Appendixes



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--> A: Female Methods Horacio Croxatto, M.D. Instituto Chileno de Medicina Reproductiva, Santiago Michael Harper, Ph.D., Sc.D. Center for Reproductive Medicine, Baylor College of Medicine Donald McDonnell, Ph.D. Department of Pharmacology, Duke University Medical Center Wylie Vale, Ph.D. 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. This, in turn, has disclosed targets within the ovary which, at the current time, appear to have the greatest potential for leading to the development of a deliverable contraceptive within the next 10 to 15 years. Interference With Prefertilization Events General Oocyte maturation and ovulation are coordinated by a series of cascading signals involving the brain, pituitary, and gonads. Fertility in mammals is modulated by multiple factors including length of day, availability of food, exposure to stressors, illness, presence or evidence of potential mates and competitors, and breastfeeding. The final common pathway for the effects of this external and internal sensory information on fertility is the collection of GnRH (gonadotropin-releasing hormone)-producing neurons in the hypothalamus that provide this neuropeptide to the anterior pituitary gland via a local vascular connection. The

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--> pituitary gonadotropes respond to GnRH by secreting the gonadotropins, LH (luteinizing hormone) and FSH (follicle-stimulating hormone); these act in concert with each other and with many other local ovarian factors to control steroidogenesis and release of mature oocytes. Each regulatory component is a potential target for interfering with oocyte maturation and ovulation and hence fertility. Among possible contraceptive targets are receptors and transcriptional regulators for GnRH, activin, inhibin, gonadotropins, and intragonadal paracrine/autocrine factors; however, much basic and applied work is still needed to generate specific pharmacologic tools for controlling these molecules. Brain Contraception can be achieved by preventing production of GnRH, a strategy that would only require steroid replacement at a physiologic level with potential health benefits. The maintenance of GnRH expression may be dependent upon tissue-specific transcription factors which, if sufficiently restricted, could be blocked pharmacologically. GnRH action can be prevented by synthetic analogues or specific antibodies. 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. Some of these could be targets for contraception, provided that cell-type-specific drugs could be developed. Hypothalamus and Pituitary The production of both LH and FSH is dependent upon receipt of periodic pulses of GnRH from the hypothalamus. GnRH binds to the GnRH receptor, a serpentine, G protein-coupled receptor, and induces its second messengers. The exposure of the pituitary to persistently high levels of GnRH or to potent longacting agonist analogues (superagonists) results in an initial stimulation that is followed by desensitization secondary to receptor down-regulation and attenuation of receptor signal transduction. Prolonged superagonist administration suppresses both LH and FSH secretion leading to hypogonadism. Superagonists are now on the market for several indications-including precocious puberty and the treatment of hormone-dependent neoplasias and dysplasias. These agents inhibit fertility in females and males, reduce steroid production, and induce postmenopausal symptoms. Thus,

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--> any continuous use of superagonists as contraceptives will necessitate steroid replacement therapy. An alternative approach, involving agents that bind to the GnRH receptor, is to inhibit gonadotrope functions with GnRH receptor antagonists. These compounds have the advantage of producing an immediate suppression of gonadotropin secretion, thereby avoiding transient stimulation of the gonadotropes, gonads, and steroid-dependent tissues. However, much higher doses of the presently available antagonists must be delivered than in the case of the agonists. The development of potent, orally active antagonists would provide a means of reversibly suppressing gonadal functions. Screening of chemical and microbiological libraries with high throughput GnRH receptor assays may provide leads for further optimization. These antagonists, given with steroid replacement, should be very effective contraceptives in both women and men. Furthermore, because GnRH antagonists do not transiently stimulate sex hormone production, they would be more appropriate than agonists for the treatment of steroid-dependent neoplasia and dysplasia. 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. There are reports in the literature of the existence of a small peptide, FSH-releasing factor (FRF), that acts at the pituitary level to stimulate FSH but not LH. If such a putative factor were identified and found to be physiologically necessary for normal FSH production, then blockers of this peptide would suppress fertility. Activin, a dimeric peptide growth factor produced locally within the pituitary, is probably the key trophic factor maintaining expression of FSH. Activin has little effect on LH production in most systems. Two inhibitors of activin have been identified, inhibin and follistatin. Inhibin, a heterodimeric protein structurally related to activin (they share a common subunit) blocks the responses of some (but not all) cells to activin; follistatin binds to activin and bioneutralizes it. Both proteins reduce the production of FSH in animals and suppress follicular development. Inhibin is secreted by the ovary under FSH stimulation and provides a negative feedback signal that shuts off further secretion of that pituitary hormone; follistatin is produced locally and serves to limit all effects of activin. The binding and signaling receptors for activin have been cloned and it may be possible to develop small molecules that would interfere with these functions. The way inhibin blocks activin is currently unknown, but studies of this process may provide insight for developing inhibin-mimetics. Because inhibin only suppresses a subset of activin effects, such drugs may be relatively specific to suppression of reproduction (DePaolo et al. 1991; Vale et al. 1994, 1990). The finding that activin and inhibin can uncouple the transcription of FSHß from that of LHß provides evidence for the existence of distinct intracellular regulatory pathways for the two proteins that may be exploitable.

