Lecture 4-Steroid Hormone Metabolism Flashcards

Question

What happens to adrenal androgens after they are released into the blood?

Answer 1

In adipose tissue: Dehydroepiadrosterone + androstenedione uses CYP 19 Aromatase to form estrogens In Extra-adrenal tissues: Dehydroepiadrosterone + androstenedione uses 17-B hydroxysteroid DH-3 to form testosterone

Answer 2

1. Cortisol synthesis is reduced. A. Congenital Adrenal Hyperplasia (CAH): One enzyme of cortisol synthesis is deficient. B. Addison Disease: Atrophy of adrenal cortex 2. Cortisol synthesis is increased. Cushing’s Syndrome: Hypercortisolism due to tumor

Answer 3

CAH is a group of autosomal recessive disorders with different onset of clinical manifestations. The low level of cortisol reduces the feed-back inhibition of ACTH and leads to overstimulation of the adrenal cortex.

Answer 4

Low blood pressure Low blood glucose Androgens are variable generally

Answer 5

High blood pressure Blood glucose can be low Androgens are low in general

Answer 6

Low blood pressure Blood glucose- Can be low Androgens are high in adrenals

Answer 7

Blood pressure- mildly elevated Blood glucose can be low Androgens are high in adrenals

Answer 8

rare and difficult to confirm. Hypotension, low fasting blood glucose, high DHEA Test for 17-OH-Progesterone is negative This results in less progesterone as pregnenolone cannot be converted As progesterone is decreased, aldosterone and Cortisol is decreased Pregnenolone increased DHEA but, less androstenedione as DHEA cannot be converted to androstenedione

Answer 9

The rare deficiency of 3b-hydroxysteroid DH has 3 different forms. In the most severe form there is a severe deficiency of all mineralocorticoids and glucocorticoids. This results in infants to have hypotension, low fasting blood glucose and salt excretion in urine. (This rare CAH is difficult to confirm. It has similar clinical signs like CYP 21 deficiency (more common) but does not show increased levels of 17-OH-progesterone which is the tested marker for CYP 21 deficiency.) There is a large clinical variability of ambiguous genitalia in newborns which results from the stimulated synthesis of the adrenal DHEA and at the same time the reduced sex hormone synthesis that occurs in the testes and ovaries. Male newborns may have male or ambiguous, female-like genitalia. Female newborns may have female or ambiguous, male-like genitalia.

Answer 10

Hypertension, often low blood glucose and decreased androgens CYP17 is responsible for adding OH to the 17-C on pregnenolone and progesterone, without it, 11-deoxycosterone increases, corticosterone increases and aldosterone increases

Answer 11

CYP 17 deficiency does not only reduce androgen synthesis in adrenals but also reduces the synthesis of sex hormones in testes and ovaries. This leads to female-like external genitalia in males and females. As ACTH is still activating the synthesis of corticoids this leads to hypertension from the high levels of the intermediates 11-deoxycorticosterone and corticosterone which can be measured in clinical tests. The abnormal high levels of ACTH stimulate first the synthesis of aldosterone which leads to hypertension. This hypertension leads to low renin and the resulting low level of angiotensin II leads then to reduced gene expression of aldosterone synthase.

Answer 12

CYP 21( 21a-hydroxylase)

Answer 13

Hypotension, often low blood glucose and increased androgens | Most common, Newborn screening test for elevated 17-OH Progesterone

Answer 14

Without CYP 21, 17-OH progesterone can’t be converted to 11-Deoxycortisol (leads to decreased Cortisol)and progesterone cannot be converted to 11-deoxycosterone(leads to decreased aldosterone) 17-OH pregnenolone -->increased DHEA DHEA and 17-OH progesterone lead to increased ADD Androgen synthesis is stimulated as it does not use CYP 21

Answer 15

Different age of onset and severity. Hypotension, hyponatremia and hyperkalemia. Hypotension and possible “salt-wasting crisis”. Aldosterone and cortisol are virtually absent in the classic form. Infants two weeks old can become critically ill. Severe loss of sodium. High potassium levels diminish cardiac output which can be fatal if not treated. Female newborns: ambiguous male-like genitalia. Milder CYP 21 deficiency leads to virilization of females later in childhood. Male newborns: external genitalia appear normal. Virilization of males in early childhood.

