drugs for reproductive endocrinology: focus on ocp therapeutics ma. stephanie fay s. cagayan, md,...
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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
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-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
The Estrogens
Biosynthesis (chemical compositions)Mechanism of actionPharmacokinetic propertiesPhysiologic and Metabolic effectsClinical / Therapeutic ApplicationAdverse Effects
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
Biosynthesis (chemical compositions)Mechanism of actionPharmacokinetic propertiesPhysiologic and Metabolic effectsClinical / Therapeutic ApplicationAdverse Effects
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
Biosynthesis (chemical compositions)Mechanism of actionPharmacokinetic propertiesPhysiologic and Metabolic effectsClinical / Therapeutic ApplicationAdverse Effects
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
Biosynthesis (chemical compositions)Mechanism of actionPharmacokinetic propertiesPhysiologic and Metabolic effectsClinical / Therapeutic ApplicationAdverse Effects
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
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
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
The Pharmacology of the Progestin Component of COCs
2 major types of synthetic progestins
1. Derivatives of 19 nortestosterone
2. Derivatives of 17α acetoxyprogesterone
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
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
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)
The Pharmacology of the Progestin Component of COCs
The Pharmacology of the Progestin Component of COCs
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.”
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
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 - Thrombosis
Thrombosis can be divided into 2 major categories:
1. Venous thromboembolismdeep vein thrombosis
pulmonary embolism
2. Arterial thrombosismyocardial infarction
stroke
COCs: Metabolic Effects - Thrombosis
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
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
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
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
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
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
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