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Uterotubal Oxygenation and Growth After Paracervical Denervation
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Uterotubal Oxygenation and Growth After Paracervical Denervation Joseph Bernard Doyle, M.D.
THE
of this paper is to describe certain effects on uterine and tubal circulation of the simultaneous interruption of both the sympathetic and parasympathetic innervation by transection of the cervical division of the plexus of Lee-Frankenhauser or "paracervical denervation." The significance of these observed effects upon problems involving growth and oxygenation of the uterus and tubes will then be discussed briefly. PURPOSE
ANATOMIC CONSIDERATIONS
We have proposed a simple procedure for denervating the uterus and proximal tubes. 9 The sensory parasympathetic fibers to the cervix and the sensory sympathetic fibers to the fundus traverse the cervical division of the vaginal plexus of Lee-Frankenhauser which lies in, under, and around the attachments of the uterosacral ligaments to the cervix. Lee and Snow-Beck of London first described this important anatomic structure in 1844, antedating Frankenhauser by 20 years. At the cervical attachment of the uterosacral ligaments can be found the sympathetic fibers which have reached the cervix accompanying the uterine arteries. 3 The parasympathetic nerve components originate from the first to the third and fourth sacral nerves and reach the plexus via the pelvic nerves (nervi erigentes). Campbell, in a study of 33 cadavers, identified parasympathetic fibers in the anterior thirds of the uterosacral ligaments, conFrom the Department of Obstetrics and Gynecology, Cambridge City and St. Elizabeth's Hospitals, Boston, Mass . Presented on the scientific program of the Eleventh Annual Meeting of the American Society for the Study of Sterility, Atlantic City, N. J., June 4-5, 1955. 213
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firming the demonstration by Latarjet and Roget, and Davis 5 of the intimate association of the uterine nerves with the uterosacral ligaments with a supply of small ganglia around the area of attachment of the ligaments to the cervix. In the uterus the nerves accompany the blood vessels through the entire musculature of the basal layer of the mucosa. Hi Davis,6 using a combined intra- and supravital methylene-blue method, traced the majority of the nerves to their termination upon the capillary walls, and also by way of spindle-shaped endings to the muscle fibers of the myometrium. At the internal os there are special pseudopacinian sensory corpuscles in the endocervix. 19 The nerves to the spiral arteries are distinct from those to the basal arteries. 25 The sympathetic component transmits vasoconstrictors and inhibitory visceromotor fibers as well as the sensory fibers from the fundus. 6 The parasympathetic component transmits vasodilator and excitory visceromotor fibers to the uterus as well as sensory fibers to the cervix and probably the parametrium. An incision through the posterior vaginal fornix and the terminal 2.5 cm. of the uterosacral ligaments transects and interrupts not only the fundic but also the cervical sensory fibers. Such an incision interrupts the parasympathetic vasodilator fibers as well as the sympathetic vasoconstrictor fibers. Hence, neurovascular imbalance is avoided. We call this procedure "paracervical uterine denervatio~." The procedure may be done through the vagina, according to the method of culdotomy,7 or through the abdomen. 1o. 11 Since the culdotomy approach is simply the first step of a vaginal hysterectomy, gynecologists may prefer the vaginal approach, particularly if the illumination is improved by the use of the pelviscope set, 8 which consists of a lighted right-angle retractor with twin lights at its tip and a set of 2 telescopes offering right-angle and foroblique fields of vision with a threefold magnification. The general surgeon may prefer the abdominal approach. It has been our practice to reserve the vaginal approach for those cases of dysmenorrhea where pelvic examination, both vaginally and rectally, revealed tenderness but no nodulation in the uterosacral ligaments and a cul-de-sac free of induration or masses. The vagina must be free of infection. In a series of 73 cases for relief of dysmenorrhea, the denervation was done by the vaginal route in 36 cases, by the abdominal route in 37 cases.10. 11 To prevent regrowth of the nerves, the posterior leaf of the peritoneal
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incision is sutured over the ends of the proximal stumps of the uterosacral ligaments to the mucosa of the top of the vagina by chromic gastrointestinal sutures (Fig. 1). The importance of the role of the cervix in dysmenorrhea and labor has recently been stressed by Reynolds,23.24 who concluded that the cervix and
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Fig. 1. Technic per vaginam. The uterosacral ligaments have been ligated and cut. The posterior peritoneum has been sutured over them to the vaginal mucosa.
the tissues adjacent to it are the site of uterine pain. Ingersoll and Meigs, White, and others concede that the cervical nerve supply is not usually interrupted by the presacral neurectomy procedure. The cervical sensory supply runs in large measure with the nervi erigentes through the parasympathetic fibers reaching the cord via sacral roots 2, 3, and 4. Relief of acquired dysmenorrhea with or without antecedent primary dysmenorrhea was obtained satisfactorily in 69 of 73 cases (94.5 per cent). The relief was complete in 63 cases (86.3 per cent) .10. 11 NEUROVASCULAR PHYSIOLOGIC CONSIDERATIONS It seems likely that the relief from dysmenorrhea that has been obtained
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in some of our cases is on a partially sensory and partially neurovascular basis. Many nerves end in the wall of small arterioles and capillaries in and between the uterosacral ligaments and in the outer layers of the back of the cervix itself (Fig. 2). Taylor 6 , 27 has described premenstrual and menstrual thickening and tension and tenderness of these ligaments and the under-
Fig. 2.
Nerves ending in small arterioles in the deep layers of the uterosacral ligaments.
lying cul-de-sac area as pathognomoniC of the pelvic autonomic syndrome or pelvic congestion. The exact mechanism of this congestion in the uterosacral ligaments is not known. POSSibly it may arise from angioneurotic edema from parasympathetically conditioned deposition of acetylcholine at the neurovascular effectors in these many small arterioles in the area. Whether tissue edema and hypoxia or acetylcholine directly then stimulates the retrocervical postganglioniC parasympathetic fibers cannot be determined at this time. Whatever the mechanism, surgical transection consistently relieves the local
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congestion of the ligaments and the severe dyspareunia that accompanies it. 7, 10, 11
That this denervation may have ameliorated a neurovascular imbalance involving the uterine-parametrial-ovarian circulation is suggested by the remarkable relief of pain in those 25 cases in the series which were associated with marked varicosities of the ovarian and the uterine venous plexuses. Hodgkinson has recently calculated the enormous 60-fold increase in the capacity of the ovarian pampiniform venous plexus as measured at the ovarian vein at full-term pregnancy. He has demonstrated the hypertrophy of the smooth-muscle fibers, which implies an active physiologic role for these veins during labor as a ballie mechanism in damping sudden high pressures, Because of the wide anastomoses which exist between the uterine and ovarian venous plexuses by way of the pampiniform veins, the release of high venous pressure in the parametrial venous system offers improvement of circulatory stasis in the ovaries, This explains the relief of ovarian and parametrial tenderness in the patients with lateral pain. Such an anatomic approach for relief of circulatory stasis is more logical than the interruption of the infundibulopelvic veins during ovarian denervation. We have raised the question whether autonomic imbalance could underlie the persistence of such venous enlargement. Coexistent cyanosis of the uterus and tubes was seen to disappear promptly during the course of the denervation procedure in 25 cases wherein uterine anteposition ruled out mechanical interference with circulation.lO Some neurovascular explanation seemed indicated. The caliber of the dilated parametrial, ovarian, and uterine venous plexuses was observed to diminish in some cases. In 2 cases dark veins at the uterovesical fold blanched out strikingly. Since these 25 women had acquired their dysmenorrhea after childbirth it appeared that in some women the postpartum uterus suffers from circulatory stasis or congestion sufficient enough for hypoxia or angiospasm or both to cause pain during the premenstrual-congestion phase of the cycle and during menstruation and occasionally to condition profuse flow during the menses. Davis 6 had warned that presacral neurectomy-a high sympathectomy-left the nervi erigentes from sacral roots 2, 3, and 4 entering the uterus through the uterosacral ligaments totally unopposed, and that the ensuing neurovascular autonomic imbalance explains the not-infrequent menometrorrhagia after such an unbalanced neurovascular procedure. We have never
