Drugs that affect gonadal hormones

FEMALE GONADAL HORMONES Refresh your memory

Ovarian hormones • Estrogen• Progesterone• Small amounts of androgens

– Testesterone(<200mcg \d)– Androstenedione

• Converted to testosterone and estrone in peripheral

– Function:1. Normal hair growth2. Female libido3. Metabolic effects

• inhibin – Inhibit FSH secretion

• Activin – Increase FSH secretion

• Relaxin – Decrease uterine contraction– Increase glycogen synthesis

Org

an sy

stem

effe

cts

f est

roge

n

Estrogen

Maturation and secndary sex

characters in females

Endocrine :1- decrease FSH &LH

2-increase the renin activity

Sebum Acne

Hair growth

Pigmentation

TG,HDLLDL

CNS:1.Excitation

2.Sense of well being

Other Estrogen effects

Increase endometrial

growth

Decrease osteocalstic

activity

Increase synthesis of

clotting factors

x,ix,vii,iiAnd increase synthesis of

antithrombin

Induce synthesis of

progesterone receptors

Affect behavior and

libido in humans

Stimulate central

component of stress system:

1-increase production of

CRH2-Increase activity of symathetic

Facilitate loss of

intravascular fluid to the

extracellular

Also estrogen elevate the levels of :thyroxine,iron copper why?

Clinical uses of estrogen

• Primary hypogonadism • Postmenopausal hormonal therapy• Contraception • Hairsutism

Uterine bleeding Increase risk of

endometrial cancer

May increase risk of breast cancer

N&V,breast tenderness,

increase the of :1-frequency of

migraine2- Cholestasis

3- hypertension

Side effects

Abnormal uterine bleeding

Thromboembolic disorders

Cholestasis and liver diseases

High risk of estrogen dependent canrcinoma

Psychosis

Smokers

Cont

rain

dica

tions

Org

an sy

stem

effe

cts

of p

roge

ster

one

Progesterone

Endocrine :1- decrease FSH &LH

2-increase the renin activity

Sebum Acne

Hair growth

CNS:1.Depression

2.Thermogenic effect 3-hypnosis

• Increase the synthesis of aldosterone• Sodium water retention Compete with

aldosterone on its receptor

• Stimulate lipoprotein lipase• Increase basal insulin levels • Increase glycogen storage• Promotes ketogenesis

Metabolic effects

1. Also progesterone is responsible for alveolobular production in the breast 2. Maturation and secretory changes of the endometrium 3. Increase the ventilatory response to PCO2

Clinical uses

• Contraception • Hormonal replacement therapy • Premenstrual syndrome • Diagnostic test:– Test the estrogen secretion • Progesterone 150mg\d or medroxyprogesterone 10mg\

day is given for 5-7 days ,this regimen will be followed by bleeding in amenorrheic pts only when the endometrium is stimulated by estrogens

Side effects

Increase BP

Androgenic progesterone

decrease HDL and have androgenic

side effects

Drugs that affect gonadal hormones

Hormonal antagonist

Progesterone antagonist

Progesterone with

antiandrogenic activity

Selective estrogen receptor

modulators

Estrogen antagonist

Sex hormones synthesis inhibitors

GnRH continuous

administration

GnRH antagonists

Aromatase inhibior

5-alpha reductase

others

Ovulation inducing agents Hormonal analogues

Oral contraceptives

Hormonal replacement

therapy

MENSTRUAL CYCLE Refresh your memory

hormonal contraception

Female contraception

Before conception

Combined pills

Monophasic

Biphasic

Triphasic Progesterone only pillsAfter

conception

Male contraception

Testosterone alone

Testosterone +progesterone

Female contraceptionbefore conception

• Pills or implants or IM injection are taken to prevent conception

• Combined or mini pills

1-Combined pills

• Contain estrogen or its derivatives and progesterone or its derivatives

• According to progesterone concentration in the pills we divide the combined pills to 3 subtypes:1. Monophasic 2. Biphasic 3. Triphasic

•Constant Estrogen &Progesterone levels throughout the cycle

Monophasic •Dose

of one(progesterone) or both (E+P) is changed once during the cycle

Biphasic

•Dose of one(progesterone) or both (E+P) is changed twice during the cycle

Triphasic

Preparations available

• Orally• Transdermal • Vaginal ring

The main advantage of bi and tri phasic administration

• Decrease the progesterone administration• Thus decrease the SE’s

Estrogen s

Ethinylestradiol Mestranol Quinestrol

Estrogen Mechanism of action as contraceptive

• Estrogen=proliferative agents

Progesterones

Highly androgenic

Norgestrel

Levo-norgestrel

Moderate-Low androgenic Norethindrone

Very low androgenic

Desogestrel

Nogestimate

Anti androgenic Cyproterone

Progesterone mechanism of action as contraceptive

• Inhibit ovulation 70-80%– Alteration in gonadotropin pulsing– Decrease pituitary gland response to GnRH

• Alter cervical mucosa • Increase endometrial secretion • Decrease peristalsis

The zygote unable to implant

Side effects and C\I of progesterones

• Increase the risk of osteoporosis• Increase risk of atherosclerosis • wt gain • Decrease in glucose tolerance

How to administer the combined pills?

