potent anti-inflammatory effects at pharmacological levels. Thus, glucocorticoids drugs are mostly used to treat inflammatory diseases nowadays. They are commonly prescribed to patients suffering from cancers affecting the lymphoid system such as lymphomas, leukemia and myelomas. They are also prescribed following organ transplantation to prevent rejection [9]. Because of these pleiotropic effects, the abnormal use of exogenous glucocorticoids as drugs may induce several adverse effects in the body such as growth retardation in children, immunosuppression, hypertension, inhibition of wound repair, osteoporosis, abdominal obesity, glaucoma and other metabolic disturbances [10]. Patients with Cushing syndrome, caused by either exogenous or endogenous cortisol excess show several functional disorders. Too much or too little cortisol can impact the body. Elevated cortisol provokes several physiological responses, including energy mobilization and homeostasis disturbance, thus implicating other actions of cortisol different from its actions in normal circumstances [2, 11]. An understanding of the biological actions of cortisol on various physiological processes may be an important step in developing new drugs to combat the deleterious impact of stress. The present chapter outlines the current knowledge on the effect of endogenous cortisol on target body cells, emphasis is made on the actions of cortisol under normal physiological conditions, (that is at baseline concentrations). We focus on some biological activity of cortisol on the immune system, cardiovascular system, reproductive systems, as well as its role in the lipid, sugar, and bone metabolism and on the sleep-wake cycle. Herein, to aid the understanding of the actions of cortisol, we review the various actions of cortisol across the tissues of the body, with emphasis on the action mechanism implicated at level of the cells of the main target tissues or organs [10, 12].

2. Cortisol and immunity

The survival of an organism heavily relies on homeostasis and for mammals, the immune and anti-inflammatory response play a major role in the maintenance of a constant internal milieu [3, 13]. The anti-inflammatory action of glucocorticoid hormones was discovered by Hench and colleagues over 50 years ago [14, 15].

Since the immune system has been known to be influenced by glucocorticoids, in the past and present centuries, glucocorticoids have been used to efficiently treat immune-related diseases [16]. Over the last half century synthetic GCs such as dexamethasone and prednisolone have been indicated as efficient for the treatment of many autoimmune, inflammatory, allergic disorders such as rheumatoid arthritis, ulcerative colitis, allergic rhinitis and are the most effective anti-inflammatory therapy for asthma [17]. Thus, to further improve effective therapies for various inflammatory diseases, the physiological pathways involved in the secretion and regulation of glucocorticoids as well as their action mechanism on the different components of the immune system has been studied. Among glucocorticoids, Cortisol specially is known to affect several components of the immune system such as the production of lymphocytes and granulocytes [1, 18]. Previous findings investigating the mechanisms of cortisol on the immune system of pigs indicate that an increase in cortisol levels may cause a decrease in circulating lymphocytes and granulocytes [19]. The biological actions of cortisol on the immune system are mostly initiated by a regulatory mechanism involving the central nervous system (CNS), neuroendocrine system, and immune system [10, 13].

The immune system of humans among other species can be challenged by difficult circumstances (stressors) such as infection, external aggression (injury), or the physiological or psychological response to such circumstances (stress responses) [3]. When the body is challenged with injury, during the early onset of infection, neural, endocrine and cytokines send signals from the site of inflammation converge to the periventricular nucleus of the hypothalamus to activate the secretion of corticotropin releasing hormone (CRH) into the hypophyseal portal system [10, 16]. For autoimmune diseases and tissue damage where various cytokines are produced, the secretion of cortisol also increases as the HPA axis is activated. Following the release of CRH, its triggers the anterior lobe of the pituitary gland to secrete and release the adrenocorticotropin hormone (ACTH) in the circulation, which then stimulate the expression and release of cortisol by the adrenal glands [1, 9, 20].