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experienced menometrorrhagia after any of our paracervical denervation procedures unless we had simultaneously removed the corpus luteum so that an anovulatory endometrium was present. In patients in whom pelvic congestion was seen to be present the complete relief of pain obtained is in some instances permanent only after 2 or 3 cycles. We believe that any transient persistence of menstrual ache is due to this gradually receding uterine and parametrial congestion. The remarkable relief of lateral pelvic pain may be due to diminished venous pressure within the ovary or to the improvement of vascularity in the ovarian spiral arterioles consequent upon denervation of the uterine artery which permits it to send more oxygen to the ovary through its ovarian branch. The congestive bleeding which usually accompanies a high superior hypogastric sympathectomy of the uterus (presacral type) does not occur since the paracervical procedure by including the parasympathetic vasodilators avoids autonomic imbalance and congestion. Moreover, we have on three occasions seen enormous parametrial varices, uterine cyanosis, and enlargement actually develop subsequent to presacral neurectomy. The associated pain was promptly relieved by re-establishing uterine autonomic balance by the para cervical denervation technic. The relief of associated menometrorrhagia, the absence of postoperative congestive bleeding, and the improvement of uterine and tubal cyanosis all suggest that there is a secondary improvement in uterine neurovascular physiology after this procedure. NEUROMUSCULAR CONSIDERATIONS The observations of Moir that dysmenorrheic women produce intrauterine tension greater than that observed during the second stage of labor led him to ascribe the pain to ischemic anoxia of the myometrium due to hypercontractility of the myometrium. Bickers! electrically stimulated the intact uterosacral ligaments during laparotomy and produced uterine blanching from myometrial spasm. In 3 patients in whom presacral neurectomy failed to change the abnormally hypertoniC uterine pattern of contractions as observed by the intrauterineballoon technic, subsequent transection of the uterosacral ligaments by oUI technic returned the pattern to nonnalcy.2 It appears that including the parasympathetic neuroexcitory fibers in the denervation ensures neuromuscular normalcy. This, in turn, will ensure adequate blood flow through
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the previously hypertoniC musculature, since Keiffer16 has showed that the tunica media of the arteries in the inner fourth of the myometrium is continuous with the smooth muscle of the myometrium itself. It is obvious that circulatory improvement means improved vitality of the myometrial sphincteric action to control excess How from the menstrually denuded orifices of the endometrial arterioles. The maintenance of neurovascular and neuromuscular autonomic balance is mutually complementary. OBSERVATIONS OF UTERINE AND TUBAL GROWTH In a previous communication9 we presented evidence that the high initial pressure recorded on the Kidde kymograph during uterotubal insufRation with C02 was consistently eliminated by uterotubal denervation. Since this admittedly denotes relief of uterotubospasm we suggested that the denervation procedure be done on the opposite tube whenever one tube was sacrificed for tubal pregnancy. If denervation improves vascularity and permits uterotubal growth, then it would be a useful addition to uterotuboplasty to aid epithelial regeneration and tubal contractility. Although we had kymographiC and motion-picture proof that the newly denervated tubes were well vascularized and more vigorous and rhythmic,9 we could not determine whether this was due merely to loss of innervation and thereby due to the elimination of the deposition of the chemical neuroeffectors, adrenin and acetylcholine, or whether there might be improved vascularity from denervation of their blood supply. We therefore raised the question of whether such improved vascularity, especially since it was balanced so as not to produce congestion, might not improve the delivery of ovarian and placental hormones to the uterus and tubes. According to the physiologic principle laid down by Cannon, denervated smooth muscle is rendered more receptive to its stimulating agents when deprived of all its autonomic nerve supply. It was noted that the increased sensitivity of the tissues is not specific for anyone hormone. Increased permeability of the cell membrane of the smooth muscle was thought to be the likely mechanism. In a given time more of the stimulating agent penetrates the cell. Having demonstrated good glandular tortuosity and secretion in a Day 25 endometrium from a uterus which had been denervated on Day 13 simultaneous to removal of three fourths of the newly formed corpus luteum, we
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suspected that such a maximal response from minimal source of ovarian steroids demanded some such explanation. 9 Raising the question whether the chronically denervated uterus might reveal any such phenomenon we did an endometrial biopsy on Day 16-
Fig. 3. Day 16 biopsy of an endometrium which was denervated 16 months previously. Note spiral arteriolar growth to margin of endometrium and tortuosity of glands.
sixteen months after the paracervical uterine denervation. The spiral arterioles were found to have grown out to the margin of the endometrium (Fig. 3). The glandular tortuosity was likewise more advanced than usual for so early in the luteal phase of the cycle. Similar early growth of spiral
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arterioles has been described by Bickersl after sympathectomy, and ascribed, by the Cannon principle, to more rapid and complete delivery and utilization of the hormones. Since the steroid output in early corpora lutea is variable, this evidence, while very suggestive, is not conclusive. However, it has been possible to devise a phYSiologic experiment which appears to offer unequivocal evidence that the miillerian system does respond to denervation by improved vascularity with greater delivery of oxygen and hormones and with increased response to the hormones. The evidence consists in sequential unilateral tubal growth after denervation of each tube on separate occasions. The embryologic fact that the miillerian ducts are paired offers a unique opportunity to subject each tube to denervation on separate occasions. If any demonstrable growth changes occur in the denervated tube we know that the exposure to hormones by improved vascularity must be acknowledged, since the un denervated tube received the same general blood level of hormones simultaneously. Any daily fluctuation in hormone levels would otherwise affect both tubes to the same extent. To minimize the source of hormones a woman with amenorrhea of considerable duration would be ideal, particularly if she had marked evidence of uterine and tubal hypoplasia.
Case 1 Miss J. c., an unmarried, 22-year-old telephone supervisor, complained of secondary amenorrhea of 18 months' duration and of deep right pelvic pain causing insomnia for 5 months. Pelvic examination revealed an infantile uterus, a cyanotic, long, conical cervix, and a bilaterally tender parametrium. Excretion of FSH was positive for 13 mouse units per 24 hours. 17-Ketosteroid excretion was 4.9 mg. per 24 hours. Total iodine was 7.6; P.B.I. was 6.4 fig· At operation, January 16, 1953, the fundus revealed no endometrium on curettage. Total uterine depth was 5 cm. Laparotomy revealed small lobulated ovaries without visible follicles or corpora lutea. The uterus and tubes were infantile and cyanotic. The fimbrial orifices did not reach the level of the uterosacral ligaments. The ovarian pampiniform plexus of veins was bilaterally engorged. The uterine and ovarian arteries were small. To relieve the pelvic pain from congestion syndrome the right uterosacral ligament was transected down to the top of the vagina, interrupting the right uterotubal sensory and neurovascular nerve supply at this point. The pelvic pain did not recur. No hormone therapy was given. The amenorrhea persisted for a total of 40 months. The patient returned because of recurrent pain in the upper abdomen. Accordingly, exploratory laparotomy was done 22 months after the right tubal denerva-
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tion on November 2, 1954. Curettage revealed no endometrium. At laparotomy under spinal anesthesia the uterus and tubes were still cyanotic, the parametrium still engorged. However, measurement of the tubes now revealed that the denervated right tube was 8.4 cm., the left tube 6.8 cm. There was an obvious increase in the tubal caliber and the size of the infundibulum and fimbriae. The left tube and the uterus were now denervated by transection of both left and right cervical-uterine divisions of the pelvic plexus by transecting both utero-
A
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Fig. 4.
Uterotubograms subsequent to sequential unilateral denervation of the tubes.
A, 6 weeks after second denervation. The right tube (22 months after its denervation)
shows a good isthmic and infundibular cavity. The left tube (6 weeks) shows no growth yet. B, 12 weeks after second unilateral denervation. The left tube (after 3 months) has now comparable isthmic length and caliber and a good infundibular shadow.
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sacral ligaments down to the vagina. Within a few minutes the cyanosis disappeared from both tubes and the uterus. To evaluate subsequent growth changes, serial uterotubograms were taken at 6- and 12-week intervals. At 6 weeks (Fig. 4A) the right tube was obviously longer than the more recently denervated left tube, and has a well-defined infundibular caliber. The left tube had not yet developed an infundibular shadow. At 12 weeks (Fig. 4B) both tubes showed well-defined infundibular caliber. The left tube had by this time achieved greater length and isthmic caliber than in the previous film.
