Where are androgens produced in the male body?
95% in Leydig cells - in the form of testosterone
(in response to LH released by Anterior Pituitary)
5% in adrenal glands - in the form of Dehydroepiandrosterone (DHEA)
(in response to Adrenocorticotrophic hormone (ACTH) released by Anterior Pituitary)
Where are androgens produced in the female body?
Equal parts of androgen are produced in:
Ovaries (testosterone from corpus luteum in response to LH)
Adrenal Cortex (DHEA in response to ACTH)
Note: Majority of testosterone made in ovaries is made and swiftly converted to estrogen
What is the mechanism of androgens?
- Androgens are steroids that readily cross through the cell membrane
- They bidn to cytosolic receptors and translocate to the nucleus
- Activated androgen receptors bind to specific response elements and activate specific genes
How is testosterone activated?
Testosterone --> Dihydrotestosterone (DHT)
Enzyme: 5alpha reductase
What are the types of 5alpha reductase enzymes?
Type I: non-genital skin, liver and bone enzyme
Type II: urogenital tissue (prostate) in men and genital skin in men and women
Where does Dihydrotestosterone act?
Androgen receptors on:
External Genetalia: (Type II 5a reductase)
- Differentiation during gestation
- Maturity during puberty (growth of penis and scrotum)
- Adulthood prostatic disease
Hair Follicles: (Type I 5a reductase)
- Increased growth during puberty
- After delay, facial hair and male pattern baldness
Where does testosterone act?
Androgen receptors on:
- Wollfian development during gestation (seminiferous tubules, seminal vesicles, epididymus, vas deferens)
- Increased muscle mass and strength during puberty
- Deepens voice during puberty
How is estradiol created?
Testosterone --> Estradiol
Enzyme: CYP19 (aromatase)
Where does estradiol act?
It acts on an estrogen receptor on:
- Epiphyseal closer
- Increased density
What are the developmental effects of androgen?
- Large increase in Testosterone during 2nd trimester
- Androgens cause virilization of the urogenital tract
From birth to puberty:
Testosterone levels are very low
- Testosterone influences internal reproductive characteristics
- DHT regulates external male characteristics
What are female side effects of androgen use?
- Growth of facial and body hair
- male-pattern baldness
- enlarged larynx (irreversible)
- Enlarged clitoris (reversible)
- Increased musculature (esp. shoulder girdle)
What is the downside of oral preparations of androgens?
They are rapidly metabolized (during first pass by the liver)
--> therefore, they are modified at the 17alpha position by a methyl or ethinyl group
What are oral forms of active androgens?
What makes oral androgens less useful?
- Relatively weak. Too weak to induce spermatogenesis
- May cause liver damage with long-term use
What is Delatestryl?
Injectable form of androgen
- esterified with fatty acids at the hydroxyl group in the 17ß position to prolong absorption
What are transdermal options for androgen delivery?
- Testoderm patch
applied to scrotum (must shave first)
- Androderm patch
applied anywhere on skin
- some skin irritation results from permation enhancers
gel of testosterone and permeation enhancers are rubbed on shoulders
- Testosterone buccal system (Striant®)
adheres to gum; allows slow release of T to buccal mucosa and drains to SVC
- Topical Testosterone Solution (Axiron®)
solution applied to axilla
What are clinical uses of androgens?
1. Replacement in hypogonadism (lack of LH/FSH)
or loss of testicles due to trauma
- Large doses induce speratogenesis in hypo.
2. Congential Adrenal Hyperplasia - Androgen excess
21-hydroxylase deficiency --> insufficient synthesis of adrenal steroids and an increase in androgenic intermediates; lack of biofeedback leads to increased release of ACTH
Males = precocious puberty
Females = virilization of urogenital tract in utero and masculinization in post-pubescent
4. Catabolic/Wasting states
5. Hereditary Angioedema
due to Testosterone effect on liver
6. Anemia (men only)
What are adverse effects of androgen therapy?
- AndroGel can be transferred to children --> cause precocious puberty
- Virilicatino in women (hirsutism, acne, clitoral enlargement, deepening voice)
- Jaundice (reversible) from orally active preps
- Sexual effects:
What are anti-androgens used to treat?
- Counter excess androgens (mostly in females)
- Block DHT formation in BPH
- Block androgen recetors in cancerous tissue (prostate cancer)
What is the mechanism of Leuprolide?
