Sex Steroids Flashcards
DHEA
- Dehydroepiandrosterone (DHEA) is a very weak androgen produced by the adrenal cortex in the zona reticularis.
- While17-hydroxypregnenolone can follow the pathway to cortisol, a significant amount is metabolized through the action of 17,20-lyase.
-The lyase is found predominantly in the ZR and gonads, and acts exclusively on 17alpha-hydroxy-containing molecules.
- Adrenal androgen production increases if glucocorticoid biosynthesis is impeded by the lack of one of the hydroxylases.
- DHEA is a prohormone, since the actions of 3beta-OHSD/∆ 5,4 - isomerase convert this weak androgen into the more potent androstenedione in the ZR and gonads.
- Some androstenedione is also formed in the ZR by the direct action of the lyase on 17alpha-hydroxyprogesterone.
- Reduction of androstenedione at the carbon-17 position in the gonads results in the formation of testosterone.
ACTH and Steroid Production
- Steroid production in the ZF/ZR is stimulated by ACTH that acts by activating several steps.
- The function of StAR is enhanced by ACTH in two ways.
1) Cyclic AMP produced in response to ACTH induces the StAR protein and
2) cAMP activates protein kinase A to phosphorylate serine residue(s) on StAR to achieve maximal function
Congenital Adrenal Hyperplasias
- The normal feedback regulation of cortisol biosynthesis occurs in the hypothalamus and pituitary.
- In the hypothalamus, elevated blood cortisol suppresses the release of CRH to abolish the effect of CRH on release of ACTH by the anterior pituitary.
- In the anterior pituitary cortisol directly suppresses the release of ACTH.
- In the event of underproduction of cortisol, these feedback controls are lost so that ACTH will then be considerably overproduced,
- Understanding the cause of the overproduction of ACTH is the key to understanding congenital adrenal hyperplasia (CAH).
- Excessive ACTH causes adrenal hyperplasia (i.e., stimulates growth of the ZF and ZR), and can cause accumulation of steroids such as DOC and DHEA that elicit hypertension and masculinization, respectively.
CAH Etiologies
1) enzyme/protein defects that affect the pathways of steroid biosynthesis
2) receptor defects that cause end organ resistance to the steroid hormones and thereby interrupt the normal physiologic feedbacks
CAH Enzyme/Protein Defects
- 21 hydroxylase (most common)
- 11 beta hydroxylase
- ∆ 5,4 -isomerase
CAH Enzyme/Protein Defects - 21 Hydroxylase
- most common
- The 21-OHase defect (adrenal hyperplasia type III) occurs in 1/50,000 live births and can, when there is zero activity, result in severe salt loss and death.
- This enzyme deficiency leads to an immense increase in ACTH due to the lack of feedback inhibition by cortisol due to its diminished circulating concentration.
- The excessive ACTH stimulates conversion of cholesterol to pregnenolone.
- With the lack of 21-OHase, pregnenolone can be metabolized only as far as progesterone or 17alpha-hydroxy intermediates.
- Consequently, neither aldosterone nor cortisol is produced. In the ZR, the accumulated 17alpha-hydroxypregnenolone is shunted to DHEA, a weak androgen, but more importantly the excess 17alpha -hydroxyprogesterone is forced to androstenedione, a stronger androgen.
CAH Enzyme/Protein Defects - 21 Hydroxylase
What happens?
- Elevated production of adrenal DHEA, as well as androgenic metabolites formed in other tissues; result in genetic females who assume male secondary sex characteristics.
- Affected males are excessively masculinized (“infant Hercules”).
- Females masculinized at 12-20 weeks in utero by excess DHEA are often raised as males by unsuspecting parents.
- Patients with 21- OHase defect are treated with glucocorticoids.
- Exogenous glucocorticoids reduce virilization, because like cortisol they limit the release of ACTH and thereby lower endogenous production of DHEA and androstenedione by the adrenals.
*Lack of aldosterone leads to salt loss, so that mineralocorticoids, like fludrocortisone (Florinef), must also be administered.
CAH Enzyme/Protein Defects - 11 beta hydroxylase
- Overproduction of DHEA also occurs with defects of 11 beta-hydroxylase
- In individuals having a defect of 11 beta-hydroxylase defect (adrenal hyperplasia type IV), pregnenolone can be processed only as far as 11-deoxycortisol or 11-deoxycorticosterone (DOC).
- The accumulation of DOC causes hypertension due to salt retention.
-Even though DOC is a weak mineralocorticoid, sufficient amounts are produced in the ZF/ZR to produce significant mineralocorticoid effects.
- These patients should be treated only with glucocorticoids.
