Lecture 27: Sex Steroid Synthesis Flashcards

1
Q

What is DHT? How is it synthesized? Where?

A

More potent form of testosterone responsible for balding
5-α-reductase: testosterone + NADPH => dihydrotestosterone (C5/6 double bond reduced) + NADP
This happens in target tissues (not much in testes)

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2
Q

What does the enzyme 17-β-hydroxysteroid dehydrogenase do? Mechanism, substrates, products?

A
  • Mechanism: C17 ketone to hydroxyl
  • Substrates: DHEA and androstenedione
  • Products: androstenediol and testosterone
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3
Q

What does the enzyme aromatase do? Mechanism, substrates, products?

A
  • Mechanism: 3 hydroxylations making the first steroid ring aromatic + C3 ketone into hydroxyl using 3 NADPH and 3 O2 + C19 is removed = P450 complex
  • Substrates: androstenedione and testosterone
  • Products: estrone and estradiol
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4
Q

What is the difference between the synthesis of sex hormones in the adrenal cortex vs testes/ovaries?

A
  • Adrenal cortex: ACTH stimulation

- Testes/Ovaries: LH stimulation

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5
Q

Can the testes/ovaries make glucocorticoids and mineralcorticoids?

A

NOPE

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6
Q

Where are 3-β-hydroxysteroid dehydrogenase/Δ5-4 isomerase more active: adrenal cortex or testes/ovaries?

A

Testes/ovaries

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7
Q

How can male baldness be treated?

A

5-α-reductase inhibitors

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8
Q

Where are estrogenS synthesized?

A
  1. Adrenal cortex
  2. Ovaries
  3. Adipose tissue
  4. Placenta/Fetal Liver
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9
Q

What is gynecomastia? What are its 5 causes? 2 Treatments?

A

Male breast development due to:

  1. Extra fat causing extra estradiol synthesis
  2. Exogenous testosterone or anabolic steroids cause excess substrate for aromatase
  3. Puberty causing excess androgens being converted to estrogens (seen in 50% of men)
  4. Old age (70% of men)
  5. Androgen insensitivity syndromes

Treatment: anti-androgen therapy or surgery

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10
Q

Where are the enzymes 17-β-hydroxysteroid, aromatase, and 5-α-reductase located inside the cell?

A

SER

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11
Q

Describe the regulation of testosterone synthesis.

A
  1. Hypo releases GnRH
  2. Ant. Pit. release LH/FSH
  3. LH stimulates Leydig cells to produce testosterone/FSH and testosterone stimulates Sertoli cells to produce ABP and inhibin
  4. Testosterone exerts negative feedback on hypo and ant pit/Inhibin exerts negtive feedback on ant pit
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12
Q

What is ABP?

A

Androgen binding protein in the seminiferous tubules

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13
Q

Describe the binding of ABP and testosterone?

A

Very strong

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14
Q

What is responsible for fertility in men?

A

The high concentration of testosterone in the testes (bound to ABP in seminiferous tubules) enables spermatogenesis

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15
Q

Why do anabolic steroids lead to infertility?

A

Anabolic steroids => high concentrations of androgens in blood => negative feedback on hypo and ant pit => less testosterone synthesis in the testes binding to ABP => infertility

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16
Q

What are the 2 blood binding proteins of testosterone? Describe their binding.

A
  1. TeBG (strong)

2. Albumin (weak)

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17
Q

Other than to testosterone, what can TeBG bind in the blood?

A
  1. Estradiol (weak)

2. DHT

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18
Q

What % of testosterone is free in blood?

A

1-3%

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19
Q

What’s are the 2 differences between ABP and TeBG?

A
  1. Same primary sequence (come from same gene) but different glycosylations
  2. ABP binds testosterone in seminiferous tubules of testes vs TeBG binds testosterone in blood
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20
Q

To what kind of receptors do testosterone and DHT bind?

A

SAME nuclear receptors (but different physiological effects)

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21
Q

What are the 3 effects of testosterone binding to its nuclear receptor?

A
  1. Gonadotropin regulation
  2. Spermatogenesis
  3. Wolffian stimulation = vas deferens, epididymis, seminal vesicles
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22
Q

What are the 3 effects of DHT binding to its nuclear receptor?

