Drugs for Reproductive Endocrinology: Focus on OCP therapeutics Ma. Stephanie Fay S. Cagayan, MD, FPOGS

Drugs for Reproductive Endocrinology:

Focus on OCP therapeuticsMa. Stephanie Fay S. Cagayan, MD, FPOGS

General Objective

To acquire an understanding of the action of the different sex hormones and other hormones utilized in the pharmacology of hormonal contraception

Reference: Chapter 40, Basic and Clinical Pharmacology 1th edition (Katzung)

Specific Objectives

1. To be able to review the physiology of normal menstrual cycle

2. To list the different sex hormones, know their biosynthesis (chemical compositions), mechanism of action, pharmacokinetic properties, physiologic and metabolic effects

3. To describe clinical/therapeutic applications of these hormones

4. To list side effects and/or adverse reactions to these drugs

Outline

I. Physiology of Reproductive HormonesII. Female Gonadal Hormones

Estrogen and Progesterone ORAL CONTRACEPTION

Different Hormones in Reproductive Endocrinology

Biosynthesis (chemical compositions)Mechanism of actionPharmacokinetic propertiesPhysiologic and Metabolic effectsClinical / Therapeutic ApplicationAdverse Effects

Outline

I. Physiology of Reproductive Hormones

II. Female Gonadal Hormones Estrogen and Progesterone ORAL CONTRACEPTION

Sex hormones = gonadal hormones

estrogens

progestins

androgens Gonadotropins

LH

FSH GnRH

Gonadal Hormones

SYNTHESIS OF SEX STEROIDS

Gonadal Hormones

SEX HORMONES:

1. 21 carbon series – PROGESTINS (pregnane nucleus)

2. 19 carbon series - ANDROGENS (androstane nucleus)

3. 18 carbon series - ESTROGENS (estrane nucleus)

What regulates the synthesis of sex hormones?What regulates the synthesis of sex hormones?

Hypothalamic-Pituitary-Gonadal Axis

Hypothalamic-Pituitary-Reproductive Axis: TWO CELL-SYSTEMS

(Androstenedione)

(Testosterone)

Hypothalamic-Pituitary-Reproductive Axis: TWO CELL-SYSTEMS

LH FSHMALE Leydig Sertoli

Testosterone synthesis

Increases production of ABP

SSpermatogenesis

FEMALE Theca Granulosa

Androstenedione synthesis

Increases aromatase activity

Prerequisites of Normal Menstruation

an intact HPO axis estrogen-induced

proliferative endometrium ovulation at midcycle progesterone-induced

secretory endometrium if pregnancy does not

occur, the hormones decline, and withdrawal bleeding occurs

Major natural estrogens in human Actions mediated by ESTROGEN RECEPTORS (alpha and beta) which are ligand-regulated transcription

factors

The Estrogens

CH3OH

H

H

H

HO

ESTRADIOL

CH3OH

H

H

H

HO

OH

ESTRIOL

CH3

H

H

H

HO

O

ESTRONE

Some synthetic estrogens

The Estrogens


Steroid Hormone and its Receptor

Estrogen Receptor

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

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

Clinical / Therapeutic Application

Primary hypogonadism

Hormonal contraception

Post-menopausal hormonal therapy

The Estrogens


Adverse Effects

Uterine bleedingEndometrial cancerOther effects: nausea, breast

tenderness

The Natural Progestins: Progesterone

The most important progestin in human Serves as a precursor to the estrogens,

androgens and adrenocortical steroids Synthesized in the ovary, testis and adrenal

from circulating cholesterol; large amounts are also synthesized and released by the placenta during pregnancy

The Synthetic Progestins

Hydroxyprogesterone acetate

Medroxyprogesterone acetate

Megestrol Dimethisterone

* Most closely related to progesterone

Desogestrel Gestodene Norgestimate

** claimed to have lower androgenic activity than older synthetic progestins

21 carbon compounds 19-nor, 13 ethyl compounds

Actions are mediated by progesterone receptors (A and B isoforms) which are ligand-activated transcription factors The concentration of progesterone receptors is dependent on previous estrogen action

The Progestins

The Progestins


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 In the liver, it is metabolized to pregnanediol and

conjugated with glucuronic acid It is excreted into the urine as pregnanediol glucuronide

The Progestins


Physiologic Effects

Promote endometrial development during luteal phase

Decreases amount of cervical mucus and increases its viscosity

Increases basal body temperature

Progesterone ATTENUATES estrogen action on the endometrium in 3 ways:

By reducing the rate of synthesis of ER molecules

By increasing the rate of enzymatic inactivation

By effecting estrogen inactivation through sulfuration

The Physiologic Effect of Progestins

The Physiologic Effect of Progestins

Physiologic Effects: Progesterone

Has little effect on protein metabolismHas more marked effect on

carbohydrate metabolism:progesterone INCREASES basal insulin levels and the insulin response to glucose

Antagonize actions of aldosterone

Physiologic Effects: Progesterone

Increases body temperatureHas depressant and hypnotic effects on

the brain Increases ventilatory response to CO2

Stimulate growth and development of breasts during pregnancy

Its effects on the uterus are essential for maintenance of pregnancy

Clinical Application

THERAPEUTIC APPLICATION:Hormonal contraceptionHormonal replacement therapyEndometriosis