- Even with treatment, ZG will continue to produce sufficient amounts of DOC as the alternate mineralocorticoid.
CAH Enzyme/Protein Defects - ∆5,4 -isomerase defect
- Overproduction of DHEA also occurs with defects of 11 beta-hydroxylase or ∆ 5,4 - isomerase (3 beta OH-SD).
- In patients with the ∆5,4 -isomerase defect (adrenal hyperplasia type I), synthesis can proceed only to pregnenolone.
- In the ZR pregnenolone is pushed to make mostly DHEA because 17 alpha-hydroxyprogesterone cannot be produced as an important precursor to androstenedione and DHEA cannot be converted to androstenedione.
- Consequently, virilization in females is relatively mild because DHEA is a weak androgen.
- In males, the ∆ 5,4 - isomerase defect elicits mild hypogonadism, because the pathway for androgen production in the testes proceeds mainly via 17 alpha-hydroxyprogesterone.
- Treatment includes glucocorticoids and mineralocorticoids because neither can be synthesized.
CAH Enyme/Protein Defects - StAR
•A defect of StAR affects the synthesis of all steroids because it prevents the efficient uptake of cholesterol by mitochondria.
This disease is known as lipoid CAH. Unlike the defects described above, this disorder leads to reduced production of adrenal androgens as well as those made in the testes. Hence males exhibit sexual infantilism.
CAH Enzyme/Protein Defects - 17 alpha OHase
- A 17 alpha-OHase defect (adrenal hyperplasia type V), is characterized by low aldosterone even though this enzyme is not needed for aldosterone biosynthesis and therefore is absent normally from the ZG.
- Aldosterone is low in this scenario because of the elevated DOC produced excessively in the ZF and ZR.
- In sufficient amounts DOC raises blood pressure to suppress the renin-angiotensin system and thereby reduce stimulation of aldosterone biosynthesis in the ZG because angiotensin II concentration is low.
- DOC is also responsible for the hypertension in this disease.
CAH Enzyme/Protein Defects - 18 hydroxylase
- A defect of 18-hydroxylase (aldosterone synthase) leads to an inability to produce aldosterone and is characterized by accumulation of both corticosterone and DOC.
- Though initially there is salt loss due to the absence of aldosterone, eventually DOC accumulates sufficiently to serve as a significant mineralocorticoid
CAH Receptor Defects - GR
- Individuals with a severely defective glucocorticoid receptor (GR) present with hypoglycemia because of an inability to induce gluconeogenic enzymes.
- Milder deficiencies in GR usually only show elevated ACTH due to broken feedback at the hypothalamus and corticotroph.
-The elevated ACTH elicits hyperplasia of the ZF and ZR cells accompanied by high concentration of cortisol.
•Other pathologies include hypertension, caused by excess DOC produced in the ZF/ZR, and virilization, caused by excess DHEA and androstenedione generated in the ZR.
CAH Receptor Defects - MR
- In contrast, a mineralocorticoid receptor (MR) defect results in life threatening salt loss in newborns.
- Neither cortisol nor androgens are affected in this type of CAH.
- Instead, there is selective pathology in the renin/angiotensin II/aldosterone axis.
- With a MR defect, aldosterone is unable to promote sodium reabsorption and potassium/proton excretion at the distal renal tubule resulting in hyponatremia, hypotension, hyperkalemia and decreased blood pH.
- The hyponatremia leads to elevated renin and angiotensin II in the circulation.
- Angiotensin II causes hyperplasia of the glomerulosa only, thus enhancing aldosterone biosynthesis, in a futile attempt to correct the hypotension.
Biosynthesis of Androgen in the Testes
- Leydig cells synthesize testicular androgens.
- In parallel to adrenal steroid metabolism, the precursor of the gonadal steroids is cholesterol with the rate-limiting step being cleavage of the cholesterol side-chain by P-450scc.
- Thus, conversion of cholesterol to pregnenolone is identical in adrenal ZR cells and testes, as well as ovaries. In the gonads (Leydig cells in the testes; theca cells in the ovaries), activation of P-450scc is promoted by LH (luteinizing hormone), which operates via cyclic AMP.
*The gonads lack both the 21-hydroxylase and 11 beta-hydroxylase enzymes so that pregnenolone and progesterone cannot be converted to glucocorticoids.*
- The conversion of pregnenolone to testosterone requires the sequential action of 5 enzymatic activities in the smooth endoplasmic reticulum (microsomes); 3 beta hydroxysteroid dehydrogenase (3 beta -OHSD), ∆5,4 isomerase, 17 alpha-hydroxylase, C17-20lyase and 17 alpha-hydroxysteroid dehydrogenase (17 alpha-OHSD).
