**2. Glucocorticoids: short metabolic review**

Store capability of body steroid hormones is limited; thus, they are synthesized from cholesterol, mainly in liver and endocrine glands. The placenta, although it produces steroid hormones, is unable to synthesize cholesterol, being, thus obliged, to take it from maternal plasma low-density and high-density lipoprotein (LDL and HDL, respectively) particles [23].

Cholesterol (27 carbons, 27C), the common precursor of all steroid hormones, is converted in placenta to pregnenolone (27C) from which progesterone (21C) is derived. Progesterone is the precursor of several steroid hormones: (a) adrenal cortex hormones (mineralocorticoids and glucocorticoids); (b) male sex hormones (androgens) (19C); and (c) female sexual hormones (oestrogens) (18C).

The adrenal cortex contains 11-, 17- and 21-hydroxylases. When hydroxylation takes place in C21, the 17-hydroxylase action is arrested and mineralocorticoids (e.g. aldosterone) are synthesized in the glomerular zone. When hydroxylation takes place in C17, glucocorticoids and sex hormones are formed in the fascicular and the reticular zones, respectively [16]. The final step production of glucocorticoids and mineralocorticoids is catalysed by two mitochondrial cytochromes P450, CYP11B1 (11b-hydroxylase or P45011b) and CYP11B2 (aldosterone synthase or P450aldo) [24]. The synthesis of steroid hormones is summarized in **Figure 1**.

**1. Introduction**

active corticoids [20–22].

(oestrogens) (18C).

Pregnancy is a very complex period where growth, development and maturity take place. The future body, in addition to increasing its cellular mass, progressively acquires functional capabilities that would permit it to live and grow out of the mother's womb [1, 2]. Two clear periods can be distinguished during pregnancy in the future mother. During the first period, a marked increase in insulin level and sensitivity occurs in the mother, with parallel increases in placenta size, amniotic volume, protein content and fat stores; however, the foetus weight gain is small in comparison with that of the mother [1–3]. During the second period, a physiological increase in insulin resistance and insulin degradation takes place in the mother, in parallel to the exponential foetal growth that partially or totally blocks the gain rhythm of maternal stores. This metabolic situation assures the availability of glucose for the maternal and foetal brains and mammary gland, reducing the uptake of glucose by other maternal tissues [1–3]. When glucose homeostasis is not physiologically balanced, changes and adaptation take place during pregnancy, predisposing the individual to degenerative diseases later in life [4–8]. In some non-diabetic women, an alteration in carbohydrate metabolism occurs during pregnancy; thus, although fasting glycaemia is normal, after a carbohydrate load, the glycaemia increases over normal values. This situation is rather more frequent at the end of

Several homeorhetic adjustments are required to assure adequate foetal anabolism, which in turn can also be affected by genetic and nutritional factors [1, 2, 10–15]. Maternal glucocorticoids, among others, clearly affect metabolites and foetal corticoids that compete with other anabolic and growth mediators as insulin and insulin-like growth factor-1 (IGF-1) [2, 16–18]. Thus, a hormonal balance seems to be of critical importance to guarantee suitable foetal and postnatal development [4, 5, 16–19]. Glucocorticoids are central hormones engaged in correct foetal growth and maturation [16, 17]; however, their excess induces intrauterine growth delay, clearly affecting glucose homeostasis and brain development and functions [20–22]. As discussed above, palliative mechanisms are available to reduce the negative effects of excess

Store capability of body steroid hormones is limited; thus, they are synthesized from cholesterol, mainly in liver and endocrine glands. The placenta, although it produces steroid hormones, is unable to synthesize cholesterol, being, thus obliged, to take it from maternal plasma low-density and high-density lipoprotein (LDL and HDL, respectively) particles [23]. Cholesterol (27 carbons, 27C), the common precursor of all steroid hormones, is converted in placenta to pregnenolone (27C) from which progesterone (21C) is derived. Progesterone is the precursor of several steroid hormones: (a) adrenal cortex hormones (mineralocorticoids and glucocorticoids); (b) male sex hormones (androgens) (19C); and (c) female sexual hormones

pregnancy and is known as gestational diabetes (GD) [1, 9].

70 Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

**2. Glucocorticoids: short metabolic review**

**Figure 1.** Steroid hormone synthesis. Notice that role of different hydroxylases. ACTH, adrenocorticotropic hormone; StAR, steroidogenic acute regulatory protein. \*Androstenedione and \*testosterone can be transformed in oestrone and oestradiol, respectively by the aromatase action. The \*\*Dehydroepiandrosterone sulphate produces oestradiol, while the \*\*17-OH-dehydroepiandrosterone, oestriol. Modified from Pascual-Leone Pascual and Goya Suárez [16] and Sibernagl and Despopoulos [25].

The fascicular zone produces cortisol (hydrocortisone) and, in much lower amounts, cortisone. Glucocorticoid synthesis and release is controlled by hypothalamus corticotropin-releasing hormone (CRH) and by the adrenocorticotropic hormone (ACTH) of the anterior hypophysis lobule [16, 25] (**Figures 1** and **2**). ACTH induces glucocorticoids releasing (and minor amounts of other cortical hormones), helping to maintain adrenal cortical structure and function and to assure cholesterol availability for hormonal synthesis. ACTH production and secretion are under negative feedback control but increased by adrenal medulla catecholamines [16, 21, 25].

Steroid hormones are fat soluble, and thus, they easily cross biological membranes, having crucial effects on cellular differentiation and organization. Cortisol binds amply to cortisol binding globulin (CBG), limiting the level and activity of free cortisol [16, 22, 26, 27].

**Figure 2.** Steroid hormone and catecholamine location in the adrenal gland. The activating and negative feedback implicated mechanisms are shown. CRH, corticotropin-releasing hormone, ACTH, adrenocorticotropic hormone. Red lines, inhibition; Green lines, activation. Modified from Nelson and Cox [26].


**Table 1.** Effects of cortisol on different systems.

Glucocorticoids interact on receptors located on skeletal, smooth, and cardiac muscles, brain, stomach, kidney, liver, lung, adipose and lymphatic cells. Those hormones bind to both mineralocorticoid and glucocorticoid receptors (MR and GR, respectively), members of the nuclear receptor's superfamily. GR are expressed since the embryonic stage [28]. GR are expressed in pancreas, liver, visceral adipose tissue, skeletal muscle and in brain areas such as hippocampus and amygdaline nuclei, where they regulate memory and behaviour [17, 22]. There are GR and MR gene polymorphisms that could explain individual response to corticoids [29]. Optimum glucocorticoid concentrations in blood and tissues are needed to assure correct homeostasis. These levels are highly variable and affected by factors such as gender and circadian cycle, thus explaining difficulties on reference value establishment. Due to space limitations in this review, the particular effects of glucocorticoids on different systems and the effects of high cortisol actions are summarized in **Table 1**.
