Contraceptive Research and Development Looking to the Future (1996) / Chapter Skim
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5 The Market for New Contraceptives: Translating Unmet Need Into Market Demand
5 The Market for New Contraceptives: Translating Unmet Need Into Market Demand
Pages 125-165
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From page 125... ...
Germ cells begin to divide rather late in fetal life after they have settled in the germinal ridge. This gonial stage is followed by cessation of mitotic cell division, differentiation, maturation, and meiosis.
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From page 126... ...
Next we would determine in what tissue and at what time each candidate gene is expressed. From its sequence we could predict whether the gene's product is a secreted extracellular product, a protein bound to cell membranes, a transcription factor, a component of the extracellular matrix, a growth factor, or perhaps a key hormone in the feedback loop that is required for reproduction.
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From page 127... ...
This makes it logical to assume that genes affecting conception that are identified in a zebrafish screen could be shown to play a similar role in the mouse by selectively "knocking out" the homologous mouse gene and observing the results. If the gene turns out to play a similar role in mouse reproduction -- and also has a human homologue with an expression pattern resembling that of the mouse and the zebrafish -- then a potential human contraceptive target has also been identified.
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From page 128... ...
Figure 4-1 displays the areas of the male and female reproductive structures where today's science points to potential targets for potentially significant advances in making more contraceptive choices available to more individuals. In both men and women, the hypothalymus secretes the gonatropin-releasing hormone (GnRH)
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From page 129... ...
The GnRH agonists available today have proved useful in the treatment of certain conditions, including prostate cancer, endometriosis, polycystic ovarian disease, and the induction of ovulation for in vitro fertilization. So far, however, they have not been potent enough to be used as contraceptives.
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From page 130... ...
Two activin inhibitors, inhibin and follistatin, have now been identified and shown to suppress both FSH production and follicular development following * Please refer to Appendix A for the full text of the authored and fully referenced paper on which this section is based.
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From page 131... ...
. Specific Targets Contraceptive Targets Between Oocyte Development and Ovulation The final stage of follicular development, follicular rupture, presents yet another promising contraceptive target.
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From page 132... ...
These agents inhibit fertility but also reduce steroid production and induce postmenopausal symptoms, and they therefore would require steroid replacement therapy. Receptor antagonists Immediate suppression of gonadotropin secretion, although higher doses are required than of the agonists.
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From page 133... ...
FSH blockers Blocking the continuing maturation of preovulatory follicles Deglycosylated FSH or causing their premature demise using apoptotic factors is antagonists one potential contraceptive target. Gonadotropins, estrogens, growth hormone, growth factors, a cytokine, and nitric oxide Extracellular fragment act to ensure preovulatory follicle survival, while androgens, of FSH receptors interleukin-6, and gonadal GnRH-like peptides are apoptotic factors.
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From page 134... ...
that codes for an enzyme whose activity is essential for follicular rupture. If this enzyme were selectively inhibited, ovulation would be eliminated without the blocking of luteinization and the synthesis of steroid hormones.
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From page 135... ...
Muc-1 (episialin) A member of the family of mucin glycoproteins and found in the endometrial epithelial cells of mouse uterus.
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From page 136... ...
Its appearance can be blocked by antiprogestins and thus may be a good contraceptive target. Trophinin and tastin Although the significance of these factors in implantation remains to be determined, they may also be useful new leads for a contraceptive acting to prevent blastocyst attachment.
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From page 137... ...
. Postovulation Contraceptive Targets After ovulation, an ovum enters the oviduct (or fallopian tube)
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. Perhaps the most promising work to date has been on leukemia inhibitory factor (LIF)
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From page 139... ...
We included in that group RU 486, the only member of the newly discovered2 group of compounds called "antiprogestins" to have become available for human use. As their categorical name suggests, these compounds are antagonists of progesterone, a steroid hormone which originates in the corpus luteum and without which pregnancy cannot be initiated or maintained (Van Look 1994)
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From page 140... ...
administered shortly after ovulation • Challenges: identifying ovulation, maintaining regular menstrual cycle FIGURE 4-2 Possible regimens for using antiprogestins as menses inducers or as oncea-month pills. SOURCES: a -- Adapted fromWorld Health Organization.
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From page 141... ...
. Expected menses inducers work by ensuring the monthly sloughing of the endometrium at the time of expected menses, regardless of whether or not an embryo has implanted.
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From page 142... ...
Sperm Development in the Testis Once spermatogenesis is initiated in the testis by reproductive hormones, * Please refer to Appendix B for the full text of the authored and fully referenced paper on which this section is based.
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From page 143... ...
Researchers have identified several sperm proteins thought to be important in fertilization and have begun to map the location of these on the sperm membrane. Because the absence of a particular sperm protein in a given region of the membrane would likely lead to dysfunctional sperm, this line of research has opened up some potential new contraceptive options (Eddy and O'Brien 1994)
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From page 144... ...