- The progesterone (or ∆4 ) pathway via androstenedione is the preferred route in human testes, rather than the dehydroepiandrosterone (or ∆5 ) pathway leading to androstenediol production.
-The latter pathway is initiated by the 17 alpha-hydroxylase reaction rather than by 3 beta-OHSD.
- Each of these activities, except for 17 alpha-OHSD, also is found in the ZR accounting for the ability of these cells to produce androstenedione but not testosterone.
- Dihydrotestosterone (DHT), the most potent androgen, is formed from testosterone by the reduction of the A ring through the action of microsomal 5 alpha-reductase-2.
-Most DHT is derived from peripheral conversion in androgen target tissues.
•The testes also make small amounts of 17 beta-estradiol (E2), the female sex hormone, but most estrogens produced by the male (estrone) are derived from peripheral aromatization of testosterone and androstenedione in adipose cells.
Biosynthesis of Estrogens
- The ovaries are bifunctional organs that produce estrogens and progestins (the female sex hormones) and ova (the female germ cells).
- The most active naturally occurring hormones of these classes are 17 beta-estradiol (E2) and progesterone.
- The general pathway and the subcellular localization of the enzymes involved in the early steps of estradiol synthesis in the ovaries are the same as are found in the adrenal glands and testes.
- Estrogens are formed by the aromatization of androgens in a process that involves three hydroxylation steps.
-Hydroxylation requires O2 and NADPH followed by decarboxylation.
•The aromatase enzyme complex, in the smooth endoplasmic reticulum (SER), includes a P450 mixed-function oxidase with the first reaction catalyzed by the 19-OHase enzyme.
-Estradiol (E2) is formed if the substrate of this enzyme complex is testosterone.
•Androstenedione, after its release by the reticularis of the adrenal cortex, can undergo aromatization in adipose tissue of both men and women to produce estrone (E1).
- This conversion of adrenal androstenedione to estrone is the major source of estrogens in postmenopausal women and helps diminish the development of osteoporosis.
- The high content of adipose tissue in obese men leads to abnormally high production of estrone and explains the gynecomastia that develops in these individuals.
- Progesterone is produced and secreted by the corpus luteum.
- The cellular source of the various ovarian steroids appears to involve two cell types.
- Theca cells, which are stimulated by LH, are the major sources of androstenedione and testosterone in the ovary.
- Testosterone is taken up by the adjacent granulosa cells in the ovaries and are the major source of estradiol.
3 Sources of Estrogen
- During pregnancy, adrenal androgens are important substrates, since up to 50% of estrogen produced during pregnancy comes from metabolism and aromatization of fetal adrenal DHEA sulfate.
- There are three potential sources of estrogens in females.
1) A premenopausal female with an active menstrual cycle produces primarily 17 beta-estradiol (E2).
- E2, the most potent estrogen, is produced and secreted by ovarian granulosa cells by aromatization of testosterone derived from ovarian theca cells.
2) Postmenopausal females (and males) produce primarily estrone (E1) by aromatization of adrenal androstenedione in adipose tissue.
- Estrone and estradiol are interconverted via oxidation (estrone formation) and reduction (estradiol formation).
3) During pregnancy estriol (E3) is produced via the fetal liver/placenta pathway culminating in aromatization of 16 alpha-OH-testosterone in the placenta. E3 can also be made from E2 in fetal and maternal liver by 16 alpha-hydroxylation
GnRH
- GnRH (gonadotropin-releasing hormone) elicits the release of LH and FSH, a typical example of how one class of releasing hormones operates on pituitary cells.
- In response to a signal, GnRH is released from the GnRH-energic neuron in the hypothalamus and travels to the anterior pituitary.
- In the anterior pituitary, GnRH binds to gonadotropic cells triggering the release of LH (luteinizing hormone) and FSH (follicle-stimulating hormone).
-GnRH signals the gonadotropic cell to release LH and FSH. This mechanism fits general schemes outlined previously and employs protein kinase C, calcium and Ca-CAMdependent-kinase to affect the release of vesicles containing the appropriate pituitary hormones. Binding of GnRH to its membrane receptor causes dissociation from Gq-protein of the alpha subunit that then activates phospholipase C (PLC). The downstream activation of calmodulin-dependent kinase by Ca2+, which is released from ER stores, and of protein kinase C, through the coordinated action of diacylglycerol and Ca2+, lead to protein phosphorylation. Protein phosphorylation, combined with the effects of Ca2+, promote the fusing of neurosecretory granules with the membrane for exocytosis of FSH and LH.
