Drugs used in gonads disorders I

Dr.Hazar

Objectives

After studying this unit, you should be able to:

1. Describe the physiological actions of estrogen as they relate to the adverse affects of estrogen replacement therapy HRT

2. Discuss the most current data relating to estrogen and progestin replacement therapy

3. List the drugs and mechanisms used to attenuate the actions of sex hormones

4. Understand the mechanisms of action of the hormonal contraceptive drugs

Outline

Hormone physiologyOvulationHormone regulation and cyclingEstrogen and progesterone / receptorsSERMs (selective estrogen receptor modulators)Hormones as drugsContraceptivesInfertility

Female Reproductive Anatomy and Female Reproductive Anatomy and Physiology: OverviewPhysiology: Overview

OvaryOvary

Fallopian tubeFallopian tube

UterusUterus– CervixCervix– EndometriumEndometrium

VaginaVagina– ClitorisClitoris

– LabiaLabia

Ovary: Details of Histology & Ovary: Details of Histology & PhysiologyPhysiology

FollicleFollicle

OocytesOocytes

Thecal cellsThecal cells

Granulosa cellsGranulosa cells– EstrogenEstrogen Corpus luteumCorpus luteum

Corpus luteumCorpus luteum– ProgesteroneProgesterone

– InhibinInhibin

Menstrual Cycle: Egg Maturation, and Endometrial Growth

Follicular phaseFollicular phase– Egg maturesEgg matures

OvulationOvulation– Egg releasedEgg released

Luteal phaseLuteal phase– Corpus luteumCorpus luteum– Endometrium Endometrium – Prep for blastocystPrep for blastocyst

No PregnancyNo Pregnancy– MensesMenses

Neuroendocrine Control of Menstrual Cycle: Follicular Phase

FSH stimulates follicular developmentFSH stimulates follicular development

Estrogen: + feedback, limits more folliclesEstrogen: + feedback, limits more follicles

Gonadotrophines & AnaloguesGonadotrophines & Analogues

1.1. Follitropin Follitropin αα -Recombinant human FSH. -Recombinant human FSH.

2.2. Follitropin Follitropin ββ -Recombinant human FSH. -Recombinant human FSH.

3.3. Lutropin Lutropin αα -Recombinant human LH. -Recombinant human LH.

4.4. ChoriogChoriogonadotropin α -Recombinant HCG. -Recombinant HCG.

5. Follitropin -FSH

6. HumanMenopausalgonadotrophin -LH&FSH

No 5&6 are made from purified extract of human Menopausal urine.

Clinical usesClinical uses

• LH &FSH are used in Infertility.

.Female Infertility

1.caused by lack of ovulation as a result of Hypopituitarism or failure of treatment with Clomiphene.

2.Induction of ovulation IVF

InVitro fertilisation(Infertility is caused by mechanical obstruction of the fallopian tubes).

Monitor to avoid ovarian

hyperstimulation →multiple pregnancy

Male infertilityMale infertility

Oligospermia (associated withOligospermia (associated with hypopituitarism + Anosmia).

HCG

In boys with Delayed puberty (Testosterone is preferred ).

Androgens and the hormonal control of the male reproductive system

LHRH from the hypothalamus acts on the anterior pituitary to release both follicle-stimulating hormone, which stimulates gametogenesis, and LH (also called interstitial cell-stimulating hormone), which stimulates androgen secretion.

The endogenous hormone is testosterone; intramuscular depot injections of testosterone esters are used for replacement therapy.

Mechanism of action is via intracellular receptors.

Effects depend on age/sex, and include development of male secondary sexual characteristics in prepubertal boys and masculinisation in women.

Clinical use of androgens and antiandrogens

Androgens (testosterone preparations) as hormone Androgens (testosterone preparations) as hormone replacement in: replacement in: – male male hypogonadismhypogonadism due to pituitary or testicular due to pituitary or testicular

disease (e.g. 2.5 mg/day patches) disease (e.g. 2.5 mg/day patches) – hyposexuality following ovariectomy (e.g. hyposexuality following ovariectomy (e.g.

300μg/day patches). 300μg/day patches).

Antiandrogens (e.g. Antiandrogens (e.g. flutamide, flutamide, cyproterone,bicalutamidecyproterone,bicalutamide) are used as part of the ) are used as part of the treatment of treatment of prostatic cancerprostatic cancer. .

5α-Reductase inhibitors (e.g. 5α-Reductase inhibitors (e.g. finasteridefinasteride) are used in ) are used in benign prostatic hypertrophy. benign prostatic hypertrophy.

