Progestins
Description: Ethinyl estradiol/desogestrel are used together as an oral contraceptive agent. At this time, desogestrel containing products have not been evaluated for postcoital contraception. Ethinyl estradiol is one of two estrogens currently used in oral contraceptive pills. The other, mestranol, is converted to ethinyl estradiol before it is biologically active. Desogestrel is a progestin with high progestational selectivity, lowered affinity for androgenic receptors, and no estrogenic action. Thus desogestrel may have less adverse influence on carbohydrate and lipid metabolism, weight gain, acne, and other side effects than older progestins. Desogestrel appears to have favorable effects on lipoproteins by slightly elevating HDL cholesterol. The clinical significance of these findings is unknown. Initial observations of minimal effects on hemostasis with desogestrel have not resulted in lowered rates of thromboembolic events. In fact, evaluations of recent clinical trials have noted an increased risk of non-fatal venous thromboembolism with desogestrel versus levonorgestrel containing contraceptives. Desogen® and Ortho-Cept™ are fixed dose combination products. Products containing desogestrel were initially FDA approved in 1992. Special product formulations have since been developed. Mircette™, approved in April 1998, provides a reduced hormone-free interval, which may be advantageous for patients experiencing migraines, dysmenorrhea or other symptoms during the week they do not take the oral contraceptive. Cyclessa®, a triphasic product containing a low-dose (25 mcg) of ethinyl estradiol in combination with a varying desogestrel dose, was approved in February 2001; a generic version, Velivet™ was FDA-approved in February 2004.
Mechanism of Action: The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In addition, viscosity of the cervical mucus increases with hormonal contraceptive use, preventing penetration of sperm. Alteration in endometrial tissues also occurs. When traditional regimens of oral contraception are discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology.
Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids, and lack of estrogen is now recognized as a risk factor for myocardial infarction. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate sebaceous gland hyperresponsiveness to androgens and lead to acne. Serious adverse events, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.
Pharmacokinetics: Following oral administration in the third cycle of use, roughly 84% of desogestrel and 83% of ethinyl estradiol survive absorption and first pass through the liver. Both hormones are widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin (CBG). Desogestrel is strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG).
Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate. Ethinyl estradiol is primarily metabolized in the liver via CYP3A4 to 2-hydroxy-ethinylestradiol. Both ethinyl estradiol and its hydroxylated and methylated metabolites undergo glucuronide and sulfate conjugation. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract and then undergo entero-hepatic recycling.
The progestin desogestrel is rapidly and completely metabolized by hydroxylation and first-pass through the liver to 3-keto-desogestrel, the active metabolite responsible for the pharmacologic actions. Some minor, non-active metabolites have been identified. These occur via conjugation to the sulfate and glucuronate salts.
Excretion of the oral contraceptive steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 38 hours for 3-keto-desogestrel and about 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormones that allows for once-daily administration.
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References
. Jick H, Jick SS, Gurewich V et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589 - 93.
[ Revised 9/15/2005 4:38:00 PM ]
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