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CONTRACEPTIVE AND
PRO-FERTILITY AGENTS
Yulia Komarova, Ph.D.
312-996-1332
[email protected]
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Knowledge Objectives
1. Know the methods of contraception
2. Understand the mechanisms of action and major pharmacological effects of
oral contraceptives (OCP’s)
3. Understand the mechanism of action of postcoital contraceptives
4. Know benefits and adverse effect of contraceptives
5. Understand the main principles of treatment of the male and female infertility
6. 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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Contraceptives
Oral contraceptives: (OCP’s)
1. Combination contraceptives – contain both estrogenic and progestogenic
agents
•
Monophasic
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Multiphasic
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Biphasic
•
Triphasic
2. Progestin-Only contraceptives, “minipill” - continuous use of progestin only
Other contraceptives:
•
ORHTO EVRA – transdermal (both estrogenic and progestogenic)
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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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Oral Contraceptives (OCP’s)
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
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 diacetate
1.0
Ovcon 50
Ethinyl estradiol
0.05
Norethindrone
1.0
Ovral-28
Ethinyl estradiol
0.05
D,L-Norgestrel
0.5
Mestranol
0.05
Norethindrone
1.0
Days 1–10
Ethinyl estradiol
0.035
Norethindrone
0.5
Days 11–21
Ethinyl estradiol
0.035
Norethindrone
1.0
Necon 1/35, Norinyl 1+, Nortrel 1/35, Ortho-Novum 1/35
Norinyl 1/50, Ortho-Novum 1/50
Biphasic combination tablets
Ortho-Novum 10/11, Necon 10/11
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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
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
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
0.25
none
Norethindrone
0.35
none
D,L-Norgestrel
0.075
Ortho-Novum 7/7/7, Necon 7/7/7
Ortho-Tri-Cyclen
Daily progestin tablets
Nora-BE, Nor-QD, Ortho Micronor, Jolivette,
Camila, Errin
Ovrette
Implantable progestin preparation
Implanon
none
Etonogestrel (one tube of 68 mg)
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Mechanism of Action
Combination 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
Lipid Metabolism
serum haptoglobins produced in the liver are depressed; delayed clearance of sulfobromophthalein and
reduce the flow of bile
increase in serum triglycerides and free and esterified cholesterol
Carbohydrate 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
Gastrointestinal Disorders
the risk of stroke is concentrated in women over age 35.
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
Cancer
in about 6% of patients
reduced risk of endometrial and ovarian cancer
risk of cervical and breast cancer is controversial
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Contraindications
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Clotting disorders
Known cancer
Hepatic disorders
Diabetes - insulin
Pregnancy
Age older than 35 years
and smoker
Relative Contraindications
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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 days
Ethinyl estradiol: 2.5 mg twice daily for 5 days
Diethylstilbestrol: 50 mg daily for 5 days
Mifepristone: 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 Study
Overall 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 FSH
Letrozole 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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