Aromatase Inhibitors

ERECTILE DYSFUNCTION Erectile function depends on complex interactions between physiological and psychological factors. Erection is caused by vasorelaxation in the arteries and arterioles supplying the erectile tissue. Innervations of the penis includes autonomic and somatic nerves. Nitric oxide is probably the main mediator of erection and is released both from nitrergic nerves and from endothelium .

Erectile function is adversely affected by several therapeutic drugs (including many antipsychotic, antidepressant and antihypertensive agents),. There are several organic causes, including hypogonadism ,hyperprolactinaemia , arterial disease and various causes of neuropathy (most commonly diabetes).

PHOSPHODIESTERASE TYPE V INHIBITORS

Sildenafil, the first selective phosphodiesterase type V inhibitor , was found incidentally to influence erectile function. Tadalafil and vardenafil are also phosphodiesterase type V inhibitors licensed to treat erectile dysfunction. Tadalafil is longer acting than sildenafil.

 

Mechanism of action

Phosphodiesterase V is the isoform that inactivates cGMP. Nitrergic nerves release nitric oxide (or a related nitrosothiol), which diffuses into smooth muscle cells, where it activates guanylate cyclase. The resulting increase in cytoplasmic cGMP mediates vasodilation via activation of protein kinase G .

Consequently, inhibition of phosphodiesterase V potentiates the effect on penile vascular smooth muscle of endothelium-derived nitric oxide and of nitrergic nerves that are activated by sexual stimulation.

Unwanted effects Many of the unwanted effects of phosphodiesterase type V inhibitors are caused by vasodilation in other vascular beds; these effects include hypotension, flushing and headache. Visual disturbances have occasionally been reported and are of concern because sildenafil has some action on phosphodiesterase VI, which is present in retina and important in vision. The manufacturers advise that sildenafil should not be used in patients with hereditary retinal degenerative diseases (such as retinitis pigmentosa) because of the theoretical risk posed by this. Vardenafil is more selective for the type V isozyme than is sildenafil , but is also C.I in patients with hereditary retinal disorders

ProlactinProlactin

Prolactin is secreted from antr.pit. Under the Prolactin is secreted from antr.pit. Under the inhibitory effect of PRIF(dopamine).inhibitory effect of PRIF(dopamine).

Its main function is to control milk production.Its main function is to control milk production.

Pit. Deficiency Pit. Deficiency → ↓PRL↓PRL → failure to lactate

Hyp. Destruction Hyp. Destruction → ↑ PRL↑ PRL →Hyperprolactinemia. In Men Hyperprolactinemia -Impotance &Gynecomastia.

In women Galactorrhea & Hypogonadism

Bromocriptine & AnaloguesBromocriptine & Analogues

Bromocriptine is a dopamine agonist (D2-R)Bromocriptine is a dopamine agonist (D2-R)

↓ ↓PRL used in :PRL used in :

1.1. Parkinsons .Parkinsons .

2.2. Acromegaly.Acromegaly.

3.3. Prolactinomas.Prolactinomas.

4.4. Galactorrhea.(hyperprolactinemia)Galactorrhea.(hyperprolactinemia)

5.5. Benign breast diseases.Benign breast diseases.

6.6. Suppression of lactationSuppression of lactation

AnaloguesAnalogues

1. Cabergoline

M.O.A ditto brom.but longer duration of action ,better tolerated than brom.used to inhibit lactation.

2.Quinagolide

M.O.A ditto brom.but S.E. Hypotension used only in hyperprolactinemia

PROTOTYPE DRUGSPROTOTYPE DRUGS::

Estrogen - ethinyl estradiolEstrogen - ethinyl estradiol

Progestin - levonorgestrel (L-Progestin - levonorgestrel (L-norgestrel)norgestrel)

SERM - tamoxifen, raloxifeneSERM - tamoxifen, raloxifene

Aromatase inhibitor - letrozoleAromatase inhibitor - letrozole

Estrogens

Physiological &pharmacological effectsovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy

uterus: endometrial growth

vagina: cornification of epithelial cells with thickening and stratification of epithelium

cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)

Estrogens

Development and maintenance of internal (fallopian tubes, uterus, vagina), and external genitalia

skin: increase in vascularization, development of soft, textured and smooth skin

bone: inhibits osteoclastic activity.

electrolytes: retention of Na+, Cl- and water by the kidney

cholesterol: hypocholesterolemic effect