1. The Pharmacology of Androgens
Neil A. Clipstone, Ph.D.

2. TESTOSTERONE Physiological effects of testosterone Male Sex Organs
Sex organ development
Sperm production
Prostate growth
Erectile function
Puberty
Development & maintenance
of secondary
sexual characteristics
Muscle
Muscle mass
Muscle strength
Bone Marrow
Red blood cell production
TESTOSTERONE
Bone
Bone density
Maintenance
Epiphyseal closure
Skin
Growth of facial & body hair
Collagen growth
Androgenic alopecia
CNS
Sex drive
Sense of well being
Confidence
Cognition & memory

3. Testosterone Mechanism of action
Testosterone is a direct agonist of the Androgen receptor (AR)
AR is an androgen-dependent nuclear transcription factor of the steroid hormone family
AR binds to the Hormone response element (HRE) in androgen target genes
AR recruits tissue-specific transcriptional cofactors and promotes androgen-specific patterns of gene expression
SHBG AR
HRE
Testosterone-target gene
1. Testosterone binds
AR in the cytosol
2. AR undergoes
conformational change
and forms dimers
3. AR dimers
translocate into
the nucleus and
bind to target
promoters
4. Promoter-bound, ligand-activated
AR receptors recruit
transcriptional co-factors
and modulate target gene expression
Testosterone
Bound to +
Transcriptional
co-factor

4. Promote spermatogenesis
Regulation of testosterone synthesis & secretion
Testes
Testosterone
FSH + LH
GnRH
Negative
feedback
Inhibin
Pulsatile LH
FSH
Leydig cell
Sertoli cell
Testosterone
Androgen-binding
protein
ABP-Testosterone
+ other FSH-induced
proteins
Promote spermatogenesis
Systemic
testosterone
responses

5. (INACTIVE METABOLITES) Hypothalamus/Skin/Bone
Testosterone Biosynthesis & Metabolism
Cholesterol
Pregnenolone
Progesterone
Androstenedione
Dehydroepi
androsterone
(DEHA)
Androstenediol
Testosterone
17b HSD
3b HSD
Side chain
cleavage enzyme
HSD- Hydroxysteroid dehydrogenase
Testes
Skin/Liver/Bone
Urogenital tissue
Dihydrotestosterone
(~10x > potent)
PERIPHERAL
TISSUES
5a-reductase
Testosterone
Estradiol
Phase I/
Phase II
Liver
Andosterone
Etiocholanolone
(INACTIVE METABOLITES)
Aromatase
(CYP19A1)
Liver/Adipose
Hypothalamus/Skin/Bone

6. Direct and Indirect effects of Testosterone
5a-reductase
Aromatase
(CYP19A1)
Dihydrotestosterone
Estradiol AR AR ER
External genitalia:
- Differentiation during puberty
- Maturation during puberty
- Prostate size & Development
Hair Follicles:
Increased facial & body hair
growth during puberty
Male pattern baldness
Internal genitalia
- Wolffian development during gestation
- Spermatogenesis
Skeletal Muscle:
- Increased mass & strength
Libido
Sexual Function
Erythropoiesis
Bone Growth
Bone:
- Epiphyseal closure
- Increased density
Libido
Sexual Function
Reduced Body Mass

7. Testosterone preparations
Ester moiety cleaved
by tissue esterases
following administration
to yield active testosterone
More lipophilic
Formulation for
Transdermal Delivery
Avoids first pass effect
Testosterone
ethanate
cypionate
Long acting
Esterification
Testosterone
Parenteral administration (e.g. IM)
Oral administration
Methyltestosterone
17a Alkylation
- Orally bioavailable
- Less androgenic than testosterone
- Increased hepatotoxicity
Rapidly orally absorbed
Low oral bioavailability
High first pass metabolism
17a alkylation
inhibits hepatic
catabolism

