Steroid hormone biosynthesis week 3

Question 1

How does the synthesis of steroid hormones and peptide hormones differ?

What are the consequences of this as it pertains to steroid hormones?

Answer 1

• While peptide hormones are encoded by specific genes, steroid hormones are synthesized from the enzymatic modification of cholesterol.
• Thus, there is no gene which encodes aldosterone, for example.
• As a result:
• There are far fewer different types of steroid hormones than peptide hormones.
• Steroid structures are the same from species to species
• The regulation of steroidogenesis involves control of the enzymes which modify cholesterol into the steroid hormone of interest.

Question 2

The first enzymatic step in the production of ANY steroid hormone begins with enzymatic modification of ____.

Answer 2

cholesterol

Question 3

What are the 3 possible sources of cholesterol that may be used for steroid hormone synthesis?

What is the first enzymatic step in steroid hormone synthesis?

What enzyme catalyzes this rxn? What is its specific cellular location?

What is the rate-limiting step in this process? What facilitates this step?

In what tissues does this enzymatic step occur?

Answer 3

• Cholesterol can be from new synthesis from acetyl CoA, cholesterol esters, or from low density lipoproteins (LDL).
• The first enzymatic step in steroid synthesis is the conversion of cholesterol into pregnenolone.
• The enzyme that catalyzes this reaction is located in the inner mitochondrial membrane.
• The rate-limiting step (note:irreversible) in this process is the transport of free cholesterol from the cytoplasm into the inner mitochondrial membrane. This transport is carried out by the Steroidogenic Acute Regulatory Protein (StAR)
• The enzyme CYP11A1 (also known as desmolase or cytochrome P450scc (for side chain cleavage)) converts cholesterol to pregnenolone in the inner membrane of the mitochondria.
• This step occurs in adrenal, ovary, and testes.

Question 4

Synthesis of pregnenolone from cholesterol involves _____ the hydrocarbon chain of cholesterol, and _____ of the ring.

What molecules are required for this rxn?

Answer 4

Synthesis of pregnenolone from cholesterol involves shortening the hydrocarbon chain of cholesterol, and hydroxylation of the ring. The reactions involve the sequential hydroxylation of carbons 20 and 22 of the side chain. This produces 22-hydroxycholesterol, then 20,22-dihydroxycholesterol,and finally the cleavage of the 20-22 carbon bond to release the 21 carbon pregnenolone. CYP11A1 catalyzes the entire sequence of 3 reactions which uses 3NADPH and 3 O2 molecules.

Question 5

What enzymes mostly convert pregnenolone to a variety of steroid hormones? What is the cellular location of these enzymes?

Answer 5

The majority of the enzymes which convert pregnenolone to a variety of steroid hormones are cytochrome P450 molecules. Remember these mixed function oxidases can be found in either the mitochondria or in the endoplasmic reticulum. These enzyme reactions take place in both cellular compartments.

Question 6

What steroid hormones do the ovaries and testes produce?

Answer 6

• ovaries and placenta - estrogens and progestins
• testes – testosterone and estrogens

Question 7

Because pregnenolone is involved in the synthesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens, it is considered a _____.

Answer 7

prohormone

Question 8

What 3 structures secrete progesterone?

What are the functions of progesterone?

Answer 8

• a progestin, it is produced from pregnenolone and is sometimes called the hormone of pregnancy x
• secreted from:
• the corpus luteum after ovulation
• the adrenal glands
• the placenta during pregnancy
• responsible for changes associated with the luteal phase of the menstrual cycle
• Decreases contractility of uterine smooth muscle during pregnancy, but a drop in progesterone levels may help facilitate the onset of labor.
• Necessary, along with estrogen, for the development of breasts
• Progesterone is used in hormone therapy for transsexual women and other women with intersex conditions

Question 9

What is the precursor to aldosterone?

In what part of which organ is aldosterone produced?

Answer 9

• The principal mineralocorticoid
• Produced from progesterone in the zona glomerulosa of adrenal cortex
• Raises blood pressure and fluid volume, increases Na+ uptake

Question 10

What is the precursor to cortisol?

