Introduction

Surgical treatment of endometriosis by bilateral oophorectomy with or without hysterectomy is usually regarded as curative therapy, even though residual disease may remain. It is used in patients with sufficient pain who have failed previous therapies and who do not desire future fertility. Despite this therapy, there have been reports [1, 2, 3, 4, 5] of symptomatic endometriosis following castration, even without estrogen replacement therapy. Although these case reports illustrate that endometriosis can be found after such surgery, their small numbers do not give a complete overview of endometriosis occurring after castration.

This report described a series of patients with endometriosis diagnosed surgically after previous castration. Using contemporaneous, prospectively gathered data, I examined anatomical considerations and response to surgical excision.

Materials and methods

Among 1677 surgical cases that I treated between July 1978 and July 18, 1993, 1318 (78.6%) had histologically proven endometriosis. The chief indication for surgery in all endometriosis patients was pain. Of those with endometriosis, 85 had previously been castrated. Ten of these 85 had histologically proven ovarian remnant at surgery and were excluded, leaving 75 castrated patients without ovarian remnant syndrome for consideration in this study. Forty-two others with previous castration or hysterectomy did not have endometriosis at surgery and were excluded.

Of the study group, 14 had been on estrogen in the past, five had never taken estrogen, and 56 were on estrogen at the time of surgery in the hope that endometriosis might be more visible. Post-castration estradiol (E2) levels obtained before surgery while the patient was not on estrogen therapy were less than 51 pg/mL in 12 cases. Of ten post-castration FSH levels without accompanying E2 levels, six were greater than 40 mIU/mL. Before surgery, 21 subjects had previous treatment with danazol, 17 with progestins, seven with GnRH agonists, seven with excision, five with laser vaporization, five with oral contraceptives, and four with electrocoagulation; nine had no treatment other than the previous castration. Six patients waited 6 months after castration before initiation of estrogen replacement therapy. Several had undergone medical therapy of endometriosis after castration.

Operative reports were available for the final castration procedure for 67 (89%) in the study group. In 49 (73%), endometriosis was seen at sites other than the uterus, tubes, or ovaries, and was treated by electrocoagulation or excision in 12 (18%). Twenty-two (33%) of the 67 operative reports described obliteration of the cul-de-sac at castration, whereas 24 (36%) described no ovarian adhesions at the time. The time interval between castration and my surgery ranged from 0.2-22.1 years, with an average of 3.8.

The comparison group consisted of 1190 patients with biopsy-proven endometriosis without previous castration, hysterectomy, or ovarian remnant who were undergoing excision of their disease for pain.

All surgery in both groups was performed by me, and tissue suspicious for endometriosis was aggressively excised whenever found. Aggressive, radical excision was performed at laparoscopy or laparotomy when necessary, using sharp [6] or monopolar electrosurgical [7] methods. Partial- or full-thickness or segmental bowel resections were performed when necessary. In the study group, hysterectomy was performed on two patients who had undergone previous supracervical hysterectomy because of surgical difficulties encountered at previous surgery elsewhere.

Excision of endometriosis was the surgical treatment of disease in all patients. Follow-up laparotomy [8] and laparoscopy [9] studies have indicated consistent efficacy of this technique in long-term reduction or eradication of disease. Endometriosis can invade several centimeters beneath the visible surface [10, 11, 12], and such disease can be detected and treated only by excision. Excision can be used to treat disease anywhere in the pelvis or intestinal tract.

Non-excisional techniques, such as electrocoagulation, electrofulguration, endocoagulation, or laser vaporization, were not used in any subject in either group. Beyond the obvious difference in surgical effect, other fundamental differences exist between excision and non-excisional techniques. Articles on electrocoagulation [13, 14, 15, 16, 17, 18] described limitations on use over vital structures and did not contain sufficient details regarding the electrosurgical generator, power settings, type of active electrode, or surgical technique to allow reproducible application. While laser vaporization techniques are better described in the literature, there remain limitations on use over vital structures. Non-excisional techniques have not been adequately described for complete treatment of deeply invasive or intestinal endometriosis. Finally, follow-up studies on non-excisional modalities have focused on the response of infertility or pain rather than documenting the efficacy of disease reduction or eradication. For these reasons, electrocoagulation, electrofulguration, endocoagulation, and laser vaporization of endometriosis cannot be considered equivalent to excision in either biologic surgical effect or in available scientific evidence of therapeutic effect. The use of non-excisional techniques would eliminate biopsy control of both the study and comparison groups, and the mixing of non-equivalent surgical techniques would confuse the study of symptom response.

