Gonadal hormones and inibitors

slides from lecture/seminar

Available for download: http://pharmacology.jfmed.uniba.sk

Supported by
Culture and Education Grant Agency project KEGA 055UK-4/2012 „Case-studies in teaching
pharmacology and clinical pharmacology - use of e-learning.“
and by
European Social Fund project "Virtual and simulation teaching as a new form of education at JSMCU in
Martin" (ITMS code: 26110230071), co-financed from EU sources.
Female: OESTROGENS
Estrogen receptors
ER alpha in the female
reproductive tract:
especially in the uterus,
vagina, ovaries,
mammary gland,
hypothalamus,
endothelial cells, and
vascular smooth muscle.

ER beta is expressed
most highly in the in
lung, brain, bone, and
vasculature.

Many cells express both

ER a and ER b, which can
form either homo- or
heterodimers.
Mechanism of action
 Physiological
effects
of estrogens

Reproductive
effect

Nonreproductive
eff.
Many
nonreproductive
tissues, including
bone, vascular
endothelium, liver,
CNS, immune
system,
gastrointestinal tract,
and heart, express
low levels of both
estrogen receptors
!!!
 OESTROGENS
Metabolic effects:
 enhance the level of coagulation factors II, VII, IX, X;
(decreased levels PAI-1 with a concomitant increase in fibrinolysis)
 alteration in lipid metabolism HDL/LDL, plasma CH, TG,
redistribution of the body fat;
 H2O metabolism – loss of intravascular fluid – compensatory sodium
retention
Other effects:
 maintenance of the normal structure of the skin (↑ E - pigmentation);
  bone resorption (antagonizing the effect of parathyroid hormones)
 acceleration of growth phase and closing the epiphyses of the long bones;
 Long-term administration of estrogen is
associated with:
 decreased plasma renin,
 angiotensin-converting enzyme,
 and endothelin-1;
 expression of the AT1 receptor for
angiotensin II is also decreased.
 increased production of NO,
 All of these changes promote vasodilation.
 Absorption:
Well absorbed by oral, parenteral & transdermal admn.
Oestradiol undergoes high first pass metabolism.

 Transport: strongly bounded on plasma proteins (SHBG,

albumin)
 Metabolism:
 Elimination by liver enzymes
 Significant entero-hepatic circulation
 Excretion by urine after conjugation
 OESTROGENS

 oral, parenteral, transdermal, or topical administration.

Steroidal - natural:
 Oestrone

 Oestradiol - AGOFOLLIN inj., ESTRACE, ESTRIMAX tbl.

CLIMARA patch, ERMESTRIL patch, ESTRADERM patch,
FEM7patch, SYSTEN patch......
VAGIFEM tbl. vag.
3-month vaginal ring ESTRING, FEMRING
ESTEVA, ESTROGEL –topical cream and gel

 Oestriol - ORTHO-GYNEST crm. vag., supp.,

OVESTIN tbl., crm., supp. vag.
 OESTROGENS
Steroidal - synthetic :

 Ethinyl oestradiol- p.o. , low first-pass effect

(TRIREGOL, DIANE 35, FEMODEN, CHLOE, JEANINE, ...)

 Mestranol- MESTRANOL

 Polyestradiol- ESTRADURIN

 Tibolon – LADYBON, LIVIAL

 OESTROGENS
Nonsteroidal synthetic:

 Chlorotrianisene

 Dienestrol

 Hexestrol

 Diethylstilbestrol - AGOSTILBEN inj.

 OESTROGENS
Therapeutic use
 replacement therapy: postmenopausal, hysterectomy, primary
hypogonadism
 treatment of amenorrhea, dysmenorhea
 p.o. contraceptives
 postmenopausal syndrome (PS)
 PS -hot flashes, atrophic vaginitis, risk of osteoporosis,
 vertebral, hip, wrist fractures, lipid changes,  risk of IM,
behavioural changes)
 OESTROGENS
Adverse effects
• endometrial hyperplasia
• nausea, breast tenderness
• hyperpigmentation
• migraine headache
• edema, hypertension?
• risk of thromboembolism
•Increase risk of cancers: uterusm cervix, breast..
• diethylstilbestrol – transplacental carcinogen
 OESTROGENS

Contraindications:

• estrogen dependent cancers of endometrium, breast

• liver disease

• thromboembolic disorder
Pharmacological goal: produce beneficial
estrogenic actions in certain tissues (e.g.,
bone, brain, and liver), but antagonist activity
in tissues such as breast and endometrium,
Name Uses Effects/location
ormeloxifen breast cancer, agonist at bone; antagonist
contraception at breast and uterus
agonist at bone; antagonist
raloxifen – EVISTA osteoporosis
at breast and uterus
tamoxifen - NOLVADEX tbl. agonist at bone and uterus,
breast cancer
antagonist at breast
toremifen breast cancer
agonist at the bone,
breast cancer, vaginal
lasoxifen antagonist at breast and
atrophy
uterus
 proliferation of breast cancer  Given orally
cells and endometrial cancer Uses
 Hormonal treatment for both early
 total cholesterol and LDL and advanced CA breast in women

 no change in HDL and TGs

 risk of DVT & pulmonary embolism

 Bone & CVS: partial agonist  Side effects:
 Endometrium & breast: increase in deep vein
antagonist thrombosis & pulmonary
 Postmenopausal women: embolism (same as oestrogen)
prevents bone loss
 Reduce LDL cholesterol
 65% reduction in risk of breast
cancer
 No increased risk of
endometrial cancer
 No relief of vasomotor
symptoms
Clomifene inhibits estrogen receptors in
hypothalamus, inhibiting negative feedback of estrogen on
gonadotropin release
 on day 3 of MC and continuing for 5 days.
 Increase GnRH secretion becomes more rapidly pulsatile,
which results in increased pituitary gonadotropin (FSH, LH)
release,stimulates growth of more ovarian follicles,
rupture of follicles resulting in ovulation

 Therapy female infertility, to reverse anovulation,

infertility in polycystic ovary syndrome....
ANTIOESTROGENS
Modify and oppose
the action of oestrogens

Clomiphene - CLOSTIBEGYT,
GRAVOSAN, SEROPHENE tbl.

interference with negative

feedback of the hypothalamus
 gonadotropins
direct stimulation of ovulation
Th - treatment of infertility,
anovulation
Cyclofenil no
AE - ovarian enlargement
 Inhibitors of aromates
Inhibition of estogen pathway

Cholesterol

Progesterone

DHEA

Aromatase
Androstenedione Estrone

Aromatase
Testosterone Estradiol
NEJM 348:2432.
 Sites of Aromatase Activity
Clemens M, Goss P. NEJM 2001;344:276-85.

The more common adverse events associated with the use of aromatase inhibitors
include decreased rate of bone maturation and growth, aggressive behavior, kidne
failure, and liver dysfunction.
 Used to inhibit estrogen-dependent tumors,
metastatic breast cancer in postmenopausal
womens (off label- gynecomastia in man)
 Breast tumours resistant to tamoxiphene
 But, serious estrogen-lacking side-effects:
increased risk of osteoporosis.
 Irreversible steroidal inhibitor: exemestane
(Aromasin),
 reversible competition for the aromatase:
anastrozol, letrozol, fadrozol
GESTAGENS
 GESTAGENS
Progesteron- ovary, testis, adrenal form cholesterol
-Metabolized to pregnanediol in the liver

-Act on the progesteron receptors (PRA, PRB)

Neuroendocrine Actions. - decreasing the frequency of GnRH pulses

Reproductive Tract. -decreases estrogen-driven endometrial proliferation and

leads to the development of a secretory endometrium,
- influences the endocervical glands, increase mucous viscosity
- decrease penetration of the cervix by sperm.

- important for the maintenance of pregnancy (suppresses menstruation and

uterine contractility)

Mammary Gland. Development of the mammary gland requires both estrogen

and progesterone.
 GESTAGENS

CNS Effects.
-Increase body temperature during ovulation
-Progesterone also may have depressant and hypnotic actions
 GESTAGENS

Metabolic effect:
 lipoprotein lipase activity (fat deposition);
 insulin level, response to glucose;
 promotes glycogen storage, ketogenesis;
 aldosteron secretion ( Na reabsorption);
 GESTAGENS
 Natural:

progesterone

 Synthetic-progestins

DERIVATIVES OF PROGESTERONE
DERIVATIVES OF NOR-TESTOSTERONE
DERIVATIVES OF TESTOSTERONE
Type Hormonal activities Progesterone Oestrogen Androgenic Anabolic
Progesterone derivatives
Progesterone (UTROGESTAN tbl., + - - -
AGOLUTIN, inj.)
Hydroxyprogesterone (DUPHASTON) + - slight -