In what part of which organ is cortisol produced?

Answer 10

∙ dominant glucocorticoid in humans

∙ synthesized from progesterone in the zona fasciculata of the adrenal cortex

∙ involved in stress adaptation, elevates blood pressure and Na+ uptake, raises blood glucose level by stimulating gluconeogenesis.

Question 11

What is the precursor to testosterone?

What are the 3 sites of primary secretion?

What is the fxn of testosterone in men?

What disease is testosterone essential for the prevention of?

Answer 11

• An androgen
• Produced from progesterone and is the primary male sex hormone; it is an anabolic steroid.
• It is primarily secreted in:
  
  • the testes of males (Leydig cells)
  • the ovaries of females,
  • although small amounts are also secreted by the adrenal glands.
• In men, it plays a key role in the development of the testes and prostate and is responsible for secondary sex characteristics such as increased muscle and bone mass and hair growth.
• Essential for prevention of osteoporosis

Question 12

What is the precursor to estrdiol (E2)? What catalyzes this rxn?

In females, how many days of each cycle is E2 produced? Where in the female is it produced? What is the function of E2 in females?

Describe the levels and rates of E2 secretion. What cells secrete E2 in males? What is the function of E2 in males?

Answer 12

• It is produced (aromatized) from testosterone (catalyzed by aromatase). It is the major estrogen in both females and males.
• Females:
  
  • It is the principal female sex hormone but is only produced for 3 days of each cycle.
  • It is produced in the ovary and is responsible for secondary female sex characteristics.
• Males:
  
  • In males, it is produced constantly but at lower levels than in females.
  • It is produced in the Sertoli cells of the testes and it is thought that it prevents apoptosis of sperm cells.

Question 13

When in life do males tend to have higher levels of testosterone?

What diseases are high levels of testosterone associated with?

Why do overweight men tend to have higher levels of estrogen? What symptoms can this lead to?

What does testosterone in women contribute to?

Answer 13

Role of estrogen in men:

• High levels of testosterone in men are generally associated with low levels of estrogen and vice versa . The balance between the two is what is important.
• Men have higher levels of testosterone and low levels of estrogen in teenage years.
• With aging, testosterone levels fall and estrogen levels rise.
• High levels of testosterone in men are associated with prostate cancer, cardiac disease and gynomastia (because some of the testosterone is aromatized to estrogen/estradiol).
• Adipose cells produce estrogen (via aromatase which is found in high levels in fat cells). Thus overweight men have a higher conversion of testosterone to estrogen/estradiol. This can lead to feminization, loss of muscle mass, fatigue, low libido, erectile dysfunction.

Role of testosterone in women:

• Produced in women’s ovaries and adrenals.
• Women have ~20x less than men.
• Contributes to:
  
  • bone and muscle mass
  • libido

Question 14

What androgen is typically synthesized in the adrenal cortex?

Answer 14

Androstenedione is typically synthesized in the adrenal cortex. Little testosterone is produced.

Question 15

We know that pregnenolone can be converted to glucocorticoids, mineralocorticoids, or androgens in the adrenal cortex. What determines which hormone is synthesized?

What is the cellular location of these enzymes?

Answer 15

What determines which pathway is taken?

• Each step of the pathway is regulated by a specific enzyme.
• Different zones of the adrenal cortex have different relative activities of enzymes, resulting in different chemical reactions taking place.
• These enzymes are located in the smooth ER.

Question 16

What is the main steroid hormone produced in the testes? What are the other steroid hormones are produced?

In males, there is peripheral conversion of its main steroid hormone to what 2 other steroid hormones? What enzymes catalyze these reactions?

Answer 16

• The main steroid produced in the male is testosterone, from the testis. In addition, the testis makes some androstenedione, dihydrotestosterone, and estradiol.
• In the male, there is peripheral conversion of testosterone to dihydrotestosterone by 5-alpha-reductase(in androgen target tissues, like muscle) and estradiol by aromatase (mostly in adipose tissue).

