1. The gonadal hormones and inhibitors
J.Cermanová

2. Sexual hormones are two types:
protein and steroids
Steroids
are liposolubile - can easily diffuse trough target cells
have intra - cellular receptors
in bloodstream can circulate only if bound to
non-specific proteins – albumin
or to specific protein – SHBG (sex hormone binding globulin)
Proteins
are hydro soluble
cannot penetrate the cells, they need membrane receptor
circulate freely in the blood

3. Ovarian hormones Steroids Estrogens
estrogenic activity is shared by a large
number of chemical substances
. Natural Estrogens
estradiol, estrone, estriol
Although some estrone is produced in the ovary, most estrone and estriol are formed in the liver from estradiol or in peripheral tissues from androstenedione and other androgens

4. In addition to the steroidal estrogens,
2. Synthetic Estrogens
In addition to the steroidal estrogens,
a variety of nonsteroidal compounds with
estrogenic activity have been synthesized
and used clinically.
These include
dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol, methallenstril and chlorotrianisene
This group is represented both steroidal as well as nonsteroidal agents
The most widely used in clinical practice is diethylstilbestrol

5. Pharmacodynamics plasma estrogens are bound to
sex hormone binding globulin,
from which they dissociate to enter the cell and bind to their receptor.
Two genes code for estrogen receptors, which are members of the superfamily of steroid and thyroid receptors.
The estrogen receptors are found predominantly in the nucleus, bound to proteins, that stabilize it.

6. Effects of Estrogens they stimulate the development of the
female maturation
they stimulate the development of the
vagina, uterus, and uterine tubes
as well as the secondary sex characteristics
endometrial effects
development of endometrial lining
effects on blood coagulation
e. enhance the coagulability of blood 
increased circulating levels of ff. II, VII, IX and X
and decreased antithrombin III.

7. responsibility for maintenance of the normal
metabolic effects
responsibility for maintenance of the normal
structure of the skin and blood vessels in women
decrease the rate of resorption on bone
(but not stimulate bone formation)
e. alter the production and activity of many proteins
 increaseed circulating levels of
thyroxine, estrogen,
testosterone, iron, cooper
e. alter the plasma lipids
 increase in the HDL, and a reduce in the LDL,
and reduce plasma cholesterol levels

8. other effects :
e. induce the synthesis of progesterone
receptors
e. facilitate the loss of intravascular fluid into
the EC space, producing oedema.
The resulting decrease in plasma volume causes a compensatory retention of sodium and water in kidney.

9. Clinical Uses Primary hypogonadism
for replacement therapy in e. deficiency patients
Postmenopausal hormonal therapy
prevention of osteoporosis
administration of e. is associated with an increased risk of endometrial carcinoma
to stop excessive uterine bleeding due to endometrial hyperplasia

10. Adverse Effects nausea brest tenderness hyperpigmentation
migraine headaches
cholestasis
hypertension
gall blader colic

11. Progestins . Natural Progestins
The most important progestin in humans
progesteron.
in the ovary, progesterone is produced
primarily by corpus luteum.
2. Synthetic Progestins
multiple group
Some compounds are active by p.o. route.

12. Pharmacodynamics
The mechanism of action of progesterone is similar to that of other steroid hormones. Progestins enter the cell and bind to progesterone receptors that are distributed between the nuncleus and the cytoplasmatic domains.

13. Effects of Progestins little effect on protein metabolism
stimulation of lipoprotein lipase activity
effect on carbohydrate metabolism:
- p. increases basal insulin levels and the
insuline response to glucose.
- in the liver p.promotes glycogen storage,
possibly by facilitating the effect of insulin.
- promotes also ketogenesis
p.increased the body temperature in humans

14. Clinical Uses for hormon replacement therapy hormonal contraception
treatment of premenstrual syndrome

15. Hormonal contraception
Two types of preparations are used for oral contraception:
/ combination of estrogens and progestins
2/ continuous progestin (without estrogens)
Mechanism of action:
selective inhibition of pituitary function that result in inhibition of ovulation.
changes in the cervical mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes decrease the likehood
of conception and implantation.

