Sex hormones

SEX HORMONES

.

2

REGULATORS

gonadotropin-releasing hormone (GnRH)

follicle-stimulating hormone (FSH)

luteinizing hormone (LH)

3

INTENSITY OF HORMONAL SECRETION IN THE CYCLE

4

FEED BACK-REGULATION

5

Biosynthesis of steroids

6

ESTROGEN-FUNCTIONS

IN WOMENDevelopmental effects,

neuroendocrine actions- in the control of ovulation-Cyclical preparation for fertilization

ACTIONS Mineral,carbohydrate,protein and lipid

metabolism

Estrogens and males on bone, spermatogenisis,& behaviour

7

STRUCTURAL FEATURES OF ESTROGENS

8

BIOSYNTHESIS

9

DIFFERENT ESTROGENS

10

BENEFITS ASSOCIATED WITH POSTMENOPAUSAL ESTROGEN REPLACEMENT

.

11

SIDE EFFECTS ---ESTROGENSNausea vomiting

Breast tenderness

Migraine headache

Uterine bleeding

Hyper pigmentation

Cholestiasis

Gall bladder disease

Edema

Hypertension

Breast cancer

12

HORMONAL CONTRACEPTIVESORAL, PARENTERAL & IMPLANTED CONTRACEPTIVES

O.C – 1.Combinations of estrogens and progestins 2.Sole progestin therapy

Monophasic Biphasic Triphasic

FORMS

No change of both componentsduring the cycle

Dosage of one or both components changed Once during the cycle

Dosage of one or both components changed twice during the cycle

13

PROGESTERONE

14Properties of commonly used progestin

15

ESTROGENS AND PROGESTINS -CLINICAL USE

Contraception

Hormone replacement therapy-post menopasal, hypogonadism, (along with

Gonadotropins/growth hormones in delay)

Antiprogestins abortifacients, contraception

Estrogen antagonists estrogen dependent

neoplasm

16

TRANSPORT - KINETICS Estradiol binds to α2 globulin (SHGB)And to albumin in lower affinity.Estradiol Liver estrone, estriol 2hydroxylated derivatives Conjugated metabolites Water soluble excreted in bile Small amounts in breast milk

Can be activated in the intestines

Hepatic first pass effect is minimized by other routes-Transdermal,Vaginal or by injection.

17

Steroid hormones diffuse across the cell membrane and bind with high affinity to specific nuclear receptor proteins

Mechanism of action

Ligand – receptor complexForms a dimer before binding DNA

PRE -OREActivate gene transcriptionhormone-specific RNA synthesis

synthesis of specific proteins that mediate a number of physiologic functions

18

MECHANISM, EFFECTS OF CONTRACEPTIVES

Combinational Contraceptives block pituitary functionLeads to inhibition of ovulation

Continuous use of progestin alone does not always inhibit ovulation

Combinational agents also produce change in the cervical mucus in the uterine tubes all of which decreaseThe likelihood of conception and implantation

Effects on ovary- depress ovarian functionEffects on uterus- Hypertrophy and polyp formationEffects on breasts- Enlargement, suppress lactation, less amt. transverse in to milkCNS--------------- estrogen excites, progestin depress the brainEndocrine –inhibition of gonadotropins, adrenal structure d function, high conc. Increase in α2 globulinBlood- increased coagulability, increased dosage of coumarin analogs required, increased sr. iron and total iorn binding capacity.

19

ANTAGONISTS AND INHIBITORS

20

Danazol, clomiphene action

21

Androgen regulation

22

Finastride, Anastrazole action

ERECTILE DYSFUNCTION

THE FIGURE BELOW SHOWS THE MECHANISM OF ACTION OF VIAGRA, AND THE OTHER PDE5 INHIBITORS, ON THE NITRIC OXIDE CYCLE.

ERECTILE DYSFUNCTION = CONSISTENT INABILITY TO OBTAIN AND/OR MAINTAIN AN ERECTION SUFFICIENT FOR SATISFACTORY SEXUAL RELATIONS

NIH 1992

MECHANISM OF PENILE ERECTION

DIAGRAM OF PENILE ERECTION

RISK FACTORS FOR ED Vasculogenic factors Age Certain medications Psychosocial/psychological factors Neurogenic factors Hormonal factors

ENDOTHELIAL DYSFUNCTION IS A RISK FACTOR FOR CVD AND ED

Heart failure Atherosclerosis Smoking

Hypertension Oxidative stress Diabetes

Endothelial dysfunction

ED

Adapted from Rubanyi GM. J Cardiovasc Pharmacol 1993; 22 (Suppl 4): S1–S4

CAUSES OF ED1. Organic (80 %)

diabetes mellitus, hypertension, hyperlipidemie, benign prostate disease, peripheral vascular disease, cardiac problems, hormonal problems (pituitary, testis, thyroid, adrenal), neurogenic (cerebral, spinal, dorsal nerve, cavernous nerve)

postsurgical: radical prostatectomy, abdominoperineal resection

2. Psychogenic, drugs (20 %)

31

DRUGS ASSOCIATED WITH ED Alcohol Estrogens Antiandrogens H2 receptor blockers Anticholinergics Ketoconazole Antidepressants Marijuana Antihypertensives Narcotics

