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Induction of stein-leventhal-like polycystic ovaries PCO in the ratA new model for cystic ovarian disease.

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THE ANATOMICAL RECORD 228:137-144 (1990)
Induction of Stein- Levent hal-Like Polycy st ic
Ovaries (PCO) in the Rat: A New Model for
Cystic Ovarian Disease
GERALD F. McCARTHY AND JAMES R. BRAWER
Departments of Anatomy, and Obstetrics and Gynecology, McGill University and The
McGill Centre for the Study of Reproduction, Montreal, Quebec, Canada
ABSTRACT
An injection of estradiol valerate (EV) in the rat produces a n
anovulatory polycystic ovarian (PCO) condition. Chronic estrogen exposure, produced by subcutaneously implanted, estradiol (E,)-containing chronic release capsules, results in acyclicity and in hypothalamic changes similar to those seen in the
EV-injected rat. We, therefore, examined the ovarian histology and plasma gonadotropin patterns in the E,-implanted rat and found that this model exhibits a
polycystic ovarian condition and a plasma gonadotropin pattern very different
from those in the EV-treated model. The plasma patterns of LH and FSH are
bimodal consisting of small frequent pulses as well a s less frequent large episodes
of long duration. The ovaries contain multiple small cysts, characterized by a n
extensively hypertrophied theca interna, and vast chords of hypertrophied secondary interstitial cells. In contrast, cystic follicles in EV-treated rats are fewer in
number, but much larger than those in the E,-implanted animals. The cystic theca
and the secondary interstitial cell clusters are also far less extensive in the EVinduced polycystic ovary. These and other differences between the two types of
PCO indicate that they are produced by fundamentally different morphogenic
mechanisms. The cystic ovary produced by the E, implants is similar in appearance to that seen in the human Stein-Leventhal condition, and thus provides a new
model for the study of cystic ovarian disease.
The estradiol valerate (EV)-induced polycystic ovarian condition (PCO) is accompanied by highly specific
abnormalities a t both the hypothalamic and pituitary
level (Brawer et al., 1978, 1980; Wilkinson et al., 1983;
Simard et al., 1987; Carriere et al., 1988). Evidence
suggests that the EV treatment engenders a n intractable defect in the hypothalamic regulation of GnRH
(Simard et al., 1987; Carriere et al., 19881, which then
produces selective secondary impairments in LH release and storage (Simard et al., 1987). This cascade of
hypothalamic and pituitary defects ultimately results
in a unique pattern of plasma LH (Grosser e t al., 1987;
McCarthy et al., 1987,1990; Farookhi et al., 1985; Carriere et al., 1989), to which the ovaries respond by expressing the characteristic polycystic morphology.
Since long term exposure to physiological plasma
concentrations of estradiol (E,) produces histologic
changes in the hypothalamus similar to those caused
by EV treatment (Brawer e t al., 19831, we have now
asked the question as to whether the anovulatory condition in E,-implanted animals resembles the polycystic ovarian condition generated by EV treatment. Accordingly, we have examined the plasma LH and FSH
patterns, as well as ovarian histology, in intact female
rats implanted with E,-containing chronic release capsules. Our results indicate that although the chronic E,
exposure produces persistent vaginal cornification and
anovulatory acyclicity, both the resultant plasma goc
1990 WILEY-LISS, INC
nadotropin patterns and the ovarian histology differ
considerably from those seen in EV-induced PCO.
MATERIALS AND METHODS
Animals and Housing
Young, Wistar female rats (175-200 g) were purchased from Charles River (Canada)Ltd. (St. Constant,
Quebec). They were each given free access to pelleted
rat food and water, and were exposed to 14 h of light
daily (lights on a t 0700 h). Estrous cycles were monitored by daily examination of vaginal smears. Only
those animals that displayed two consecutive normal
4-day cycles were used in the study.
Treatment of Animals
Six animals each received an E,-containing subcutaneous implant ( 2 mm long) made from polydimethylsiloxane (silastic) tubing (0.d. 3.18 mm, i.d. 1.98 mm).
Each E,-filled implant was first implanted (subcutaneously) in host rats and maintained for 1 week. This
Received October 17, 1989; accepted February 1, 1990.