As in the patients with dysmenorrhea and pelvic congestion described above, this relief of cyanosis appears to be a local neurovascular effect due to the interruption of both types of neurovascular autonomic fibers which course through this area to the many small arterioles in the area itself as well as to those of the uterine and tubal musculature and mucosa. Since the pre-existing cyanosis was unrelieved by spinal anesthesia, a cord reflex mechanism is untenable. No extrinsic hormones were given after the operation. It appears therefore that sequential unilateral uterotubal denervation resulted in sequential growth of each tube. The prompt relief of cyanosis suggests that some local neurovascular effect of transecting the retrocervical nerve structures ameliorates uterine and tubal circulation and hence improves oxygenation and delivery of hormones. We applied the same de nervation test to determine the responsiveness of the lower half of the miillerian system as described in Case 2: Case 2 Mrs. M. H., a 32-year-old married patient, had had 3 spontaneous abortions, each occurring at 6 weeks' gestation. X-ray studies elsewhere had revealed a congenital defect, uterus bicornuatus unicollis, for which excision of one horn had been advised. Since a repeat uterotubogram revealed equality of the cornua this surgery seemed illogical. The filling of the uterus and tubes required 5 cc. contrast medium (Fig. 5A). Accordingly, a paracervical denervation was done by culdotomy on February 8, 1954. No hormones were given and pregnancy was avoided for 1 year postoperatively. On January 17, 1955, 10 cc. of contrast medium filled the uterus and only partially outlined one of the tubes. Making due allowance for the distortion of retroversion and distention by the dye in the latter film (Fig. 5B), both cornual cavities appeared to be broader and blunter at the cornual tubal junction. The cervical cavity appeared to be larger. Since both films were taken during the
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postmenstrual phase they are comparable. They are meaningful when the evidence for controlled unilateral tubal growth is considered. The patient delivered a live 1758-Gm. male infant at 33 weeks which died of hyaline membrane disease 8 hours after cesarean section for slight intrapartum separation of the placenta.
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Fig. 5. Uterotubogram of a uterus bicornuatus unicollis. A, before denervation, 5 cc. Salpix. B, 1 year after denervation, 10 cc. Salpix his distended both cornua but only one tube. The cornual cavities are apparently broader and blunter.
If it has been demonstrated that such a uterus with its faulty shape, faulty connective tissue, and faulty musculature responds to denervation by improvement in growth, the usefulness of the denervation procedure to evaluate the clinical problems associated with uterine growth and vascularity during pregnancy is obvious.
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CLINICAL CONSIDERATIONS IN OBSTETRICS Theoretical Considerations R~ynolds23
has shown that hormonal and vascular effects work together to elicit structural changes in the uterus which are characteristic of estrogen and progesterone: Noone has ever shown that estrogen acts upon the excised uterus to initiate rhythmic contractility. Uterine circulation is essential to provide materials for an assimilation type of metabolism. Myometrial activity depends on a normally functioning vasculature. Whereas, in turn, the rhythmic activity apparently serves the purpose of forcing blood through a small undeveloped vasculature in an endometrial tissue having a low metabolism. Not only does the pumping action of the muscular movements assist venous drainage from the organ, but metabolites which are locally produced by the tissue contribute to the continued vasodilation of the capillary vessels of the organ. By elimination of autonomic neurovascular imbalance through the interruption of both sympathetic and parasympathetic pathways, the local vasospasm disappears. The more constant uterine circulation can now deliver a higher concentration of estrogen and proges"terone to the tissues of the myometrium and endometrium. But greater estrogenic hormone concentration in the myometrium means better myometrial growth. Since myometrial elasticity and contractility in the last trimester depend upon greater growth and vascularity of the myometrium in the early trimesters, it is now suggested that the autonomic denervation procedure should aid the prolongation of pregnancy without the use of extrinsic oral or parenteral hormones. Reynolds 22 has demonstrated that the uterus reaches its greatest transverse diameter at the thirty-second week. Thereafter it virtually ceases to grow, although the fetus continues to increase in size. Unless the vessels of the myometrium and the decidua have also obtained optimal growth, the result may be ischemia, anoxia, thrombosis, and necrosis of the decidua. This is the ordinary hazard of the third trimester of pregnancy. If severe, the thrombosis and infarction of the vascular bed of the decidua at the site of implantation of the placenta may provide the environment for premature separation of the placenta. These lesions may accompany toxemia, or be present in the absence of toxemia. Reynolds 23 has raised the question: Are toxemias, miscarriages "without a known etiology," or so-called idiopathic abortion the result of failure of one of these mechanisms? If so, we look too late
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for the cause of the condition. We think of toxemia as a crisis at the moment it appears when, in fact, it may have a morphological and physiological basis dating much earlier in gestation. Thus we should consider faulty metabolism, faulty shape, faulty connective-tissue development or faulty vasculature as possible contributing factors to these obstetrical complications. One or more of the complications of pregnancy may have their basis in abnormal mechanisms of uterine accommodation of the products of conception. The integrity of the vascular supply to the placenta depends upon the integrity of the placental site rather than any intrinsic strength of the vessels themselves. It then becomes evident that dissolution of the placental site will result in rupture of the decidual sinusoids, leading to placental separation. Perhaps vascular spasm of the spiral arterioles without demonstrable lesions may play the major role, as Hertig and Page have postulated. Clinical Evaluation The ultimate objective index of the persistence of optimal homeostasis and oxygenation of the uteroplacental lake is the microscopic normalcy of the decidual tissues at the site of implantation as well as that of the chorionic villi. Mter this type of balanced denervation, decidual biopsies at the placental site as well as microscopic appearance of the chorionic villi have been consistently within normal limits. The course of pregnancy has been observed in 39 women, of whom 32 were under fertility study. The others were incidental pregnancies following the operation for dysmenorrhea. Eight are now undelivered. Thirty-one patients have delivered once. Six have delivered twice. There have been no intrauterine deaths. There were only 2 blighted-ovum abortions. There have been 38 live-born infants, including 1 set of twins at 35 weeks. This mother had chronic pyelonephritis and impending renal shut-down. Yet there was no sign of toxemia in her eyegrounds. The placenta revealed no gross infarcts nor microscopic syncytial degeneration, despite the fact that prior to her denervation she had a full-term eclampsia with abruptio placentae and postpartum hemorrhage and then 8 successive spontaneous abortions. Following her delivery as with all the others there was minima] blood loss in the third stage and the puerperium. Two women with subpubescent uteri whose pregnancies commenced 1 and 3 months respectively subsequent to denervation were delivered at 40 and 41~ weeks respectively without vascular accident. No hormones were given.
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Two other patients with small uteri had previously had circumvallate placentas and had 2 pregnancies each complicated by premature separation. One patient had 6 previous premature separations at 24 to 28 weeks, all breech presentations with 5 neonatal deaths. After denervation her next 2 pregnancies went to 32 and 39 weeks with live births and no hemorrhages. The ensuing presentations were vertex, suggesting easier accommodation within a roomier uterus. Placental site biopsies showed no necrosis (Fig. 6).
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Fig. 6. Biopsy of decidua at placental site after second delivery since denervation. Before denervation, 6 pregnancies terminated at 24-28 weeks with separation of the placenta. Chorionic villi and decidua show no necrosis or thrombosis.
Further evidence that this type of uterine denervation is superior to that obtained by the presacral neurectomy can be seen from the absence of uterine cramps and backache during the first stage of labor. If the fetal head was held out of the pelvis by a tight cord there was absolutely no pain with uterine contractions during the course of a 12-hour labor until the head became engaged deeply enough to press upon the pelvic floor. The aggravating low sacral ache, so frequently present during the course of posteriorocciput presentation was absent in these cases as long as the head impinged only on the cervix and not on the pelvic floor. The usual complaint then was recurrent tension at the insertion of the round ligaments into their inguinal attachment to the abdominal wall. Later, pressure on the rectum and perineum occurred. None of the 31 patients who have delivered 38 live
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jnfants to date subsequent to this type of denervation either had a precipitate labor nor one of less than 2 hours' duration. This is in contrast to the not-infrequent precipitous labors after presacral neurectomy due to the unopposed stimulation of the detrusor parasympathetic system. The uterine contractions are regular in rhythm and of good 40-50-second duration. There is good uterine relaxation between the contractions. The uterus acts normally to oxytocics such as Pitocin when induction of labor is desired. The third stage of labor is brief and unaccompanied by excessive blood loss.
UTEROTUBAL DENER.VATION DivisiDn Df Frankenhaus.ril Pl.xus in and betws8D 'h. Uterosacral Ligaments I~ SYMPATHETIC FIBRES
PARASYMPATHETIC FIBRES
"euromotor 11\l\lbltOl' t. uterus
WeuromOlor IXcilor to utera. tub •• leJ\IDry to camx V••• oUlltora from "narYi .rlgmtt.-
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IlnlOI'J' to runda.r V'loconllrieton hom "pre,"cral 1\.rna·
Re~ AUTONOMIC IMBALANCE
UTERO TUBOSPASM
wIeWt Conditiom MYOMETRIAL UTERINE VASOSPASM
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IRRITABILITY
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Occ:1alion Pregnancy
Dym.nmhea
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EndO. metria1 ThJmltl'ieNlcrosi,
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Fetal Malnutrition
Fig. 7.
