Effects of Hyperprolactinemia Treatment With The Dopamine Agonist Quinagolide On Endometriotic Lesions in Patients With Endometriosis-Associated Hyperprolactinemia

Effects of hyperprolactinemia treatment with the
dopamine agonist quinagolide on endometriotic

lesions in patients with endometriosis-associated
hyperprolactinemia
Raul Gomez, Ph.D.,a Antonio Abad, M.D.,b Francisco Delgado, Ph.D.,a Silvia Tamarit, M.D.,b
on, M.D.,a and Antonio Pellicer, M.D.a,c
Carlos Sim
a
Instituto Universitario Instituto Valenciano de Infertilidad, Valencia University School of Medicine and (Fundacion)
on Clınico Valencia; b Hospital Universitario Dr. Peset; and c Hospital Universitario La Fe, Valencia, Spain
Investigaci
Objective: To assess whether dopamine receptor 2 agonists reduced the size of peritoneal lesions in women with
endometriosis and elucidate whether affectation of vascular endothelial growth factor (VEGF)/VEGF receptor 2
(VEGFR2)–dependent angiogenesis was mediating the observed effects.
Design: Proof-of-concept study.
Setting: University hospital and a university-affiliated private IVF research center.
Patient(s): Hyperprolactinemic patients (n ¼ 9) with endometriosis requiring a first surgical intervention (L1) and
benefiting from a second-look laparoscopy (L2) were evaluated.
Intervention(s): During L1, four to six peritoneal red lesions were identified. One-half of the lesions were removed
and the remaining one-half were labeled with silk knot sutures. After L1, quinagolide was administered in a titrated
manner (25–75 mg/d) for 18–20 weeks. During L2, the remaining lesions were surgically excised.
Main Outcome Measure(s): Both L1 and L2 were video recorded to compare the effects of quinagolide treatment
on lesion size. Lesions removed at L1 and L2 were compared by means of: 1) histologic analysis; 2) immunohis-
tochemical quantitative analysis of angiogenesis; and 3) quantitative fluorescence polymerase chain reaction array
analysis of 84 chemokines and pro-/antiangiogenic molecules.
Result(s): Quinagolide induced a 69.5% reduction in the size of the lesions, with 35% vanishing completely.
Histologic analysis showed tissue degeneration, which was supported by down-regulation of VEGF/VEGFR2,
three proangiogenic cytokines (CCL2, RUNX1, and AGGF1) and plasminogen activator inhibitor (PAI) 1,
a potent inhibitor of fibrinolysis in the L2 lesions.
Conclusion(s): By interfering with angiogenesis, enhancing fibrinolysis, and reducing inflammation, quinagolide
reduces or eliminates peritoneal endometriotic lesions in women with endometriosis. (Fertil Steril 2011;95:882–8.
2011 by American Society for Reproductive Medicine.)
Key Words: Endometriosis, endometrium, dopamine, dopamine agonists, quinagolide, angiogenesis, dopamine
receptor 2, VEGF, VEGF receptor 2
Current treatment of endometriosis consists of surgical removal of dis- Analysis of endometriotic lesions has demonstrated that a prereq-
eased tissue and/or hormonal manipulation to create a hypoestrogenic uisite for their formation and maintenance is the development of an
milieu (GnRH agonist, aromatase inhibitors) (1). Unfortunately, the adequate blood supply (4). The regulation of the ‘‘endometriotic
success of this treatment is often limited, and recurrence of the disease vasculature’’ involves canonic pathways of angiogenesis, including
is very common (1). Therefore, new approaches to its treatment are vascular endothelial growth factor (VEGF) acting through the
necessary (2, 3). VEGF receptor 2 (VEGFR2) (5).
Several antiangiogenic agents that target this pathway have been
successfully used in animal models of endometriosis (6). However,
Received May 2, 2010; revised September 10, 2010; accepted October these agents can induce severe side effects (7), preventing their use
13, 2010; published online November 5, 2010. for treating endometriosis in young and otherwise healthy women.
R.G. has nothing to disclose. A.A. has nothing to disclose. F.D. has nothing
We theorized that dopamine receptor 2 agonists (Drd2-A) might
to disclose. S.T. has nothing to disclose. C.S. has conducted clinical re-
search sponsored by Ferring. A.P. has conducted clinical research
be an alternative to commercial antiangiogenic agents. In animal
