6
A RESEARCH AGENDA FOR DEPARTMENTS OF OBSTETRICS AND GYNECOLOGY

The previous chapters developed the themes that identifiable weaknesses exist in the OB/GYN research enterprise and that actions to strengthen and support investigation are needed. This chapter describes research topics, the accomplishment of which would significantly improve the health of women and the results of pregnancy. The breadth and depth of this research agenda underscore the importance of ensuring a thriving research enterprise in OB/GYN.

The criteria for inclusion of topics in the research agenda and the process used by the committee to develop the agenda axe described in Chapter 2. They are reiterated here because they emphasize the sense of the committee that OB/GYN has the potential to make important contributions to health. They also point to the committee's insistence that research topics included in the agenda should be directed toward the melioration of significant health problems and be particularly suited to the work of departments of OB/GYN. To ensure that the research agenda fulfills its purpose of highlighting the need for expanded research efforts in OB/GYN, the following criteria were applied:

  • The research should contribute to the resolution of an important health problem. Importance can be defined in terms of high prevalence or incidence of a problem, or the serious effect of the problem on individuals who experience it. Importance can also be defined in terms of impact on the health care system where the costs of caring for the problem axe incurred.

  • The research approach should be promising. That is to say, there should be reason to think that following the selected avenue of investigation will provide solutions or that answering the question posed by the research is an essential step in finding a solution.



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Strengthening Research in Academic OB/GYN Departments 6 A RESEARCH AGENDA FOR DEPARTMENTS OF OBSTETRICS AND GYNECOLOGY The previous chapters developed the themes that identifiable weaknesses exist in the OB/GYN research enterprise and that actions to strengthen and support investigation are needed. This chapter describes research topics, the accomplishment of which would significantly improve the health of women and the results of pregnancy. The breadth and depth of this research agenda underscore the importance of ensuring a thriving research enterprise in OB/GYN. The criteria for inclusion of topics in the research agenda and the process used by the committee to develop the agenda axe described in Chapter 2. They are reiterated here because they emphasize the sense of the committee that OB/GYN has the potential to make important contributions to health. They also point to the committee's insistence that research topics included in the agenda should be directed toward the melioration of significant health problems and be particularly suited to the work of departments of OB/GYN. To ensure that the research agenda fulfills its purpose of highlighting the need for expanded research efforts in OB/GYN, the following criteria were applied: The research should contribute to the resolution of an important health problem. Importance can be defined in terms of high prevalence or incidence of a problem, or the serious effect of the problem on individuals who experience it. Importance can also be defined in terms of impact on the health care system where the costs of caring for the problem axe incurred. The research approach should be promising. That is to say, there should be reason to think that following the selected avenue of investigation will provide solutions or that answering the question posed by the research is an essential step in finding a solution.

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Strengthening Research in Academic OB/GYN Departments The research should be done in a department of OB/GYN or in collaboration with members of such departments. The mere fact that patients with the problem are first seen by an OB/GYN professional is not sufficient justification. Rather, OB/GYN must be the discipline with the knowledge or skill needed to accomplish the research. If the research is interdisciplinary, OB/GYN should be a necessary element. Lack of interest by other specialties would also be sufficient justification (i.e., the work would not be accomplished if OB/GYN did not do it). During the period of this study, NIH initiated three activities that will result m research agendas that overlap many areas of the committee's work. The first of these is the Pregnancy, Birth, and Infant Research Plan of the National Institute of Child Health and Human Development. The second is a research agenda being developed by the Task Force on Opportunities for Research on Women's Health. This group, which was assembled by the Office of Research on Women's Health, has been asked to identify the research needed to improve the health of women at all stages of their lives. Its deliberations therefore include such areas as reproductive science and early developmental biology. Discussion at a workshop held by the task force emphasized the need to stress the epidemiological and behavioral aspects of research on women's health. Finally, NIH is engaged in an effort to develop a strategic plan and to that end has drawn on the expertise of several panels, including one on reproductive biology and development and one on infant health and mortality. In their initial work, both panels emphasized the personal and social consequences of unsolved problems in these areas. The panel on reproductive biology and development highlighted seven areas, each of which in whole or in part covers topics that the committee included in its research agenda: the control of reproductive function, infertility, contraception, the molecular basis of embryonic development in animal and plant models, environmental factors affecting reproductive biology and development, and postnatal growth. In light of these large-scale efforts, the committee felt that it would be duplicative to produce a comprehensive and detailed research agenda. Instead, individual committee members were asked to highlight areas of investigation that meet the criteria listed above and that exemplify the range of questions that might fruitfully be investigated. Because there were no committee members with expertise in behavioral sciences, technology assessment, and outcomes analysis, the agenda outlined in the following sections does not sufficiently emphasize those areas. The committee therefore wishes to stress its opinion that departments of OB/GYN, in conjunction with individuals with relevant

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Strengthening Research in Academic OB/GYN Departments expertise, are well suited to undertake investigation of many topics related to behavior that affects reproductive health, the technologies used by the field of OB/GYN, and the outcomes of care provided by OB/GYNs. The large number of patients who receive care in the OB/GYN clinics of academic centers represents an opportunity for clinically relevant epidemiological research—including research on the efficacy of treatment, on the natural history of disease, and on the prevention of disease. Faculty of departments of OB/GYN, in collaboration with epidemiologists, sociologists, statisticians, and health services researchers, have the patient base and the discipline-specific interests needed to investigate questions that other disciplines are not likely to undertake. The committee also believes that the advantages of the patient base and the knowledge that resides in departments of OB/GYN suggest that these departments should organize and conduct clinical/epidemiological trials that are often now initiated by other departments. The following sections were written by committee members, as acknowledged, and are in large part based on background papers prepared for the committee, whose contributions are gratefully recognized (see Appendix C for a list of background papers). Oocyte and Follicular Development in the Ovary* This section identifies areas of research within the broad field of ovarian function that are best and most appropriately pursued in departments of obstetrics and gynecology. The ovary, an ever-changing tissue, is a multicompartmental tincture with different and variable biological properties. Responding to cyclic pituitary hormone secretion the various types of ovarian cells interact in a highly integrated manner to secrete sex steroids, elaborate a variety of regulatory proteins, and produce a fertilizable oocyte or egg. This section focuses on key unresolved areas in ovarian physiology. All axe viewed as important not only to the understanding of ovarian function but also to the promotion of fertility and fertility control. *    This section was written by Mary Lake Polan and based on papers by Eli Y. Adashi and Robert D. Koos.

