Steroid Biosynthesis

Question 1

Progesterone and pregnancy

Answer 1

supports gestitation (pregnancy) and embryogenesis and is also involved in the maintenence of the menstrual cycle

it regulates the voltage gated Ca channels on the spermatozoa, prepares the uterus for implantation, and causes smooth muscle relaxation

also decreases the maternal immune responses

decrease in progesterone levels precedes menstruation, labor, and lactation

Question 2

Glucocorticoids and infant respiratoory distress syndrome

Answer 2

In normal term, infants, a burst of glucocorticoids during delivery alters the lung structure by stimulating the production of surfactant which allows for the air spaces to expand

in preterm neonates, this process is defective leading to infant respiratory distress syndrome (IRDS)
-can be prevented by giving glucocorticoids to expectant mothers

Question 3

Metabolic modulation of steroid effects

Answer 3

the response of target tissues to a steroid hormone is determined by furthur metabolism of the hormone

i. e: mineralcorticoid target tissues in the kidneys, colon, and parotid gland contain a receptor that has equal affinities for both mineral and glucocorticoids but normally there is a much higher amount of circulating glucocorticoids so the body will metabolize the cortisol to cortisone by 11B Hydroxysteroid dehydrogenase so that the affinity is much lower
- natural licorice can inhibit this process and lead to hypertension due to increase corticoid and Na/H20 retention

i.e: conversion of testosterone by 5a reductase to DHT makes testosterone mouch more potent for its processes

Question 4

what is finasteride?

Answer 4

inhibitor of 5a-reductase that prevents the potentiation of testosterone and has helped with treating benign prostatic hyperplasia, and male pattern baldness

Question 5

what are all steroids synthesized from in the adrenal cortex?

Answer 5

Cholesterol

Question 6

what is the function of Desmolase, where is it found, other names, and what stimulates its activity

Answer 6

Desmolase is an enzyme that produces pregnenolone from cholesterol, this is the rate limiting and first step to making steroids

Desmolase is also called cytochrome P450scc or CYP11A1

Found in all steroid producing tissues: Adrenal gland, testes, ovaries, and placenta

regulated by adrenocorticotropic hormone (ACTH)
-stimulates the production of pregnenolone

Question 7

what is the Pregnenolone and what is it important for?

Answer 7

The most important biochemical intermediate for the steroid making process

Used as a substrate to produce:

• Progesterone
• Aldosterone
• Cortisol
• Testosterone
• Estradiol

Pregnenolone contains a double bond to an O at its end

Question 8

Rennin-angiotensin-aldosterone system (RAAS)

Answer 8

Controls the blood pressure and fluid balance

kidneys release the enzyme renin into the circulation when low blood volume is sensed

renin will vleave the zymogen angiotensinogen made by the liver that will turn to angiotensin 1 which will be proteolytically processed into the vasoconstrictor angiotensin II in the lung by Angiotensin converting enzyme (ACE)

Angiotensin II also stimulates the release of vasopressin from the pituitary gland and aldosterone from the adrenal gland via the mineralcorticoid cells

these are important in the retention of Na+ and H20 that help raise the blood pressure

Question 9

how do globulins play a role in steroid hormones

Answer 9

Steroid hormones are transported in the blood complexed to specific carrier proteins

THe human corticosteroid binding globulin is important in carrying 80-90 percent of thhe plasma glucocorticoid hormones and also progesterone

sex steroids such as testosterone, dihydrotestosterone, and estradiol are transported via the sex steroid hormone binding globulin (SHBG) and to a lesser extent albumin

• saturated in men
• patially saturated in females

both globulins are made in the liver

Question 10

Adrenal Hyperplasia

Answer 10

Classic and non classic forms of the disease but both are caused by deficiencies in the adrenal enzymes tht are used to synthesized glucocorticoids

increased production from the adrenal gland of both cortisol precursors and androgens

can lead to:

• sinus infections
• pulmonary infections
• orthostatic syncope
• shortened stature
• severe acne

women present with hirsutism: excessive body hair

• General oligomenorrhea: infrequent or light menstruation
• infertillity

Question 11

how to determine if a paitent has Adrenal hyperplasia

Answer 11

Determined using human leukocyte antigen haplotype

demonstation of excess cortisol precursors in amniotic fluid

Question 12

Patient treatment for Adrenal hyperplasia

Answer 12

Carefully monitored hormone replacement therapy

• recognition of the problem
• timely replacement therapy
• reduces morbidity and enhances quality of life

Question 13

what are the two enzymes deficient in Adrenal hyperplasia

Answer 13

21 hydroxylase (Cyp21A2)