Pathological physiology remediable by paracervical uterotubal denervation.
Involution of the fundus is rapid and satisfactory even without oxytocics. There was complete absence of so-called "after pains" from uterine contractions. Placental Permeability. The most interesting result was that obtained subsequent to denervation at the third month of an Rh-negative mother gravida V whose last two pregnancies had resulted in hydrops and neonatal death at 39 weeks and intrauterine death at 36 weeks, respectively; her first infant was unaffected and the second saved by a prompt transfusion. The husband was Rh positive, "probably homozygous." The maternal titers
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for anti-Rh antibodies were: 12 weeks, 1:4; 13 weeks, 1:16; 15 weeks, 1:32; 21 weeks, 1:16; 36 weeks, 1:8; and 38~ weeks, 1:4 in albumin. However, because conflicting titers of 1:128 and 1:256 were obtained from two other excellent laboratories, labor was induced by artificial rupture of the membranes and Pitocin. After a 12-hour test of painless unmedicated labor, because of a variation in rate and strength of the fetal heart sounds from 160 to 170, a low transverse cervical cesarean section was performed under spinal anesthesia. A living male infant, 20 inches long and weighing 2420 Gm., was delivered and cried at once spontaneously. Although the infant developed a pulmonary hyaline membrane and died 8 hours later, gross and microscopic examination of the liver, spleen, lungs, and the placenta and decidua at the placental site revealed no evidence of erythroblastosis fetalis or vascular damage. The infant cord blood was Group A, Rh positive, with an antibody titer of 1: 32 in albumin, 1: 1 in saline, and a positive Coombs test. One raises the question: did the denervation permit the homeostatic uterine decidua to minimize the permeability of the placental barrier to antigens and antibody? Does uterine hypoxia underlie the permeability of the endothelium of decidual vessels and the chorionic epithelium? If oxygenation of the decidua is maintained the chorionic villi will be better oxygenated via the uteroplacentallake. That this may minimize the passage of antigens by preventing breakdown of the villi is suggested by the integrity of the villi observed. That the integrity of the villi may in turn prevent the return of the antibody-a chemically larger molecule-seems more likely. Although the possibility of lessened reactivity of the mother cannot be overlooked, this factor seems unlikely in view of her past history. Since there is nothing else to offer the Rh-positive infant in Rh-negative patients with a history of repeated intrauterine and neonatal fetal death from Rh-isoimmunization, we suggest that the procedure of uterine denervation which will normalize the vascular and myometrial tension phenomena and minimize ischemia may prove useful in preserving the oxygenation of the decidua and chorionic villi through maximal oxygenation of the uteroplacental lake.
DISCUSSION Although the other causes of infant death in association with the birth process are often obscure, there is general agreement that by far the most
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important cause is anoxia. The principal cause of death before birth and in the first few weeks of life is interference with oxygenation. The human infant in utero is completely dependent for its oxygen supply upon the vagaries of uteroplacental circulation. A uterus which has been relieved of neurogenic muscle tension and vasospastic ischemia should deliver hormones and oxygen more constantly to the myometrium and endometrium. If the stability of the blood supply of the uterus is maintained so that the placenta-nature's most potent hormone factory-can enjoy physiologic homeostasis and oxygenation, it will produce more hormones intrinsically and deliver them maximally. Since the placental trophoblast obtains its nourishment from the maternal intervillous sinuses it is an obvious corollary that both the production and delivery of the placental hormones are likewise dependent on the integrity of the decidual stroma and its vascular endothelium. Maximal delivery and utilization of the endogenous ovarian and placental hormones appear to be physiologically sound therapy. SUMMARY 1. Transection of the sympathetic and parasympathetic supply of the uterus and tubes by paracervical denervation has been described. 2. The color changes and growth phenomena indicate release of vasospasm and congestion and improved oxygenation. 3. Ovarian and parametrial congestion is relieved. 4. Growth phenomena after sequential unilateral tubal denervation suggest improved vascularity and maximal receptivity to hormones. 5. The usefulness of the procedure in the prevention of ectopic pregnancy during tuboplasty or associated with heterolateral salpingectomy for tubal pregnancy is suggested. 6. Study of the integrity of the placental site decidua suggests that during pregnancy physiologic homeostasis has been achieved probably by diminishing angiospasm and myometrial tension. 7. The possible role of decidual hypoxia in the etiology of isoimmunization from the interchange of Rh factor antigens and antibodies through the chorionic villi is suggested. REFERENCES 1.
BICKERS, W. Dysmenorrhea and the pelvic autonomic system. Assn. 48:10, 889-893, 1950.
]. South. Med.
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2. BICKERS, W. Personal communication. 3. CAMPBELL, R. M. Anatomy and histology of uterosacral ligaments. Am. J. Obst. & Gynec. 59:1, 1950. 4. CANNON, W. B., and ROSENBLUETH, A. Autonomic Neuro Effector Systems. New York, Macmillan, 1937, Chap. 14. 5. DAVIS, A. A. Intrinsic dysmenorrhea. Proc. Roy. Soc. Med. 29:931, 1936. 6. DAVIS, A. A. Dysmenorrhea: Aetiology, Pathology and Treatment. Oxford, England. Oxford Monograph Publications, Oxford Univ. Press, 1938. 7. DOYLE, J. B. Relief of dysmenorrhea by culdotomy: Preliminary report. ]. Irish M. Sc. 326:73, 1953. 8. DOYLE, J. B. Use of the pelviscope in culdotomy. ].A.M.A. 151 :605, 1953. 9. DOYLE, J. B. Ovulation and the effects of selective uterotubal denervation. Fertil. & Steril. 5:105, 1954. 10. DOYLE, J. B. Paracervical uterine denervation for dysmenorrhea. Tr. New England Obst. & Gynec. Soc. 8:143,1954. 11. DOYLE, J. B. Paracervical uterine denervation by transection of the cervical plexus for the relief of dysmenorrhea. Am. J. Obst. & Gynec. 70:1, 1955. 12. FRANKENHAUSER, G. Die Bewegungsnerven der Gebarmutter. Ztschr. Med. u. Naturwiss. 1 :35, 1864. 13. HERTIG, A. T., and KELLOGG, F. Surg. Clin. North America 4:585, 1955. 14. HODGKINSON, C. P. Physiology of ovarian veins during pregnancy. Obst. & Gynec. 1 :26, 1953. 15. INGERSOLL, F., and MEIGS, J. V. Presacral neurectomy for dysmenorrhea. New England]. Med. 238:357, 1948. 16. KEIFFER, H. Physiologie du systeme nerveux genital chez la femme. Rev. frant;. gynec. et obst. 128:449, 1933. 17. KEIFFER, H. La structure nerveuse du col uterin chez la femme. Bull. Acad. roy. mid. belgique 15:581, 1935. 18. LATARJET, A., and ROGET, P. Le plexus hypogastrique chez la femme. GynE~c. et obst. 6:225, 1922. 19. LEE, R., and SNow-BECK. Proc. Roy. Soc., London, s.B 1944, quoted by DAVIS,5 p.78. 20. MOIR, C. Recording contractions of the human uterus. Tr. Edinburgh Obst. Soc. 93: 120, 1933. 21. PAGE, E. W. Normal and Pathological Physiology of Pregnancy. Baltimore, Md., Williams & Wilkins, 1948. 22. REYNOLDS, S. R. M. Physiology of the Uterus (ed. 2). New York, Hoeber, 1949. 23. REYNOLDS, S. R. M. Physiologic Bases of Gynecology and Obstetrics. Springfield, Ill., Thomas, 1952. 24. REYNOLDS, S. R. M., HARRIS, J., and KAISER, 1. Clinical Measurement of Uterine Forces in Pregnancy and Labor. Springfield, Ill., Thomas, 1954. 25. STATE, D., and HIRSCH, E. Nerves of the adult endometrium. Arch. Path. 32: 939, 1941. 26. TAYLOR, H. J., JR. Vascular congestion and hyperemia. Am.]. Obst. & Gynec. 57:211; 637; 654, 1949. 27. TAYLOR, H., JR. Pelvic pain based on a vascular and autonomic nervous system disorder. Am.]. Obst. & Gynec. 67:1177, 1954. 28. WHITE, J. c. Conduction of visceral pain. New England]. Med. 246:686, 1952.