Address reprint requests to Dr. James R. Brawer, Department of
Anatomy, Strathcona Building, McGill University, 3640 University
Street, Montreal, PQ, Canada H3A 2B2.
Dr. McCarthy’s current address IS Montreal Childrens Hospital,
Research Institute, 2300 “upper Street, Montreal, PQ, Canada H3H
1P3.
138
G.F. McCARTHY A N D J.R. RRAWER
procedure allows equilibration of hormone release. The
implants were removed after 1 week and immediately
re-implanted in the six animals comprising the present
experiment. These specifications were selected to
maintain the plasma E, concentration within the physiological range (Brawer et al., 1983; Wilkinson et al.,
1985). Each animal was housed in a separate cage.
Seven weeks after receiving the implants, the animals
were each surgically fitted with a chronic indwelling
atrial catheter using a modification (Grosser et al.,
1987) of the technique previously described by Tannenbaum and Martin (1976). Post-operative care of the animals and the catheters has been described in detail
previously (Grosser et al., 1987).
An additional 15 animals each received a n E,-containing subcutaneous implant (as above). Seven weeks
later, these animals were decapitated and trunk blood
was assayed for estradiol. Trunk blood from 22 normally cycling rats, decapitated a t the same time, was
used to determine the mean normal control plasma E,
concentration. Since the control samples were intended
to establish the normal physiologic range, they were
taken without regard to the stage of the estrous cycle.
Serial Blood Sampling
After a post-operative interval of 1 week, each animal was placed (between 0845 and 0900 h) into a n
isolation cage. A 64 cm length of PE-100 tubing (Clay
Adams, Parsippany, NJ, 0.034 in. in i.d. and 0.060 in.
in 0.d.) was fed into the cage through the bore of a
tightly coiled spring. The spring was held in place by a
pivot a t the top of the cage that permitted the animal
free movement during the sampling procedure.
From 1000 h, 0.5 ml blood samples were drawn
through the sampling line at 10 minute intervals for a
period of 4 h. At each sampling interval, each blood
sample was centrifuged for 2 minutes in a Beckman
Microfuge (15,600g). Two 100 pl plasma aliquots were
removed from this sample and immediately frozen on
dry ice. The remaining blood cells were resuspended in
200 pl of bacteriostatic 0.9% saline, containing 10 IU
heparinlml, and were returned to the animal via the
same sampling line during the next sampling interval.
The two sets of 24 serial plasma samples were stored a t
-80°C for later determination of LH and FSH concentrations.
The plasma gonadotropin patterns characterizing
the EV-induced PCO condition and those occurring a t
normal estrus have been described by us and published
previously (Grosser et al., 1987; McCarthy et al., 1989,
1990; Convery et al., 1990). There is no variation whatsoever in the gonadotropin patterns in EV-treated rats.
Nonetheless, in order to facilitate comparison between
gonadotropin patterns in the two models, a n LH and
FSH pattern from one EV-treated animal is presented.
Hormone Assays
One set of 24 samples per animal was assayed for
LH, while the duplicate set was assayed for FSH. Radioimmunoassay kits were obtained from the National
Pituitary Agency, NIAMDD, Bethesda, MD. The
NIAMDD reference preparations used for the LH and
FSH assays were LH-RP-2 and FSH-RP-1 respectively.
The assay procedures have been described previously
(Grosser et al., 1987).The intraassay coefficient ofvari-
ation in the LH assay at the 20%, 5096, and 80% level
of counts, for a n arbitrary dose relative to that of a zero
dose, (B/Bo) was 4.5%, 6%, and 12% respectively. The
limit of detection for LH was 70 pg. The intraassay
coefficient of variation for the FSH assay was 9.5%, 6%,
and 696, respectively, a t the 20%, 50%, and 80%level of
counts (B/Bo).The limit of detection for FSH was 36 ng.
The estadiol assay has been described previously
(Brawer et al., 1983). The intraassay coefficient of variation a t 35% and 70% level of binding was 3.7% and
21.6% respectively. The assay was capable of detecting
2.4 pg.
Data Analysis
LH and FSH pulses were defined, for the most part,
using the criteria established by Gallo (1981) and later
modified by Ellis and Desjardins (1982). In our pulse
analysis, a n LH or FSH determination and associated
CV was assigned only to the lowest-most point (nadir)
of the ascending phase of a potential pulse. An LH and
FSH value was also assigned to the highest-most point
(peak) of a potential pulse. A pulse was defined when
the peak value was greater than the nadir value plus
two times the CV of the nadir value. The lowest-most
point of the descending limb of a pulse, as long as it
differed from the peak value plus twice its associated
CV, marked the end of a pulse.