8. Testosterone indications and therapeutic uses
Male hypogonadism
Primary Disease of testes - Sperm & testosterone < normal
- LH & FSH > normal (no negative feedback)
Secondary Hypothalamus/ - Sperm & Testosterone < normal
Pituitary Disease - LH & FSH < normal
Symptoms:
In utero - ambiguous sexual organ development
- micropenis at birth
Prepubertal - failure to undergo complete puberty
Adult - energy & libido
- infertility
- muscle mass, bone density & sexual hair

9. Treatment: - Testosterone replacement therapy
adolescents at the time of puberty
in symptomatic adult men
Note: Treatment of older men with age-related declines in testosterone levels, but no overt hypogonadal symptoms or underlying hypothalamic/pituitary or testicular disease is controversial.
Goal of treatment: - to restore testosterone levels to the normal range
Serum testosterone levels are monitored for clinical efficacy
Clinical Benefit: - development/maintenance of secondary sexual characteristics
- libido (mediated in part by estradiol)
- muscle strength
- fat-free mass (mediated in part by estradiol)
- bone density (mediated by estradiol)
- improved mood & cognition (+/-)

10. Adverse effects: - Acne
- Increased risk of prostate cancer/benign prostatic hyperplasia
- Worsening of sleep apnea
- Increased cardiovascular disease risk (HDL & LDL)
- Increased risk of venous thromboembolic disease
- Erythrocytosis – increase in red cell mass (increased risk of VTE)
- Hepatic dysfunction (- 17a alkylated derivatives)
- Suppression of spermatogenesis
inhibition of LH production results in reduction of high level endogenous local testicular testosterone known to be required for sperm production
Contraindications: - Pre-existing Prostate cancer
- High levels of PSA in men at high risk for prostate cancer
- Untreated sleep apnea

11. Androgen abuse as a performance enhancing drug
Androgens and related compounds are used by athletes (both professional & recreational)
at supraphysiological levels ( X) to boost athletic performance & physical appearance
Rationale: Androgens known to increase - muscle mass
- strength
- fat-free mass
Types of compounds used:
Exogenous & synthetic testosterone (readily detected by drug testing)
Androgen precursors e.g. andorstenedione & dehydroepiandrosterone (DHEA)
- often present in dietary supplements
- non androgenic in men (do not elevate testosterone)- but do increase estrogen levels
- low affinity AR binding- act as partial agonists to block effects of testosterone in vivo
rHCG – to stimulate endogenous testosterone production
Aromatase inhibitors - to boost testosterone by preventing in vivo conversion to estradiol
Synthetic Selective Androgen Receptor Modulators (designer drugs)
- nonsteroidal molecules that selectively activate AR in muscle & bone

12. Adverse Effects:
Cardiovascular - Coronary heart disease, cardiomyopathy, erythrocytosis, coagulation abnormalities, dyslipidemia & hypertension
Tendon rupture
Neuropsychiatric - mood disorders, increased aggression/violence
Liver (17a derivatives)- cholestasis, hepatitis, hepatic neoplasms
Men - hypogonadism, reduced testicular volume, suppression of spermatogenesis (can be prolonged in the case of chronic use)
- gynecomastia (tamoxifen & aromatase inhibitors taken to prevent)
- increased risk of benign prostatic hypertrophy and prostate cancer
Women - acne, hirsutism, male pattern baldness, clitoromegealy
- deepening of the voice (irreversible)
- Irregular menstrual cycle

13. The role of androgens in prostate cancer development
GnRH
Pharmacological Interventions:
Androgen deprivation
Androgen synthesis inhibitors
Androgen receptor antagonists
Pulsatile
FSH + LH
Testes
Testosterone AR
5a-Reductase
Dihydrotestosterone

14. Androgen deprivation therapy for the treatment of advanced prostate cancer
Rationale: Androgens stimulate prostate cancer growth
Goal: Reduction of serum testosterone to castration levels
- palliative not curative (sometime combined with chemotherapy)
- results in tumor responses in 80-90% of patients
Approach: Suppression of the Hypothalamic/Pituitary-gonadal axis to inhibit pituitary production of gonadotropins and reduce testicular production of testosterone
- Historically ADT was achieved using estrogen therapy to suppress FSH & LH
GnRH agonists- Leuprolide, Goserlin, Buserelin, Triptorelin & Naferelin
- sustained GnRH signaling inhibits pituitary release of FSH & LH to
decrease endogenous testosterone production
- initial flare of GnRH can also cause a cancer flare
GnRH antagonist- Degarelix
- GnRH antagonist prevent GnRH signal from stimulating FSH & LH

