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
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
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
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)
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Some synthetic estrogens
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
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
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
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
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
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
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)
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
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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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Combination Oral Contraceptives (COCs) – PROGESTIN component
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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
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
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
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
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
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
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.”
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
synthetic progestins Ethinyl estradiol
COCs
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
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Oral Contraceptive Pills
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
COCs: Metabolic Effects
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
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
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
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
COCs: Metabolic Effects - Conclusion
“ LOW DOSE oral contraceptives are VERY SAFE
for healthy young women.”
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
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.”
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
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
COCs: Noncontraceptive Benefits
1. Incidental benefits2. Benefits to treat and manage problem and
disorders
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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)
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
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
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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
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
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
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
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
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
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
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)
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
COCs: Clinical Problems Breakthrough bleeding Amenorrhea Weight gain Acne Ovarian cysts
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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
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
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
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
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
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)
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
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
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
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
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
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Progestin-Only Pills (POPs)
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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)
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
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)
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
POPs: Contraceptive Benefits
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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
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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The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
POPs: Problems Irregular menstrual bleeding – major reason
why women discontinue POPs More functional ovarian cysts Levonorgestrel associated with acne
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
SERMs Competitive partial agonist inhibitor of
estradiol at the estrogen receptor
Clomiphene Tamoxifen Raloxifene
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
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
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
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)
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Male Gonadal hormones
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Hypothalamic Pituitary Testicular Axis
hypothalamus
Pituitary
testes
Androgens T DHT
+ GnRh
+ LH and FSH
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
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
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
The Gonadal Hormones and Inhibitors : Drugs for Reproductive Endocrinology
Some synthetic androgens
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
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
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