contraceptive and pro-fertility agents

1

CONTRACEPTIVE AND PRO-FERTILITY AGENTS

Yulia Komarova, Ph.D.312-996-1332

[email protected]

2

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

3

Control of the Menstrual Cycle

4

Neuroendocrine Control of Gonadotropin Secretion

5

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 and NORPLANT II- implantable progestin

only• IUD and MIRENA – insert and an intrauterine device -

progestin only

6

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)

7

Oral Contraceptives (OCP’s)Triphasic combination tablets

Enpresse, Triphasil, Tri-Levlen, Trivora

Days 1–6 Ethinyl estradiol 0.03 L-Norgestrel 0.05



Ortho-Novum 7/7/7, Necon 7/7/7

Days 1–7 Ethinyl estradiol 0.035 Norethindrone 0.5



Ortho-Tri-Cyclen

Days 1–7 Ethinyl estradiol 0.035 Norgestimate 0.18



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)

8

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

9

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

10

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)

11

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

12

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

13

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

14

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

• 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.

15

Treatment of Infertility

16

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

17

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 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• 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

18

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

19

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

20

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.

21

Ovulation Induction• Gonadotropins are also used for

controlled ovarian hyperstimulation in assisted reproductive technology procedures.

Toxicity & Contraindications• the ovarian hyperstimulation syndrome in 0.5–4%, which is characterized by

ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock.

• multiple pregnancies in 15–20% cases. • headache, depression, edema, precocious puberty, and rarely production of

antibodies to hCG.

22

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

23

Structures of GnRH and GnRH AnalogsAMINO ACID RESIDUEGnRH 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

24

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.

25

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.

26

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

Moy I, Ekpo G. Clomiphene citrate use for ovulation induction: When, why, and how? 2011

http://www.accessmedicine.com/content.aspx?aid=4515213

http://www.accessmedicine.com/content.aspx?aid=4515213

contraceptive and pro-fertility agents

Documents