Full Text HD-94-023


NIH GUIDE, Volume 23, Number 16, April 29, 1994

RFA:  HD-94-023

P.T. 34

  Reproductive Endocrinology 

National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  June 8, 1994
Application Receipt Date:  August 19, 1994


The National Institute of Child Health and Human Development (NICHD)
invites research grant applications for the support of investigations
into uterine bleeding and steroid hormones that may lead to improved
bleeding patterns in women receiving progestin-only contraceptives.
A National Institutes of Health/World Health Organization conference
held in May 1992 recommended that such studies be conducted
(Alexander, N.J., d'Arcangues, C. Steroid Hormones and Uterine
Bleeding. 1992.  AAAS Press. 344 pp.).


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 Request
for Applications (RFA), Uterine Bleeding and Steroid Hormones, 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 20402-9352 (telephone


Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Minority individuals,
persons with disabilities, and women are encouraged to apply.


This RFA will use the NIH individual research project 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.  The expected award date is April 1,

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.

Because the nature and scope of the research proposed in different
applications in response to this RFA may vary, the size of each award
will vary also.


It is expected that up to four new applications will be funded by the
$800,000 set aside 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, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.



Steroids in contraceptive products are some of the most effective
fertility regulators.  However, their propensity to induce
unpredictable endometrial bleeding results in a significant problem
to many women.  In fact, breakthrough bleeding is the most common
complaint among oral contraceptive (OC) users, frequently leading to
the discontinuation of the methods.  The bleeding problem has been
exacerbated with the introduction of OCs with a low estrogen content,
especially in new users during the first three to four months of use.
The widespread introduction of long-acting progestin-only injectable
contraceptives and the recent introduction of the implant Norplant
have focussed attention on the need to investigate the causes of
bleeding and to develop effective treatments.  Clinicians have
utilized empirical methods to stop or minimize the bleeding,
including switching to a different OC product, instructing patients
to temporarily double up on pills, or prescribing estrogens.  But,
since the causes of these bleeding disturbances are poorly
understood, reliable, scientifically sound treatment regimens have
not been developed.

During the normal menstrual cycle, the maturation of the endometrium
is relatively uncomplicated and solely dependent on two hormones,
estrogen and progesterone.  The first half of the menstrual cycle
until ovulation is an estrogen-dominated phase.  Although the
majority of circulating estradiol has its origin from the ovary, the
endometrium has the ability to aromatize androgens into estrogens,
which further adds to the estrogenic environment.  The binding of
estradiol to its receptor results in the production of growth
factors.  These growth factors stimulate mitogenesis within the
glandular and stromal compartments of the endometrium.  During this
phase of the menstrual cycle, called the proliferative phase,
menstruation stops and the endometrial lining thickens.  The
estradiol stimulates the acquisition of estrogen and progesterone
receptors within the endometrium.

After ovulation, the menstrual cycle becomes progesterone dominated.
Progesterone, via its antiestrogenic actions, halts the growth of the
endometrium and then stimulates the endometrium to undergo
with secretory activity within the glandular epithelium.  The several
ways in
which progesterone antagonizes the action of estrogen include:
reduces the number of estrogen and progesterone receptors, induces
17-hydroxysteroid dehydrogenase, which converts estradiol to estrone,
a less
potent estrogen, and stimulates the sulfotransferase enzyme, which
estradiol rendering it inactive.

While bleeding during normal menstruation may result from uniform,
shedding of the endometrium and bleeding from the endometrial spiral
arterioles, breakthrough bleeding that occurs in the absence of
pelvic organ
disease or a systemic disorder, probably originates from capillaries
and seems
to be limited to patchy areas of the endometrial surface.