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Strengthening Research in Academic OB/GYN Departments Follicular Formation The primordial germ cells that will become the ovarian eggs originate near the bottom of the embryo where they can be identified as early as the end of the third week of gestation. Migration of germ cells to their final location is accomplished prior to the fifth week of gestation. Whereas some chemotaxis is clearly operational, the precise cellular mechanism or mechanisms underlying the guidance of germ cells to the future ovary remain uncertain. Most importantly, germ cells appear unable to persist elsewhere, and thus the future ovary may be viewed as the only bodily region competent to sustain oocyte development. By the same token, these germ cells play an indispensable role in the induction of gonadal development. During the subsequent 2 weeks of intrauterine life (weeks 5–7 of gestation), often referred to as the "indifferent stage," the primordial ovarian structure constitutes no more than a bulge on the medial aspect of the urogenital ridge. By about 8 weeks of intrauterine life, the future eggs are subject to three simultaneous ongoing processes: mitosis, meiosis, and atresia. As a result of the combined impact of these processes, the number of germ cells peaks by 20 weeks of gestation only to be followed by relentless lifelong and irreversible attrition to a point when the oocytic complement is finally exhausted, thereby giving rise to the menopause. The prophase of the first meiotic division occurs between week 8 and week 13 of fetal life. Once formed, these primary oocytes persist in prophase until ovulation decades later when meiosis is resumed and the first polar body is formed and extruded. Although the exact cellular mechanism or mechanisms responsible for this meiotic arrest remain uncertain, it is generally presumed that the granulosa cells surrounding the oocyte secrete a putative oocyte meiosis inhibitor (OMI) that arrests egg development. This hypothesis is predicated on the observation that denuded (granulosa cell-free) oocytes are capable of spontaneously completing meiotic maturation under in vitro circumstances. It is not until the first luteinizing hormone (LH) surge occurs, indicating ovulation at puberty, that the first meiotic division is in fact completed. Again, little consensus exists as to the cellular events at play. The first primordial ovarian follicle is noted by around 16 weeks of intrauterine life. It is generally accepted that primordial follicle formation ends no later than 6 months postpartum. There is little information regarding the morphogenic principles responsible for the follicular organization surrounding the oocytes, but it is certain that formation of primordial follicles, the first step in ovarian follicular development, is independent of pituitary hormonal secretion. This presumption is strongly supported by the recognition that gonadotropin resistance, such as that

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Strengthening Research in Academic OB/GYN Departments encountered in the so-called "resistant ovary syndrome," does not preclude primordial follicle formation. The mechanisms responsible for recruiting some, but not other, primordial follicles for further development are unknown. However, this phenomenon underlies the presumed waves of follicular growth responsible for follicular replenishment. Although other factors are undoubtedly at play, it is virtually certain that even the earliest phases of follicular development beyond the primordial follicle stage are dependent on the pituitary hormones, follicle-stimulating hormone (FSH) and LH. Support for this conclusion is again derived from studies of the so-called "resistant ovary syndrome," whereto the ovaries display no evidence of follicular maturation beyond the primordial follicle stage. As such, this experiment of nature demonstrates the virtually absolute gonadotropin dependence of early follicular growth beyond the primordial follicle stage. Proposed Research Elucidation of the events responsible for the transformation of endodermal cells into germ cell elements. Have the cells in question been somehow imprinted so as to form a germ cell lineage? Or is the endodermal cell totipotential and thus in a position to form unique cellular elements such as a germ cell? Understanding of the forces responsible for guiding the germ cell toward the proper location in the future ovary. Clearly, chemotaxis appears to be at work. However, tissue remodeling appears equally inevitable, thus implicating extracellular matrix in the genesis of the required path. Clarification of the cellular origins of the somatic follicular cells—for example, the steroid hormone producing granulosa and theca-interstitial cells surrounding the egg. There is reason to believe that the germ cells may play a morphogenic role by inducing the appearance of their somatic counterparts. Similarly, new information is required as to why germ cells are unable to subsist in bodily regions other than the future ovary Analysis of the cellular mechanism or mechanisms responsible for the initiation of meiosis and for its arrest at the prophase stage of the first division. Clearer understanding of the ability of the mid-cycle surge to reinitiate meiotic division is required. The apparent biological differences between the cumulus

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Strengthening Research in Academic OB/GYN Departments granulosa cells around the egg and those cells incorporated into the surrounding follicle must play a role. Improved understanding of the role of putative intraovarian paracrine and autocrine regulators. Understanding such cytokine-mediated mechanisms could eventually lead to improved therapeutic strategies. Follicular Atresia Literally translated, atresia (a Greek term) means the closure or obliteration ("a," not) of a normal body orifice or passage ("tresos," perforated). In the context of ovarian physiology, follicular atresia denotes the still enigmatic process whereby oocytes are lost from the ovary by means other than ovulation. In fact, atretic follicles are rendered incapable of ovulation. First noted in utero around month 6 of human gestation, atresia continues uninterrupted throughout life, thereby resulting in relentless and irreversible attrition of the ovarian germ cell endowment. It is noteworthy that the newborn human female enters life having lost as much as 80 percent of her egg cell endowment. By the onset of puberty, virtually 95 percent of all follicles have been lost. Of the residual follicular mass, only 400 to 500 follicles (i.e., less than 1 percent of the total) will ovulate in the course of a reproductive life span. Although clear-cut conclusions cannot be drawn at this time, it is generally presumed that postpubertal follicular atresia comprises an underlying tonic component reflecting a lifelong process on which losses of a cyclic, ovulatory nature are superimposed. The forces guiding most but not all follicles toward certain demise remain unknown. Since all follicles appear to have comparable pituitary stimulation, one is forced to invoke the existence of as yet unrecognized intraovarian principles, the highly regionalized and exquisitely timed expression of which may well determine the direction of follicular development. This reasoning provides compelling arguments in favor of the concept of putative intraovarian regulators, presumably to exert in situ paracrine or autocrine modulatory effects at the follicular level. The precise identity of the inciting atretic signal notwithstanding, recent advances suggest that follicular atresia represents an example of apoptosis, or programmed cell death, a relatively well-defined process first described by Kerr and colleagues in 1972. An active, energy-requiring process, apoptosis propels affected cells toward selective deletion. Viewed in this light, regulation of the