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--> Follicular Development A unique organ, the ovary is made up of hundreds of thousands of primary follicles that die during the lifetime of a female. Of the 400,000 follicles found in the human female at puberty, only about 400 will ever make it to ovulation. From before birth, and throughout the reproductive years, small cohorts of follicles start growing continuously, one after the other, out of the pool of primary follicles. The vast majority undergo atresia after reaching different stages of growth. 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. The fact that a single follicle is selected to complete the process of maturation in each menstrual cycle is remarkable. This dominant follicle survives the other partners of its cohort, which enter atresia, and it proceeds to ovulation. It has been suggested that this process is regulated in part both by hormonal gradients within the ovary and by the ability of the developing follicle to respond to these signals by virtue of its physical location. However, the fidelity of the system and the usual outcome, that is, the production of one ovum, suggests that follicle selection is a tightly controlled process, the molecular basis for which has yet to be determined. It has been established that most ovarian cell turnover occurs as a consequence of programmed cell death or apoptosis, an important cellular process by which superfluous or unwanted cells are deleted from an organism during tissue remodeling and differentiation. Although not identical in all cells, it has received much attention recently as a consequence of the identification of several transcription factors involved in regulating the process and the definition of the external stimuli that modulate the function of these proteins. Within the ovary, several substances have been shown to modulate the rate of cellular apoptosis by acting as follicular survival factors or mediators of cell death. From among the factors identified thus far, gonadotropins, steroid hormones, cytokines such as IGF-1, and interleukins seem likely to be important (Artini et al. 1994; Erickson and Danforth 1995). Modulation of Ovarian Follicle Apoptosis as a Potential Contraceptive Approach Follicular atresia is a well-regulated apoptotic event and not the result of cell necrosis. The ovary is a unique tissue with massive cell death throughout reproductive life. As suggested above, more than 99 percent of ovarian follicles endowed at early life are destined to undergo apoptosis. Based on extensive literature dealing with follicle selection and ovulation, as well as recent analysis of follicle apoptosis and follicle recruitment, one can propose a multistep model for the life cycle of ovarian follicles (Figure A-1).

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--> Figure A-1 Life cycle of ovarian follicles. FSH = follicle-stimulating hormone; FSHR = follicle-stimulating hormone receptor; LH = luteinizing hormone; and LHR = luteinizing hormone receptor. Source: Prepared for this report by Aaron Hsueh. At early stages of ovarian development, a fixed number of primordial follicles are endowed in the ovary. Later on, no mitosis of germ cells can be detected in the ovary, and gradual depletion of the follicle pool begins as subpopulations of follicles initiate growth. As they reach the early antral stage, all follicles undergo degeneration through apoptosis. However, after the activation of the hypothalamic-pituitary axis at puberty, circulating gonadotropins (mainly FSH) act as survival factors to prevent the demise of a small subgroup of early antral follicles (Hsueh et al. 1994). From these, a dominant follicle is selected for final maturation and ovulation. Throughout reproductive life, the cyclic process of follicle recruitment, atresia selection, and ovulation continues until the follicle pool is exhausted around the time of reproductive senescence (or menopause in women). Ovarian cell apoptosis in early antral follicles, before their final selection into preovulatory ones, represents a unique stage for contraceptive intervention. Recent studies have demonstrated that gonadotropins, estrogens, growth hormone, growth factors (IGF-I, EGF/TGFß, basic FGF), a cytokine (interleukin-1), and nitric oxide act in concert to ensure the survival of preovulatory follicles. In contrast, androgens, interleukin-6, and gonadal GnRH-like peptide are apoptotic factors. The selection of these follicles and their continuing maturation can be blocked by treatment with antagonists for the follicle survival factors or by increasing the levels of apoptotic factors. Promising candidates include the FSH blockers, such as deglycosylated FSH antagonists, and the extracellular fragments of FSH re-