Ovarian Histology
Immediately following the sampling procedure, each
animal was killed by decapitation, and the ovaries
were removed, fixed in Bouin’s solution, and embedded
in paraffin. Ten micron thick sections were cut and
stained with hematoxylin and eosin (Brawer et al.,
1986).
Five additional animals were given E, implants (as
above) and 8 weeks later, the ovaries were fixed by
vascular perfusion (Brawer et al., 1989). Blocks of ovarian tissue were then dehydrated in a graded methanol
series and embedded in Epon. The Epon blocks were
trimmed and 1 pm thick sections were cut and stained
with 1%toluidine blue.
Sets of ovaries from ten animals with EV-induced
PCO were prepared by the methods described above to
allow comparisons with the ovaries of the E2-treated
animals. Five sets of ovaries were perfusion fixed and
embedded in Epon, and five were immersed in Bouin’s
solution and embedded in paraffin.
RESULTS
Cyclicity and Mean Plasma E2 Concentration
All animals displayed irregular cycles for 2 weeks
following the placement of the E, implants. By week 3,
however, all animals were acyclic, and exhibited persistent vaginal cornification. This condition continued
throughout the remainder of the experiment. The
mean ( ? SEMI plasma E2 concentration in E2implanted animals was 47.1 t 2.5 pgiml. That in the
controls was 44.0 3.7 pgiml. These values were not
significantly different and thus indicate that the E,implanted animals were chronically exposed to physiological levels of estadiol.
*
139
A NEW RAT MODEL FOR PCO
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TIME (rnin)
Fig. 1. Plasma gonadotropin patterns in E,-implanted rats. Plasma
patterns of LH (left) and FSH (right) for each individual animal displayed. The animal number ( # ) is in the upper left of each graph.
Pulses identified according to criteria detailed in Materials and Methods are indicated by asterisks. Note that the scales for both LH and
FSH patterns of animals #2 and #3 differ from the others.
140
G.F. M(CARTHY AND .J.R. BRAWER
EV -TRE ATE D
TIME ( m i d
Fig. 2. Plasma gonadotropin patterns in an EV-treated rat. Plasma LH (left)and FSH (right) patterns
from a single EV-treated animal are displayed. Defintive pulses are indicated by asterisks. The scale is
identical to those for animals 1, 4, 5, and 6 in Fig. 1.
Plasma LH Pattern
Each of the six animals exhibited a n episodic pattern
of plasma LH. Two general varieties of LH episode
were apparent. One class (Fig. 1,animals 2 and 3) consisted of broad-based episodes of approximately 2 hours
duration. The peaks of these episodes were in the vicinity of 10 ngiml. Secondary pulses of lower amplitude
and duration were identified (according to criteria detailed in the Materials and Methods section) on the
ascending (animals 2 and 3) and descending (animal 2)
limb of the major episode. The second class of LH episode (Fig. 1, animals 1, 4-6) appeared as sharply delineated pulses of relatively short duration (mean
SEM = 43 2 13 min), and low, but variable amplitude
(0.224 0.165 ngiml). Although this pattern in animal
4 remained uniform throughout the sampling period,
both nadirs and peaks (i.e., the baselines) in animals 5
and 6 increased with time. These small, short duration
pulses also occurred prior to, and on the ascending
phases of the large episodes in animals 2 and 3. The
gonadotropin patterns characterizing the EV-induced
polycystic ovarian condition have been reported previously (Grosser et al., 1987; McCarthy et al., 1987,1990;
Convery e t al., 1990). An LH and FSH pattern from a
single EV-treated animal is shown in Fig. 2.
*
*
Plasma FSH Pattern
All animals exhibited a n episodic pattern of plasma
FSH (Fig. 1).As with the LH patterns, those of FSH
exhibited marked variability. In general, types of episodes t h a t characterized the LH patterns were observed for FSH a s well. Despite the general similarity
between the FSH and corresponding LH patterns in
these animals only 60% of FSH peaks coincided with
LH peaks. Similarly, only 60% of LH peaks coincided
with FSH peaks. Peaks were regarded as coincident
when separated by no more than 10 minutes (i.e., one
sampling interval).