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Strengthening Research in Academic OB/GYN Departments cellular complement revolves the concurrent and reciprocal processes of mitosis and apoptosis. Much of the evidence identifying ovarian follicular atresia as an apoptotic process is morphologic in nature. Many of the morphologic features of atresia are reminiscent of the apoptotic process, suggesting that the two may be identical. However, these findings suggest that gonadotropin-primed follicles may respond to an as yet undescribed atretic signal with apoptosis. Proposed Research Understanding of the molecular events responsible for determining follicular fate, which is a central goal of reproductive physiology. Clearly, if we could pharmacologically control and perhaps arrest the process of atresia, premature ovarian failure might be successfully treated and the age of the menopause substantially delayed. Likewise, fertility objectives could be served by an improved and augmented germ cell endowment. Development of a reliable, reproducible experimental model for improved understanding of the atretic process. None exist at this time. Understanding of the apoptotic nature of the atretic process and, in particular, of the ionic events that appear to trigger the molecular enzymatic events. Focused investigation of potential putative intraovarian regulators concerned with the atretic process. Although sex steroids have been extensively implicated in the genesis and prevention of atresia, the body of literature remains equivocal and insufficient. Follicular Recruitment, Selection, and Dominance The term recruitment is used to indicate that a follicle has entered the so-called growth trajectory, that is, the process whereto the follicle leaves the resting pool to begin a well-characterized pattern of growth and development leading to ovulation. Clearly, recruitment is a necessary but not sufficient condition for ovulation to occur. Follicular selection implies the final winnowing of the maturing but not yet quite dominant follicular cohort to the size of the species-characteristic ovulatory quota, which for the human is a single follicle each month. In the human,

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Strengthening Research in Academic OB/GYN Departments follicular selection is presumed to occur during the first 5 days of the cycle when the leading follicular diameter is 5–10 mm. The term dominance refers to the status of the follicule destined to ovulate, given its presumed key role in regulating the size of the ovulatory quota. It is generally agreed that a selected follicle becomes dominant about a week before ovulation, that is, as early as days 5–7 of the cycle when the diameter is around 10 mm. The earliest hormonal index reflecting dominance, which is evident at times as early as days 3–5 of the cycle, is an increase in the circulating levels of estradiol in the vein draining the ovary later shown to bear the corpus luteum. According to one view, the follicle selected for ovulation is functionally (not merely morphologically) dominant in that it inhibits the development of other competing follicles on both ovaries. Presumably then, the dominant follicle takes on an active role in ensuring its preferred status. Inevitably, and for reasons not entirely clear, the dominant follicle continues to thrive under physiologic circumstances it has made inhospitable to others. Proposed Research Development of more specific markers capable of predicting the general well-being of the follicle in question and most importantly the quality of the resident oocyte. Such parameters would be of clinical relevance to in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT). Improved understanding of existing known cytokine and growth factor regulators and the elucidation of the potential role of as yet unrecognized peptides. Although the central role or roles of gonadal steroids m folliculogenesis are well accepted, the variable fate of follicles afforded comparable gonadotropic stimulation strongly suggests the existence of additional intraovarian modulatory systems. This kind of investigation should yield clues as to how a follicle is selected and spared from atresia. Corpus Luteum Function As interesting as cell growth during follicular development is the cessation of cell growth and/or cell death. Granulosa cells divide on average only once following the preovulatory LH surge and then differentiate into luteal cells.

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Strengthening Research in Academic OB/GYN Departments Proposed Research • It would be interesting to determine if the block to cell proliferation involves known genes associated with suppression of cell growth (perhaps one or more of the recently discovered tumor-suppressor genes, such as the retinoblastoma, or RB) or new examples of similarly functional genes. Action of the RB gene product involves TGF-B. Relatively little is known about TGF-B in the ovary except for cent reports by Schomberg and co-workers that at least forms of this factor axe synthesized there and that the expression of TGF-B2 is hormonally regulated. It is now recognized that the extracellular matrix and cell surface molecules that specifically bind to matrix components play an important role in the regulation of cell growth and function. These include various glycosaminoglycans, like heparinsulfate, which are known to be synthesized by granulosa cells and axe present in the ovarian follicle. Almost nothing is known about the extracellular matrix or adhesion molecules in the ovary during the differentiation process from granulosa to luteal cell and during the lifetime of the corpus luteum. Not surprisingly, numerous growth factors have been reported to be synthesized in the ovary. Despite the common belief that these factors play important roles in follicle rupture and corpus luteum formation and function, very little hard evidence about their specific actions and receptors is available. The only exception may be the insulin-like growth factors (IGFs), which have been the focus of several groups. Most of the studies on growth factors in the ovary have involved the addition of these factors to granulosa cells or other ovarian cell types in vitro and an examination of their effect on gonadotropin binding, steroid synthesis, and other markers of differentiated cell function. In the absence of adequate information about the spatial and temporal production of these factors and their receptors in the ovary, however, such studies are of limited value; the findings may or may not be of physiological importance. The availability of sensitive molecular techniques such as in sire hybridization and reverse transcription-polymerase chain reaction now makes it possible to accurately determine where and when the genes for growth factors and their receptors are expressed in the ovary.