ß-blockers Psychotropics Cigarettes Cocaine Spironolactone Lipid-lowering agents NSAIDs Cytotoxic drugs Diuretics

CAUSES OF ED Neurogenic

Parkinson´s disease – 60%Multiple sclerosis – 70%Spinal cord trauma, tumor etc.Peipheral neuropathy: diabetes,

alcoholism, chronic renal failure

DIAGNOSIS OF ED MAY UNCOVER OTHER SERIOUS TREATABLE DISORDERS Hypertension

68% of men with hypertension had ED to some degree

Dyslipidemia60% of men with ED had dyslipidaemia

Heart disease56% of men with ED were found to have a

positive stress test40% of men with ED had significant

coronary occlusions

ORAL THERAPY

PDE 5 inhibitors (95%) 2-blockers (Yohimbin) hormonal therapy (testosterone)

PHOSPHODIESTERASES Main role: termination of cyclic nucleotide

second messenger signal, often cGMP 11 PDE groups (PDE 1-11) PDE-5 breaks down cGMP (the second

messenger of Nitric Oxide—NO), reversing the muscle-relaxant effect of NO

PDE-5 is found in corpus cavernosum, vascular and visceral muscles, and in platelets

N.O. Release Increases Penile Bloodflow

Lue,T. NEJM 2000. 342:1802

PDE5 INHIBITORS

cGMPSildenafil

Tadalafil

Vardenafil

NN

O

N

O

OO

ONH2 N

NH

N

NH

O

OP O

O 0H

0H

N

NHN

NO

S

O

O ON

N

N

NH NO

S

O

O O

N

N

N

Caffeine

OCH3

CH3

H3C

O

PDE5: LOCALIZATION PDE5 is localized in vascular smooth

muscle cells PDE5 is not localized in the following:

cardiac myocytesendothelial cells lymphatic cellscardiac conduction tissue

PDE5 INHIBITION WITH SILDENAFIL

PDE5

cGMP

GMP

GTP

Sexualstimulation

Smoothmusclerelaxationof the cavernosal arteries &the corpora

Erection

Corpus cavernosum

NONANC

NO=nitric oxide; NANC=nonadrenergic-noncholinergic neurons;PDE5=phosphodiesterase type 5

PDE5 INHIBITORS: PHARMACOKINETICS

1Klotz et al. ACCP. 2002;2 As reported in Kim et al. Formulary. 2002;37. *Median (range).

Tadalafil(Cialis)20mg

Vardenafil(Levitra)

20mg

Sildenafil(Viagra) 100mg

T1/2, h 17.5 4.6 3.7

Tmax, h* 2.0 (0.5-12) 0.8 (0.3-2.0) 1 (0.5-2)

Metabolism CYP3A4 CYP3A4CYP3A5CYP2C9

CYP3A4 CYP2C9

PDE5 INHIBITORS – SIDE EFFECTSsildenafil tadalafil

vardenafil(N = 724/379)

(N = 1812/793)

headache 15% 14,5 / 5,5% - placebo 16 / 6%dyspepsia 6% 12,3 / 1,8% 4 / 1%backache 0% 6,5 / 4,2% 0%rhinitis 2% 4,3 / 3,2% 10 / 4%myalgia 0% 5,7 / 1,8% 0%flushing 14% 4,1 / 1,6% 12 / 1%abnormal vision 5% 0% <2 / 0%

PDE5 INHIBITORS

sildenafil vardenafil tadalafil apomorfinEffect PDE5, PDE6

inhibitionPDE5, PDE6

inhibitionPDE5, PDE11 -

inhibitioncentral effect

efficacy 82 % 80 - 86 - 92 % 81 % 45 %

Start time to efficacy

12 - 37 min 15 - 30 min 30 min 18 min

Time of efficay 3,5 - 5 h. 4 - 5 h. 24 - 36 h. 2 h.

Side effect nausea

contraindication nitrates taking nitrates taking nitrates taking

timing 1x / 24 h. 1x /24 h. No-every 24 h. 1x/ 8 h.

cost 4 x 100 mg 1832,61 Kč

4 x 10 mg1528,01 Kč

4 x 20 mg1538,80 Kč

4 x 3 mg1414,32 Kč

CONTRAINDICATIONS Since PDE5 inhibitors such as

sildenafil, tadalafil, and Vardenafil may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrates within this timeframe may increase the risk of life-threatening hypotension.