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A syndrome characterized by recurrent symptomatic functional ovarian cysts in young women
A syndrome characterized by recurrent symptomatic
SERGIO C. STONE. M.D. WILLIAM
.J.
SWARTZ,
PH.D.
Nn1• Or/P(ml, Louisiana A syndrome characterized by the persistent recurrence of symptomaiic functional ovarian cysts, elevated plasma estradiol levels, and infertility in four young patients is described. Two of the
patients experienced recurring ovarian cysts
foUow~ng
total abdomina! hysterectomy
a~
bilateral
salpingo-oophorectomy. Pathologic findings confirmed the presence of ovarian tissue in all cysts. Recurrent cysts formation is attributed to either an increased production of gonadotropins or a hypersensitive response to normal gonadotropins. The development of recurrent cysts following bilateral oophorectomy indicates that some ovarian or "ovarian-like" tissue is present within the pelvic cavity, anatomically unrelated to the normally positioned ovaries. This extraovarian tissue may become sensitive to circulating gonadotropin levels in the absence of normal ovarian tissue. The souice of this extiaovaiian tissue is discussed from an embr~yologic standpoint. (AM. J. 0BSTET. GYNECOL. 134:310, 1979.)
are commonly classified as either nonneoplastic or epithelial. 1 Nonneoplastic cysts can be functional. that is, they respond to circulating estrogens and gonadotropins. 1 ' 2 Functional ovarian cysts of this type may develop as a result of a hypothalamic-pituitary dysfunction with an abnormal process of cyclical follicular maturation and corpus luteum formation. 1 Follicle cysts, the most common type of functional cyst, are usually small and asymptomatic. They generally undergo spontaneous resorption and, thus, for the most part remain undiagnosed. On occasion, however, such cysts become large enough to produce discomfort or pain. They may become hemorrhagic and torsion of the pedicle may occur. 1 Such functional cysts are capable of producing estrogena and are the most common cause of pseudoprecocious puberty in girls.'· 4 The appearance of functional follicular cysts during
BENIGN OVARIAN CYSTS
the normal reproductive life of women may cause irregular menstrual cycles. L 2 Treatment of young women is expectant and ovarian suppression is advocated to accelerate the pn..v~e;s of resorption. 1. 2 Surgical intervention is rarely indicated since such cvsts disaooear soontaneouslv. 2 The present report details the persistent recurrence of symptomatic functional cysts and accompanying elevations of plasma estradiol levels in four young patients. Two of the patients experienced recurring cysts following total abdominal hysterectomy and bilateral salpingo-oophorectomy. The others. developed recurrent. ovarian cysts upon interruption of ovarian suppression. These symptoms were accompanied by infertility. This study offers explanations of this syndrome and suggests that such condition may not be as rare as generally indicated. /
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l.
i
.L
Case reports From the Section of Reproductive Endocrinology ~~the Department of Obstetrics and Gynecology and the De,hartment of Anatom.~, Loui1iana State Unir•ersiM· Medical School. Received for publiration june 12. 1978. Acceptedjuly 13, 1978. Reprint requests: Dr. Sergio Stone, Section of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of California College of Medicine, Orange, California 92668.
310
Case 1. V. B., a 28-year-o\d, white woman, gravida 0, had a long history of primary infertility irregular cycles, and anovulation. Prior to consultation in our Section of Reproduction, this patient experienced recurrent symptomatic ovarian cysts necessitating exploratory laparotomy on two occasions. On each occasion large, simple follicular cysts were removed. During the last surgical procedure, bilateral ovarian wedge resection and cauterization of pelvic endometriosis were also performed. She was placed on a regirnen of oral contraceptive therapy for several months. 1
0002-937R/79/ll0310+05$00.50/0
©
1~)79 The C V. Mosby Co.
Volume 134 Number 3
Pain and a right lower quadrant mass recurred a few weeks after discontinuation of the ovarian suppression, at which time she was referred to us. A right pelvic mass adjacent to the uterus was easily palpable and the plasma estradiol level was 102 pg/ml. Suppression of the mass with oral contraceptives (Norlestrin, 2.5 mg) was initiated. Within three weeks the right adnexal mass had disappeared and the plasma estradiol ievei had decreased to 11 pg/ml. Oral contraceptive suppression \vas stopped. Three weeks later the patient returned, again complaining of right lower quadrant pain. A right pelvic mass was palpable and the plasma estradiol level had risen to 149 pg/ml. A regimen of long-term ovarian suppression was started and has continued for the past six months. This patient strongly desires to become pregnant. Case 2. S. Z., a 21-year-old, white woman, gravida 0, had a long history of recurrent ovarian cysts beginning at age 10. Exploratory laparotomy at that time revealed a 10 em left ovary, twisted and infarcted. The right ovary was also enlarged and cystic. A left oophorectomy and partial resection of the right ovary were performed. Pathologic findings revealed both ovaries to contain serous, hemorrhagic follicular cysts with stron1al hen1orrhage and capsular fibrosis. The patient began using oral contraceptives at 14V2 years of age. Later, the patient desired pregnancy and oral contraceptives were discontinued. One month later, she complained of right lower quadrant abdominal pain. Pelvic examination revealed a 6 to 8 em right adnexal mass. Oral contraceptive therapy was reinitiated and two weeks later she was asymptomatic and the cystic mass had decreased in size. Oral contraceptives \vere administered for only one cycle. One month later the patient again complained of right lower quadrant abdominal pain associated with nausea and dizziness. Plasma estradiol at this time was 581 pg/ml. Oral contraceptives were again begun and the patient displayed subjective improvement after 5 days of hormonal suppression, at which time pelvic examination revealed a smaller right ovary and a plasma estradiol level of 21 pg/ml. The patient remained asymptomatic for one year with normal pelvic examinations. Ovarian suppression was then stopped. One month later she complained of abdominal pain and a pelvic examination revealed the right ovary to be 5 em in diameter. She was observed without therapy for 2 weeks, remaining symptomatic. Oral contraceptives were begun again and the pelvic examination became normal. The patient, presently on a regimen of long-term oral contraceptive therapy, remains asymptomatic with low plasma estrogen levels. However, she still desires pregnancy. Case 3. P. M. M., a 26-year-oid, white woman, gravida 1, para 1, had a normal delivery in 1971. Following delivery the patient used oral contraceptive
