Research
The clinical faculty have provided partial support for Dr. Danforth’s research
activities, which are detailed below. Our research interests focus on the
regulation of preantral follicle growth in the ovary. We are interested in the
mechanisms and factors regulating primordial and primary follicle growth, as
well as investigating potential therapies for preserving ovarian function during
chemotherapy.
The Regulation of Early Follicle Growth by Vascular Endothelial Growth Factor (VEGF)
Douglas R. Danforth, Ph.D., Chad I. Friedman, M.D., Pravin Kaumaya, Ph.D., David
Cohn, M.D.
The regulation of folliculogenesis in the mammalian ovary is a complex process.
Whereas the later stages of gonadotropin-dependent follicle growth have been
more thoroughly studied, the early stages of folliculogenesis, especially the
initiation of follicle growth remain enigmatic. Accumulating evidence during the
past decade suggests that the initiation of folliculogenesis is a continuous
process regulated by a variety of endocrine and paracrine signals. Moreover,
there are likely species differences in this process as well. It has been
suggested that the availability of an adequate vascular supply to provide
endocrine and paracrine signals may also play a key role in the initiation of
follicular growth as well as the latter stages of follicle selection and
dominance. Recent advances in our understanding of the physiology of vascular
endothelial growth factor/vascular permeability factor (VEGF/VPF) and its
identification in the mammalian ovary suggest that this important regulator of
new blood vessel formation and vascular permeability may modulate many aspects
of ovarian function and may participate in the regulation and/or initiation of
the early stages of follicular growth. We hypothesize that ovarian VEGF is an
integral paracrine regulator of early follicle growth and is essential for
primordial follicle survival in the ovary. To test these hypotheses, we are
investigating the cellular and molecular pathways involved in VEGF regulation of
preantral follicle growth. Experiments are being performed to identify which
VEGF receptors are involved, assess changes in angiogenesis vs. vascular
permeability, evaluate potential direct actions of VEGF on follicle growth and
survival in vitro, and explore the apoptotic pathways involved in follicle
destruction. In addition, the consequences of VEGF neutralization on
reproductive lifespan will be assessed.
Taken together, these studies will provide the first meaningful information on
the role of VEGF in early follicle growth. Aside from providing key information
on preantral growth and survival, these experiments may have immediate clinical
applicability. The potential devastating effects of anti-angiogenic therapy on
long term reproductive potential are especially critical given the frantic pace
of clinical studies on angiogenic therapy for cancer treatment. Conversely,
understanding the role of VEGF in early follicle growth could provide real
benefit for ovarian transplantation to preserve/extend fertility. As such,
unraveling the role of angiogenesis in early follicle growth and survival is of
critical importance.
Manipulation of Vascular Endothelial Growth Factor (VEGF) to Regulate
Reproductive Efficiency
Douglas R. Danforth, Ph.D., Pravin Kaumaya, Ph.D., Joseph Ottobre, Ph.D.
Reproductive inefficiency is a source of major economic loss in the animal
industry, and causes both emotional and financial stress among humans who
experience infertility. Studies designed to enhance our basic understanding of
reproductive physiology, including ovarian function will ultimately benefit both
domestic animals and humans. The purpose of this research program is to
investigate the role of Vascular Endothelial Growth Factor (VEGF) in the
regulation of early follicle growth in the sheep ovary. The specific aims of the
project are to 1) investigate the role of VEGF and Endocrine Gland VEGF (EG-VEGF)
in the regulation of early follicle growth, 2) investigate whether disruption of
endogenous VEGF or EG-VEGF impairs fertility or alters ovarian function, and 3)
investigate the mechanism(s) whereby VEGF administration or depletion alters
ovarian function. These experiments will provide the first detailed information
on the potential role of VEGF in the regulation of early follicular growth in
the sheep ovary. The identification, characterization, and regulation of VEGF
and its effects on follicular growth and angiogenesis will provide important
insight on this potential novel mediator of the earliest stages of
folliculogenesis. This project is funded through a grant from the Ohio
Agricultural Research and Development Center.
The Role of GnRH Analogues in Primordial Follicle Growth and Survival
Douglas R. Danforth, Ph.D., and Chad I. Friedman, M.D.
GnRH analogs have been used for more than two decades to indirectly manipulate
ovarian function by stimulating or inhibiting the hypothalamic-pituitary axis.
Agonists, which transiently stimulate then suppress gonadotropin secretion
through desensitization and receptor down-regulation, have been used clinically
since the mid- 1970’s, and are now a staple of Assisted Reproductive Technology
(ART) programs worldwide. GnRH agonists have also been used in clinical practice
with some success to lower the incidence of ovarian failure following
chemotherapy. However, the benefit of gonadotropin suppression during
chemotherapy is not universally accepted and other investigators have failed to
demonstrate a protective effect of agonists on ovarian reserve. The mechanism(s)
whereby GnRH agonists could prevent ovarian failure is not clear but presumably
involves the suppression of endogenous gonadotropin secretion. However, the
early stages of follicular growth (primordial through preantral) are
gonadotropin insensitive if not completely gonadotropin independent (reviewed in
7). This “gonadotropin insensitivity” may account for the relatively limited
success of GnRH agonists in protecting the ovary, since the agonists do not
completely suppress gonadotropin secretion even at high doses.
Apart from inhibiting pituitary gonadotropin secretion, GnRH analogs have the
potential to modulate ovarian function via a direct effect on the ovary.
Numerous studies have documented a functional ovarian GnRH and GnRH receptor
system in the rat ovary, and the direct effects of GnRH agonists on the rat
ovary are well established. Although newer, GnRH antagonists have also been
demonstrated to directly modulate ovarian function in the rat. The goals of this
project are to examine the effects of GnRH antagonists on preantral follicle
survival in the murine and primate ovary and investigate the potential of GnRH
antagonists to abate the chemotherapy-induced depletion of primordial follicles.
This project is funded by the National Institutes of Health.
Active Funding
Effect of GnRH antagonist on primordial follicle survival in the primate ovary.
National Institutes of Health, $149,500 2006-2008 (Dr. Douglas Danforth,
Principal Investigator).
