Gonadal hormones Flashcards
Average age of menarche
12.43 years
Average age of menopause
45 years
How long do mentrual cycles last overall?
32 years
GnRH name
gonadotropin releasing hormone
GNRH number of amino acids?
decapeptide
Receptor of GNRH, what is stimulated, cascade
GPCR - Gq/11-PLC/DAG+IP3
Function of GnRH
Stimulates release of
LH- lutenizing hormone
FSH - follicle stimulating hormone
both from anterior pituitary
Inhibin
Inhibin A alpha+ betaa or Inhibin B alpha+ beta-b
produced by granulosa cells
function: inhibit FSH release - inhibit double ovulation
How is GnRH released?
In a pulsatile manner, if want ovulation: higher pulsatile frequency
Theca cells function pathway
Has LH receptors
LH binds
cAMP
PKA
Converts cholesterol –> androstenedione
Subsequent granulosa cell pathway
Has FSH receptors
FSH stimulates FSHr –> cAMP –> PKA
activates aromatase
Aromatase converts androstenedione –> estrone
17HSD 1 converts to estradiol
17HSD 2 converts estradiol back into estrone
AMH
anti-muellerian hormone
GNRH signalling
Binds to GNRH receptor– GPCR
PLC pathway
PIP2 –> DAG + IP3
DAG –> PKC direct LH FSH gene expression + secretion
PKC –> Raf –> MEK –> ERK –> PLA2–> LH FSH gene expression and secretion
IP3 –> ER –> Increased Ca++–> will activate PKC and downstream effects
Where are GnRH receptors?
in pituitary bc GnRH released from hypothalamus
LH FSH hCG what is similar
amino acids
other similar
alpha subunit
92 aa
TSH
LH FSH hCG what is different amino acid #
beta subunit unique
FSH - 111aa
LH - 120aa
hCG- 144aa
half lives hours
LH
FSH
hCG
FSH 3-4
LH 20
hCG 24
where is hCG from
placenta
function and receptors of FSH
stimulate growth and recruitment of immature follicles
receptors GPCRs Gs (Gq, Gi)
promiscuous receptors prinicple
if low concentration, will bind to main receptor
if high, will bind to various G proteins
LH functions
Triggers ovulation
maintains corpus luteus
LH receptors and what they bind
Receptor - GPCR Gs (Gq)
binds LH and hCG
Ana301 says that you can stimulate ovulation with hCG as well
Pharma types of gonadotropins
Long-acting GnRH agonists
GnRH agonists
GnRH antagonist
Synthetic progestins
Long-acting GnRH agonist
Lutrepulse, Zoladex
against amenorrhea – inducing ovulation
GnRH agonist
Lupron
inhibit estrogen production - shrink fibroids
GnRH antagonists
For fertility treatment
Ganirelix Cetrolerix
Prevent premature ovulation
Synthetic progestins
For fertility treatment
DHEA Fertinorm
hCG - pregnyl
increase testosterone production–> aromatase –> estrone…
Classical ER signalling
receptor in cell
bind estrogen
hetero homodimerization
in nucleus
estrogen response element
altered transcription
Estrogen effects
Growth
Reproduction
Bone
Cardio-vascular (heart and vessels)
Gonadotropin regulation
is classical ER pathway only?
no
estrogen activates GPCR and other kinase pathways
ER alpha vs beta
ER alpha: breast, ovary, endometrium, bone
ER beta: bone, endothelium, brain, heart
Progesterone functions
Uterine development
Gonadotropin negative feedback
Suppresses ovulation
Thermogenesis
Where are progesterone receptors expressed?
Not cv system, that’s estrogens job
Brain, uterus, ovary, mammaries
Pharma uses of estrogens and progestins
Female maturation, primary hypogonadism
Fertility control: Oral contraceptives
Menopause: Hormone replacement
Menstrual disorders: amenorrhea- no menses; dysmenorrhea - irregular menses; dysfunctional menstrual bleeding
Endometriosis
Goal of oral contraceptives
Prevent ovulation
inhibit LH surge
inhibit development of endometrium
Contraceptive =
Estrogen + progestins
Mechanism of estrogen in contracep
Sensitize hypothalamus and pituitary to progestin
Maintains sex characteristics
Mechanism of progestin in contracep
Negative feedback FSH LH
Inhibit ovulation
Prevent implantation
Thickening of cervical mucus prevent motility of sperm
Course of oral contraceptives
Estrogen + Presestin 21 days on + 7 days off
menses are 3 days after being off
Three formulations of oral contraceptives
Monophasic - all 21 pills - same amt of estrogen+ progesterone
Biphasic - 2 different amounts of estrogen(ethinyl estradiol) and progestin - norethindrone
Triphasic- 3 different amt estrogen and progestin - d-norgestrel
the estrogen used in formulation
ethinyl estradiol
progestins in biphasic and triphasic
biphasic - norethindrone
triphasic - d-norgestrel
Advantage of multi-formulation
Resemble physiology
optimal suppression of gonadotropins
best endometrial support
limited steroid exposure
Benefits of birth control
> 98 effective birth control
against:
menstrual disorders
iron deficiency, anemia
benign breast disease
ovarian cysts or cancer
chance of endometrial carcinoma
osteoporosis
colon cancer
Adverse effects of birth control
Lower:
glucose tolerance
lipid metabolism
Higher:
Stroke risk
DVT - thrombosis on flight
Nausea edema
Headache, migrane
Hypertension
Liver disease risk
Therapeutic amenorrhea
365 day contraception menstrual supression
Lybrel, Seasonale
Mode of administration
Lybrel Seasonale
Oral combined, sometimes only progestin / daily
Combined transdermal/weekly
Vaginal rings - monthly
SQ depot medroxy progesterone acetate / 12 weeks
Side effects Lybrel/seasonale
Spontaneous breakthrough bleeding in early use
Another side effect in lybrel or seasonale
Thromboembolic disease
3 fold increased risk
due to estrogen concentration
Should not take after 35 years age
smoking increases risk
Emergency contraception and chemical abortion
Plan B - Levonorgestrel
Ulipristal - Ella
RU - 486 Mifepristone
Levonorgestrel
Plan B
OTC in Canada
Within 72 hr
80% effective
Inhibits ovulation, fertilization
Ulipristal
Ella
Progesterone antagonist/partial agonist
Delays ovulation
Antagonist at endometrium
emergencies within 5 days
RU 486
Mifepristone
Within month-2
Terminate pregnancy
Progesterone antagonist Mioprostol (prostaglandin) administered 48 hr later
What happens in menopause and what are risks?
