Progestins for contraception

Between the time of their filing the patent application and its issue, the company was planning several clinical studies when it came to their attention that another issued U.S. patent existed, which was filed before their chemist synthesized the compound of formula I. The patent of concern was directed to steroidal compounds, although it did not disclose their particular compound of formula I, nor did it indicate any specific utility in combination with a progestin for contraception. The patent specification (the entirety of the document) disclosed a number of Markush structures of varying scope as well as a description of the compounds as having utility for the treatment of prostate cancer. Claim 13 from the issued patent is illustrated in Figure 1.5 and it particularly concerned them. 

Table 2. Progestins Marketed in the United States and Europe for Contraceptive and Noncontraceptive Uses...

As of 1994, there were approximately 47 progestin-containing contraceptive dmg formulations sold in the United States for use as oral contraceptives (Table 3). In addition, there are three nonoral contraceptive formulations containing progestins ie, one injectable (Depo-Provera), one as an intrauterine device (lUD) (Progestasert), and one implantable (Norplant). Of the oral formulations, all but two also contain an estrogen component, ethynylestradiol. 

Progestin-only contraceptives (Fig. 4) contain low-doses of progestins (e.g. 350 pg norethindrone or 75 pg norgestrel) that have to be administered daily without interruption. The lowest expected failure rate during the first year of use is 0.5%, while the typical failure rate amounts to 3%. Subdermal implants of norgestrel (216 mg) for sustained release provides for long-term (for up to 5 years) contraceptive effects characterized by failure rates of only 0.05%. Reliable contraception for 3 months can be achieved by an intramuscular injection of a crystalline suspension of 150 mg medroxyprogesterone acetate (Fig. 3) (failure rate 0.3%). 

Small doses of progestins administered orally or by implantation under the skin can be used for contraception. They are particularly suited for use in patients for whom estrogen administration is undesirable. They are about as effective as intrauterine devices or combination pills containing 20-30 meg of ethinyl estradiol. There is a high incidence of abnormal bleeding. 

Some biochemical natural products have caused cardiotoxicity. Synthetic estrogens and progestins have been linked to cardiovascular disorders in women taking them for contraceptive purposes. Various animal and insect venoms and plant alkaloids may have adverse cardiovascular effects. There is some evidence to suggest that anabolic steroids, commonly linked to scandals involving athletes who take them to enhance performance, have caused cardiovascular disorders. 

Type TV hyperlipoproteinemia is common and occurs in adulthood primarily in patients who are obese, diabetic, and hyperuricemic and do not have xanthomas. It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral contraceptives, thiazides, or 8-blockers. Two genetic patterns occur in type IV hyperlipoproteinemia familial hypertriglyceridemia, which does not carry a great risk for premature CAD, and familial combined hyperlipidemia, which is associated with increased risk of cardiovascular disease. 

Many practitioners recommend progestin-only contraceptives for breast-feeding women because progestins provide effective contraception without diminishing the amount of breast milk produced. 

Women receiving anticonvulsants for a seizure disorder require special attention with regard to hormonal contraception. Giving a hormonal contraceptive concomitantly with phenobarbital, carba-mazepine, or phenytoin reduces the contraceptive s efficacy, and many anticonvulsants (e.g., phenytoin) are known teratogens. The use of condoms in conjunction with high-estrogen OCs, injectable progestin-only contraceptives, or intrauterine devices may be considered for these women. ... 

The two most frequent uses ofprogestins are for contraception, either alone or with an estrogen, and in combination with estrogen for hormone therapy ofpostmenopausal women. Progestins also are used for secondary amenorrhea, abnormal uterine bleeding in patients without underlying fibroids or cancer, luteal-phase support to treat infertility, and premature labor. 

In women for whom estrogens are contraindicated or undesirable, progestin-only contraceptives are an option. The progestin-only minipill may have enhanced effectiveness in nursing mothers and women over 40 in whom fertility may be decreased. 

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