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CONTRACEPTIVE AND PRO-FERTILITY AGENTS

Yulia Komarova, Ph.D.ykomarov@uic.edu

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Control of the Menstrual Cycle

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Neuroendocrine control of gonadotropin secretion

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ContraceptivesOral contraceptives: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 and NORPLANT II- implantable progestin

only• 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

Contraceptive Agents

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Contraceptive Agents

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

. . .   Norethindrone 0.35

  Ovrette . . .   D,L-Norgestrel  0.075

Implantable progestin preparation 

  Implanon . . .   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• 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

• Reduction 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

Effects on Endocrine Function The inhibition of pituitary gonadotropin secretion; increase in the plasma concentration of the corticosteroid-binding globulin;

Effects on 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 similar to that reported in patients with hepatitis

Effects on the Liver Serum haptoglobins produced in the liver are depressed

Effects on Lipid Metabolism estrogens increase serum triglycerides and free and esterified cholesterol.

Effects on Carbohydrate Metabolism reduction in the rate of absorption of carbohydrates from the gastrointestinal tract; glucose tolerance

Effects on the Cardiovascular System increases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate

Effects on the Skin increase pigmentation of the skin (chloasma)

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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 patients

Cancer reduced risk of endometrial and ovarian cancer

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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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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 mcg once1

 

L-Norgestrel: 0.75 mg twice daily for 1 day (eg, Plan B2) 

Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (eg, Ovral, Preven2): Two tablets and then two in 12 hours

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Progesterone Antagonist: Mifepristone and Ulipristal

• 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

• limited clinical studies suggest that mifepristone may be useful in the treatment of endometriosis, Cushing's syndrome, breast cancer

• Ulipristal, a derivative of 19-norprogesterone, a partial agonist of the progesterone receptor

• inhibits LF release and LH-induced follicular rupture, and blocks endometrial implantation of the fertilized egg.

• remains effective for 5 days after intercourse.

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Pro-fertility agents:Estrogen Inhibitors and Antagonists

• tamoxifen , a competitive partial agonist inhibitor of estradiol at the estrogen receptor,

• is used in the palliative treatment of breast cancer in postmenopausal women and for chemoprevention of breast cancer in high-risk women;

• may increase the risk of endometrial cancer

• raloxifene ,estrogen agonist-antagonist, is approved for the prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in women with risk factors.

• clomiphene, partial agonist, is used as an ovulation-inducing agent

cyclophenanthrene structure

triphenylethylene structure

benzothiophene structure

triphenylethylene structure

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Clomiphene• Clomiphene increases the amplitude of LH and FSH pulses without a

change in pulse frequency

• Clomiphene is used in the treatment of ovulation disorders in patients who wish to become pregnant. It stimulates ovulation in 70% of women.

• The compound is of no value in patients with ovarian or pituitary failure.

• Clomiphene is also used in men to stimulate gonadotropin release and enhance spermatogenesis

Adverse Effects

• hot flushes, headache, constipation, allergic skin reactions, and reversible hair loss

• multiple pregnancy is approximately 10%.

Contraindications

• enlarged ovaries

• treatment with clomiphene for more than a year may be associated with a risk of low-grade ovarian cancer

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Other Therapies for Induction of Ovulation

Gonadotropins

Synthetic GnRH Analogues

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Gonadotropins

Follicle-Stimulating Hormone (FSH)• Urofollitropin (uFSH), is a purified preparation of human FSH that is

extracted from the urine of postmenopausal women,

• is used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes and to treat male infertility.

• Recombinant forms of FSH (rFSH): follitropin-α and follitropin-β, are used for controlled ovulation hyperstimulation in women, infertility in men due to hypogonadism

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 ovarian follicle development in women with hypogonadotropic hypogonadism

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Ovulation Induction

• Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity.

• Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures.

Toxicity & Contraindications• the ovarian hyperstimulation syndrome in 0.5–4% and multiple pregnancies

in 15–20% cases.

• the ovarian hyperstimulation syndrome is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock.

headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG.

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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.

• ln 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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Regulation of Gonadotropin Synthesis and Secretion

• the hypothalamic peptide GnRH is the predominant regulator of gonadotropin synthesis and secretion.

• GnRH release is pulsatile and is crucial for the proper synthesis and release of the gonadotropins;

• the continuous administration of GnRH leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes

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Structures of GnRH and GnRH Analogs

AMINO ACID RESIDUE

GnRH CONGENER (TRADE NAME) 

1 2 3 4 5 6 7 8 9 10 DOSAGE FORMS

Agonists                       

GnRH (FACTREL, LUTREPULSE) 

PyroGlu His Trp Ser Tyr Gly Leu Arg Pro Gly-NH2

 

IV, SC

Goserelin (ZOLADEX)  — — — — — D-Ser(tBu) — — — AzGly-NH2

 

SC implant

Nafarelin (SYNAREL)  — — — — — D-Nal — — — — IN

Triptorelin (TRELSTAR DEPOT, LA) 

— — — — — D-Trp — — — — IM depot

Buserelin* (SUPREFACT)  — — — — — D-Ser(tBu) — — Pro-NHEt

  IN, SC

Deslorelin* — — — — — D-Trp — — Pro-NHEt

  , depot

Histrelin (VANTAS, SUPPRELIN LA) 

— — — — — D-His(Bzl) — — Pro-NHEt

  SC implant

Leuprolide (LUPRON, ELIGARD) 

— — — — — D-Leu — — Pro-NHEt

  , depot

Antagonists                       

Abarelix* (PLENAXIS)  Ac-D-Nal D-Cpa D-Pal — Tyr(N-Me) D-Asn — (iPr) — D-Ala-NH2

 

SC depot

Cetrorelix (CETROTIDE)  Ac-D-Nal D-Cpa D-Pal — — D-Cit — — — D-Ala-NH2

 

SC

Ganirelix (ANTAGON)  Ac-D-Nal D-Cpa D-Pal — — D-hArg(Et)2

 

— D-hArg(Et)2

 

— D-Ala-NH2

 

SC

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Synthetic GnRH Agonists

• Gonadorelin is an acetate salt of synthetic human GnRH.

• 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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Therapeutic Uses of Synthetic GnRH Agonists

• Female and Male Infertility

• Diagnosis of LH Responsiveness

• Controlled Ovarian Hyperstimulation

• 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.

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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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Side effects of synthetic fertility drugs

• headache

• flushing

• abdominal discomfort

• hot flashes, osteoporosis

• vaginal dryness

• altered lipid metabolism

• multiple births

• emotional lability

• acne

• weight gain

• hirsituism

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Literature:

Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e,

Chapter 40. The Gonadal Hormones & Inhibitors

Chapter 37 Hypothalamic & Pituitary Hormones