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Strengthening Research in Academic OB/GYN Departments Leukocytes, Cytokines, and Ovarian Function It has long been recognized that various leukocytes are present in the ovary and that their numbers increase dramatically in the corpus luteum. However, almost nothing is known about their possible role in ovarian function. There have been numerous recent reports of the presence of various cytokines in the ovary and of the effects of cytokines on the differentiated function of ovarian cells. These include various interleukins, tumor necrosis factor (TNF), transforming growth factors, platelet activating factor (PAF), and heparin. Heparin, a product of mast cells, appears to play an important role in the actions of various growth factors. Proposed Research Determine the physiological role of immune system—derived products on ovarian function. Follicular Fluid We know surprisingly little about the specialized microenvironment of the follicle, and until we do, it will be impossible to understand completely how the follicle (1) synthesizes the hormones that integrate all reproductive function and (2) nurtures the gamete to maturity. This applies to the follicular fluid, which bathes the granulosa cells and developing oocyte. While follicular fluid has been readily available, we have only the most rudimentary knowledge of the biologically active materials that it contains. We know that human follicular fluid is a potent enhancer of serum-stimulated endothelial cell proliferation. Recent reports indicate that follicular fluid stimulates sperm motility and contains a chemoattractant for sperm. The level of chemoattractant activity correlates with fertilizability of the egg from the same follicle. Proposed Research • The identification of this factor might lead to ways to identify healthy eggs and to promote the fertilization process with direct benefit for women using the new reproductive techniques of IVF and GIFT.

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Strengthening Research in Academic OB/GYN Departments Conclusion Although traditional wisdom ascribes the role of ''master gland'' to the pituitary, the ovary may, in fact, play an active rather than a passive role in the initiation and maintenance of reproductive cyclicity and function. Thus, the ovary is central to a woman's reproductive capacity. Our limited under-standing of these reproductive events mandate continued and focused research in the areas of ovarian function described above. Not only is there an abundance of basic research topics that have important implications for solving problems of human fertility and infertility, but a better understanding of ovarian function would illustrate other normal and pathologic processes involving the regulation of cell growth and differentiation in many other organ systems. The basic questions of physiology, cell growth, and differentiation are relevant to many human disease states that result in infertility and clinical aberrations of ovarian function. Such clinical problems as premature ovarian failure and anovulation, polycystic ovarian disease, and luteinized unruptured follicle syndrome are the province of gynecologists and obstetricians. It is, therefore, most appropriate that research on the intricacies of ovarian function be performed in departments of gynecology and obstetrics. These physician-scientists have the critical ability to investigate basic biological questions with the full knowledge and understanding of their relevance to human disease states. Not only does the gynecologist's interest, by definition, lie in the realm of ovarian function, but his or her understanding of the myriad facets of clinical aberration and disease allows for the critical link between basic scientific investigation and its applications to human disease with the potential for cure. Fertilization* Reproductive cell biology can be considered the science basic to obstetrics and gynecology, but the literature, cell biology, physiology, and biochemical information dealing with the fertilization process is primarily comparative. Most of the information is derived from invertebrates, nonmammalian vertebrates, mammals such as rats and mice, and nonhuman primates. Little is derived from studies of humans. *    This section was written by Everett Anderson.

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Strengthening Research in Academic OB/GYN Departments Contraception Bardin, C.W.: NORPLANT contraceptive implants. Obstetrics and Gynecology Report 2:96–102, 1990. Bardin, C.W.: Long-acting steroidal contraception: An update. International Journal of Fertility 34:88–95, 1989. Bardin, C.W., Sivin, I., Nash, H., Robertson, D. et al.: Norplant R. contraceptive implants. Fertility Regulation Today and Tomorrow. (E. Diczfalusy and M. Bygdeman, eds.), Raven Press, New York, pp. 143–152, 1987. Djerassi, C.: The bitter pill. Science 245:356–361, 1989. Lincoln, R., Kaeser, L.: Whatever happened to the contraceptive revolution? Family Planning Perspectives 20:20–24, 1988. Mishell, D.R., Jr.: Medical Progress-Contraception. New England Journal of Medicine 320:777–787, 1989. Sivin, I., El Mahgoub, S., McCarthy, T., Mishell, D.R., Jr. et al.: Longterm contraception with the levonorgestrel 20 mcg/day (LNg 20) and the copper T 38OAg intrauterine devices: A five-year randomized study. Contraception 42:361–378, 1990. Sivin, I., Mishell, D.R., Jr., Victor, A., Diaz, S. et al.: A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. II-Subjective and objective measures of effects. An internal comparative trial. Contraception 24:359–376, 1981. World Health Organization Task Force on the Safety and Efficacy of Fertility Regulating Methods. The TCu380A, TCu220C, Multiload 250 and Nova T IUDS at 3,5 and 7 years of use-Results from three randomized multicentre trials. Contraception 42:141–158, 1990. Infertility Bongso A., N.G., S-C, Fong, C-Y, Ratman S., Cocultures: a new lead in embryo quality improvement for assisted reproduction, Fertil. Steril. 1991:56,179. Calvo L., Vantman D., Banks S.M., et al., Follicular fluid-induced acrosome reaction distinguishes a subgroup of men with unexplained infertility not explained by semen analysis, Fertil. Steril. 1989:52,1048. Cohen B.L., The postcoital test, Infert. Reprod. Med. Clinics 1991:2,317. Edwards R. G., Causes of early embryonic loss in human pregnancy. Human Reprod. 1986:1,185. Gleicher N., El-Roeiy A., Confino E., Friberg J., Is endometriosis an autoimmune disease?, Obstet.Gynecol. 1987:70,115. Griffith C.S. and Grimes D.A., The validity of the postcoital test, J. Obstet. Gynecol. 1991:162,615. Guzick D.S., Clinical Epidemiology of endometriosis and infertility, Obstet.Gynecol.Clin.NorthAmer. 1989:16,43. Iritani A., Current status of biotechnological studies in mammalian reproduction, Fertil, Steril. 1988:50,543. Kennedy S.H., Autoantibodies in endometriosis-epiphenomenon?, Letter to the editor, Fertil. Steril. 1990:54,544. Mosher W.D. and Pratt W. F., Fecundity and infertility in the United States: incidence and trends, Fertil. Steril. 1991:56,192.