Clinical Application:

D

I

A

G

N

O

S

T

I

C

A test of estrogen secretion:

Progesterone challenge test - MPA 10mg/d for 5 days

- when endometrium has been stimulated by estrogens (+) withdrawal bleeding

Adverse Effects

HeadacheDizzinessBloating Weight gainReversible reduction of glucose

tolerance

Hormonal contraception in women

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

Progestin only pills (POPs)

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

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

COMBINATION ORAL CONTRACEPTIVES (COCS) – PROGESTIN COMPONENT

42

The Pharmacology of the Progestin Component of COCs

2 major types of synthetic progestins

1. Derivatives of 19 nortestosterone

2. Derivatives of 17α acetoxyprogesterone


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


ESTRANES Norethindrone Norethynodrel Norethindrone

acetate Ethynodiol acetate

GONANES Levonorgestrel Norgestimate* Gestodene* Desogestrel*

* With greater progestational activity

19 NORTESTOSTERONE

Other progestins Levonorgestrel is the active isomer of norgestrelNew 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 mineralocorticoid receptor and antimineralocorticoid effect (Yasmin)



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

17 α ACETOXYPROGESTERONE

COCs

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

synthetic progestins Ethinyl estradiol

Definitions

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

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

2nd 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

Types of COCs

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)

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 secretion

Estrogen suppresses FSH secretion

Progestin

the effect of a progestational agent will always take precedence over estrogen

Estrogen in the COCs

ESTROGEN serves 2 other purposes: 1) it provides STABILITY to the endometrium so that

irregular shedding and unwanted breakthrough bleeding can be minimized

2) It potentiates the action of the progestational agents -- allowed reduction of the progestational dose in the pill increasing the concentration of intracellular progestational receptors.

* Therefore a minimal pharmacologic level of estrogen is necessary to maintain the efficacy of the COCs

Oral Contraceptive Pills

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

COCS: METABOLIC EFFECTS

COCs: Metabolic Effects - Thrombosis

Thrombosis can be divided into 2 major categories:

1. Venous thromboembolismdeep vein thrombosis

pulmonary embolism

2. Arterial thrombosismyocardial infarction

stroke


Pharmacologic estrogen increases the production of clotting 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


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


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


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

COCs: Metabolic Effects - Conclusion

“ LOW DOSE oral contraceptives are VERY SAFE for healthy young women.”

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

COCs : Carbohydrate Metabolism

“ It can be stated definitely that oral contraceptive use DOES NOT produce

an increase in diabetes mellitus.”

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 very small increase in the number of actual cases

May be due to:

1.) detection/surveillance bias

2.) accelerated growth of already present malignancies

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

COCs: Contraceptive Benefits68

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 staff

COCs: Noncontraceptive Benefits

69

1. Incidental benefits

2. Benefits to treat and manage problem and disorders

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

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

COCs: Noncontraceptive Benefits

72

1. Incidental benefits2. Benefits to treat and manage problem

and disordersDysmennorheaEndometriosisReplacement therapy in ovarian dysfunctionDUBPostmenopausal symptoms

COCs: Absolute Contraindications

1. 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

COCs: Relative Contraindications

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

COCs: Relative Contraindications

10. Hepatic disease

11. Obstructive jaundice in pregnancy

12. Gallbladder disease

13. Mitral valve prolapse

14. Uterine leiomyomas

15. Elective surgery

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

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

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

Progestin-Only Pills (POPs)

89

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)

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

POPs: Contraceptive Benefits

93

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

POPs: Noncontraceptive Benefits

94

May decrease menstrual crampsMay decrease menstrual bleedingMay improve anemiaProtect against endometrial cancerDecrease benign breast diseaseDecrease ectopic pregnancyProtect against some causes of PID

POPs: Clinical Decisions

2 situations in which excellent efficacy is achieved:

1. Lactating women

- no evidence of any adverse effect on breastfeeding

- women breastfeed longer and add supplementary feeding at a later time

- can be started IMMEDIATELY after delivery

2. Women age over 40

Postcoital contraception

Types:

estrogen (ethinyl estradiol) + progestin (norgestrel); estrogen alone

progestin aloneHigh doses but for a few daysEffectiveness: 90-98% if taken within 72

hours of unprotected intercourse

Mechanism of action• If fertilization has occurred: prevents

implantation, promotes menstrual bleeding

• If fertilization has not occurred: decrease the amount and increase the viscosity of cervical mucus, suppress the hypothalamic-pituitary- gonadal axis, impair ovum transport

Adverse effects• nausea and vomiting, headache, dizziness,

breast tenderness, abdominal and leg cramps

Post-coital contraception

Schedules for Use of Post-coital Contraceptives

Conjugated Estrogens

10mg TID for 5 days

Ethinyl Estradiol 2.5mg BID for 5 days

Mifepristone 600mg once (with Misoprostol 400 ucg once)

L-Norgestrel 0.75mg BID for 1 day

NorgestrelEE

0.5mg 2 tab and 0.05mg 2 tabs in 12 hours

Documents

Drugs for Reproductive Endocrinology: Focus on OCP therapeutics Ma. Stephanie Fay S. Cagayan, MD, FPOGS