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Comparison of Human to Macaque Uterosacral–Cardinal Ligament Complex and Its Relationship to Pelvic Organ ProlapseMount Sinai School of Medicine, Department of Obstetrics and Gynecology, New York, New York, USA Correspondence: Azin Shahryarinejad MD, MPH, Mount Sinai School of Medicine, Department of Obstetrics and Gynecology, Division of Female Pelvic Medicine and Reconstructive Surgery, 1176 5th Avenue Box 1170, New York, NY 10029, USA; e-mail:azin.shahryarinejad{at}mssm.edu.
The uterosacral–cardinal ligament complex is thought to be the critical structure responsible for uterine and apical vaginal support. It is ill defined and can be difficult to dissect in the cadaver lab and in the operating room. Even less information is available on the analogous structures in the monkey model. We present this report to bring together what little is known to aid in studying this model and pelvic organ prolapse (POP), and to point out the need for critical assessment of this hormone-responsive tissue in the process of drug development. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. The authors did not declare any other competing interests.
Key Words: animal models • female reproduction • nonhuman primate Abbreviations: CEE/MPA, conjugated equine estrogens plus medroxyprogesterone acetate • CL, cardinal ligament • EE/NA, ethinyl estradiol plus norethindrone acetate • ER, estrogen receptors • MMP, matrix metalloproteinases • POP, pelvic organ prolapse • PR, progesterone receptor • RL, round ligament • USCL, uterosacral, cardinal ligament • USL, uterosacral ligament
Pelvic organ prolapse (POP) is a very poorly understood process that, in humans, is thought to be caused by structural defects in the connective tissue and the muscles that support the pelvic viscera. POP may occur as an adverse event reported in clinical drug trials, for example it contributed to the withdrawal of the selective estrogen receptor modulator levomeloxifene (Warming et al. 2003). The primary ligaments of support of the uterus are thought to be the uterosacral–cardinal ligament (USCL) complex (Singh et al. 2003). This complex provides apical support by suspending the uterus and the upper third of the vagina to the bony sacrum; it can be described as two separate entities: the cardinal ligament (CL) and the uterosacral ligament (USL). The cardinal ligament is a fascial sheath of collagen that envelops the internal iliac vessels and then continues along the uterine artery, merging into the visceral capsule of the cervix, lower uterine segment, and upper vagina. The uterosacral ligament is denser and more prominent than the cardinal ligament. Collagen fibers of the uterosacral ligament fuse distally with the visceral fascia over the cervix, lower uterine segment, and upper vagina, forming the pericervical ring; proximally these fibers end at the presacral fascia overlying the second, third, and fourth sacral vertebrae. This complex appears to be the most supportive structure of the uterus and upper third of the vagina. Disruption of the uterosacral–cardinal complex may result in uterine descensus or apical vaginal vault prolapse (Miklos et al. 2002). This complex is seen on magnetic resonance imaging (MRI) to hold the upper vagina and cervix over the levator plate (Figure 1) (DeLancey 1994). Understanding what factors cause or predispose to weakness or failure of these ligaments may contribute to our understanding of the process of POP.
In 1994 DeLancey divided the connective tissue attachments in vaginal support into three anatomical levels of support from cadaveric dissections (see Figure 2): level 1 described the superior (apical) attachment of the cervix and upper vagina by the uterosacral–cardinal ligament complex; level 2 is the lateral attachments of the superior lateral insertion points of the anterior vaginal wall and rectovaginal fascia; and level 3 is the distal attachment of the perineal body and perineal membrane (DeLancey 1994).
