BIOLOGY OF REPRODUCTION 45, 411-416 (1991)

411

Prevalence and Laparoscopic Appearance of Spontaneous Endometriosis in the Baboon

(Paplo anubis, Papio cynocephalus)1

T. M. D’HOOGHE,2’3 C. S. BAMBRA,4 F. J. CORNILLIE,3 M. ISAHAKIA,4 and P. R KONINCKX3

Department of Obstetrics and Gynecology,3 UZ Gasthiasberg (KU Leuven), B-3000 Leuven, Belgium

Institute of Primate Research,4 Department of Reproduction, Karen, Nairobi, Kenya

ABSTRACT

The prevalence of spontaneous endometriosis was investigated by laparoscopy in 52 baboons (Papio anubis and Papio cy-

nocephalus) of proven fertility. Clinical endometriosis was diagnosed in 9 (17%) and 4 (8%) baboons with or without a previous

hysterotomy, respectively. Endometriosis was confirmed by histology in 75% of these animals. The 37 endomethotic lesions

were classified as typical (13%), subtle (57%), or suspicious (30%); and the percentage of histological confirmation was 100%,

61%, and 50%, respectively. Lesions were found on the uterosacral ligaments and in Douglas’ pouch (46%), on the uterine

peritoneum and the uterovesical fold (38%), and on uterine-omental adhesions (11%). Only 5% of the lesions were localized

on the ovarian Ligament, whereas ovarian endometriosis was not found. This study for the first time demonstrates that spontaneous

endomethosis occurs in healthy baboons with proven fertffity. It also shows that the laparoscopic appearances, the histological

aspect, and the localization of the pelvic lesions are comparable to those found in women. We therefore conclude that the baboon

is a good animal model for the study of endometriosis.

INTRODUCTION

Endometriosis is a common and important gynecologi-

cal disease. The diagnosis is made during laparoscopy and

confirmed by histology. The reported prevalence of en-.

dometriosis varies from 1 to 50% [1]. It depends mainly on

the surgeon’s awareness of all types of lesions [2] and on

the symptoms of the patients selected to undergo surgery.

The highest prevalence, up to 90% [3], can be found in

women with infertility and/or chronic pain. In asympto-

matic women undergoing tubal ligation, percentages of 2

[4] and 7.5 [51 have been reported. This is probably the best

possible estimation of the prevalence of endometriosis in

the general population.

The etiology and the physiopathology of endometriosis

are not well understood. No current hypothesis can explain

all its localizations. The spontaneous evolution of endo-

metriosis is also poorly understood. Redwine [61 found that

endometriosis does not involve more pelvic areas in older

age groups. In a prospective study of 17 placebo-treated

infertile women with asymptomatic endometriosis, second-

look laparoscopy after 6 mo showed elimination, improve-

ment, and deterioration of the visual endometriosis in 23%,

29%, and 47% respectively [7].

The lack of a useful nonprimate animal model probably

explains the discrepancy between the high frequency and

serious health problems of endometriosis, and our poor

knowledge of etiology, physiopathology, and long-term

Accepted May 13, 1991.

Received December 5, 1990.‘Supported by the Commission of the European Communities (DG VIII Devel-

opment and DG XII Science, Research and Development) and by the VLIR (FlemishInteruniversity Council).

‘Correspondence and current address: Dr. T.M. D’Hooghe, Institute of Primate

Research, P.O. Box 24481, KAREN, NAIROBI, KENYA.

spontaneous evolution of this enigmatic disease. Sponta-

neous endometriosis has been described in the rhesus

monkey [8], the pigtailed macaque [9], and the cynomolgus

[10], and the De Brazza monkeys [11]. Case reports of min-

imal [121 and disseminated [13] endometriosis in the ba-

boon have been published. Most cases of spontaneous en-

dometriosis in primates have been diagnosed in post-mortem

studies or during a laparotomy, performed because of poor

condition of the animal [14-16]. Therefore, this study was

undertaken to evaluate the prevalence and laparoscopic ap-

pearance of spontaneous endometriosis in a baboon col-

ony.

