Vaginal delivery of contraceptives

Although a steady increase in contraceptive use has been observed both in developed and less-developed countries, the large number of unplanned pregnancies may indicate that the contraceptive needs of a significant percentage of couples have so far not been met. Several new contraceptive products have reached the market during the last 2 years. Among these is a new contraceptive vaginal ring, which has become available for prescription. This new female method has been developed to expand the contraceptive choices available to couples. This review will address the specifics of the vaginal route for delivering contraceptive steroids and describe the various systems available or under evaluation

New progestogens: A review of their effects in perimenopausal and postmenopausal women

The progestins have different pharmacological properties depending upon the parent molecule, usually testosterone or progesterone, from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. In postmenopausal women with an intact uterus, progestins are used in combination with estrogen as hormone-replacement therapy (HRT). The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone-receptor (PR) agonists have been synthesised as well, although the latter are still in a very early stage of development. Several new progestins, which have been synthesised in the last 2 decades, may be considered fourth-generation progestins. These include dienogest, drospirenone, Nestorone® (Population Council, New York, NY, USA), nomegestrol acetate and trimegestone. The fourth-generation progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone progesterone. Drospirenone differs from the classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. Trimegestone and Nestorone® are the most potent progestins synthesised to date, followed by two of the older progestins, 3-keto-desogestrel and levonorgestrel. The new molecules trimegestone, drospirenone and dienogest also have antiandrogenic activity. Following the publication of the results of the Women\u27s Health Initiative study, the role of progestins in HRT became controversial. Unfortunately, this concern has been directed towards progestins as a class, although striking differences exist among the progestins. Natural progesterone and some of its derivatives, such as the 19-norprogesterone molecules, and the new molecules drospirenone and dienogest are not androgenic and, therefore, have no negative effect on the lipid profile. The effects of progestins on breast tissue remain controversial as well. However, depending on the progestin and the duration of application, breast cell differentiation and apoptosis may predominate over proliferation. It is still unclear if the currently available progestins are able to bind specifically to the PR isoforms PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is also unclear. Although it is likely that the new progestins may have neutral effects on the risk of coronary heart disease or breast cancer in younger postmenopausal women, this hypothesis must be confirmed in large randomised, well controlled clinical trials

Hormonal contraception and thrombosis

The safety of combined hormonal contraceptives (CHCs) has been documented by years of follow-up, and the occurrence of venous thromboembolism (VTE) possibly related to their use is rare in the young population exposed to these agents. The balance between the benefits and risks of contraceptive steroids is generally positive, in particular when compared with pregnancy\u27s risks. Epidemiological studies led to different results showing either no difference in VTE risk between CHCs (active surveillance prospective studies) or an increase in risk (observational or database studies). The discrepancy may be explained by different study designs and the fact that important risk factors such as overweight, family history of thrombosis, and smoking were not adjusted for in some observational studies. To improve the safety of CHC, modifying the estrogen dose and type, selecting newer progestins, and alternative routes of delivery were implemented. Ethinyl- E_2 (EE) exerts a stronger effect than E_2 on estrogen-dependent markers such as liver proteins and coagulation factors. To circumvent the metabolic changes induced by EE, more natural compounds such as E_2 and E_2 valerate (E_2V) were developed, as well as new progestins structurally closer to P. Progestins when given alone do not increase VTE risk, and their risks and benefits depend upon their chemical structure, the type and dose of combined estrogen, and the delivery route. The lower impact of E_2-based CHCs on metabolic markers may result in an improved safety profile. A recent study on clinical outcomes supports this hypothesis. In conclusion, CHCs remain a safe and effective choice to prevent unwanted pregnancy, and the risk of VTE is in general low. Careful consideration of individual risk factors should be given before prescribing to avoid cumulative risks and minimize the occurrence of unwanted events

New hormonal therapies and regimens in the postmenopause: Routes of administration and timing of initiation

Since the publication of the Women\u27s Health Initiative (WHI) study followed by the results of the Million Women Study (MWS), the role of hormonal therapy in postmenopausal women has been further challenged. The risks attributed to hormone therapy have been overestimated and the data has been wrongly extrapolated to the whole class of therapies. The trends in postmenopausal hormonal therapy seem now to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus, based on the assumption that a lesser stimulation of the liver proteins and a neutral metabolic profile would be more favorable in terms of cardiovascular and venous risk. The combination of non-oral administration of estradiol and local delivery of progesterone or a progestin such as levonorgestrel by means of gels, sprays, vaginal rings or intrauterine systems would represent new methods of replacement therapy for the menopausal woman, improving compliance and minimizing the risks of hormone replacement. Several of these systems are either available or in development. Long-term studies on the risk/benefit of various non-oral formulations are certainly warranted