The uterosacral–cardinal ligament complex in humans is difficult to evaluate in vivo, and most studies have been cadaveric or imaging studies, with a few post-surgical studies. A nonhuman primate model, such as the macaque (Macaca fascicularis), has greatly enhanced our ability to study POP; this model allows controlled experimentation and thorough sampling of the key pelvic supportive tissues. Although much of the basic research has been on the rodent model owing to cost and accessibility, this may be an inappropriate model because of poor correlations to humans in anatomy, parturition, reproductive cycles, and posture. Other primates have also been used to study the female pelvis. Coates et al. (1995) have reported on the squirrel monkey as a useful model for POP; however, because of their larger size, prevalence of POP, and their similarities to human female anatomy and parturition, macaques are currently thought to be the best model (Weber et al. 2004). There is little in the literature regarding the anatomy, topography, biochemistry, and biomechanics of pelvic support ligaments in this species. The purpose of this article is to gain a better anatomical understanding of the uterosacral–cardinal ligament complex in the macaque model by comparing anatomic images obtained at necropsy with the complex of the human pelvis, and thus improving the utility of this species as a model for future studies of POP.
In human anatomy, the attachment points of the USL have been debated since 1917 (Blaisdell 1917). Most authors acknowledge that the borders of the uterosacral–cardinal ligament complex are difficult to establish on dissection, and the removal of the ligament can be somewhat arbitrary (Campbell 1950; DeLancey 1994; Nichols and Randall 1996). In 1950, Campbell described the USL as originating from the posterolateral aspect of the cervix at the level of the internal cervical os, as well as from the lateral vaginal fornix, then attaching to the fascia covering the levator ani, coccygeus, and obturator muscles, as well as the presacral fascia (Campbell 1950). Fritsch and Hotzinger (1995) could not find direct attachment of the USL to the sacrum in plastinated cross-sections. Umek et al. (2004) used MRI to study eighty-two asymptomatic healthy women’s endopelvic fascia, USL, and related structures to identify origin points from the genital tract and insertion points on the pelvic sidewall. In 87% of subjects, the USL was visible on MRI, with a mean cranio–caudal length of 21 +/– 8 mm (10–50 mm) bilaterally, and with 50% of subjects having a longer ligament on the right side (Umek et al. 2004). This length difference was attributed to the rotation and attachment of the sigmoid mesentery, causing the left USL to appear less prominent. The origin of the USL was characterized by three distinct regions where the connective tissue condensed to a bandlike structure lateral to the genital tract: 33% of the origins were from cervix alone; 63% cervix and vagina; and 4% vagina alone. Insertion points, defined as the point on the pelvic side-wall where the USL ended, were also found in three distinct regions: 82% overlaid the sacrospinous ligament/coccygeus muscle complex; 7% the sacrum; and 11% the piriformis muscle, the sciatic foramen, or the ischial spine. This study shows evidence that the USL connects mostly to structures that lie ventral or lateral to the sacral bone rather than to the bone or its periosteum (Umek et al. 2004). In another human study, Buller et al. (2001) used fifteen female cadavers to describe USL and adjacent anatomy as well as suture pullout strengths. By placing tension on the distal aspects of the USL, they were able to identify the anterior edge of the ligament. Although the posterior edge was not visible before dissection, it was identifiable after removal of the peritoneum and reflection of the rectum. The origin of the USL was fanlike at the sacrum, narrowing to its smallest width just proximal to the cervix. Fibers of uterosacral and cardinal ligaments were intermingled consistently at the cervical portion, which created a smaller, fanlike insertion with fibers that extended anterior above the internal cervical os and posterior onto the proximal third of the vagina. Siddique et al. (2006) dissected six pelvic blocks from adult females with intact uteri and measured topographical relations of the uterosacral ligament with adjacent anatomy. They found the USL from the cervix to its origin at the sacrum measured 8.7 cm in