Estrogen ,progestogen and contraceptives 1

Goals 1.To grasp the pharmacological effects, clinical uses, adverse drug reactions and precautions of oral contraceptives. 2. To understand the pharmacological characteristic of estrogen and anti-estrogen drugs, and progestational hormone.

Mainly by the gland secretion, belongs to the steroid compounds Estrogen (estrogen) : mainly by the secretion of ovarian theca cells ,Estradiol (estradiol, E2)

Mainly by the gland secretion, belongs to the steroid compounds Progesterone (progestogen) : mainly secreted by the corpus luteum of pregnancy Androgen (androgen) : mainly secreted by the leydig cells.

I. Female Hormone System Hypothalamus Gonadotropin-Releasing Hormone (GnRH) Gonadotropin Hormone: Follicle-Stimulating Hormone (FSH) Luteinizing Hormone (LH) Estrogen/Progesterone; Inhibin

The secretion of hormones — ultrashort feedback + hypothalamus（GnRH) +positive feedback + anterior pituitary gland (FSH,LH) -negative feedback Long feedback + Ovary (testes) Long feedback + sex hormone

Stimulate spermatogenesis Stimulate follicular development; estrogen Hypothalamus GnRH FSH LH Stimulate follicular development; estrogen anterior pituitary gland Corpus luteum generated, secretion of progesterone; Promote the secretion of leydig cells androgens Stimulate spermatogenesis

Sex Hormone Secretion in Ovarian Cycle Luteal Phase Follicular Phase Sex Hormone Secretion in Ovarian Cycle Cell type Granulosa cells Lutein cells Estrogen Hormone Estrogen Progesterone (Inhibin) Estrogen Progesterone

Hypothalamus GnRH FSH LH Estrogen Progesterone Estrogen

Section 1 Estrogen and anti-estrogen drugs Natural: estradiol Metabolites:estrone, estriol Synthesis: ethinylestradiol, quinestrol, pentanoic acid estradiol diethylstilbestrol

Estrogen Functions of Estrogen Effect on the uterus and female sex organs; Effect on the fallopian tubes and breast; Effect on the Skeleton; ;

Estrogen Functions of Estrogen Effect on hair distribution and skin; Effect on protein Deposition, fat deposition and body metabolism; Effect on hair distribution and skin; Effect on electrolyte balance; ;

oral effect is good, more durable. Synthetic ethinylestradiol , quinestrol or diethylstilbestrol damage slowly in liver. oral effect is good, more durable.

Oil solution preparation or with adipose acidification in synthesis of ester, by i.m, can delay the absorption, prolong the action time.

Mechanism of estrogen Estrogen receptors (ER) are members of the nuclear receptor superfamily are activated by small lipophilic molecules

Two distinct estrogen receptor molecules exist: ERa and ERß.

Mechanism of estrogen When combined with estrogen: estrogen appears to inhibit gene transcription when bound to ERß whereas transcription is activated when estrogen is bound to ERa.

Estrogens act as signaling molecules by interacting with specific target cells: Include breast, uterus, brain, heart, liver, and bone.

Pharmacological effects To promote development of secondary sex characteristics and sexual organ

Pharmacological effects To participate in the formation of menstrual cycle (proliferation of endometrial thickening and the synergistic by progesterone, the endometrium into secretory phase)

Pharmacological effects Resistance of ovulation function and inhibit secretion of milk (in large doses)

Pharmacological effects Water and salt metabolism: mild water and sodium retention

Pharmacological effects Bone calcium deposition, accelerate the epiphyseal closure Promote growth and development in adolescent.

Pharmacological effect Prevention bone loss of postmenopausal women. Other: lower LDL, increase HDL.

Pharmacological effect Also lower the glucose tolerance. Still promote clotting.

1．Primary hypogonadism Clincal uses 1．Primary hypogonadism Ovarian hypoplasia or low function, artificial menstrual cycle. Be used extensively for replacement therapy in estrogen-deficient patients

2. Dysfunctional uterine bleeding : Clinic application 2. Dysfunctional uterine bleeding : Promote hyperplasia of endometrium, repair, wound hemostasis state. (combined with progestin)

3．Menopausal syndrome: Clincal uses 3．Menopausal syndrome: Sweating, nausea, insomnia, obesity and emotional upset. Appropriate supplementary estrogen, can feedback inhibition secretion of GnRH, FSH and LH, relieve symptoms.

3．Menopausal syndrome: With the lowest dose of estrogen required for symptomatic relief Treatment may be required for only a limited period of time Because the possible increased risk for breast cancer avoided.

4. Prevention and treatment osteoporosis in postmenopause Clinic application 4. Prevention and treatment osteoporosis in postmenopause

[Clincal uses] high-dose estrogen can inhibit the FSH secretion. 5．Contraception : high-dose estrogen can inhibit the FSH secretion.