15. Adverse Effects of Androgen Deprivation Therapy:
Sexual dysfunction
Osteoporosis & bone fractures
Vasomotor responses (hot flashes)
Loss of lean body mass & increased fat mass
Fatigue
Anemia (>90%)
Gynecomastia
Decreased penis and testicular size
Emotional & cognitive changes
Cardiovascular & metabolic abnormalities

16. Androgen synthesis inhibitor for treatment of Prostate cancer: Abiraterone
MOA: Abiraterone inhibits the synthesis of testosterone
- an irreversible inhibitor of CYP17A1 (aka 17a hydoxylase and 17,20 lyase)
- Sequential enzymes involved in androgen biosynthesis
- Inhibition of androgen production reduces androgen-dependent tumor growth
Clinical Use: Used in combination with either GnRH Agonist/Antagonist to prevent
compensatory upregulation of the HPG axis
Adverse Effects: Adrenocorticol insufficiency (ameliorated by co-administered prednisone)
Mineralocorticoid excess (fluid retention and hypokalemia)
Hepatotoxicity (potentially severe)
Cholesterol
Pregnenolone
Progesterone
Androstenedione
Dehydroepi
androsterone
(DEHA)
Androstenediol
Testosterone
17b HSD
3b HSD
Side chain
cleavage enzyme
17a-OH pregnenolone
17a-OH progesterone
CYP17A1

17. Adverse Effects: Abiraterone
Adrenocorticol insufficiency & mineralocorticoid excess
Cholesterol
Pregnenolone
Progesterone
Androstenedione
Dehydroepi
androsterone
(DEHA)
Androstenediol
Testosterone
17b HSD
3b HSD
Side chain
cleavage enzyme
17a-OH pregnenolone
17a-OH progesterone
CYP17A1
ALDOSTERONE
(MINERALOCORTICOID)
CORTISOL
Prevented by
co-administered
PREDNISONE
Cortisol deficiency

18. Androgen Receptor Antagonists for the treatment of Prostate Cancer
First Generation: Flutamide, Bicalutamide, Nilutamide
Second Generation: Enzalutamide (8x >potent)
Description: Non steroidal selective antagonists of the androgen receptor
MOA: Blocks the action of testosterone and dihydrotestosterone at the AR
Indications: Treatment of advanced prostate cancer
- not used as monotherapy because inhibiting testosterone results in
an increase in LH leading to enhanced endogenous testosterone
synthesis
- used in combination with either GnRH agonist or GnRH antagonist
attenuates the effect of initial GnRH agonist induced flare
Flutamide also used for treatment of hyperandrogenism in women
e.g. PCOS- acne, hirsutism, androgenic alopecia

19. Adverse Effects of Androgen Receptor Antagonists:
Men - typical effects of androgen deprivation
e.g. sexual dysfunction, gynecomastia, vasomotor responses etc
Women - generally well tolerated
Rare side affects associated with either sex
First Gen associated with serious hepatotoxicity (including deaths)
Enzalutamide associated with increased seizures (~1%)
- crosses the BBB and inhibits the GABAA receptor

20. Additional Pharmacotherapy Indications

21. The role of dihydrotestosterone in the development of male pattern baldness
(10X > Potent)
5a-Reductase
DHT

22. Inhibitors of 5a-Reductase Finasteride & Dutasteride
Description: Finasteride & Dutasteride are inhibitors of 5a reductase, the enzyme involved
in the conversion of testosterone to the more potent dihydrotestosterone
MOA: Finasteride & Dutasteride reduce serum levels of dihydrotestoseterone
Indications: Male pattern hair loss, Benign Prostatic Hyperplasia (BPH) & Female Hirsutism
Adverse Effects: Male sexual dysfunction, gynecomastia & depression
Contraindications: Pregnancy (due to birth defects)
Testosterone
Dihydrotestosterone
(10x > potent)
5a-reductase
Finasteride