16. Other Effects the inhibition of pituitary gonadotropin secretion
serious thrombembolic risk
increasing TAG and cholesterol
small increases in cardiac output  associated with systolic and diastolic BP
hyperpigmentation

17. Adverse Effects Mild AE: nausea, mastalgia – breast pain
changes in serum proteins
hadeache
withdrawal bleeding may occurs
Moderate AE
bleeding (progestin alone)
weight gain
increased skin pigmentation – chloasma, acne
vaginal infection
amenorrhea

18. Severe AE: Vascular disorders Venous thrombembolic disease
Myocardial infarction
Cerebrovascular disease
! CAVE 35 years of age or older, heavy smokers !
GIT disorders
Cholestatic jaundice
Depression
Cancer – this efect is not uniform
was describe higher risk of cervical CA
on the other hand reduction of endometrial and ovarian CA

19. Estrogen and Progesterone inhibitors and antagonists
Tamoxifen
competitive partial agonist inhibitor of estradiol
at the estrogen receptor
is extensively used in paliative treatment of
advanced breast CA in postmenopausal
women
Clomiphene
partial agonist, that also acts as a competitive
inhibitor of endogenous estrogens
use as an ovulation-inducing agent

20. Danazol
- derivate of ethisterone
- used to suppress ovarian function
Anastrazole
selective nonsteroidal inhibitor of aromatase
( the enzyme required for estrogen synthesis)
used in treatmen of breast CA in the case of resistance to therapy with tamoxifen
others aromatase inhibitors in clinical trials:
letrozole, fadrozole

21. II. Testicular hormones
Androgens and Anabolic Steroids
the most important androgen secreted by testis is testosterone.
in many target tissues, testosteron is converted to
dihydrosterone by the 5 α- reductase.
- like other steroids testosterone acts intracellulary.
in some tissues occurs the conversion of t. to estradiol.
- androstenedion, dehydoepiandrosterone (DHEA)and dehydoepiandrosterone sulfate (DHEAS) are also produced in significant amounts in humans, though largely in the adrenal gland rather in the testes.

22. Testosterone and derivatives have been used for
Synthetic Steroids with Androgenic and Anabolic Action
are derivatives of testosterone – propionate, enanthate, undercaonate, or cypionate
Testosterone and derivatives have been used for
their anabolic effects
as well as for the replacement of testosterone deficiency.

23. Clinical Uses Androgen replacement therapy in men
Gynecologic disorders
androgens are sometimes given in combination with estrogens for replacement therapy in the postmenopausal women to eliminate the endometrial bleeding that may occur when only estrogens are used
Use as protein anabolic agents
to reverse protein loss after trauma, surgery or immobilization and in patients with debilitating diseases

24. Anemia
as aplastic anemia
Osteoporosis
Use as growth stimulators
a separate problem is abuse of androgens in sport
Adverse effects:
masculinizing actions
which are most noticeable in women and
prepubertal children
hirsutism, acne, depression of menses,
deepening of the voice….

25. Androgen supression and antiandrogens
- treatment of advanced prostatic CA
leuprolide acetate, goserelin
gonadotropin-releasing hormones,
which produce in continuous administration
gonadal supression
The therapy often requires orchiectomy or large
doses of estrogens to reduce available androgen.
AE: gynecomastia

26. Antiandrogens The potential usefulness of antiandrogens is
for the treatment of patients producing
excessive amounts of testosterone.
Ketoconazole
- used primarily for the tretment of fungal disease
- is an inhibitor of adrenal and gonadal steroid synthesis
inhibits P 450scc
- cholesterol side chain cleavage enzyme
This compound has been used with succes for the
treatment of patients with Cushing syndrome.

27. Finasteride
- inhibitor of 5 α- reductase,
reduces dihydrotestosterone levels
Receptor inhibitors
Cyproterone
- for treatment of hirsutism in women,
for decrease excessive sexual drive in men
Flutamide, bicalutamide
for treatment of prostatic CA
Spironolacton
competitive inhibitor of aldosterone

28. Therapy of Osteoporosis
Osteoporosis is defined as
abnormal loss of bone predisposing to fractures
- is most common in postmenopausal women, but also
occurs in men.
it may occur as a side effect of chronic administration of glucocorticoids
as manifestation of endocrine disease such as
thyreotoxicosis or hyperaldosteroidism
as manifestation of alcohol abuse….

29. The postmenopausal form of osteoporosis
may be accompanied by lower 1,25(OH)2 D levels
and reduced intestinal calcium transport.
This form appears to be due estrogen deficiency and is best treated with cyclic doses of estrogen.
Vitamin D is often employed in addition to dietary.
Calcium supplementation.

30. Etidronate, pamidronate and alendronate
Bisphophonates
Etidronate, pamidronate and alendronate
These drugs exert a variety of effects on bone mineral homeostasis.
Able to dissolute of hydroxyapatite crystals within and outside the skeletal system
However the exact mechanism by which they selectively inhibit bone resorption is not clear