sponsored by Organon, Schering-Plough, Serono, Merck Serono, and models, Drd2-A inhibit pathologic angiogenesis in tumors (8) by
Ferring Pharmaceuticals. inactivating VEGFR2 signaling (9). However, this type of medica-
The first two authors contributed equally to this work. tion has an acceptable safety profile and does not interfere with the
Clinicaltrials.gov identifier: NCT 00625950. normal establishment and progression of pregnancy (10, 11). We
Supported by grant SAF2007–65334 from the Spanish Government, a Lilly previously demonstrated in a well established experimental
Foundation Grant for Research in Clinical Medicine, and Ferring Phar-
endometriosis model that cabergoline prevented the formation of
maceuticals, Copenhagen, Denmark.
Reprint requests: Raul Go mez, Ph.D., Instituto Valenciano de Infertilidad, typical endometriosis lesions by inhibiting angiogenesis (12). These
Plaza de la Policıa Local, 3, 46015, Valencia, Spain (E-mail: apellicer@ results encouraged us to perform a pilot study to evaluate the efficacy
ivi.es). of Drd2-A in the treatment of peritoneal endometriosis in humans.
882 Fertility and Sterility Vol. 95, No. 3, March 1, 2011 0015-0282/$36.00
Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2010.10.024
Downloaded for Gabryel Castro (gabryelcastromaia@hotmail.com) at Centro Universitario Christus Unichristus from ClinicalKey.com by Elsevier on September 27, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
MATERIALS AND METHODS Glostrup, Denmak), Drd2, VEGFR2 (Santa Cruz, Santa Cruz, CA), and
Human Subjects and Study Design VEGFR2Y951, VEGFR2Y1054, and VEGFR2Y1075 (Cell Signaling, Danvers,
MA) for each determination. Slides incubated overnight with the primary
The study was designed as a proof-of-concept pilot study and approved by
antibodies were revealed by using the Dako Kit (Dakocytomation). For
the ETHICS COmmittee of Hospital Universitario Dr. Peset. We were re-
immunofluorescence purposes, directly labeled primary antibodies or
quested to involve only patients newly diagnosed with hyperprolactinemia
tyramide signal–amplification fluorescein (TSA; Perkin Elmer;) instead of
(PRL >30 ng/mL), who were simultaneously suffering from severe endome-
3,30 -diaminobenzidine was used.
triosis in whom a first surgical intervention (L1) was indicated, but the likeli-
hood and benefit of a second-look laparoscopy (L2) was high owing to the
risk of adhesion formation. Informed consents from prospective subjects (n Quantification of Immunohistochemistry
¼ 10) were obtained before their inclusion in the study. Additional inclusion For each immunohistochemical parameter evaluated, three noncontiguous
criteria were: 1) open fallopian tubes; 2) patients not on any other treatment slides were photographed in four random high-power (40) fields with a Ni-
for endometriosis or family planning before or after L1; 3) body mass index kon Eclipse E800 (Nikon, NY) camera and were analyzed using Image-Pro
<22 kg/m2; and 4) at least four red endometriotic lesions located in the cul- Plus 6.3 analysis software to outline, highlight, and quantify stained areas.
de-sac and situated R2 cm away from all other lesions, as diagnosed during
L1. These red lesions were labeled index lesions. L1 and L2 were performed
by two experienced surgeons using modern laparoscopic equipment, and
mRNA Analysis by PCR Superarray of Genes Involved in
were recorded by video. During L1, four to six peritoneal red (index) lesions Inflammation and Angiogenesis
were identified before surgery was initiated. One-half of these index lesions To evaluate how inflammatory and angiogenic pathways were modulated by
were surgically removed and stored as described below. The remaining one- quinagolide, we used a commercially available superarray (PAHS-072E-4;
half were marked with a nonabsorbable silk sutures at a distance of 1 cm. SAB Biosciences, Frederick, MD) containing 84 cytokines, quimoquines,
All nonindex lesions were subsequently removed and discarded. growth factors, and inhibitors of angiogenesis. The cDNAs from L1 and
One week after L1, oral administration of quinagolide (Norprolac; Ferring L2 index lesions were amplified using the ABI Prism 7900 (Perkin Elmer)