Endometriosis was diagnosed histologically on resected tissue in all patients based on the presence of glands and stroma. Perioperative medical therapy for endometriosis was not given to anyone in either group. Estrogen, usually conjugated equine estrogens, 1.25 mg/day without progesterone supplementation, was prescribed immediately post operatively to all patients in the study group.

Contemporaneous records are kept on all patients, including birth date, date of surgery, gravidity, parity, stage of disease as represented by the revised American Fertility Society classification system for endometriosis [19], anatomical names and total number of pelvic and gastrointestinal areas involved by endometriosis, prior surgical or medical treatment, and the presence of intestinal adhesions.

Before surgery, the women completed a five-point verbal analogue pain scale to measure subjective pre-operative symptom levels (Table 1). Since 1989, questionnaires have been mailed annually to patients who underwent surgery at least 6 months earlier, and the patients are requested to complete the same pain scale each year. The results of this study include responses to questionnaires mailed in May 1993. Follow-up beyond 1 year is not available for 13 patients who underwent surgery by me after May 1992 and for five others who did not reply to any questionnaire, although preoperative pain scales were tabulated for most patients in the study group. When subsequent surgery by another physician was detected by follow-up questionnaire, the operative report and pathology report, if one existed, were obtained for review. Questionnaire responses were available for 58 patients followed for at least 1 year postoperatively. If a woman did not participate in an activity such as coitus or exercise preoperatively or postoperatively, that response was either left blank or answered with a level of 1 ("not a problem").

* A similar appropriately worded scale was completed to evaluate symptoms before surgery.
† Items b and c are not included in this scale for these patients because these points are related to uterine symptoms that do not apply to patients with previous hysterectomy. Patients without previous hysterectomy undergoing conservative excision of endometriosis complete an identical pain scale including b and c.

All data and questionnaire responses were tabulated on a Macintosh IIfx computer (Apple Corp., Sunnyvale, CA) using a programmable data base application (FoxBase+Mac; Microsoft, Redmond, WA) programmed in dBASE source code. Age at surgery was calculated by subtracting the Julian day number of the birth date from the Julian day number of the surgery date and dividing the resulting number of days by 365.25.

Age at surgery was compared by the standard error of the difference of means, with 95% confidence intervals (CI) calculated on the difference between the means. The null hypothesis, that no difference exists between the study and comparison groups with respect to frequency distribution of sites of pelvic involvement, was tested by x² analysis, with further illumination by computation of the relative risk (RR) of intestinal disease with corresponding 95% CIs. The Mann-Whitney test was used to compare preoperative pain scales with postoperative pain scales, with the resultant z value evaluated for significance on a two-tailed distribution table.

Results

Previously castrated endometriosis patients were significantly older (mean ± standard deviation [SD] 37.8 ± 8.1 years, range 23.9-74.8) than those with endometriosis who were not castrated (31.3 ± 6.9 years, range 13.0-57.7) (P < .001, 95% CI 4.9-8.1, df = 1263), and were slightly more likely to have intestinal involvement (Table 2).

GI = gastrointestinal
Some patients had more than one area of intestinal involvement.
Involvement of the appendix is not tabulated, as many patients had previous appendectomy.
* X² analysis of distribution frequencies of areas of pelvic involvement common to both groups: 46.96, 9 df, P < .001.
† Comparing only gastrointestinal involvement in castrated patients versus non-castrated patients: relative risk = 1.3, 95% confidence interval 0.94-1.8.

Among 340 comparison group subjects with no previous therapy for endometriosis, 49 (14.4%) had intestinal endometriosis. The incidence of intestinal endometriosis was significantly greater in the study group than in this untreated subgroup (RR 2.3, 95% CI 1.5-3.5).

In the castrated study group, complete laparoscopic excision of retained disease was possible in 46 (61%), whereas laparotomy was necessary in the remaining cases because of intestinal endometriosis that could not be handled laparoscopically. Twenty (27%) had concomitant pelvic or intestinal adhesions when I performed the surgery. In the comparison group, laparoscopic excision was possible in 726 (61%). The remainder underwent laparotomy for intestinal endometriosis or for removal of a large myomatous uterus in those undergoing hysterectomy. Forty-four (3.7%) in the comparison group had endometriosis confined to the uterus, tubes, or ovaries with no other peritoneal or intestinal involvement.