Recent research has concentrated on the role of endothelial cells in
bleeding and angiogenesis.  These cells synthesize and metabolize
many vasoactive substances, including prostacyclin, nitric oxide and
endothelin-1, that maintain patency of the vasculature and regulate
the blood flow.  Some of these vasoactive factors have very short
biological half-lives and are important in modulating regional
circulation.  Prostacyclin and nitric oxide are potent vasodilators
that also prevent adhesion and aggregation of platelets.
Endothelin-1, in contrast, is a potent vasoconstrictor and a
modulator of human uterine artery and vein tone.  During pregnancy,
endothelin may contribute to the pathogenesis of preeclampsia and
endothelin may regulate similar changes in cycling women.  Estrogen
is associated with decreased uterine vascular resistance and
increases blood flow, and progestins, such as levonorgestrol, are
associated with changes in endometrial capillary structure.  These
steroid effects may be mediated by production of endothelin or other
locally produced factors.  Circulating progesterone and estrogen
levels do not correlate well with bleeding because they are not
sufficiently predictive of the production and metabolism of local
vasoactive factors.


The purpose of this RFA is to stimulate research that will lead to a
better understanding of the causes of endometrial bleeding induced by
exogenous hormones and, with time, the development of effective
therapies.  Research grant applications may include, but are not
limited to:

o  Defining the characteristics of the endometrial microvascular bed
and angiogenesis including growth, repair, as well as the regression
of the vascular bed.

o  Defining the characteristics including the biochemical composition
and steroid receptor content of the sites that may be prone to

o  Investigating whether endothelial cells lining endometrial blood
vessels differ from endothelial cells of other organs.

o  Determining the morphological and biochemical effect of different
steroid regimens, including long-term progestin exposure on the
capillaries of the superficial epithelium

o  Delineating the distribution of estrogen and progesterone
receptors under different steroid regimens

o  Differentiating whether dysfunctional uterine bleeding on certain
treatment regimens is a function of unsuppressed ovarian function or
exogenous hormones.

o  Conducting clinical studies to determine
1) whether there are serum markers that can predict the onset of
breakthrough bleeding
2) if there is an association between blood pressure and
dysfunctional bleeding
3) whether the causes of bleeding from an atrophic endometrium is
different from bleeding that occurs during early phases of
progestin-only treatment.

o  Studies of a non-human primate model, if one can be found in which
relevant studies of steroid induced uterine bleeding are appropriate.



It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 9, 1994 (FR 59 11146- 11151) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Prospective applicants are strongly encouraged, but not required, to
submit, by June 8, 1994, a letter of intent that includes a
descriptive title of the proposed research, the name, address and
telephone number of the Principal Investigator, the identities of
other key personnel and participating institutions, and the number
and title of the RFA in response to which the application may be

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows NICHD staff to estimate the potential review
workload and to avoid conflict of interest circumstances in the
review process.

The letter of intent is to be sent to Dr. Nancy J. Alexander at the
address listed under INQUIRIES.


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 offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.

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 be sent to:

Susan Streufert, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
Building 6100, Room 5E03
6100 Executive Boulevard
Bethesda, MD  20892

Applications must be received by August 19, 1994.  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.


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, it will be returned to the
applicant, who may then submit it to DRG for review in competition
with unsolicited applications at the next available review cycle.

Responsive applications may be triaged by a peer review group to
determine their 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 evaluation for scientific merit, in accordance
with the criteria stated below, by a review committee convened solely
for that purpose by the Division of Scientific Review, NICHD.  The
second level of review will be conducted by the National Advisory
Child Health and Human Development (NACHHD) Council at its January,
1995, meeting.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications, including:

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

o  appropriateness and adequacy of the experimental approach and
methodology 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 the resources necessary to perform the research;

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

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.


The anticipated date of award is April 1, 1995.  Funding decisions
will be based on peer review and NACHHD Council recommendation,
program relevance, and availability of funds.  In some cases, if the
proposed research has relevance to the research program of the
National Center for Research Resources (NCRR) as well as that of the
NICHD, the application may be dually assigned to, and considered for
funding by, the NCRR.  Any such assignment will be made independently
of peer review procedures.


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

Direct inquiries regarding scientific issues to:

Nancy J. Alexander, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
Building 6100, Room 8B13
Bethesda, MD  20892
Telephone:  (301) 496-1661
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
Building 6100, Room 8A17
Bethesda, MD  20892
Telephone:  (301) 496-5481


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 CRF 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12374 or health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American


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