Animals

MATERIALS AND METHODS

Diagnostic laparoscopies were performed in 52 healthy

adult female baboons (47 olive baboons- Papio anubis-

and 5 yellow baboons-Papio cynocephalus) housed at the

Institute of Primate Research (IPR), Nairobi, Kenya. These

animals had been captured in the wild and had been preg-

nant at least once. Fifteen baboons had subsequently be-

come pregnant in captivity. Fourteen of them had under-

gone at least one hysterotomy for early embryo recovery

on Day 33 of the pregnancy. Their previous history also

contained at least one nonsurgical uterine flush for early

embryo recovery (12 cases) and at least one laparotomy for

uterine needle puncture (5 cases). The mean weight of the

olive baboons (n = 47) and of the yellow baboons (n =

5) was 12.8 ± 2.1 and 13.4 ± 1.2 kg, respectively. They had

been at IPR for 2.6 ± 2.7 and 4 yr, respectively, and were

properly housed and fed in either group cages or single

cages. The animal health care was in accordance with the

IPR Guide for Care and Use of Laboratory Animals, which

has been adapted from the National Institutes of Health Guide

412 D’HOOGHE ET AL.

[17]. Additionally, the study protocol was reviewed and ap-

proved by the Institution Scientific Resources Evaluation and

Research Committee.

Menstrual Cycle

Menstrual cycle length was determined from the first day

of overt menstrual flow (Day 1) to the onset of the next

bleeding. The average length of 33 days [18] is comparable

to the mean cycle length of the screened baboons during

the 6 mo preceding laparascopy: 35.1 ± 4.1 days. Perineal

cycle length is determined by counting from the first day

of perineal turgescence of one cycle up to the onset of per-

meal turgescence in the following cycle. The cyclic perineal

changes were examined daily by two technicians, each ob-

serving the perineum from opposite sides of the cage, andwere noted on a breeding chart kept for each female, using

a numerical grade point system [18]. During stage 0, the

perineum is at rest (deflated), and has many wrinkles and

a pinkish color. Stage 1 begins when the perineal area starts

to swell; the wrinkles disappear and the color becomes more

red. Stages 2 and 3 are transition stages of increasing in-

flation, leading to stage 4 with maximal perineal inflation.

At stage 5, a further increase in turgescence is observed.

Stage 6 begins when the perineal area starts to deflate and

ends in Stage 7, menstruation. Stage 8, pregnancy, is similar

to stage 0, but the color of perineum and buttocks turns

more reddish [181. The turgescent and deturgescent phases

of the perineal cycle described above approximate the fol-

licular and luteal ovarian phases, respectively. The length

of the turgescent phase is about 17 days and of the detur-

gescent phase about 16 days. Menstruation begins approx-

imately 2-4 days before the onset of perineal turgescence

and lasts about 2-5 days [18]. In the screened baboons,

menstruation lasted 3.0 ± 1.2 days during the 6 mo before

laparoscopy. Laparoscopies were done at random during

the cycle. Twelve laparoscopies were done during the fol-

licular phase (perineal stages 1, 2, and 3). Six laparoscopies

were performed during the mid-cycle (perineal stages 4 and

5). During the luteal phase (perineal stages 6 and 0), 24

baboons underwent laparoscopy. Laparoscopies were done

in 6 and 4 animals during menstruation (perineal stage 7)

and pregnancy (perineal stage 8), respectively.

Laparoscopy

A mixture of 7 ml ketamine (100 mg/ml) and 3 ml xy-

lazine (2% solution) was given i.m. (0.1 ml/kg body weight).

The baboon fell asleep 3-5 mm after the injection, was

shaved abdominally, transported to the surgery, and intu-

bated; full inhalation anesthesia was given with a mixture

of N20/02 (70% /30%) with 1-2% halothane. Duration of

the anesthesia and actual laparoscopy were 50 ± 25 mm

and 40 ± 20 mm, respectively.