Estrogen levels decrease
High FSH LH circulation
some peripheral conversion of adrenal androgens
Medical risks:
Bone loss
CVD
Alzheimer’s
When and for what was HRT used for women
Used for over 20 years to prevent heart disease and osteoporosis in post-menopausal women
why was HRT for menopausal women discontinued?
Study with Premarin with and without Provera (progestin)
Heart disease
Breast cancer
Clots strokes
but:
lower colon cancer
lower hip fractures
Safer HRT administration
Use <5 years after menopause
Lower premarin dose safer
What happens when safer administration
Decreased menopausal symptoms 90%
Decreased mortality
No increase in heart disease
No increase in breast cancer
Typical menopause symptoms
Hot flashes
Vaginal atrophy
Bladder overactive
HRT Contraindications absolute
Thromboembolytic disease
CVD
Estrogen-dependent cancer
Liver disorder
Uterine bleeding
Pregnancy
Migrane
HRT contraindications relative
Hypertension
Gestational diabetes
Elective surgery
3 estrogen drugs
As hrt
17 beta estradiol
Premarin
17-alpha alkyl estrogen
17 beta estradiol
Administration
patch tablets creams
Premarin
from mare urine
Tablets creams
17 alpha-alkyl estrogen
Tablets oral contraceptives
3 Progestins
Medroxyprogesterone acetate - Provera also used in seasonale
17-alpha-alkyl-19 nor testosterones
Drospirenone
Medroxyprogesterone acetate - Provera
administration
when to use
3 oxo delta 4 progesterone derivative
Injectable depot
Endometriosis
HRT
17 alpha alkyl testosterones
Norethindrone
Norgestrel
Desogestrel
oral contraceptives
Drospirenone
Yazmin - Yaz - oral contraceptives
Anti-mineralocorticoid activity
thromboembolism risk increase
Which drugs decrease efficacy of steroids
Anticonvulsants
Antibiotics
Sedatives
Steroids affect efficacy of which drugs?
Antidiabetic drugs - decreased glucose tolerance
Caffeine/theophylline/corticosteroids/ beta blockers
Antiestrogens
Stilbenes
Tamoxifen
Stilbenes
Trans conformation
Estrogen antagonist ERalpha
Tamoxifen
mixed agonist antagonist
Antagonist in breast cancer
Retains uterine, bone and serum lipids
Tamoxifen and metabolism
endoxifen 100x more potent
produced via CYP3A4 and CYP2D6
and in other order
Contraindications for tamoxifen
CYP2D6 poor metabolizer 7-10%
SSRIs inhibit CYP2D6 (Paroxetine/Paxil - hot flashes, depression)
What is tamoxifen replaced with
Aromatase inhibitors
Aromatase conversion
Testosterone –> Estradiol
Andostenedione –> Estrone
Estrone converts to Estradiol without Aromatase
Non steroidal aromatase inhibitors
Anastrazole (Arimidex)
Letrozole (Femera)
Competitive
Steroidal aromatase inhibitors
Examestane (Aromasin)
Non-competitive
How aromatase inhibit used
How long used
As adjuvant therapy
5 years max
Side effects of aromatase inhibitors
Hot flashes
bone
lipids
arthralgia - joint swelling
Bioactive metabolites of testosterone +enzyme
Aromatase –> Estradiol - bone protection in males
5alpha reductase –> Dehydroxytestosterone
DHT for?
External genitalia differentiation
hair growth at puberty
libido
what is testosterone for
Wolffian duct development
libido
Erythropoiesis
Skeletal muscle mass/strength
BPH
Benign prostatic hyperplasia
Symptoms of BPH
Urinary frequency and urgency
Weak intermittent urine stream
Incomplete voiding of bladder
BPH prevalence
20-50% of males 40-60 years old
Causes of BPH
uncertain
DHT in prostate
Pharma treatment of BPH
Aza-steroids
5alpha reductase inhibitors
Finasteride
Dutateride
action and onset of BPH
Of 5 alpha reductase inhibitor
Slow onset 3-6 months
inhibit growth shrink gland
