Full Text HD-93-04

PATHOPHYSIOLOGY OF ENDOMETRIOSIS AND LEIOMYOMATA UTERI

NIH GUIDE, Volume 21, Number 16, May 1, 1992

RFA:  HD-93-04

P.T. 34

Keywords: 
  Pathophysiology 
  Reproductive Endocrinology 
  Reproductive Physiology 
  Growth Factors 
  Pregnancy 


National Institute of Child Health and Human Development
Office of Research on Women's Health

Application Receipt Date:  July 24, 1992

PURPOSE

The National Institute of Child Health and Human Development (NICHD)
and the Office of Research on Women's Health (ORWH) invite research
grant applications for support of investigations into the biology and
pathophysiology of endometriosis and leiomyomata uteri ("myoma").
Directives from the 102nd U.S. Congress included in Reports 102-121 of
the House of Representatives and 102-104 of the Senate accompanying the
NIH Appropriation Bill, H.R. 2707, for fiscal year 1992, have urged the
NIH to address research efforts toward several diseases and conditions
related to women's health including endometriosis and myoma.

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 RFA,
Pathophysiology of Endometriosis and Leiomyomata Uteri, is related to
the priority area of family planning.  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 may be submitted by domestic for-profit and non-profit
organizations, public and private.  Minority individuals, persons with
disabilities, and women are encouraged to apply.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research grant (R01).
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period for applications submitted in response to the present
RFA may not exceed five years.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review
procedures.

FUNDS AVAILABLE

It is expected that up to five applications will be funded, within the
total cost limit of $1,000,000 available for the first year.  This
level of support is dependent on the receipt of a sufficient number of
applications of high scientific merit.  Although this program is
provided for in the financial plans of the NICHD and the ORWH, awards
pursuant to this RFA are contingent upon the availability of funds for
this purpose.

BACKGROUND

o  Endometriosis

Endometriosis is the growth of endometrial tissue outside of the
uterine cavity, most often on the peritoneal lining of pelvic organs
such as the ovaries and uterus.  A common, poorly understood disorder,
it can cause infertility and pain due to growth of implants, bleeding,
and scarring.  The cause is not known, although proposed etiologies
have included retrograde menstruation, abnormal immune function, and a
genetic contribution.

Treatments are largely empirical.  Medical treatment has been aimed at
suppressing the natural menstrual cycle.  Since endometriosis is the
growth of endometrial tissue, it is responsive to sex steroids, such as
the combined oral contraceptive (OC).  Thus, OCs became a standard
therapy.  Some patients did not tolerate OCs well, while others desired
fertility.  In the late 1970s, danazol, a so-called "impeded" androgen,
became available as an alternative to oral contraceptives.  Danazol
produces a low estrogenic state, thus inhibiting endometrial growth.
It is considerably more expensive than oral contraceptives, and some
women experience androgenic side effects.

More recently, endometriosis has been treated experimentally with
analogs of the hypothalamic hormone, gonadotropin releasing factor
(GnRH), which normally stimulates the pituitary gland to secrete the
gonadotropin hormones that stimulate the ovary.  The analogs "turn off"
the stimulation.  Beyond, or sometimes instead of, medical therapy,
surgery has been offered.  Definitive treatment of endometriosis has
historically consisted of radical surgery to remove the uterus,
ovaries, and any other sites of endometrial implants.  This treatment
is not recommended for mild cases and for women who might wish to
become pregnant.  Modern advances have included use of improved lasers
and laparoscopy to avoid major abdominal surgery.  Still, the ablation
of lesions does not always correlate with symptomatic relief or
alleviation of infertility.