6. Breast cancer (!) [Clincal uses] Large doses of estrogen can inhibit gonadotropic hormone secretion reduce endogenous estrone, for advanced breast cancer more than 5 years in patients postmenopausal .

estrogen therapy available, remission rate of 40% Before menopause fornbided patients

7．Prostate cancer High-dose estrogen inhibits gonadotropic hormone secretion, as the role of antagonism androgen. 8．Breast pain : Interfere with the prolactin, inhibition the secretion of milk

Through influencing lipoprotein metabolism and direct effect on 9．Others To Cardiovascular disease: Through influencing lipoprotein metabolism and direct effect on blood vessels Small doses, prevention of coronary heart disease---- myocardial infarction.

Untoward effects Uterine bleeding Especially in postmenopausal Unfortunately, vaginal bleeding at this time(in postmenopausal ) may also be due to carcinoma of the endometrium.

Untoward effects Uterine bleeding In order to avoid confusion, should be treated with the smallest amount of estrogen possible.

Untoward effects Anorexia, nausea ( should start from small doses ) Long used may be as the cause of excessive endometrial hyperplasia

Untoward effects Increase the risk of endometrial carcinoma Sodium water retention, high blood pressure Liver function is bad

Contraindications With estrogen-dependent neoplasms such as carcinoma of the endometrium At high risk for—carcinoma of the breast. With undiagnosed genital bleeding liver disease Thromboembolic disorder.

Tamoxifen (tamoxifen) Antiestrogen drugs Tamoxifen (tamoxifen) a competitive antagonist of estradiol at the estrogen receptor

Tamoxifen (tamoxifen) extensively used in the palliative treatment of breast cancer in postmenopausal women is approved for chemoprevention of breast cancer in high-risk women

Tamoxifen (tamoxifen) Hot flushes , nausea , vomiting occur in 25% of patients

been approved for the prevention of postmenopausal osteoporosis Antiestrogen drugs Raloxifene (raloxifene) been approved for the prevention of postmenopausal osteoporosis prophylaxis of breast cancer in women with risk factors

The secretion of hormones — ultrashort feedback + hypothalamus（GnRH) +positive feedback + anterior pituitary gland (FSH,LH) -negative feedback Long feedback + Ovary (testes) Long feedback + sex hormone

Antiestrogen drugs Clomiphene citrate (clomifene ) in the hypothalamic level, prevent normal negative feedback modulation promote the secretion of GnRH and gonadotropin stimulate the secretion of the ovaries -----estrogen

Can be used to amenorrhea, infertility and dysmenorrhea , etc Clomiphene citrate (clomifene ) Can be used to amenorrhea, infertility and dysmenorrhea , etc

Section 4 Contraceptives

Natural: progesterone Section 2 Progestins Natural: progesterone 17-hydroxyprogesterone Active similar to progesterone Synthetic Progestins Progesterone +Mild androgen 19-methyl testosterone

Progesterone in the major natural progestin. Secretion: Mainly by the corpus luteum of the ovary during the second phase of the menstrual cycle.

Functions of progesterone Effect on the uterus, fallopian tubes and breast; Effect on the body temperature;

Before Ovulation After Ovulation

Functions of progesterone The abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation.

Functions of progesterone Effect on the body temperature; Feedback effect on Anterior Pituitary Gland

Physiological Effects: Development of the endometrium. Development of the mammary gland during pregnancy.

Physiological Effects: Milk secretion stats when its level decrease with birth. Thermogenic action.

Pharmacokinetics Progesterone destroyed rapidly in gastrointestinal and liver after oral, effect is poor The injection is adopted. The oil solution can play a long-acting role by intramuscular.

Pharmacological effects Progesterone suppresses menstruation and uterine contractility. Inhibition of the anterior pituitary LH secretion, thereby inhibiting the ovaries during ovulation.

Pharmacological effects Make endometrial from proliferation to the development of a secretory endometrium It is advantageous to embryo implantation and development.

Pharmacological effects Can promote mammary gland development, prepare for lactation.

Pharmacological effects Metabolism: competitive against aldosterone, diuresis. Elevated temperature:

Clinic application Dysfunctional uterine bleeding Dysmenorrhea when estrogens are contraindicated

Clinic application Threatened abortion and habitual abortion Endometrial adenocarcinoma, hypertrophy of prostate and prostate cancer

Untoward effects With less adverse reaction, accidentally dizziness, nausea, breast tenderness, etc.

Untoward effects Long-term use can cause endometrial atrophy, decrease menstrual flow, and prone to vaginal fungal infection.

Untoward effects Large doses 19-Nortestosterone can cause liver dysfunction

Section 3 androgen drugs and anabolic steroids Natural: testosterone Synthesis: testosterone and its derivatives

Pharmacokinetics Testosterone is administered by oral, but was quickly destroyed by liver A testosterone not easily destroyed under the tongue.

Function: Increased protein synthesis, promote muscle development, increase appetite, bring comfort.