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Uterotubal Oxygenation and Growth After Paracervical Denervation Joseph Bernard Doyle, M.D.
THE
of this paper is to describe certain effects on uterine and tubal circulation of the simultaneous interruption of both the sympathetic and parasympathetic innervation by transection of the cervical division of the plexus of Lee-Frankenhauser or "paracervical denervation." The significance of these observed effects upon problems involving growth and oxygenation of the uterus and tubes will then be discussed briefly. PURPOSE
ANATOMIC CONSIDERATIONS
We have proposed a simple procedure for denervating the uterus and proximal tubes. 9 The sensory parasympathetic fibers to the cervix and the sensory sympathetic fibers to the fundus traverse the cervical division of the vaginal plexus of Lee-Frankenhauser which lies in, under, and around the attachments of the uterosacral ligaments to the cervix. Lee and Snow-Beck of London first described this important anatomic structure in 1844, antedating Frankenhauser by 20 years. At the cervical attachment of the uterosacral ligaments can be found the sympathetic fibers which have reached the cervix accompanying the uterine arteries. 3 The parasympathetic nerve components originate from the first to the third and fourth sacral nerves and reach the plexus via the pelvic nerves (nervi erigentes). Campbell, in a study of 33 cadavers, identified parasympathetic fibers in the anterior thirds of the uterosacral ligaments, conFrom the Department of Obstetrics and Gynecology, Cambridge City and St. Elizabeth's Hospitals, Boston, Mass . Presented on the scientific program of the Eleventh Annual Meeting of the American Society for the Study of Sterility, Atlantic City, N. J., June 4-5, 1955. 213
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firming the demonstration by Latarjet and Roget, and Davis 5 of the intimate association of the uterine nerves with the uterosacral ligaments with a supply of small ganglia around the area of attachment of the ligaments to the cervix. In the uterus the nerves accompany the blood vessels through the entire musculature of the basal layer of the mucosa. Hi Davis,6 using a combined intra- and supravital methylene-blue method, traced the majority of the nerves to their termination upon the capillary walls, and also by way of spindle-shaped endings to the muscle fibers of the myometrium. At the internal os there are special pseudopacinian sensory corpuscles in the endocervix. 19 The nerves to the spiral arteries are distinct from those to the basal arteries. 25 The sympathetic component transmits vasoconstrictors and inhibitory visceromotor fibers as well as the sensory fibers from the fundus. 6 The parasympathetic component transmits vasodilator and excitory visceromotor fibers to the uterus as well as sensory fibers to the cervix and probably the parametrium. An incision through the posterior vaginal fornix and the terminal 2.5 cm. of the uterosacral ligaments transects and interrupts not only the fundic but also the cervical sensory fibers. Such an incision interrupts the parasympathetic vasodilator fibers as well as the sympathetic vasoconstrictor fibers. Hence, neurovascular imbalance is avoided. We call this procedure "paracervical uterine denervatio~." The procedure may be done through the vagina, according to the method of culdotomy,7 or through the abdomen. 1o. 11 Since the culdotomy approach is simply the first step of a vaginal hysterectomy, gynecologists may prefer the vaginal approach, particularly if the illumination is improved by the use of the pelviscope set, 8 which consists of a lighted right-angle retractor with twin lights at its tip and a set of 2 telescopes offering right-angle and foroblique fields of vision with a threefold magnification. The general surgeon may prefer the abdominal approach. It has been our practice to reserve the vaginal approach for those cases of dysmenorrhea where pelvic examination, both vaginally and rectally, revealed tenderness but no nodulation in the uterosacral ligaments and a cul-de-sac free of induration or masses. The vagina must be free of infection. In a series of 73 cases for relief of dysmenorrhea, the denervation was done by the vaginal route in 36 cases, by the abdominal route in 37 cases.10. 11 To prevent regrowth of the nerves, the posterior leaf of the peritoneal
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incision is sutured over the ends of the proximal stumps of the uterosacral ligaments to the mucosa of the top of the vagina by chromic gastrointestinal sutures (Fig. 1). The importance of the role of the cervix in dysmenorrhea and labor has recently been stressed by Reynolds,23.24 who concluded that the cervix and
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Fig. 1. Technic per vaginam. The uterosacral ligaments have been ligated and cut. The posterior peritoneum has been sutured over them to the vaginal mucosa.
the tissues adjacent to it are the site of uterine pain. Ingersoll and Meigs, White, and others concede that the cervical nerve supply is not usually interrupted by the presacral neurectomy procedure. The cervical sensory supply runs in large measure with the nervi erigentes through the parasympathetic fibers reaching the cord via sacral roots 2, 3, and 4. Relief of acquired dysmenorrhea with or without antecedent primary dysmenorrhea was obtained satisfactorily in 69 of 73 cases (94.5 per cent). The relief was complete in 63 cases (86.3 per cent) .10. 11 NEUROVASCULAR PHYSIOLOGIC CONSIDERATIONS It seems likely that the relief from dysmenorrhea that has been obtained
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in some of our cases is on a partially sensory and partially neurovascular basis. Many nerves end in the wall of small arterioles and capillaries in and between the uterosacral ligaments and in the outer layers of the back of the cervix itself (Fig. 2). Taylor 6 , 27 has described premenstrual and menstrual thickening and tension and tenderness of these ligaments and the under-
Fig. 2.
Nerves ending in small arterioles in the deep layers of the uterosacral ligaments.
lying cul-de-sac area as pathognomoniC of the pelvic autonomic syndrome or pelvic congestion. The exact mechanism of this congestion in the uterosacral ligaments is not known. POSSibly it may arise from angioneurotic edema from parasympathetically conditioned deposition of acetylcholine at the neurovascular effectors in these many small arterioles in the area. Whether tissue edema and hypoxia or acetylcholine directly then stimulates the retrocervical postganglioniC parasympathetic fibers cannot be determined at this time. Whatever the mechanism, surgical transection consistently relieves the local
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congestion of the ligaments and the severe dyspareunia that accompanies it. 7, 10, 11
That this denervation may have ameliorated a neurovascular imbalance involving the uterine-parametrial-ovarian circulation is suggested by the remarkable relief of pain in those 25 cases in the series which were associated with marked varicosities of the ovarian and the uterine venous plexuses. Hodgkinson has recently calculated the enormous 60-fold increase in the capacity of the ovarian pampiniform venous plexus as measured at the ovarian vein at full-term pregnancy. He has demonstrated the hypertrophy of the smooth-muscle fibers, which implies an active physiologic role for these veins during labor as a ballie mechanism in damping sudden high pressures, Because of the wide anastomoses which exist between the uterine and ovarian venous plexuses by way of the pampiniform veins, the release of high venous pressure in the parametrial venous system offers improvement of circulatory stasis in the ovaries, This explains the relief of ovarian and parametrial tenderness in the patients with lateral pain. Such an anatomic approach for relief of circulatory stasis is more logical than the interruption of the infundibulopelvic veins during ovarian denervation. We have raised the question whether autonomic imbalance could underlie the persistence of such venous enlargement. Coexistent cyanosis of the uterus and tubes was seen to disappear promptly during the course of the denervation procedure in 25 cases wherein uterine anteposition ruled out mechanical interference with circulation.lO Some neurovascular explanation seemed indicated. The caliber of the dilated parametrial, ovarian, and uterine venous plexuses was observed to diminish in some cases. In 2 cases dark veins at the uterovesical fold blanched out strikingly. Since these 25 women had acquired their dysmenorrhea after childbirth it appeared that in some women the postpartum uterus suffers from circulatory stasis or congestion sufficient enough for hypoxia or angiospasm or both to cause pain during the premenstrual-congestion phase of the cycle and during menstruation and occasionally to condition profuse flow during the menses. Davis 6 had warned that presacral neurectomy-a high sympathectomy-left the nervi erigentes from sacral roots 2, 3, and 4 entering the uterus through the uterosacral ligaments totally unopposed, and that the ensuing neurovascular autonomic imbalance explains the not-infrequent menometrorrhagia after such an unbalanced neurovascular procedure. We have never