Previous studies have shown that changes in levels of cortisol after exercise or changes in circadian rhythms are marked by an increase in cytokine levels and production of leukocytes. Thus, after its secretion, cortisol mainly acts by modulating the transcription of genes involved in the inflammatory response [16]. The glucocorticoid receptor (GR) (NR3C1) mediates the end point tissue effect of glucocorticoids. After binding to their cytoplasmic receptor (GR), a ligand-inducible transcription factor, the GC-GR complex may regulate the expression of gene via several mechanisms after translocation into the nucleus. But first, the GC-GR complex binds to the promoter region of steroid-sensitive genes of the glucocorticoid-response elements found in the nucleus [21]. Foremost, it switches off multiple activated inflammatory genes that encode cytokines, chemokines, adhesion molecules inflammatory enzymes and receptors [22]. The mechanisms result in the decrease transcription of genes coding for

• inflammatory cytokines such as interleukines (IL2, IL3, IL4, IL-5, IL-6, IL-13, IL-15), Tumornecrosis factor (TNF-α) and other factors such as GM-CSF, SCF, TSLPTNF-α, GM-CSF, SCF, TSLP

• Chemokines such as CCL1, CCL5, CCL8: CCL1, CCL5, CXCL8

• Various inflammatory enzymes including Inducible nitric oxide synthase, (iNOS), inducible cyclooxygenase, inducible phosopholipase A2 (cPLA2)

• Endothelin-1(inflammatory peptides) Inflammatory peptides: Endothelin-1

• Neurokinin-1, bradykinin B2 receptors (mediator receptors [9, 17].

In addition to the “switch off” mechanism, the major action of cortisol is to activate many anti-inflammatory genes [22], resulting in the increase transcription (trans-activation) of:

• Lipocortin-1

• β2-Adrenoceptors

• Secretory leukocyte inhibitory protein

• Glucocorticoid inducible Leucine zipper

• Anti-inflammatory or inhibitor cytokines IL-10, IL-12, IL-1 receptor agonist [12, 17]. The various anti-inflammatory action mechanism of cortisol also include the repression of the NFkB known as the major factor responsible for the regulation of cytokines and other elements of the immune response; thus resulting immunosuppression [6, 12].

3. Cortisol and glucose and lipid metabolism

3.1 Effects of cortisol and glucose metabolism

Cortisol mostly has a catabolic effect favoring liberation of energy stores, critical for adaptation to acute stress or illness. The maintenance of blood glucose homeostasis is among the central physiological functions regulated by glucocorticoids, and more specifically cortisol [23]. Cortisol and the other glucocorticoids influence all aspects of glucose metabolism by exerting their collective effects on the liver, endocrine pancreas, skeletal muscle, and adipose tissue [24]. Thus, disruption in cortisol rhythms often leads to disease, with chronic CORT excess (hypercortisolism) commonly associated with the impairment of glucose metabolism and the development of secondary type 2 diabetes [25].

Cortisol exerts its action after uptake of free hormone from the circulation and binding to intracellular corticoid receptors (GRs), being members of the steroid receptor hormone superfamily of nuclear transcription factors that regulate various physiological functions [26, 27].

In the liver, Cortisol is known to inhibit glucose utilization and accelerate hepatic gluconeogenesis, thereby preventing hypoglycaemia. Gluconeogenesis is the process by which glucose is generated from the non-carbohydrate substrates lactate, glycerol, and amino acids. Furthermore, cortisol also positively regulates hepatic gluconeogenesis, by stimulating the activation of key regulatory enzymes such as the glucose-6-phosphatase and the phosphoenolpyruvate carboxykinase. As in inflammation, this is achieved through the induction of the binding of GR to the glucocorticoid response elements in the promoter region of several genes encoding these enzymes [28], the rate limiting step of gluconeogenesis. In the liver, cortisol and other GCs also induce glycogen formation by increasing the activity of glycogen synthase [29].

In muscles, cortisol and the other GCs mainly impair insulin-stimulated glycogen synthesis by decreasing the activity of glycogen synthase. They also act to promote insulin resistance in skeletal muscle by regulation of a few GR target genes involved in the insulin-signaling cascade, that may lead to the malfunctioning or an apparent post-receptor defect with reduced downstream phosphoninositide-3-kinase and AKT activities. Further studies also showed that Cortisol may prevent hypoglycemia by stimulating glycogenolysis in muscle through epinephrine induced activation of glycogen phosphorylase [30]. Cortisol is thought to stimulate the generation of gluconeogenic precursors such as glycerol and gluconeogenic amino acids, by promoting lipolysis of triglyceride stores in adipose tissue and protein degradation in muscle [26].

In the adipocyte, cortisol acts by inhibiting glucose uptake and oxidation but also promotes lipolysis to provide glycerol as precursor for gluconeogenesis. The processes contributing to decreased glucose utilization by glucocorticoids in the adipocyte are less clear. However, currently, the modulation of glucose transporter GLUT4 function and the insulin signaling cascade are reported as plausible mechanisms involved herein [31]. Additionally, GCs are also involved in the differentiation and expansion of adipocyte precursors, a process that may further intensify insulin resistance and adipocyte dysfunction [24].

