SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018 - 221A

Scientific Abstracts

CONCLUSION: Our data demonstrate that FSCs exhibit increased
baseline DNA damage and defective DDR and DNA DSB repair activity
as compared to MSCs. Our studies suggest that dysfunctional DNA
damage repair may contribute to UF development. More studies are needed
to reveal early changes in MSCs or FSCs leading to UF development.
Support: R01 ES028615-01 (AA) and 1F30HD089585-01A1 (LPF).

F-118

F-119
An Innovative Way to Identify Novel Drug Targets for Abnormal
Uterine Bleeding from FDA Reported Drug-Related Clinical Events.
Joerg Mueller, Djork-Arne Clevert, Bertram Weiss, Thomas M Zollner*.
Bayer AG, Berlin, Germany.
INTRODUCTION: Uterine fibroids (UFs) are steroid dependent
benign tumors and 30-70% of women at reproductive age are affected
by symptomatic UFs. Typical symptoms are abnormal uterine bleeding
(AUB), menses related anaemia, pelvic pain and reproductive
dysfunction. The mechanisms involved in UF-associated AUB are only
partially understood and current treatment options are limited to surgery
(hysterectomy, myomectomy, uterine artery embolization) and few drug
treatments (GnRH agonists, progesterone receptor modulators). To get

221A

a better understanding of the pathogenesis of AUB and to support the
development of novel therapies we harnessed the FDA Adverse Event
Reporting System (FAERS) to spot drug treatment related AUB events.
Objectives: The objective of the current study was to identify drugs and
their mode of actions (MoAs) which might impact AUB in treated patients
to uncover potential novel therapeutic options.
METHODS: AUB related clinical phenotype terms coded by Medical
Dictionary for Regulatory Activities (MedDRA) terms in the FAERS were
identified. Drug names in the FAERS were mapped to their MoAs (based
on DrugBank) and related events were consolidated by their respective
targets. Increased or decreased occurrence of AUB causal with specific
treatments was calculated by Fisher's Exact Test.
RESULTS: Overall more than 100k reports mentioning AUB related
events, such as menorrhagia or amenorrhea, were found in the FAERS.
As expected, patients treated with GnRH agonists or progesterone
modulators showed a strong enrichment of AUB related events. Also
clinically effective plasminogen inhibitors show up. A couple of cancer
medications seem to be effective for AUB as well since they might block
proliferation and decidualization of the endometrium. Further interesting
candidate MoAs, e.g. androgen, retinoic acid and PPAR signaling, were
found and are discussed as well.
CONCLUSION: This study emphasizes the value of this method to
identify potentially novel clinically addressed MoAs which might impact
AUB or other clinical phenotypes covered by the FAERS.

F-120
Identification of a Preclinical Phenotype for the Development of
Painful Bladder Syndrome in Women with Isolated Dysmenorrhea.
Kevin M Hellman*, Frank Tu, Ellen Garrison, Folabomi Oladosu.
NorthShore University HealthSystem, Evanston, IL, United States.
INTRODUCTION: A new clinical treatment paradigm is needed to
prevent painful bladder syndrome (PBS) or interstitial cystitis since the
pain is often long-term and can be debilitating. Therefore, we determined
whether bladder hypersensitivity is seen concurrently with dysmenorrhea
in women without chronic pain elsewhere. Demonstrating this would
suggest that there is a shared preventable mechanism responsible for
visceral hypersensitivity.
METHODS: A cohort of women without complaints of chronic pain
elsewhere was divided into two groups based on whether the women had
dysmenorrhea (n=98) or limited menstrual pain (n=35). After drinking
water, participants serially rated bladder pain and had sonographic
bladder volume measurements at standard cystometric thresholds. Bladder
sensitivity was also measured separately by a rapid filling test, during a
physical exam, and through self-report.
RESULTS: Women with dysmenorrhea had more urinary symptoms
than controls and had less volume at maximum capacity (498 ± 18 mL
vs. 619 ± 34 mL, p<0.001) and more bladder filling pain (24 ± 3 vs. 12
± 3, p<0.001). The subset of women with dysmenorrhea (24/98, 24%)
who reported bladder pain during the assessment visit also reported
elevated bladder pain during the screening rapid bladder test (p<0.01), in
response to transvaginal bladder palpation (p<0.01), and in data recorded
in prospective daily diaries (p<0.01).
CONCLUSION: The association of dysmenorrhea with bladder pain
suggests menstrual pain and bladder sensitivity occur via a shared
peripheral or central mechanism. This non-invasive test can be used to
identify otherwise healthy women harboring a level of visceral sensitivity
similar to those with symptomatic chronic pelvic pain, who might be
targeted for interventions to prevent painful bladder syndrome.

Friday Posters

Expression of CXCR4 in Leiomyomas from Humans and Non Human
Primates. Graciela Krikun, Carmen J Booth*. Yale University, New
Haven, CT, United States.
INTRODUCTION: While the high prevalence and major negative impact
of uterine leiomyomas (fibroids) on women's health is highly significant,
their pathogenesis remains largely unidentified. Fibroids represent one of
the most benign tumor types in women of fertile age affecting up to 80% of
women between 30-50 years old. However, currently there are no proven
medical therapies and surgical treatment comes at a significant physical
and psychological cause. Additionally, most animal models do not develop
spontaneous disease and fail to reflect the reproductive biology in humans.
However, non human primates closely resemble human reproductive
biology. In order to better understand this phenomenon, we compared
fibroids in humans and non-human primates. Specifically we identified
the expression of CXCR4, the receptor for CXCL12 (SDF1). CXCL12
acting via its receptor is a potent chemokine that results in proliferation
and angiogenesis. We hypothesized that CXCR4 expression would be
higher in fibroids compared to normal myometrium.
METHODS: Tissues were obtained from women undergoing
hysterectomy who were consented for tissue acquisition. Monkey samples
were obtained at time of necropsy for unrelated issues. All tissues were
formalin fixed and paraffin embedded. CXCR4 immunohistochemistry
was conducted on control myometrium vs. fibroids by Yale Research
Pathology. The CXCR4 antibody was used at a dilution of 1:50 (clone
AB124823 Abcam, USA) and mouse horseradish peroxidase antihuman
IgG (The Jackson Laboratory, Bar Harbor, ME) was used for visualization
with 3,3'diaminobenzidine.
The level of staining was assessed in a blinded fashion (CB).
RESULTS: Fibroids derived from human and non-human primates
expressed intense CXCR4 staining compared to controls. Specifically,
human uteri with fibroids consistently stained the majority of leiomyoma
tumor cell nuclei strongly positive in contrast to normal myometrium
which displayed weak to mild staining. Uteri from female rhesus macaques
(Macaca mulatta) showed similar strong positive staining in leiomyomata
also in the nuclei of the smooth muscle cells and weak to mild staining
in non tumor uterine myometrium.
CONCLUSION: We posit that the inflammatory milieu such as that
occurring in fibroids induces CXCR4 and likely CXCL12 leading to a
feed-forward cycle of growth within the tumors themselves. The studies
of the expression of CXCL12 in these tissues are now under investigation.
In addition, others have shown that bone marrow derived cells express
CXCR4 and are recruited to sites of inflammation. Hence further studies
will be conducted to ascertain the nature of the cells expressing CXCR4
in fibroids. The ultimate goal of these studies is to find novel interventions
which can reduce or abolish disease as a prerequisite for human trials.

Reproductive Sciences Vol. 25, Supplement 1, March 2018
Table of Contents for the Digital Edition of SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018
