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