mean length along its superiorlateral edge (95% CI; 7.5, 10.0 cm) (Siddique et al. 2006). The mean width ± standard deviation (SD) of the USL was 5.2 ± 0.9, 2.7 ± 1.0, and 2.0 ± 0.5 cm in the sacral, intermediate, and cervical portions, respectively (Buller et al. 2001). The ischial spine was consistently found beneath the intermediate portion of the ligament; however, its position beneath the ligament varied greatly. The ligament was attached broadly to the sacrum at level 1 to 3 (S1–S3) and variably to the sacrum at level 4 (S4). They also noted fibrous attachments of the USL to the sacral periosteum. The superior gluteal vein, which lay medial to the superior gluteal artery, was consistently found directly beneath the sacral portion of the ligament. In the intermediate portion, the middle rectal artery was consistently found near the inferior margin of the USL. The ureter was always found in proximity to the anterior margin of the USL. The mean (± SD) distance from the ureter to the USL at the level of the sacrum was 4.1 ± 0.6 cm. The mean (± SD) distance from the ureter to the USL at the level of the ischial spine was 2.3 ± 0.9 cm. The mean distance (± SD) from the ureter to the USL at the level of the cervix was 0.9 ± 0.4 cm. Also, the mean (SD) distance from the ureter to the ischial spine was 4.9 ± 2.0 cm. At all weights tested, the effect on the ureter was greatest at the level of the cervix (p < .001). USL tension was transmitted to the ureter, most notably near the cervix. The cervical and intermediate portions of the USL supported more than 17 kg of force of weight before failure (Buller et al. 2001). These findings suggested that the major supporting element is the intermediate portion of the USL, 1 cm posterior to its most anterior palpable margin, with the ligament under tension. A trend of lower pullout strengths at the sacral portion of the ligament was observed (Buller et al. 2001). These few human studies provide some understanding of the normal (nonprolapsed) human uterosacral–cardinal ligament complex. However, greater understanding of the ligament’s normal function can be found better by evaluating the anatomy and physiology of the ligaments in a failed state, such as in POP. Pelvic relaxation may be considered as the herniation of the pelvic floor, and it has also been related to connective tissue insufficiency (Kökçü et al. 2002). The top layer of the pelvic floor is created by the endopelvic fascia, which attaches the pelvic organs, especially the vagina and the uterus, to the pelvic walls, thereby suspending these organs. The interaction between the levator ani muscles and the supportive fascia and ligaments is critical to the support of these pelvic organs (Cole et al. 2005). As long as the levator ani muscles function normally, the pelvic floor is closed and the ligaments and fascia are under no tension (Cole et al. 2005). When the pelvic floor muscles relax or are damaged, the pelvic floor opens. In this abnormal situation, the vagina and uterus are held in place by the endopelvic fascia and the ligaments. If these structures are strong enough, they are able to maintain normal support; if they are not strong enough, they will fail to hold the pelvic organs in place (Cole et al. 2005).
Our understanding of the physiology of tissue failure comes from several studies that have suggested that inherent abnormalities of the supporting connective tissues contribute to the development of prolapse. Connective tissue provides the supporting matrix for almost every organ in the body; it consists of cells such as fibroblasts and smooth muscle cells surrounded by fibers and amorphous ground substance (Liu et al. 1995). Fibroblasts are derived from mesenchymal connective tissue cells responsible for the synthesis and secretion of fibrous proteins. Smooth muscle cells may also synthesize these proteins. Connective tissue fibers are assembled mainly from protein, collagen, and elastin, and the ground substance consists mostly of proteoglycans. Elastic fibers have rubberlike properties, meaning that they stretch easily and return to their original length when the deforming force is removed. These fibers are found in tissues that are normally subject to stretching and expansible force (Ewies et al. 2003). Collagen is the main supportive protein within the connective tissue. Mutation in the collagen genes may cause weakness of the collagen network (Jackson et al. 1996; Liapis et al. 2001). Collagen is a predominant component of the