Androgens

recall the facts about androgens

• the term “androgen” denote a number of related hormones and not a single molecule

• the synthesis of androgens and related steroid hormones are made from cholesterol

• androgen have actions on multiple areas of the body including bone, muscle, skin, liver, kidney, brain, immune system, bone marrow, and genital organs

• testosterone is the primary and most well known androgen

• testosterone (while active) is converted to a more active form of DHT

• testosterone is made in testes (men) and in ovaries (women) and in adrenals (both)

describe the steps of androgen synthesis

start = 17-hydroxypregnenolone

dehydroepiandrosterone (enzyme = 3-beta HSD) → androstendione (enzyme = 17-beta HSD) → testosterone

roles of androgens in women

• regulate menstruation

• aid in conception and pregnancy

• minimize bone loss

• stimulate pubic and underarm hair growth

roles of androgens in men

• deep voice (vocal cord lengthening)

• hair growth on the face, scalp, chest, underarms and genitals

• sperm development

roles of androgens in both genders

• bone density

• muscle development

• puberty

• RBC production

• sexual desire and function

list the steps and hormones in androgen synthesis for men

1. LH stimulates testicular Leydig cells to increase synthesis of testosterone

2. testosterone diffuses into Sertoli cells

3. in the Sertoli cell, FSH stimulation increases production of androgen binding protein (ABP) → maintains high testicular concentrations of testosterone necessary for spermatogenesis

androgenic effects of testosterone

pertains to development of male characteristics

• differentiation and growth of male reproductive organs (prostate and seminal vesicles)

• control of male sexual behavior and development/maintenance of male secondary characteristics (involving muscle, bone, larynx and hair)

anabolic effects of testosterone

constructing larger molecules from smaller ones

• nitrogen retention by increasing the rate of protein synthesis and muscle mass while decreasing the rate of protein catabolism

• improve bone mineral density

MOA of testosterone

testosterone + 5-alpha reductase/NADPH → dihydrotestosterone (DHT)

regional effects of testosterone

AR action in muscle, bone, brain, and bone marrow (anabolic effects are prevalent)

regional effects of DHT

AR action in genitalia, prostate, skin, and hair follicles due to higher expression of 5-alpha reductase enzyme in these tissues

process/hormones involved in hypothalamic pituitary testicular axis

hypothalamus (LHRH or GnRH secreted) → pituitary (LH goes to Leydig/FSH goes to Sertoli) → testosterone + 5-alpha reductase = DHT

testosterone and estradiol concentrations for positive feedback control

low

testosterone and estradiol concentrations for negative feedback control

high

what is released for feedback control of testosterone and estradiol production

GnRH, LH, and FSH

what is male hypogonadism

inability of the testes to produce sufficient testosterone to maintain sexual function, muscle strength BMD, and fertility

list conditions associated with primary hypogonadism

• Klinefelter syndrome (2 or more X chromosomes with a Y)

• hemochromatosis (too much iron in blood)

• injury or trauma to testicles (depends on extent of injury)

• undescended testicles (generally self-correcting or may require surgery)

list conditions associated with secondary hypogonadism

• Kallmanns syndrome

• Pituitary disorders

• radiation or chemotherapy

what labs to look at to evaluate for hypogonadism

LH, FSH, serum testosterone

what labs to look at to differentiate between primary and secondary hypogonadism

GnRH and/or LH

relative activity of oral androgen formulations

none; very poor bioavailability

rank bioavailability of transdermal formulations of androgens

DHT > testosterone > androstenedione > DHEA

what structures should be in an androgen for optimal potency

• 3-keto

• no 4,5 double bond

• 17-beta alcohol

• *17-alpha alkyl

what happens if a 17-alpha alkyl is added to an androgen (activity)

increases oral activity to 0.5 but decreases overall potency to half of testosterone

list the types of androgen antagonists

• androgen receptor inhibitors (out compete endogenous testosterone)

• 5-alpha reductase inhibitors (reduce formation of DHT)

• inhibitors of testosterone

list indications for androgen antagonists

• hormonal treatment for prostate cancer (suppression therapy - non curative)

• benign prostatic hyperplasia

• hair loss in males

• excessive hair growth in females

when is hormone therapy used for prostate cancer

the cancer has spread too far to be cured by surgery or radiation; reoccurrence of cancer; before (to shrink) or along with (for high risk of reoccurrence) radiation

how does hormone therapy work for prostate cancer

decrease androgen levels or block the action

• usually combined with a luteinizing hormone-releasing hormone (LHRH) agonist like leuprolide or goserelin for medical castration

risks of prolonged treatment of hormone therapy for prostate cancer

can lead to mutation in AR decreasing therapeutic potency

SAR for androgen antagonist structures

• Ortho EWG groups on terminal benzene ring (cyano, trifluoro, chloro, nitro)

• amide or thioamine linkage between EWG benzene and rest of molecule

• hydroxyl or carbonyl group to function as H-bond acceptor

• lipophilic group (benzene ring with a polar group)

what is the role of 5-alpha reductase inhibitors

antagonizes the effect of androgens by inhibiting the conversion of testosterone to its more potent metabolite (DHT)

• both can improve BPH, frequent or difficult urination, male pattern hair loss

what are the 5-alpha reductase inhibitors

finasteride and dutasteride