A bladder catheter and a speculum were inserted with

the animal in the genupectoral position. The uterus was

probed in the 4 pregnant animals for early embryo recov-

ery by uterine flush and in the first 11 cases. Because this

was difficult, the uterus was not probed in the other 37

baboons. The baboons were then placed in the lithotomy

position with a 20-degree Trendelenburg’s position. The

abdomen was disinfected with isobetadine, and sterile drapes

were put around the abdomen. A Verress needle was in-

serted through a small subumbilical incision, and the ab-

domen was mnsufflated with CO2 (1-2 L/min). After exten-

sion of the incision, an operative laparoscope (diameter 11

mm, Storz, Tuttlingen, Germany) was inserted through a

trocart and connected with a cold light fountain. Following

the insertion of 2 trocarts (diameter 5.5 mm) on the left

and right suprapubic sides, systematic inspection of the ab-

dominal cavity was performed. The subumbilical incision

was closed with Vicryl 2/0 in two layers (peritoneum +

fascia with interrupted stitches, skin with continous suture).

The two suprapubic incisions were closed with one stitch.

After extubation, the baboon was kept in a single cage for

further observation during the next 7 days. If general con-

dition and wound healing were normal, the baboon was

subsequently brought back to her group cage.

Endometriosis Screening

All laparoscopies were performed by a qualified gyne-

cologist, trained specifically in the recognition of pelvic en-

dometriosis at the University of Leuven, Leuven, Belgium.

After the omentum and the intestine were pushed down-

ward, the peritoneal fluid was aspirated and its volume was

measured. The internal genitalia and pelvic peritoneum were

screened for clinical endometriosis (the presence of typical

and/or subtle lesions). Typical lesions were defined as white

plaques containing pigmented spots, or as blue cysts. Sub-

tle lesions were defined as white plaques with or without

vesicles or as (un)pigmented vesicles (white, red, blue-black)

only. Orange zones and red spots with irregular blood ves-

sel patterns were considered suspicious lesions. All lesions

were photographed, and 20 were biopsied with a biopsy

forceps. The biopsies were fixed in a 10% phosphate-buff-

ered formalmn solution and embedded in paraffIn, and 4-p.

sections were stained with hematoxylmn and eosin. Endo-

metriosis was diagnosed when endometrial-like glands to-

gether with stroma were present.

Statistics

Means and standard deviations are indicated unless stated

otherwise. Statistical significance was evaluated with the SM

package [19] using Student’s t-test and Fisher’s Exact Test.

An ANOVA with a multiple-mean test was used for the sta-

tistical analysis of the peritoneal fluid volumes.

Laparoscopy in Baboons

RESULTS

Baboon pelvic anatomy. Apart from some minor dif-

ferences, the pelvic anatomy of the baboon was essentially

SPONTANEOUS ENDOMETRIOSIS IN BABOONS 413

*p < 0.001.

TABLE 1. Ovarian follicles, corpora lutea, ovulation stigmata, and volume of peritoneal fluid during the menstrualcycle (mean ± SD).

Perinealstage

Ovarian cyclephase Animals

Ovarian

follicle

Corpus

luteumOvulation

stigmaPeritoneal

fluid (ml)

Turgescent(stages 1-3)

Turgescent

(stages 4-5)

Deturgescent

(stage 6) or

flat (stage 0)Stage 7

Stage 8

follicular

mid-cycle

luteal

menstruation

pregnancy

12

6

24

6

4

4

-

2

-

-

1

4

11

5

3

1

2

2

1

0

1.2 ± 1.5

(range: 0-5)

2.4 ± 2.9(range: 0-8)

1.8 ± 1.7

(range: 0-6)

2.1 ± 1.6

(range: 0-4)

0.2 ± 0.5

(range: 0-1)

*F = 1.23; p > 0.1.

comparable to that of the human. In the baboon, the omen-

tum was thinner, stickier and more velamentous than in the

human, and contained many blood vessels. The uterus was

found to be in retro position (Trendelenburg’s position 25

degrees). The corpus uteri was very soft on palpation, com-

pared to the harder cervix and to the human uterus. The

uterus and ovaries were more mobile than in the human.

