Régine Sitruk–Ware
Speeches:
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Future contraceptive methods: What to look forward to?
Regine Sitruk-Ware (United States)
Rockefeller University and Population Council, New York, United States
regine@popcbr.rockefeller.edu
Contraceptive research will build upon advances in biomedical research, which have created new opportunities for studying the basic biology of reproduction. Basic research could, in turn, lead to the discovery of novel targets for contraception. The novel technologies of genomics, proteomics, lipidomics, and glycomics, has great potential in the identification of protein targets and their regulatory genes specific to the reproductive system. Developing small molecules that will inhibit these targets to stop the reproductive processes would allow more specific approach to contraception. In addition the progress made in the drug delivery area may also facilitate the development of advanced contraceptive systems in the future.
New methods currently under development are designed to meet the challenges of expanding contraceptive choices for both women and men and, of answering an unmet need for contraceptives that would satisfy new categories of users. Long-acting systems would be preferred to improve compliance and easiness of use. Both IUDs and implants are now widely available; transdermal gels and sprays are in early stages of research and a one-year contraceptive vaginal ring is in the last stages of development. All these delivery systems are based on the use of steroidal hormones delivered continuously at very low doses, which suppresses ovulation in cycling women.
In other cases, the provision of an additional health benefit may increase compliance with contraceptive use. Current contraceptive methods do have many benefits: some improve menstrual bleeding patterns, alleviate dysmenorrhea and acne, and sometimes pre-menstrual syndrome. Others can produce amenorrhea and help prevent anemia. Should new contraceptive methods provide additional protection against breast cancer they would also have wide appeal. In addition, dual-protection methods which join contraceptives to antiretroviral agents to protect women against both unwanted pregnancy and transmission of human immunodeficiency virus (HIV), would meet a major need. Men now tend to accept the concept of taking responsibility for the control of the couple’s fertility, leading to a growth in requests for male contraceptives, an emerging and challenging area of research.
Above all, new contraceptives, which are designed to be used by healthy men and women, should be very safe and easy to use, reversible, as well as affordable.
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New developments in contraception
Regine Sitruk-Ware, MD
Adjunct Professor Rockefeller University and Population Council, New York, USA
By 2015, the population growth rate will decline but the total world population will reach the
6 billion mark, a 25% increase above today population. Although a steady increase in
contraceptive use has been observed both in developed and less-developed countries, the
contraceptive needs of a significant percent of couples have not yet been met, with an
increase in unplanned pregnancies. Several new products have reached the market during
the last 2 years. Among these are new implants, medicated intrauterine systems,
contraceptive vaginal rings, transdermal patches with longer duration of action, and
several new combined oral contraceptives. In addition new options such as transdermal
sprays and gels, progesterone receptor modulators for a bleed-free, estrogen-free
contraception are under evaluation. These new methods have been developed to meet the
objectives of expanding contraceptive choices for both women and men and, of answering
an unmet need for contraceptives with long-term action that meet the expectations of
consumers. Women give preference to methods that do not interfere with sexual
intercourse and that result in regular withdrawal bleeding or, at least, no unpredictable
bleeding. Men now tend to accept the concept of taking responsibility for the control of the
couple’s fertility, leading to a growth in requests for male contraceptives, an emerging area
of research. Simplicity, reversibility, and effectiveness are the desired features of a male
contraceptive. Implants, gels and combinations of orals and injections are under clinical
development for male contraception.
New areas of basic research include the genomic and proteomic as well as studies of
enzymes involved in the reproductive system. Identifying specific genes and the proteins
induced by these genes and finding molecules that specifically antagonize gene action will
open new avenues for the development of contraceptives that do not modify the hormonal
profile of the individual. The new methods will be targeted to specific interactions within
the reproductive system at the level of the ovary and testis, as well as between
spermatozoa and the ovum. These new approaches also require the engineering of
original drug-delivery methods that reach the target very specifically but do not interactwith other tissues in the body.
In the future, contraceptives may be combined with other medicinal agents to provide dual
protection against both pregnancy and another preventable condition, such as sexually
transmitted infections. Vaginal gels are under development to meet this goal. Some
existing methods prevent other disorders, such as menorrhagia and the anemia it causes.When a contraceptive method provides dual benefits, women or men may have a greater
motivation to use a contraceptive method, thus reducing contraceptive failures and
unwanted pregnancies. -
New frontiers in contraception research
Regine Sitruk-Ware USA
Regine L. Sitruk-Ware is a reproductive endocrinologist and holds the position of executive director of product research and development at the Population Council’s Center of Biomedical Research. She organizes pre-clinical research and clinical development of new molecules designed for reproductive healthcare in men and women suitable for use in developing countries. She is a program director for a cooperative contraceptive research center of the NICHD. Prior to joining the Council, Sitruk-Ware had successively an Academic career and then a career in Industry in Research and Development. She taught and conducted clinical research in reproductive endocrinology at the University of Paris for ten years. She was a member of the International Committee for Contraceptive Research, which was established by the Population Council in 1970. She is a member of several national and international medical societies.