II. Inhibition of FSH It is generally agreed that FSH is required for spermatosecretion and/or action genesis along with testosterone; therefore, a method targeting FSH or its receptor could disrupt spermatogenesis without affecting steroid hormones.
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From page 145... ...
Further exploration into its origins and development is necessary to isolate potential contraceptive targets. • Centriole attachment and tail formation occur only in sper matids, although centrioles have the potential to germinate flagella or cilia in all cells.
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From page 146... ...
IX. Induction of premature Delivery of a ZP3 mimic to the sperm at some point prior to acrosome reaction ejaculation could induce the acrosome reaction prematurely and thus make the sperm ineffective at penetrating the egg's outermost layers.
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From page 147... ...
These final developments take place in the epididymis, which also serves as a sperm storage reservoir. Because this organ is where sperm specifically acquire their ability to fertilize eggs, it makes a promising male contraceptive target.
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From page 148... ...
One is that ZRK binds, in nature, to ZP3 after full sperm capacitation within the female reproductive tract -- a poorly understood process that involves changes in the sperm cell membrane -- and introducing a ZP3 mimic before this stage may not be sufficient to induce the acrosome reaction. Second, because sperm are present at such high concentrations in the epididymis, any agent that acts there would
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From page 149... ...
, secondary binding to the zona pellucida, penetration through the zona pellucida, and fusion of the sperm and egg plasma membranes (which occurs after the acrosome reaction)
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From page 150... ...
Immunogens of the Early Conceptus Some of the most advanced immunocontraceptive products are based on human chorionic gonadotrophin (hCG) , a hormone released by the early embryo that is involved in several events crucial to maintaining early pregnancy, including maintenance of the corpus luteum, progesterone production and, perhaps, implantation.
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From page 151... ...
A woman's immune system could attack and incapacitate sperm at several points as they progress through the reproductive tract, including the vagina, cervix, uterus, and oviduct. Researchers have thus far identified and begun to study a number of different sperm antigens (see Table 5-6)
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From page 152... ...
This immunogen would require no exogenous androgen supplementation, has shown no toxicity in rats and monkeys, and is reversible. One of the more promising reversible male contraceptive options, the formula is likely to be based on recombinant proteins or synthetic peptides based on human or primate FSH, rather than the sheep hormone formulas currently in use.
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From page 153... ...
Others 99 other sperm or sperm proteins have been assigned immunocontraceptive candidacy, based on sperm surface labeling. continued on next page
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From page 154... ...
Recently, researchers sequenced PH-20 and found that the protein is the same in guinea pigs, mice, monkeys, and humans. They have now cloned and sequenced the monkey protein and are beginning studies to test its efficacy as a contraceptive in primates.
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From page 155... ...
A clear advantage of the FSH immunogen is that, unlike GnRH, it does not require androgen supplements to maintain libido and secondary sexual characteristics. In immunocontraceptive research to date, the best efficacy results have been at the level of 80 percent (for the hCG-based immunogen)
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From page 156... ...
The surface area of this complex system is nearly 400 square meters and, within it, nearly 80 percent of all immunoglobulin-producing plasma cells reside in the intestinal mucosa, making this organ the largest reservoir of immune cells in the body. Because stimulation of the mucosal immune system at one site could elicit an immune response at a distant site, researchers believe that oral administration of immunogens could lead to effective localized immunity in the urogenital tract (Haneberg et al.
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From page 157... ...
stimulation of an appropriate protective immune response. Researchers face several challenges to developing an oral immunization (e.g., Challacombe and Tomasi 1980; Mowat 1987)
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From page 158... ...
Chen DB, R Hilsenrath, ZM Yang, et al. Leukemia inhibitory factor in human endometrium during the menstrual cycle: Cellular origin and action on production of glandular epithelial cell pros taglandin in vitro.
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From page 159... ...
for fertility regulation. Human Reproduction 8:870–873, 1993.
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From page 160... ...
Specific binding of murine leukemia inhibitory factor to normal and leukemic monocytic cells. Proceedings of the National Academy of Sciences, USA 85:5971–5975, 1988.
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From page 161... ...
Ovarian histopathology of bitches immunized with porcine zonae pellucidae. American Journal of Reproductive Immunology and Microbiol ogy 18:94–103, 1988.
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A role for the migrating sperm surface antigen PH-20 in guinea pig sperm binding to the egg zona pellucida. Journal of Cell Biology 101:2239–2244, 1985.
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Blastocyst implantation depends on maternal expression of leukemia inhibitory factor. Nature 369:76–79, 1992.
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Willson TA, D Metcalf, NM Gough. Cross-species comparison of the sequence of the leukemia inhibitory factor gene and its protein.
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From page 165... ...
The embryo develops into a fetus at about 8 weeks after fertilization or 10 weeks after the last menstrual period (Cook 1989)
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