Medroxyprogesterone (PROVERA tbl.) + - + -

Combine oral contraceptives
Cyproteron (ANDROCUR) + - - -
Nomogestrol (LUTENYL)
Testosterone derivative
Dimethisterone slight - - -

Nor-testosterone derivatives
Norethisterone (NORETISTERON) slight + + +

Lynestrenol slight + + +
Norethindrone (+ estrogens in OA) + slight + +
L-Norgestrel (+ estrogens in OA, IUD + - + -
MIRENA)
 GESTAGENS
Therapeutic use:
 Hormonal replacement therapy
 Postmenopausal syndrome (replacement + decrease hypetrophy
of myometrium)
 Compound of hormonal contraceptives
 Therapy of premenstrual syndrome
 Therapy of amenorrhea
 Suppression of lactation
 GESTAGENS + ESTROGENS COMBINATIONS
THERAPY OF POSTMENOPAUSAL SYNDROM

•Peroral

Estradiol
+ DH gesteron FEMOSTON
+ Levonorgestrel –CYCLO MENORETTE
KLIMONORM
+ cyproteron CLIMEN
+ medroxyprogesteron CYCLOPROMELLA
+ norethisteron- NOVOFEM

•Transdermal patch:

Estradiol + norethistern –SYSTEN CONTI

+ Levonorgestrel FEM7 combi
 GESTAGENS
Adverse effects:
 Weight gain
 Acne
 Hepatal disorders
 Gastrointestinal disturbances
 Unfavorable influence on lipid's levels
 Salt-retaining effect
 ANTIGESTAGENS
ANTIPROGESTINS:

Mifepristone
• dual action – antiglucocorticosteroidal + antiprogestin
• abortion (combination with prostaglandins),
• 600 mg – emergency postcoital contraceptive
•treatment progesteron dependent tumours and
glucocorticosteroids releasing cancers
•
Side effects!!!:
Disturbances of menstrual cycle, strong pelvic, abdominal pain,
severe vaginal bleeding..........
 Hormonal contraceptives
= drugs that decrease fertility

1, according to route of administration:

oral, parenteral, implanted

2, according to composition:
estrogen + gestagen
gestagen alone = minipills
 Hormonal contraceptives
Mechanism of action
of hormonal

Estrogens: contraceptives

 Inhibition of hypothalamus – pituitary negative

feedback
 Inhibit ovulation

Gestagens:

 Decrease the amount of cervical mucus and its

water content to facilitate sperm penetration of the
cervix
 decrease the frequency of GnRH pulses
 Hormonal contraceptives
1. Monophasic
(NEOGEST, GRAVISTAN, DIANE 35, MICROGYNON,
FEMODEN , NON-OVLON)

- application of invariable E+G doses

2. Biphasic (11/10)
(BI-NOVUM)

- 11days=1st phase E,
- 10 days=2nd phase G

3. Triphasic (6/6/9)

(TRIREGOL, TRIQUILAR, TRINOVUM, TRISEQUENS)

 Hormonal contraceptives

 150 µg of the progestin norelgestromin

 20 µg of the estrogen ethinylestradiol per
day
 Hormonal contraceptives
Adverse effect of combined contraceptives:
• ovary-depressed activity
• uterus -hypertrophy of cervix
• breast- enlargement,
• CVS- thromboembolism, hypertension,  incidence of
myocardial infarction (E)
• CNS- depression, migraine
• skin-  pigmentation (E)

CI- cardiovascular diseases, thromboembolic disease,

liver disease, migraine, smoking, estrogen - dependent
cancer
Hormonal contraceptives – only gestagens
PROGESTINE IMPLANTS
MIRENA
NORPLANTS
intrauterine device
levonorgestrel containing
with hormonal compound
ministicks for subcutaneous
implantation
Hormonal contraceptives – only gestagens

minipill"; low doses of progestins (e.g., 350 mg of

norethindrone [NOR-QD, MICRONOR] or 75 mg of
norgestrel [OVRETTE]) taken daily without
interruption;

medroxyprogesterone acetate (DEPO-PROVERA)

for intramuscular injection of 150 mg of drug, which
provides effective contraception for 3 months
 Hormonal contraceptives
Postcoital contraceptives
- „Emergency“ contraceptives - ??? Side effects
1. d. of estrogens (ethinylestradiol, dietylstilbestrol)
------within 72 hours after intercourse- --2xdaily for 5 days