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--> ceptors that may serve as a neutralizing binding protein. These agents would act in an ovary-specific manner. It should be realized, however, that this approach must be complemented with physiologic replacement therapy, since preventing the emergence of the dominant follicle would probably lead to hypoestrogenism. The fact that all but one follicle within a selected cohort degenerates indicates that selective regulation of atresia within the ovary actually occurs. Understanding the molecular events that control follicle selection could have a major impact on contraceptive research. Disruption of the Ovulatory Process The ovulatory process comprises several coordinated changes that occur in mature follicles, triggered by the ovulatory stimulus (the gonadotropin surge). They include resumption of meiosis, cumulus expansion with detachment from the mural granulosa, onset of luteinization expressed as a new steroidogenic pattern, and the collagenolitic cascade that leads to rupture of the follicle wall and release of follicle contents. Although all these events are triggered by the same stimulus, they can be dissociated by specific pharmacologic interventions. It is therefore possible to prevent follicular rupture without interfering with luteinization and steroidogenesis. 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: CAMP-dependent protein kinase, the protein kinase C, and the calcium/calmodulin-dependent protein kinase II pathway (Kugu et al. 1995). In addition, the LH surge induces the expression of the prostaglandin synthase 2 gene (PGS-2), which codes for an enzyme whose activity is essential for follicular rupture. This enzyme could be selectively inhibited, eliminating ovulation without blocking luteinization and the synthesis of steroid hormones (Morris and Richards 1993, 1995). Luteinizing hormone induces prostaglandin endoperoxide synthase-2 and luteinization in vitro by A-kinase and C-kinase pathways (Sirois 1995). It should also be possible to intervene with the onset of meiosis, advancing it to such a point that, by the time the oocyte is released, it is no longer fertilizable. Meiotic cell division is a process, unique to the gonads, which is designed to permit the exchange of genetic material between maternal and paternal DNA. While this process of what is essentially the creation of genetic diversity is tightly regulated, because of its unique mode and site of action it has potential as a realistic target for contraceptive intervention. Based on work in mammalian cells, as well as in species as diverse as Drosophila and Xenopus, it has become clear that meiotic and mitotic cell division and the way they are regulated are sufficiently distinct to assume that process-specific regulatable targets can be identified. One point of intervention might be the regulation of progression of primary oocytes from prophase I to metaphase II (Grigorescu et al. 1994). The

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--> oocyte contained in each follicle rests in an animated state, arrested in the prophase I of the first meiotic division, until the follicle matures and receives the ovulatory stimulus. The ovulatory stimulus has the peculiar property of stimulating resumption of meiosis only of the oocyte contained in the mature follicle. The processes that maintain the oocyte in a quiescent stage for between 12 and 50 years remain largely unknown. Fully grown oocytes resume meiosis when they are separated from granulosa cells or when isolated cumulus-oocyte complexes are stimulated with FSH. 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), a prerequisite for completion of meiosis. Purines produced by follicular cells and transmitted to the oocyte via gap junctions are known to be involved in preventing resumption of meiosis (Downs 1993). Unusual sterols present in human follicular fluid and bovine testis have been shown recently to activate mouse oocyte meiosis in vitro and are believed to play a crucial role in the resumption of meiosis in mammals (Byskov et al. 1995). It is likely that synthetic analogues may be efficient both as agonists and as antagonists for pharmacologic manipulation of the onset of meiosis. An intracellular factor that regulates the transition from first meiotic prophase to metaphase II—maturation promoting factor (MPF)—has been identified and determined to be a heterodimer comprised of the regulatory subunit cyclin B and the catalytic subunit, the cyclin-dependent protein kinase p34cdc2 (Dorce 1990). These concepts introduce two specific areas that must be investigated further, one to define the precise chemical messenger(s) responsible for keeping the oocyte in the dormant state, the second to define the events responsible for the termination of dormancy and the resumption of meiosis. There are, of course, specific concerns about intervention in the process of meiosis. Most of these deal with the possibility of consequences from interfering with the process of genetic exchange and any effects on an ovum or resulting fetus were an oocyte to escape regulation by a pharmaceutical agent. Although these are valid considerations, they are premature until such time as the events that regulate the meiotic process are defined. Granulosa Cell-specific Targets The granulosa cell layer is the innermost lining of the follicle wall and surrounds the oocyte. Under the influence of FSH, granulosa cells proliferate and produce estradiol. It is likely that targeting the FSH receptor (different ways to achieve this are discussed in Appendix B) would be useful in interrupting the process of follicular development. However, the ensuing decrease in circulating estrogens on a long-term basis would be contraindicated, owing to the important role of estrogen in regulating the processes responsible for maintenance of bone

