BASIC AND APPLIED STUDIES ON ANTIPROGESTINS

NIH GUIDE, Volume 22, Number 5, February 5, 1993



PA NUMBER:  PA-93-48



P.T. 34



Keywords:

  Human Reproduction/Fertility 

  Hormones 

  Contraceptives 

  Reproductive Endocrinology 



National Institute of Child Health and Human Development



PURPOSE



The National Institute of Child Health and Human Development (NICHD)

invites investigator-initiated research grant applications to conduct

basic research on antiprogestins and to explore the potential

clinical utilization of antiprogestins in the treatment of a variety

of reproductive disorders as well as for contraception.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This Program

Announcement (PA), Basic and Applied Studies on Antiprogestins, is

related to the priority areas of family planning, prevention of

teenage pregnancies and unintended pregnancies.  Potential applicants

may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.

017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications for research grants may be made by public and private,

for-profit and non-profit organizations, such as universities,

colleges, hospitals, and laboratories.  Women and minority

investigators, in particular, are encouraged to apply.  Applicants

for First Independent Research Support and Transition (FIRST) Awards

(R29) must meet specific eligibility requirements.  In addition,

foreign applicants are not eligible for the FIRST Award.



MECHANISM OF SUPPORT



Mechanisms available for the support of this program are the

traditional research project grant (RO1), and the FIRST Award (R29).



RESEARCH OBJECTIVES



Summary



The purpose of this initiative is to stimulate research that will

attempt to further characterize and define the mechanism(s) of action

of antiprogestins, their use for treatment of disorders of the

reproductive system, and their utility for application as

contraceptive agents or in facilitating parturition.  It is

recognized that this class of compounds may act through a variety of

mechanisms, some of which may not involve antagonism of the

progesterone receptor system.



Background



Progesterone plays a crucial role in female reproduction.  Some of

the important reproductive events attributable to progesterone

influence include:  (1) regulation of cellular function via control

of synthesis of specific proteins, (2) ovulation induction, (3)

regulation of tubal transport of fertilized ova, (4) transformation

of the endometrium for implantation, and (5) maintenance of

pregnancy.  Because these reproductive events physiologically involve

progesterone mediated regulatory events, antiprogestins can be

utilized to antagonize progesterone actions in a manner regulating or

blocking gonadal, uterine or cervical functions associated with the

menstrual, conception, and parturition processes.  These effects

offer promise for molecular, preclinical and clinical applications in

the fields of veterinary and human medicine.



In addition to interfering with the effects of progesterone on normal

physiological events, antiprogestins could be utilized

therapeutically when the presence of progesterone is contraindicated.

It has been suggested, but not fully documented, that antiprogestins

could be utilized for treatment of endometriosis, breast cancer,

meningiomas and other disorders.  Existing evidence indicates that

certain antiprogestins can inhibit estrogenic, glucocorticoid and

androgenic actions.  These activities may be differential among

various antiprogestins.



The molecular basis of antiprogestin action is not fully known.

Whether antiprogestins bind solely to progesterone receptors or to

other functionally related sites is not clear.  Displacement of bound

progesterone from its receptor sites indicates that the antiprogestin

enters the target cells and interacts with specific

progesterone-binding sites without exhibiting agonistic activity.



Scope



Some examples of research topics that would be considered responsive

to this solicitation include, but are not limited to, the following:



o  Clarification of the intracellular mode of progesterone action.



o  Understanding ovulatory function and dysfunction.  Pituitary

gonadotropin secretion appears to be modulated in part by

progesterone.  Antiprogestins could help to determine the effects of

this and other regulatory factors in normal and aberrant gonadotropin

secretion and the relationship of the mechanism to some forms of

ovulatory dysfunction.



o  Studies on implantation.  Information could be gained to further

the understanding of: (a) uterine receptivity for blastocyst

implantation, (b) decidualization of the endometrium, (c)

significance of the morphological parameters that are used for

"dating" of endometrial maturation and (d) clarification of

mechanisms by which progesterone may render the uterus an

immunologically privileged site.