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experienced menometrorrhagia after any of our paracervical denervation procedures unless we had simultaneously removed the corpus luteum so that an anovulatory endometrium was present. In patients in whom pelvic congestion was seen to be present the complete relief of pain obtained is in some instances permanent only after 2 or 3 cycles. We believe that any transient persistence of menstrual ache is due to this gradually receding uterine and parametrial congestion. The remarkable relief of lateral pelvic pain may be due to diminished venous pressure within the ovary or to the improvement of vascularity in the ovarian spiral arterioles consequent upon denervation of the uterine artery which permits it to send more oxygen to the ovary through its ovarian branch. The congestive bleeding which usually accompanies a high superior hypogastric sympathectomy of the uterus (presacral type) does not occur since the paracervical procedure by including the parasympathetic vasodilators avoids autonomic imbalance and congestion. Moreover, we have on three occasions seen enormous parametrial varices, uterine cyanosis, and enlargement actually develop subsequent to presacral neurectomy. The associated pain was promptly relieved by re-establishing uterine autonomic balance by the para cervical denervation technic. The relief of associated menometrorrhagia, the absence of postoperative congestive bleeding, and the improvement of uterine and tubal cyanosis all suggest that there is a secondary improvement in uterine neurovascular physiology after this procedure. NEUROMUSCULAR CONSIDERATIONS The observations of Moir that dysmenorrheic women produce intrauterine tension greater than that observed during the second stage of labor led him to ascribe the pain to ischemic anoxia of the myometrium due to hypercontractility of the myometrium. Bickers! electrically stimulated the intact uterosacral ligaments during laparotomy and produced uterine blanching from myometrial spasm. In 3 patients in whom presacral neurectomy failed to change the abnormally hypertoniC uterine pattern of contractions as observed by the intrauterineballoon technic, subsequent transection of the uterosacral ligaments by oUI technic returned the pattern to nonnalcy.2 It appears that including the parasympathetic neuroexcitory fibers in the denervation ensures neuromuscular normalcy. This, in turn, will ensure adequate blood flow through
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the previously hypertoniC musculature, since Keiffer16 has showed that the tunica media of the arteries in the inner fourth of the myometrium is continuous with the smooth muscle of the myometrium itself. It is obvious that circulatory improvement means improved vitality of the myometrial sphincteric action to control excess How from the menstrually denuded orifices of the endometrial arterioles. The maintenance of neurovascular and neuromuscular autonomic balance is mutually complementary. OBSERVATIONS OF UTERINE AND TUBAL GROWTH In a previous communication9 we presented evidence that the high initial pressure recorded on the Kidde kymograph during uterotubal insufRation with C02 was consistently eliminated by uterotubal denervation. Since this admittedly denotes relief of uterotubospasm we suggested that the denervation procedure be done on the opposite tube whenever one tube was sacrificed for tubal pregnancy. If denervation improves vascularity and permits uterotubal growth, then it would be a useful addition to uterotuboplasty to aid epithelial regeneration and tubal contractility. Although we had kymographiC and motion-picture proof that the newly denervated tubes were well vascularized and more vigorous and rhythmic,9 we could not determine whether this was due merely to loss of innervation and thereby due to the elimination of the deposition of the chemical neuroeffectors, adrenin and acetylcholine, or whether there might be improved vascularity from denervation of their blood supply. We therefore raised the question of whether such improved vascularity, especially since it was balanced so as not to produce congestion, might not improve the delivery of ovarian and placental hormones to the uterus and tubes. According to the physiologic principle laid down by Cannon, denervated smooth muscle is rendered more receptive to its stimulating agents when deprived of all its autonomic nerve supply. It was noted that the increased sensitivity of the tissues is not specific for anyone hormone. Increased permeability of the cell membrane of the smooth muscle was thought to be the likely mechanism. In a given time more of the stimulating agent penetrates the cell. Having demonstrated good glandular tortuosity and secretion in a Day 25 endometrium from a uterus which had been denervated on Day 13 simultaneous to removal of three fourths of the newly formed corpus luteum, we
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suspected that such a maximal response from minimal source of ovarian steroids demanded some such explanation. 9 Raising the question whether the chronically denervated uterus might reveal any such phenomenon we did an endometrial biopsy on Day 16-
Fig. 3. Day 16 biopsy of an endometrium which was denervated 16 months previously. Note spiral arteriolar growth to margin of endometrium and tortuosity of glands.
sixteen months after the paracervical uterine denervation. The spiral arterioles were found to have grown out to the margin of the endometrium (Fig. 3). The glandular tortuosity was likewise more advanced than usual for so early in the luteal phase of the cycle. Similar early growth of spiral
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arterioles has been described by Bickersl after sympathectomy, and ascribed, by the Cannon principle, to more rapid and complete delivery and utilization of the hormones. Since the steroid output in early corpora lutea is variable, this evidence, while very suggestive, is not conclusive. However, it has been possible to devise a phYSiologic experiment which appears to offer unequivocal evidence that the miillerian system does respond to denervation by improved vascularity with greater delivery of oxygen and hormones and with increased response to the hormones. The evidence consists in sequential unilateral tubal growth after denervation of each tube on separate occasions. The embryologic fact that the miillerian ducts are paired offers a unique opportunity to subject each tube to denervation on separate occasions. If any demonstrable growth changes occur in the denervated tube we know that the exposure to hormones by improved vascularity must be acknowledged, since the un denervated tube received the same general blood level of hormones simultaneously. Any daily fluctuation in hormone levels would otherwise affect both tubes to the same extent. To minimize the source of hormones a woman with amenorrhea of considerable duration would be ideal, particularly if she had marked evidence of uterine and tubal hypoplasia.
Case 1 Miss J. c., an unmarried, 22-year-old telephone supervisor, complained of secondary amenorrhea of 18 months' duration and of deep right pelvic pain causing insomnia for 5 months. Pelvic examination revealed an infantile uterus, a cyanotic, long, conical cervix, and a bilaterally tender parametrium. Excretion of FSH was positive for 13 mouse units per 24 hours. 17-Ketosteroid excretion was 4.9 mg. per 24 hours. Total iodine was 7.6; P.B.I. was 6.4 fig· At operation, January 16, 1953, the fundus revealed no endometrium on curettage. Total uterine depth was 5 cm. Laparotomy revealed small lobulated ovaries without visible follicles or corpora lutea. The uterus and tubes were infantile and cyanotic. The fimbrial orifices did not reach the level of the uterosacral ligaments. The ovarian pampiniform plexus of veins was bilaterally engorged. The uterine and ovarian arteries were small. To relieve the pelvic pain from congestion syndrome the right uterosacral ligament was transected down to the top of the vagina, interrupting the right uterotubal sensory and neurovascular nerve supply at this point. The pelvic pain did not recur. No hormone therapy was given. The amenorrhea persisted for a total of 40 months. The patient returned because of recurrent pain in the upper abdomen. Accordingly, exploratory laparotomy was done 22 months after the right tubal denerva-
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tion on November 2, 1954. Curettage revealed no endometrium. At laparotomy under spinal anesthesia the uterus and tubes were still cyanotic, the parametrium still engorged. However, measurement of the tubes now revealed that the denervated right tube was 8.4 cm., the left tube 6.8 cm. There was an obvious increase in the tubal caliber and the size of the infundibulum and fimbriae. The left tube and the uterus were now denervated by transection of both left and right cervical-uterine divisions of the pelvic plexus by transecting both utero-
A
B
Fig. 4.
Uterotubograms subsequent to sequential unilateral denervation of the tubes.
A, 6 weeks after second denervation. The right tube (22 months after its denervation)
shows a good isthmic and infundibular cavity. The left tube (6 weeks) shows no growth yet. B, 12 weeks after second unilateral denervation. The left tube (after 3 months) has now comparable isthmic length and caliber and a good infundibular shadow.
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sacral ligaments down to the vagina. Within a few minutes the cyanosis disappeared from both tubes and the uterus. To evaluate subsequent growth changes, serial uterotubograms were taken at 6- and 12-week intervals. At 6 weeks (Fig. 4A) the right tube was obviously longer than the more recently denervated left tube, and has a well-defined infundibular caliber. The left tube had not yet developed an infundibular shadow. At 12 weeks (Fig. 4B) both tubes showed well-defined infundibular caliber. The left tube had by this time achieved greater length and isthmic caliber than in the previous film.