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Strengthening Research in Academic OB/GYN Departments Mosher W.D. and Pratt W. F., Fecundity and infertility in the United States, 1965–1988. Advance data from vital and health statistics, No. 192, Dec. 4, 1990. Hyattsville, MD: National Center for Health Statistics. Mosher W.D., New from NCHS: Fecundity and infertility in the United States, Am.J.Public Health, 1988:78,181. Roberts C. J. and Lowe C. R., Where have all the conceptions gone?, Lancet, 1975:1,498. Sauer M. V., Paulson R. J., and Lobo R. A., A preliminary report on oocyte donation extending reproductive potential to women over age 40, N.Engl.J.Med. 1990:323,1157. Society for Assisted Reproductive Technology, In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1989 results from the IVF-ET registry , Fertil.Steril. 1991:55,14. Strathy J. H., Molgaard C. A., Coulam C. B., et al., Endometriosis among fertile and infertile women, Fertil.Steril. 1982. 38,667. Vlanderen W. and Treffers P., Prognosis of subsequent pregnancies after recurrent spontaneous abortion in first trimester. Brit.Med.J 1987:295,92. West C. P., Age and infertility, Brit.Med.J. 1987:294,853. Wrambsy H. Fradga K., and Liedholm P., Chromosome analysis of human oocytes recovered from preovulatory follicles in stimulated cycles, New England Journal of Medicine. 1987:361,121. Premenstrual Syndrome MacDonald P.C., Dombroski R, Casey ML: The recurrent secretin of progesterone in large amounts: An endocrine/metabolic disorder unique to young women? Endocrine Rev., November 1991. The Brain and Reproduction 1. Dolais, J., A-J. Valleron, A-M. Grapin and G. Rosselin. Etude de l'hormone luteinisante humaine (HLH) au cours du nycthemere. C.R. Acad. Sci. (Paris) 270:3123, 1970. 2. Dierschke, D.J., A.N. Bhattacharya, L.E. Atkinson and E. Knobil. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology 87: 850, 1970. 3. Knobil, E. The GnRH Pulse Generator. Control of puberty in the rhesus monkey. In: Control of the Onset of Puberty. III, H.A. Delemarre van-de Waal, T.M. Plant, G.P. Van Rees, J. Schoemaker (eds.), Exerpta Medica, Amsterdam, 1989, p. 11. 4. Leyendecker, G., S. Waibel-Treber and L. Wildt. The central control of maturation and ovulation in the human. In: Oxford Review of Reproductive Biology, Vol. 12, S.R. Milligam (ed.), Oxford University Press, Oxford, 1990, p. 93. 5. Hutchison, J.S. and A.J. Zeleznik. The rhesus monkey corpus luteum is dependent upon pitutiary gonadotropin secretion throughout the luteal phase of the menstrual cycle. Endocrinology. 115:1780, 1984. 6. Knobil, E. The neuroendocrine control of the menstrual cycle. Rec. Prog.Hormone Res. 36:53, 1980. 7. Crowley, W.F., Jr., M. Filicori, D. Spratt and N. Santoro. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Rec. Progr. Hormone Research 41:473, 1985.

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Strengthening Research in Academic OB/GYN Departments 8. Reame, N., S.E. Sander, G.D. Case, R.P. Kelch and J. C. Marshall. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion in the mechanism of persistent anovulation. J. Clin. Endocrinol. Metab. 61:851, 1985. 9. Wray, S. Evidence that cells of the gonadotropin releasing hormone system are derived from progenitor cells in the olfactory placode. In: Control of the Onset of Puberty. III, H.A Delemarre-van de Waal, T.M. Plant, G.P. Van Rees, J. Schoemaker (eds.), Exerpta Medica, Amsterdam, 1989, p. 23. 10. Schwanzel-lukuda, M., D. Dick and D.W. Pfaff. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal Kallmann syndrome. Brain Research 6:311, 1989. 11. Precis IV: Update in Obstetrics and Gynecology, H.C. Visscher (ed.), American College of Obstetrics and Gynecology, 1990, p. 315. 12. Liu, J.H. Hypothalamic amenorrhea: clinical perspectives, pathophysiology and management. Amer. J. Obstet. Gynecol. 163:1732, 1990. 13. O'Byrne, K.T., J-C. Thalabard, P.M. Grosser, R.C. Wilson, C.L. Williams, M-D. Chen, D. Ladendorf, J. Hotchkiss, and E. Knobil. Radiotelemetric monitoring of hypothalamic gonadotropin-releasing hormone pulse generator activity throughout the menstrual cycle of the rhesus monkey. Endocrinology 129:1207–1214, 1991. 14. Gindoff, P.R., and M. Ferin. Endogenous opioid peptides modulate the effects of corticotropin releasing factor on gonadotropin release in the primate. Endocrinology 121:837, 1987. 15. Kesner, J.S., J.M. Kaufman, R.C. Wilson, G. Kuroda, and E. Knobil. The effect of morphine on the electrophysiological activity of the hypothalamic luteinizing hormone releasing hormone pulse generator in the rhesus monkey. Neuroendocrinology 43: 686, 1986. 16. McNeilly, A.S. Suckling and the control of gonadotropin secretion. In: The Physiology of Reproduction. Vol. 2, E. Knobil and J.D. Neill (eds.), Raven. Press, New York, 1988, p. 2323. 17. The Menstrual Cycle and its Disorders: Influences of Nutrition, Exercise and Neurotransmitters, K.M. Pirke, W. Wuttke, U. Schweiger (eds.), Springer-Verlag, Berlin, 1989. 18. Medamurthy, R., S.A Abeyawardene, M.D. Culler, A. Negro-Vilar and T. M. Plant. Immunoneutralization of circulating inhibin in the hypophysiotropically clamped male rhesus monkey (Macaca mulatta) results in a selective hypersecretion of follicle-stimulating hormone. Endocrinology 126:2116, 1990. 19. McLachlan, R.I., K.D. Dahl, W.J. Bremner, R. Schwall, C.H. Schmelzer, A.J. Mason and R.A. Steiner. Recombinant human activin-A stimulates basal FSH and GnRH-stimulated FSH and LH release in the adult male macaquize Macaca fasciculans, Endocrinology 125:2787, 1989. 20. Plant, T.M., M.D. Fraser, R. Medamurthy and V.L. Gay. Somatogenic control of GnRH neuronal synchronization during development in primate: a speculation. In: Control of The Onset of Puberty III, H.A. Delamarre-van de Waal, T.M. Plant, G.P. Van Rees, J. Schoemaker (eds.), Exerpta Medica, Amsterdam, 1989, p. 111. 21. Wilson, R.C., J.S. Kesner, J-M. Kaufman, T. Uemura, T. Akema and E. Knobil. Central electrophysiologic correlates of pulsatile luteinizing hormone secretion in the rhesus monkey. Neuroendocrinology, 39:256, 1984.

