The gonadal hormones:

agonist and inhibitors

dr. Flori R. Sari, Ph.D
Departemen Farmakologi FKIK UINSH
Unit Pelayanan Laboratorium Kedokteran dan Kerjasama Riset
PPKM FKIK UINSH

Scope
Estrogen
Estrogen inhibitor
Progestin
Progestin inhibitor
Other ovarian hormones
Oral contraceptives
Ovulation inducing agents
Estrogen
The major natural estrogens produced by women
Estradiol ovary

Estrone
Estriol
Synthetic estrogens (estrogen-mimetic
compounds) chemical substances that share the
same activities as estrogen
Flavonoids, palmetto, soybeans, some phenols
(bisphenols, alkyl phenols), modified estrogens.
ovary, liver (synthesized from estradiol by dehidrogenase type II
enzyme), peripheral tissues (androstenedione / androgens)
In menopause women, main source of estrogen is adipose tissues
Steroidal
Non-steroidal
Pharmacokinetics
In the circulation estrogen binds strongly to
2-globulin (sex hormone binding globulin) and
weakly to albumin.
Bound estrogen is unavailable for diffusions into
cells free fraction that is physiologically active
hydrolized in the intestine to active,
reabsorbable compounds return to
enterohepatic circulation (results in hepatic
effects such as increased synthesis of clotting
factors and plasma renin substrate).
Hepatic effects can be reduced by routes that
avoid first-pass liver exposure non oral
(vaginal, transdermal patch, injection)
and
ERE
Pharmacodynamics
Female maturation
Normal sexual maturation (vagina, uterus and
uterine tubes)
Growth (accelerated growth phase)
Secondary sex characteristics (development and
ductal growth of breast)
Endometrial effects
Development of endometrial lining,
menstrual cycle regulation together with
progesterone.
Pharmacodynamics
Metabolic and cardiovascular effect
Decrease the rate of calcium resorption of bone,
continuous remodelling through apoptosis of
osteoclast and stimulation of osteoblast bone
growth.
Increased triglyceride, HDL; decreased total
cholesterol, LDL
Blood coagulation
Enhance the coagulity of blood.
Pharmacodynamics
Other effects
Induces progesteron synthesis
Libido in humans (female)

Clinical uses
Primary hypogonadism (Prader-Wili syndrome)
Small doses given in early age to stimulate secondary sex
characteristics, growth and menstrual cycle (5-10 ug
ethinyl estradiol on days 1 21 each month)
Post-menopausal hormonal therapy (hormonal
replacement therapy / HRT)
To prevent from menopausal changes such as
acceleration of bone loss (pathological fracture),
aceleration of atherosclerotic process, mood and
psychological changes, hot flushes, sleep disturbances
(0.01 0.02 mg/d ethinyl estradiol on days 1 21)
severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing
genital hypoplasia and pubertal insufficiency; characteristic facial features; early-
childhood onset obesity and hyperphagia; developmental delay/mild intellectual
disability; short stature; and a distinctive behavioral phenotype
Genetics in Medicine (2012) 14, 1026
Clinical uses
Contraception
In combination with progestin
Available preparat
For primary hypogonadism or HRT
Estriol tablet 1 and 2 mg, 2 4 tablet/day
Estradiol valerat tablet 2 mg, 1 tablet/day
17- estradiol patch 100 ug/day
Ethinyl estradiol tablet 50 ug
For contraception
Adverse effect
Menstrual cycle disturbances (dysfunctional
uterine bleeding / amenorrhea)
Cancer
Nausea
Breast tenderness
Hyperpigmentation
Migraine-type headache
Increased blood pressure
Increased body weight
Edema
Contraindication
Pregnant women
Breastfeeding women
Liver disturbances
Thromboembolic disorders
Hypertension
Lipid profile disturbances
Estrogen-dependent neoplasm
Interaction
Metabolized in Cyp3A4
Stimulation of Cyp3A4 decreased of effect
Phenobarbital, carbamazepin, rifampicin
Inhibition of Cyp3A4 increased of effect
Erithromycin, ketoconazole, itraconazole, grapefruit
juices
Estrogen Inhibitors
Clomiphene
Pure estrogen antagonist in all tissues
structurally mimics the estrogen without
estrogenic activity.
Bound to ligand binding pocket from and
receptor of estrogen result in negative feed-
back inhibition of estrogen increased GnRH
secretion stimulate ovulation
Clinical use : woman infertility without
disturbances in hypothalamus hipophysis
ovarium axis
Estrogen Inhibitors
Clomiphene
Metabolized by liver, excreted through feses.
Long half-life : 5 7 days, accumulated in lipid
tissues.
Dose : 50 150 mg (single or twice a day
depends on response) start from day 5 to day
10.
Adverse effect : ovarium cyst, dryness of
vagina, headache.
Contraindication : pregnancy
Selective estrogen receptor modulator
(SERM)
Genetically modified works as agonist in
some tissues and works as antagonist in other
tissues to get the maximum benefit of
estrogen (in bone, brain and liver) by reducing
its negative proliferative effect (in breast).
First generation : tamoksifen, toremifen
Second generation : raloksifen
Pharmacodynamics : agonist estrogen (in
bone and endometrium) and antagonist
estrogen in breast.
Clinical uses : adjuvant therapy for breast
cancer.
Selective estrogen receptor modulator
(SERM) : Tamoksifen
Pharmacodynamics : agonist estrogen (in
bone, plasma lipid, endothelium) and
antagonist estrogen (in breast ans uterus).
Clinical uses : osteoporosis prevention in post-
menopausal women.
Selective estrogen receptor modulator
(SERM) : Raloksifen
Progestins
The most important progestin in human :
progesterone.
Synthesized in the ovary (corpus luteum),
testis and adrenal from circulating cholesterol.
Large amounts are also synthesized and
released by the placenta during pregnancy.