Recurrent ovarian cysts in young women
311
therapy intermittently for one yeaL vue mouth after cessation of oral contraceptives the patient developed heavy vaginal bleeding and a large right ovarian cyst. This was to mark the beginning of several years of almost constant symptomatology as a result of frequent recurrent cysts. She underwent laparoscopy followed by laparotomy and removal of the right ovarian cyst. A bilateral wedge resection was also performed with the clinical impression of polycystic ovarian syndrome that \vas not confirmed by pathologic examination. One month following operation, a cystic, tender adnexal mass was palpated. For the next year and a half, she had numerous episodes of low abdominal pain, irregular vaginal bleeding, and palpable pelvic masses, treated intermittently with oral contraceptives and estrogen therapy. She was finaily hospitalized for pulmonary embolism, at which time estrogen therapy was stopped. Six months after estrogen treatment was stopped, she developed severe left lower quadrant pain and a large, left, tender, cystic mass was palpated. Exploratory laparotomy was performed during which a left salpingo-oophorectomy was done, in addition to freeing of multiple pelvic adhesions. One month later she developed severe low pelvic pain and a right cystic adnexal mass (6 em) was easily palpable. Due to this chronic problem she underwent a total abdominal hysterectomy and right salpingo-oophorectomy. One month later she developed left lower quadrant pain and a left lower pelvic mass was again palpated and treated with ovarian suppression. A year later .she developed right lower quadrant pain and a pelvic mass was palpated and confirmed on ultrasound. Operation \Yas performed during \vhich a large pelvic mass 'vas removed from the vaginal cuff with dissection of multiple pelvic adhesions. The presence of ovarian tissue was confirmed by pathologic examinations. Nine months later she underwent another exploratory laparotomy for symptoms of bowel obstruction. No mass was found and lysis of multiple intestinal adhesions was performed. Three months later she returned, complaining of severe progressive dyspareunia. Large; bilateraL tender pelvic masses were easily palpable. Exploratory laparotomy revealed two large cystic masses that were removed. Pathologic diagnosis confirmed the presence of active ovarian tissue. She was referred to us two weeks after operation. She had no complaints and a pelvic examination proved negative. The plasma estradiol level was 7 pg/ml. She was placed on a regimen of medroxyprogesterone acetate (Depo-Provera, 150 mg intramuscularly). Long-term suppression was planned with the need for further medroxyprogesterone acetate injections to be periodicaily evaluated by determinations of plasma estradiol levels. She again developed severe lower abdominal pain and dyspareunia and a right cys-
312
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plasma estradiol level was less than 5 pg/ml but three days later she underwent a seventh laparotomy. A large cystic mass was removed from the right pelvis and multiple intestinal adhesions and numerous nodules were found throughout the abdominal and pelvic cavities. The pathologic diagnosis was "'peritoneal rvst, foreign body reaction, chronic inflarrnnation, fa.tt} d.t.~ generation, and fibrosis.'' 1\"o ovarian tissue was identihPd. She ha~ hPPn on a rt•P"inwn nwdroxvnrn---- ---·- -----· ----- kent --.--------o-------- of ---------/,gesterone acetate, and the plasma estradiol levels han· remained less than 5 pg/ml for the past four months. Case 4. D. L., a 24-vear-old, white woman, gravida 0, had a long history of recurrent ovarian cysts. A uterine suspension and left cystectomy were performed for a left pelvic mass, after which the patient was placed on~~ regirnen of oral contraceptives (()rtho-l'Jovum 1 + .~0) for two years. Three months after stopping oral contraceptive therapy. she complained of abdominal pain. Laparoscopy revealed an 8 hv 8 em right follicular nst from which 75 ml of blood was aspirated. Because of dense adhesions to the pelvic colon, no left adnexa could be dearly identified. Two months later pain and a left adnexal mass developed. At laparotomy a large left ovarian cyst was found \vith dense adhesions to the colon and uterine wall. The cyst was multilocular with very thin walls and leaked a clear hemorrhagic fluid when incised. The left cyst was dissected from the ovary and an "endometrioma" removed from the right ovary. Pathologic findings revealed corpus hemorrhagica in the right sample and normal ovarian tissue with corpus albicans and hemosiderin deposit in the left. No endometriosis was f(nmd. Five months later the svmptomatology reappeared in the left lower quadrant. A blood sample was taken and senr to our laboratory. An elevated plasma estradiol level of 557 pg/ml was reported. Ovarian suppression with oral contraceptives was started. The patient became asymptomatic with plasma estradiol levels decreasing to 79 pg/ml in one month and to 24 pg/ml the second month. Six months later ovarian suppression was terminated because of side effects. Following cessation of treatment, the patient again developed left lower quadrant pain and a palpable left ovarian cyst. An explorator~ laparotomy (the fourth surgical procedure) revealed multiple pelvic adhesions. several left ovarian cysts (one measuring 5 by 7 em), and complete obliteration of the architectural structure of the pelvic cavity. A complete loss of the adnexal anatomy on both sides without evidence of tubal patency prompted a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Eight months following operation the patient consulted our Section of Reproduction, complaining of similar symptomatology ongoing f(H· the past few months. Plasma estradiol level was 272 pg/ml and a large left adnexal mass was palpated at that initial visit.