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Strengthening Research in Academic OB/GYN Departments 22. Kimura, F., M. Nishihara, H. Hiruma, and T. Funabashi. Naloxone increases the frequency of the electrical activity of luteinizing hormone releasing hormone pulse generator in long-term ovariectomized rats. Neuroendocrinology 53:97, 1991. 23. Chronic recording of electrophysiological manifestation of the hypothalamic gonadotropin-releasing hormone pulse generator activity in the goat. Neuroendocrinology 53–393, 1991. 24. Kesner, J.S., R.C. Wilson, J-M. Kaufman, J. Hotchkiss, Y. Chen, H. Yamamoto, R.R. Pardo and E. Knobil. Unexpected responses of the hypothalamic gonadotropin-releasing hormone ''pulse generator'' to physiolcgical estradiol inputs in the absence of the ovary. Proc. Natl. Acad. Sci., 84:8745, 1987. 25. Williams, C.L, J-C. Thalabnard, K.T. O'Byrne, P.M. Grosser, M. Nishihara, J. Hotchkiss and E. Knobil. Duration of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator phasic electrical activity and the dynzmics of luteinizing hormone (LH) pulses in the rhesus monkey. Proc. Natl. Acad. of Sci. 87:8580, 1990. Menopause Bergkvist L., Adami H-O, Persson I., Hoover R. Schairer C.: The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 321:293–297, 1989. Matthews K.A., Meilahn E., Kuller L.H., Kelsey S.F., Caggiula A.W., Wing R.R.: Menopause and risk factors for coronary heart disease. N Engl J Med 321:641–646, 1989. Nordin B.E.C., Need A.G., Chatterton B.E., Horowitz M., Morris H.A.: The relative contributions of age and years since menopause to postmenopausal bone loss. J Clin Endocrinol Metab 70:83–88, 1990. Rubin G.L., Peterson H.B., Lee N.C., Maes E.F., Wingo P.A. Becker S.: Estrogen repalcement therapy and the risk of endometrial cancer: Remaining controversies. Am J Obstet Gynecol 162:148–154, 1990. Williams S.R., Frenchek B., Speroff T., Speroff L: A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement. Am J Obstet Gynecol 162:438–446, 1990. Oncology Ovarian Neoplasms Cancer Facts & Figures-1991. American Cancer Society, 1991. Andolf E, Jorgensen C, astedt B. Ultrasound examination for detection of ovarian carcinoma in risk groups. Obstet Gynecol 75:106–9, 1990. Baiocchi G, Davanagh JJ, Talpaz M et al. Expression of the macrophage colony-stimulating factor and its receptor in gynecologic malignancies. Canc 67:990–6, 1991. Baker VV, Borst MP, Dixon D et al. C-MYC amplification in ovarian carcinoma. Gynecol 38:340–3,1990. Bauknecht T, Birmelin G, Kommoss F. Clinical significance of oncogenes and growth factors in ovarian cancer. Steroid Biochem Mol Biol 37:855–62, 1990. Herbst AL. Neoplastic diseases of the ovary, in Herbst AL, Mishell DR, Stenchever M, Droegemueller W. Comphrehensive Gynecology, 2nd edition, Mosby-Year Book, Inc., St. Louis, 1992.