Clinical used Malnutrition Recovery after surgery Fracture healing Senile osteoporosis

Clinical used Anemia Severe burns tumor chemotherapy period, etc.

Section 4 Contraceptives

Female contraceptives Oral 1.Combined pill 2.Phased regimens 3.Minipill(progestin only pill) 4.Postcoital(emergency) contraception Injectable Male contraceptive

Female contraceptives

Types of Oral Contraceptives Pills: Combined Oral Contraceptives Phased regimen Mini Pills (Progesterone Only Pills) Postcoital (Emergency Contraceptives) Pills

A large number of oral contraceptives containing estrogens or progestins (or both) are now available for clinical use

Section 4 Contraceptives

1. Pharmacological effects To inhibit ovulation Chronic use of combination agents depresses ovarian function combinations of estrogens and progestins

Alter cervical mucus Alter endometrial form and function Alter function of fallopian tube

1. Pharmacological effects To inhibit ovulation Prevention of implantation stimulates more glandular atrophy ，endometrial fibrosis

Inhibition of Ovulation: Estrogen Inhibits ovulation by suppressing FSH and LH Alters endometrium secretions Progestin Suppresses LH secretion Thickens cervical mucus preventing/hindering sperm transport

Inhibition of Ovulation: Thins endometrium preventing ovum implantation Interferes with secretory /peristaltic function inside fallopian tubes

Oral Contraceptives Generation: 1st Generation Norethindrone Norethynodrel -derivative of Norethindrone 2nd Generation Norgesterl Levonorgestrel 3rd Generation Desogestrel Norgestimate Gestodene Estrogen Derivatives Mestranol Ethinyl Estradiol

Combine Oral Contraceptives (COCs): Contains estrogen ( ethinylestradiol ) dose 20-50µg Progestin ( levonorgestrel , desogestrel ) dose 0.15- 1.5mg

Combine Oral Contraceptives (COCs): Both synergies to inhibit ovulation, Progestin ensures prompt bleeding at end of cycle and blocks the risks of endometrium carcimona

Combination Preparation: Estrogens and Progesterone from the beginning to the end in small doses. 99- 100% successful. Mechanism: The above two types inhibit both FSH and LH so prevent ovulation.

Female Oral Contraceptive Sequential Preparations: Estrogens for 16 days then Estrogen and Progesterone for 5- 6 days. 98- 99% successful.

Phased Regimens: Biphasic and Triphasic Estrogen step down and Progestin Step up type regimens Estrogen kept constant or slightly changed while Progestin is high in 2 nd and 3 rd phase.

Phased Regimens: Uses for better menstrual cycle control and increase efficacy Recommended for women > 35 yrs or other risk factors present like massive menstrual bleeding

Minipill (progesterone only Pill): Small doses of Progesterone from the beginning to the end. 97- 98% successful.

Minipill (progesterone only Pill): Mechanism: Alter the structure of the endometrium. Increase consistency of the cervical mucus.

Minipill (progesterone only Pill): Risk of ectopic pregnancies among users not so common Recommended for Smokers, breast feeding , older women's and other health problems

Postcoital (emergency) contraception: 3 regimen usually available (levonorgestrel 0.5mg + ethinylestradiol 0.1 mg ) Levonorgestrel along 0.75 mg

Postcoital (emergency) contraception: Should be taken as early as possible within 72 hours of unprotected intercourse repeated after 12 hrs

Adverse Effects: Common nausea, vomiting, breast tenderness, breakthrough bleeding (progestin) , migrane precipitation etc. Frequent in 1-3 cycles and gradually disappear

Adverse Effects: Long term use effect weight gain, chloasma intolerence

Adverse Effects: carbohydrate intolerence , mood swing increase body hair Newer contraceptives have less effects

Contraindication: < 6 weeks postpartum if breastfeeding Smoker over the age of 35 (≥ 15 cigarettes per day) Hypertension (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg)

Contraindication: Current or past history of venous thromboembolism (VTE) Ischemic heart disease History of cerebrovascular accident Complicated valvular heart disease Migraine headache with focal neurological symptoms

Contraindication: Breast cancer (current) Diabetes with retinopathy/nephropathy/neuropathy Severe cirrhosis Liver tumour (adenoma or hepatoma )

2.Preventing fertilised ovum nidation Endometrium is either hyperproliferative or hypersecretory or atrophic and in any case----not suitable for nidation(mainly by minipills and postcoital)

2.Preventing fertilised ovum nidation not limited by the menstrual cycle, no matter developing follicles, ovulation or corpus luteum , can prevent nidation.

3.Male contraceptive The only way is to inhibit spermatogenesis But no satisfactory solution is tangible

Reasons are: affect other tissues 2. Spermatogenesis takes 64 days 1.Complete suppression of spermatogenesis is difficult without affect other tissues 2. Spermatogenesis takes 64 days no drugs take a long period 3.Men don’t get pregnant

Estrogens, progestins, contraceptives: action, use, mechanism of action, adverse reactions.