o  Clarification of the roles of progesterone accumulating neurons in

reproductive neuroendocrinological phenomena, such as sexual

behavior, ovulation, and feedback mechanisms in the

hypothalamo-pituitary-gonadal axis.



o  Studies on gamete maturation, interaction, fertilization and

activation of development.



o  Effects on sperm.  There is preliminary evidence that progesterone

is involved in sperm capacitation and changes in sperm motility in

the female tract.  Whether antiprogestins could affect male fertility

by altering sperm maturation or the fertilizing capacity of

spermatozoa is not known.



o  Studies on blocking ovulation.



o  Post-coital emergency contraception (morning-after pill).



o  Mini-pill or sequential contraceptive pill regimen.



o  Cervical dilatation and induction of parturition.



o  Treatment of endometriosis.  Antiprogestins may have a beneficial

effect in the medical treatment of endometriosis through suppression

of pituitary gonadotropin secretion and the resulting inhibition of

follicular development and ovulation, as well as noncompetitive

antiestrogenic actions that inhibit endometrial proliferation.



o  Medical treatment of uterine fibroids.



o  Ovarian hyperstimulation syndrome treatment.



These areas of interest are not listed by priority and they are only

suggested examples of areas of research that could be undertaken

under this program announcement.  Applicants are encouraged to

propose other areas that are related to the objectives and the scope

described above.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities in study

populations so that research findings can be of benefit to all

persons at risk of the disease, disorder or condition under study;

special emphasis must be placed on the need for inclusion of

minorities in studies of diseases, disorders and conditions which

disproportionately affect them.  This policy is intended to apply to

males and females of all ages.  If minorities are excluded or

inadequately represented in clinical research, particularly in

proposed population-based studies, a clear compelling rationale must

be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, such issues

should be addressed in developing a research design and sample size

appropriate for the scientific objectives of the study.  This

information must be included in the form PHS 398 (rev. 9/91) in

Sections 1-4 of the Research Plan AND summarized in Section 5, Human

Subjects.  Applicants are urged to assess carefully the feasibility

of including the broadest possible representation of minority groups.

However, NIH recognizes that it may not be feasible or appropriate in

all research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for

studies on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  The receipt dates for

applications for AIDS-related research are found in the PHS 398 (rev.

9/91) instructions.



Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

301/496-7441.  The title and number of the announcement must be typed

in Section 2a on the face page of the application.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Applications will be assigned on the basis of established Public

Health Service referral guidelines.  Applications will be reviewed

for scientific and technical merit by study sections of the Division

of Research Grants, NIH, in accordance with the standard NIH peer

review procedures.



Following scientific-technical review, the applications will receive

a second-level review by an appropriate national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding

decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

The NICHD has received assurance from the pharmaceutical

manufacturers of mifepristone and onapristone that they will assist

in this research effort by making supplies of the antiprogestin

available for funded projects.  Applicants are encouraged to contact

NICHD staff, who will facilitate access and referral to the

appropriate industry officials to discuss the proposed research and

the compounds available.



Direct inquiries regarding programmatic issues regarding

contraceptive development, basic and reproductive disorder research,

or gestational and pregnancy research, respectively, to:



Nancy J. Alexander, Ph.D.

Contraceptive Development Branch

Center for Population Research

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 8B13

Bethesda, MD  20892

Telephone:  (301) 496-1661



Michael E. McClure, Ph.D.

Reproductive Sciences Branch

Center for Population Research

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 8B91A

Bethesda, MD  20892

Telephone:  (301) 496-6515



Donald McNellis, M.D.

Pregnancy and Perinatology Branch

Center for Research for Mothers and Children

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 4B03

Bethesda, MD  20892

Telephone:  (301) 496-5575



Direct inquiries regarding fiscal matters to:



Melinda Nelson

Grants Management Branch

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 8A07

Bethesda, MD  20892

Telephone:  (301) 496-5001



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.864, Population Research.  Awards are made under

authorization of the Public Health Service Act, Title IV, Part A

(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and

285) and administered under PHS grants policies and Federal

Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not

subject to the intergovernmental review requirements of Executive

Order 12372 or Health Systems Agency review.



.

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