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--> mass and cardiovascular tone, and in regulating vasomotor function (Barzel 1988), so that FSH receptor blockers would have to be given in conjunction with steroid replacement therapy. The new generation of tissue-selective steroid receptor agonists, for example, raloxifene, may be available for use in contraception. It is not clear that blocking FSH actions in the granulosa cell has to result only from a pharmacological action at the receptor. It is possible that an understanding of the intermediate steps from the cell surface to the nucleus, and of the genes within the ovary that respond to this hormonal stimulus, may permit the development of specific agents that uncouple the synthesis of estrogen from other gene products required for follicular development. Ovary-specific Gene Transcription One of the most exciting areas of reproductive research has to do with whatever is involved in determining the expression and role of novel hormone-dependent transcription factors within the ovary, including follicular and corpus luteum cells and the oocyte. In the last 10 years, the cloning and characterization of the steroid hormone receptors has been accomplished and has assisted in our understanding of the mechanism of action of the reproductive hormones estrogen and progesterone (Evans 1988). The specific impact of these observations will be discussed below. Emanating from this research was the unexpected finding that the family of proteins to which the steroid hormone belongs comprises up to 50 members that are related structurally but, for many of which, no ligands have been identified (O'Malley 1991). 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. This contention has received some support from the discovery in 1992 of a ligand for the orphan nuclear receptor RXR (Heyman et al. 1992). This ligand is 9-cis retinoic acid, a metabolite of retinoic acid. Since then, progress has been slow in defining specific ligands for other such receptors, although agents that regulate their biological activity indirectly have been identified. In this category, the identification of a nuclear receptor that responds to the addition of farnesyl pyrophosphate (FAR) (Forman et al. 1995) and a family of related receptors (peroxisome proliferator-activated receptors [PPAR]) that are transcriptionally regulated by fatty acid derivatives, are intriguing examples of an emerging new endocrinology (Kliewer et al. 1992). Of particular relevance to reproduction is the recent discovery that the transcriptional effects of melatonin, a hormone intimately involved in reproduction, are manifested through the orphan receptor RZR (Becker-Andre et al. 1994). A combination of melatonin and a synthetic progestin is being studied as a novel type of oral contraceptive preparation. It is possible that the slow pace of the discovery of ligands for additional orphan receptor members of this subfamily may indicate that they do not, in fact,

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--> have ligands but are regulated in other ways. This contention is supported by a series of independent findings that indicate that some orphan receptors can be activated by membrane depolarization, as well as by agents such as dopamine and nerve growth factor that act at the cell surface (Power et al. 1991; Lydon et al. 1992). Nevertheless, the recent discovery that the orphan receptor PPARy is the target for the biological efficacy of the thiazolidinediones, a class of drugs used for the treatment of non-insulin-dependent diabetes, indicates that these receptors are realistic pharmaceutical targets (Lehmann et al. 1995). The discovery of this compound, which binds to PPARy with high affinity and permits it to activate target gene transcription, is an important result from a pharmaceutical perspective. It demonstrates that, without knowing whether or not an orphan receptor has an endogenous ligand, it can be regulated by a synthetic pharmaceutical in a manner that impacts on a relevant biological process. This paradigm is likely to be reiterated with other orphan receptors, some of which may be relevant to oocyte maturation. 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) is restricted in expression to developing gametes and is detectable in all stages of oocyte development justifies this contention (Chen et al. 1994). Although a direct link between its expression and function has not yet been established, GCNF's unique pattern of expression would imply a critical function. Efforts to identify the target genes that are responsive to GCNF, as well as identification of an endogenous ligand or a synthetic molecule that could regulate its transcriptional activity, will be required at a minimum to evaluate its potential role as a target for contraception. In addition to GCNF, the nuclear receptor SF-1 (steroidogenic factor1) may also play a key regulatory role in gametogenesis (Ikeda et al. 1994; Lala et al. 1992; Luo et al. 1994). This receptor, identified initially as a positive transcriptional regulator of steroidogenic enzymes, has now been determined to have a much more central effect on gonadal development. Although a ligand has not yet been identified, there have been significant advances in our understanding of the biology of SF- 1. In recent published experiments in which the SF-1 protein has been genetically disrupted in mice, it was determined that the ensuing progeny failed to develop gonads and their pituitary lacked gonadotropes. The mechanism by which SF-1 may exert its regulatory activities is just beginning to become clearer. The gene-encoding Mullerian inhibiting substance (MIS), a cytokine required for male reproductive tract development, is positively regulated by SF-1 (Shen et al. 1994). All these examples illustrate the impact of basic nuclear factor research on our understanding of the molecular events underlying the development of reproductive capacity.

