contraceptive and pro-fertility agents
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CONTRACEPTIVE AND PRO-FERTILITY AGENTS
Yulia Komarova, Ph.D.312-996-1332
ykomarov@uic.edu
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Knowledge Objectives
1. Know the methods of contraception2. Understand the mechanisms of action and major
pharmacological effects of oral contraceptives (OCP’s)3. Understand the mechanism of action of postcoital
contraceptives4. Know benefits and adverse effect of contraceptives5. Understand the main principles of treatment of the male
and female infertility6. Know the first-line and second-line pro-fertility agents:
clomiphene and exogenous gonadotrophins 7. Know the major therapeutic uses of synthetic GnRH
agonists and antagonists
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ContraceptivesOral contraceptives: (OCP’s)1. Combination contraceptives – contain both estrogenic and
progestogenic agents• Monophasic• Multiphasic
• Biphasic• Triphasic
2. Progestin-Only contraceptives, “minipill” - continuous use of progestin only
Other contraceptives:
• ORHTO EVRA – transdermal (both estrogenic and progestogenic)
• NUVARING – hormone-releasing intravaginal ring (both hormones)
• DMPA – injection of progestin• IMPLANON (etonogestrel) – implantable • IUD and MIRENA – insert and an intrauterine device -
progestin only
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Estrogen (mg) Progestin (mg)Monophasic combination tablets Alesse, Aviane, Lessinea, Levlite Ethinyl estradiol 0.02 L-Norgestrel 0.1
Levlen, Levora, Nordette, Portia Ethinyl estradiol 0.03 L-Norgestrel 0.15
Crysella, Lo-Ovral, Low-Ogestrel Ethinyl estradiol 0.03 Norgestrel 0.30
Yasmin Ethinyl estradiol 0.03 Drospirenone 3.0 Brevicon, Modicon, Necon 0.5/35, Nortrel 0.5/35
Ethinyl estradiol 0.035 Norethindrone 1.0
Ortho-Cyclen, Sprintec Ethinyl estradiol 0.035 Norgestimate 0.25
Necon 1/35, Norinyl 1+, Nortrel 1/35, Ortho-Novum 1/35
Ethinyl estradiol 0.035 Norethindrone 1.0
Ovcon-35 Ethinyl estradiol 0.035 Norethindrone 0.4 Demulen 1/50, Zovia 1/50E Ethinyl estradiol 0.05 Ethynodiol
diacetate1.0
Ovcon 50 Ethinyl estradiol 0.05 Norethindrone 1.0 Ovral-28 Ethinyl estradiol 0.05 D,L-Norgestrel 0.5 Norinyl 1/50, Ortho-Novum 1/50 Mestranol 0.05 Norethindrone 1.0
Biphasic combination tablets Ortho-Novum 10/11, Necon 10/11 Days 1–10 Ethinyl estradiol 0.035 Norethindrone 0.5 Days 11–21 Ethinyl estradiol 0.035 Norethindrone 1.0
Oral Contraceptives (OCP’s)
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Oral Contraceptives (OCP’s)Triphasic combination tablets Enpresse, Triphasil, Tri-Levlen, Trivora Days 1–6 Ethinyl estradiol 0.03 L-Norgestrel 0.05 Days 7–11 Ethinyl estradiol 0.04 L-Norgestrel 0.075 Days 12–21 Ethinyl estradiol 0.03 L-Norgestrel 0.125 Ortho-Novum 7/7/7, Necon 7/7/7 Days 1–7 Ethinyl estradiol 0.035 Norethindrone 0.5 Days 8–14 Ethinyl estradiol 0.035 Norethindrone 0.75 Days 15–21 Ethinyl estradiol 0.035 Norethindrone 1.0 Ortho-Tri-Cyclen Days 1–7 Ethinyl estradiol 0.035 Norgestimate 0.18 Days 8–14 Ethinyl estradiol 0.035 Norgestimate 0.215 Days 15–21 Ethinyl estradiol 0.035 Norgestimate 0.25Daily progestin tablets
Nora-BE, Nor-QD, Ortho Micronor, Jolivette, Camila, Errin
none Norethindrone 0.35
Ovrette none D,L-Norgestrel 0.075Implantable progestin preparation
Implanon none Etonogestrel (one tube of 68 mg)
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Mechanism of ActionCombination contraceptives • prevent ovulation• selectively suppress FSH and LH secretion and depresses
ovarian function• decreases chance of conception and implantation
secondary to changes in the cervical mucus and uterine endometrium
Progestin-Only Contraceptives• is used if there is a contraindication to estrogen or if the
patient is post-partum and breastfeeding (theoretical risk of decreasing milk production)
• prevent ovulation only 60-80% of cycles• cause a thickening of cervical mucus and prevent sperm
penetration• cause endometrial alterations that impair implantation
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Benefits of Oral Contraceptives
• Reduction of pregnancies• Reductions of menstrual disorders• Reduction of premenopausal/menopausal symptoms• Reduction of reproductive organ neoplasms• Treatment of reproductive disorders (pelvic
inflammatory disease & endometriosis)• Reduced incidence of ectopic pregnancies• Other: reduction of acne, anemia, ulcers, rheumatoid
arthritis
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Pharmacologic Effect of Contraceptive Agents
Ovary follicular development is minimal; corpora lutea, larger follicles, stromal edema are absent; the ovaries become smaller
Uterus hypertrophy and polyp formation in the cervix; thickening the cervical mucus;
Breast enlargement; suppression of lactation
Endocrine Function the inhibition of pituitary gonadotropin secretion; increase in the plasma concentration of the corticosteroid-binding globulin; increase in plasma renin activity
Blood serious thromboembolic phenomena; an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III; an increase in serum iron and total iron-binding capacity
Liver serum haptoglobins produced in the liver are depressed; delayed clearance of sulfobromophthalein and reduce the flow of bile
Lipid Metabolism increase in serum triglycerides and free and esterified cholesterolCarbohydrate Metabolism
reduction in the rate of absorption of carbohydrates from the gastrointestinal tract; glucose tolerance
Cardiovascular System increases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate
Skin increase pigmentation of the skin
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Severe Adverse Effects
Vascular Disorders thromboembolism; the risk of venous thrombosis or pulmonary embolism increases 3 times;
venous thromboembolism appears to be related to the estrogen but not the progestin content of oral contraceptives
Myocardial Infarction a slightly higher risk of myocardial infarction in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes. There is a much higher risk in women who smoke.