USLs. In one study of 41 postmenopausal Caucasian women, 84% of USL had more than 20% smooth muscle cells surrounded by moderately dense collagenous connective tissue with numerous blood vessels (Gabriel et al. 2005). Although the uterosacrals are thought of as ligaments, their histomorphological composition is not comparable to other ligaments such as the anterior cruciate ligament of the knee, which is composed of dense regular connective tissue (Gabriel et al. 2005). USLs are composed of less than 10% Collagen I, 15%–25% Collagen III, and 25%–30% smooth muscle cells (Gabriel et al. 2005). Comparing the USL in the prolapsed versus the nonprolapsed uterus, there was no difference in Collagen I content (6% vs. 6.5%); however, a higher percentage of Collagen III was found in prolapsed patients (22.9% vs. 13.7%). Vaginal fascias associated with uterine descent have shown an increase in Collagen III and a decrease in fibroblast content (Yamamoto et al. 1997). This alteration has been considered to constitute abnormal fascia. Connective tissue is known to undergo remodeling in response to various factors or stress, such as the stretch of a prolapsed organ. Ligaments recover from these stresses and are healed by collagen scarring. The connective tissue becomes elongated and has reduced elasticity and strength after the healing process. Although the amount of collagen within the connective tissues responsible for pelvic support appears to be increased in women with genital prolapse, this increase is mostly in the weaker, type III collagen and perhaps may be a form of weakened healing. It appears that elastin does not undergo a remodeling process similar to collagen (Yamamoto et al. 1997). The resilience of connective tissues is thought to be affected by two factors: an increased ratio of weaker, type III collagen to stronger, type I collagen, often seen with wound healing after injury or trauma such as childbirth or hysterectomy; and it is an inherent abnormality of the tissues histologically characterized by a decrease in tissue cellularity (Kökçü et al. 2002). Phillips et al. (2006) compared tissue markers of collagen metabolism, such as matrix metalloproteinases (MMP), of USLs with vaginal tissue in women with and without uterine prolapse. No significant increase in pro MMP-2 or MMP-9, or expression of hydroxyproline content, was seen in USLs of women with or without prolapse, but there was elevated MMP activity in the vaginal skin of women with prolapse. Strong correlations were seen for almost all markers of collagen metabolism between vaginal skin and USLs, with an apparent exaggerated effect in the vaginal tissue. This may represent a resistance to stretching within the USL (Phillips et al. 2006). Reay-Jones et al. (2003) found no change in USL biomechanical resilience with increasing age, history of vaginal delivery, surgery, or years since menopause. Later, Cole et al. (2005) used cadaveric specimens and found organized ligamentous tissue was present bilaterally only in specimens from a young cadaver with no history of pelvic surgery, which suggested that the ligamentous complex weakens not from stretching but because of discrete breaks in its various portions.
In humans, estrogen replacement therapy restores the paraurethral connective tissue of postmenopausal women toward premenopausal conditions by increasing the proteoglycan-to-collagen ratio and decreasing collagen content and crosslinking (Ulmsten and Falconer 1999). On a molecular level, estrogen influences the structure and function of these deep vaginal support tissues. An improved understanding of the molecular and structural changes that occur in these critical muscles and ligamentlike attachments under varying hormonal conditions is, for many reasons, essential to an improved understanding of POP. In humans steroid hormone receptor status in the USLs of twenty-five surgical specimens in women without prolapse was evaluated using immunohistochemical staining. Estrogen and progesterone receptors were detected in the nuclei of smooth muscle cells of the USL in all patients, regardless of age, race, menopausal status, parity, body mass index, and medications affecting serum steroid hormone levels (Mokrzycki et al. 1997). Hormone receptors were not found in the collagen, vascular, or neuronal components. The presence of estrogen and progesterone receptors in the USLs suggests that this structure may be an end organ for estrogen and progesterone response (Mokrzycki et al. 1997).