Pharmaceuticals, Madrid, Spain) was titrated, starting at 25 mg/d for the first with universal QF-PCR conditions. The final results, expressed as n-fold
15 days, followed by 50 mg/d during the next 15 days and 75 mg/d for the differences normalized to five constitutive housekeeping genes were deter-
remaining treatment period of 18–20 weeks, to avoid intolerance to the mined by the 2DDCt method using specific software form SAB Bioscience.
medication.
During the 4-month treatment period (i.e., between L1 and L2), patients Statistical Analysis
were monitored on a monthly basis to assess the severity of the side effects
Statistical analysis was carried out using the Statistical Package for Social
of Drd2-A, which include dizziness, nausea, and vomiting (13). During these
Sciences (SPSS, Chicago, IL). Data were expressed as mean SD. A Wil-
visits, blood was drawn for subsequent enzyme-linked immunosorbent assay
coxon matched pairs test was used to determine differences in lesion size
measurement of serum PRL, a marker of the level of Drd2 activity, to monitor
and PRL levels. A Mann-Whitney test was used for quantitative analysis
compliance with taking the medication.
of immunohistochemistry. Significance was defined to be P<.05.
When treatment had terminated, L2 was performed and video recorded.
During surgery, the silk sutures were removed and the index lesions that
had been untouched in L1 were surgically excised. If significant adhesion for- RESULTS
mation was detected, lysis of adhesion was performed. The index lesions Compliance with Taking Medication and Side Effects
removed at L1 and L2 were fixed in formalin (75% of each lesion tissue) Lowered PRL levels 1 month after initiation of quinagolide treatment
for histologic analysis and immunohistochemical quantification of vascular-
and subsequent maintenance below baseline levels (<20 ng/mL) pro-
ization, vessel immaturity, Drd2 expression, cell proliferation, VEGFR2
vided evidence that patients were taking the medication as prescribed
expression, and VEGFR2 activation. The remaining portion of each lesion
tissue (25%) was homogenized in Trizol and cryopreserved at 80 C for (Supplemental Fig. 1, available online). No major complications were
subsequent superarray quantitative fluorescence polymerase chain reaction detected except for one patient who discontinued her participation
analysis (QF-PCR). in the study owing to vomiting when the dose of quinagolide was
In addition, during both L1 and L2, endometrial tissue was obtained to increased to 75 mg/kg/d.
confirm the proliferative phase of the menstrual cycle by histologic methods.
Macroscopic Appearance and Surface Area of
Macroscopic Analysis Endometriotic Lesions
All laparoscopies were recorded with a Karl Storz (Munich, Germany) video All index endometriotic lesions removed during L1 and those left
camera. Video recordings were displayed to find illustrative frames of a blunt untouched and recovered during L2 had a red appearance. In two
metal probe with black/gray cap of known size, in perpendicular position in of the nine patients, all index endometriotic lesions were absent
relation to the lesion. Eligible frames were captured and opened with Image- during L2 (Figs. 1A–1D), suggesting that quinagolide induced
Pro Plus version 6.03 (Media Cybernetics, Bethesda, MD) software for regression of peritoneal endometriotic lesions. Indeed, in three
image processing. The size of the black/gray cap served as a reference for patients some lesions vanished and those that persisted decreased
measuring at L2 the changes in size induced by quinagolide on the area of
in size (Figs. 1E and 1F). In the remaining four patients, despite
the lesions left untouched during L1.
all of the index lesions persisting at L2, they had all shrunk in
size. Of a total of 23 red index lesions labelled at L1, eight vanished
Morphologic Studies and only 15 were recovered at L2, of which one was larger, one un-
Tissue samples of active endometriotic lesions were evaluated for histologic changed, and the remaining 13 smaller in size than in L1 (Fig. 2A).
hallmarks, including the presence and appearance of glands and stroma, by mi- Assuming that vanished lesions represent a 100% decrease in size,
