Full Text PA-95-006

BIOLOGY OF THE MENOPAUSE:  CHANGE OF OVARIAN FUNCTION

NIH GUIDE, Volume 23, Number 40, November 18, 1994

PA NUMBER:  PA-95-006

P.T. 34

Keywords: 
  Human Reproduction/Fertility 
  Urogenital System 
  Biology, Cellular 
  Biology, Molecular 


National Institute on Aging
National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

The National Institute on Aging (NIA), in collaboration with the
National Institute of Child Health and Human Development (NICHD) and
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), is interested in receiving applications to support research
that elucidates the molecular and cellular mechanisms of the
menopausal process.  This program announcement addresses age- and
menopause-related changes in the pituitary-ovarian axis that result
in the dramatic hormonal changes experienced across the menopausal
transition.  These changes lead to the menopause-related increase in
health problems associated with the cardiovascular, skeletal, and
genitourinary systems.  The primary focus of this program
announcement is on understanding the biology of the processes
involved in the change in ovarian function across the menopausal
transition, using appropriate animal models, human cells or tissue
specimens.  To increase the number of individuals trained to conduct
high quality molecular and cellular research in the combined aging-
and reproductive biology-related research areas, the individual
postdoctoral fellowship (F32) mechanism is included as eligible for
support in this program announcement.

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 PA,
Biology of the Menopause: Change of Ovarian Function, is related to
the priority area of chronic disabling conditions.  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 foreign and domestic, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Applicants for the
individual postdoctoral fellowship (F32) must be U.S. citizens,
noncitizen nationals or individuals who have been lawfully admitted
to the U.S. for permanent residence.  More information on eligibility
requirements for, and features of, individual postdoctoral
fellowships is available in the program announcement, "National
Research Service Awards for Individual Postdoctoral Fellows",
PA-94-055, NIH Guide for Grants and Contracts, Vol. 23, No. 15, April
15, 1994.  Applications from minority individuals and women are
encouraged.

MECHANISM OF SUPPORT

Support for this program will be by research project grants (R01),
FIRST Awards (R29), and the individual postdoctoral fellowship (F32).

RESEARCH OBJECTIVES

Background

The ovary of the premenopausal non-pregnant human female, as well as
the ovary of various animal species, serves as the body's primary
source of estradiol-17 beta (E2), the steroid hormone associated with
protection of the premenopausal woman from a variety of potential
postmenopausal health problems, such as increased risk for decline in
cardiovascular, skeletal, and genitourinary system function, and for
increased incidence of hot flashes.  In addition to E2, the
premenopausal ovary also secretes other steroid hormones, such as
progestins and androgens.  The ovary also produces the glycoprotein
inhibin.  Progestins, androgens and inhibin all have reasonably well-
defined actions within the hypothalamic-pituitary-ovarian (H-P-O)
axis but much less well-defined roles in the proper functioning of
peripheral tissues.

Entry into the climacteric period is associated with declining
fertility.  Many women experience menstrual cycle irregularity during
this period.  Early follicular phase FSH levels begin to rise about
five years preceding the menopause, even in regularly cycling women.
Inhibin, a potential biomarker of ovarian function in the pre- and
perimenopausal woman, is reported to decline with an inverse
relationship to rising serum FSH levels, although information
regarding the roles and temporal relationships of specific forms of
inhibin is lacking.  There is evidence that pulsatile characteristics
of pituitary gonadotropin secretion change in women in their 40s with
normal cycles and hormonal levels, suggesting age-related changes in
the P-O axis are likely to play an important role in the menopausal
process.

LH levels become elevated roughly one year prior to menopause.  The
forms of gonadotropins secreted during the climacteric and
postmenopause are reported to differ from forms secreted during the
premenopause; perhaps the functions of these alternate forms differ
also.  Data on the serum levels of E2 in the latter years of the
climacteric are conflicting: some studies report a decline of serum
E2 while others describe an elevation.  Changes in the formation and
function of the corpus luteum during the perimenopause are not well
described.  Following menopause, both serum E2 and progesterone
levels decline.

Thus, the time of menopause marks a dramatic change in ovarian
function.  Prior to menopause the ovary participates as a key
component of the dynamic hormonal orchestration of the H-P-O axis
resulting in the release of oocytes; subsequent to menopause the
ovary functions as a relatively quiescent androgen-secreting organ in
a hypergonadotropic environment.  The molecular and cellular
mechanisms involved in the rise in early follicular phase FSH, the
development of menstrual cycle irregularity, the rise in LH late in
the climacteric period, and the regulation of E2 and inhibin levels
during the climacteric period are largely unknown.

The change in ovarian function across the menopause is accompanied by
the loss of virtually all of the primordial and developing follicles
residing within the ovary.  From a non-replenishable store of several
million primordial follicles formed within the developing human ovary
during gestation, approximately 25,000 follicles remain at the start
of the last decade of menstrual cycling.  These remaining follicles
appear to undergo an accelerated rate of loss of over twice that of
the first two decades of reproductive life.  Consequently only
several hundred or less gonadotropin-insensitive follicles remain in
the ovary at the time of menopause, a number apparently too low to
sustain the H-P-O interactions required for regular menstrual
cyclicity.  The molecular and cellular mechanisms responsible for
this apparent acceleration of follicular loss are virtually unknown.