Cerebrovascular Disease
the risk of stroke is concentrated in women over age 35.
Gastrointestinal Disorders
cholestatic jaundice; symptomatic gallbladder disease, including cholecystitis and cholangitis; ischemic bowel disease secondary to thrombosis of the celiac and superior and inferior mesenteric arteries and veins
Depression in about 6% of patientsCancer reduced risk of endometrial and ovarian cancer
risk of cervical and breast cancer is controversial
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Contraindications Relative Contraindications
Clotting disorders Known cancer Hepatic disorders Diabetes - insulin Pregnancy Age older than 35
years and smoker
Migraine Hypertension Varicose veins Cardiac/renal
dysfunction Diabetes w/o insulin Hepatitis Hypercholesterolemia
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Drug Interactions
• Drugs that can decrease the effectiveness of combination-type birth control pills:
• antibiotics (cephalosporins, chloramphenicol, macrolides, penicillins, tetracyclines, sulfas, rifamycins),
• aprepitant (anti-nausea and -vomiting), • bexarotene (T-cell lymphoma), • bosentan (PAH), • dapsone (Dermatitis herpetiformis), • griseofulvin (antifungal), • certain HIV protease inhibitors (amprenavir, nelfinavir, ritonavir,
nevirapine), • modafinil (narcolepsy, obstructive sleep apnea, and shift work
disorder), • seizure medications (barbiturates, carbamazepine, phenytoin,
primidone, topiramate)
• Birth control pills may significantly intensify the effects of alcohol.
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Postcoital Contraceptives
Conjugated estrogens: 10 mg three times daily for 5 daysEthinyl estradiol: 2.5 mg twice daily for 5 daysDiethylstilbestrol: 50 mg daily for 5 daysMifepristone: 600 mg once with misoprostol, 400 mg once L-Norgestrel: 0.75 mg twice daily for 1 day (Plan B) Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (eg, Ovral, Preven): Two tablets and then two in 12 hours
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Progesterone Antagonist as Contraceptives
• Mifepristone, a "19-norsteroid“, that binds strongly to the progesterone receptor and inhibits the activity of progesterone
• In the early stage of pregnancy causes detachment of the blastocyst following decrease in hCG and progesterone production, which facilitates expulsion of blastocyst.
• is used as postcoital contraceptive for termination of early pregnancy with >90% success
• The combination of a single oral dose of 600 mg of mifepristone and a vaginal pessary containing 1 mg of prostaglandin E1 or oral misoprostol can effectively terminate pregnancy in over 95% of patients treated during the first 7 weeks after conception.
Drug Interactions• "blood thinners" such as warfarin and aspirin can increase the risk
of bleeding • long-term corticosteroid therapy • drugs affecting liver enzymes such as azole antifungals, macrolide
antibiotics (erythromycin, dexamethasone, rifamycins) • anti-seizure medicines
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Case Study• A 23-year-old G0 P0 female presents with complaints of irregular
cycles since menarche. • She also has noticed an increase in facial hair and acne for many
years. • She has a strong family medical history of diabetes.
• On examination, she is noted to have a normal blood pressure, pulse, respiratory rate, and temperature.
• She is obese with a body mass index of 34. • She is noted to have some hirsutism and acanthosis nigricans. • Her pelvic examination is normal. Her pregnancy test is negative.
Clinical Approach to Polycystic Ovarian Syndrome (PCOS)• Laboratory studies to be considered are TSH, prolactin, lipid
profile, glucose-intolerance screening, endometrial biopsy, 17-hydroxyprogesterone.
• Testosterone and dehydroepiandrosterone (DHEAS) levels should be assessed when clinical signs of excess androgen stimulation are present.