• cant turn progesterone to deoxycorticosterone to make aldosterone
• cant turn 17hydroxy progesterone to 11-deoxycortisol to make cortisol

11-B hydroxylase (CYP11B1(

• cant turn deoxycorticosterone to corticosterone to make aldosterone
• cant turn 11-deoxycortisol to cortisol

Question 14

Primary Aldosteronism

Answer 14

Adrenal cortex (zona glomerulosa)

• promotes the retention of Na+ amnd H20 in the kidneys
• promotes excretion of H+ and K+

Question 15

Conn syndrome

Answer 15

Endocrine disorder of the adrenal glands

• excessive secretion of aldosterone
• retention of sodium
• loss of potassium
• high blood pressure (hypertension)

Question 16

What steroids can activate the MR?

Answer 16

Mineralcorticoid reeptor

• Aldosterone
• 11-deoxycorticosterone
• testosterone
• hydrocorticosone (cortisol)
• cortisone

in order of most efficacious to least
all these lead to increase Na retention

Question 17

how does an 11B hydroxylase deficiency lead to hypertension

Answer 17

even though this is decreasing the amount of aldosterone production and cortisol production, there is an increase in levels of 11-deoxycorticosterone and 11-deoxycortisol

11-deoxycorticosterone has a relatively high affinity for Mineralcorticoid receptor that will produce the retention of Na+ and then the hypertension that follows

Question 18

Cortisol suppression of the

Answer 18

Glucocorticoids such as cortisol cause immunosuppressive behaviors by inhibiting both cellular and humoral immune responses

induce the production of i-kBa inhibitory protein that helps sequester the transcription factor nuclear factor kappa B which is necessary for the synthesis of many cytokines such as IL-2 (important for T-cell proliferation)

cortisol also promotes T cell apoptosis and decreased IL-2 and its receptor will lead to an inhibition of clonal expansion of B lymphocytes as well

Question 19

what is the HPA axis for cortisol

Answer 19

Hypothalamus releases CRH (Corticotropin releasing hormone) this acts on the anterior pituitary that releases ACTH (Adrenocorticotropic hormone) on adrenal cortex which releases Cortisol

Question 20

what is the regulation of Cortisol synthesis

Answer 20

when the cortisol levels fall the hypothalamus produces CRH which stimulates the release of ACTH from the anterior pituitary which then acts on the adrenal gland to release cortisol

cortisol levels will serve as a negative feedback loop to CRH and ACTH

Question 21

How does ACTH act on the adrenal gland? and its receptor?

Answer 21

acts on the adrenal Cortex specifically the zona Fasciculata that stimulates the secretion of glucocorticoid steroid hormones

acts by binding to cell surface ACTH receptors which is a 7 membrane spanning GPCR which is located primarily on adrenocortical cells of the adrenal cortex

Question 22

difference between the ACTH activation in a normal cell a tumor cell

Answer 22

normal cell: activation of adenylcyclase to produce cAMP that activates PKA that activates CREB to produce cortisol

Tumor cell: constitutively active pKA promoting CREB and cell proliferation

Question 23

Influences ACTH has on steroid hormone secretion

Answer 23

in minutes: stimulates desmolase to promote the production of pregnenolone

in hours:

• stimulation of lipoprotein uptake in cortical cells
• increases bioavailability of cholesterol
• stimulation of transcription genes coding for steroidogenic enzymes
• p450scc (desmolase)
• steroid 11B-hydroxylase
• associated electron transfer proteins

Question 24

what 17,20 lyase important for? what happens if there are mutations associated with this enzyme

Answer 24

also known as CYP17A1

key enzyme in the steroidogenic pathway that produces progestins, mineralcorticoids, glucocorticoids, androgens, and estrogens

• Dehydroepiandrosterone (DHEA)
• Androstenedione

mutations in the 17a-hydroxylase/17,20 lyase lead to pseudo-hermaphroditism and adrenal hyperplasia
as well as 46,XY disorders of sex development

Question 25

how is Cholecalciferol obtained in the body? and how is it converted to its active form in the body

Answer 25

Cholecalciferol (vitamin D3) is obtained in two ways:

Through the diet of eating ergocalciferol (vitamin D2) that is absorbed in the intestine from dietary sources
-converted from 7-dehydrocholesterol in the skin via UV radiation

In the kidney 1,25 Dihydroxycholecalciferol (calcitrol to active form vitamin D) is synthesized by 1-a hydroxylase

• done via PTH and low Phosphate
• inhibited by calcitrol (negative feedback loop)

25-hydroxycholecalciferol is found exclusively in the liver via the conversion by 25-hydroxylase from cholecalciferol