gonadal hormones and inhibitors

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology Drugs for Reproductive Endocrinology Leonila A. Estole-Casanova, MD Department of Pharmacology and Toxicology University of the Philippines – College of Medicine September 9, 2008 The GONADAL HORMONES and INHIBITORS

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Page 1: gonadal hormones and inhibitors

The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Drugs for Reproductive Endocrinology

Leonila A. Estole-Casanova, MDDepartment of Pharmacology and Toxicology

University of the Philippines – College of Medicine

September 9, 2008

The GONADAL HORMONES and INHIBITORS

Page 2: gonadal hormones and inhibitors

The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Outline

I. Review of the Menstrual Cycle & Steroidogenesis

II. Female Gonadal Hormones Estrogen and Progesterone ORAL CONTRACEPTION

I. Estrogen and Progesterone Inhibitors and antagonists

II. Male Gonadal Hormones III. Antiandrogens

Page 3: gonadal hormones and inhibitors

The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Outline

I. Review of the Menstrual Cycle & Steroidogenesis

II. Female Gonadal Hormones Estrogen and Progesterone –ORAL CONTRACEPTION

I. Estrogen and Progesterone Inhibitors and antagonists

II. Male Gonadal Hormones III. Antiandrogens

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Hypothalamic Pituitary Ovarian Axis

hypothalamus

Pituitary

ovary

progesteroneestrogen

Follicular growth and ovulation

+/-

+/-

+ GnRh

+ LH and FSH

Page 5: gonadal hormones and inhibitors

The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Gonadal Hormones Steroid hormones are derived from cholesterol Normal human ovary produces all three classes of

SEX STEROIDS divided into main groups according to the number of carbon atoms they possess:

1. 21 carbon series – PROGESTINS (pregnane nucleus)

2. 19 carbon series - ANDROGENS (androstane nucleus)

3. 18 carbon series - ESTROGENS (estrane nucleus)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Page 9: gonadal hormones and inhibitors

The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Outline

I. Review of the Menstrual Cycle and Steroidogenesis

II. Female Gonadal Hormones Estrogen and ProgesteroneORAL CONTRACEPTION

I. Estrogen and Progesterone Inhibitors and antagonists

II. Male Gonadal Hormones III. Antiandrogens

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Estrogens Major natural estrogens in human:

Actions mediated by ESTROGEN RECEPTORS (alpha and beta) which are ligand-regulated transcription factors

CH3OH

H

H

H

HO

ESTRADIOL

CH3

H

H

H

HO

O

ESTRONE

CH3OH

H

H

H

HO

OH

ESTRIOL

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Some synthetic estrogens

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Estrogens: Physiologic Effects Required for sexual maturation of the female Promote endometrial proliferation during

follicular phase Block resorption of bone Increase the levels of HDL and triglycerides and

decrease the levels of LDL and total cholesterol Increase SHBG, TBG, CBG, renin substrate Increase the levels of Factors II, VII, IX, X Induce the synthesis of progesterone receptors

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Estrogens: Pharmacokinetics Estradiol (E2) binds STRONGLY to α globulin (SHBG) LOWER affinity to albumin

E2 (liver) → Estrone (E1) and Estriol (E3) → hydroxylated derivatives and

conjugated metabolites

Orally administered estrogens have HIGH ratio of hepatic to peripheral effects

→ responsible for the increased clotting factors and increased renin substrate

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Progestins

Promote endometrial development during luteal phase

Decreases amount of cervical mucus and increases its viscosity

Increases basal body temperature

Progesterone is the most important progestin in human

Actions mediated by progesterone receptors (A and B isoforms) which are ligand-activated transcription factors

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Progestins

Stimulate growth and dev’t of breasts during pregnancy

Its effects on the uterus are essential for maintainance of pregnancy

Antagonize actions of aldosterone

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Progestins: Pharmacokinetics Progesterone is rapidly absorbed following

administration by any route t ½ is 5minutes Almost completely metabolized in one

passage through the liver

Page 17: gonadal hormones and inhibitors

The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Outline

I. Review of the Menstrual Cycle & Steroidogenesis

II. Female Gonadal Hormones

Estrogen and Progesterone

Oral contraceptionI. Estrogen and Progesterone Inhibitors and

antagonists

II. Male Gonadal Hormones

III. Antiandrogens

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Hormonal contraception in women