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Strengthening Research in Academic OB/GYN Departments Howell SB, Kirmani S, McClay EF et al. Intraperitoneal cisplatin-based chemotherapy for ovarian carcinoma. Semin Oncol 18:5–16, 1991. Isola J, Kallioniemi OP, Korte JM et al. Steroid receptors and Ki67 reactivity in ovarian cancer and in normal ovary: correlation with DNA flow cytometry, biochemical receptor assay, and patient survival . J Pathol 162:295–301, 1990. Jacobs I, Oram D, Fairbanks J et al. A risk of malignancy index incorporating CA125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynecol 97:922–929, 1990. Khoo SK, Hurst T, Kearsley J et al. Prognostic significance of tumor ploidy in patients with advanced ovarian carcinoma. Gynecol Oncol 39:284–8, 1990. Li SB, Schwartz PE, Lee WH, Yang-Geng TL. Allele loss at the retinoblastoma locus in human ovarian cancer. J National Canc Inst 83:637–40, 1991. Schilthuis MS, Aalders JG, Bouma J et al. Serum CA125 levels in epithelial ovarian cancer:relation with findings at second look operations and their role in the detection of tumor recurrence. Br J Obstet Gynecol 94:202–7, 1987. Slotman BJ, Baak JP, Rao BR. Correlation between nuclear DNA content and steroid receptor status in ovarian cancer. Eur J Obstet Gynecol Reprod Biol 38:221–7, 1991. Van Niekerk CC, Boerman OC, Ramaekers FC, Poels LG. Marker profile of different phases in the transition of normal human ovarian epithelium to ovarian epithelium to ovarian carcinomas. Am J Path 138:455–63,1991. Viel A, De Pascale L, Toffoli G et al. Frequent occurrence of Ha-ras allelic deletion in human ovarian adenocarcinomas. Tumori 77:16–20, 1991. Uterine Neoplasms Ayhan A, Yarall H, Ayhan A. Endometrial carcinoma: a pathologic evaluation of 142 cases with and without associated endometrial hyperplasia. J Surg Oncol 46: 182–4,1991. Ayoub J, Audet-Lapointe P, Methot Y et al. Efficacy of sequential cyclical hormone therapy in endometrial cancer and its correlation with steroid hormone receptor status. Gynecol Oncol 31:327,1988. Berchuck A, Rodriguez G, Kinney RB et al. Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease. Amer J Obstet Gynecol 164:15–21,1991. Borazjani G, Twiggs LB, Leung BS et al. Prognostic significance of steroid receptors measured in primary metastatic and recurrent endometrial carcinoma. Amer J Obstet Gynecol 161:1253–57, 1989. Borst MP, Baker VV, Dixon D et al. Oncogene alterations in endometrial carcinoma. Gynecol Oncol 38:364–6,1990. Bourne TH, Campbell S, Steer CV et al. Detection of endometrial cancer by transvaginal ultrasonography with color flow imaging and blood flow analysis: a preliminary report. Gynecol Oncol 40:253–9, 1991. Brumm C, Riviere A, Wickens C, Loning T. Immunohistochemical investigation and northern blot analysis of c-erbB-2 expression in normal, premalignant, and malignant tissues of the corpus and cervix uteri. Virchows Arch A 417:477–84, 1990. Creasman WT, Henderson D, Hinsshaw W, Clarke-Pearson DL. Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 67:326–30, 1986.

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Strengthening Research in Academic OB/GYN Departments Herbst AL. The Bethesda System for cervical/vaginal cytologic diagnoses: a note of caution. Obstet Gynecol 76:449–,1990. Hayashi Y, Hachisuga T, Iwasaka T et al. Expression of ras oncogene product and EGF receptor in cervical squamous cell carcinomas and its relationship to lymph node involvement. Gynecol Oncol 40:147–51,1991. Khoury GG, Bulman AS, Joslin CA, Rothwell AI. Concomitant pelvic irradiation, 5-fluorouracil and mitomycin C in the treatment of advanced cervical carcinoma. Br J Radiol 64:252–60,1991. Kurman RJ, Malkasian GD, Sedlis A, Soloman D. From Papanicolaou to Bethesda: the rationale for a new cervical cytologic classification. Obstet Gynecol 77:779–82,1991. Matorras R, Ariceta JM, Rememteria A et al. Human immunodeficiency virus-induced immunosuppression: a risk factor for human papillomavirus infection. Amer J Obstet Gynecol 164:42–4,1991. Naisell K, Roger V, Naisell M. Behavior of mild cervical dysplasia during long-term follow-up. Obstet Gynecol 67:665, 1986. Palefsky J. Human papillomavirus infection among HIV-infected individuals. Implications for development of malignant tumors. Hematol Oncol Clin N Am 5:357–70,1991. Pinion SB et al. Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of the cervix. Lancet 337 (8745):819,1991. Piver MS. Invasive cervical cancer in the 1990s. Semin Surg Oncol 6:359–63,1990. Riou G, Le MG, le Doussal V et al. C-myc Proto-oncogene expression and prognosis in early carcinoma of the uterine cervix. Lancet 1:761–3,1987. Riou G, Bourhis J, Le MG. The c-myc proto-oncogene in invasive carcinomas of the uterine cervix: clinical relevance of overexpression in early states of the cancer. Anticanc Res 10:1225–32,1990. Sagae S et al. RAS oncogene expression and progression in intraepithelial neoplasia of the uterine cervix. Canc 66:295, 1990. Schafer A, Friedman W, Mielke M et al. The increased frequency of cervical dysplasias-neoplasia in women infected with the human immunodeficiency virus if related to the degree of immunosuppression. Amer J Obstet Gynecol 164:593–9,1991. Scheffner M, Munger K, Byrne JC, Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Nation Acad Sci 88:5523–27,1991. Smiley LM, Burke TW, Silva EG et al. Prognostic factors in stage lb squamous cervical cancer patients with low risk for recurrence. Obstet Gynecol 77:271–5,1991. Villa LL and Schlegel R. Differences in transformation activity between HPV-16 map to the viral LCR-E6-E7 region. Virology 181:373–7,1991. Wang CC. Altered fractionation radiation therapy for gynecologic cancers. Cancer 60:2064–2067,1987. Vulvar Neoplasms Burke TW, Stringer CA, Gershenson DM et al. Radical wide excision and selective inguinal node dissection for squamous cell carcinoma of the vulva. Gynecol Oncol 38:328–32,1990. Daling JR, Chu J, Weiss NS et al. The association of condyloma accuminata and squamous carcinoma of the vulva. Br J Canc 50:533–35,1984.