The infundibulopelvic ligament was covered by extensive

fatty adhesions around the ovary. These were part of the

normal anatomy and should not be interpreted as postin-

fectious adhesions. The oviducts (diameter 4-5 mm) were

thinner than the concomitant large veins of the utero-ovar-

ian plexus. The parietal peritoneum was shiny and had a

remarkable lack of fat tissue. The blood vessel pattern was

evident and could be inspected in detail.

Pbysiological phenomena during the baboon cycle (Ta-

ble 1). Through the smooth white capsule of the ovaries,

maturing follicles, corpora lutea, ovulation stigmata, and

corpora albicantia were clearly seen at laparoscopy during

several stages of the cycle (Table 1). Corpora lutea were

present throughout the cycle, but their size was larger dur-

ing the luteal phase and further increased during early

pregnancy. The mean volume of peritoneal fluid fluctuated

between 0 and at least 4 ml throughout the cycle. It ap-

peared to be maximal during the mid-cycle and the luteal

phase, but this was not statistically significant (p > 0.1; Ta-

ble 1). Bilateral retrograde menstruation was observed in

2 of the 6 animals that underwent laparoscopy during stage

7 on the first day of menstruation.

Spontaneous Endometriosis

Clinical endometriosis (Table 2). Clinical endometri-

osis was found in 25% of the screened baboons (Table 2)

and confirmed by histology in 75%. The prevalence of en-

dometriosis was higher in animals with a history of pre-

vious hysterotomy: 9 of 13 (69%) of the baboons with clin-

ical endometriosis had undergone at least one hysterotomy

in the past, compared to 5 of 33 (15%) of the baboons with

normal internal genitalia (p < 0.001). The mean number

of previous hysterotomies and uterine needle punctures in

baboons with clinical endometriosis and with normal in-

ternal genitalia was 1.5 ± 1.8 and 0.4 ± 1.2 respectively (p

< 0.001). Clinical endometriosis was found in 3 of the 4

baboons (all with previous hysterotomy) that underwent la-

parascopy during the cycle of conception. Six baboons were

found to have suspicious lesions only, containing histolog-

ical endometriosis in 1 of 3 baboons assessed by pathology

(Table 2).

A peritoneal pocket was found in 2 baboons with clinical

endomethosis, in one baboon with a suspicious lesion only,

and in another baboon without laparoscopic evidence of

endometriosis.

Dense pelvic adhesions were present in 13 of 14 ba-

boons after previous laparotomy for hysterotomy or uter-

ine needle puncture. Only 2 baboons of 38 without pre-

vious uterine surgery had adhesions in Douglas’ pouch (p

<0.001).Laparoscopic appearance, histology, and localization of

the endometriotic lesions (Table 3). In 19 of 52 animals,

TABLE 2. Prevalence of spontaneous end ometriosis in 5 2 baboons.

n = 52

Histological

endometriosis

Previous hysterotomy

No (n = 38) Yes In = 14)

Baboons with clinical endometriosis 13 9/12 4 9

Baboons with suspicious lesions only 6 1/3 6 0

Baboons without endometriosis 33 - 28 5

414 D’HOOGHE ET AL.

TABLE 3. Laparoscopic appearance, histological confirmation, and localization of the endometriotic lesions.

No. of implants!

Localizatio n of implants

Uterosacral Uterine

no. of biopsies ligaments! peritoneum Uterine-1% confirmed Douglas’ pouch posterior/anterior Uterovesical omental Ovarian

Totals

by histology) (Total) (Total) fold adhesion ligament

37/20 (65%) 14/3(17) 7/3(10) 4 4 2

Laparoscopic appearance

I. Typical lesions 5/3 (100%) 3/0 (3) 0 0 1 1

White plaque with 3/2 (100%) 2/0 (2) 0 0 1 0

pigmented spotsBlue cyst 2/1 (100%) 1/0 (1) 0 0 1 0

II. Subtle lesions 21/13 (61%) 6/2 (8) 4/3 (7) 2 3 1

White plaque with 7/4 (50%) 2/1 (3) 2/0 (2) 0 2 0

or without vesiclesVesicles only:

White 7/6 (67%) 1/1 (2) 2/3 (5) 0 0 0

Red 4/1 (100%) 2/0 (2) 0 2 0 0

Blue-black 3/2 (50%) 1/0 (1) 0 0 1 1

Ill. Suspicious lesions 11/4 (50%) 5/1 (6) 3/0 (3) 2 0 0Peritoneal orange zones 7/3 (66%) 4/0 (4) 2/0 (2) 1 0 0Peritoneal red spots 4/1 (0%) 1/1 (2) 1/0 (1) 1 0 0

(irregular blood

vessel pattern)

37 endometriotic lesions were identified and classified as

typical (13%, Fig. 1), subtle (57%, Fig. 2), or suspicious (30%).

Twenty implants were biopsied, and 65% were confirmed

by histology. The histological confirmation was 100% and

61% in typical (n = 3) and subtle (n = 13) lesions, re-

spectively. Endometriotic glands were lined by endome-

trial-like epithelial secretory and ciliated nonsecretory cells.

In most positive biopsies, few small endometriotic glands

were embedded in ectopic stroma. In some foci, cystic di-

lation of a single gland was seen. Either endometriotic glands

with stroma (59%) or stromal endometriosis only (8%) were

evident in subtle implants. Ectopic stroma without endo-

metriotic glands was found in 2 of the 4 suspicious lesions

that were biopsied. Examination of stromal endometriosis

demonstrated the presence of endometrial-like stromal

fragments implanted on the peritoneal surface. The under-

lying mesothelial cells were intact with mesothelium partly

covering the stromal fragment. Within these stromal im-

plants, giant cells were evident, especially in areas with nec-

rotic changes.

Most lesions were found on the uterosacral ligaments

and in Douglas’ pouch (46%), on the uterine peritoneum

and uterovesical fold (38%), and on uterine-omental adhe-

sions (11%). Only 5% of the lesions were localized on the

ovarian ligament, whereas ovarian endometriosis was not

found. The mean diameters of the white plaques, cysts, and

vesicles were 7 mm, 8 mm, and 3 mm, respectively. Sus-

picious lesions were variable in size (2-9 mm diameter).

Complications

One baboon died suddenly at the end of laparoscopy.

Another baboon had a subumbilical wound dehiscence on

Day 3 after the operation. The

further recovery was normal.

wound was resutured, and

DISCUSSION

Laparoscopical Technique

To the best of our knowledge, this is the first report of

a systematic laparoscopical screening of healthy baboons

with proven fertility for the presence of endometriosis. The

laparoscopic technique used in the baboon is largely com-

parable to the technique used in women. Some peculiari-

ties, however, are noteworthy. The speculum and bladder

catheter should be inserted in the genupectoral position,

because inspection of the cervix in the lithotomy position

is difficult due to the sharper angle of the baboon’s pubic

arch. Probing of the uterus should be performed only if

endometrial cells or tissue are required, since it is a diffi-

cult and dangerous procedure. It is difficult because the

cervix is hard (especially during the follicular phase), and

its canal is S-shaped (18]. Uterine perforation occurred in

3 of 11 cases during the follicular phase, but not during

early pregnancy (4 cases). Because of this problem, the other

37 baboons underwent laparoscopy without uterine prob-

ing. Two small suprapubic trocart sheaths were used to ma-

nipulate the uterus and round ligaments to allow full in-

spection of the pelvis. Blunt manipulation was preferable,

because use of a grasping forceps resulted in slight round

ligament bleeding in 3 of 8 cases. Laparoscopy in baboons

appears to be a safe and feasible technique. The one ba-

boon that died at the end of the laparoscopy had severe

gastric dilation (with grain and gas impaction) and respi-

ratory collapse. Perineal staging is a good method to de-

FIG. 1. Typical lesion: white plaque with brown pigmented spot at the right uterosacral ligament.

FIG. 2. Subtle lesion: white vesicle in Douglas’ pouch.

SPONTANEOUS ENDOMETRIOSIS IN BABOONS 415

termine the ovarian cycle phase, although one corpus lu-

teum with ovulation stigma was seen as early as stage 3.