One study group subject had postoperative ileus. No one required a blood transfusion. Significant amelioration of symptoms associated with endometriosis was consistent for all symptoms evaluated in the study group (Figure 1). No symptom was completely eliminated.

Figure 1. Response of symptoms to excision of endometriosis in patietns with previous castration. *P > .003 compared to preoperative levels by Mann-Whitney test; **P > .005 compared to preoperative levels by Mann-Whitney test. Numbers in italics represent the number of patietns replying to a question. For all charts: 1 = not a problem; 2 = mild; 3 = moderate; 4 = severe; 5 = debilitating (unable to perform normal functions for at least 1 day each month). Subjects followed for 1-2 years are included in the "1 year" category, those followed for 2-3 years are in the "2 year" category, etc. Because of small numbers, results beyond 4-5 years are not tabulated. Preop = preoperative.

In an effort to detect any significant preoperative or intraoperative difference that might predict poor pain relief, I considered separately the symptom of non-discrete general pelvic pain at 12 months after my surgery (Figure 1a). Five patients who reported continuing severe or debilitating general pain 1 year after my surgery were found to be slightly older (mean ± SD 39.43 ± 6.58 years, range 31.58-46.72) than 40 others with no more than moderate general pelvic pain at 1 year (36.98 ± 5.6 years, range 26.9-49.5) (P > .05, 95% CI - 3.05 to 7.85, df = 43) and were more likely to have intestinal involvement (Table 3). Two of those with continuing severe or debilitating pain had repeat surgery beyond 1 year after my surgery, and neither was found to have pelvic endometriosis or adhesions, despite previous segmental bowel research of the lower rectosigmoid colon.

GI = gastrointestinal
Some patients had more than one area of intestinal involvement.
Involvement of the appendix is not tabulated, as some patients had previous appendectomy.
* X² analysis of distribution frequencies of areas of pelvic involvement: 9.04, 8 df, P < .10, not significant.
† Comparing only gastrointestinal involvement in patients with poor pain relief at 1 year versus patients with better pain relief at 1 year: relative risk = 1.8, 95% confidence interval 1.02-3.10.

Thirteen women in the study group with continuing pelvic pain after my surgery had re-operation. One was thought to have endometriosis at reoperation by another physician, but all biopsies were negative; she had had extensive invasive endometriosis at my surgery. A second was thought to have pelvic endometriosis at reoperation by another physician, although no biopsy was taken; she had minimal endometriosis at my surgery. One patient had a small biopsy-proven endometriotic lesion near the vaginal cuff, and another had an endometriotic lesion near the right anterior rib cage, which had been missed at previous laparotomy necessitated by severe intestinal involvement. No others had endometriosis at reoperation.

Discussion

The surgical diagnosis of endometriosis is fraught with the possibility of error when visual identification alone is used [20]. Although review of their previous operations revealed that 49 of the study group had disease described at sites other than the uterus, tubes, or ovaries at castration, it was impossible to determine from the remaining 18 available operative reports whether endometriosis was truly absent in other sites. Such disease may have been present but overlooked, or observed but not mentioned in the operative report. In any event, the majority of castrated patients had disease left untreated at the time of castration, making it likely the disease encountered at my surgery was persistent rather than recurrent disease.

Endometriosis may be unique among benign diseases in that it is frequently treated surgically by removal of something else. Many gynecologists have been taught to remove the uterus, tubes, and ovaries and to leave surgically identified endometriosis behind, with the expectation that low estrogen levels will cause the disease to be eradicated or at least asymptomatic thereafter. Castration with hysterectomy is commonly referred to as "definitive" treatment for endometriosis, whether the disease is removed or not. Castration with retention of the disease was the treatment applied to the subjects in this study. The study patients reside throughout North America, which indicates that this form of "definitive" surgical treatment is widely taught and widely applied. Although a literature review [21] suggested that most women experience symptom reduction after hysterectomy and castration with retention of the disease, there is no scientific evidence that endometriosis is physically destroyed by either removal of the ovaries or menopausal levels of E2. Given the low and varying levels of hormone receptors in endometriosis compared with native endometrium [22, 23, 24, 25], it is unsurprising that endometriosis does not respond predictably to endogenous hormonal influence [26, 27] and that it is not completely destroyed by low levels of E2 at the conclusion of GnRH therapy [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38]. In fact, abundant clinical evidence supports the ability of symptomatic endometriosis to exist after menopause without estrogen replacement therapy [5, 39, 40, 41, 42, 43]. Absence of estrogen seems to be the postulated main effector of the beneficial effect of castration on endometriosis, yet estrogen deficiency may not only result in bothersome vasomotor symptoms, but also increase the risk of development of osteoporosis and cardiovascular disease. Thus, if estrogen is withheld in order to render a patient less symptomatic, she is exposed to new risks. Therefore, treatment of endometriosis by castration followed by permanent estrogen deprivation is untenable in modern clinical practice. There is no scientific evidence that withholding estrogen for 6 month after castration has any cytocidal effect on endometriosis.

