Endocrinology/Objectives/Lecture 9
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Adrenal steroid synthesis
RECOGNIZE the structure of steroid hormones and their precursors.
Steroids are cholesterol derivatives, cholesterol being composed of isoprenoid units (hence the classification of steroids as isoprene derivatives). The most basic steroid precursors therefore include cholesterol and isoprenoid units. Other precursors can be found along the pathway of steroid synthesis (see page 3-15 of the syllabus).
DISCUSS how the hydrophobic nature of steroids affects their biological activity.
As hydrophobic molecules are lipid-soluble, they are able to freely diffuse across the plasma membrane. Thus they cannot be stored in membrane-bound vesicles, and instead must be synthesized on demand.
Another consequence of lipid-solubility is that steroid receptors must be cytoplasmic or nuclear, i.e. not membrane-bound. (One unexpected finding is that eicosanoids—a class of nonsteroidal hormones—have membrane-bound receptors despite being lipid-solubule.)
Also, steroids are poorly solubule in polar solvents such as plasma. Poorly solubule substances are easily degraded and have short half-lives. To prolong their plasma lives, steroids are often bound to carriers, which increases their half-lives and allows them to have prolonged physiological effects.
KNOW the general mechanisms of steroid hormone inactivation.
In general, the liver modifies steroids (e.g. by hydroxylation, glucuronidation, sulfation) to make them more hydrophilic and therefore more plasma-soluble. More hydrophilic steroids bind carrier proteins with decreased affinity and are therefore excreted rapidly.
Active glucocorticoids are 11β-hydroxylated and can be inactivated in mineralocorticoid-sensitive tissues by 11β-hydroxysteroid dehydrogenase. This is necessary since both mineralocorticoids and glucocorticoids bind each others' receptors in vitro and yet have very different effects in vivo. 11β-HSD converts glucocorticoids to their 11-ketone derivatives and inactivates them. Note that this does not happen to aldosterone even though it has an 11-hydroxyl. Aldosterone can assume a hemiacetal arrangement which cannot be processed by 11β-HSD.
NAME the sites of synthesis of steroid hormones and UNDERSTAND peripheral conversion.
Steroids are produced either in the mitochondrion or endoplasmic reticulum of the adrenal cortex, gonads, and elsewhere.
Steroids can be converted in the periphery into other active derivatives. For example, testosterone in the brain and adipose tissue can be converted into estradiol by aromatase.
80% of estradiol production in males is due to peripheral aromatization of testosterone. 50% of estradiol production in pregnant females is due to peripheral aromatization of adrenal androgens.
STATE which parts of the adrenal cortex produce which steroids.
| Zone | Major hormone | Major control mechanism |
|---|---|---|
| Zona glomerulosa | Aldosterone (mineralocorticoid) | Renin-angiotensin |
| Zona fasciculata | Cortisol (glucocorticoid) | ACTH |
| Zona fasciculata | DHEA (weak androgen) | ACTH |
EXPLAIN how the quantitative and qualitative levels of specific enzymes determine hormone synthesis in the adrenal.
Qualitatively, the presence of an enzyme is used to determine whether a given pathway for steroid synthesis is possible. For example, without 21-hydroxylase, progesterone will be the main end product of steroid synthesis.
Quantitatively, the relative amounts of enzymes determines which synthetic pathway will be favored. For example, if there is much more 3β-hydroxysteroid dehydrogenase Δ5-4 isomerase present, then one would expect little DHEA to formed in the synthesis of estradiol, for example (see page 3-15 for figure). This changing of pathways that depends on relative enzyme amounts is simply a result of the law of mass action (also Le Chatlier's principle).
STATE the order of chemical reactions that produce adrenal steroids.
See pages
- 3-7
- 3-12
- 3-15
DISCUSS changes in steroid synthesis in patients with defects in specific hydroxylases.
| Deficient enzyme | Major product |
|---|---|
| 21-hydroxylase | Progesterone |
| 11β-hydroxylase | 11-DOC |
| 18-hydroxylase | Corticosterone |
| Deficient enzyme | Major product | Associated conditions |
|---|---|---|
| 17αhydroxylase | Corticosterone | Cushing's syndrome? |
| 21-hydroxylase | Androgens (by mass action) | Adrenogenital syndrome |
| 11β-hydroxylase | Androgens (by mass action) | Adrenogenital syndrome |
| Deficient enzyme | Major product |
|---|---|
| 17α-hydroxylase | Mineralocorticoids (aldosterone, corticosterone) |
DISCUSS cellular mechanisms that discriminate between mineralocorticoids and glucocorticoids.
Both mineralocorticoids and glucocorticoids act on the MR and GR receptors. Tissues respond differentially to the two hormones by cellular mechanisms, specifically by the inactivation of glucocorticoids in mineralocorticoid-sensitive tissues. Such tissues express 11β-hydroxysteroid dehydrogenase, which removes the 11-hydroxyl group found on glucocorticoids. Since glucocorticoids are only active if they are 11-hydroxylated, the removal of the 11-hydroxyl group renders them inactive. (Note that aldosterone has an 11-hydroxyl, but it is not susceptible to inactivation because of its conversion to a hemiacetal.)
DISCUSS the importance of adrenal androgens.
Adrenal androgens (e.g. DHEA) play little role in males since the major male site of androgen synthesis is the testis. In females, however, the adrenal gland is the major source of androgens.
STATE the major factors controlling cortisol production.
Corticotropin-releasing hormone (CRH) is synthesized by the paraventricular nucleus of the hypothalamus and acts on the anterior pituitary to stimulate the synthesis of proopiomelanocortin (POMC). POMC is a precursor for ACTH (as well as MSH and opiods), which stimulates the zona fasciculata to produce cortisol. Cortisol has long-loop negative feedback on the hypothalamus as well as the anterior pituitary.
EXPLAIN the symptoms of diseases of the adrenal cortex.
Addison's disease results from an inability of the adrenal cortex to produce sufficient glucocorticoids. Intolerance to stress results from the inability to synthesize cortisol, which is the main hormone released in response to stress. Insulin sensitivity also results because cortisol and insulin antagonize each other's effects; without cortisol, insulin's effects are enhanced. Lack of cortisol removes the long-loop negative feedback on POMC (and therefore ACTH) production. POMC is the precursor of ACTH as well as MSH and opiods. Elevated levels of MSH (melanocyte-stimulating hormone) result in increased pigmentation.
Secondary adrenal insufficiency results from a lack of ACTH, perhaps from a deficiency in anterior hypothalamic enzymes. Without ACTH, cortisol cannot be produced. The symptoms are generally the same as in Addison's disease, but without the hyperpigmentation (because POMC isn't elevated).
Cushing's syndrome results from glucocorticoid excess due to overproduction of ACTH (e.g. from a pituitary tumor), adrenal tumor, exogenous glucocorticoid administration. Excess glucocorticoids