Question 17

What hormone stimulates Leydig cells to produce androgens?

What forms of cholesterol do Leydig cells rely on for the production of androgens?

How is androgen production different Leydig cells than in the adrenal cortex?

Answer 17

• Leydig cells: respond to luteinizing hormone (LH) with steroid production (primarily testosterone).
• Leydig cells are unusual in that they rely on de novo synthesis of cholesterol more than other cells (50%). Thus, only about 50% of cholesterol used in steroid production is obtained from LDL.
• In the testis, the production of androgens from cholesterol is identical to that in the adrenal, except that it continues from androstenedione to testosterone.

Question 18

What is the primary source of cholesterol for steroid synthesis in the ovaries?

What are the 2 sites of primary ovarian steroid secretion?

Answer 18

• The ovary produces estrogens (primarily estradiol), progesterone, and androgens.
• It relies largely on LDL as a source of cholesterol for steroid synthesis (compare with testis).
• Ovarian steroids are secreted primarily from ovarian follicles and corpora lutea.

Question 19

What is the basic functional unit of the ovary? What is it composed of?

When the functional unit of the ovary ruptures, what does it become?

Answer 19

• The follicle is the basic functional unit of the ovary.
• It is composed of an oocyte, granulosa cells, and theca cells.
• When the follicle ruptures, it becomes a corpus luteum.

Question 20

Explain the 2 cell theory of estrogen production in the ovary.

Answer 20

• In the ovary, estradiol is formed from the conversion of testosterone into estradiol by the enzyme cytochrome P450 aromatase. This occurs in granulosa cells.
• However, granulosa cells do not have the enzyme 17a-hydroxylase/lyase, and thus cannot convert progesterone into androgens.
• Where do the androgens required for estrogen production in granulosa cells come from?
• Numerous studies have now shown that the androgens required for aromatization come from the neighboring theca cells.

Question 21

What hormone regulates estradiol production?

Answer 21

• The rate of estradiol production from follicles varies greatly during the menstrual cycle.
• Estradiol production is regulated by the effects of FSH on P450 aromatase. Similarly, LH and FSH influence the expression of P450scc in granulosa cells.

Question 22

In the most common form of congenital adrenal hyperplasia (CAH), what enzyme is missing or deficient?

What does this result in as far as hormone production is concerned?

What are the symptoms of this disease?

What is measured in plasma do dignose this disease?

How is this disease treated?

Answer 22

Defects in the synthesis of steroid hormones lead to serious metabolic imbalances. You are expected to know the most common CAH, 21-alphahydroxylase deficiency. ∙ In ~90% of CAH individuals, the 21-hydroxylation enzyme is blocked thus leading to mineralcorticoid and glucocorticoid deficiency and buildup of androgenic by-products with resulting masculization of the female fetus and early virilization in males.

∙ ~75% of CAH individuals have salt-wasting nephropathy (and lose large amounts of sodium in the urine).

∙ CAH is often diagnosed after birth of a female baby. Diagnosis is confirmed by an elevated serum level of 17-hydroxyprogesterone.

∙ Treatment: glucocorticoid replacement therapy. This not only alleviates glucocorticoid (i.e. cortisol) deficiency, but also provides negative feedback to suppress ACTH secretion and prevent continued adrenal stimulation.

∙ Only female fetuses need to be treated

Question 23

Describe the molecular actions of steroid hormones.

Answer 23

Steroid hormones can act in genomic fashion: affect transcription through promoters or can act at cell surface (non-genomic): second messengers. faster acting response. (cAMP-PKA, IP3, etc.)

attached is slide 40 of notes

Question 24

Steroid hormones summary:

• Are made from cholesterol, are lipophilic & can enter target cell
• Are immediately released from cell after synthesis
• Interact with cytoplasmic or nuclear receptors
• Activate DNA for protein synthesis
• Are slower acting and have longer half-life than peptide hormones. Note that binding to plasma proteins lengthens the half life of steroid hormones.
• Examples: cortisol, aldosterone, estrogen & testosterone

Note: PKA induces StAR, free cholesterol (attached pic)