croscopic analysis of hematoxylin and eosin–stained sections from L1 and L2. quinagolide reduced the surface area of index lesions by 69.5%
(Fig. 2B)
Immunohistochemistry/Immunofluorescence of L1 and L2
Lesions Histologic Appearance
Standard immunohistochemistry was performed using specific primary Index lesions surgically removed during L1 exhibited histologic
antibodies to CD31 (Abcam, Cambridge, UK), Ki-67 (Dakocytomation, characteristics typical of peritoneal endometriosis: Glandular tissue
Fertility and Sterility 883
FIGURE 1
The effect of quinagolide treatment on lesion size in three different patients (A-B, C-D, and E-F). Images in the first column show index lesions
left untouched during first laparoscopy (L1). Images in the right column show the appearance of the same index lesions during second-look
laparoscopy (L2) after quinagolide administration. The corresponding index lesions or the place where lesions were expected to be found
during L2 have also been circled. White arrows point to original L1 lesions which had vanished at L2. Black arrow points to a lesion originally
labelled during L1 and whose size has been reduced. Paired images A-B and C-D show two cases in which all index endometriotic samples
disappeared after quinagolide treatment. Paired images E-F show a case in which lesions had either vanished or been reduced in size after
quinagolide treatment. Blue arrowhead in F points to a silk suture marking an index lesion left untouched during L1.
G
omez. Effects of quinagolide on endometriotic lesions. Fertil Steril 2011.
was often circular, with a hollow center with glandular secretions, 3J). Signals obtained for VEGFR2-Tyr1054 and VEGFR2-
and the stroma was highly organized with clearly visible fibroblasts Tyr1212 were extremely faint and were not quantified. The reduc-
and noncellular stroma filling the intercellular space. After quinago- tion in phsosphorylation of VEGFR2-Tyr 951 paralleled that
lide administration, the typical highly organized gland/stroma pat- observed for VEGFR2 (almost 50%). Therefore, it is likely that the
tern had disappeared, with the matrix of the stroma becoming decreased VEGFR2 phosphorylation was due to reduced VEGFR2
looser and less cellular, thus indicating that a process of tissue re- expression.
gression had been initiated (Figs. 3A–3D).
PCR Array in Endometriotic Lesions
Immunohistochemical Evaluation To assess the pattern of angiogenic and inflammatory pathways
Comparison of L1 and L2 lesions showed no difference in vascular modulated by Drd2 activation, we performed a PCR superarray
density (Figs. 3E and 3F), quantity of immature vessels, or cell pro- with 16 (L1 ¼ 9; L2 ¼ 7) pooled (per patient) endometriotic
liferation (data not shown). Drd2 staining was found to be spotty and cDNA index lesion samples. Statistical analyses showed significant
up-regulated by quinagolide treatment (Figs. 3G and 3H). Surpris- (P<.05) up-regulation of Serpine 1, CCL2, VEGF, AGGF1, and
ingly, Drd2 staining was absent in vessel structures. The density RUNX1 and down-regulation of CXCL10 genes (Table 1) by
of VEGFR2 was reduced by twofold in L2 lesions (Figs. 3I and quinagolide.
884 Gomez et al. Effects of quinagolide on endometriotic lesions Vol. 95, No. 3, March 1, 2011
FIGURE 2
Image-Pro Plus software size measurements of the same endometriotic lesion during the first (L1) and second (L2; after 4 months of
quinagolide therapy) laparoscopies. Lesion size area is expressed in mm2. (A) Each of the lesions analyzed during the study period is
represented by a case (‘‘serie’’) number. Note that all but two endometriotic lesions undergo a reduction in size or disappear (value 0) after
quinagolide treatment. A Wilcoxon paired test was used for statistical comparison: *P< .05. (B) Hatched bar represents mean SD surface
area of index lesions left untouched and video recorded during L1. Bricked bar represents mean SD surface area of the same (paired) index
lesions after 4 months of quinagolide treatment (L2). Note an overall 69.5% decrease in lesion size after quinagolide treatment. A Mann
Whitney test was used for statistical comparison, *P< .05.
A 100 Lesion size before and after quinagolide treatment Serie1