Ovarian suppression was begun and the pLtsma ,.,. tradiollevel dropped to 7 pg/ml in 2 motrth, .. \II wmptoms disappeared and estradiolle\Tis ,.,.,_-n: m;u111airwd around 20 pg/ml. Ovarian suppression was again interrupted Lccutsc of side effn Is. Within a short time the left hmt.'t quadrant palll reappeared and the ptt-;llta e~u ddiol level increased to 2H l pg/rnl. A soft. irregular rna'', <>Uld he felt in the left adnexal ;~rea. nw patie!!l lt"fu:-cd further suppression and demanded a "final smgit
very painful cystic ma" fixed to the pelvic wall was palpated. A retrograde catheter was placed Ill the left ureter and hn symptom.., impron:d. The plasma estradiol len'! "a' 86 pg!ml and 'uppression with medroxyprogesterone acetate (Depo-Pnwera, 1,->0 mg intrarnnscularlvl and an oral contr;;ceptiH' i '\orlestrin, 2.?1 mg t11itt' dailv) \\:1' started ..\ secoud imra1enom pvelogram 7 davs hun tT\ealed no furthn extrinsic compression of the urete1 and a smaller ;md less painful mass wa!-. felt on pehic examination. The patient was discharged oll a regimen of oral contraceptives (Norlestrin. 2.5 mg/dav) with a plasma estradiol level of 16 pg/ml and with plans fm prolonged supprt·s,iou with medroxvprugesterone acetate. She ha.; remained a:o.ymptomatic tor the p
Comment Patients with ovarian nst;.. an· frequenth found in clinical practice. 1 However. tt'}JOrt' oi o\ ari,m rvsts of the functional tvpe are uncommon since the Yast majority of these arc asymptomatic and pao;s undiagnosed. Most regress spontaneously or aftc'r ovarian suppression never again to affect the patient. The f(mr patients described in this report present a similar, interesting. and unusual dini{·a! syndrome characterit.t:~d by the fre<.1'uent ft'TlllTt:~nce of hlJILi.-itJnal ovarian cvst~. The cysts were symptomatic t
Volurue 134
Recurrent ovarian cysts in young women
313
Number 3
was accompanied by elevated plasma estradiol levels in three of the four patients in whom blood studies are available. The pathology report confirmed the presence of ovarian tissue in each case. During ovarian suooression. these oatients remained asvmotomatic. plasma estradiol levels were low, and the patients were free of pelvic masses. Reports of recurrent ovarian cysts, such as those present in our group of patients, are most uncommon. Several explanations may be offered to elucidate the etiology of this syndrome. One causative factor may be an increased production of gonadotropins. It would appear that these ovarian cysts did not develop in response to elevated gonadotropins, as occurs in molar pregnancies. or from a complication of ovulation induction, L 2 since elevated gonadotropins were not found on any occasion. Whether a considerable rise in gonadotropin levels occurred before the appearance of the cysts is not known, since no hormonal levels were obtained prior to the patients' becoming symptomatic and since normal low levels of gonadotropins found during the cyst-free periods were the direct result of the ovarian suppression therapy. It is possible, therefore, that high gonadotropin levels may have initiated growth of the cysts and then decreased as a result of the elevated estrogen production by the cyst, at which time the patient sought consultation. A second explanation may be that the ovarian tissue elicits a hypersensitive response to normal gonadotropins by forming these recurrent functional cysts. Such hypersensitivity of ovarian tissue could be due to an unknown error in the metabolic pathway of granulosa and/or theca cells. This hyperresponse to normal gonadotropin levels could be the counterpart of the unresponsive ovarian syndrome in which normal ovarian tissue does not respond to normal or increased gonadotropin levels."· 6 The mechanism by which normalappearing follicles fail to respond to gonadotropins is not clear. The above possibilities can be used to explain the clinical manifestations in Cases 1 and 2. However, they cannot provide the complete explanation of the recurrence of "ovarian-like" cysts foiiowing biiaterai oophorectomy in Cases 3 and 4. The ovarian cellular composition of the recurring cysts along with the increased estrogen levels indicates that there is some ovarian or "ovarian-like" tissue within the pelvic cavity that responds to normal gonadotropin levels. Ovarian tissue remaining within the pelvic cavity following bilateral oophorectomy could be a result of one of the following: I. Incomplete surgical removal of the ovaries is a possibility since the oophorectomy was performed after l
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several surgical procedures which have produced extensive pelvic adhesions and distortion of the normal position of the ovaries. However, this possibility seems remote since extreme caution was exercised at the time of oophorectomy and in the surgical procedures performed after bilateral oophorectomy to ensure complete removal of all ovarian tissut>_ 2. Accessory ovaries in which the extraovarian tissue is situated near to and usually connected with the normally placed ovary could be the source of the recurrent follicle cysts. Origin of such accessory ovaries is probably similar to that of the normally placed ovaries. Usually this accessory ovarian tissue is quite small and thus remains unrecognizable prior to pathologic evaluation. Wharton 7 in an excellent review article reported only 18 authors who had described this pathologic finding with only three seeing more than one case. In all of these cases tissue with the distinct structure and function of a normal ovary was present. Our two cases do not appear to be conditions of accessory ovaries since the cystlike structures were distant from and not connected to the site of the normal ovaries. 