Cortisol is known as a potent regulator of the action metabolism of insulin secretion by pancreatic beta cells of the pancreas. Cortisol acts as a counter-regulatory hormone to insulin, and it effects may create an insulin resistance [26, 32]. Imbalanced cortisol concentrations in glycogen storage disease type I show evidence for a possible link between endocrine regulation and metabolic derangement [24]. Cortisol may impair Glucose-stimulated insulin secretion on multiple levels [30]. Primarily, it promotes the degradation of glucose transporter present in β cells, the GLUT2 and reduces expression levels of glucokinase [24, 33]. Additionally, the activity of glucose-6-phosphatase (G6P) is increased, further impairing the entry of G6P into the glycolytic cycle [34]. Cortisol also increases glucagon secretion in α cells [23, 24]. Once insulin resistance occurs, due to elevated levels of cortisol, glycogenesis is no longer stimulated and glucose storage by the liver as glycogen is thus inhibited; thereby contributing to the hyperglycaemic effects of cortisol [24].

3.2 Effects of cortisol on lipid metabolism

The implication of cortisol in lipid metabolism is well known. Previous experiments have shown that short-term administration of cortisol in vivo may promote adipose tissue lipolysis [35]. This could result from insulin resistance or inhibition of the action of insulin by glucocorticoid, as insulin is known to inhibit lipolysis [36]. Glucocorticoids are also though to promote lipolysis by stimulating lipoprotein lipase (LPL), thereby increasing the activity of lipolysis itself [37, 38]. Cortisol and glucocorticoids have been also shown to influence adipogenesis via the development of mature adipocytes, by stimulating the differentiation of pre-adipocytes into mature adipocytes and thus literally increasing the adipose tissue [39]. According to Lindroos et al. [40] Cortisol also acts by upregulating the glucocorticoid-dependent gene LIM domain only 3 (LMO3) known to influence the expression of 11β-HSD1. Following its upregulation, LMO3 modulates adipocyte differentiation via PPARγ which in turn regulates a set of adipocyte specific genes [40]. In addition to these, cortisol also influences de novo lipogenesis (DNL); a process whereby endogenous free fatty acids (FFAs) are produced from dietary carbohydrates [41]. The increase in DNL hepatic rates may decrease the available cytosolic triacylglycerol (TAG) pool, thereby increasing the export of TAGs to adipose tissues, resulting in hepatic steatosis (fatty liver) [42].

4. Cortisol effects on bone metabolism and bone growth

4.1 Cortisol effects on bone metabolism

In chronic stress circumstances, GCs have been shown to cause several adverse effects on the skeleton. However, at physiological levels, GCs play an important anabolic role as they appear to be vital for normal skeletogenesis and bone mass accrual [43, 44]. In normal physiologic conditions, endogenous cortisol regulates the expression of target genes through GR signaling within bone cells, affecting bone mineral density and the rate of bone loss [44]. The effects of cortisol on bone depend on intracellular enzymes, namely 11β-HSDs (1 and 2), that interconvert (Figure 2) cortisol between its inactive and active forms i.e., cortisol and cortisone [45, 46, 47]. 11β -HSD1, promotes the conversion of cortisone to cortisol in the presence of NADPH, whereas 11β-HSD2 in the presence of its cofactor nicotinamide adenine dinucleotide (NAD), potently inactivates cortisol to cortisone that is inactive in bone [43, 46, 48]. Previous research studies have demonstrated that the anabolic role of cortisol on bone mainly involves bone modeling and remodeling, as it promotes osteoblastogenesis to maintain the bone architecture. Osteoblasts (the bone forming cells) and osteocytes (long-lived cells related to osteoblasts which are resident within bone tissue) are the primary cortisol target cells in bones [43, 45, 49]. Within bone cells, via the Wnt/b-catenin pathway cortisol stimulates mesenchymal cells (usually derived from bone marrow) to differentiate into mature osteoblasts and thus increase bone formation [43]. Also, cortisol stimulates expression of a range of cellular markers of osteoblast function, including osteocalcin and alkaline phosphatase [47]. Cortisol was also proven to additionally drive differentiation of osteoclasts from mesenchymal precursors and enhance the bone resorption activity of mature osteoclasts [50]. The mechanism herein implicates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) and the suppression of the expression of the RANKL decoy receptor osteoprotegerin (OPG). Although cortisol has a stimulatory effect on osteoblasts at low doses, they are inhibitory at higher doses, where they instead promote apoptosis of osteoblasts [47, 51].