Very large FSH episodes of long duration were also
observed in animals 2 and 3. Although the ascending
phases of these episodes coincided with those of the
large LH episodes in the same animals, the FSH episodes exhibited no decline, in contrast to the corresponding LH episodes. The plateaus of the large FSH
episodes exhibited 1 or 2 pulses of lower amplitude and
short duration.
Morphology
The ovaries from E,-treated animals were large and
smooth-surfaced. They contained no corpora lutea and
healthy secondary follicles were rare (Figs. 3, 5). Type
I11 large follicular structures characteristic of polycystic ovaries in EV-treated rats (Brawer et al., 1989; Desjardins and Brawer, 1989) were never observed in ovaries of the E,-implanted animals. Small cystic follicles
were distributed largely in the peripheral cortical region of the ovary. These cysts were considerably
smaller and more numerous than their counterparts in
the ovaries of EV-treated animals (Figs. 3-6). The
cysts in the E,-treated animals were characterized by
a n unusually thick theca interna, comprised of hypertrophied, polygonal cells loaded with lipid ghosts (Figs.
7, 8). This thecal cell layer was 4 to 5 times the thickness of that occurring in cysts of EV-treated animals
(Figs. 5, 6, 8-10]. The membrana granulosa in these
small cysts often consisted of only a single layer of cells
(Fig. 7),although in other cysts, it contained several
layers of degenerating cells (Fig. 8).
In addition to the major differences in appearance
between cysts of EV-treated and E,-treated animals,
the stromal tissue in the two models also differed considerably. In both cases the stroma contained numerous
clusters of secondary interstitial cells. These were, however, far more numerous and extensive in the E,-treated
ovaries than in their EV-treated counterparts (Figs.
3-6). Moreover, the secondary interstitial cell clusters
in the E,-treated animals stained far less intensely and
exhibited a frothy appearance (Figs. 5, 7, 9) reflecting
the fact that the large cells comprising these clusters
were engorged with lipid ghosts. Some secondary interstitial cell clusters exhibited the approximate shape
and size of the small cystic follicles (Fig. 9) suggesting
that these structures derive from collapsed cysts.
DISCUSSION
Although both E,-implanted, and EV-treated
(Grosser et al., 1987; Brawer et al., 1986; McCarthy et
al., 1987) rats develop polycystic ovaries, the plasma
A NEW RAT MODEL FOR PCO
141
Fig. 3. Ten micron thick paraffin section (stained with hematoxylin
and eosin) of a n ovary from E,-implanted animal. Multiple small cystic follicles are distributed mostly in the periphery of the extensive
stroma. x 12.
Fig. 4. Ten micron thick parafin section (stained with hematoxylin
and eosin) of an ovary from an EV-treated animal. Several large cystic follicles are obvious in the section. As in the case of Fig. 2, corpora
lutea are absent and healthy secondary follicles are scarce. Unlike
Fig. 2, stromal tissue is scant. x 12.
pattern of gonadotropins and ovarian histologies differ
markedly in the two cases, indicating that polycystic
ovaries do not define a single disorder, but rather a
general class of conditions encompassing a variety of
individual expressions. The fact that the polycystic
ovaries in both the EV-treated and E,-implanted models resume normal appearance and function following
hemiovariectomy (in the former case) (Farookhi et al.,
1985; Convery et al., 19901, or removal of the E,-containing implant (in the latter case) (unpublished results) suggests t h a t the expression of a particular polycystic ovarian morphology represents the response of
a n essentially normal ovary to a specific abnormal pattern of hormonal stimulation.
Since the present study described a new form of experimentally induced PCO in the rat, the relationship
between the gonadoptropin patterns and the ovarian
histology remains to be ascertained. However, if indeed
the gonadotropin patterns play a n important role in
cystic ovarian conditions, it is not surprising that the
different histologic expressions of cystic ovaries in the
EV- and E,-induced models are associated with correspondingly different patterns of plasma gonadotropins.