Sitruk-Ware has written eight books and over 200 articles and reviews, mostly dealing with women’s healthcare issues. She served as adviser in several ad hoc committees of the WHO and the NIH. She received her medical doctorate at the University of Paris and is currently an Adjunct Professor at Rockefeller University.
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Estimates predict that by 2015, the population growth rate will decline but that the total world population will reach the 6 billion mark, a 25% increase above the present day population. More than 26 million new couples will need contraceptives. Although a steady increase in contraceptive use has been observed both in developed and less-developed countries, the contraceptive needs of a significant percent of couples have not yet been met, and the number of unplanned pregnancies continue to increase. The actual usage of contraception differs from region to region. Although no new methods were registered for many years, several new products have reached the market during the last 2 years. Among these are new implants, medicated intrauterine systems, contraceptive vaginal rings, transdermal patches, and several new combined oral contraceptives.
New methods have been developed to meet the objectives of expanding contraceptive choices for both women and men and, of answering an unmet need for contraceptives with long-term action that meet the expectations of consumers. When interviewed, women request affordable methods that are highly effective and reversible, easy to use, and under their own control. Preference is given to methods that do not interfere with sexual intercourse and that result in regular withdrawal bleeding or, at least, no unpredictable bleeding. Men now tend to accept the concept of taking responsibility for the control of the couple’s fertility, leading to a growth in requests for male contraceptives, an emerging area of research. Simplicity, reversibility, and effectiveness are the desired features of a male contraceptive but no method is yet available.
New areas of basic research include studies of genes, proteins, and enzymes involved in the reproductive system. Identifying specific genes and the proteins induced by these genes and finding molecules that specifically antagonize gene action will open new avenues for the development of contraceptives that do not modify the hormonal profile of the individual. The new methods will be targeted to specific interactions within the reproductive system at the level of the ovary and testis, as well as between spermatozoa and the ovum.
Genes involved in the regulation of human reproduction are explored first in animal models but these models must then be validated by studies in humans. As an example, spermatogenesis requires a complex interaction between various cellular compartments of
the testis, and proteins involved in these interactions are now targets for contraceptive methods. These new approaches also require the engineering of original drug-delivery methods that reach the target very specifically but do not interact with other tissues in the body.
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 another preventable condition, such as sexually transmitted infections. Some preliminary studies suggests that certain contraceptive methods, given alone, may not only prevent pregnancy but may also prevent common disorders of the female reproductive system, such as menorrhagia and the anemia it causes. When a contraceptive method provides dual benefits, women may have a greater motivation to use a contraceptive method, reducing contraceptive failures and unwanted pregnancies.
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New progestogens in contraception
Regine Sitruk-Ware, MD, Population Council & Rockefeller University, New York, USA
The synthetic progestins used for contraception are structurally related either to testosterone (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor interactions. Dienogest (DNG), and drospirenone (DRSP) exhibit antiandrogenic activity and DRSP has predominent antimineralocorticoid properties. The 19-norpregnanes include Nestorone® (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG) and possess a high specificity for binding to the progesterone receptor with no or little interaction with other steroid receptors. DRSP has been developed as combination oral pills with ethinyl-estradiol (EE) and dienogest which shows 40 percent of the antiandrogenic action of cyproterone acetate, has been successfully combined in contraceptives either with EE and more recently with estradiol valerate (E2V). NOMAc, exerts a high antigonadotropic action and has been used as a progestin only method and more recently combined with estradiol (E2) in an oral monophasic contraceptive. Nestorone* is not active orally but proved to be the most active antiovulatory progestin when used parenterally. It has been developed in various formulations such as implants, one-year vaginal ring, in combination with EE, or transdermal gel or spray, in combination with the natural estrogen E2. Active derivatives of older progestins have proven high effectiveness in preventing ovulation and low doses of these steroids have been used combined with EE in non-oral delivery systems e.g etonogestrel in a 3-year progestin-only contraceptive implant or combined with EE in a monthly vaginal ring; norelgestromin in combination with EE in a transdermal weekly patch. Risks and benefits of the newer progestins used in contraception depend upon the type of molecular structure, the type of estrogen associated in a combination and the route of administration.