Serie2
Serie3
90 Serie4
Serie5
80 Serie6
Individual lesion area in mm2
Serie7
70 Serie8
Serie9
60 Serie10
* Serie11
50 Serie12
Serie13
40 Serie14
Serie15
30 Serie16
Serie17
20 Serie18
Serie19
10 Serie20
Serie21
0 Serie22
L1 L2 Serie23
lesion size before and after quinagolide treatment

B 60
50
40
Mean lesion area in mm2
30
*
20
10
L1 L2
G
DISCUSSION time that peritoneal endometriotic lesions in humans decrease in

Recently we showed for the first time that Drd2-A prevented ovarian size or disappear when exposed to prolonged treatment with the
hyperstimulaton syndrome in women (14, 15) by blocking VEGFR- Drd2-A quinagolide. Histologic evaluation suggested that quinago-
2–mediated vascular permeability (16). Herein we show for the first lide induced tissue degeneration of endometriotic lesions. In areas
FIGURE 3
(A–D) Histologic analysis of index lesions obtained during first (L1) and second (L2) laparoscopies. Intermediate-power (20) representative
images of index red lesions obtained during L1 (A) and L2 (B). Morphological analysis confirms glandular (purple) presence of endometrium
surrounded by dried blood (redish color) typical of red lesions. High-power magnification of L1 untreated (C) and L2 quinagolide-treated (D)
index red lesions. Endometriotic lesions in L1 show a typical high cellular stroma and glands well defined and surrounded by peritoneal tissue.
In L2 lesions, a lax stroma is observed with a nonprominent glandular epithelium suggesting an atropic or degenerative status of tissue (B).
(E–L) Representative paired images of immunohistochemical analysis in index endometritic lesions removed before (L1; left column) and left
behind and recovered after (L2; middle column) quinagolide treatment.. Vascularizaton (vessel density) was assayed by immunostaining
against CD31 antigen (brown color) in blood vessels (E, F). Repesentative images (G, H) of dopamine receptor 2 (Drd2; brown staining). Note
the significant increase in brown staining after quinagolide treatment in H vs. G. Broad expression of vascular endothelial growth factor
receptor 2 (VEGFR2) (I, J) staining (brown staining) was detected in both untreated and treated lesions. A slight decrease in VEGFR2 levels is
observed in treated vs. untreated lesion. An antibody recognizing VEGFR2 specifically phosphorylated at tyrosine site 951 reveals faint
antigen expression (brown color) before (K) and after (L) quinagolide treatment. The right column shows corresponding quantitative analyses
of the stained areas in the row pair. Positive-stained area for each immunohistochemical parameter was outlined by setting a background
noise level automatically with Image-Pro Plus. Area of interest was subsequently highlighted, quantified, compared with the total tissue, and
expressed as percentage stained area. Results represent the ratio of stained/total area multiplied by 100. A Mann-Whitney test was used for
comparisions, *P< .05.
G
immune system and where human endometrial vessels are replaced
TABLE 1 by host endothelial cells.
Statistical analysis using SAB Bioscience software to Endometriotic lesions contain mature vessels not expected to be
identify genes significantly deregulated by quinagolide in susceptible to the antiproliferative effects of antiangiogenic therapy,
cDNA from L1 and L2 index endometriotic samples after so additional effects must be exerted by quinagolide to induce
quantitative fluorescence polymerase chain reaction shrinking and vanishing of peritoneal lesions. Recent studies suggest
amplification using superarray (PAHS-072E-4) plates. that even mature endometriotic vessels are somehow different to
those present in the eutopic endometrium, and thus can be selec-
P value vs. Fold regulation tively disrupted by targeting aberrantly expressed tissue factor in
Symbol control vs. control their endothelium (20). Because endometriotic vessels lacked
Drd2, a hypothetical selective disruption of pathologic mature ves-
SERPINE1 .03254a 19.8491
AGGF1 .0376a 3.1954
sels by quinagolide would be mediated by paracrine mechanisms.