Although there is speculation that add-back therapy [44] (giving small does of estrogen to achieve E2 levels of approximately 30 pg/mL) may allow effective prophylaxis against hypoestrogenic side effects, this experimental concept has not been adequately proven and would require a biologic precision and consistency that may not exist. The expense of chronic GnRH agonist therapy and frequent serum E2 determinations would be enormous and contribute to spiraling health care costs.

Another speculative advantage of hysterectomy for the treatment of endometriosis is that Sampson's theory [45] (reflux menstruation with seeding of the pelvis by viable endometrial cells) cannot occur after hysterectomy, resulting in arrest of the spread of endometriosis. However, because the sine qua non of proof of Sampson's theory probably is not the mode of origin of endometriosis. Indeed, microscopic investigation of normal peritoneum [46, 47, 48, 49, 50, 51, 52] or of minimally visually abnormal peritoneum [53] in hundreds of patients with endometriosis has failed to provide any evidence of such attachment. All cases of "microscopic" endometriosis appear to be retroperitoneal groups of glands and stroma with no evidence of a trail of peritoneal penetration. Furthermore, the geographic "dandelion" spread, which might be predicted in older patients by Sampson's theory does not seem to occur [54, 55], and the severity of endometriosis as measured by the revised American Fertility Society classification is not greater in older groups of patients with newly diagnosed disease [56].

All of the women in this study had been told previously that their disease would be cured or definitively treated by removal of the pelvic organs with retention of the disease. Estrogen was withheld from many for months following castration, and several received medical therapy for endometriosis for continuing pain even though the pelvic organs had been removed. It is illogical to use medicine to suppress ovarian function when ovarian tissue is absent.

Sampson [45] noted that peritoneal disease is more common and clinically more important than ovarian disease, and pelvic mapping at this center confirms his observation. Therefore, castration with hysterectomy would rarely remove all endometriosis. If only the strict anatomical areas of the uterus, tubes, and ovaries had been removed in the 1190 patients in the comparison group, peritoneal or intestinal disease would have remained in 96.3% of the patients. Most of the study group had no treatment of endometriosis at castration, and the finding of persistent endometriosis in these patients would be predictable. It is impossible to know how accurately intestinal endometriosis was recognized at castration, as the operative reports reviewed for this study varied in descriptive detail, and frequently the intestinal tract was not mentioned.

Intestinal endometriosis was found more frequently among castrated than among non-castrated individuals. Because the referral population was skewed and may not be representative of a general gynecologist's practice, I examined a subgroup of 340 cases without previous medical or surgical treatment, which would be expected to be more comparable to those found by general gynecologists. Intestinal endometriosis was significantly more frequent in castrated than in non-treated patients.

Staging the extent of disease is problematic in those with previous castration and hysterectomy. The revised American Fertility Society classification system of endometriosis attempts to give a prognosis for conception according to the severity of disease, although most of its points score not for endometriosis, but for adhesions involving the tubes and ovaries. The points available for endometriosis are heavily weighed toward ovarian involvement; only six points are available for discrimination of peritoneal involvement, and no consideration is given for intestinal involvement. Therefore, those without pelvic organs are virtually transparent in the context of the classification system. Anatomical mapping of involved areas, as used in this study, allows an alternative descriptive classification of the extent of disease by the frequency of involvement of pelvic areas or by the total number of pelvic or intestinal areas involved. Prognostic classification systems are rational only with well-defined diseases [57]. Given the confusion surrounding endometriosis and the rarity of previous reports of disease diagnosed after castration, an attempt to produce a prognostic classification system for patients with previous castration seems premature.

