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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 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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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 diacetate

1.0

  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 0.25

Daily progestin tablets 

  Nora-BE, Nor-QD, Ortho Micronor, Jolivette, Camila, Errin

none   Norethindrone 0.35

  Ovrette none   D,L-Norgestrel  0.075

Implantable 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 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

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 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 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 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.