Contraceptive Research and Development Looking to the Future (1996) / Chapter Skim
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Appendix A: Female Methods
Appendix A: Female Methods
Pages 349-380
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Appendixes
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The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, Calif. INTRODUCTION The advent of modern molecular and cell biology has permitted a detailed look at the regulation of ovarian secretory function, follicular and oocyte maturation, and ovulation.
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The GnRH-producing cells in the hypothalamus secrete this peptide in a rhythmic fashion that is critical for normal gonadotropin secretion and work is under way to determine the cellular and molecular basis of the "GnRH pulse generator." Pharmacologic disruption of pulse parameters can have differential effects on the secretion of the two pituitary hormones, FSH and LH; thus, it may be possible to selectively disorganize gametogenesis. Superimposed upon the GnRH pulse generator are numerous neural and hormonal inputs mediated by monoamines, neuropeptides, prostaglandins, nitric oxide, sex and adrenal steroids, thyroid hormones, cytokines, and peptide growth factors that stimulate or inhibit GnRH production.
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The recent development of tissue-specific steroids raises the possibility that new steroids might be found that are specific for GnRH cells of the hypothalamus or pituitary gonadotropes. The selective regulation of pituitary FSH is achieved physiologically by the interplay of GnRH, gonadal steroids, and peptide hormones/growth factors.
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Beginning with puberty, growing follicles are periodically subjected to a process of recruitment and selection, from which a dominant follicle emerges in each menstrual cycle. This follicle proceeds to grow to maturity, a condition that makes it responsive to the ovulatory stimulus.
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Recent studies have demonstrated that gonadotropins, estrogens, growth hormone, growth factors (IGF-I, EGF/TGFβ, basic FGF) , a cytokine (interleukin-1)
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In other words, although the oocyte is prevented from leaving the follicle to be fertilized, at the same time the normal hormonal oscillations of the menstrual cycle are preserved. Recent data indicate that LH uses at least three signal transduction pathways to produce follicular rupture: CAMPdependent protein kinase, the protein kinase C, and the calcium/calmodulindependent protein kinase II pathway (Kugu et al.
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This has led to the concept that the cell layer surrounding the oocyte produces a substance -- oocyte maturation inhibitor (OMI) -- which is inhibitory, and that the ovulatory stimulus releases this inhibition and adds a stimulatory factor for germinal vesicle breakdown (GVB)
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. These "orphan receptors" are so structurally related to those of the steroid receptors that it is considered likely that some, if not all, will be found to have an endogenous ligand.
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More research into the role of nuclear hormone receptors in the regulation of the transcriptional program within the oocyte and in the ovary is needed. The recent finding that the nuclear receptor germ cell nuclear factor (GCNF)
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The cloning of the estrogen and progesterone receptors and the ability to use these tools to dissect the progesterone- and estrogen-mediated signal transduction pathways indicate that, in addition to the receptor, its environment impacts on the biological efficacy of the hormone. A recent and unexpected finding is that different ligands induce distinct alterations in receptor structure, the consequence of which is that these ligands can then promote unique sets of protein-protein interactions and subsequently regulate gene transcription in a differential manner (Allan et al.
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After attachment, the trophoblastic cells of the blastocyst start to invade through the endometrial epithelial lining into the stromal compartment, where the stromal cells begin a process of differentiation known as decidualization. Implantation is considered the process
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On the other hand, an agent that stimulated only enough uterine contractility to cause embryonic expulsion, even when the embryo entered the uterus at the normal time, would also provide effective contraception. In the human female there is a three-day window from the moment the egg enters the uterus until blastocyst adhesion to the endometrium begins.
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. A major advantage of combination therapy is that, although in the United States no postcoital contraceptive preparation is marketed as such, administration of four marketed oral contraceptive pills taken two and two, 12 hours apart, provides effective postcoital contraception.
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Mifepristone can delay ovulation due to temporary arrest of the growth of the dominant follicle, can offset the positive feedback of estrogen on the discharge of gonadotropin from the pituitary gland, and can disrupt the required secretory changes of the endometrium. These features make an antiprogestin effective for preventing either fertilization or implantation, depending on the stage of the menstrual cycle at which it is taken.
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Single doses of 2 or 10 mg/kg given 2 days after ovulation to rhesus monkeys were highly effective for preventing pregnancy (Ghosh and Sengupta 1993)
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The distribution of several α and β integrin subunits has been studied in the human endometrium during the menstrual cycle. It was noted that the collagen/laminin receptors (α2, α3, and α6)
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At least in the rat, HB-EGF is regulated by progesterone with expression in the uterine stromal cells and suppression in epithelial cells. It appears that it is involved in the development and maintenance of the decidual cells that are required for subsequent stages of implantation after attachment.
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Unless agents that act in this manner have a long biological half-life, there will also be practical difficulties in determining the optimal time during the cycle for administration. Cytokines/Growth Factors Within the last 10 years there has been a veritable explosion of research and interest in a variety of endogenous glycoproteins that are known as growth factors and/or cytokines.
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In human endometrial stromal cells in culture, secretion of macrophage CSF is progesterone dependent and should therefore be increased during the luteal phase of the cycle (Hatayama et al. 1994; Kariya et al.
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Binding of these cytokines to their receptor complexes activates a signal transduction pathway, resulting in rapid tyrosine phosphorylations, followed by activation of a protein kinase cascade and early gene responses. These appear to be nonreceptor tyrosine kinases.
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Studies in nonhuman primates have identified a variety of other growth factors whose secretion by the endometrium is hormonally regulated. There are cell-specific changes in gene expression of the receptors for insulin-like growth factor I (IGF-I)
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. FGFs have a dual receptor system; one component is the FGF receptor with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain, and the other is a series of heparin or heparin sulfate proteoglycans required for FGF binding.
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Mifepristone has been given as a single dose of 600 or 400 mg, or 100 mg for four consecutive days in the late luteal phase to women who had detectable levels of the β subunit of hCG; actual failure rates, expressed as percentages of subjects continuing to be pregnant, were from 17 to 19 percent. This level of efficacy is similar to that observed after use of mifepristone to interrupt pregnancy when given up to 11 days after a missed menses.
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Relationship between human oocyte maturity, fertili zation and follicular fluid growth factors. Human Reproduction 9:902–906, 1994.
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Gearing DP, CJ Thut, T VandenBos, et al. Leukemia inhibitory factor is structurally related to the IL-6 signal transducer gp130.
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Roles of growth factors during peri-implanta tion development. Molecular Human Reproduction 10:712–718, 1995.
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Progesterone-dependent secretion of macrophage colony stimulating factor by human endometrial stromal cells of nonpregnant uterus in culture. Jour nal of Clinical Endocrinology and Metabolism 79:86–90, 1994.
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Simón C, GN Piquette, A Frances, et al. Localization of interleukin-1 type I receptor and interleukin 1ß in human endometrium throughout the menstrual cycle.
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95/11: Peptide Growth Factors and Their Receptors II. New York: Springer Verlag.
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Zhang Z, C Funk, D Roy, et al. Heparin-binding epidermal growth factor-like growth factor is differentially regulated by progesterone and estradiol in rat uterine epithelial and stromal cells.
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