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Strengthening Research in Academic OB/GYN Departments De Villers EM, Schneider A, Gross g, Zur Hausen H. Analysis of benign and malignant urogenital tumors for human papillomavirus infection by labelling cellular DNA. Med Microbiol Immunol 174:281–6, 1986. Heaps JM, Fu WS, Montz FJ et al. Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 38:309–14, 1990. Herbst AL. Premalignant and malignant diseases of the vulva, in Comprehensive Gynecology. Herbst AL, Mishell DR, Stenchever MA, and Droegemueller W (editors), 2nd edition, Mosby-Year Book, Inc., St. Louis, 1992. Homesley HD, Bundy BN, Sedlis A et al. Assessment of current international Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors of survival (a Gynecologic Oncology Group Study). Amer J Obstet Gynecol 164:997–1003,1991. Mabuchi K, Bross DS, Kessler I. Epidemiology of cancer of the vulva. A case-control study. Cancer 55:1843–48, 1985. MacNab JCM, Wilkinshaw SA, Cordiner JW, Clements JB. Human Papillomavirus in clinically and histologically normal tissues of the patients with genital cancer. N Eng J Med 315:1052–1058,1986 Newcombe PA, Weiss NS, Daling JR. Incidence of vulvar carcinoma in relation to menstrual, reproductive and medical factors. JNCI 73:391–396,1984. Park JS, Jones RN, McLean MR et al. Possible etiologic heterogeneity of vulvar intraepithelial neoplasia. A correlation of pathologic characteristics with human papillomavirus detection by in situ hybridization and polymerase chain reaction. Cancer 67:1599–607,1991. Pilotti S, Rotola A, D'Amato L et al. Vulvar carcinomas: search for sequences homologous to human papillomavirus and herpes simplex virus DNA. Mod Pathol 3:422–8,1990. Podczaski E, Sexton M, Kaminski P et al. Recurrent carcinoma of the vulva after conservative treatment for "microinvasive" disease. Gynecol Oncol 39:65–8,1990. Rusk D, Sutton GP, Look KY, Roman A. Analysis of invasive squamous cell carcinoma of the vulva and vulvar intraepithelial neoplasia for the present of human papillomavirus DNA. Obtset Gynecol 77:918–22,1991. Breast Neoplasms Cancer Facts & Figures-1991. American Cancer Society, 1991. Clark GM and McGuire WL. Follow-up study of HER-2/neu amplification in primary breast cancer. Canc Research 51:944–8,1991. Cross SS and Ismail SM. Endometrial hyperplasia in an oophorectomized woman receiving Tamoxifen therapy-case report. Br J Obstet Gynecol 97:190,1990. Dickson RB. Stimulatory and inhibitory growth factors and breast cancer. J Steroid Biochem Mol Biol 37:795–803,1990. Fornander T, Rutqvist LE, Cedermark B et al. Adjuvant Tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1:117–120,1989. Gusberg SB. Tamoxifen for breast cancer: associated endometrial cancer. Canc 65:1463,1990. Howe G, Rohan T, Decarli A et al. The association between alcohol and breast cancer risk: evidence from the combined analysis of six dietary case control studies. Int J Canc 47:707–10,1991. Kelsey JL, Gammon MD. The epidemiology of breast cancer. CA 41:146,1991. Love RR. Prospects for antiestrogen chemoprevention of breast cancer. JCNI 82:18–21,1990.

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Strengthening Research in Academic OB/GYN Departments Malfetano JH. Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients. Gynecol Oncol 39:82–84,1990. Miller AB. Risk/benefit considerations of antiestrogen/estrogen therapy in healthy postmenopausal women. Prev Med 20:79–85,1991. Paffenbarger RS, Fasal E, Simmons ME et al. Cancer risk as related to the use of oral contraceptives during fertile years. Cancer 39:1887,1977. Prentice RL. Tamoxifen as a potential preventive agent in healthy postmenopausal women. JNCI 82:1310–1311, 1990. Ravnihar B, Seigel DG, Linder J. An epidemiologic study of breast cancer and benign breast neoplasias in relation to oral contraceptives and estrogen use. Eur J Canc 15:395, 1979. Romieu I, Berlin JA, Colditz G. Oral contraceptives and breast cancer. Review and meta analysis. Cancer 66:2253–63, 1991. Chachter LP, Rosencweig M, Canetta R, et al. Overview of hormonal therapy in advanced breast cancer. Semin Oncol 17 (suppl 6):38–46, 1990. Spicer D, Pike MC, Henderson BE. The question of estrogen replacement therapy in patients with a prior diagnosis of breast cancer. Oncology-Williston-Park 4:49–54, 1990 Vessey MP, Doll R, Sutton PM. Oral Contraceptives and breast neoplasia: A retrospective study. Br Med J 3:719, 1972. Trophoblastic Disease Herbst AL. Gestational trophoblastic disease, in Comprehensive Gynecology, 2nd edition. Herbst AL, Mishell DR, Stenchever MA, and Droegemueller W (editors). Mosby-Year Book, Inc., St. Louis, 1992. Bagshawe KD. Risk and prognostic factors in trophoblastic neoplasia. Cancer 38:1373, 1976. Curry SL, Blessing J, DiSaia P et al. A prospective randomized comparison of methotrexate, actinomycin D, and chlorambucil (MAC) versus modified Bagshawe regimen in "poor prognosis" gestational trophoblastic disease. Gynecol Oncol 26:407, 1987. Jacobs PA, Szulman AE, Funkhouser J et al. Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole. Ann Hum Genet 46:223, 1982. Li MC, Hertz R, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med 93:361, 1956. Lurain JR, Brewer JI. Treatment of high-risk gestational trophoblastic disease with methotrexate, actinomycin D, and cyclophosphamide chemotherapy. Obstet Gynecol 65:830, 1985. Lurain JR, Brewer JI, Torok EE et al. Natural history of hydatidiform mole after primary evacuation. Amer J Obstet Gynecol 145:591, 1983. Morrow P, Nakamura R, Schlaerth J et al. The influence of oral contraceptives on the postmolar human chorionic gonadotropin regression curve. Amer J Obstet Gynecol 151:906, 1981. Vaitukaitis JL, Braunstein GD, Ross GT. Radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Amer J Obstet Gynecol 113:751, 1972. Wong LC, Choo YC, Ma HK. Modified Bagshawe's regimen in high-risk gestational trophoblastic disease. Gynecol Oncol 23:87, 1986. Yordan EL Jr, Schlaerth J, Gaddis O et al. Radiation therapy in the management of gestational choriocarcinoma metastatic to the central nervous system. Obstet Gynecol 69:627, 1987.

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Strengthening Research in Academic OB/GYN Departments Sexually Transmitted Diseases National Institute of Allergy and Infectious Diseases: Sexually Transmitted Diseases Research Program, National Institutes of Health, Rockville, Md. 1990.

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