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--> protein uterine levels are increased by progesterone and unaltered by estrogen. In endometrial specimens from women during nonconception cycles, both LIF message and protein are low or absent during the proliferative phase and high during the secretory phase, remaining high to the end of the cycle (Charnock-Jones et al. 1994; Kojima et al. 1994). LIF secretion from human endometrial cell cultures, however, shows a peak at the mid-luteal phase (around the time of implantation in a conception cycle) (Chen et al. 1995). LIF and IL-6 are both found in pig uterine secretions just prior to embryo attachment (Anegon et al. 1994). The reason for the discrepancy between message and protein levels and secretion in the human may be due to changes between cell-associated and secretory forms or between conception and nonconception cycles. In mice and rabbits, no examination was done for LIF expression in pseudopregnant animals after the equivalent time of implantation in pregnant animals. In sum, the data in hand suggest that LIF may be an important lead in the development of specific anti-implantation agents. There are, nonetheless, some possible problems. There are significant similarities in primary amino acid sequences and predicted secondary structures of LIF with other cytokines, e.g., oncostatin M (OSM), IL-6, ciliary neurotrophic factor (CNTF), and granulocyte colony-stimulating factor (G-CSF) (Horseman and Yu-Lee 1994; Rose and Bruce 1991). These structurally related cytokines modulate differentiation in a variety of cells so that there is a possibility that, in some cells at least, they could substitute for each other, although the present understanding is that LIF and related cytokines are not functionally equivalent (Piquet-Pellorce et al. 1994) despite similarities in receptor structure (see below). The importance of LIF is underscored by the high degree of conservation in the coding regions and high degree of similarity of the protein across species (Willson et al. 1992). Actions of these cytokines on cells are mediated through membrane-bound receptors. 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. Specificity of response may be ensured by intracellular structure of the cytokine receptor dictating which signaling molecules are activated and expression levels of signaling molecules in the different cell types (Taniguchi 1995). Similarities between the receptor signal transducing units of CNTF, G-CSF, IL-6, IL-11, and LIF have been reported (Horseman and Yu-Lee 1994). There are two LIF receptor types, a high- and a low-affinity type (Hilton et al. 1988; Yamamoto-Yamaguchi et al. 1986). The cloned LIF receptor (LIFR) only binds LIF with low affinity, but after the binding of a common receptor component gp 130 (the signal transduction unit for IL-6R), LIFR is converted to the high-affinity type (Gearing et al. 1991, 1992). The receptors for all the above cytokines involve gp130 binding, acting as a signal transduction unit. The IL-6R comprises a homodimer of gp130, but OSMR,