2. ethinylestradiol + levonorgestrel
-------within 72 hours after intercourse---12 hours later

3. levonorgestrel - POSTINOR
------- 1 tbl. within 1 hour after intercourse- -----1tbl. 12
hours later –-maximal dose 4. tbl per month !!!!!!!
Pearl index – fallibility of
contraception
-will be determined by the number of unintentional pregnancies
related to 100 women per year.
ANDROGENS
 ANDGROGENS

5-alpha-reductase
Un-direct
type I: predominantly
activity on
in non-genital skin,
AR
liver, and bone.
Type II: predominantly
in urogenital tissue
Direct
activity on AR
 ANDROGENS
 Testosteron

male-Leydig cells in the testes (95%)

female – ovary (corpus luteum)
both- adrenal gland (5%)

Physiologic effect:
 development of male sexual characteristic
 metabolic-anabolic action - protein synthesis
 ANDGROGENS
Therapeutic use:

1.replacement therapy- hypogonadism-Leyding cells

dysfunction, hypothalamic failure

2. anabolic action - reverse protein loss after trauma,

treatment of osteoporosis,
growth- prepubertal boys - pituitary disturbance

3. non-approved use in sport-  body mass,

muscle strenght, erythrocytes production
(testosterone precursors, -androstenedione and
dehydroepiandrosterone -DHEA),
ANDROGENS

More lipophilic,
long duration of
action
(parenteral)

Peroral
administration
Hepatotoxic
effects
 Absorption: testosteron and esters undergo high first pass
metabolism - Therefore i.m. injections
 P.o. - alkylated derivates (less first- pass metabolism in the liver)

 Transport: highly protein bound (98%, SHBG, albumin)

 Metabolism:
 by liver enzymes
 excretion by urine after conjugation
Transdermal delivery
 Transdermal delivery systems
systems of of testosterone:
androgens:

 ANDRODERM – transdermal patch

 ANDROGEL, TESTIM – gels

 STRIANT a buccal tablet

Differences in pharmacodynamic effect -
Drug Anabolic
Androgenic ratio
testosteron 1:1
testosteron cypionate 1:1
testosteron enanthate 1:1

Stanozolol 3:1
Ethyloestrenol 3:1
Oxandrolone 3:1
Fluoxymesterone 2:1
Methyltestosterone 1:1
 ANDGROGENS
 Other synthetic derivates

 mesterolon- PROVIRON tbl., 2 : 1

3-oxoandrosten- RAVERON inj., 2 : 1
nandrolon- SUPERANABOLON inj., 4:1
 ANDGROGENS
ADVERSE EFFECTS:
• masculinisation (acne, growth of facial hair, deepening of the
voice, excessive muscle development, menstrual disturbance)
• males- impotence,  spermatogenesis
• general- LDL/HDL ratio, risk of coronary
heart disease, edema

!!!! young sportsmans – closing of epiphysis of the long bones,

(gynecomastia –high doses)
hepatic abnormalities, aggression

CONTRAINDICATIONS:
• pregnant women;
• carcinoma of prostate;
• renal, cardiac disease
ANTIANDGROGENS

finasteride

flutamid
nelutamid
cyproterone
 ANTIANDGROGENS

Interfere with synthesis:

 ketoconazole- inhibitor of adrenal, gonadal steroid synthesis

 finasteride – PROSCAR, inhibitor 5 - reductase

Competetive inhibitors of androgen receptors:

 cyproterone- ANDROCUR

 flutamide- FLUCINOM

 nelutamide- ANANDRON

Treatment of prostatic cancer,  androgen activity in the women (hursutism)

 5  reductase inhibitors
Finasteride
Orally active Prostate volume
DHT levels Symptom score
Benign prostatic hyperplasia
Dose: 5mg/day

Also used for prevention of hair loss

Side effects: Loss of libido & impotence in 5 % pts.