Following excision of endometriosis, the reduction of symptoms was consistent and predictable. The surgical techniques used could have been applied instead of or in addition to castration. All operated patients replying to at least one questionnaire noted improvements in at least one measured symptom, for a crude response rate of 100%. The reduction of symptoms has persisted for many years postoperatively, indicating that symptomatic endometriosis was indeed the cause of pain in these patients. Although the absence of a sham-operated control group does not allow exclusion of a placebo effect, such an effect seems unlikely for two reasons. First, all patients had undergone castration for endometriosis and were not experiencing a placebo effect from that surgery. Second, with the passage of time after surgery, the likelihood of recurrent symptoms did not increase, indicating a lasting beneficial effect of surgery for at least several years, whereas one might expect a placebo effect to be temporary.

Steege and Stout [58] documented pain relief in a majority of patients with previous hysterectomy undergoing laparoscopic adhesiolysis. Because only 20 study cases (27%) had pelvic or abdominal adhesions noted at their surgery by me, it seems unlikely that most of the postoperative pain relief was due to lysis of adhesions. However, this cannot be excluded because all patients also underwent excision of endometriosis, and no control group underwent only adhesiolysis.

Reduction of symptoms was incomplete in some members of the study group following excision of disease. The results of reoperations indicated that endometriosis did not seem to be the cause of persistent pain, as documented pelvic endometriosis was found in only one reoperated woman. This suggests that, in some cases, pain was not due to endometriosis in the first place. To examine this matter further, I studied in more detail those with a poor symptomatic outcome for general pelvic pain 1 year after my surgery. This symptom was chosen for further study because it is more likely to represent a patient's overall assessment of symptomatic outcome that is a more detailed symptom such as dyspareunia. In addition, whereas not all women may have participated in sexual intercourse postoperatively, all would be expected to have a general opinion on pelvic pain, although not all respondents answered all points on all questionnaires. The response of severe or debilitating pelvic pain at 12-24 months after surgery was selected because most clinicians would agree that any improvement following surgery should be present by 1 year. Those with a poor symptomatic outcome were older and more likely to have intestinal endometriosis, but no preoperative or intraoperative indices allowed effective clinical discrimination of these cases. Vague descriptions of generalized abdominal pain or inability to reproduce pain on examination seemed to predict a poorer prognosis. Other factors may allow better patient selection, although the results of this study suggest that empirical excision of endometriosis is beneficial in patients with continuing pain following castration.

Patients with ovarian remnant syndrome were excluded, and aggressive removal of all abnormal tissue, frequently requiring radical retroperitoneal dissection, failed to disclose ovarian tissue in any of the 75 study patients. Although there is no question that endometriosis symptoms may vary directly with serum E2 levels, alleviation of symptoms accompanying low levels of E2 does not prove eradication of disease. Although serum E2 levels were not measured routinely before surgery, menopausal levels would not exclude the possibility of a previously functioning ovarian remnant. Therefore, biopsy-proven absence of ovarian tissue may be a more sensitive test to exclude ovarian remnant syndrome. The absence of ovarian tissue at surgery should suffice for exclusion of the syndrome, particularly given that tissue review committees would object to the diagnosis of this condition in the absence of supportive pathology.

Is post-castration endometriosis persistent disease or recurrent by virtue of metaplasia? In at least one-half of the study group, it seemed clearly persistent, as disease was described at the time of castration which was not treated. Although metaplasia is an attractive explanation for the recurrence of endometriosis, it remains unproven and speculative. Metaplastic recurrence might not be surgically preventable, so considering post-castration disease as recurrence would direct clinical attention away from the most important question of how completely endometriosis should be treated surgically at the time of castration. This study suggests that invasive disease of the uterosacral ligaments or intestinal tract is more likely to remain symptomatic following castration with retention of disease. In the absence of studies showing the long-term efficacy of castration with retention of disease, it is illogical to leave endometriosis surgically untreated at castration.

This study cannot answer the question of how frequently endometriosis remains symptomatic after castration. My referral population was skewed and may not be representative of the population of a general gynecologist. Removal of the pelvic organs with retention of endometriosis thankfully seems to provide adequate pain relief in many patients, but some of the pain relieved might be of uterine, tubal or ovarian causes and erroneously attributed to coexistent endometriosis. The belief that castration is "definitive" or "curative" therapy for endometriosis may be based more on the classic epidemiologic mistake of observing the response of symptoms rather than the response of the disease.

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