Figure 2.

Cortisol and bone metabolism: Actions of corticosteroids through the conversion of cortisone to cortisol and their effect in osteoclasts, osteocytes and osteoblasts (Modified from Martin et al. [45]).

4.2 Cortisol effects on bone growth

Major insights into the role of cortisol on bone are limited to their metabolism, although findings have shown that they appear to be essential for normal bone growth and maintenance though not directly implicated in endochondral ossification [52]. Findings show glucocorticoids among which cortisol may have negative as well as positive effects on bone growth. Glucocorticoids were demonstrated to inhibit proliferation of chondrocytes in the resting and proliferation zones of the growth plate of bone through the inhibition of pro-proliferative growth hormone (GH) and Insulin-like growth hormone 1 (IGF-I), as well as inhibition of ERK-dependent AP-1 activation; but may increase or decrease their differentiation [52, 53].

5. Cortisol and circadian rhythm

Circadian rhythm is a pattern that occurs throughout a period of 24-h comprising light-dark cycles wherein physiological functions adjust or synchronize with the beginning or ending of each cycle of the environment [54, 55]. As in many other mammals, in human, the circadian system coordinates physiology and behaviors to adapt daily to the environment.

Adaptation here is achieved via endogenous circadian clocks, with the central circadian pacemaker (CCP) located in the suprachiasmatic nucleus (SCN) of the hypothalamus being the main clock and other peripheral clock located in other tissues of the body (Figure 3). The latter will then enable the body to act like a finely harmonized clock. The circadian clock is sustained by linked of transcriptional–translational feedback loops comprising clock genes namely CLOCK and BMAL1 [57, 58]. The expression of these genes activates the synthesis of other proteins that act on their own targets to produce an integrated output over the 24-h cycle [56]. Under normal conditions or fully circadian-aligned conditions the CCP, synchronizes peripheral clocks throughout the body using hormonal and neural signals [8, 59] that participate in the entrainment of peripheral clocks by the master genes and, hence, with the light: darkness cycle. Cortisol appears to be the main metabolic or hormonal central synchronizing signal between the CCP and peripheral clocks in body tissues. In mammals, cortisol secretion is also subjected to a circadian rhythm. In normal individuals, without the occurrence of any stressors, the secretion of cortisol follows a distinct pattern; with very low or undetectable levels at midnight, to progressively increasing levels that build up overnight to peak in the morning [55, 60]. Following this, cortisol levels then decline slowly throughout the day [61]. To date, the exact mechanism through which cortisol enhances the activity of the main circadian oscillator is not well elucidated. However, it has been shown that the pivotal role of cortisol in the synchronization circadian is achieved via direct interaction between the cell-autonomous clocks in the metabolic tissues of the body i.e., the principal storage sites for glycogen, protein, and fat of the liver, muscle, and adipose tissue; or ligand-activated glucocorticoid receptor that bind to nucleal GRE at the level of regulatory regions of Bmal1, Cry1, Per1 and Per2 known as core clock genes [8]. Evidence of the crucial role of cortisol in circadian rhythmicity of the body are demonstrated in cases of diseases such as Cushing syndrome characterized by increased levels of cortisol, may result in a disturbed circadian rhythm seen through physical frailty, mood disorders, impaired spatial cognition and memory deficits [8, 62]. Whilst Addison’s disease where there are reduced levels of cortisol is a condition characterized by attention deficit hyperactivity disorder, and dyslexia. Circadian rhythm impairments. Also studies to evaluate the consequences of circadian misalignment have shown that cortisol secretion was impaired and delayed in most individuals undergoing shift in behavioral cycles.

Figure 3.

Schematic representation of the circadian rhythm synchronization between the central circadian pacemaker (CCP) and peripheral clock located in other tissues of the body. Cortisol secretion is stimulated via interactions between the CCP (thick blue arrow) from the suprachiasmatic master clock nuclei (SCN) and autonomic nervous system (yellow lines) and hypothalamic pituitary axis, (blue lines and circles). Following this, cortisol (red line and circles) enhances the activity of the main circadian via synchronizing systems (thick green arrow) comprising multiple signals from metabolic fluxes, cytokines, and peripheral modulation of the ligand-activated glucocorticoid receptor (modified from Minnetti et al. [56]).