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--> LIFR, and CNTFR involve only one gp 130 subunit plus the LIFR ß subunit, all complexed with a third element, a specific a subunit, which may be membrane-bound or act as a soluble factor, and regulate the binding of factors to the ß subunits (Davis et al. 1993; Hirano et al. 1994; Ip et al. 1992; Murakami et al. 1993). Receptor activation results from binding of gp130 which converts the a:ß complexes to the high-affinity form. These receptor components constitutively associate with Jak-Tyk kinases, which are activated by receptor dimerization (Lütticken et al. 1994; Murakami et al. 1993; Stahl et al. 1994). A family of proteins known as STATs (signal transduction and activation of transcription) are involved in the actions of many polypeptide ligands on cells. STAT3 is activated through phosphorylation on tyrosine as a DNA binding protein by the LIF-IL-6CNTF family of ligands (Zhong et al. 1994). Selection of the particular substrate STAT3 is specified not by the particular Jak activated but by the tyrosine-based motifs in the receptor components gp130 and LIFR (Stahl et al. 1995). Blockade of the tyrosine kinases prevents phosphorylation of the receptor subunits and gene induction. Since gp130 is involved in signal transduction for all members of this receptor family, inactivation of the gp130 signaling function may not provide a good contraceptive target owing to lack of specificity. Nevertheless, inhibition of tyrosine kinase activity itself has been suggested as a potential drug target (Levitzki and Gazit 1995), although whether sufficient specificity can be ensured is again an unresolved question. However, specific blockade of the formation of the LIFR a:ß complex, given the essential need of LIF for implantation, appears a much more appealing target, if it can be established that LIF plays the same role in other species that it does in the mouse. Such inhibition targeted at the essential LIFR a subunit should provide the specificity needed to avoid interference with function of OSM, CNTF, and IL-6. Although LIF has actions at sites other than the uterus, the fact that the mutant mice deficient in LIF were apparently normal gives hope that short-term inhibition of LIF action in the uterus will be without other adverse consequences. 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) and epidermal growth factor (EGF), and for the secreted proteins IGF-binding protein 1 and retinol-binding protein (Fazleabas et al. 1994). In human endometrial cell cultures, IGF-I, its receptor, and the IGF-binding proteins 1-4 are all localized to the epithelial cells and highest at the early- to midsecretory phase of the cycle (Tang et al. 1994). It is postulated that these changes are modulated by the embryo and are essential for implantation. However, at present the data are purely correlative. Fibroblast growth factors (FGFs) are involved in angiogenesis, cell growth, and cell differentiation, and disruption of the gene for FGF-4 in mice causes severe inhibition of the growth of the blastocyst inner cell mass (the cells that form the embryo) and failure of pregnancy just

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--> after implantation (Feldman et al. 1995). 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. There are several binding sites for these proteoglycans on FGF, and thus design of compounds able to modulate FGF action should be possible (Ornitz et al. 1995). In summary, there are several new and promising approaches that could form the basis for a once-a-month contraceptive pill. Yet, all this research must still be brought to proof of concept stage and, even when an LIFR blocker that blocks implantation is developed, many questions will remain. There will be a need to determine specific dosages and frequencies, all of which will depend on the half-life of the compound being used. Will it be necessary to deliver the agent locally, or will an oral preparation suffice? If the agent is given too late, will the effect be simply a normal pregnancy and is there a risk of a teratogenic effect? Is there likely to be a shortening of the cycle that causes difficulties in determining the time for optimal dosing in the next cycle? Obviously, there are difficulties; still, those may be fewer than those produced through hormonal manipulation, making the approach worthy of further investigation. Inhibition of hCG Production As discussed above, peptide agonists and antagonists of GnRH have been developed and their actions in blocking the central hypothalamic-pituitary axis have been extensively investigated as a method of contraception in both men and women, as discussed above. Investigations are under way to develop nonpeptide antagonists since they are likely to be simpler and cheaper. Whether such agents could block the action of trophoblast GnRH in stimulating the hCG secretion necessary for luteal support and pregnancy maintenance is unknown. It may also be that other factors are involved in regulation of early hCG production that might be amenable to attack. Inhibition of the early hCG production necessary for luteal maintenance would cause early pregnancy failure without disrupting menstrual cyclicity. Induction of Luteolysis In nonprimates, it has been relatively easy to develop agents that cause luteolysis, that is, premature demise of the corpus luteum with interference in progesterone secretion and consequent failure of pregnancy. In primates, in whom the mechanisms of luteal support appear to differ significantly from those of nonprimates, this has proven difficult. At this time, induction of luteolysis does not appear to be a promising avenue, but basic research on regulation of the corpus luteum may provide new leads. One alternative means to achieve the same effect is by blockade of progesterone synthesis in the corpus luteum. Such