Endometriosis

All the baboons studied had been captured in the wild

and used for fertility regulation studies at the Institute of

Primate Research. For this reason, they were of proven fer-

tility. Therefore only baboons with the nipples hanging

downward (proof of at least one breast-feeding period) had

been trapped. The high prevalence of endometriosis (25%)

in this baboon population with at least one offspring is re-

markable. Moreover, 15 baboons subsequently became

pregnant in captivity. Last but not least, clinical endometri-

osis was diagnosed in 3 of 4 baboons that underwent la-

416 D’HOOGHE ET AL.

parascopy during the cycle of conception. To the best of

our knowledge, this is the first time endometriosis has been

reported during pregnancy in primates.

Spontaneous endometriosis was found in 8% of the ba-

boons without previous hysterotomy and was confirmed

histologically in 75% of the cases. This prevalence is high

and comparable to the 7.5% of spontaneous endometriosis

found in asymptomatic women undergoing tubal ligations

[5].

A previous hysterotomy is a known risk factor for the

development of endometriosis in primates [20]. Spillage of

viable endometrial cells into the pelvis could result in im-

plantation and subsequent development of endometriosis.

In women, however, an increased incidence of endome-

triosis has not been reported after cesarean section, al-

though vesical [21] and abdominal scar [221 endometriosis

may be found.

Obtaining a good biopsy of small lesions was technically

difficult; nevertheless, the histological confirmation rate

(65%) was high and comparable to that reported in women

[23]. A high frequency of subtle lesions was found, whereas

typical lesions were less frequent. The absence of ovarian

endometriosis was remarkable but can probably be ex-

plained by the fact that all animals were of proven fertility,

whereas ovarian endometriotic cysts are usually found in

moderate and severe cases of endometriosis in women. Ac-

cording to the human classification of the disease, the ba-

boons studied had only minimal endometriosis.

Orange zones and red spots with irregular blood vessel

pattern were initially suspected to bear endometriosis and

were biopsied in 4 baboons. Because they were seen often

during the subsequent laparascopies, they were not further

noted or biopsied but interpreted as a normal feature of

the baboon translucent peritoneum. Unexpectedly, at his-

tological assessment, 2 of 3 orange-zone biopsies contained

stromal endometriosis. Therefore, we assume that these

suspicious lesions should be studied in detail and may rep-

resent very early stages of disease. If most orange zones

contain histological endometriosis, this disease should be

considered as a common and possibly physiological con-

dition in baboons. The clinical significance of peritoneal

pockets is unclear but-as in women [24]-seems to be

related to minimal endometriosis. Retrograde menstruation

was seen in one third of the menstruating baboons and is

probably a physiological phenomenon in primates, as in

women [25].

In conclusion, this study for the first time demonstrates

that spontaneous endometriosis occurs in healthy baboons

of proven fertility. Additionally, the laparoscopic appear-

ances, the histological aspect, and the localization of the

lesions are shown to be comparable to those found in

women. The baboon is also phylogenetically close to the

human and a model for reproductive studies [26]. We con-

clude that this primate is a promising animal model for the

study of endometriosis.

ACKNOWLEDGMENTS

We thank the collaborating European centers, i.e., Prof. Dr. M. Bruhat, Clermont-

Ferrand, France; Prof. Dr. J. Calaf, Barcelona, Spain; Prof. Dr. Fl. Evers, Maastricht,

The Netherlands; Prof. Dr. J. Raus, Diepenbeek, Belgium, and Prof. Dr. D. Vandek-

erckhove, Ghent, Belgium. The help of advisers Prof. Dr. A.F. Haney, Duke University,

NC; Prof. Dr. RS. Schenken, San Antonio, TX; and Prof D.C. Martin, Memphis, TN, is

greatly appreciated.

Mrs. Storz-Rehling is thanked for the generous supply of the endoscopv equip-

ment (Storz Company, D-7200 TUttlingen, Germans’).

The WOB (Flemish Association for Development Cooperation and Technical As-

sistance) provided logistic support. We are grateful to Mies Vanderhevden for the

histology processing. The secretarial and organizational assistance of Diane Wolput

was indispensable and is greatly appreciated.

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