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 growth 2.Female libido 3.Metabolic effects inhibin – Inhibit FSH secretion Activin – Increase FSH secretion Relaxin – Decrease uterine contraction – Increase glycogen synthesis

Organ system effects f estrogen Estrogen Maturation and secndary sex characters in females Endocrine : 1- decrease FSH &LH 2-increase the renin activity Sebum Acne Hair growth Pigmentation TG,HDL LDL 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,ii And 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 CRH 2-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 migraine 2- Cholestasis 3- hypertension Side effects

Abnormal uterine bleedingThromboembolic disordersCholestasis and liver diseases High risk of estrogen dependent canrcinoma Psychosis Smokers Contraindications

Organ system effects of progesterone 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 MonophasicBiphasicTriphasic Progesteron e only pills After conception Male contraception Testosterone alone Testosterone +progesterone

Female contraception before 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 sEthinylestradiolMestranolQuinestrol

Estrogen Mechanism of action as contraceptive Estrogen=proliferative agents

Progesterones Highly androgenic NorgestrelLevo-norgestrel Moderate-Low androgenic Norethindrone Very low androgenic DesogestrelNogestimateAnti androgenicCyproterone

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 3 rd 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 site or 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 is 1.Decrease the spermatogenesis Difficult to reach bec. Inhibition of 99% of sperms would result in enough sperms for fertilization 2.No erectile dysfunction 3.No decrease in libido

Mechanism of action of both testosterone and progesterone in male contraception Decrease gonadotropins Decrease FSH &LH Decrease spermatogenesis

Hormonal antagonist We have talked about progesterone agonist and cyproterone Now,we will talk about Selective estrogen receptor modulators SERM

SERMTamoxifenRalixofenClomipheneTormiphene

Mechanism of action

DrugEffect 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 mg twice daily Tamoxifen Has no thing to do with pituitary failure Taken 100mg\day for 5 days usually at 3 rd —5 th 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 cancer Clomiphene