Evidence accumulated in our laboratory indicates that
a specific plasma LH pattern is of central importance to
the development and maintenance of polycystic ovaries
in the EV-treated rat (Grosser et al., 1987; McCarthy e t
al., 1990; Convery et al., 1990). We would predict,
therefore, that the singular plasma LH pattern (and
perhaps FSH pattern) observed in the present study is
likewise of causal significance in the histogenesis of
the polycystic ovarian condition unique to the E,-implanted model. This does not, of course, preclude the
possibility that other factors (e.g., intra-ovarian signals) may also contribute to PCO.
Unlike the EV-treated model (Grosser et al., 1987;
McCarthy et al., 1990) the E,-implanted rat exhibits a
complex plasma LH pattern. This pattern is also unlike that characterizing any stage of the normal estrous cycle (Grosser et al., 1987; Gallo, 1981; Fox and
Smith, 1985; Ronnekleiv and Kelly, 1988). The variations in the LH pattern in the E,-implanted rats suggest a bimodal schedule of LH release. One mode would
consist of short, frequent, low amplitude pulses occurring on a very low baseline. This pattern is very similar to that observed in EV-induced PCO (compare
Figs. 1 and 2). This low level of activity appears to be
interrupted a t intervals of 4 to 5 hours, by large LH
bursts, of about 2 hours duration, which would constitute the second mode of release. Although this schema
represents a n interpretation constructed from separate
observations in six animals, i t is the simplest consistent with all of the data. The patterns in animals 1 and
4 reflect the first mode, whereas those in animals 2 and
3 exhibit the second. Animals 5 and 6 display transitions from the first to the second mode.
The FSH patterns exhibit large scale conformity
with the LH patterns, as is evidenced by the similarity
of the shapes of the LH and corresponding FSH graphs
for each animal. The occurrence of definitive FSH
142
G.F. McCARTHY AND J.R. BRAWER
Fig. 5. One micron thick epon section (stained with toluidine blue)
of an ovary from a n E,-implanted animal. A small cyst (C) surrounded
by a massive thecal cell layer appears in the top of the field. Several
follicles (F) occur scattered in the stroma. In the lower right (arrowheads), the extensive stroma, comprised of numerous large clusters of
secondary interstitial cells, has a frothy appearance reflecting the
large amount of lipid contained in these cells. x 100.
Fig. 6. One micron thick Epon section (stained with toluidine blue)
of an ovary from an EV-treated animal. At the top are segments of two
large cystic follicles (C). The stroma consists mostly of connective
tissue in which discrete clusters of secondary interstitial cells are
distributed. One such cluster appears in the section (arrowheads). The
secondary interstitial tissue stains more intensely than that in Fig. 4,
because the cells contain less lipid. x 100.
peaks does not, however, correlate well with those of
LH. This contrasts sharply with the highly synchronous gonadotropin patterns that characterize EV-induced PCO (Grosser et al., 1987).
The most obvious difference between the two types of
PCO, aside from the number and size of the cysts, is the
appearance of the stromal tissues (theca interna and
secondary interstitial cell clusters). These are much
more extensive in the E,-implanted model. Moreover,
the individual cells comprising these compartments
are larger and contain more lipid than their counterparts in the EV-treated rat. The extensive development
of the thecal and secondary interstitial tissues in the
E,-implanted rat may reflect the periodic large plasma
LH episodes characterizing this model, since both of
these cell types express LH receptors (Bortolussi et al.,
1979; Shaha and Greenwald, 1982). Conversely, the
suppressed LH pattern characterizing the EV-treated
rat may explain the sparse stromal development and
relatively modest thecal hypertrophy in this model. We
would predict, on the basis of the gonadotropin patterns as well as on the histological appearance of the
ovaries, that the polycystic ovary in the E,-implanted
rat is far more active in synthesizing androgen than is
its counterpart in the EV-treated model (Hemmings et
al., 1983).
Whatever the causal mechanism, i t is clear that the
histogenesis of the polycystic ovary in the E,-implanted rat follows a different pattern than in the EVtreated animal. A prominent feature of the EV-induced
polycystic ovary is the type I11 large follicular structure
Fig. 7. One micron thick Epon section of a follicular cyst from an
E,-implanted animal. The antrum ( A ) is lined by a single layer of
flattened granulosa cells apposed to the basement membrane. Several
macrophages occur in the lumen. The massive thecal cell layer (asterisk) consists of numerous large polygonal cells crowded with lipid
ghosts. At the right edge of the field are numerous secondary interstitial cells, identical in appearance to the cystic thecal cells. x 275.
