hormones of contraception Flashcards
GnRH agonists- +/-
when administered constantly, they inhibit
when pulsatile, stimulate
Gonadotropins (drug list by types)
Menotropins (hMG)
Follicle stimulating hormone
- Follitropin alfa, beta
- Urofollitropin (uFSH)
Leuteinizing hormone
- Lutropin alfa
Human choriogonadotropin hormone (rhCG)
Gonadotropin-releasing hormone analogs
- Leuprolide (prototype)
- Goserelin, Histrelin, Nafarelin, Triptorelin
- Gonadorelin (synthetic human GnRH)
Gonadotropin-releasing hormone antagonists
- Cetrorelix, Degarelix, Ganirelix
General Clinical Use of Estrogens & Progestins
Hormone contraception
- Estrogen-progestin combinations or progestin only
Treatment of hyperandrogenism and primary hypogonadism
- Estrogen-progestin combinations or progestin only
Postmenopausal hormone replacement therapy
- Estrogen alone or in combination with progestins
Treatment of hormone-responsive breast cancer and infertility
- Anti-estrogens
Prevention of breast cancer and osteoporosis
- Selective Estrogen Receptor Modulators (SERMs)
Medical abortion
- Anti-progestins
Endogenous Estrogens- effects on various systems
Female maturation
- Required for the normal sexual maturation and growth of the female
- Responsible for the accelerated growth phase and the closing of epiphyses of long bones that occur at puberty
Endometrial effects
- With progesterone causes regular periodic bleeding and shedding of the endometrial lining
Metabolic and cardiovascular effects
- Decrease the rate of bone resorption
- Increase HDL and TGs, slightly reduce LDL, and reduce total cholesterol levels
Effects on blood coagulation
- Enhance the coagulability of blood
most oral contraceptives include
ethinyl estradiol
natural estrogens
conjugated– Premarin (often used in hormone replacement therapy)
synthetic, steroidal estrogens
estradiol valerate
ethinyl estradiol
mestranol
Therapeutic Estrogens: Risks
Adverse effects
Nausea, breast tenderness, hyperpigmentation, increased frequency of migraines, cholestasis, gallbladder disease, hypertension
Uterine bleeding
Breast Cancer (frequently studied and debated)
Endometrial Cancer (concomitant use of a progestin is protective)
Contraindicated/use caution in patients with:
Estrogen-dependent neoplasms or at high risk
Undiagnosed genital bleeding
Liver disease
A history of thromboembolic disorder
Heavy smokers (≥15 cigarettes/day and age ≥ 35 years)
Cardiovascular disease (e.g., uncontrolled hypertension, stroke, ischemic heart disease)
Migraine with aura
Natural Progestins: Progesterone
Production during the luteal phase of the cycle decreases the frequency of GnRH pulses
Decreases estrogen-driven endometrial proliferation
Abrupt decline at the end of the cycle is the main determinant of the onset of menstruation
Key in maintaining pregnancy and mammary gland development (with estrogen)
Therapeutic Progestins- clinical uses and benefits
Clinical Uses
Primarily used for HRT (usually with estrogens), hormonal contraception (alone or in combination with estrogens), and emergency contraception
Also used to treat dysmenorrhea, endometriosis, bleeding disorders, and hot flushes in some menopausal women when estrogens are contraindicated
Benefits
Multiple administration routes, including long-acting reversible contraceptives (LARCs)
Useful when estrogen is poorly tolerated or contraindicated
therapeutic progestins- adverse effects and cautions
Adverse Effects and Cautions
Breakthrough bleeding is common with progestin-only contraceptives
HRT with an estrogen and progestin may increase the breast cancer risk compared to the risk in women taking estrogen alone
Progestins with androgenic effects – weight gain, acne, hirsutism, reduce plasma HDL levels
conditions in which a progestin-only contraceptive may be desirable
migraine headaches
age over 35 years and smoker or obese
history of thromboembolic disease
cardiac disease, especially coronary artery disease or heart failure
cerebrovascular disease
early postpartum period
htn with vascular disease or older than 35 years of age
SLE with vascular disease, nephritis, or antiphospholipid antibodies
hypertriglyceridemia
medroxyprogesterone acetate
(depo provera)
IM, PO
pK is favorable for IM/ PO
Diversity in Progestational Agents
Progestins vary in their estrogenic and androgenic potencies
More androgenic activity (e.g., L-Norgestrel, Norethindrone) leads to acne, hirsutism, weight gain, etc.