• Take it daily for 21 days then 7 days free why?– To resemble the normal menstrual cycle

Benefits

• Decrease ovarian cancer• Decrease the endometrial cancer – Estrogen only products increase the risk of

endometrial cancer why?

Side effects of long term use of OC’s

• DVT• PE• Studies fail to approve the increased risk of

breast cancer• Gall bladder disease

Do OC’s cause infertility ?

• Chronic use depresses ovarian function • Ovaries become smaller• Majority of pts return to normal menstrual

patterns when the drug is discontinued • 75% will ovulate in the first posttreatment cycle• 97% will ovulate by the 3rd posttreatment cycle • About 2% remain amenorrheic for periods up

to several yrs

2- Minipills

• Contain only progesterone or its derivatives • Norgestrel and norethindrone are the most

widely used progesterone • Minipills must be used continuously without

free intervals like combined pills• Used in women when:– Estrogen is not desiered or C\I• Lactating women bec. Estrogen suppress the lactation

– Lactating women seeking contraception

Emergency Contraception

• Plan B / Morning After Pill– 0.75 mg levonorgestrel X 2 - within 5 days of unprotected

sex• Mechanism:– Inhibit LH surge – Thickens cervical mucus– Possible interference with fertilization or implantation

• WILL NOT HARM AN ESTABLISHED PREGNANCY!!!

• Now OTC!!!

Medical Abortion

• Mifepristone / RU-486– Inhibits progesterone receptors causing disruption at

implantation siteor

• Methotrexate– Inhibits dihydrofolate reductase (stops rapidly dividing

cells)

• Used with misoprostil– Prostaglandin analog produces uterine contractions

• Cheap, common medication also used for: arthritis, ulcers, constipation, cervical ripening

Preparation available

• Oral tablet• Implants – Norgestrel implant

• Intramuscular injection – Medroxyprogesterone

• Vaginal rings • Hormonal Intrauterine devices

Day after contraception

• Taken after unprotective sexual intercoarse• Exact mechanism of action unknown may be:

1. Inhibit ovulation 2. Inhibit transport of fertilized egg

• Efficacy 75-80%when taken within 72 hr after fertilization

• 3 approaches :1. High dose of estrogen and progesterone 2. Estrogen only • Must be combined with antiemetic drug

3. Mifeproston +misoprostol

Mifeproston

• Progesterone receptor antagonist– Also it is aglucocorticoid antagonist

• Used as an abortifacient in the first two months of pregnancy

• In smaller doses as an emergency contraceptive– Given along with misoprostol once within 72 hr

from unprotective coitus

Male contraception

• The identical agent is1. Decrease the spermatogenesis• Difficult to reach bec. Inhibition of 99% of sperms

would result in enough sperms for fertilization

2. No erectile dysfunction3. No decrease in libido

Mechanism of action of both testosterone and progesterone in male contraception

Decrease gonadotropins Decrease FSH

&LHDecrease

spermatogenesis

Hormonal antagonist

• We have talked about progesterone agonist and cyproterone

• Now ,we will talk about Selective estrogen receptor modulators SERM

SERM

Tamoxifen

Ralixofen

Clomiphene

Tormiphene

Mechanism of action

Drug Effect on Breast

Effect on endometrium

Bone

Tamoxifen + +

Ralixofen ++

Estrogen +++ +++ +++

SERMs uses

Tamoxifen,toremifene

• Breast cancer treatment • Prevent breast cancer in

high risk pts • Adjuvant in pts after

lumpectomy • May improve manic

episodes in pts with bipolar disorder(2007 study)

• Angiogenesis in cancer(see next slide)

• Gynecomastia• Anovulatory cycle in

inferile women • Retroperitoneal fibrosis

Ralixofen

• Osteoprosis treatment and prevention

• May have preventive effect on breast cancer

Clomiphene

• Induce ovulation

SERMs special considerations• Increase the risk of endometrial cancer• Not to be used more than 5 yr• Hot flushes N&V are common side effects• Taken 10-20 mg twice daily

Tamoxifen

• Has no thing to do with pituitary failure• Taken 100mg\day for 5 days usually at 3rd—5th day of the

menstrual cycle • SE: hot flushes, N&V, ovarian enlargement ,heavy

menses,headache,wt gain, multiple pregnancy(10%),may increase risk of ovarian cancerClomiphene