Combination of progestins and estrogens – Combination oral contraceptives (COCs)

Progestin only pills (POPs)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Combination Oral Contraceptives (COCs)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Combination Oral Contraceptives (COCs) – ESTROGEN component

20

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Pharmacology of the Estrogen Component of COCs E2 is the most potent natural estrogen ---

inactive orally E2 + ethinyl group at the 17 position =

Ethinyl Estradiol --- orally active

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Pharmacology of the Estrogen Component of COCs Metabolism of EE VARIES SIGNIFICANTLY

from individual to individual, and from one population to another

ESTROGEN CONTENT of the pill is of major clinical importance ---- THROMBOSIS is dose-related

DOSE OF ESTROGEN – a critical issue in selecting an oral contraceptive

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Combination Oral Contraceptives (COCs) – PROGESTIN component

23

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Pharmacology of the Progestin Component of COCs 2 major types of synthetic progestins1. Derivatives of 19 nortestosterone2. Derivatives of 17α acetoxyprogesterone

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Pharmacology of the Progestin Component of COCs

Removal of 19-carbon from ethisterone formed NORETHINDRONE → changed major hormonal effect from an androgen to progestational agent

→ 19 nortestosterone - all progestational agents have some degree of androgenic activity

ETHISTERONETESTOSTERONE NORETHINDRONE

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Pharmacology of the Progestin Component of COCs

ESTRANES Norethindrone Norethynodrel Norethindrone

acetate Ethynodiol acetate

GONANES Levonorgestrel Norgestimate* Gestodene* Desogestrel*

* With greater progestational activity

19 NORTESTOSTERONE

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Norethindrone family(most are converted to the parent compound, norethindrone) Norethindrone Norethynodrel Norethindrone acetate Ethynodiol diacetate Lynestrenol Norgestrel

The Pharmacology of the Progestin Component of COCs

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Other progestins Levonorgestrel is the active isomer of

norgestrel New progestins

Desogestrel, gestodene, norgestimate are derivatives of levonorgestrel

Reduced androgenicity (increased sex hormone binding globulin, decreased free testosterone)

Drospirenone – analogue of spironolactone, has affinity for mineralcorticoid receptor and antimineralcorticoid effect (Yasmin)

The Pharmacology of the Progestin Component of COCs

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

The Pharmacology of the Progestin Component of COCs

C21 progestins PREGNANES Structurally related to progesterone Medroxyprogesterone acetate and megestrol acetate Marketed for noncontraceptive usage Injectable depomedroxyprogesterone acetate

17 α ACETOXYPROGESTERONE

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs

“ Current formulations of COCs are made from SYNTHETIC steroids and contain no natural estrogens or progestins.”

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

synthetic progestins Ethinyl estradiol

COCs

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Definitions

Low Dose Oral Contraceptives – products with <50ug of EE

1st generation COCs – products with > 50ug of EE2nd generation COCs – products with

levonorgestrel, norgestimate, and other members of the norethindrone family and <50ug EE

3rd generation COCs – products with desogestrel or gestodene and <50ug of EE

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Usually containing ethinyl estradiol and norethindrone

Administered with interruption (21 days on, 7 days off)

Monophasic: All 21 active pills contain same amount of Estrogen/Progestin (E/P)

Biphasic: 21 active pills contain 2 different E/P combinations (e.g., 10/11)

Triphasic: 21 active pills contain 3 different E/P combinations (e.g., 6/5/10)

Types of COCs

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Suppress ovulation

Change endometrium making implantation

less likelyThicken cervical

mucus (preventing sperm penetration)

Reduce sperm transport in upper

genital tract (fallopian tubes)

COCs Mechanism of Action

Progestin suppresses LH secretionEstrogen suppresses FSH secretion

Progestin

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Oral Contraceptive Pills

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Efficacy Perfect use failure rate: 0.1% Typical use failure rate: 7.6% Pregnancies usually occur because initiation of

the next cycle is delayed Strict adherence to 7-pill free days is critical to

obtain contraception If with vomiting & diarrhea → back-up method

for 7days → put pill in the

vagina

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects - Thrombosis

Thrombosis can be divided into 2 major categories:

1. Venous thromboembolismdeep vein thrombosis

pulmonary embolism

2. Arterial thrombosismyocardial infarction

stroke

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects - Thrombosis Pharmacologic estrogen increases the production

of clottign factors (II, VII, IX, X)

Progestins have no significant impact on clotting factors

Past users of oral contraceptives DO NOT have an increases incidence of cardiovascular disease

Hypertension is a very important additive risk factor for stroke in OC users

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects - Thrombosis All low dose OCs, regardless of progestin type,

have an increased risk of VTE, concentrated in the 1st 2 years of use

Recent studies reinforce the belief that the risks of arterial and venous thrombosis are a consequence of the ESTROGEN component of COCs

Smoking has a lesser effect on the risk of venous thrombosis compared with arterial thrombosis

Smoking and estrogen have an additive effect on the risk of arterial thrombosis

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects - Thrombosis Low dose OCs DO NOT increase the risk of MI

or stroke in healthy, non-smoking women, regardless of age

Almost all MI and strokes in OC users occur in users of HIGH dose products or users WITH CARDIOVASCULAR RISK FACTORS

Cardiac deaths occurred in only in women who smoked >15 cigarettes per day

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects - Thrombosis New studies emphasize the importance of good

patient screening- arterial thrombosis is limited to older women

who smoke or have cardiovascular risk factors- no increase in mortality due to MI or stroke

in healthy, non-smoking women

If a patient has a family history of idiopathic thromboembolism, an evaluation to search for an underlying abnormality in the coagulation system is warranted

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Metabolic Effects - Conclusion

“ LOW DOSE oral contraceptives are VERY SAFE

for healthy young women.”

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs : Carbohydrate Metabolism Older high dose OCs – (+) impaired glucose

tolerance

Insulin sensitivity is affected mainly by the PROGESTIN component of the pill

Glucose intolerance is dose-related

Insulin and glucose changes with low dose monophasic and multiphasic OCs are so minimal and clinically insignificant

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs : Carbohydrate Metabolism

“ It can be stated definitely that oral contraceptive use DOES NOT produce an increase in diabetes

mellitus.”

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: The Risk of Breast Cancer Current and recent (1-4years) use of OCs may

be associated with 20% increased risk of early (<35) premenopausal breast cancer, essentially limited to localized and a vey small increase in the number of actual cases

May be due to: 1.) detection/surveillance bias2.) accelerated growth of already present malignancies

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: The Risk of Breast Cancer NO EFFECT of past use or duration of OC use

(up to 15 years of continuous use) NO INCREASED RISK on use of high dose OCs Previous use may be associated with a

REDUCED RISK of metastatic cancer LATER in life, and REDUCED RISK of postmenopausal breast cancer

NO INCREASED RISK in women with positive family history for breast cancer/women with benign breast disease

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Contraceptive Benefits Most important use is for ORAL

CONTRACEPTION Pelvic examination not required to initiate

use Do not interfere with intercourse Few side effects Convenient and easy to use Client can stop use Can be provided by trained non-medical

staff48

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Noncontraceptive Benefits

1. Incidental benefits2. Benefits to treat and manage problem and

disorders

49

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Incidental Benefits LESS ENDOMETRIAL CANCER

Use for 12 months reduces the risk by 50%

Greatest protective effect if use for >3 years

LESS OVARIAN CANCER

Risk is reduced by 40% (3 years) to 80% (>10 years of use)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Incidental Benefits Fewer ectopic pregnancies More regular menses – less flow,

dysmenorrhea, anemia Less salpingitis Increased bone density Possibly less benign breast disease Possibly fewer ovarian cysts

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Noncontraceptive Benefits

1. Incidental benefits2. Benefits to treat and manage problem

and disordersDysmennorheaEndometriosisReplacement therapy in ovarian dysfunctionDUBPostmenopausal symptoms