CCL2 .04389a 6.1199 Most immune cell subtypes express Drd2 (21), and among these,
VEGF .04428a 5.8199 macrophages are known to express large amounts of VEGF (6). Drd2
CCL10 .04770a 6.7693 activation decreases VEGF production (22) and VEGF-mediated
RUNX1 .04901a 4.3878 angiogenesis (8), and the ability of macrophages to reduce angiogen-
CXCL12 .08206 3.3952 esis when activated by dopamine has recently been described (23).
BTG1 .086207 3.3776 Therefore, we suggest that the paracrine cross-talk between Drd2
FST .10483 3.0136 and the VEGF/VEGFR2 system and the additional effects exerted
RHOB .12902 1.7303 by quinagolide in the present study may be mediated by macro-
FGFBP1 .15187 3.0283
phages. In this regard, Drd2 activation in macrophages is known to
FGF1 .165346 2.5955
SERPINF1 .183201 1.9339
increase their phagocytic activity (24). In addition, our PCR arrays
STAB .19273 5.4869 revealed that PAI-1, a potent inhibitor of fibrinolysis, was the most
down-regulated gene in L2 lesions. Therefore, we hypothesize
Note: The table shows a list of the 14 genes most likely to be deregu- that, by promoting selective fibronolytic activity, macrophages
lated among the 84 angiogenic and inflammatory citokines included
in the kit. Gene candidates are sorted according to their P values
destabilize the peritoneal lesions scaffolding when activated by
(middle column). A lower P value indicates a higher probability that quinagolide.
the deregulaton observed is not due to random variation. The right The composition of peritoneal fluid (25) and endometriotic lesions
column shows the down-regulation (negative values) and up- (26) suggests that inflammatory pathways involving macrophages are
regulation (positive values) of genes in L2 (quinagolide-treated index
highly up-regulated during endometriosis. A role for inflammatory
lesion) vs L1 (index lesions not treated with quinagolide).
a
P< .05. angiogenesis is supported by our finding that the cytokine
CXCL10, a potent antiangiogenic regulator (27), was up-regulated
G
by quinagolide. In addition, we also found that three proangiogenic
cytokines (CCL2, RUNX1 and AGGF1 (28–30) and VEGF (25),
also a potent chemoattractor (31)) were down-regulated in L2 lesions.
This body of evidence suggests that a major mechanism of action of
where the lesions had disappeared, the normal peritoneal tissue quinagolide consists of reverting a proangiogenic environment
organisation had been reestablished. associated with untreated lesions into an antiangiogenic/inflammatory
Endometriosis is a progressive disease (17) which deteriorates environment by affecting the inflammatory process.
significantly over a short period of time in R50% of patients (18). Because their different mechanism of action, Drd2-A are not ex-
In the absence of medical intervention, mature endometriotic lesions pected to interfere with the menstrual cycle, offering an important
such as those identified in the present study are expected to increase advantage over medication such as GnRH agonists and aromatase
or maintain their size over a 6-month period (18). Therefore, inhibitors, which induce osteoporosis and hot flashes by creating
medication-naive endometriotic lesions removed during L1 are a hypoestrogenic milieu (32, 33), in the treatment of women who
comparable to hypothetically placebo-exposed lesions removed are infertile due to the disease. Nevertheless, in vitro experiments
during L2. Given that this was a proof-of-concept study, the nine pa- showed that cabergoline blocks P4 production by granulose cells,
tients eventually included were sufficient for achieving its goal and suggesting that Drd2-A might exert an aromatase inhibitory action
will serve as groundwork for a larger clinical trial. (34). Moreover, PRL deprivation may affect reproductive functions
Based on findings in animal models (9, 12, 16), we expected that by inhibiting intermittent GnRH (35). Thus, by affecting the
quinagolide would up-regulate Drd2 in endothelial cells, leading to hypothalamic-pituitary axis, Drd2-A might influence endometriotic