As in the patients with dysmenorrhea and pelvic congestion described above, this relief of cyanosis appears to be a local neurovascular effect due to the interruption of both types of neurovascular autonomic fibers which course through this area to the many small arterioles in the area itself as well as to those of the uterine and tubal musculature and mucosa. Since the pre-existing cyanosis was unrelieved by spinal anesthesia, a cord reflex mechanism is untenable. No extrinsic hormones were given after the operation. It appears therefore that sequential unilateral uterotubal denervation resulted in sequential growth of each tube. The prompt relief of cyanosis suggests that some local neurovascular effect of transecting the retrocervical nerve structures ameliorates uterine and tubal circulation and hence improves oxygenation and delivery of hormones. We applied the same de nervation test to determine the responsiveness of the lower half of the miillerian system as described in Case 2: Case 2 Mrs. M. H., a 32-year-old married patient, had had 3 spontaneous abortions, each occurring at 6 weeks' gestation. X-ray studies elsewhere had revealed a congenital defect, uterus bicornuatus unicollis, for which excision of one horn had been advised. Since a repeat uterotubogram revealed equality of the cornua this surgery seemed illogical. The filling of the uterus and tubes required 5 cc. contrast medium (Fig. 5A). Accordingly, a paracervical denervation was done by culdotomy on February 8, 1954. No hormones were given and pregnancy was avoided for 1 year postoperatively. On January 17, 1955, 10 cc. of contrast medium filled the uterus and only partially outlined one of the tubes. Making due allowance for the distortion of retroversion and distention by the dye in the latter film (Fig. 5B), both cornual cavities appeared to be broader and blunter at the cornual tubal junction. The cervical cavity appeared to be larger. Since both films were taken during the
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postmenstrual phase they are comparable. They are meaningful when the evidence for controlled unilateral tubal growth is considered. The patient delivered a live 1758-Gm. male infant at 33 weeks which died of hyaline membrane disease 8 hours after cesarean section for slight intrapartum separation of the placenta.
A
B
Fig. 5. Uterotubogram of a uterus bicornuatus unicollis. A, before denervation, 5 cc. Salpix. B, 1 year after denervation, 10 cc. Salpix his distended both cornua but only one tube. The cornual cavities are apparently broader and blunter.
If it has been demonstrated that such a uterus with its faulty shape, faulty connective tissue, and faulty musculature responds to denervation by improvement in growth, the usefulness of the denervation procedure to evaluate the clinical problems associated with uterine growth and vascularity during pregnancy is obvious.
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CLINICAL CONSIDERATIONS IN OBSTETRICS Theoretical Considerations R~ynolds23
has shown that hormonal and vascular effects work together to elicit structural changes in the uterus which are characteristic of estrogen and progesterone: Noone has ever shown that estrogen acts upon the excised uterus to initiate rhythmic contractility. Uterine circulation is essential to provide materials for an assimilation type of metabolism. Myometrial activity depends on a normally functioning vasculature. Whereas, in turn, the rhythmic activity apparently serves the purpose of forcing blood through a small undeveloped vasculature in an endometrial tissue having a low metabolism. Not only does the pumping action of the muscular movements assist venous drainage from the organ, but metabolites which are locally produced by the tissue contribute to the continued vasodilation of the capillary vessels of the organ. By elimination of autonomic neurovascular imbalance through the interruption of both sympathetic and parasympathetic pathways, the local vasospasm disappears. The more constant uterine circulation can now deliver a higher concentration of estrogen and proges"terone to the tissues of the myometrium and endometrium. But greater estrogenic hormone concentration in the myometrium means better myometrial growth. Since myometrial elasticity and contractility in the last trimester depend upon greater growth and vascularity of the myometrium in the early trimesters, it is now suggested that the autonomic denervation procedure should aid the prolongation of pregnancy without the use of extrinsic oral or parenteral hormones. Reynolds 22 has demonstrated that the uterus reaches its greatest transverse diameter at the thirty-second week. Thereafter it virtually ceases to grow, although the fetus continues to increase in size. Unless the vessels of the myometrium and the decidua have also obtained optimal growth, the result may be ischemia, anoxia, thrombosis, and necrosis of the decidua. This is the ordinary hazard of the third trimester of pregnancy. If severe, the thrombosis and infarction of the vascular bed of the decidua at the site of implantation of the placenta may provide the environment for premature separation of the placenta. These lesions may accompany toxemia, or be present in the absence of toxemia. Reynolds 23 has raised the question: Are toxemias, miscarriages "without a known etiology," or so-called idiopathic abortion the result of failure of one of these mechanisms? If so, we look too late
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for the cause of the condition. We think of toxemia as a crisis at the moment it appears when, in fact, it may have a morphological and physiological basis dating much earlier in gestation. Thus we should consider faulty metabolism, faulty shape, faulty connective-tissue development or faulty vasculature as possible contributing factors to these obstetrical complications. One or more of the complications of pregnancy may have their basis in abnormal mechanisms of uterine accommodation of the products of conception. The integrity of the vascular supply to the placenta depends upon the integrity of the placental site rather than any intrinsic strength of the vessels themselves. It then becomes evident that dissolution of the placental site will result in rupture of the decidual sinusoids, leading to placental separation. Perhaps vascular spasm of the spiral arterioles without demonstrable lesions may play the major role, as Hertig and Page have postulated. Clinical Evaluation The ultimate objective index of the persistence of optimal homeostasis and oxygenation of the uteroplacental lake is the microscopic normalcy of the decidual tissues at the site of implantation as well as that of the chorionic villi. Mter this type of balanced denervation, decidual biopsies at the placental site as well as microscopic appearance of the chorionic villi have been consistently within normal limits. The course of pregnancy has been observed in 39 women, of whom 32 were under fertility study. The others were incidental pregnancies following the operation for dysmenorrhea. Eight are now undelivered. Thirty-one patients have delivered once. Six have delivered twice. There have been no intrauterine deaths. There were only 2 blighted-ovum abortions. There have been 38 live-born infants, including 1 set of twins at 35 weeks. This mother had chronic pyelonephritis and impending renal shut-down. Yet there was no sign of toxemia in her eyegrounds. The placenta revealed no gross infarcts nor microscopic syncytial degeneration, despite the fact that prior to her denervation she had a full-term eclampsia with abruptio placentae and postpartum hemorrhage and then 8 successive spontaneous abortions. Following her delivery as with all the others there was minima] blood loss in the third stage and the puerperium. Two women with subpubescent uteri whose pregnancies commenced 1 and 3 months respectively subsequent to denervation were delivered at 40 and 41~ weeks respectively without vascular accident. No hormones were given.
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Two other patients with small uteri had previously had circumvallate placentas and had 2 pregnancies each complicated by premature separation. One patient had 6 previous premature separations at 24 to 28 weeks, all breech presentations with 5 neonatal deaths. After denervation her next 2 pregnancies went to 32 and 39 weeks with live births and no hemorrhages. The ensuing presentations were vertex, suggesting easier accommodation within a roomier uterus. Placental site biopsies showed no necrosis (Fig. 6).
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Fig. 6. Biopsy of decidua at placental site after second delivery since denervation. Before denervation, 6 pregnancies terminated at 24-28 weeks with separation of the placenta. Chorionic villi and decidua show no necrosis or thrombosis.
Further evidence that this type of uterine denervation is superior to that obtained by the presacral neurectomy can be seen from the absence of uterine cramps and backache during the first stage of labor. If the fetal head was held out of the pelvis by a tight cord there was absolutely no pain with uterine contractions during the course of a 12-hour labor until the head became engaged deeply enough to press upon the pelvic floor. The aggravating low sacral ache, so frequently present during the course of posteriorocciput presentation was absent in these cases as long as the head impinged only on the cervix and not on the pelvic floor. The usual complaint then was recurrent tension at the insertion of the round ligaments into their inguinal attachment to the abdominal wall. Later, pressure on the rectum and perineum occurred. None of the 31 patients who have delivered 38 live
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jnfants to date subsequent to this type of denervation either had a precipitate labor nor one of less than 2 hours' duration. This is in contrast to the not-infrequent precipitous labors after presacral neurectomy due to the unopposed stimulation of the detrusor parasympathetic system. The uterine contractions are regular in rhythm and of good 40-50-second duration. There is good uterine relaxation between the contractions. The uterus acts normally to oxytocics such as Pitocin when induction of labor is desired. The third stage of labor is brief and unaccompanied by excessive blood loss.
UTEROTUBAL DENER.VATION DivisiDn Df Frankenhaus.ril Pl.xus in and betws8D 'h. Uterosacral Ligaments I~ SYMPATHETIC FIBRES
PARASYMPATHETIC FIBRES
"euromotor 11\l\lbltOl' t. uterus
WeuromOlor IXcilor to utera. tub •• leJ\IDry to camx V••• oUlltora from "narYi .rlgmtt.-
tub ..
IlnlOI'J' to runda.r V'loconllrieton hom "pre,"cral 1\.rna·
Re~ AUTONOMIC IMBALANCE
UTERO TUBOSPASM
wIeWt Conditiom MYOMETRIAL UTERINE VASOSPASM
l\
IRRITABILITY
Tu'bal
Tultal
Occ:1alion Pregnancy
Dym.nmhea
~
MYjmetril1
EndO. metria1 ThJmltl'ieNlcrosi,
Rlp.at ~aratl.n Aliortion" placenta
Fetal Malnutrition
Fig. 7.