52

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Absolute Contraindications1. Thrombophlebitis, thromboembolic disorders,

cerebrovascular disease, coronary occlusion or past history of these conditions

2. Severe hypercholesterolemia or hypertriglyceridemia

3. Untreated hypertension4. Smokers over the age of 355. Known or suspected breast cancer6. Markedly impaired liver function7. Undiagnosed abnormal vaginal bleeding8. Known or suspected pregnancy

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Relative Contraindications

1. Systemic lupus erythematosus2. Sickle cell disease 3. Gestational diabetes mellitus4. Diabetes mellitus5. Hyperlipidemia6. Controlled hypertension7. Smoking8. Migraine headaches9. Seizure disorder

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Relative Contraindications

10. Hepatic disease11. Obstructive jaundice in pregnancy12. Gallbladder disease13. Mitral valve prolapse14. Uterine leiomyomas15. Elective surgery

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Clinical Decisions: Surveillance Can be prescribed without a clinical breast and

pelvic examination Patients need be seen only every 12months Perform yearly breast and pelvic examination on

follow up Reassess new users within 1-2months “ COCs are safer than most people think.

” FEAR OF SIDE EFFECTS: most common

reason why patients discontinue oral contraception

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Clinical Decisions: Surveillance Laboratory surveillance should be used only when

indicated The ff patients should be monitored with blood

screening tests for glucose, lipids and lipoproteins:Young women, at least onceWomen >35 y/oWomen with strong family history of heart disease, DM,HPNWomen with GDMObese womenDiabetic women

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Choice of Pill The therapeutic principle remains:

“ Utilize the formulations that give effective contraception and the greatest margin of safety.”

Current data support that there is GREATER safety with low dose preparations

There is LITTLE difference between the low dose monophasics and the multiphasics

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Pill taking Effective contraception is present during the

first cycle of pill use, provided the pills are started not later than the fifth day of the cycle and no pills are missed

Starting COCs on Day 1 o f menses ensure immediate protection

Some suggest starting on first Sunday following onset of menses Usually avoids menstrual period on weekends

Most clinicians recommend backup for 7 days

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Initiating Method

“Quick start” Starting the day of the counseling visit

regardless of patient’s day in her cycle Ensure not pregnant before starting Use backup method for 7 days Patients will not experience an increase

in BTB (breakthrough bleeding)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Pill taking Monthly, periodic or no bleeding is an

individual patient’s choice • No rationale for recommending a pill-

free interval to “rest” Serious side effects are not eliminated by

pill-free intervals (e.g. risk DVT) If pill free intervals are used, important to

not exceed 7 pill-free days However, studies have shown patients

who lengthened pill-free interval up to 11 days failed to show signs of ovulation

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Pill taking

How important is it to take OC at the same time

every day?

Precise pill taking minimizes breakthrough bleeding

Compliance is improved by a fixed schedule that is habit forming

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical Problems Breakthrough bleeding Amenorrhea Weight gain Acne Ovarian cysts

63

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical problems

BREAKTHROUGH BLEEDING1. Irregular bleeding in the first few months after

starting oral contraception2. Unexpected bleeding after many months of use

* There is NO evidence that the onset of bleeding is associated with decreased efficacy; no matter what oral contraceptive formulation is used, even the lowest dose products

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical problems

BREAKTHROUGH BLEEDING Most frequently encountered occurs in the first

few months of use Higher in women who smoke Best managed by ENCOURAGEMENT &

REASSURANCE Disappears by the 3rd cycle Represents tissue breakdown as the

endometrium adjusts from its usual thick state to the relatively thin state allowed by hormones in OC

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical problems

BREAKTHROUGH BLEEDING BB after many months of use is a

consequence of progestin-induced decidualization

Endometrium and blood vessels within the endometrium tend to be fragile and prone to breakdwon and asynchronous bleeding

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical problems

BREAKTHROUGH BLEEDING 2 factors associated with BB:1. Inconsistency of pill taking- more important

and has a greater effect in later cycles2. Smoking – exerts a general effect at any

time

REINFORCEMENT OF CONSISTENT PILL-TAKING can help minimize BB

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical problems

BREAKTHROUGH BLEEDING If bleeding occurs before the end of the cycle –

stop the pillswait 7 daysstart a new cycle

If BB is prolonged or is aggravating to the patient --

Conjugated estrogen 1.25mgEstradiol 2mg

7 days

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical problems

BREAKTHROUGH BLEEDING Taking of 2-3 pills is NOT effective The PROGESTIN component will always

dominate – doubling the pills → double the progestational impact → double the decidualizing and atrophic effect on the endometrium and destabilizing effect on endometrial blood vessels