*Nestorone has been developed by the Population Council with grants from USAID, NICHD and UNFPA
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Update on contraceptive
developments Although contraceptive use showed a steady
increase worldwide, the needs of a significant
percent of couples have not yet been met, as
unscheduled pregnancies increased.
While implants and IUDs require a health provider
for a proper insertion, vaginal rings, a mid-acting
method, have the advantage of being user-
controlled. While long-acting methods seem
preferable for women with compliance issues,
daily transdermal gels or sprays have shown high
acceptability as the methods can be used privately.
Progesterone receptor modulators (PRMs) to be
used within 120 hours of unprotected intercourse
have a definite role as emergency contraceptives.
Continuous low-dose administration of a PRM
from a vaginal ring has been shown to block
ovulation and induce amenorrhoea.
Contraceptives combined with other agents
should provide dual protection against both
pregnancy and another preventable conditions.
Dual protection methods are tested as vaginal
gels or rings delivering both a contraceptive and
an agent active against HIV transmission. In
addition, the potential of PRMs to prevent breast
cell proliferation or the neuroprotective effects
of progesterone and derived molecules are new
areas of research for contraception with added
medical benefits. These dual-purpose methods
may increase users’ compliance, thus reducing
failures and unwanted pregnancies.Men now tend to accept responsibility for the
couple’s fertility control, leading to a growth in male
contraceptives needs. Non-hormonal methods
for men target the maturation of germ cells, or the
sperm motility and activity. Novel approaches in
women target meiosis as well as genes involved
in follicular rupture. These methods will hopefully
enter clinical testing during the current decade. -
Why do we need new contraceptives?
Regine Sitruk-Ware (United States)
Rockefeller University and Population Council, New York, United States
regine@popcbr.rockefeller.edu
The total world population is predicted to reach the 6 billion mark in 2015. Although a steady increase in contraceptive use has been observed both in developed and less-developed countries, the contraceptive needs of a significant percent of couples have not yet been met, with an increase in unplanned pregnancies of which 60% lead to abortion.
Although several methods of contraception are available, access may be limited due to poor quality of services or to costs of methods not endorsed by health systems and insurances. In addition, a high discontinuation rate is observed during the first year of use of currently available methods due to inconvenience or poor tolerability. Safer methods are still needed in order to minimize the side-effects and increase compliance.
In addition different needs appear according to the stage of reproductive life. Adolescent girls would need easy to use and remember methods that would improve compliance. Also, on-demand methods for occasional sexual relationship may be favored. During their reproductive life, men and women would need methods that may help to space out pregnancies and both partners may alternate the endorsement of a contraceptive method. Finally women who would have completed their family may rather need long-acting methods that would also treat possible gynecological diseases of the later years of fertile age.
In other cases, the provision of an additional health benefit may increase compliance with contraceptive use. Current contraceptive methods do have many benefits: some improve menstrual bleeding patterns, alleviate dysmenorrhea and acne, and sometimes pre-menstrual syndrome. Others can produce amenorrhea and help prevent anemia. Should new contraceptive methods provide additional protection against breast cancer they would also favor wider use and compliance.
New methods under development are designed to meet the challenges of expanding contraceptive choices for both women and men and, of answering unmet needs for contraceptives such as pre and post-coital methods, user-controlled long-acting delivery systems, long-acting methods for men, methods with dual protection and additional medical benefits.
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Is there a need for male contraception?
Régine Sitruk-Ware Population Council, New York, USA - regine@popcbr.rockefeller.edu
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. In comparison to female methods, the two existing male methods, condom and vasectomy, appear limited and are not always well accepted. Vasectomy is an irreversible method although new micro-surgical techniques would allow reversibility in some men. While clinical research on hormonal methods is advanced, and several combinations of androgen and progestin proved effective, no method has been fully developed and approved. Currently development of a tissue specific androgen 7-methyl nortestosterone (MENT), a molecule that does not affect the prostate, is ongoing as a method bringing additional health benefits. Non-hormonal methods are still at an early stage of research. New areas of basic research include studies on genes, proteins and enzymes involved in the reproductive system. New approaches target the maturation of germ cells, a critical component of sperm development, or the sperm motility. These methods aim at inducing reversible infertility without interfering with hormones secreted by the hypothalamus, pituitary gland, and testis. There is an obvious need to provide men with choices for their fertility regulation but advocacy for this research needs to expand and convince the industry that there is a market with unmet needs that deserves attention and investments.