6. Cortisol and cardiovascular system

6.1 Actions of cortisol on the heart

Among its numerous effects on different tissues of the body, cortisol is also known to have effects on cardiac and vascular tissues. Diseases related to excess cortisol such as hypercortisolism (Cushing’s syndrome) are usually associated with central obesity, insulin resistance, dyslipidemia, and alterations in clotting and platelet function but also hypertension, myocardial infarct size, ventricular remodeling post-acute myocardial infarction; the later representing risk factors of cardiovascular diseases [63, 64, 65]. The effects of cortisol on the cardiovascular system are not only linked to excess cortisol but cortisol is an important modulator of numerous processes with relevance for cardiovascular health [60, 66]. The effects of cortisol on the cardiovascular system are mostly potentiating effects. Further, cortisol has been shown to influence visceral-afferent signals or heartbeat even though the mechanisms underlying this action have not yet been clearly elucidated. Previous studies on knockout mice suggest that glucocorticoids also regulate cardiac function through the binding of mineralocorticoid receptor (MR), a nuclear receptor that appear to exert antagonistic transcriptional regulatory effects on the contractile function of the heart [4, 67, 68].

6.2 Actions of cortisol on vascular smooth muscles

The actions of cortisol on cardiovascular system do not only affect the heart but also comprise effects on vascular smooth muscles. Glucocorticoids are known to regulate the vascular tone [69]. They have been reported to enhance or potentiate the action of vasoconstrictor hormones namely Angiotensin II and norepinephrine. The potentiation action of glucocorticoids implicates receptor and non-receptor mechanisms. Studies investigating the receptor mechanisms have demonstrated that since corticosteroids are transcription factors, they could possibly induce synthesis of receptors for vasoconstrictors. For instance, for α-adrenergic receptors, Storm and Webb [70] have demonstrated that receptor number might be increased and binding affinity unchanged; whereas Schiffrin et al. [71] showed that in contrast to α-adrenergic receptors, angiotensin II surface receptors appear to be upregulated by corticosteroids. The non-receptor mechanisms have been shown to target vasoconstrictor synthesis by increasing the formation of angiotensinogen or by inducing the activity of angiotensin converting enzyme. In addition to increase vasoconstrictors synthesis, glucocorticoids may act on ion transport as to influence the membrane potential of vascular smooth muscle cells [69, 72].

7. Effects on the reproductive system

The biological effects of cortisol on reproduction are diverse as cortisol act in both male and female. In mammalian female, GR receptors are present in follicular cells of ovaries. Even though ovaries are site of synthesis of other steroid hormones namely progesterone and 17 alpha-hydroxy-progesterone but specific enzymes catalyzing the synthesis of cortisol are absent. In ovaries the activity of cortisol is modulated or regulated by the binding of other steroid hormones (progesterone and 17 alpha-hydroxy-progesterone) on GR receptors. Consequently, when the ovarian steroids bind to cortisol-binding protein receptors, there will be an increase of unbound cortisol. Thus, increased levels of the latter increasing its availability to act on the follicles. Ovarian steroids also contribute to regulating the expression of two types of 11 beta-hydroxysteroid dehydrogenase (i.e. 11 beta-HSD type 1 and type 2). Consequently, a high concentration of cortisol available for biological action may be present in the preovulatory follicle just prior to ovulation [73]. Under normal physiological circumstances, cortisol levels increase in the preovulatory follicle just prior to ovulation [74, 75]. This preovulatory increase has been shown to promote receptive behavior, stimulate gonadotropins and facilitate ovulation [76, 77]. It has been suggested that cortisol may function to reduce the inflammatory-like reactions occurring in connection with ovulation [78].

In addition to its anti-inflammatory action, cortisol in the follicular fluid at ovulation may also affect the function of the oviduct and induce the formation and function of the corpus luteum, whereas the surrounding developing follicles may experience negative effects [73]. In cattle, findings from Komiya et al. show that cortisol may act to maintain corpus luteum function at early and midluteal stages by suppressing or regulating the apoptosis of luteal cells [79].