Fig. 8. Follicular cyst from an E,-implanted animal (epon section).
This cyst is similar to that in Fig. 4, with the exception that the
antrum is lined by several layers of degenerating granulosa cells.
x 520.
Fig. 9. Secondary interstitial cell cluster in an E,-implanted animal
(epon section). This chord of secondary interstitial cells has the general shape and approximate size of the cystic structures in Figs. 7 and
8, suggesting that it is derived from a collapsed cyst. The large, lipid
filled cells are identical in appearance to cystic thecal cells. x 520.
Fig. 10. Segment of follicular cyst from an EV-injected animal (Epon
section).The antrum ( A ) is lined by a single layer of granulosa cells
(arrowheads),surrounded by a modest thecal cell layer (compare with
Fig. 8 ) . x 520.
A NEW RAT MODEL FOR PCO
Figs. 7-1 0.
143
144
G.F.MrCARTHY AND .J.R. KRAWER
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ACKNOWLEDGMENTS
(PCO) occur in response to a specific pulsatile pattern of luteinThe authors gratefully acknowledge the invaluable
izing hormone (LH).Biol. Reprod., 36(Suppl lJt172 (Abstract).
assistance of Mr. Lorne Aaron (currently a second year Ronnekleiv O.K., and M. Kelly 1988 Plasma prolactin and luteinizing
hormone profiles during the estrous cycle of the female rat: Efmedical student a t McGill) in implanting the capsules
fects of surgically induced persistent estrus. Neuroendocrinology,
and in sampling the animals. We are also grateful to
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Ms. Dalia Chen for the preparation of the ovaries for Shaha C., and G.S. Greenwald 1982 Autoradiographic analysis of
changes in ovarian binding of FSH and hCG during induced folmicroscopy. This work was supported by a n operating
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grant to J.R. Brawer from the Medical Research Coun- Simard
M., J.R. Brawer, and R. Farookhi 1987 An intractable ovarycil of Canada.
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the estradiol valerate-induced polycystic ovarian condition in the
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Brawkr J.R., M. Munoz, and R. Farookhi 1986 Development of the
(Brawer et al., 1989; Desjardins and Brawer, 1989;
Convery et al., 1990). These are exceedingly large follicles that express LH receptors on the membrana
granulosa. We have preliminary data (unpublished)
that these structures are antecedent to precystic and
subsequently, to cystic follicles. No such structure occurs in the ovary of the E,-implanted rat. Given the
similarity in size and shape between the small cysts
and clusters of secondary interstitial cells, and considering that secondary interstitial cell clusters derive
from the hypertrophied theca of atretic follicles
(Erickson et al., 1985), i t seems likely to us that the
follicular cysts in the E,-implanted rat are simply terminally atretic follicles just prior to collapse. The large
number of these structures, possibly recruited by the
large FSH episodes and driven toward atresia by the
large LH episodes, would account for the extensive development of the secondary interstitial cell compartment.
The EV-induced and the E,-induced polycystic ovarian conditions are similar to two expressions of cystic
ovarian disease in the human. The EV-induced polycystic ovary resembles what has been called the multifollicular ovary seen in women with hypothalamic
amenorrhea associated with weight loss (Adams et al.,
1985).The ovaries in these women contain several very
large cystic follicles, and do not exhibit stromal hypertrophy. Interestingly, both human hypothalamic
amenorrhea (Wildt and Leyendecker, 1987; Khoury et
al., 1987) and the EV-induced cystic condition in the
rat (Carriere et al., 1989) are ameliorated by opiatergic
blockade. Moreover, both conditions are also characterized by a suppressed plasma pattern of LH (Grosser e t
al., 1987; Khoury et al., 1987). In contrast, the human
polycystic ovary in the classical Stein-Leventhal syndrome is similar to that in the E,-implanted rat in that
it is enlarged and contains multiple small cysts and a n
extensively hypertrophied stroma (Adams e t al., 1986).
Although much remains to be done in order to characterize the E,-implanted model, we now have, for the
first time, a n experimental system that appears to correspond to the Stein-Leventhal condition. This should
provide us with a n important added dimension in investigating cystic ovarian disease.
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