Oral Contraceptives

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Norethynodrel Mestranol Norethynodrel Mestranol Norethynodrel Mestranol

Year of discovery: 1950s; Year of introduction: 1960 (GD Searle & Company); Drug category: Oral contraceptives; Main uses: Prevention of unplanned pregnancy; Commercial names: Ortho Tri-Cyclen, Triphasil, Alesse, Cyclessa, Ortho-Cept, Yasmin, etc,.

Estrogens and progestins are natural steroidal hormones that are vital in sexual development and in the regulation of the physiological process associated with reproductive fertility in women. The combination of such biological knowledge with chemistry led to the development of effective contraceptives for prevention of unplanned pregnancy.

The fertility cycle in women is controlled by a complex cascade of events involving signaling by protein and steroid hormones between the hypothalamus, the pituitary, and the ovaries. In the first phase of the cycle, maturation of the Graafian follicle is stimulated by the follicle stimulating hormone (FSH), which is secreted in the pituitary gland along with the luteinizing hormone (LH) in response to pulsative release of gonadotropin-releasing hormone from the hypothalamus. Luteinizing hormone stimulates estrogen secretion from the ovaries which inhibits pituitary release of FSH and initiates thickening of the inner lining of the uterus (endometrium). Increased estrogen levels spur an acute release of LH that triggers ovulation. The residual follicle (corpus luteum) produces progesterone, causing further changes in the endometrium that prepare it for implantation of the fertilized egg. Progesterone is also essential for suppressing ovulation during pregnancy.

Estrone Progesterone Ethinyl estradiol

Estrone Progesterone Ethinyl estradiol

The role of progesterone as an inhibitor of ovulation was first observed in the 1930s, but was not further investigated as a mechanism of contraception until the 1950s (by Gregory Pincus). Since the dose of progesterone required to prevent fertilization was high,

Pincus had to screen more then 200 progestin analogs to find a useful contraceptive. The search culminated in the discovery of norethynodrel. Although subsequent clinical trials were successful, some of those treated experienced breakthrough bleeding. Investigation of the synthetic drug revealed that when it was contaminated with -2% of mestranol, an estrone derivative, the occurrence of bleeding was decreased. Based on this finding, mestranol was later deliberately incorporated into the drug, leading to the development of the first combined oral contraceptive, Enovid, which gained approval in 1960. Oral contraceptives are now used by about 100 million women worldwide. The introduction of contraceptives has had a major impact on society.

Currently used contraceptives are taken at considerably lower dosages than Enovid. The estrogen component of current drugs most frequently is ethinyl estradiol, which is combined with any of several available potent progestin derivatives. Monophasic oral contraceptives contain the same dose of the progestin component in each tablet, whereas bi- or triphasic drugs contain variable amounts depending on the stage of the fertility cycle.

In addition to the traditional formulation, newer delivery methods have been developed including transdermal patch, intrauterine device, or injectable hormonal agents. Extended-cycle contraceptives consisting of 84 active pills and 7 inactive pills are also available. Progestin only pills (POP) are mainly used by women who are breastfeeding or cannot take estrogen. Emergency contraceptives are available to prevent pregnancy after unprotected intercourse.1,2

1. N. Engl. J. Med. 2003 349, 1443-1450; 2. Mayo din. Proc. 2006, 81, 949-955; Refs. p 105


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