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Case StudyOverall treatment goals• Reduce circulating androgen levels• Protect the endometrium from unopposed estrogen and reduce risk
of endometrial cancer• Encourage weight loss and healthy lifestyle changes• Induce ovulation when pregnancy is desired• Monitor for the development of diabetes and cardiovascular disease
Treatment with Combination oral contraceptives • to regulate dysfunctional bleeding and limiting unopposed estrogen
thus reducing endometrial cancer risk• to suppresses ovarian androgen production
Secondary• Weight loss can reduce both the hyperinsulinemia and
hyperandrogenism with as little as 5% weight loss from initial weight. • Insulin-lowering agents such as metformin can be used for reducing
the hyperinsulinism
• For patients desiring pregnancy, clomiphene citrate while metformin as an adjunct.
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Pro-fertility Agents: Clomiphene citrate
• a selective estrogen receptor modulator • leads to depletion of estrogen receptors at
the level of pituitary and hypothalamus interrupting the negative feedback of estrogen
• improves GnRH secretion and increase the amplitude of LH and FSH pulses without a change in pulse frequency
• LH and FSH in turn drives follicular growth and maturation
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The Use of Clomiphene• Clomiphene citrate is used for the
treatment of ovulation disorders: anovulation or oligo-ovulation (normal basal levels of endogenous estradiol) including women with polycystic ovary syndrome (PCOS), luteal phase deficiency, and in women with unexplained infertility
• Dosage: 50 mg daily/5 days per cycle. The dose may be increased to 100 mg.
• The compound has no value in patients with ovarian or pituitary failure.
• Clomiphene is also used in men to stimulate gonadotropin release and enhance spermatogenesis
Adverse Effects• vasomotor flushes, abdominopelvic discomfort/bloating, headache, nausea and
vomiting, prolonged treatment may be associated with a risk of low-grade ovarian cancer
Contraindications• pregnancy, the presence of significant ovarian cysts
Drug Interactions: unknown
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Second-line Pro-fertility Agents: Aromatase Inhibitors
Letrozole or anastrozole are used alone in inducing ovulation. Letrozole results in higher pregnancy rates in PCOS patients as compared to clomiphene and FSHLetrozole doses is 2.5 mg to 7.5 mg for 5 days in the follicular phase
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Second-line Pro-fertility Agents: Gonadotropins
Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, PCOS, obesity.
Follicle-Stimulating Hormone (FSH)• Urofollitropin (uFSH), is a purified human FSH from the urine of
postmenopausal women
• Recombinant forms of FSH (rFSH): follitropin-α and follitropin-β
Luteinizing Hormone (LH)• Lutropin-α , the recombinant form of human LH, has only been approved for
use in combination with follitropin-α for stimulation of follicular development in infertile women with profound LH deficiency.
Human Chorionic Gonadotropin (hCG) • Choriogonadotropin -α (rhCG), a recombinant form of hCG, is used for
controlled ovulation and hyperstimulation in women with hypogonadotropic hypogonadism
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Male Infertility
• both LH and FSH are used for treatment of infertility in hypogonadal men
• initial treatment for 8–12 weeks with injections of 1000–2500 IU hCG several times per week following human menopausal gonadotropins (hMG) injection at a dose of 75–150 units three times per week.
• In men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate.
• an advance that has indirectly benefited gonadotropin treatment of male infertility is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian hyperstimulation of a female partner.
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Ovulation Induction• Gonadotropins are also used for
controlled ovarian hyperstimulation in assisted reproductive technology procedures.Side Effects
• the ovarian hyperstimulation syndrome in 0.5–4%
• multiple pregnancies in 15–20% cases
• headache, depression, edema, precocious puberty, and rarely production of antibodies to hCG.Contraindications
• androgen-dependent tumors, prostate cancer • an enlarged ovary or ovarian cysts, or an enlargement or tumor of the
pituitary gland • an active blood clot, brain lesions • unexplained uterine or genital bleeding • pregnancy
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Synthetic GnRH Agonists• Gonadorelin is an acetate salt of synthetic human GnRH. • pulsatile intravenous administration of gonadorelin every 1–4 hours
stimulates FSH and LH secretion. • continuous administration of gonadorelin or its longer-acting analogs
produces a biphasic response. The first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females.
• The continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids.
• Synthetic GnRH analogs: goserelin, histrelin, leuprolide, nafarelin, and triptorelin.
• These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10.
• Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin.
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Synthetic GnRH Receptor Antagonists• GnRH antagonists are approved for preventing the LH surge during
controlled ovarian hyperstimulation. • GnRH antagonists produce an immediate antagonist effect, their use
is delayed until day 6–8 of the in vitro fertilization cycle.
Ganirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures, they inhibit the secretion of FSH and LH in a dose-dependent manner.
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Literature:
• Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor
Basic & Clinical Pharmacology, 12e,
Chapter 40. The Gonadal Hormones & Inhibitors
Chapter 37 Hypothalamic & Pituitary Hormones
• Eugene C. Toy, Benton Baker III, Patti Ross, John Jennings Case Files® Obstetrics and Gynecology, Fourth Edition (LANGE Case Files), 2012.
• Moy I, Ekpo G. Clomiphene citrate use for ovulation induction: When, why, and how? 2011.
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