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)
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
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
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
5
Q
Can the testes/ovaries make glucocorticoids and mineralcorticoids?
A
NOPE
6
Q
Where are 3-β-hydroxysteroid dehydrogenase/Δ5-4 isomerase more active: adrenal cortex or testes/ovaries?
A
Testes/ovaries
7
Q
How can male baldness be treated?
A
5-α-reductase inhibitors
8
Q
Where are estrogenS synthesized?
A
- Adrenal cortex
- Ovaries
- Adipose tissue
- Placenta/Fetal Liver
9
Q
What is gynecomastia? What are its 5 causes? 2 Treatments?
A
Male breast development due to:
- Extra fat causing extra estradiol synthesis
- Exogenous testosterone or anabolic steroids cause excess substrate for aromatase
- Puberty causing excess androgens being converted to estrogens (seen in 50% of men)
- Old age (70% of men)
- Androgen insensitivity syndromes
Treatment: anti-androgen therapy or surgery
10
Q
Where are the enzymes 17-β-hydroxysteroid, aromatase, and 5-α-reductase located inside the cell?
A
SER
11
Q
Describe the regulation of testosterone synthesis.
A
- Hypo releases GnRH
- Ant. Pit. release LH/FSH
- LH stimulates Leydig cells to produce testosterone/FSH and testosterone stimulates Sertoli cells to produce ABP and inhibin
- Testosterone exerts negative feedback on hypo and ant pit/Inhibin exerts negtive feedback on ant pit
12
Q
What is ABP?
A
Androgen binding protein in the seminiferous tubules
13
Q
Describe the binding of ABP and testosterone?
A
Very strong
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
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
16
Q
What are the 2 blood binding proteins of testosterone? Describe their binding.
A
- TeBG (strong)
2. Albumin (weak)
17
Q
Other than to testosterone, what can TeBG bind in the blood?
A
- Estradiol (weak)
2. DHT
18
Q
What % of testosterone is free in blood?
A
1-3%
19
Q
What’s are the 2 differences between ABP and TeBG?
A
- Same primary sequence (come from same gene) but different glycosylations
- ABP binds testosterone in seminiferous tubules of testes vs TeBG binds testosterone in blood
20
Q
To what kind of receptors do testosterone and DHT bind?
A
SAME nuclear receptors (but different physiological effects)
21
Q
What are the 3 effects of testosterone binding to its nuclear receptor?
A
- Gonadotropin regulation
- Spermatogenesis
- Wolffian stimulation = vas deferens, epididymis, seminal vesicles
22
Q
What are the 3 effects of DHT binding to its nuclear receptor?
A
- External virilization
- Sexual maturity at puberty
- Penis, penile urethra, and scrotum development IN UTERO
23
Q
How can testosterone and DHT have different effects when they bind to the same nuclear receptors? 2 mechanisms
A
- Upon binding they induce different conformational changes allowing the hormone-receptor complex to bind different transcriptional coactivators
- DHT binds more tightly than testosterone
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
25
When can a small penis be treated? How?
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)
26
What is 5-α-reductase deficiency? 3 Symptoms?
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
27
What is Complete Androgen Insensitivity Syndrome (CAIS)? 2 Symptoms?
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
28
What is the main estrogen for premenopausal women of childbearing age?
Estradiol
29
Where is estradiol produced?
Ovaries
30
What is the main estrogen for postmenopausal women? Describe its potency.
Estrone = WEAK estrogen
31
Where is estrone produced?
Adrenal cortex
32
What is the main estrogen during pregnancy?
Estriol
33
Where is estriol produced?
Placenta
34
Why does production of progesterone need to be separated from production of estrogen?
Or else all of the progesterone would be converted to estrogen
35
What cells of the ovaries produce progesterone? What enzyme do they lack to make this possible?
Granulosa cells
| Lack 17-α-hydroxylase
36
What cells of the ovaries produce testosterone?
Theca cells
37
How is estrogen produced in ovaries?
Testosterone is first produced by theca cells and transferred to granulosa cells where it's converted to estrogen by aromatase
38
Describe the fetus/placenta/mother hormone production pathway.
