Endocrine 2 Exam 1: Androgens (p28-37)

What is the primary androgen secreted in the body?

testosterone

The release of testosterone is ____ with highest plasma concentrations occuring at ___ AM

pulsatile, 8

Testosterone is often converted to ____ (DHT) by 5-alpha reductase

dihydrotestosterone

DHT binds to the androgen receptor with higher ___ and activates gene transcription more ___

affinity, efficiently

There are 2 forms of 5-alpha reductase:

Type 1: found in __-___ skin and liver

non-genital

There are 2 forms of 5-alpha reductase:

Type 2: found in the __ tract and ___ skin (in both males and females)

genital, genital

Even though DHT is more potent than testosterone, both are involved in the maturation and maintenance of the primary and secondary sex characteristics of the __

male

testosterone can also be converted into ___ via aromatases in the extraglandular tissues (adipose tissue and liver)

estradiol

testosterone can also be converted into estradiol via aromatases, and this accounts for ___ (85%) of estrogen synthesis in males (the other 15% comes from the ___)

most, testes

Besides males, testosterone is secreted by the ___ (corpus luteum) and __ ___ in females

ovaries, adrenal cortex

DHT specifically acts on:

____ genitalia development

____ follicles

external, hair

testosterone specifically acts on:

____ genitalia development

skeletal ____ (increase mass and strength during puberty)

internal, muscle

estrogen specifically acts on the following in men:

-____

-possible effects on ____

bone, libido

There are __ times in a male's life when testosterone levels rise

3

3 times testosterone levels rise

1) _____

2) ____

3) ____

embryo, neonatal, puberty

Testosterone rise-embryo: in the ___ trimester, which helps to __ the urogenital tract (ie develop male physical characteristics)

second, virilize

Testosterone rise- infancy: ____ development

CNS

Testosterone rise- puberty: produces ____ sex characteristics, growth of seminal vesicles and ___ gland.

secondary, prostate

During puberty, in parallel with the production of testosterone (steroidogenesis) is the production of ___ (spermatogenesis)

sperm

Age-related low testosterone = ____

andropause

The synthesis of testosterone occurs via activation of the ___ and __ ___

hypothalamus, pituitary axis

1) Testosterone is released in a pulsatile manner

2) ___ is released from hypothalamus

3) GnRH interacts with the GnRH receptor on anterior pituitary gland to promote release of __ and __

GnRH, FSH, LH

1) Testosterone is released in a pulsatile manner

2) GnRH is released from hypothalamus

3) GnRH interacts with the GnRH receptor on anterior pituitary gland to promote release of FSH and LH

4) LH interacts with ___ cells of the testes. FSH promotes ___ in the seminiferous tubules

Leydig, spermatogenesis

When LH interacts with the Leydig cells of the testes, this causes conversion of ___ to ___ (testosterone and DHT)

cholesterol, androgens

When LH interacts with the Leydig cells of the testes, this causes conversion of cholesterol to androgens by turning on enzymes dependent on ___ levels

cAMP

summary

FSH→_____

LH → _____ (testosterone and DHT)

spermatogenesis, steroidogenesis

Testosterone is involved with both the ___ and ___ of sperm

production, maturation

Testosterone and Estradiol (converted from testosterone) both exert feedback ___ on the axis

inhibition

When DHT interacts with the AR, this can have favorable effects in the:

-bone

-anabolism

-____ development/virilization

sexual

When DHT interacts with the AR, this can create adverse effects in the:

-____ (increase LDL, increase clotting protein)

-____ (increase risk of cancer)

liver, brain

Androgen receptors are located in many regions of a male's body:

-___

-___ gland

-gonads

-face

-muscle

-bone

hypothalamus, pituitary

The only way for androgens to have effects on the body is through binding to androgen ___

receptors

When testosterone or DHT bind to the ligand binding pocket of the androgen receptor, this causes it to ___ to the nucleus and bind to genes that contain ___ ___ ___ (ARE)

translocate, androgen response element

When testosterone or DHT bind to the ligand binding pocket of the androgen receptor, this causes it to translocate to the nucleus and bind to genes that contain ARE, causing an increase in gene ____ resulting in ___ of males/females

transcription, virilization

We use ___ therapy when an individual expresses a phenotype that resulted from a lack of testosterone or androgen

replacement

replacement therapy uses

1) ____

2) delayed ____

3) ___ disease (decreased muscle/bone)

4) enhance ___ performance (abuse potential here)

hypogonadism, puberty, wasting, athletic

Testosterone is usually not given orally because it is readily absorbed into the __ circulation

hepatic

Most pharmaceutical preparations of Testosterone are designed to bypass hepatic clearance (given ___)

