Reproductive Hormonal Pharmacology

Douglas Danforth, Ph.D.The Ohio State University

Objectives

1. Describe the feedback mechanisms related to stimulation and inhibition of the hypothalamic, pituitary, and gonadal hormones involved in male and female reproduction

2. Describe the effects, medical uses, and consequences of abuse and androgens3. Describe the effects and consequences of testosterone insufficiency or suppression4. Describe the medical uses of antiandrogens and their mechanism of action

Explain the endocrinology of the male reproductive system and the physiological processes of testosterone production and spermatogenesis

1. Describe the difference types of estrogens and progestins, their effects, and their medical uses2. Describe the medical uses of SERM’s and antiprogestins, as well as possible problems associated with

their use3. Describe the mechanism of action of aromatase inhibitors and their use in cancer patients

Describe the interplay of feedback mechanisms that affect the menstrual cycle.

leuprolide (GnRH Agonist)

NH2pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly

NHEtpGlu His Trp Ser Tyr Leu Arg ProD-Leu

NH2

NAcD2Nal D4CIPhe

D3Pal Ser Tyr

DhArg(Et2) hArg (Et2)

Pro D-AlaLeu

Antagon (GnRH Antagonist)

1 2 3 4 5 6 7 8 9 10AminoAcidNumber

GnRH

GnRH

Agonist

U

U

Short Term

LH

FSH

Effects of GnRH AgonistU

U

UU

U

U

U

U

U

U

U

U

UU

U

U

U

U

UU U

U

U

U

UU

U

U

U

UU

Long TermU

U

UUU

U

U

U

UU U

U

Days

T, E

2 , P

4

LH, F

SH

0

10

20

30

0

10

20

30

Hours

E 2 , P

4

LH, F

SH

Start Administration

GnRH Agonist

GnRH Antagonist

X

Short Term

X

X

X

XX

X

X

X

U

UU

U

U

U

U

U

U

U

U

X

X

XX

X

X

X

X

Long Term

X

X

X

X

XX

X

X

X

U

U

U

U

U

U

U

U

U

U

X

X

X

X

XX

XX

GnRH

Antagonist

U

LH

FSH

Effects of GnRH Antagonist

Days

T, E

2 , P

4

LH, F

SH

0

10

20

30

0

10

20

30

Hours

T, E

2 , P

4

LH, F

SH

Start Administration

GnRH Agonist

GnRH Antagonist

Stimulation – Pulsatile GnRH or GnRH agonist• Delayed puberty• Ovulation induction in hypogonadotropic hypogonadism

Suppression – Continuous GnRH agonist – side effect of bone loss due to hypoestrogenism caused by ↓ FSH/LH.

• Prostate/Breast Cancer • Endometriosis• Precocious puberty

GnRH analogs – clinical uses

GnRH Agonist

GnRH Antagonist

Suppression – Daily GnRH Antagonist• Assisted Reproduction Technologies – IVF – prevent LH surge• Prostate Cancer – suppress testicular androgen production

Gonadotropins– clinical uses

• Stimulation of spermatogenesis• rFSH vs hMG vs hCG

• Assisted Reproduction Technologies• FSH for gonadal stimulation• hCG vs LH for ovulation induction

Progestin(Progesterone)

Estrogen(Estradiol)

Testosterone Dihydrotestosterone

5-α reductase

Type 1

Type 2

• Skin, liver• 1/3 circulating DHT

• Reproductive tissues (prostate, penis, scrotum), skin

• 2/3 circulating DHT

Androgen effects

Male Hypogonadism – Low T• Low libido• Decreased erection• Alopecia• Bone loss• Gynecomastia• Decreased testicular size

Side effects• Infertility – feedback suppression of LH/FSH• Gynecomastia – T is precursor for E

• Androgens – abusesPerformance enhancement

• Androstenedione• Precursor for T• Dietary supplement

• Dihydrotestosterone• Much more potent than T

Side effects• Infertility• liver damage• hypertension• heart disease• prostatic hypertrophy• testicular atrophy

Antiandrogens5 α-reductase inhibitors• Finasteride/Dutasteride

• BPH, alopecia

Androgen antagonists• Flutamide/bicalutamide/nilutamide

• Prostate Cancer

• Spironolactone• Androgen and aldosterone antagonist• Also inhibits 17 α hydroxylase • ↓ T and androstenedione, ↑ Na

• Hirsutism and hypertension

Estrogen

• Oral contraceptives – usually include progestin to block proliferation• Hormone Replacement Therapy – need progestin if intact uterus

• Hot flashes• Vaginal dryness• Osteoporosis

• Infertility Treatment – followed by progestin to prepare uterus for implantation in frozen embryo transfer cycles

Estrogen – clinical uses

Estrogen – abuses?

Clinical Profile of Ideal Selective Estrogen Receptor Modulator (SERM)

Site of action Effect Clinical outcome

Bone ER agonist Prevent osteoporosisReduce fracture risk

CNS ER agonist Reduce hot flushes and other menopausal symptoms

Cardiovascular/lipids ER agonist Lower cardiovascular risk

Breast ER neutral or antagonist

Prevent or no increase in breast cancer (and limit proliferation)

Uterus ER neutral or antagonist

Prevent or no increase in endometrial cancer (and limit proliferation)

Menopause. 16(3): 609–615, 2009

Raloxifene (Evista)

Tamoxifen (Nolvadex)

Clomiphene (Clomid)

Tissue Selective Estrogen Complex

(TESC)

Bone +Breast -Uterus -

Breast -Uterus +

CNS - Bazedoxifene• Breast – • Uterus – Estrogen• Bone +

Selective Estrogen Receptor Modulator (SERMS)

bazedoxifene

+

Aromatase Inhibitors

Competitive (reversible) inhibitors• Anastrazole• Letrozole

Irreversible (covalent) inhibitors• Exemestane• Formestane

Progesterone Effects• Gonadotropin Secretion• Cervical mucus production• Uterus• Mammary Gland• Basal Body Temperature

Progesterone

Progesterone antagonist• Mifepristone (RU486)

• Blocks P receptor in endometrium• Causes endometrium to slough• Combined with prostaglandin for

pregnancy termination

Progesterone Clinical Uses• Gonadotropin Secretion• Combined with E for OC• P only mini-pill – thicken cervical mucus• Long acting Injectable P – inhibit ovulation

• Uterus• HRT to stop endometrial proliferation

GnRH

Testosterone

GnRH agonist – short term flare, long term suppressionGnRH antagonist – immediate suppression

LH/hCG – induce ovulationFSH – follicle simulation for IVF/ARTFSH/hMG – stimulate spermatogenesis

Estrogen

Aromatase inhibitors

Gene transcription

SERMs

Progesterone

Gene transcription

Testosterone

Dihydro-testosterone

Gene transcription

Mifepristone

5 α reductaseinhibitors

Androgen ReceptorAntagonists

Pituitary

Quiz 1

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