Follicular atresia is the predominant fate of ovarian follicles.  Of
the millions of follicles initially present in the ovary, well over
99 percent are depleted over the woman's reproductive life span
through atresia.  Except for the single ovulatory follicle per month
in a normally cycling woman, all of the growing pool of antral
follicles are resorbed within the ovary by atresia.  Even women not
cycling due to oral contraceptive usage or pregnancy lose ovarian
follicles at the same rate as cycling women.  The underlying
mechanism of atresia of antral follicles in diverse species,
including humans, appears to involve apoptosis in the granulosa cell
layer surrounding the oocyte.  The molecular and cellular mechanisms
through which these apoptotic processes are regulated are largely
unexplored.

Health- and biology-related issues of the menopausal process, from
basic ovarian and neuroendocrine biology through clinical,
psychosocial and biobehavioral aspects, were presented and discussed
at the NIH Workshop on Menopause held in Bethesda, MD from March 22
to 24, 1993.  Proceedings of this workshop are published in
Experimental Gerontology (vol 29 (3/4), 1994).

Goals of the Program Announcement

This program announcement focuses on (a) the molecular and cellular
regulatory mechanisms acting within and external to the pituitary-
ovarian axis that are involved in the enhancement of the rate of
ovarian follicular loss in the decade prior to the menopause, and (b)
the identity, and molecular and cellular mechanisms regulating the
levels and activities, of hormones,cytokines and growth factors
secreted from the P-O axis of the climacteric woman that serve to
maintain extra-ovarian tissue function.

The goal is to increase the understanding of the molecular basis of
the normal menopausal process occurring in women generally between
the ages of 45 and 55.  Premature ovarian failure, due either to
iatrogenic or pathologic processes, is not within the scope of this
program announcement.  However, this restriction is not intended to
exclude research with animal or other models in which ovarian
follicular exhaustion is manipulated experimentally or genetically to
explore relationships of reproductive aging with follicular number.

In addition to research project grants, the individual postdoctoral
fellowship (F32) mechanism is included as eligible for support in
this program announcement in order to permit the training of
postdoctoral investigators in the specific research areas outlined
below.  In particular, investigators trained in non-aging ovarian
reproductive research related to this program announcement may bring
their expertise to, and gain additional training in, a laboratory
experienced in age-related reproductive research through the F32
fellowship.  Alternatively individuals trained in reproductive aging
research may conduct the appropriate work in a non-aging ovarian
reproductive research laboratory, or in a laboratory focused on an
appropriate animal model.  An intended outcome is to increase the
number of investigators interested in and qualified to conduct high
quality molecular and cellular research appropriate for this program
announcement.

Applicants interested in the effect of menopause- and age-related
changes on the hypothalamus and higher brain centers are referred to
a complementary program announcement ("Neuroendocrinology of Aging",
PA-94-087, NIH Guide for Grants and Contracts, Vol. 23, No. 28, July
29, 1994).

Although molecular and cellular mechanistic approaches to the issues
described in this program announcement are strongly desired, the
acquisition of more baseline data may be necessary in some areas to
formulate a mechanistic hypothesis.  Research questions of interest
include, but are not limited to, the following:

o  What regulates the process responsible for the enhanced rate of
follicular loss in the last decade of menstrual cycling; what role do
the hormonal interactions of the P-O axis play in this process;

o  How do the declining numbers of ovarian follicles, and associated
changes in the secretory products, in the aging ovary influence the
process of the P-O intercommunication to result in acyclicity and
eventual cessation of menstruation;

o  How do paracrine and autocrine processes within the aging ovary
influence its function, and how are these processes regulated by
extra-ovarian tissues;

o  What is the role of age- and ovarian-related changes in the
pattern of pulsatile hypothalamic GnRH secretion on gonadotropin
synthesis and release; how do these changes affect ovarian function;

o  What changes occur in the secreted forms of gonadotropins, by what
mechanisms do these changes occur, and how do these changes affect
ovarian function;

o  Why are follicles remaining in the postmenopausal ovary apparently
insensitive to the hypergonadotropic environment;

o  To what extent and by what mechanism(s) does normal peri- or
postmenopausal ovarian stromal tissue, either alone or in combination
with resorbed ovarian follicular and luteal tissues/cells, influence
the autocrine, paracrine and endocrine interactions of the aging
ovary with the P-O axis and other extra-ovarian tissues;

o  What ovarian secretory products other than estrogen are potential
regulators of extra-ovarian tissues involved in decline of tissue
function associated with the menopause, and how are the secretions
and activities of these substances regulated by the ovary and other
tissues during the menopausal process;

o  If age-related changes in vascular supply to the ovary play an
important role in change of ovarian function across the menopause,
what are the mechanisms for these changes and how do they influence
ovarian function.

Research Resources

The ability to conduct definitive studies into the molecular and
cellular mechanisms of the menopausal transition and the associated
change in tissue function is restricted in women by ethical concerns
as well as by issues of practicality and experimental design.
Consequently, it is necessary to utilize appropriate experimental
models of the human menopausal process and development of
pathophysiologic sequelae associated with the menopause.