Progestins with lower (Norgestimate) or anti-androgenic (Drospirenone) potency used treat acne
Drospirenone containing OCs (Yasmin, Yaz) improve hirsutism and decrease blood pressure
Yaz has been shown to improve symptoms of premenstrual dysphoric disorder (PMDD)
Basic Molecular Mechanism of ER/PR-Induced Activation of Gene Transcription
use nuclear receptor
Heat shock protein
hormone response element
Combination Oral Contraceptives (COCs) MOA
MOA: Act by preventing ovulation via feedback inhibition of the hypothalamic-pituitary axis
Direct measurements of plasma hormone levels indicate
- LH and FSH levels are suppressed
- The mid-cycle surge of LH is absent
- Endogenous steroid levels are diminished
Block ovulation in 90-95% of cycles
Although either component alone can exert these effects, the combination synergistically decreases plasma gonadotropin levels and suppresses ovulation more consistently than either alone
Progestin-Only Pills (POPs) MOA
Highly efficacious but block ovulation in only ~60% of cycles
Effectiveness thought to be due largely to a thickening of cervical mucus (decreases sperm penetration) and to endometrial alterations that impair implantation
Depot injections are thought to exert similar effects, but also yield plasma levels of drug high enough to prevent ovulation in virtually all patients
Thought to be due to decreases in GnRH pulse frequency
Adverse Effects of Contraceptive Agents
Mild adverse effects
Nausea, mastalgia, breakthrough bleeding, and edema
Transient and mild headache; migraines often made worse (discontinue)
Moderate adverse effects Breakthrough bleeding (most common with progestins alone); bi- and triphasic contraceptives decrease this phenomenon Androgenic effects (acne improved with higher amounts of estrogens and anti-androgenic progestins) Amenorrhea (return to normal in a few months to several years)
Severe adverse effects
Vascular disorders – thromboembolic disease (due to estrogens), myocardial infarction and cerebrovascular disease (elevated risk in smokers)
Gastrointestinal disorders
Depression
Cancer (colorectal and ovarian cancer risk is reduced, endometrial cancer risk increases with estrogen and mitigated by addition of progestin, effects on risk of breast and cervical cancers is controversial)
Non-Contraceptive Benefits of COCs
Osteoporosis prevention
Reduce total cholesterol, increase HDL
Reduce risk of ovarian and colon cancers
Lower incidence of ectopic pregnancy
Lower incidence of benign breast disease
Reduction in dysfunctional uterine bleeding & dysmenorrhea
Improvement in premenstrual symptoms, hirsutism, & acne
Alternative Preparations: Progestin Only
Injectable preparations
- Medroxyprogesterone acetate (Depo-Provera, Depo-SubQ Provera 104)
- Injected intramuscularly or subcutaneously every 3 months
- The return of fertility can be delayed for 6-12 months after the last injection
Intrauterine Contraceptive Devices (IUDs)
- Several different levonorgestrel-containing devices that vary in size, hormone concentration, and duration of efficacy (3-7 years)
- Mirena effective for up to 7 years; FDA approved for up to 5 years of use
- Rapid return to fertility after removal; reduce dysmenorrhea
Implantable preparations
- Etonogestrel - only implantable preparation in the United States
- Placed under the skin of the upper arm and is effective for 3 years
- Bleeding abnormalities are common
- Fertility returns rapidly after removal in most patients
failure of contraceptive agents
Failure has been observed in patients who miss one or more doses
Drug-drug interactions are also known to reduce efficacy
- cytochrome P450 inducing agents (e.g., phenytoin, rifampin) may increase liver catabolism of estrogens or progestins
- antibiotics (because normal GI flora increase enterohepatic cycling and bioavailability of estrogens)
Mifepristone (RU-486)
pregnancy termination
MOA: a 19-norsteroid that acts as a progesterone receptor antagonist and induces luteolysis
Effective as an emergency postcoital contraceptive (but not available in the US for this indication) and may result in delayed ovulation in the following cycle (12-72 hr half-life may prolong the follicular phase of the subsequent cycle after large doses)
Primarily used in combination with a synthetic prostaglandin E1 (misoprostol)
Effectively terminates >95% of pregnancies when administered during the first 7 weeks after conception
Major adverse effect is prolonged bleeding – requires intervention in 5% of cases and is therefore only administered in the clinic by a physician
Levonorgestrel
(Plan B One-Step, Next Choice)- Morning After
MOA: progesterone receptor agonist; precise mechanism in emergency contraception is unknown
Does not reverse a pregnancy that has already occurred
More effective than estrogen-progesterone combinations and less likely to cause nausea and vomiting
No prescription required for women age 17 or older
Ulipristal acetate
Morning After
(Ella)
As effective as levonorgestrel (same mechanism) when used within 3 days and may be more effective 3-5 days after unprotected intercourse
May interfere with a pregnancy that has already been established
Requires prescription