23. Spironolactone
Description: Antagonist/very weak partial agonist of the androgen receptor
Also a Mineralocorticoid Receptor antagonist
- used as a diuretic to treat heart failure, nephrotic syndrome,
ascites, essential HTN, hypokelemia etc
MOA: Antagonist/very weak partial agonist of the androgen receptor
- antagonizes androgenic responses in the presence of high levels of androgen
Indications (as AR antagonist) : Treatment of women with acne, hirsutism or androgenic alopecia (Hyperandrogenism)
Adverse Effects: menstrual irregularities, breast tenderness, orthostatic hypotension
Contraindications: Males with prostate cancer- due to its partial agonist activity

24. Hormonal Therapy for treatment of Transgender Individuals

25. GENDER CONFIRMING SURGERY
Transgender Female: Male-to-Female
Transgender Male: Female-to-Male
GOAL
INITIAL
THERAPY
MAINTENANCE
Suppress male secondary sex characteristics
Induce female physical changes:
Elimination of facial hair growth
Induction of breast development
Promote female fat/muscle distribution
Maintain hormone levels in normal female range
Suppress female secondary sex characteristics
Induce male physical changes:
Stop Menses
Promote virilization
Promote male pattern sexual hair
Promote male physical body contours
Maintain hormone levels in normal male range
Antiandrogen- GnRH agonist (e.g. leuprolide)
- spironolactone
suppress Testosterone production & allows
reduced estrogen dosing to avoid side effects
Estrogen therapy- transdermal estradiol
- oral estradiol ester
Androgen therapy- Testosterone ethanate
Suppresses estrogen production
Promotes male characteristics
Due to fewer side effects high dose
testosterone can be used
Discontinue Antiandrogen therapy
Maintain Estrogen to protect against
Sex hormone deficiency conditions
e.g. osteoporosis
Maintain testosterone to protect against
GENDER CONFIRMING SURGERY

26. Summary Material

27. Testosterone INDICATIONS MOA Adverse Effects Misc. Androgen Receptor
Male hypogonadism
Direct agonism
of the AR
To restore testosterone
to the normal level
Contraindications:
Prostate cancer
High level of PSA
Untreated sleep apnea
Androgen Receptor
Antagonists
Flutamide
Bicalutamide
Nlutamide
Enzalutamide
Treatment of advanced
Used in combination
with androgen
deprivation therapy
(e.g. GnRH agonist/antagonist)
Flutamide also used
For treatment of
hyperandrogenism in women
Directly inhibits
action of testosterone
and
Dihydrotestosterone
at the AR
Men- typical effects
Of androgen deprivation
e.g. sexual dysfunction,
gynecomastia ,
vasomotor responses
Rare side effects:
1st Gen- Hepatotoxicity
2nd Gen-increased seizure risk
Abiraterone
Hormone-resistant
prostate cancer
Not responding to
androgen deprivation therapy
Inhibition of CYP17A1
Inhibits synthesis
of testosterone
(also effects corisol,
but not aldosterone)
Spironolactone
Treatment of women
with acne, hirsutism,
or androgenic alopecia
Antagonist/
weak partial agonist of AR
Also mineralocorticoid
receptor antagonist- used
as diuretic to treat HF
Menstrual irregularities
Breast tenderness
Orthostatic HTN
Contraindication:
Should not be used
in men with
Acne
Increased risk prostate cancer
Increased risk BPH
Worsening of sleep apnea
Erythrocytosis
Increased risk VTE
Increased risk CVD
Hepatic dysfunction
Suppression of spermatogenesis
Adrenocorticol insufficiency
Mineralocorticoid excess
5a-reductase
Inhibitors
Finasteride
Dutasteride
BPH
Male pattern baldness
Female hirsutism
Inhibits peripheral conversion
of testosterone to
dihydrotestosterone
Male sexual dysfunction
Pregnancy