Investigators are encouraged to develop and/or utilize appropriate
animal models.  A non-primate animal model of menopause may be
acceptable for particular studies provided that the selection of the
animal model is based on current and expanding knowledge available
regarding (a) the human menopausal process and associated changes in
tissue or organ function, and (b) characteristics and appropriateness
of particular animal species to answer the research questions posed
using relevant experimental approaches.  For example, it may be
possible to experimentally manipulate in a physiologic fashion
ovarian follicle number or rate of follicular decline in order to
explore their relationship to reproductive aging and associated
tissue decline.  Although extensive research experience and
background data on female reproductive aging has been accumulated in
the rodent, some features of reproductive aging in the female rodent
are substantially different from the human menopausal process.  Since
for other species less extensive background data on female
reproductive aging are available, more preliminary data from the
investigator will be required if use of these animal species is
proposed.

An obvious choice for a model of the human menopause based both on
the phylogenetic relationship of species and the known physiologic
similarities is the non-human primate.  From the limited data
available, the rhesus monkey and baboon may be suitable animal models
of both the menopausal process and the subsequent decline in tissue
function due to both menopause and aging.  Investigators may choose
to utilize non-human primates, particularly in collaboration with
established primate research centers, including the Regional Primate
Research Centers (RPRC) supported by the National Center for Research
Resources (NCRR), NIH.  However, there are drawbacks to the extensive
and immediate use of these species, such as the high cost of
husbandry (which is partially offset by maintenance of groups of
aging animals at the RPRC by the NIA), relatively long life span,
limited availability, and the absence of substantial published
baseline data on female reproductive aging in non-human primates.
Efforts are currently underway to expand the baseline data available
for female reproductive aging in non-human primates, thus making them
more attractive to investigators planning molecular and cellular
mechanistic studies of the menopausal process and associated changes
in tissue or organ function.

Other appropriate experimental models include (a) in vitro cell and
tissue culture models using human tissues, or specimens derived from
human tissues, (b) use of human post-mortem tissue where appropriate,
and (c) implantation of relevant human tissues into pertinent animal
species to approach questions regarding the behavior of that tissue
under suitable experimental conditions. While clinical and
epidemiologic studies are not strongly encouraged in response to this
program announcement, the use of clinically derived data in
characterizing the human tissues used for these studies would be
appropriate.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

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 14508-14513), 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.

APPLICATION PROCEDURES

Applications for R01 or R29 awards must 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.
Individuals applying for the F32 postdoctoral fellowship must use PHS
416-1 (rev. 10/91) application forms.  Application receipt dates for
the F32 award are April 5, August 5, and December 5.

Application kits are available at most institutional business offices
and may be obtained 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 title and
number of the program announcement must be typed in Section 2a on the
face page of the application.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

The completed original and five legible copies of the PHS 398 or the
original and two copies of the PHS 416-1, must be sent or delivered
to:

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

REVIEW CONSIDERATIONS

Applications will be assigned to Initial Review Groups on the basis
of established PHS 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, R01
and R29 applications will receive a second-level review by the
appropriate national advisory council.  Second-level review for F32
applications will be carried out by institute staff.

The following criteria will be used in evaluating R01 and R29
applications submitted in response to this program announcement:

o  Scientific and technical merit, significance, and originality of
the proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology to be used;

o  Qualifications of the principal investigator and staff in the area
of research, and the principal investigator's prior research
experience and record;

o  Adequacy of the available facilities.

Criteria used in review of F32 postdoctoral fellowship awards are:

o  the applicant;

o  the research proposed (both its scientific merit and training
potential;

o  the training resources and environment, including the sponsor.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following criteria will be considered when making
funding decisions:

o  Scientific and technical merit of the application as determined by
peer review;
o  Availability of funds;
o  Program balance.

INQUIRIES

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

Direct inquiries regarding programmatic issues:

Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  fqb@cu.nih.gov

Sherry Sherman, Ph.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Suite 3E327
Bethesda, MD  20892-9205
Telephone:  (301) 496-6761
FAX:  (301) 402-1784
Email:  sherman%nihniagw.bitnet@cu.nih.gov

Donna Vogel, M.D., Ph.D.
Reproductive Sciences Branch
National Institute of Child Health and Human Development
Building 61E, Room 8B01
6100 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-6515
FAX:  (301) 496-0962
Email:  vogeld@hd01.nichd.nih.gov

Philip Smith, Ph.D.
Pituitary and Neuroendocrinology Research Program
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7531
FAX:  (301) 594-9011
Email:  phils@dvsgate.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance: No. 93.866, Aging Research, No. 93.864, Population
Research, and No. 93.847, Diabetes, Endocrinology and Metabolic
Diseases Research.  Research grant awards (R01, R29) 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.  Postdoctoral fellowship
awards (F32) are made under the authority of Section 487 of the
Public Health Service Act as amended (42 USC 288), and Title 42 of
the Code of Federal Regulations, Part 66.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 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
people.

.

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