Pharmacology of
Reproductive Hormones

clinical uses

Progestogens

Contraception/infertility

Hormone replacement therapy (in elderly)

specific cancer treatments (breast, prostate)

Hypothalamus-Pituitary-Gonadal axis

Hypothalamus secretes GnRH

GnRH acts on the Anterior pituitary

Anterior pituitary releases FSH and LH

Gonadotropin Releasing Hormone (GnRH)

decapeptide

released from hypothalamic neurons

receptors (GqPCR)

action

pulsatile release

continuous (non-physiological) release

low frequency: favours FSH release

High frequency: favours LH release

desensetisation to GnRH

down-regulation of GnRH Receptors => inhibition of FSH & LH release

GnRH agonists

e.g. gonadorelin, leuprorelin

uses:

pulsatile dosing

male infertility

rarely female infertility

continuous dosing

ovulation induction

prostate cancer

endometriosis

precocious puberty

GnRH antagonists

e.g. ganirelix, dagarelix

uses:

ovulation induction (+ gondaotropins, for ART)

prostate cancer

Gonadotropins

heterodimeric glycoproteins

released from

common alpha subunit,
different beta subunits

FSH, LH, hCG

anterior pituitary

FSH & LH

placenta

hCG

receptors (GsPCRs)

FSH actions

in females

Stimlate oestrogen production in follicele (friom androgen precursors, 1st haf of cycle)

stimulates follicle development

LH actions

in females

in males

important in the first stage of the cycle

important in mid and late stage of the cycle

hCG

almost identical to LH (acts on LH receptors)

actions

maintain corpus luteum (CL) function in the 1st trimester of pregnancy

Drugs

urofollitropin (uFSH)

uses

male infertility

female ovulation induction

diagnosis

hCG is detected by pregnancy kits

LH detected in ovulation kits

Oestrogens

natural

17-B oestradiol

very short half life

synthetic

produced by

receptors

ovaries (follicle, CL)

placenta

ligand activated transcriptional factors

GPER1 - oestrogen responsive GPCR

actions

female development

feedback action

cyclical effects
on uterus

endrometial proliferative phase

fertilisation-favouring cervical secretion

low oestrogen => decreased LH&FSH release

non-reproductive tissues

metabolic

anabolic

retention of salt and water

cardiovascular

maintain normal vascular function

facilitate blood coagulation

increase [HDL], and dicrease [LDL] and [cholesterol]

reduce bone resorption

uses

contraception (+progestogen)

hormone replacement therapy

oestrogen antagonists

clomiphene

molecular mechanisms of nuclear
Estrogen receptors (ERs)

natural

progesterone

synthetic

levonorgestrel

produced by

CL

Placenta

receptor

ligand-activated transcription factors

action

feedback

dicrease the frequency of GnRH pulses

decrease FSH and LH release

cyclical effects on uterus

endometrial secretory phase

implantation-favouring cervical secretion

decrease volume

increase viscosity

in preganncy

development of uterus and breast

suppression of contractility in uterus

uses

contraception

hormone replacement therapy

Progesterone antagonists

Mifepristone

Contraception

most common conttaception

oestrogen + progestogen

pills taken for 21 days, followed by 7 drug-free days

mechanism of action

oestrogen

reduced FSH release

follicle fails to develop and mature

no endogenous oestrogen surge

Progestogen

Inhibition of LH surge => no ovulation

cervical mucus unfavourable for fertilisation

Oestrogen + Progestogen

abnormal endometrial development

conitions unfavourable for implantation

adverse effects

small increase of risk of cervical cancer

increased risk of venous thromboembolic disease

increase risk of stroke and myocardial infraction (only for woman

Progestogen

administration

oral

injectables

patches

implants

continuous administration => irregular bleeding

mechanism of action

cervical mucus unfavourable for fertilisation

endometrium unsuitable for implantation

in some preparations: inhibition of LH surge => no ovulation

adverse effects

irregular bleeding

reversible bone resorption

Hormone Replacement Therapy

post menopausal syndrome

vasomotor symptoms

urogenital atrophy

increased bone resorption (osteoporosis)

increased atheroma formation

adverse effects

treatments

oestrogen + progestogen

oestrogen alone (hysterectomized women)

Raloxifen

Tibolone

older studies

increase risk of cardiovascular disease

increased risk of cancer (breast)

recent studies

dicreased risk of cardiovascular disease

small increase of ovarian cancer

Female

Male

FSH stimulates development of the early follicle, directs estrogen synthesis and release from the dominant follicle

LH, in the first half of the cycle, acts by increasing expression of precursors for estrogen. In later stages, it directs the final proliferation of follicular cells, release of ovum and conversion of the ruptured follicle to Corpus Lateum. The early follicle releases mainly Estrogen, while the CL releases mainly Progesterone. Progesterone has negative feedback action on Anterior pituitary and Hypothalamus. Estrogen initially (at lowish concentrations) has a similar negative action, but when it reaches high circulating concentrations that are sustained for 36 hours or more, the feedback switches to positive, and this results in the midcycle LH (and FSH) surge

FSH stimulated gametogenesis

LH stimulates release of testosterone

increase LH receptor expression in follicle

in males

stimulate Sertoli cells to nourish sperm

stimulate androgen synthesis in follicle (estrogen precursors)

stimulate dominant follicle development and rupture (ovulation)

ruptured follicle => CL - directs steroid production

stimulates testosterone production

produced by placenta

follitropin (rFSH)

lutropin (rLH)

choriogonadotropin (rhCG)

oestrone

oestriol

mestranol

ethinyl-oestradiol

high oestrogen => increased LH&FSH release

increased expression of Progestrone

increase volume, decrease viscosity

acts on AP and Hypothalamic receptors

induces ovulation in infertility

ER-agonisit-DNA complex recruits coactivators

ER-antagonist-DNA complex recruits corepressors

SERM

acts as agonist in some tissues and antagonist in others

Raloxifene

Tamoxifen

used to prevent osteoporosis

antagonist in breast and uterus

partial agonist in bones and liver

used to treat breast cancer

partial agonist in bones, liver and uterus

acts at Progesterone Receptors in uterus

uses

early pregnancy termination

prodrug metabolised to low potency estrogen