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
What is DES?
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
What is a teratogen?
Agent that can disturb the development of the embryo or fetus
41
What are SERMs? How do they work? Example?
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
What is polysystic ovarian disease? Most common symptom? 4 other symptoms? Cause? How to diagnose?
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
Why does osteoporosis happen in postmenopausal women?
Estrogen levels are not high enough to maintain bone mass
44
How does estrogen affect males?
Male fertility and brain development
45
What do the Sertoli cells make up?
The seminiferous tubules
46
How can I recognize estriol?
It has a C16 (-OH)
47
What is another name for Complete Androgen Insensitivity Syndrome (CAIS)?
Testicular feminization syndrome
48
What does the enzyme 3-α-reductase do? Mechanism, substrates, products?
- Mechanism: C3 ketone to hydroxyl group
- Substrate: DHT
- Product: androstanediol
49
How can erect penis length be measured?
1. Prostaglandin E1 injection
| 2. Stretching with a 450 g force
50
How do DHT and testosterone contribute to male genitalia development?
1. Testosterone: Wolffian development: vas deferens, epididymis, seminal vesicles
2. DHT: penis, penile urethra, scrotum
51
What develops testes?
JUST the XY genotype
52
What sex hormone is responsible for the development of the clitoris, labia, and lower vagina?
Estradiol
53
What is responsible for the development of the uterus, fallopian tubes, and upper vagina??
Absence of Mullerian inhibiting factor (which blocks this development in males)
54
What is Partial Androgen Sensitivity (PAIS)?
Weak androgen binding so some are in excess and converted to estrogens causing gynecomastia
55
Can gynecomastia be treated with aromatase inhibitors?
NOPE
56
Which 2 reactions are stimulated by LH in the ovary?
1. Cholesterol to pregnenolone
| 2. Progesterone to 17-hydroxyprogesterone
57
Which 2 reactions are stimulated by FSH in the ovary?
1. Cholesterol to pregnenolone
| 2. Aromatase reactions
58
What enzyme is missing in the fetal adrenal cortex?
3-β-hydroxysteroid dehydrogenase
59
What 2 tissues in humans take on a sexual identity at or near birth?
1. Brain
| 2. Liver
60
What primarily determines phenotypes in birds?
Genes
61
What are anabolic steroids?
Drugs that resemble androgenic hormones such as testosterone
62
What is the function of androstenadiol?
Another potent androgen like DHT
63
What is another name for polycystic ovary syndrome?
Stein-Leventhal syndrome
64
What steroid do leydig cell and arrhenoblastoma tumors produce in excess?
Testosterone
65
What steroid do granulosa-theca cell tumors produce in excess?
Estrogens
66
What steroid do intraovarian adrenal rests produce in excess?
Cortisol
67
What steroid do hydratiform moles/choriocarcinoma produce in excess?
hCG
68
What happens during benign prostatic hypertrophy? How common is this condition?
Androgens and estrogens play a role in the uncontrolled growth of prostate cells
This happens in 75% of men over 60
69
What is gender dysphoria?
Distress caused when an individual's assigned gender at birth is not the same as the one they identify with
70
How can one delay puberty? Is this reversible?
Inhibit hormone surges with GnRH agonist which causes it to act as an antagonist.
Yes, reversible
71
What does propecia do? Side effects?
It inhibits 5α-reductase to prevent male balding
Side effects (which may last forever): less energy, less libido
72
What can inhibiting 5α-reductase also prevent?
Prostate cancer
73
Can patients with 5α-reductase be fertile?
Yes
74
What sex steroids binds albumin?
1. Progesterone
| 2. Testosterone
75
What sex steroids binds CBG?
Estrone
76
To what receptors does testosterone bind?
1. Cytoplasmic
| 2. Nuclear
77
Is the development of the testes hormone dependent?
NOPE, only need XY genotype
78
What prevents the development of the Mullerian ducts and uterus in males?
Testes produce Mullerian Inhibiting Factor (MIF)