GnRH analog with agonist properties when used in pulsatile fashion
--> antagonist propertie when used in continous fashion (downregulates GnRH receptor in pituitary, leading to decreased FSH/LH)
What is the clinical use and toxicity of Leuprolide?
Prostate Cancer (continuous and used with flutamide)
What is the mechanism of Finasteride?
What is it used to treat?
A 5a-reductase inhibitor
(decreased conversion of testosterone to DHT)
Useful in BPH and male pattern baldness (promotes hair growth)
What is the mechanism of Flutamide, bicalutamide, and enzalutamide?
What is it used to treat?
A nonsteroidal competitive inhibitor of androgens at the testosterone receptor
Used in prostate carcinoma
Risk of hepatotoxicity
What is the mechanism of Ketoconazole and Spironolactone?
What is it used to treat?
Inhibits steroid synthesis
Used to treat:
Polycystic ovarian syndrome
(Note: Also used as a K-sparing diuretic)
Gynecomastia and amenorrhea
What mechanisms can be used to improve urine flow caused by BPH?
1. a1 adrenergic receptor antagonist:
Tamsulosin blocks constriction of smooth muscle in lining of urethra by endogenous norepinephrine
Side effect: floppy iris syndrome
2. 5a-reductase Inhibitor:
Finasteride blocks production of DHT, thus reducing teh size of teh prostate due to BPH
Side effect: erectile dysfunction
What is the mechanism, clinical use, and side effects of Sildenafil and vardenafil?
Mechanism: Inhibit cGMP phosphodiesterase (PDE5), causing increase in cGMP, smooth muscle relaxation in the c. cavernosum, increased blood flow, and penile erection
Clinical Use: Erectile Dysfunction
impaired blue-green color vision
Risk of life-threatening hypotension when taken with nitrates
Which erectile dysfunction treatments require injection into the penis?
1. Alprostadil: PGE1 analog --> increased cAMP --> relaxation of smooth muscle
2. Papaverine: Nonselective PDE inhibitor --> increased cGMP and cAMP --> relaxation of smooth muscle
3. Phentolamine: alpha adrenergic receptor antagonist --> block a1 adrenergic receptor mediated vasoconstriction and relax intracorporal smooth muscle
What androgen deficiencies would not benefit from androgen treatment?
XY genotype, XX phenotype
Lack of 5a reductase
--> T not converted to DHT
Treatment: Plastic surgery and estrogen
- Mutations in Androgen Receptor
(aka testicular feminization)
External female phenotype
Treatment: surgery and estrogen
How is estrogen made orally active?
Adding an ethinyl group at the 17alpha position
- in order to avoid 1st pass metabolism
What are orally active estrogen preparations?
Equilenin and Equilin
What are the therapeutic uses of estrogens?
- Replacement therapy
(ovaries stop producing estrogen)
What are the pros and cons of estrogen therapy after menopause?
- prevent osteoporosis
- reverses vaginal dryness
- Increaesd HDL, decreased LDL
- E alone: increased endometrial carcinoma; E+P: decreased endometrial carcinoma
- hot flushes
- increased risk of:
What are SERMs? What are they used to treat?
Selective Estrogen Receptor Modulators
- Used to treat postmenopausal osteoporosis
- Used to treat and prevent the recurrence of breast cancer
- Perhaps could be used to treat symptoms of menopause
What is Tamoxifen?
SERM - estrogen antagonist in breast but agonist in endometrium
--> used to decrease risk of breast cancer recurrence
- E agonist on bone; protects against osteoporosis
- E agonist in increasing clotting factors --> increased risk of thrombosis
- E antagonist in hypothalamus --> increased hot flashes
What is Raloxifene?
E antagonist in breast and endometrium
E agonist in bone --> protects from osteoporosis
E agonist in increasing clotting factors --> increased risk of VTE (less than tamoxifene)
E antagonist in hypothalamus --> increased hot flashes
What is ospemifene?
The only SERM taht is an E agonist on vaginal epithelium
--> used to treat Dyspareunia (pain during intercourse due to dryness)
- E agonist in bone and endometrium
- antagonist in breast --> decreased risk of Breast cancer
- E antagonist in hypothalamus--> increased hot flashes
What is Clomiphene Citrate?
E antagonist in hypothalamus and pituitary gland
--> used to induce ovulation in premenopause by blocking estrogen negative feedback at hypothal. and ant. pituitary resulitng in increased FSH and LH release