IM

Replacement Therapy Formulations were designed to:

1) ___ absorption

2) ___ cross-contamination

increase, decrease

Adverse Effects of Replacement Therapy in men

-persistent erection called ___

-feminizing effect in male due to conversion of testosterone to estradiol (____)

priapism, gynecomastia

Adverse Effects of Replacement Therapy in men

-____ (accounts for weight gain)

-_____ (due to effects on the liver)

edema, jaundice

Adverse Effects of Replacement Therapy in men

-____ (lack of sperm in semen)

-liver or brain _____

azoospermia, cancer

Adverse Effects of Replacement Therapy in men

-alterations in ___ profiles (increase LDLs), which predisposes one to ___ disease

lipid, cardiovascular

Adverse Effects of Replacement Therapy in women

-____ of body (including acne, facial hair, male-pattern baldness, hirsutism, hypertrophy of clitoris and muscles)

masculinization

Adverse Effects of Replacement Therapy in children

-premature ___ closure (so basically the kids are short)

epiphyseal

Adverse Effects of Replacement Therapy in neonate

-____ of the female fetus

masculinization

The goal of anti-androgens and androgen receptor antagonists is to ___ androgen levels and prevent effects of androgens on the body

reduce

Why use anti-androgens or androgen receptor antagonists ?

1) ___ cancer

2) female ____(women growing thick, dark, male-pattern hair)

3) alopecia

prostate, hirsutism

Why use anti-androgens or androgen receptor antagonists ?

4) acne

5) precocious ____ (ie too early)

puberty

Why use anti-androgens or androgen receptor antagonists ?

6) benign and metastatic ___ tumors/cancer

7) inhibit sex drive in ___ ____ (chemical castration)

prostatic, sex offenders

Approaches to anti-androgen/AR antagonist treatment either:

1) decrease ___ of androgens in the body

2) block androgen ___ at the receptor

levels, action

Approaches to decreasing LEVELS of androgens

1) decreased actions of ___ at GnRH receptor

2) inhibit P450 enzymes involved in androgen ___ in the testes

3) inhibit __-___ ___

GnRH, biosynthesis, 5-alpha-reductase

Approaches to decreasing LEVELS of androgens

1) inhibit the actions of GnRH at the GnRH receptor using ____ ____ ___ (like leuprolide, goserelin, triptorelin)

GnRH continuous analogs

Approaches to decreasing LEVELS of androgens

2) inhibit the ___ enzymes involves in androgen biosynthesis in the testes

P450

we can inhibit the P450 enzymes involved in androgen biosynthesis in the testes by using ___ or ____ (but not common due to hepatotoxicity), or more commonly by using ____ ____

ketoconazole, aminoglutethamide, abiraterone acetate

Abiraterone acetate

-inhibits ___ and so inhibits testosterone production in the prostate cancer cells and androgen precursors (DHEA and androstenedione)

-causes tumor to starve

CYP 17

Abiraterone acetate

-expressed in ___, ___, and ___ tumor tissue

testicular, adrenal, prostatic

Approaches to decreasing LEVELS of androgens

3) inhibit the enzyme ___-___ ___ to prevent the conversion of testosterone into DHT

5-alpha-reductase

we can inhibit the 5-alpha reductase to prevent the conversion of testosterone into DHT (more potent form) using ___ and ____

finasteride, dutasteride

Finasteride (Proscar)

-blocks the type ___ 5-alpha reductase in male external genitalia, making it useful for the treatment of ___

-also used to treat male patterned ____

II, BPH, baldness

Dutasteride (Avodart)

-blocks type __ and ___ 5-alpha reductase

I, II

Approaches to blocking ACTIONS of androgens at ARs in the body

1) use androgen receptor ___

antagonists

Androgen Receptor Antagonists

-____ (Eulexin)

-_____ (Casodex)

-____ (Nilandron)

-_____ (Xtandi)

flutamide, bicalutamide, nilatamide, enzalutamide

Androgen Receptor Antagonists interrupt the ___ ___ on the axis resulting in increased testosterone levels

negative feedback

Androgen Receptor Antagonists interrupt the negative feedback on the axis resulting in increased testosterone levels thus attenuating the loss of ___ and ___

libido, potency

Flutamide, Bicalutamide, and Nilatamide are commonly used in combination with a ___ ___ (like leuprolide or nafarelin)

GnRH analog

Flutamide, Bicalutamide, and Nilatamide are commonly used in combination with a GnRH analog to suppress the initial ___ in androgens from GnRH analogs

increase

Flutamide, Bicalutamide, and Nilatamide are commonly used in combination with a GnRH analog.

-this type of therapy is called ___ (combination androgen receptor blockers)

CAB