decreased VEGFR2 phosphorylation in an autocrine fashion, lesions by mechanisms other than the ones suggested in the present
thereby reducing vessel proliferation and density. Indeed, quinago- study.
lide increased Drd2 expression and decreased VEGF/VEGFR2 Despite the good safety profile of Drd2-A, as has been demon-
expression, but it did not reduce vessel density in L2 lesions. We strated in women treated for prolactinomas (36), potential side
do not rule out that, by taking place in vanished/regressed tissue, effects should be reduced by using alternative routes of administra-
the antiangiogenic actions exerted by Drd2-A might have been tion, such as vaginal delivery of the drug. In the future, a combination
masked. In fact a very recent report on the successful treatment of of drugs can be the treatment of choice in endometriosis patients.
rectal endometriosis (19) supports our hypothesis that Drd2-A Quinagolide is a nonergot-derived Drd2-A which lacks an effect
manifests its antiangiogenic effect by acting via VEGFR2. on the serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 2b
We speculate that the effects of quinagolide on ectopic lesion size at relevant concentrations. This may be clinically important,
may be mediated by different molecular mechanisms from those because stimulation of 5-HT2b receptors in cardiac valve tissue
suggested by our heterologous nude mice model (12), who lack an can lead to proliferation of fibroblasts (37). Drd2-A are also
differentiated by their pharmacokinetic profile; quinagolide has lesions, causing some to completely disappear. The long-term side
a much shorter half-life (17 hours) than Cb2 (63–69 hours) effect profile of dopamine agonists is favorable over the antisteroido-
(38), thus minimizing exposure during organogenesis in women genic agents. Before adding this very promising type of medication
who may wish to become pregnant. to the armamentarium for the treatment of endometriosis, larger clin-
In summary, this is the first study in humans that shows unequiv- ical trials need to be conducted to confirm our results and investigate
ocally that the Drd2-A quinagolide reverses the size of endometriotic in more depth its mechanism of action.
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SUPPLEMENTAL FIGURE 1
Prolactin levels as measured by enzyme-linked immunoassay in
blood serum obtained from our nine parients at different time
points during the quinagolide treatment. Patients started daily
quinagolide administration 1 week after surgery (QX) and
continued for 4 months. Pre-QX ¼ blood samples taken with first
laparoscopy just before starting the quinagolide treatment.
Post-Qx 1 month ¼ blood samples taken during the first monthly
visit after 1 month of quinagolide administration. Post-QX 3
months ¼ blood samples taken during the third monthly visit after
3 months of quinagolide administration. Prolactin levels were
found to be <20 ng/mL in all cases after 1 month of quinagolide
treatment and continued below that baseline during treatment.
Wilcoxon paired test was for statiscal comparision: ** P< .01
compared with Pre-QX.
G
Fertility and Sterility 888.e1

Effects of Hyperprolactinemia Treatment With The Dopamine Agonist Quinagolide On Endometriotic Lesions in Patients With Endometriosis-Associated Hyperprolactinemia

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Effects of Hyperprolactinemia Treatment With The Dopamine Agonist Quinagolide On Endometriotic Lesions in Patients With Endometriosis-Associated Hyperprolactinemia

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Effects of hyperprolactinemia treatment with the

dopamine agonist quinagolide on endometriotic

Fertility and Sterility 883

A 100 Lesion size before and after quinagolide treatment Serie1

lesion size before and after quinagolide treatment

DISCUSSION time that peritoneal endometriotic lesions in humans decrease in

Fertility and Sterility 885

Fertility and Sterility 887

Fertility and Sterility 888.e1

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