Pharmacokinetics
Rapidly absorbed by any route
Short half life : 5 minutes.
Completely metabolized in one passage in
liver quite ineffective if administered orally
high-dose oral micronized preparats is
synthesized.
In the liver, metabolized as pregnanediol and
conjugated with glucuronic acid
pregnanediol glucuronide ( used as an index
of progesterone secretion)
Pharmacodynamics
Endometrium maturation
Participates in LH surge and secretory changes of
endometrium increased viscosity of endocerviks
secret prevent from pregnancy
Metabolism
Stimulates lipoprotein lipase activity fat deposition
Increase basal insulin levels and insulin response to
glucose
Temperature-regulating center increases body
temperature
Depressant and hypnotic effects in brain

Clinical uses
Post-menopausal hormonal therapy (hormonal
replacement therapy / HRT)
Contraception
Dysfunctional uterine bleeding
Threatened abortion
Abortus habitualis
Diagnostic uses as a test of estrogen secretion
(hypothalamus hypophisis axis) 150 mg
progesterone/day or MP 10 mg/day (5 7 days)
will be followed by withdrawal bleeding in
amenorheic patient only if estrogen is stimulated.
Still in debate
Adverse effect and contraindication
Adverse effect
Increased blood pressure
Androgenic progestins reduce HDL level
Breast cancer careful watch as HRT treament
Contraindication
Progesterone inhibitor :
Mifepriston, Onapriston
Potent antagonist of progesteron
Clinical use : Termination of early pregnancy
(<49 days) with the medical indication (ectopic
pregnancy, incomplete abortus, massive
bleeding) by eliminating the decidua and
blastocyst.
Major metabolism : liver; excretion : feses
Adverse effect : vaginal bleeding, abdominal
pain, uteric pain, nausea, vomit and diarrhea.

Hormonal contraception
Estrogen-based contraception : to increase
estrogen level increased negative feed-
back, GnRH inhibition decreased FSH level
(inhibit folicle maturation) decreased LH
level (inhibit ovulation)
Progesteron-based contraception: to increase
endocervix secret viscosity disturbances in
sperm motility inhibition in fertilization.
Menekan ovulasi

Mengurangi transpor sperma di
bagian atas saluran genital
(tuba fallopii)

Mengganggu pertumbuhan
endometrium, sehingga
menyulitkan proses implantasi
Memperkental lendir serviks
(mencegah penetrasi sperma)

Available preparat
ORAL
Combined Oral Contraceptions (COC): estrogen
and progestin derivatives
Single preparat : progestin

Available preparat
Morning after / post-coital contraception
Sold as emergency contraceptive kits
Available preparat
INJECTIONS
Single progesteron derivatives (MPA) 150
mg for 90 days
Combined MPA and cipional estradiol for
30 days
Available preparat
SUBCUTANEOUS IMPLANT
Etonogestrel-based for 3 years
Levonorgestrel-based for 5 years
Available preparat
Hormonal IUD
IUD that contains levonorgestrel
levonorgestrel-releasing intrauterine system
Double contraception effect IUD effect +
hormonal effect
Contraindications
Pregnancy
Women > 40 y.o
Liver disturbances
Thrombophlebitis, thromboemboli,
cerebrovascular / cardiovascular disease
Suspected estrogen / progesteron dependent
neoplasm
Hypertension / heart failure
Adolescent in whom epiphyseal closure is not
complete

Choosing the contraception
Usia
Pendidikan
Latar belakang penyakit
Jangka waktu
Efisiensi dan efektivitas
Biaya
Ketersediaan fasilitas
Efek samping
Gangguan haid, gangguan menyusui, mual,
peningkatan tekanan darah, peningkatan
berat badan, gangguan toleransi glukosa, sakit
kepala (progesteron).
Oxytoxics and tocolytics
Oxytoxic
Drugs that stimulate uterine contraction.
Main category :
Ergot and alcaloid ergot
Oxytocin
Prostaglandin
Alcaloid ergot
Main source Claviceps purpurea (fungal
parasitic in wheat and rye).
Main compound : alcaloid ergot,
carbohydrate, steroid, histamin, tiramin.
History : ancient Syrrian people (600 BC)
documented that eating contaminated wheat
result in abortus.
Preparat : ergotamin, ergometrin, ergonovin.
Alcaloid ergot
Pharmacokinetics :
Low bioavailability not effective per oral
First pass metabolism low level in plasma
Pharmacodynamics :
Increasing uterine contraction (uterotonics)
High dose result in tetanic contraction
Vascular constriction
Increased amplitude of cranial artery pulsation (good
for migraine)


Clinical use
Migraine (parenteral dose 0,25 0,5 mg s.c /
i.m effective in 5 minutes; for oral dose
effective in 5 hours).
Uterotonic

Adverse effects
Nausea
Vomit
Diarrhea
Weak pulse
Confusion
Lemot

Contraindication
Pregnancy
Vascular disease : arteriosclerosis, Raynaud
disease, thromphlebitis, et al
Available preparat
Ergotamin tartrat
Ergonovin maleat
Metilergonovin maleat (methergin)
Metisergid maleat
Ergotamin tartrat
Metisergid maleat
Ergotamin tartrat
Oxytocin
Stimulate uterinal smooth muscle cells and
breast gland (uterotonics).
Pharmacokinetics
Best results in parenteral route
Degraded by gastric acid
Pharmacodynamics :
Estrogen-dependent uterine contraction
Myoepitel contraction in breast milk secretion

Clinical use
Partus induction (syntocinon i.m or i.v)
Inersia uteri

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