3. Another possibility involves the formation of extraovarian tissue not associated with the normally placed ovary. Wharton 7 described a rare condition called supernumerary ovary in which ovarian tissue was located in a position not associated with that of may be functional. Kosasa and associates 8 reported on one patient with elevated total plasma estrogen after_ bilateral oophorectomy. The source of the estrogen was a retroperitoneally located supernumerary ovary. Wharton 7 theorized that such aberrant ovaries were the result of the failure of migrating germ cells to reach the developing genital ridge. That such germ cells do find their way to extrag;onadal areas and are viable and may be the source of tumors has been demonstrated in a variety of animal species. 9 Such primary germ cell tumors have been found in the anterior mediastinum 10 and in a retroperitoneal location. ll In our study, the pathologic findings show the cysts to contain granulosa luteal and theca luteal cells and ovarian stroma. No oocytes were observed. In association with Wharton's theory, presumably the extragonadai germ cells induced the surrounding mesenchymal cells to differentiate into ovarian cellular components. Another explanation would be that of Printz and associates 12 who reported a case of a 23-year-old, black woman in which they found ovarian tissue embedded in the omentum. They theorized that a portion of the genital ridge. after colonization by the germ cells, became detached and then reattached in a neighboring area. This would explain the normal ovarian
jww
314 Stone and Swartz
tissue contents of the cyst in the pathologic fiudiugs. From our findings it appears that whatever the source of this ovarian tissue it becomes functional and produces large amounts of estradiol to levels much higher than those found after the removal of both normal ovaries. Such tissue may become extremely sensitive to circulating gonadotropins in the absence o! normal ovarian tissue. Greenwald 1:3 showed in hamsters that after unilateral ovariectomy the remaining ovary hyperovulates. Biskind and Biskind 14 in rats and McLaren 13 in mice demonstrated that an ovary transplanted to the spleen hypertrophied only after the in situ ovary was also removed. Furthermore, Chihal and associates'" demonstrated that '"extraovarian" tissue affects the number of eggs ovulated and the plasma levels of progesterone in postpuberal rats receiving ovarian homografts. This has not been shown in humans; however, it is certainly possible that aberrant embrvonir gonadal tissue in the absence of normal ovarian tissue may develop under the influence of normal gonadotropins and thus be responsible for recurrent ovarian cyst formation. Infertility is an important secondary effect of either the syndrome or its long-term therapy. Only one of the patients presented here has been pregnant and this
REFERENCES
.\w. _l
~)IJ.-.tet
l, 19i~.l
(~\llt'(ol.
p1 uu lu the developn1e1H of the -..yndroill\:". Despite the desire for children in Patients I and ;!, ovarian cyst' have developed each time ovarian suppression was stopped. The development of recurrent ovarian cysts either before or after bilateral oophorectomy is con5idercd otLUtTed
I':ln' .
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It i~ n
---~.
-;vnrlronw he mort' ) -- - - rnav ----
prevalent than a review of the literature leads one to believe. In tact. we have diagnosed four case' of llm condition in the past two years, The need for ovarian suppression and the monitoring of long-term therapy with plasma estradiol levels is recommended. ~urgical approach to treat t hi;,; svndrome does not 'eem adequate, and after the lirsr recurrence probably no further 'urgen is indicated. Presently we lind no alternative to ovarian suppression for the treatment of these patient.;,. It is possible that this syndrome may regress after menopause. <1 time at which the ovarv does not normal!\ respond to markedly elevated gonadotropin leveb. We hope that by charactcriling this S\ndrome we will encourage mon· reports of patients like these and therefore find a better wav of evaluating and treating recurreni ~vmptomalic functional ovarian c~ sts.
I. Novak, E. R .. and Woodruff, J.D.: ~ovak's Gynecologic and Obstetric Pathology, ed. 7, Philadelphia 1974. W. B. Saunders Co., chap. 20, pp. 357-366. 2. Griffiths, C. T.: In Kistner, R. W.: Gynecology, Principles and Practice, ed. 2, Chicago, 1971. Year Book Medical Publishers, Inc., chap. 8, pp. 344-347. :~. Wieland, R. G., Bendezu, R., Hallberg, M. C., Tang. P ..
M., and Naftolin. F.: Diagnosis of a supernumerary ovary with human chorionic gonadotropin. <>bstet. Gynewl. 47:236, 1976. 9. Swartz, W. J., and Domm, L. \'.: A study on di\ision of primordial germ cells in the earh chick embryo. Am . .J. An at. 135:5!. ! 972. 10. Luna, M. A.. and Valenzuela-Tamariz. J.: l;erm-tell tumors of the mediastinum, postmortem lindi1igs, Am . .J.
and \Vebster~ K.: Hormonal evaluation of premature menarche produced by a follicular cyst, AM.]. 0BSTET. GYNECOL. 126:731, 1976. Monteleone, J. A., Monteleone, P. L., and Danis, R. K.: Pseudoprecocious puberty associated with isolated follicular cysts of the ovary, J. Pediatr. Surg. 8:949, 1973. Jones, G. S., and DeMoraes-Ruehsen, M.: A new syndrome of amenorrhea in association with hypergonadotrooism and aooarentlv normal ovarian follicular appa;atus, AM. j.'0BSTET_' GYNECOL. 104:597, 1969. . Starup, J., Sele, V ., and Henriksen, B.: Amenorrhea ass
II. l!tz. D. C., and Buscemi, M. F.: Extra~onadal testicular tumors, .J. t_; rol. 105:271. 1971. 12. Printz,]. L., Choate,J. W., Townes, P. L, and Harper. R. C.: The embryology of supernumerary ovarie,, Obstet. Gynecol. 41:246. 197~~1:~. Greenwald, G. S.: The effect of unilateral o\"ariectomy on follicular maturation in the hamster, Fndocrinolo~y 66:89, 1960. 14. Biskind, G. R., and Biskind, M. S.: Atrophy of ovarie' transplanted to the spleen in unilaterally castrated rats: proliferative changes following subsc:quent removal of intact oval"), Science 108:1~17, 1948. 15. McLaren, A.: Regulation of ovulation rate after remuval of one ovary in mice, Proc Soc. Med. 166:3-\.6, 1966. 16. Chihal, H.J. W., Stone, S.C., and Peppler, R. D.: Effects of "extra"' ovarian tissue on ovulation number and ovarian steroids in rats, .J. Rep rod. Fertil. 47:107, 197n.