In females, the biological actions of cortisol are not only limited to the ovary. The actions of cortisol are also important in the uterine biology during pregnancy and labor [80]. This hormone is important for early pregnancy as previous studies have shown that glucocorticoids can promote proliferation in a variety of cell types in the uterus. Cortisol is known to increase the expression of some growth factors via the Wnt/β-catenin and PI₃K/AKT signaling pathways and to promote proliferation of bovine endometrial epithelial cells (BEECs) [79]. Peterson et al. [81] demonstrated that dexamethasone administered at low doses to human lens epithelial cells in cultures may induce a moderate proliferation of these cells. The role of cortisol in the immune response is also crucial in establishing endometrial receptivity. In addition to this, cortisol may also be important during the decidualization process, as the glucocorticoid signaling in uterus may be required for the cell-fate decision of stromal cells [80]. Besides these actions, in mammals, GC levels increase towards parturition, and are partially involved in its onset through the promotion of prostaglandins. Studies in sheep have indicated that glucocorticoids may drive the shift to estrogen-primed contractile myometrium via the placental enzyme P450 17α-hydoxylase. Following this, prostaglandins may induce myometrial contractions, ripening of the cervix and rigger the rupture of foetal membrane [80]. In species such as cattle, goat and sheep, GCs are low throughout pregnancy and only rise prior to parturition [82].

In males, glucocorticoids physiological levels and stress-induced cortisol are known to influence the testicular function. Previous studies have shown that cortisol influences the production of androgens by modulating the biosynthesis of enzymes and testicular LH receptors [73, 83]. In adrenalectomized rats, testosterone production was shown to increase. The number of spermatids also decreased and was restored after dexamethasone treatment. Moreover, in zebrafish (Danio rerio), studies in ex-vivo culture system demonstrated that cortisol may stimulate spermatogenesis i.e., spermatogonia proliferation and differentiation. This is achieved through using paracrine pathway (androgen independent manner) through the modulation of transcription of some genes involved in the testicular function. Further findings also demonstrated that cortisol promotes meiosis and spermiogenesis, thus increasing the number of spermatozoa in the testes [84]. In a previous study carried out on fragments of immature Japanese eel fish, Ozaki et al. demonstrated that cortisol activate spermatogonia differentiation and DNA replication via 11-ketotestosterone [85]. Besides the testicular function, cortisol also modulates or regulates the erectile function and sexual behavior in humans. In a recent study by Rahardjo et al. [86] demonstrated that cortisol may act as a mediator of the erectile function, by acting as an antagonist of the normal sexual response in adults. Their results also highlighted that an impaired secretion of cortisol may induce erectile dysfunction. Moreso, cortisol was also proven that cortisol might be an important modulator of sexual behavior. Although the mechanism are still unclear, Rodriguez-Nieto et al. [87] suggested cortisol may act as a neuromodulator and may associates with the anteromedial prefrontal cortex region during the approach before sexual stimuli. It appears that the response to cortisol response varied among individuals in sexual inhibition and mood from sexual activity.

8. Conclusion

From this chapter describing the biological actions of cortisol, it can be concluded that cortisol plays a very important role in the various physiological processes in the body, important for its development and its homeostasis. Therefore, from the knowledge summarized herein, the importance of the use of cortisol derived drugs in decreasing the inflammation process is clearly understood. From this chapter it appears that the effects of cortisol on glucose metabolism are very vital for homeostasis as its various actions also influence lipid metabolism and may be at the origin of metabolic diseases. This chapter also shows the implication of cortisol in bone metabolism and growth even though more is still to be elucidated especially regarding the biological actions of cortisol on growth that is not very well known. The actions of cortisol on vascular systems, circadian rhythm and reproductive system further explains the disturbances observed due to environmental stimuli (stress). Transcriptional activation, modification of receptors, changing enzyme activity, stimulation of release or production, appear as the mechanisms, via which cortisol mostly exert its action; however, some pathways are still unknown. This suggests that many more experiments need to be performed to fully understand the pathways involved in the actions of cortisol in the different target tissues. Finally, because of all the different processes cortisol has effects on, there also are different possible changes in cortisol levels which may affect several systems in the body. Thus, corticosteroids treatments may have important adverse effects inhibiting processes important for the body. This confirms the necessity of carrying out further research on the various actions of cortisol, describing mechanisms involved to better corticosteroid-based treatments.

In spite of the knowledge about the biological actions of cortisol, there is still a lot to understand. Hence, every little discovery counts and will eventually help to explain physiological mechanisms in cortisol-related syndromes.

Acknowledgments

The authors would like to thank the Universities of Bamenda and Douala for the facilities which enabled them to write this chapter.

Conflict of interest

The authors declare no conflict of interest.