Unfortunately, only a limited amount of information can be ascertained from human studies. A translational model, an animal model that mimics humans, allows for better manipulation and consequent understanding of POP. The attributes of the macaque pelvic floor as a model for POP and its many muscular anatomic similarities to the human vaginal support structures has been described, as well as a thorough analysis of the hormone receptor status and histological interrelationships between the paravaginal attachment and levator ani muscles (Otto et al. 2002). The evolution of the human female pelvis from early mammals has been influenced by several forces, including the transition from quadruped ambulation to modern bipedalism and the loss of the tail (Abitbol 1996). In addition to gravitational forces on the pelvic viscera when upright, walking provides the challenge of supporting moving organs. Over time, muscles that once supported a tail have evolved into supporting the pelvic viscera (Abitbol 1996). With upright posture, the levator ani muscles close the opening of the bony pelvis, and dysfunction of these muscles is a likely risk for POP. Short, round muscle bodies seen in the levator muscles in quadrupeds are in contrast to the flattened and thinned levators seen in biped mammals (Swindler and Wood 1973). Examining the contribution of the analogs to the human levator ani group in macaques confirms their role in pelvic visceral support. All three levator muscles have decreased in size over time in males, but in females of the same species, the pubocaudalis has been preserved, whereas the iliocaudalis and ischiocaudalis have decreased (Ankel-Simons 2007; Wilson 1972). In humans, MRI has demonstrated muscle loss and decreased levator ani muscle thickness in women with pelvic organ prolapse (DeLancey 1998). Motion of the tail in macaques, when present, is the primary function of the levator ani muscles (Abitbol 1996). In general, the size of the tail positively correlates with the size of the pelvocaudal musculature in macaques (Abitbol 1996). When pulled under the body of a quadruped, a tail provided passive tone as well as active contraction of the pubocaudalis and iliocaudalis muscles for support. The pubocaudalis muscle serves as a strong flexor and abductor of the tail assisted by the iliocaudalis and ischiocaudalis muscles for lateral movement as well as the sacrocaudalis dorsalis muscle, which is not found in humans, for posterior motion (Akita et al. 1995). When these animals were climbing, the tail was not available for visceral support, and the pelvic floor would have had to be strong enough to support the viscera despite increased demand. The muscles have shortened and broadened through time, occluding most of the pelvic outlet. The function of the tail in balance became negligible with a terrestrial lifestyle, and it was lost. In parallel, the pubocaudalis muscle increased in size and the iliocaudalis muscle decreased markedly compared to the ischiocaudalis muscle (Elftman 1932). One of the trends in the evolution of the pelvic floor is the conversion of monkey and ape musculature to human fibrous tissue and fascia, lending strong support and requiring less constant tone. In assuming a chief role in pelvic support, the pubococcygeus muscle developed a midline raphe, losing some coccygeal muscle attachments as the need to support the tail became irrelevant. The origin of the human pubococcygeus and iliococcygeus muscles is similar to that of the apes, from the pubic bone and fascia overlying the obturator internus; however, this fascial origin is purely muscular in monkeys, unlike in humans (Ankel-Simons 2007). The urogenital diaphragm, which appears to be at least partially derived from the pubococcygeal fascia, provides support at the weakest areas in the pelvic floor: the vaginal, urethral, and rectal orifices (Frieden and Adams 1985). However, with bipedal posture, the pressure of a distended bladder or rectum rests on the respective sphincter, a situation that does not exist in quadrupeds. The area of the urogenital diaphragm between the vagina and rectum is primarily connective tissue. It has been renamed the perineal membrane and is a uniquely human adaptation (Ulfelder 1956). It serves as an insertion point for the levator muscles and the bulbocavernosus muscles, providing support to the distal vagina (Schimpf and Tulikangas 2005). The other pelvic connective tissues such as the uterosacral and cardinal ligaments have not been described in the monkey model.
To characterize the pelvic floor of the rhesus macaque as an experimental model for human pelvic organ prolapse, Otto et al. (2002) initiated an evaluation of the effects of estradiol and progesterone on the rhesus paravaginal attachments; histologic specimens were prepared from the paravaginal attachment of thirteen oophorectomized rhesus macaques. Three animals were treated with estradiol for three months; six animals were treated with estradiol and progesterone for three to five months, and four animals were untreated (hormone deprived). Immunocytochemistry was used to localize steroid receptors in the paravaginal attachment. Macaques were used for three reasons: (1) spontaneous pelvic organ prolapse was observed in rhesus macaques (Adams et al. 1985); (2) the paravaginal attachment is composed of dense collagen and elastic fibers that infiltrate the levator ani muscle; and (3) the fibroblasts of this attachment are estrogen and progesterone receptor