4.
5.
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SERGIO C. STONE. M.D. WILLIAM
.J.
SWARTZ,
PH.D.
Nn1• Or/P(ml, Louisiana A syndrome characterized by the persistent recurrence of symptomaiic functional ovarian cysts, elevated plasma estradiol levels, and infertility in four young patients is described. Two of the
patients experienced recurring ovarian cysts
foUow~ng
total abdomina! hysterectomy
a~
bilateral
salpingo-oophorectomy. Pathologic findings confirmed the presence of ovarian tissue in all cysts. Recurrent cysts formation is attributed to either an increased production of gonadotropins or a hypersensitive response to normal gonadotropins. The development of recurrent cysts following bilateral oophorectomy indicates that some ovarian or "ovarian-like" tissue is present within the pelvic cavity, anatomically unrelated to the normally positioned ovaries. This extraovarian tissue may become sensitive to circulating gonadotropin levels in the absence of normal ovarian tissue. The souice of this extiaovaiian tissue is discussed from an embr~yologic standpoint. (AM. J. 0BSTET. GYNECOL. 134:310, 1979.)
are commonly classified as either nonneoplastic or epithelial. 1 Nonneoplastic cysts can be functional. that is, they respond to circulating estrogens and gonadotropins. 1 ' 2 Functional ovarian cysts of this type may develop as a result of a hypothalamic-pituitary dysfunction with an abnormal process of cyclical follicular maturation and corpus luteum formation. 1 Follicle cysts, the most common type of functional cyst, are usually small and asymptomatic. They generally undergo spontaneous resorption and, thus, for the most part remain undiagnosed. On occasion, however, such cysts become large enough to produce discomfort or pain. They may become hemorrhagic and torsion of the pedicle may occur. 1 Such functional cysts are capable of producing estrogena and are the most common cause of pseudoprecocious puberty in girls.'· 4 The appearance of functional follicular cysts during
BENIGN OVARIAN CYSTS
the normal reproductive life of women may cause irregular menstrual cycles. L 2 Treatment of young women is expectant and ovarian suppression is advocated to accelerate the pn..v~e;s of resorption. 1. 2 Surgical intervention is rarely indicated since such cvsts disaooear soontaneouslv. 2 The present report details the persistent recurrence of symptomatic functional cysts and accompanying elevations of plasma estradiol levels in four young patients. Two of the patients experienced recurring cysts following total abdominal hysterectomy and bilateral salpingo-oophorectomy. The others. developed recurrent. ovarian cysts upon interruption of ovarian suppression. These symptoms were accompanied by infertility. This study offers explanations of this syndrome and suggests that such condition may not be as rare as generally indicated. /
J_
l.
i
.L
Case reports From the Section of Reproductive Endocrinology ~~the Department of Obstetrics and Gynecology and the De,hartment of Anatom.~, Loui1iana State Unir•ersiM· Medical School. Received for publiration june 12. 1978. Acceptedjuly 13, 1978. Reprint requests: Dr. Sergio Stone, Section of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of California College of Medicine, Orange, California 92668.
310
Case 1. V. B., a 28-year-o\d, white woman, gravida 0, had a long history of primary infertility irregular cycles, and anovulation. Prior to consultation in our Section of Reproduction, this patient experienced recurrent symptomatic ovarian cysts necessitating exploratory laparotomy on two occasions. On each occasion large, simple follicular cysts were removed. During the last surgical procedure, bilateral ovarian wedge resection and cauterization of pelvic endometriosis were also performed. She was placed on a regirnen of oral contraceptive therapy for several months. 1
0002-937R/79/ll0310+05$00.50/0
©
1~)79 The C V. Mosby Co.
Volume 134 Number 3
Pain and a right lower quadrant mass recurred a few weeks after discontinuation of the ovarian suppression, at which time she was referred to us. A right pelvic mass adjacent to the uterus was easily palpable and the plasma estradiol level was 102 pg/ml. Suppression of the mass with oral contraceptives (Norlestrin, 2.5 mg) was initiated. Within three weeks the right adnexal mass had disappeared and the plasma estradiol ievei had decreased to 11 pg/ml. Oral contraceptive suppression \vas stopped. Three weeks later the patient returned, again complaining of right lower quadrant pain. A right pelvic mass was palpable and the plasma estradiol level had risen to 149 pg/ml. A regimen of long-term ovarian suppression was started and has continued for the past six months. This patient strongly desires to become pregnant. Case 2. S. Z., a 21-year-old, white woman, gravida 0, had a long history of recurrent ovarian cysts beginning at age 10. Exploratory laparotomy at that time revealed a 10 em left ovary, twisted and infarcted. The right ovary was also enlarged and cystic. A left oophorectomy and partial resection of the right ovary were performed. Pathologic findings revealed both ovaries to contain serous, hemorrhagic follicular cysts with stron1al hen1orrhage and capsular fibrosis. The patient began using oral contraceptives at 14V2 years of age. Later, the patient desired pregnancy and oral contraceptives were discontinued. One month later, she complained of right lower quadrant abdominal pain. Pelvic examination revealed a 6 to 8 em right adnexal mass. Oral contraceptive therapy was reinitiated and two weeks later she was asymptomatic and the cystic mass had decreased in size. Oral contraceptives \vere administered for only one cycle. One month later the patient again complained of right lower quadrant abdominal pain associated with nausea and dizziness. Plasma estradiol at this time was 581 pg/ml. Oral contraceptives were again begun and the patient displayed subjective improvement after 5 days of hormonal suppression, at which time pelvic examination revealed a smaller right ovary and a plasma estradiol level of 21 pg/ml. The patient remained asymptomatic for one year with normal pelvic examinations. Ovarian suppression was then stopped. One month later she complained of abdominal pain and a pelvic examination revealed the right ovary to be 5 em in diameter. She was observed without therapy for 2 weeks, remaining symptomatic. Oral contraceptives were begun again and the pelvic examination became normal. The patient, presently on a regimen of long-term oral contraceptive therapy, remains asymptomatic with low plasma estrogen levels. However, she still desires pregnancy. Case 3. P. M. M., a 26-year-oid, white woman, gravida 1, para 1, had a normal delivery in 1971. Following delivery the patient used oral contraceptive