ADD ESTROGEN ( do not add progestin)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical Problems

AMENORRHEA With low dose pills, the estrogen content is not

sufficient to stimulate endometrial growth Progestational effect dominates to such a degree

that a shallow atrophic endometrium is produced, lacking sufficient tissue to yield withdrawal bleeding → AMENORRHEA

There is no harmful permanent consequence of amenorrhea while on OC

ANXIETY in both patient and clinician -- major problem

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical Problems

AMENORRHEA Patient is anxious because of uncertainty regarding

pregnancy Clinician is anxious because of medicolegal

concerns stemming from old studies which indicated increased risk of congenital abnormalities

Recent reviews showed that there is NO ASSOCIATION between oral contraception and increased risk for congenital malformation and there is NO increased risk of having abnormal children

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical Problems

AMENORRHEA Incidence <2% in the 1st year of use Incidence INCREASES with duration of use

(5%) Management problem → ADEQUATE

COUNSELLING

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Clinical ProblemsWEIGHT GAIN Frequently cited as a major problem with compliance Studies FAIL to demonstrate a significant weight

gain with OC Major problem of perception – supported by the

finding that weight gain was identical in treated and placebo groups

Clinician has to REINFORCE the LACK OF ASSOCIATION between low dose OCs & weight gain and FOCUS on the real culprit: diet and level of exercise

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs : Ovarian Cysts Functional ovarian cysts occurred less

frequently in women on higher dose oral contraception

- this protection is reduced with current lower dose products

Ovarian cysts can be encountered in patients taking any of the oral contraceptive formulation

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Drugs that Affect Efficacy No evidence that antibiotics can affect OC

efficacy

Patients on the ff medications should choose an alternative contraceptive:CarbamazepinePhenytoinPhenobarbitalRifampicinEthosuzimide

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

COCs: Drugs that Affect Efficacy OCs potentiate the action of

DiazepamChlordiazepoxideTricyclic antidepressantsTheophylline

LOWER doses of the above agents in OC users

OCs alter clearance rates of Paracetamol and ASA

LARGER doses may be required in OC users

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Progestin-Only Pills (POPs)

77

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

POPs: Mechanisms of Action

Suppress ovulation (not consistently suppressed)

Change endometrium making implantation

less likelyThicken cervical mucus

(preventing sperm penetration)

? Reduce sperm transport in upper genital tract

(fallopian tubes)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

POPs: Mechanisms of Action Contains a small dose of a progestational

agent Must be taken daily in a continuous fashion Must be taken every day of the SAME TIME Change in cervical mucus

- requires 2-4hours to take effect

- impermeability diminishes 22 hours after administration

- by 24hours sperm penetration is essentially unimpaired

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

POPs: Efficacy Effective when taken at the same time every

day (0.05–5 pregnancies per 100 women during the first year of use)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

POPs: Contraceptive Benefits

81

Pelvic examination not required prior to use Do not interfere with intercourse Do not affect breastfeeding Immediate return of fertility when stopped Few side effects Convenient and easy-to-use Client can stop use Can be provided by trained nonmedical staff Contain no estrogen

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

POPs: Noncontraceptive Benefits

May decrease menstrual cramps May decrease menstrual bleeding May improve anemia Protect against endometrial cancer Decrease benign breast disease Decrease ectopic pregnancy Protect against some causes of PID

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POPs: Problems Irregular menstrual bleeding – major reason

why women discontinue POPs More functional ovarian cysts Levonorgestrel associated with acne

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

POPs: Pill taking Minipill should be started on the first day of menses Back-up method must be used for the 1st seven

days because some women may ovulate as early as 7-9 days after menses

Pill intake should be keyed to a daily event to ensure regular administration at the same time of the day

Missed pills – take missed pill ASAP, back-up method should be used until resumed for at least 2 days