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--> a functional luteolysis has been demonstrated following administration of either azastene or epostane during the luteal phase of the cycle to rhesus monkeys (Schane et al. 1978; Snyder and Schane 1985); in pregnant monkeys, pregnancy was terminated (Schane et al. 1978). Even with a luteolytic agent in hand, it might prove to be effective only during the period before the trophoblast provides luteal support, although this was not the case with the progesterone synthesis inhibitors (Asch et al. 1982; Snyder and Schane 1985). In such cases, the agent would not be luteolytic at the end of the cycle but only until the peri-implantation period, after which cycle disruption might ensue. Expected Menses Induction Another possible once-a-month contraceptive modality aims at insuring the occurrence of endometrial sloughing at the time of expected menses, regardless of whether or not an embryo has implanted. Since progesterone is essential to maintain the integrity of the endometrium, it is theoretically possible that a single high dose of an antiprogestin given at, or shortly before, the time of expected menses might achieve this purpose. 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 ß 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. In order to improve effectiveness, WHO/HRP is conducting a two-center study in which mifepristone is followed by administration of misoprostol, an orally active prostaglandin that has been shown to increase significantly the rate of pregnancy termination when both are combined after missed menses. Data from this study may be available during 1996. Recommendations Available evidence suggests that there are several promising targets that can be pursued now and we therefore make the following recommendations: There should be expeditious examination of combinations of antiprogestins and other hormonal or antihormonal drugs, given orally or vaginally, as a method of emergency or once-a-month contraception. A more effective combination could be developed in a relatively short time frame. Studies in nonhuman primates should be conducted to develop the concept and test the safety of immunization against progesterone as a simple and easily reversible contraceptive method. The most promising of the adhesion molecules should be studied to deter-

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--> mine how essential they are for initial blastocyst attachment to the endometrial epithelium. Experiments using active or passive immunization should be conducted to determine whether, for example, LIF is essential for implantation in species other than the mouse. If such experiments prove positive, then means to disrupt uterine LIF function for a short period should be sought; the most specific approach would appear to be through interference with binding of the specific LIFRa subunit. Examination of the obligatory requirement for other growth factors/cytokines should be carried out. Nonpeptide GnRH antagonists, which would be useful for applications both before and after fertilization, should be developed. References Adams CE. Retention and development of eggs transferred to the uterus at various times after ovulation in the rabbit. Journal of Reproduction and Fertility 60:309-315, 1980. Allan GF, X Leng, ST Tsai, et al. Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation. Journal of Biological Chemistry 267:19513-19520, 1992. Anegon I, MC Cuturi, A Godard, et al. Presence of leukemia inhibitory factor and interleukin 6 in porcine uterine secretions prior to conceptus attachment. Cytokine 6:493-499, 1994. Artini PG, C Battaglia, G D'Ambrogio, et al. Relationship between human oocyte maturity, fertilization and follicular fluid growth factors. Human Reproduction 9:902-906, 1994. Asch RH, CG Smith, et al. Luteolytic effect of azastene in the nonhuman primate. Obstetrics and Gynecology 59:303-308. 1982. Barzel US. Estrogens in the prevention and treatment of postmenopausal osteoporosis. American Journal of Medicine 85:847-850, 1988. Baumann H, GG Wong. Hepatocyte-stimulating factor. III. Shared structural and functional identity with leukemia inhibitory factor. Journal of Immunology 143:1163-1167, 1989. Becker-Andre M, I Wisenberg, N Schaeren-Wiemers, et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. Journal of Biological Chemistry 269:28531-28534, 1994. Bhatt H, LJ Brunet, CA Stewart. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proceedings of the National Academy of Sciences, USA 88:11408-11412, 1991. Birgerson L, A Lund, V Odlind, et al. Termination of early human pregnancy with epostane. Contraception 35:111-120, 1987. Birgerson L, V Odlind. Early pregnancy termination with antiprogestins: A comparative clinical study of RU 486 given in two dose regimens and epostane. Fertility and Sterility 48:565-570. 1987. Blye RP. The use of estrogens as postcoital contraceptive agents. American Journal of Obstetrics and Gynecology 116:1044-1050, 1973. Braga VMM, SJ Gendler. Modulation of Muc-1 mucin expression in the mouse uterus during the estrus cycle, early pregnancy and placentation. Journal of Cell Science 105:397-405, 1993. Byskov AG, CY Andersen, L Nordholm, et al. Chemical structure of sterols that activate oocyte meiosis. Nature 374:559-562, 1995. Charnock-Jones DS, AM Sharkey, et al. Leukemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. Journal of Reproduction and Fertility 101:421-426, 1994.

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