Recurrent ovarian cysts in young women
311
therapy intermittently for one yeaL vue mouth after cessation of oral contraceptives the patient developed heavy vaginal bleeding and a large right ovarian cyst. This was to mark the beginning of several years of almost constant symptomatology as a result of frequent recurrent cysts. She underwent laparoscopy followed by laparotomy and removal of the right ovarian cyst. A bilateral wedge resection was also performed with the clinical impression of polycystic ovarian syndrome that \vas not confirmed by pathologic examination. One month following operation, a cystic, tender adnexal mass was palpated. For the next year and a half, she had numerous episodes of low abdominal pain, irregular vaginal bleeding, and palpable pelvic masses, treated intermittently with oral contraceptives and estrogen therapy. She was finaily hospitalized for pulmonary embolism, at which time estrogen therapy was stopped. Six months after estrogen treatment was stopped, she developed severe left lower quadrant pain and a large, left, tender, cystic mass was palpated. Exploratory laparotomy was performed during which a left salpingo-oophorectomy was done, in addition to freeing of multiple pelvic adhesions. One month later she developed severe low pelvic pain and a right cystic adnexal mass (6 em) was easily palpable. Due to this chronic problem she underwent a total abdominal hysterectomy and right salpingo-oophorectomy. One month later she developed left lower quadrant pain and a left lower pelvic mass was again palpated and treated with ovarian suppression. A year later .she developed right lower quadrant pain and a pelvic mass was palpated and confirmed on ultrasound. Operation \Yas performed during \vhich a large pelvic mass 'vas removed from the vaginal cuff with dissection of multiple pelvic adhesions. The presence of ovarian tissue was confirmed by pathologic examinations. Nine months later she underwent another exploratory laparotomy for symptoms of bowel obstruction. No mass was found and lysis of multiple intestinal adhesions was performed. Three months later she returned, complaining of severe progressive dyspareunia. Large; bilateraL tender pelvic masses were easily palpable. Exploratory laparotomy revealed two large cystic masses that were removed. Pathologic diagnosis confirmed the presence of active ovarian tissue. She was referred to us two weeks after operation. She had no complaints and a pelvic examination proved negative. The plasma estradiol level was 7 pg/ml. She was placed on a regimen of medroxyprogesterone acetate (Depo-Provera, 150 mg intramuscularly). Long-term suppression was planned with the need for further medroxyprogesterone acetate injections to be periodicaily evaluated by determinations of plasma estradiol levels. She again developed severe lower abdominal pain and dyspareunia and a right cys-
312
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Stone and Swartz \TTl
tic n1ass \Vas felt attached to the vaginal cuff.
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plasma estradiol level was less than 5 pg/ml but three days later she underwent a seventh laparotomy. A large cystic mass was removed from the right pelvis and multiple intestinal adhesions and numerous nodules were found throughout the abdominal and pelvic cavities. The pathologic diagnosis was "'peritoneal rvst, foreign body reaction, chronic inflarrnnation, fa.tt} d.t.~ generation, and fibrosis.'' 1\"o ovarian tissue was identihPd. She ha~ hPPn on a rt•P"inwn nwdroxvnrn---- ---·- -----· ----- kent --.--------o-------- of ---------/,gesterone acetate, and the plasma estradiol levels han· remained less than 5 pg/ml for the past four months. Case 4. D. L., a 24-vear-old, white woman, gravida 0, had a long history of recurrent ovarian cysts. A uterine suspension and left cystectomy were performed for a left pelvic mass, after which the patient was placed on~~ regirnen of oral contraceptives (()rtho-l'Jovum 1 + .~0) for two years. Three months after stopping oral contraceptive therapy. she complained of abdominal pain. Laparoscopy revealed an 8 hv 8 em right follicular nst from which 75 ml of blood was aspirated. Because of dense adhesions to the pelvic colon, no left adnexa could be dearly identified. Two months later pain and a left adnexal mass developed. At laparotomy a large left ovarian cyst was found \vith dense adhesions to the colon and uterine wall. The cyst was multilocular with very thin walls and leaked a clear hemorrhagic fluid when incised. The left cyst was dissected from the ovary and an "endometrioma" removed from the right ovary. Pathologic findings revealed corpus hemorrhagica in the right sample and normal ovarian tissue with corpus albicans and hemosiderin deposit in the left. No endometriosis was f(nmd. Five months later the svmptomatology reappeared in the left lower quadrant. A blood sample was taken and senr to our laboratory. An elevated plasma estradiol level of 557 pg/ml was reported. Ovarian suppression with oral contraceptives was started. The patient became asymptomatic with plasma estradiol levels decreasing to 79 pg/ml in one month and to 24 pg/ml the second month. Six months later ovarian suppression was terminated because of side effects. Following cessation of treatment, the patient again developed left lower quadrant pain and a palpable left ovarian cyst. An explorator~ laparotomy (the fourth surgical procedure) revealed multiple pelvic adhesions. several left ovarian cysts (one measuring 5 by 7 em), and complete obliteration of the architectural structure of the pelvic cavity. A complete loss of the adnexal anatomy on both sides without evidence of tubal patency prompted a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Eight months following operation the patient consulted our Section of Reproduction, complaining of similar symptomatology ongoing f(H· the past few months. Plasma estradiol level was 272 pg/ml and a large left adnexal mass was palpated at that initial visit.