New progestagens for contraceptive use

The progestins have different pharmacologic properties depending upon the parent molecule, usually testosterone or progesterone (P), from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. In hormonal contraceptives, progestins represent the major agent designed for suppressing ovulation and are used in combination with estrogen (E) usually ethinyl-estradiol (EE). The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone receptor (PR) agonists have been synthesized as well, although the latter are still in a very early stage of development. Several new progestins, have been synthesized in the last two decades. These include dienogest (DNG), drospirenone (DRSP), Nestorone (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG). These new progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone P. DRSP differs from the classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. TMG and NES are the most potent progestins synthesized to date, followed by two of the older progestins, keto-desogestrel (keto-DSG) and levonorgestrel (LNG). The new molecules TMG, DRSP and DNG also have antiandrogenic activity. Striking differences exist regarding the side effects among the progestins and the combination with EE leads to other reactions related to the E itself and whether the associated progestin counterbalances, more or less, the estrogenic action. The 19-norprogesterone molecules and the new molecules DRSP and DNG are not androgenic and, therefore, have no negative effect on the lipid profile. Given their pharmacological properties, it is likely that the new progestins may have neutral effects on metabolic or vascular risks. However, this hypothesis must be confirmed in large clinical trials

Pharmacology of different progestogens: The special case of drospirenone

The pharmacological properties of progestins used in contraception and hormone replacement therapy (HRT) vary, depending upon the molecules from which they are derived. Very small structural changes may induce considerable differences in effects. It is unclear if the currently available progestins are able to bind specifically to the progesterone receptors, PR-A or PR-B. The clinical relevance of more specific binding to one or the other isoforms of the progesterone receptor is still unknown. The development of new generations of progestins, with improved receptor-selectivity profiles, has been a great challenge. Steroidal and non-steroidal progesterone agonists have also been synthesized, although these molecules are at a very early stage of development. Several new progestins have been synthesized in the past decade, including dienogest, drospirenone, Nestorone, nomegestrol acetate and trimegestone. Drospirenone differs from the classic progestins in its derivation from spirolactone. The major effect of drospirenone is antimineralocorticoid activity. By that property, drospirenone causes decreased salt and water retention, and thus lowering of blood pressure. The affinity of drospirenone for the mineralocorticoid receptor is about five times that of aldosterone, the naturally occurring mineralocorticoid. In addition, drospirenone has no androgenic effect, but does exhibit partial antiandrogenic activity; its antiandrogenic potency is about 30% of that of cyproterone acetate, the progestin with the most potent antiandrogenic activity. This property, shared by several new progestins, may counteract the negative effect of androgens on hair growth, lipid changes, insulin and, possibly, body composition in postmenopausal women. Drospirenone has a long terminal half-life (about 32 hours), and its bioavailability is about 76%. Drospirenone, which has pharmacodynamic properties very similar to those of progesterone, has been developed as a combined oral contraceptive (30 μg ethinylestradiol/3 mg drospirenone; Yasmin®, Schering AG, Berlin, Germany). Drospirenone is also available in combination with estradiol as an HRT preparation (1 mg 17β-estradiol/2mg drospirenone; Angeliq®, Schering AG)

Routes of delivery for progesterone and progestins

The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies

Delivery options for contraceptives

Although a steady increase in contraceptive use has been observed in developed and less-developed countries, the contraceptive needs of a significant proportion of couples have not yet been met, resulting in an increase in unplanned pregnancies. Several new contraceptive products have reached the market during the past few years. Among these are new implants, a medicated intrauterine device, contraceptive vaginal rings, transdermal patches and several new regimen of combined oral contraceptives. These new or improved methods have been developed to expand the contraceptive choices available to women and men as well as to respond to the unmet need for contraceptives with long-term activity. New targets are being identified both in the ovary and the testes for a more specific non-hormonal contraception. This futuristic approach still keeps in mind the need for better access to existing contraceptive methods, as well as the discovery of new contraceptives that are simple to use, safe, reversible and inexpensive. In recent years, there has been great interest in agents that provide dual protection against pregnancy and sexually transmitted infections (STI), especially human immunodeficiency virus (HIV). A contraceptive method providing dual medical benefits might increase motivation for consistent use, thus reducing contraceptive failures and unwanted pregnancies

Contraception: An international perspective

Although it is estimated that the population growth rate will decline to a replacement level by 2050, it is also now predicted that the total world population will reach 8.9 billion in that year - far higher than the 2004 estimate of 6.4 billion. More than 26 billion new couples will need contraceptives in the next half century. Although a steady increase in contraceptive use has been observed in both developed and developing countries, the contraceptive needs of a high percentage of couples have not yet been met and the number of unplanned pregnancies continues to increase. The actual use of contraception differs from region to region. Although no new method has been registered for many years, several new products have been marketed during the last 5. Among these are new implants, medicated intrauterine systems, contraceptive vaginal rings, transdermal patches and several new combined oral contraceptive formulations. New contraceptive methods have been developed to meet the objectives of expanding contraceptive choices for both women and men and answering an unmet need for contraceptives with a long-term action that meet the expectations of consumers. Simplicity, reversibility and effectiveness are the desired features of a male contraceptive, but no new male contraceptive method is yet available. New areas of basic research include studies on genes, proteins and enzymes involved in the reproductive system. The new methods will be targeted to specific interactions within the reproductive system at the level of ovaries and testes, as well as between spermatozoa and ova. This futuristic approach still keeps in mind the need for better access to existing contraceptive methods, as well as the discovery of new contraceptives that are simple to use, safe, reversible and inexpensive. In the future, contraceptives may be combined with other medicinal agents to provide dual protection against both pregnancy and other preventable conditions, such as sexually transmitted infections