A
  1. External virilization
  2. Sexual maturity at puberty
  3. Penis, penile urethra, and scrotum development IN UTERO
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23
Q

How can testosterone and DHT have different effects when they bind to the same nuclear receptors? 2 mechanisms

A
  1. Upon binding they induce different conformational changes allowing the hormone-receptor complex to bind different transcriptional coactivators
  2. DHT binds more tightly than testosterone
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24
Q

What is hypogonadism? 2 causes? 2 symptoms? Possible origin?

A

Not enough androgens/testosterone produced

  • Causes: fault in testes (primary hypogonadism usually due to genetic deficiency for an enzyme needed for synthesis) or fault in ant pit (secondary hypogonadism)
  • Symptoms: failure or regression of secondary sex characteristics
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25
Q

When can a small penis be treated? How?

A

Before puberty if there has been a failure of androgen production by using an androgen cream on the penis (no more receptor on penis after that)

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26
Q

What is 5-α-reductase deficiency? 3 Symptoms?

A

Male inability to produce DHT: FEMALE looking BABY starts looking like A MAN AT PUBERTY
Symptoms:
1. Male internal genitalia (inguinal testes: have not fallen but still produce testosterone) but external female genitalia (no penis, penile urethra, nor scrotum)
2. Ambiguous genitalia: cliteromegaly or micropenis
3. Certain degree of masculinization during puberty: “penis” growth, testes fall down, but urethra is at the base of the penis

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27
Q

What is Complete Androgen Insensitivity Syndrome (CAIS)? 2 Symptoms?

A

No androgen receptors in males
Symptom:
1. Total failure of male phenotype development, except they have testes producing androgens
2. Female phenotypical features: breast, little/no sex hair due to conversions of androgens to estrogens

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28
Q

What is the main estrogen for premenopausal women of childbearing age?

A

Estradiol

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29
Q

Where is estradiol produced?

A

Ovaries

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30
Q

What is the main estrogen for postmenopausal women? Describe its potency.

A

Estrone = WEAK estrogen

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31
Q

Where is estrone produced?

A

Adrenal cortex

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32
Q

What is the main estrogen during pregnancy?

A

Estriol

33
Q

Where is estriol produced?

A

Placenta

34
Q

Why does production of progesterone need to be separated from production of estrogen?

A

Or else all of the progesterone would be converted to estrogen

35
Q

What cells of the ovaries produce progesterone? What enzyme do they lack to make this possible?

A

Granulosa cells

Lack 17-α-hydroxylase

36
Q

What cells of the ovaries produce testosterone?

A

Theca cells

37
Q

How is estrogen produced in ovaries?

A

Testosterone is first produced by theca cells and transferred to granulosa cells where it’s converted to estrogen by aromatase

38
Q

Describe the fetus/placenta/mother hormone production pathway.

A

ESTRIOL

  1. Fetal adrenal glands makes DHEA
  2. Fetus sends DHEA to its liver
  3. Fetus liver converts DHEA to 16-α-hydroxy-DHEA
  4. 16-α-hydroxy-DHEA sent to placenta and used as precursor for estriol synthesis

PROGESTERONE

  1. Placenta makes progesterone from pregnenolone
  2. Progesterone from placenta goes to fetus adrenal gland for cortisol production because fetus adrenal gland is not able to make its own
39
Q

What is DES?

A

Diethylstibesterol: synthetic estrogen marketed to prevent miscarriages in the early 70s, but was taken off market for teratogenic effects:

  1. Increased risks of vaginal/cervical cancer in babies
  2. Reproductive tract structural differences
  3. Pregnancy complications
  4. Infertility
40
Q

What is a teratogen?

A

Agent that can disturb the development of the embryo or fetus

41
Q

What are SERMs? How do they work? Example?

A

Selective Estrogen Receptor Modulators: have antagonistic effects based upon the tissue they bind to by inducing different conformations in the estrogen receptor causing different transcriptional factors to bind the hormone-receptor complex

Mechanism: make use of the different positions of helix 12 on different estrogen receptors

Eg: tamoxifen binds breast receptors tightly to treat breast cancer and gynecomastia but binds bone receptors weakly so does not interfere with healthy bone maintenance

42
Q

What is polysystic ovarian disease? Most common symptom? 4 other symptoms? Cause? How to diagnose?