Ovarian suppression was begun and the pLtsma ,.,. tradiollevel dropped to 7 pg/ml in 2 motrth, .. \II wmptoms disappeared and estradiolle\Tis ,.,.,_-n: m;u111airwd around 20 pg/ml. Ovarian suppression was again interrupted Lccutsc of side effn Is. Within a short time the left hmt.'t quadrant palll reappeared and the ptt-;llta e~u ddiol level increased to 2H l pg/rnl. A soft. irregular rna'', <>Uld he felt in the left adnexal ;~rea. nw patie!!l lt"fu:-cd further suppression and demanded a "final smgit
very painful cystic ma" fixed to the pelvic wall was palpated. A retrograde catheter was placed Ill the left ureter and hn symptom.., impron:d. The plasma estradiol len'! "a' 86 pg!ml and 'uppression with medroxyprogesterone acetate (Depo-Pnwera, 1,->0 mg intrarnnscularlvl and an oral contr;;ceptiH' i '\orlestrin, 2.?1 mg t11itt' dailv) \\:1' started ..\ secoud imra1enom pvelogram 7 davs hun tT\ealed no furthn extrinsic compression of the urete1 and a smaller ;md less painful mass wa!-. felt on pehic examination. The patient was discharged oll a regimen of oral contraceptives (Norlestrin. 2.5 mg/dav) with a plasma estradiol level of 16 pg/ml and with plans fm prolonged supprt·s,iou with medroxvprugesterone acetate. She ha.; remained a:o.ymptomatic tor the p
Comment Patients with ovarian nst;.. an· frequenth found in clinical practice. 1 However. tt'}JOrt' oi o\ ari,m rvsts of the functional tvpe are uncommon since the Yast majority of these arc asymptomatic and pao;s undiagnosed. Most regress spontaneously or aftc'r ovarian suppression never again to affect the patient. The f(mr patients described in this report present a similar, interesting. and unusual dini{·a! syndrome characterit.t:~d by the fre<.1'uent ft'TlllTt:~nce of hlJILi.-itJnal ovarian cvst~. The cysts were symptomatic t
Volurue 134
Recurrent ovarian cysts in young women
313
Number 3
was accompanied by elevated plasma estradiol levels in three of the four patients in whom blood studies are available. The pathology report confirmed the presence of ovarian tissue in each case. During ovarian suooression. these oatients remained asvmotomatic. plasma estradiol levels were low, and the patients were free of pelvic masses. Reports of recurrent ovarian cysts, such as those present in our group of patients, are most uncommon. Several explanations may be offered to elucidate the etiology of this syndrome. One causative factor may be an increased production of gonadotropins. It would appear that these ovarian cysts did not develop in response to elevated gonadotropins, as occurs in molar pregnancies. or from a complication of ovulation induction, L 2 since elevated gonadotropins were not found on any occasion. Whether a considerable rise in gonadotropin levels occurred before the appearance of the cysts is not known, since no hormonal levels were obtained prior to the patients' becoming symptomatic and since normal low levels of gonadotropins found during the cyst-free periods were the direct result of the ovarian suppression therapy. It is possible, therefore, that high gonadotropin levels may have initiated growth of the cysts and then decreased as a result of the elevated estrogen production by the cyst, at which time the patient sought consultation. A second explanation may be that the ovarian tissue elicits a hypersensitive response to normal gonadotropins by forming these recurrent functional cysts. Such hypersensitivity of ovarian tissue could be due to an unknown error in the metabolic pathway of granulosa and/or theca cells. This hyperresponse to normal gonadotropin levels could be the counterpart of the unresponsive ovarian syndrome in which normal ovarian tissue does not respond to normal or increased gonadotropin levels."· 6 The mechanism by which normalappearing follicles fail to respond to gonadotropins is not clear. The above possibilities can be used to explain the clinical manifestations in Cases 1 and 2. However, they cannot provide the complete explanation of the recurrence of "ovarian-like" cysts foiiowing biiaterai oophorectomy in Cases 3 and 4. The ovarian cellular composition of the recurring cysts along with the increased estrogen levels indicates that there is some ovarian or "ovarian-like" tissue within the pelvic cavity that responds to normal gonadotropin levels. Ovarian tissue remaining within the pelvic cavity following bilateral oophorectomy could be a result of one of the following: I. Incomplete surgical removal of the ovaries is a possibility since the oophorectomy was performed after l
I
'
I
I
1
several surgical procedures which have produced extensive pelvic adhesions and distortion of the normal position of the ovaries. However, this possibility seems remote since extreme caution was exercised at the time of oophorectomy and in the surgical procedures performed after bilateral oophorectomy to ensure complete removal of all ovarian tissut>_ 2. Accessory ovaries in which the extraovarian tissue is situated near to and usually connected with the normally placed ovary could be the source of the recurrent follicle cysts. Origin of such accessory ovaries is probably similar to that of the normally placed ovaries. Usually this accessory ovarian tissue is quite small and thus remains unrecognizable prior to pathologic evaluation. Wharton 7 in an excellent review article reported only 18 authors who had described this pathologic finding with only three seeing more than one case. In all of these cases tissue with the distinct structure and function of a normal ovary was present. Our two cases do not appear to be conditions of accessory ovaries since the cystlike structures were distant from and not connected to the site of the normal ovaries. 