Therefore, it has become a high-priority area for the NICHD and the
ORWH to stimulate research into the etiology and pathophysiology of
endometriosis, in search of leads for improved diagnosis and therapy.

o  Myoma

Leiomyomata uteri are benign tumors of the muscular layers of the
uterus.  They are a frequent cause of abnormal uterine bleeding and the
leading indication given for hysterectomy.  Since they are estrogen
dependent, they affect women of reproductive age for the most part.
There appears to be a genetic component, but the cause is unknown.  The
relationship between myoma and infertility is not well defined, but
there appears to be an association with early fetal wastage.  In
addition to bleeding and infertility, myomata can cause pelvic pain.

The estrogen dependence of leiomyomata has led to empirical treatment
with many of the same therapies as were mentioned above under
endometriosis, including progestins, danazol, and GnRH analogs to
prevent or oppose the action of estrogen.  However, the long-term
safety and efficacy of analogs have not been determined, the long-term
hypoestrogenic state raises the risk of osteoporosis, and the tumors
regrow promptly upon the cessation of treatment.  For this reason, they
are often used as an adjunct to facilitate surgery, rather than as
definitive therapy.

There is a great need for more knowledge about the process of myoma
initiation and growth.  If safe, long-term medical therapies were
developed based on solid scientific rationales, thousands of women
annually might be spared surgery, with resulting reduced morbidity and
preservation of fertility.

RESEARCH OBJECTIVES

Areas that will be considered responsive to this RFA include, but are
not limited to:

o  Mechanisms by which endometriotic lesions arise and proliferate;

o  Elucidation of effectors of myoma growth regulation, specific to
leiomyomata uteri rather than tumorigenesis in general;

o  New approaches to intervention based on established responses of
endometriosis or myoma cells to hormonal, immune, or growth factors;

o  Use of improved animal or cell culture model systems for the study
of endometriosis or myoma relating to the above;

o  Elucidation of factors contributing to reduced incidence of clinical
pregnancy in women with endometriosis or myoma.

While applicants are encouraged to include a clinical research
component, it is not the intent of this RFA to support clinical trials.
Applications proposing clinical trials will not be considered
responsive to this RFA.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements are required to include
minorities and women 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 and women in studies of diseases, disorders and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  For the purpose of
this RFA, investigations are limited to disorders occurring only in
women.  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 racial/ethnic group.  In addition, racial/ethnic issues must
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information, as well as the limitation of studies to women, must be
included in the form PHS 398 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 should 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.
This definition is independent of "involvement" of human subjects (see
below).

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.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
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 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

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional business offices; and 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 RFA label available in the PHS 398 application form must be affixed
to the bottom of the face page of the application.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.  In addition,
the RFA title and number must be typed on line 2a of the face page of
the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Laurance Johnston, Ph.D.
Division of Scientific Review
Institute or Division
National Institute of Child Health and Human Development
Executive Plaza North, Room 603
Bethesda, MD  20892

For courier delivery use:  Rockville, MD 20852

Applications must be received by July 24, 1992.  If an application is
received after that date, it will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing
the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NICHD staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by a peer review group on the basis of
relative competitiveness.  The NIH will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are complete
and responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by a peer review group convened by
the DRG.  The second level of review will be provided by the National
Advisory Child Health and Human Development (NACHHD) Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach,
methodology, and analysis proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, and of collaborators, if applicable;

o adequacy of time and effort dedicated to the project;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research

AWARD CRITERIA

The anticipated date of award is September 30, 1992.  Funding decisions
will be based on initial review group and NACHHD Council
recommendations, program relevance, and availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Donna L. Vogel, M.D., Ph.D
Reproductive Sciences Branch
Center for Population Research
National Institute of Child Health and Human Development
Executive Plaza North, Room 603
Bethesda, MD  20892
Telephone:  (301) 496-6515
FAX:  (301) 496-0962

Direct inquiries regarding fiscal matters to:

Melinda Nelson
Office of Grants and Contracts
National Institute of Child Health and Human Development
Executive Plaza North, Room 505
Bethesda, MD  20892
Telephone:  (301) 496-5481

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 12374 or a Health Systems Agency
review.

.

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