Pathological physiology remediable by paracervical uterotubal denervation.
Involution of the fundus is rapid and satisfactory even without oxytocics. There was complete absence of so-called "after pains" from uterine contractions. Placental Permeability. The most interesting result was that obtained subsequent to denervation at the third month of an Rh-negative mother gravida V whose last two pregnancies had resulted in hydrops and neonatal death at 39 weeks and intrauterine death at 36 weeks, respectively; her first infant was unaffected and the second saved by a prompt transfusion. The husband was Rh positive, "probably homozygous." The maternal titers
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for anti-Rh antibodies were: 12 weeks, 1:4; 13 weeks, 1:16; 15 weeks, 1:32; 21 weeks, 1:16; 36 weeks, 1:8; and 38~ weeks, 1:4 in albumin. However, because conflicting titers of 1:128 and 1:256 were obtained from two other excellent laboratories, labor was induced by artificial rupture of the membranes and Pitocin. After a 12-hour test of painless unmedicated labor, because of a variation in rate and strength of the fetal heart sounds from 160 to 170, a low transverse cervical cesarean section was performed under spinal anesthesia. A living male infant, 20 inches long and weighing 2420 Gm., was delivered and cried at once spontaneously. Although the infant developed a pulmonary hyaline membrane and died 8 hours later, gross and microscopic examination of the liver, spleen, lungs, and the placenta and decidua at the placental site revealed no evidence of erythroblastosis fetalis or vascular damage. The infant cord blood was Group A, Rh positive, with an antibody titer of 1: 32 in albumin, 1: 1 in saline, and a positive Coombs test. One raises the question: did the denervation permit the homeostatic uterine decidua to minimize the permeability of the placental barrier to antigens and antibody? Does uterine hypoxia underlie the permeability of the endothelium of decidual vessels and the chorionic epithelium? If oxygenation of the decidua is maintained the chorionic villi will be better oxygenated via the uteroplacentallake. That this may minimize the passage of antigens by preventing breakdown of the villi is suggested by the integrity of the villi observed. That the integrity of the villi may in turn prevent the return of the antibody-a chemically larger molecule-seems more likely. Although the possibility of lessened reactivity of the mother cannot be overlooked, this factor seems unlikely in view of her past history. Since there is nothing else to offer the Rh-positive infant in Rh-negative patients with a history of repeated intrauterine and neonatal fetal death from Rh-isoimmunization, we suggest that the procedure of uterine denervation which will normalize the vascular and myometrial tension phenomena and minimize ischemia may prove useful in preserving the oxygenation of the decidua and chorionic villi through maximal oxygenation of the uteroplacental lake.
DISCUSSION Although the other causes of infant death in association with the birth process are often obscure, there is general agreement that by far the most
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important cause is anoxia. The principal cause of death before birth and in the first few weeks of life is interference with oxygenation. The human infant in utero is completely dependent for its oxygen supply upon the vagaries of uteroplacental circulation. A uterus which has been relieved of neurogenic muscle tension and vasospastic ischemia should deliver hormones and oxygen more constantly to the myometrium and endometrium. If the stability of the blood supply of the uterus is maintained so that the placenta-nature's most potent hormone factory-can enjoy physiologic homeostasis and oxygenation, it will produce more hormones intrinsically and deliver them maximally. Since the placental trophoblast obtains its nourishment from the maternal intervillous sinuses it is an obvious corollary that both the production and delivery of the placental hormones are likewise dependent on the integrity of the decidual stroma and its vascular endothelium. Maximal delivery and utilization of the endogenous ovarian and placental hormones appear to be physiologically sound therapy. SUMMARY 1. Transection of the sympathetic and parasympathetic supply of the uterus and tubes by paracervical denervation has been described. 2. The color changes and growth phenomena indicate release of vasospasm and congestion and improved oxygenation. 3. Ovarian and parametrial congestion is relieved. 4. Growth phenomena after sequential unilateral tubal denervation suggest improved vascularity and maximal receptivity to hormones. 5. The usefulness of the procedure in the prevention of ectopic pregnancy during tuboplasty or associated with heterolateral salpingectomy for tubal pregnancy is suggested. 6. Study of the integrity of the placental site decidua suggests that during pregnancy physiologic homeostasis has been achieved probably by diminishing angiospasm and myometrial tension. 7. The possible role of decidual hypoxia in the etiology of isoimmunization from the interchange of Rh factor antigens and antibodies through the chorionic villi is suggested. REFERENCES 1.
BICKERS, W. Dysmenorrhea and the pelvic autonomic system. Assn. 48:10, 889-893, 1950.
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2. BICKERS, W. Personal communication. 3. CAMPBELL, R. M. Anatomy and histology of uterosacral ligaments. Am. J. Obst. & Gynec. 59:1, 1950. 4. CANNON, W. B., and ROSENBLUETH, A. Autonomic Neuro Effector Systems. New York, Macmillan, 1937, Chap. 14. 5. DAVIS, A. A. Intrinsic dysmenorrhea. Proc. Roy. Soc. Med. 29:931, 1936. 6. DAVIS, A. A. Dysmenorrhea: Aetiology, Pathology and Treatment. Oxford, England. Oxford Monograph Publications, Oxford Univ. Press, 1938. 7. DOYLE, J. B. Relief of dysmenorrhea by culdotomy: Preliminary report. ]. Irish M. Sc. 326:73, 1953. 8. DOYLE, J. B. Use of the pelviscope in culdotomy. ].A.M.A. 151 :605, 1953. 9. DOYLE, J. B. Ovulation and the effects of selective uterotubal denervation. Fertil. & Steril. 5:105, 1954. 10. DOYLE, J. B. Paracervical uterine denervation for dysmenorrhea. Tr. New England Obst. & Gynec. Soc. 8:143,1954. 11. DOYLE, J. B. Paracervical uterine denervation by transection of the cervical plexus for the relief of dysmenorrhea. Am. J. Obst. & Gynec. 70:1, 1955. 12. FRANKENHAUSER, G. Die Bewegungsnerven der Gebarmutter. Ztschr. Med. u. Naturwiss. 1 :35, 1864. 13. HERTIG, A. T., and KELLOGG, F. Surg. Clin. North America 4:585, 1955. 14. HODGKINSON, C. P. Physiology of ovarian veins during pregnancy. Obst. & Gynec. 1 :26, 1953. 15. INGERSOLL, F., and MEIGS, J. V. Presacral neurectomy for dysmenorrhea. New England]. Med. 238:357, 1948. 16. KEIFFER, H. Physiologie du systeme nerveux genital chez la femme. Rev. frant;. gynec. et obst. 128:449, 1933. 17. KEIFFER, H. La structure nerveuse du col uterin chez la femme. Bull. Acad. roy. mid. belgique 15:581, 1935. 18. LATARJET, A., and ROGET, P. Le plexus hypogastrique chez la femme. GynE~c. et obst. 6:225, 1922. 19. LEE, R., and SNow-BECK. Proc. Roy. Soc., London, s.B 1944, quoted by DAVIS,5 p.78. 20. MOIR, C. Recording contractions of the human uterus. Tr. Edinburgh Obst. Soc. 93: 120, 1933. 21. PAGE, E. W. Normal and Pathological Physiology of Pregnancy. Baltimore, Md., Williams & Wilkins, 1948. 22. REYNOLDS, S. R. M. Physiology of the Uterus (ed. 2). New York, Hoeber, 1949. 23. REYNOLDS, S. R. M. Physiologic Bases of Gynecology and Obstetrics. Springfield, Ill., Thomas, 1952. 24. REYNOLDS, S. R. M., HARRIS, J., and KAISER, 1. Clinical Measurement of Uterine Forces in Pregnancy and Labor. Springfield, Ill., Thomas, 1954. 25. STATE, D., and HIRSCH, E. Nerves of the adult endometrium. Arch. Path. 32: 939, 1941. 26. TAYLOR, H. J., JR. Vascular congestion and hyperemia. Am.]. Obst. & Gynec. 57:211; 637; 654, 1949. 27. TAYLOR, H., JR. Pelvic pain based on a vascular and autonomic nervous system disorder. Am.]. Obst. & Gynec. 67:1177, 1954. 28. WHITE, J. c. Conduction of visceral pain. New England]. Med. 246:686, 1952.