3. Another possibility involves the formation of extraovarian tissue not associated with the normally placed ovary. Wharton 7 described a rare condition called supernumerary ovary in which ovarian tissue was located in a position not associated with that of may be functional. Kosasa and associates 8 reported on one patient with elevated total plasma estrogen after_ bilateral oophorectomy. The source of the estrogen was a retroperitoneally located supernumerary ovary. Wharton 7 theorized that such aberrant ovaries were the result of the failure of migrating germ cells to reach the developing genital ridge. That such germ cells do find their way to extrag;onadal areas and are viable and may be the source of tumors has been demonstrated in a variety of animal species. 9 Such primary germ cell tumors have been found in the anterior mediastinum 10 and in a retroperitoneal location. ll In our study, the pathologic findings show the cysts to contain granulosa luteal and theca luteal cells and ovarian stroma. No oocytes were observed. In association with Wharton's theory, presumably the extragonadai germ cells induced the surrounding mesenchymal cells to differentiate into ovarian cellular components. Another explanation would be that of Printz and associates 12 who reported a case of a 23-year-old, black woman in which they found ovarian tissue embedded in the omentum. They theorized that a portion of the genital ridge. after colonization by the germ cells, became detached and then reattached in a neighboring area. This would explain the normal ovarian
jww
314 Stone and Swartz
tissue contents of the cyst in the pathologic fiudiugs. From our findings it appears that whatever the source of this ovarian tissue it becomes functional and produces large amounts of estradiol to levels much higher than those found after the removal of both normal ovaries. Such tissue may become extremely sensitive to circulating gonadotropins in the absence o! normal ovarian tissue. Greenwald 1:3 showed in hamsters that after unilateral ovariectomy the remaining ovary hyperovulates. Biskind and Biskind 14 in rats and McLaren 13 in mice demonstrated that an ovary transplanted to the spleen hypertrophied only after the in situ ovary was also removed. Furthermore, Chihal and associates'" demonstrated that '"extraovarian" tissue affects the number of eggs ovulated and the plasma levels of progesterone in postpuberal rats receiving ovarian homografts. This has not been shown in humans; however, it is certainly possible that aberrant embrvonir gonadal tissue in the absence of normal ovarian tissue may develop under the influence of normal gonadotropins and thus be responsible for recurrent ovarian cyst formation. Infertility is an important secondary effect of either the syndrome or its long-term therapy. Only one of the patients presented here has been pregnant and this
REFERENCES
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p1 uu lu the developn1e1H of the -..yndroill\:". Despite the desire for children in Patients I and ;!, ovarian cyst' have developed each time ovarian suppression was stopped. The development of recurrent ovarian cysts either before or after bilateral oophorectomy is con5idercd otLUtTed
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prevalent than a review of the literature leads one to believe. In tact. we have diagnosed four case' of llm condition in the past two years, The need for ovarian suppression and the monitoring of long-term therapy with plasma estradiol levels is recommended. ~urgical approach to treat t hi;,; svndrome does not 'eem adequate, and after the lirsr recurrence probably no further 'urgen is indicated. Presently we lind no alternative to ovarian suppression for the treatment of these patient.;,. It is possible that this syndrome may regress after menopause. <1 time at which the ovarv does not normal!\ respond to markedly elevated gonadotropin leveb. We hope that by charactcriling this S\ndrome we will encourage mon· reports of patients like these and therefore find a better wav of evaluating and treating recurreni ~vmptomalic functional ovarian c~ sts.
I. Novak, E. R .. and Woodruff, J.D.: ~ovak's Gynecologic and Obstetric Pathology, ed. 7, Philadelphia 1974. W. B. Saunders Co., chap. 20, pp. 357-366. 2. Griffiths, C. T.: In Kistner, R. W.: Gynecology, Principles and Practice, ed. 2, Chicago, 1971. Year Book Medical Publishers, Inc., chap. 8, pp. 344-347. :~. Wieland, R. G., Bendezu, R., Hallberg, M. C., Tang. P ..
M., and Naftolin. F.: Diagnosis of a supernumerary ovary with human chorionic gonadotropin. <>bstet. Gynewl. 47:236, 1976. 9. Swartz, W. J., and Domm, L. \'.: A study on di\ision of primordial germ cells in the earh chick embryo. Am . .J. An at. 135:5!. ! 972. 10. Luna, M. A.. and Valenzuela-Tamariz. J.: l;erm-tell tumors of the mediastinum, postmortem lindi1igs, Am . .J.
and \Vebster~ K.: Hormonal evaluation of premature menarche produced by a follicular cyst, AM.]. 0BSTET. GYNECOL. 126:731, 1976. Monteleone, J. A., Monteleone, P. L., and Danis, R. K.: Pseudoprecocious puberty associated with isolated follicular cysts of the ovary, J. Pediatr. Surg. 8:949, 1973. Jones, G. S., and DeMoraes-Ruehsen, M.: A new syndrome of amenorrhea in association with hypergonadotrooism and aooarentlv normal ovarian follicular appa;atus, AM. j.'0BSTET_' GYNECOL. 104:597, 1969. . Starup, J., Sele, V ., and Henriksen, B.: Amenorrhea ass
II. l!tz. D. C., and Buscemi, M. F.: Extra~onadal testicular tumors, .J. t_; rol. 105:271. 1971. 12. Printz,]. L., Choate,J. W., Townes, P. L, and Harper. R. C.: The embryology of supernumerary ovarie,, Obstet. Gynecol. 41:246. 197~~1:~. Greenwald, G. S.: The effect of unilateral o\"ariectomy on follicular maturation in the hamster, Fndocrinolo~y 66:89, 1960. 14. Biskind, G. R., and Biskind, M. S.: Atrophy of ovarie' transplanted to the spleen in unilaterally castrated rats: proliferative changes following subsc:quent removal of intact oval"), Science 108:1~17, 1948. 15. McLaren, A.: Regulation of ovulation rate after remuval of one ovary in mice, Proc Soc. Med. 166:3-\.6, 1966. 16. Chihal, H.J. W., Stone, S.C., and Peppler, R. D.: Effects of "extra"' ovarian tissue on ovulation number and ovarian steroids in rats, .J. Rep rod. Fertil. 47:107, 197n.
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