A

Most common reproductive disorder among women of reproductive age.
Most common symptom: infertility
Other symptoms: irregular menstruation, hirsutism, acne, male-pattern baldness
Cause: increase in stress/obesity = increase in cortisol = increase in insulin = ovaries secrete elevated androgens
Diagnose: polycystic ovaries by sonography

43
Q

Why does osteoporosis happen in postmenopausal women?

A

Estrogen levels are not high enough to maintain bone mass

44
Q

How does estrogen affect males?

A

Male fertility and brain development

45
Q

What do the Sertoli cells make up?

A

The seminiferous tubules

46
Q

How can I recognize estriol?

A

It has a C16 (-OH)

47
Q

What is another name for Complete Androgen Insensitivity Syndrome (CAIS)?

A

Testicular feminization syndrome

48
Q

What does the enzyme 3-α-reductase do? Mechanism, substrates, products?

A
  • Mechanism: C3 ketone to hydroxyl group
  • Substrate: DHT
  • Product: androstanediol
49
Q

How can erect penis length be measured?

A
  1. Prostaglandin E1 injection

2. Stretching with a 450 g force

50
Q

How do DHT and testosterone contribute to male genitalia development?

A
  1. Testosterone: Wolffian development: vas deferens, epididymis, seminal vesicles
  2. DHT: penis, penile urethra, scrotum
51
Q

What develops testes?

A

JUST the XY genotype

52
Q

What sex hormone is responsible for the development of the clitoris, labia, and lower vagina?

A

Estradiol

53
Q

What is responsible for the development of the uterus, fallopian tubes, and upper vagina??

A

Absence of Mullerian inhibiting factor (which blocks this development in males)

54
Q

What is Partial Androgen Sensitivity (PAIS)?

A

Weak androgen binding so some are in excess and converted to estrogens causing gynecomastia

55
Q

Can gynecomastia be treated with aromatase inhibitors?

A

NOPE

56
Q

Which 2 reactions are stimulated by LH in the ovary?

A
  1. Cholesterol to pregnenolone

2. Progesterone to 17-hydroxyprogesterone

57
Q

Which 2 reactions are stimulated by FSH in the ovary?

A
  1. Cholesterol to pregnenolone

2. Aromatase reactions

58
Q

What enzyme is missing in the fetal adrenal cortex?

A

3-β-hydroxysteroid dehydrogenase

59
Q

What 2 tissues in humans take on a sexual identity at or near birth?

A
  1. Brain

2. Liver

60
Q

What primarily determines phenotypes in birds?

A

Genes

61
Q

What are anabolic steroids?

A

Drugs that resemble androgenic hormones such as testosterone

62
Q

What is the function of androstenadiol?

A

Another potent androgen like DHT

63
Q

What is another name for polycystic ovary syndrome?

A

Stein-Leventhal syndrome

64
Q

What steroid do leydig cell and arrhenoblastoma tumors produce in excess?

A

Testosterone

65
Q

What steroid do granulosa-theca cell tumors produce in excess?

A

Estrogens

66
Q

What steroid do intraovarian adrenal rests produce in excess?

A

Cortisol

67
Q

What steroid do hydratiform moles/choriocarcinoma produce in excess?

A

hCG

68
Q

What happens during benign prostatic hypertrophy? How common is this condition?

A

Androgens and estrogens play a role in the uncontrolled growth of prostate cells
This happens in 75% of men over 60

69
Q

What is gender dysphoria?

A

Distress caused when an individual’s assigned gender at birth is not the same as the one they identify with

70
Q

How can one delay puberty? Is this reversible?

A

Inhibit hormone surges with GnRH agonist which causes it to act as an antagonist.
Yes, reversible

71
Q

What does propecia do? Side effects?

A

It inhibits 5α-reductase to prevent male balding

Side effects (which may last forever): less energy, less libido

72
Q

What can inhibiting 5α-reductase also prevent?

A

Prostate cancer

73
Q

Can patients with 5α-reductase be fertile?

A

Yes

74
Q

What sex steroids binds albumin?

A
  1. Progesterone

2. Testosterone

75
Q

What sex steroids binds CBG?

A

Estrone

76
Q

To what receptors does testosterone bind?

A
  1. Cytoplasmic

2. Nuclear

77
Q

Is the development of the testes hormone dependent?

A

NOPE, only need XY genotype

78
Q

What prevents the development of the Mullerian ducts and uterus in males?

A

Testes produce Mullerian Inhibiting Factor (MIF)