Answer 16

Mild hypertension, low fasting blood glucose, increased

Answer 17

CYP 11B1 is responsible for 11-deoxycorticosterone —> corticosterone(subsequent decreased in aldosterone) As well as 11-deoxycortisol (subsequent decrease in Cortisol in deficiency) Increased DHEA(from 17-OH pregnolone )and increased ADD from increased DHEA and 17-OH progesterone

Answer 18

Hypothalamus releases GnRH Anterior pituitary releases LH - FSH LH causes Leydig cells to release testosterone into the blood FSH stimulates spermatogenesis in Sertoli cells

Answer 19

Leydig cells contain 17b-hydroxysteroid DH3 which forms testosterone from androstenedione. The synthesis of DHEA and androstenedione is activated by LH and needs CYP 17. The pathway is similar to the one found in the adrenal cortex. Testosterone and other androgens are released and can be taken up by sertoli cells or be distributed in the blood

Answer 20

Cholesterol—> pregnolone —>17-OH pregnolone Pregnenolone—> progesterone —> 17 OH progesterone 17 OH pregnonolone —> 17 OH progesterone 17 OH pregnonolone —> DHEA—> androstenedione 17-OH progesterone —> androstenedione 17 B-hydroxysteroid DH-3–> testosterone

Answer 21

Formation of dihydrotestosterone (DHT) by 5-alpha-reductase Testosterone is mainly released by Leydig cells and then activated to dihydrotestosterone in prostate and hair follicles and other cells. DHT has a considerably higher affinity for the androgen receptor.

Answer 22

GnRH from hypothalamus to release anterior pituitary gland LH & FSH LH stimulates theca cells to release testosterone FSH stimulates follicle granulosa cells to release estradiol ( and released into the blood) Follicle granulosa cells take up testosterone and use it for synthesis of estradiol which is released into the blood.

Answer 23

The theca cells have receptors for LH which activates synthesis and secretion of androgens, mainly testosterone and androstenedione. The follicle granulosa cells have receptors for FSH and contain aromatase (CYP 19). They use androgens for estrogen synthesis and secrete primarily estradiol formed from testosterone.

Answer 24

Aromatase (CYP 19) uses ID: SOM.1ai.BPM2.1.ER.2.BCHM.EC.0508 CYP19 androgens for estrogen synthesis. CYP 19 cuts carbon #19 and forms estrogens with 18C and an aromatic ring A. The aromatic ring bends part of the molecule upward. This is needed for the recognition by the estrogen receptor.

Answer 25

Addison Disease: Primary adrenal insufficiency All corticoids are low and high ACTH, Hypotension, Hyponatremia, Hyperkalemia 1. Insufficiency and atrophy of the adrenal cortex due to: a. Autoimmune destruction or tumors. b. Infections like HIV, tuberculosis, fungi. 2. Low level of cortisol lead to: a. Low blood glucose during prolonged gluconeogenesis. b. High level of ACTH which does not lead to CAH because of the atrophy of the adrenal cortex. 3. Low level of aldosterone leads to: a. Low blood pressure and salt craving. b. Low sodium and high potassium blood levels.

Answer 26

Hyper cortisolism Cushing’s Syndrome is a collection of signs and symptoms due to abnormally high levels of cortisol in the blood resulting from: 1. Tumor in the Z. fasciculata leads to very high levels of cortisol and high adrenal androgens. The high cortisol level leads to a low ACTH level. 2. Tumor in Pituitary (Cushing Disease) leads to very high ACTH release which results in very high cortisol levels. 3. Prolonged administration of high doses of corticosteroidal drugs.

Answer 27

1. Characteristic fat distribution: a. Increased fat in upper body. b. Fatty hump between the shoulders. c. Red round face. 2. Rapid weight gain with central obesity. 3. Pink purple stretch marks in the skin (collagen). 4. Hirsutism and early pubic hair development. 5. Thin arms and legs, severe muscle weakness (cortisol stimulates muscle protein degradation). 6. Elevated blood glucose up to twice normal (cortisol stimulates gluconeogenesis). 7. High blood pressure from epinephrine or a mineralocorticoid effect of cortisol. 8. Reduced inflammatory response (cortisol has anti-inflammatory action). 9. Suppressed Immune System (reduced protein synthesis in lymphoid tissue)

Answer 28

1. Bronze pigmentation of skin and gum line is due to high level of melanocyte stimulating hormone. The lack of cortisol leads to increased release of CRH which stimulates the synthesis of the large precursor protein Proopio- melanocortin (POMC) which is cleaved to: ACTH, melanocyte stimulating hormone and others. Note: you find this also in Cushing’s disease. 2. Failure to thrive. 3. Weight loss. 4. Muscle weakness and salt craving. 5. Thinning of axillary and pubic hair in some females. 6. Abdominal pain.