If more than 3hrs late – back-up method for 2 days

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POPs: Clinical Decisions 2 situations in which excellent efficacy is achieved:1. Lactating women

- no evidence of any adverse effect on breastfeeding- women breasfeed longer and add summplementray feeding at a later time- can be started IMMEDIATELY after delivery

2. Women age over 40

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Outline

I. Review of the Menstrual Cycle & Steroidogenesis

II. Female Gonadal Hormones Estrogen and Progesterone - Oral contraception

I. Estrogen and Progesterone Inhibitors and antagonists

II. Male Gonadal Hormones III. Antiandrogens

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

SERMs Competitive partial agonist inhibitor of

estradiol at the estrogen receptor

Clomiphene Tamoxifen Raloxifene

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Selective estrogen receptor modulators (SERMs) and estrogen receptor antagonists

Bone Breast CV system

Uterus

estradiol Ag Ag Ag Ag

Clomiphene

ICI 182 780

Antag Antag Antag Antag

tamoxifen Ag Antag Ag Ag

raloxifen Ag Antag Ag Antag

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Ovulation Induction: Stimulate ovulation in women with

oligomenorrhea or anovulation Blocks the feedback inhibitory influence of

estrogens on the hypothalamus → surge of gonadotropins → ovulation

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Ovulation Induction Clomiphene at the start of the menstrual

cycle to prevent inhibitory effect of estrogen on FSH secretion

Clomiphene followed by FSH to stimulate follicular growth and hCG to stimulate ovulation

Long acting GnRH agonists (or antagonists) to inhibit pituitary function followed by FSH to stimulate follicular growth and hCG to stimulate ovulation

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Aromatase inhibitors

Inhibits conversion of testosterone to estradiol Useful in treatment of breast cancer Can be steroidal (formestane and

exemestane) or non steroidal ( anatrazole, letrozole)

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

RU 486 (mifepristone) Used for abortion (together with a

prostaglandin agonist) Post coital contraception Also a glucocorticoid receptor antagonist

ZK 98734 (lilopristone) Experimental stage Also a glucocorticoid receptor antagonist

Progesterone receptor antagonists

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Male Gonadal hormones

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Hypothalamic Pituitary Testicular Axis

hypothalamus

Pituitary

testes

Androgens T DHT

+ GnRh

+ LH and FSH

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Androgens and Anabolic Steroids Testosterone – most important androgen

secreted by the testis 95% produced by the Leydig cells; 5% by

the adrenal gland 65% of circulating T is bound to SHBG 2% remains free and available to enter cells

and bind to intracellular receptors T is converted to DHT by 5α reductase Conversion of T to E2 by P450 arom

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Testosterone Ineffective when given orally but can be

administered transdermally or parenterally Testosterone esters can be given

intramuscularly 17 - alkylated androgens are effective

when given orally but has more side effects, especially hepatic toxicity

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Physiologic Effects: Androgens General growth promoting properties of

androgens on body tissues Responsible for penile and scrotal growth and

changes in the skin ( appearance of pubic, axillary and beard hair)

Stimulate skeletal growth and epiphyseal closure Play an important role in stimulating and

maintaining sexual function in men Increase lean body mass Decrease SHBG, HDL; Increase LDL

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Some synthetic androgens

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Mechanism of Action: Androgens T acts intracellularly T → DHT (skin, prostate, seminal vesicles,

epididymis) All actions are mediated by the androgen

receptor which is a ligand activated transcription factor

T and DHT bind to intracellular androgen receptor → growth, differentiation, synthesis of proteins

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

Androgen therapy Main use as replacement therapy in male

hypogonadism Treatment of catabolic states

Adverse reactionsVirilization (in females, prepubertal boys)Feminization (males)Suppression of HPG axisEdema, jaundice, hepatic carcinoma

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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology

5 reductase inhibitors: Finasteride: treatment of BPH and male

pattern baldness Androgen receptor antagonists

Cyproterone acetate – for hirsutism

Flutamide, biclutamide, nilutamide:

treatment of prostate cancer, hirsutism, CAH and male precocious puberty

Spironolactone – aldosterone antagonist , for hirsutism

Anti-androgens