positive, and the receptors are hormone responsive (Otto et al. 2002). Thus the fibroblast activity may be modified by estrogen treatment in a manner similar to that reported in human pelvic connective tissue (Otto et al. 2002). The connective tissue of the paravaginal attachment is within the levator ani muscle cells, which suggests that this muscle plays a critical role in the pelvic floor. Otto et al. (2002) found that estrogen receptors (ER) were detectable in all the fibroblasts of the vaginal submucosa, including those in the paravaginal attachment and in the connective tissue fibroblasts that infiltrate the levator ani muscles. ER was not detectable in the nuclei of the levator ani skeletal muscle cells. Immunostaining for ER in the paravaginal attachment did not differ noticeably among the hormone-deprived, estradiol-treated animals or estradiol-plus-progesterone–treated animals. Otto et al. (2002) found no difference among the three groups they tested in terms of ER levels measured by binding assay. Additionally, ER was detected in the nuclei of the vaginal smooth muscle cells and basal epithelial cells. In contrast, immunostaining for progesterone receptor (PR) did vary among hormone treatment groups. Hormone-deprived macaques had no detectable PR in the nuclei of the vaginal fibroblasts, smooth muscle cells, basal epithelial cells, and paravaginal fibroblasts, although estradiol treatment greatly increased the staining intensity of PR in the nuclei of these ER-positive cells. Combined estradiol plus progesterone treatment for five months did not change PR staining noticeably from the level seen in the estradiol-treated group. As with ER, PR was not found in the nuclei of the levator ani muscle under any treatment (Otto et al. 2002). Otto et al. (2002) described the hormonal influences on the macaque levator ani muscles and paravaginal attachments, yet these hormonal influences on the uterosacaral–cardinal ligament complex have not yet been described at the histologic level. However, we know these ligaments are also hormonally responsive, since their biomechanical properties change with hormonal influence. In our recently published work (Vardy et al. 2005), fifty-eight Macaca fascicularis were ovariectomized and exposed to conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) or ethinyl estradiol plus norethindrone acetate (EE/NA) for twelve months. Both hormonal regimens greatly increased the stiffness in the USL while decreasing stiffness in the round ligament (RL) (Vardy et al. 2005). Little is known about the effect of selective estrogen receptor modulators on these ligaments; however, preliminary data from our group suggest that their effect may be, in some cases, anti-estrogenic. The macaque model of menopause may be uniquely suited to answer some very basic questions regarding hormonal effect on ligament biomechanics and may ultimately lead to medical therapy.
In our necropsy specimens, we have found that the uterosacral–cardinal ligament in Macaca fascicularis grossly resembles attachments in the human pelvis. The uterosacral–cardinal ligament complex can best be identified on the posterior of the uterus on anterior stretch. The USLs are a collective connective tissue condensation of endopelvic fascia beginning on the sacrum and extending to the fusion of the vagina with the levator ani muscles below; they start at the cervix toward the sacrum on both sides of the colon. The cardinal ligaments start at the cervix and continue laterally toward the ischial spines (Figure 3).
The histologic appearance of the uterosacral and round ligaments is shown in Figure 4; the animal depicted was an estrogentreated positive control animal from a recently reported trial of selective estrogen receptor modulators (Sikoski et al. 2007). The uterosacral ligament consists of a condensation of fibrous connective tissue interspersed with bundles of smooth muscle; as reported by others, we found that the smooth muscle cells of the USL express progesterone receptor. We similarly assessed the round ligaments in this study and found them to consist of a mixture of skeletal muscle and smooth muscle, with nuclear progesterone receptor expression in the smooth muscle component.
A review of the literature on the levator ani and paravaginal attachments in macaques and similar primates, as well as histomorphologic studies on these supportive ligaments, show great similarities to human pelvic floor levators and paravaginal attachments (Adams et al. 1985; Coates et al. 1995; Otto et al, 2002; Weber et al. 2004). The paucity of information on the macaque uterosacral–cardinal ligament complex is evident, and further anatomical evaluation is needed to improve this primate model of human pelvic organ prolapse. Our current studies have found that the macaque uterosacral–cardinal ligament complex shares some similarities with human female ligaments in their insertion and attachment points and hormonal receptivity (Cline et al. 2001; Vardy et al. 2005). Our future work is directed toward further understanding of the receptor status, histology, and topography of the uterosacral–cardinal ligament complex in providing pelvic floor support in the macaque monkey, in hopes of a more complete model for human prolapse.
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This version was published on December
1, 2008 Toxicologic Pathology, Vol. 36, No. 7 Suppl,
101S-107S (2008)
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Abstract
Introduction
