{"paper_id":"ea3d12c8-91e9-4800-9731-bb1a8280843a","body_text":"Ovarian pregnancy occurs when a fertilized\novum implants in or on the ovary. This entity is\na rare variant of extrauterine pregnancy and represents 1.1-3% of all ectopic pregnancies or one\novarian pregnancy per 7000-90000 live births ( 1 - 4 )\nSerous cyst adenoma is a cystic ovarian tumor\ncontaining serous fluid and solid- tissue component. This tumor is benign form, presenting as\ncystic unilocular or multilocular ovarian mass with\nthin wall and minimal papillary projections ( 5 ).\nPolycystic ovarian syndrome (PCOS) is the most\ncommon endocrinopathy among subfertile women\n( 6 ). The most prominent presenting characteristics\nare oligo/anovulation and hyperandrogenism ( 7 ).\nCurrently, metformin, an insulin-sensitizing agent,\nwas accepted as a favorable medication for ovulation induction in PCOS ( 8 ,  9 ).\nInfertility and subfertility managements including induction of ovulation seem to be responsible\ncauses in the occurrence of the ectopic pregnancies ( 10 - 12 ).\nIn some retrospective studies, an association has\nbeen found between fertility drugs use and ovarian\nneoplasia risk in infertile patients ( 13 - 15 ).\nThe case presented here is interesting in term of\nthe rarity of ovarian pregnancy and coincidence\nwith serous cyst ovarian tumor, and also occurring\nafter ovulation induction by metformin.\n\nIn January 2013, a 28-year-old primigravida\nwoman with sever lower abdominal pain presented to the emergency room of our hospital (Tehran Women General Hospital, Tehran,\nIran). She suffered from vaginal spotting and lower abdominal pain for 5-6 consecutive days.\nShe revealed a history of primary infertility\nwith 3 years duration. Because of clinical and\nparaclinical manifestations of polycystic ovarian syndrome, metformin (1500 mg/day) has\nbeen prescribed for induction of ovulation since\n8 months ago. After starting this medication,\nshe developed regular menstruation pattern.\nHer last menstrual period was 25 days prior to\nadmission date. She had no previous history of\npelvic inflammatory disease, abdominal surgery, abortion, or use of any intrauterine contraceptive device (IUCD). Her hysterosalpingography (HSG) demonstrated an otherwise\nnormal image without uteroovarian fistula. On\ngeneral examination, she was pale. Abdominal\nexamination showed abdominal distention and\nguarding. On vaginal examination, the uterus\nwas normal in size and the cervix was tender\nin motion. There was a tenderous mass in deep\npalpation of right fornix. Clinical investigation\nshowed hematocrit level of 25.2%, and betahuman chorionic gonadotropin (β-hCG) titer of\n3569 m IU/mL. Vaginal ultrasonography demonstrated empty uterus with 6 mm endometrial\nthickness, free fluid in the peritoneal cavity,\nand a right sided heterogeneous adnexal mass\n(52×61 mm) beside the uterus. These findings\nwere suggestive of ruptured ectopic gestation.\nBased on the above findings, the patient underwent emergency laparotomy in which demonstrated an enlarged and bluish right ovary with\na 4 cm hemorrhagic and ruptured ovarian mass\nand a leaking hematoma on its surface. A 3×3\ncm multicystic structure was identified in the\nother side of right ovary and was presumed to\nbe a tumorous lesion. The uterus, both tubes\nand the left ovary appeared to be normal in appearance. The right tube had normal fimbriated\nend without dilation. There was no obvious\nevidence of endometriosis, metastatic lesions,\npelvic inflammation, or adhesion. We found\n1500 mL bloody fluid in abdominal cavity.\nThe diagnosis of ovarian pregnancy was made.\nTherefore, surgical resection of hemorrhagic\nmass with conservation of the right ovary was\ndone carefully. Because of bad looking appearance of the concurrent cyst in the right ovary,\novarian cystectomy and endometrial curetting\nwere performed, respectively. The final pathologic analysis revealed vascularized chorionic\nvilli and trophoblastic cells within ovarian paranchymal tissue (Figes 1 ,  2 ). Histopathological\nstudy demonstrated that the excised cyst was\na benign serous cyst adenoma ( Fig 3 ). The endometrial sample showed decidual change, but\nno gestational tissue. The post-operative course\nwas uneventful. On monitoring of β-hCG lev-\nels, they were undetectable (<5 m IU/ mL) on\nthe 21 st \npostoperative day. The patient menstru-\nated 37 days after the surgical operation.\nPhotomicrograph identified trophoblastic cells within\nthe ovarian parenchyma (H&E); ×200.\nPhotomicrograph identified chorionic villi (H&E);\n×100.\nPhotomicrograph identified serous cyst adenoma\n(H&E); ×400.\n\nOvarian pregnancy is a rare variant of ectopic\npregnancy ( 1 -  4 ). This entity must be documented\nby the four criteria of Spiegelberg: I. separation of\nintact tubes from the ovaries, II. a gestational sac\noccupying the normal position of the ovary, III. the\novary and sac connected to the uterus by the uteroovarian ligament, and IV. ovarian tissue histologically demonstrated in the sac wall ( 16 ).\nIts true incidence is underestimated. Some\nof the suspected tubal pregnancies that are approached with conservative managements, without laparoscopic validation, are in fact ovarian\npregnancies ( 2 ,  10 ,  17 ). However, there is a rising in incidence of ovarian pregnancy in the last\ndecade, its true incidence is undetermined ( 3 ,  10 ,\n 18 ). Furthermore, some studies suggested infer-\ntility and the medications, which are prescribed\nfor ovulation induction, were associated with\nan increased incidence of ovarian pregnancies\n( 3 ,  10 - 12 ). The suspected predisposing factors\nwere increased levels of estrogen and progesterone after ovulation induction ( 19 ). However, the\nother reports did not support this hypothesis ( 2 ,\n 10 ,  20 ,  21 )\nThe exact etiologic factors of increased risk of\novarian pregnancy after ART programs are unclear, but the most likely mechanisms are as follows: reverse migration of embryo after deep deposition, the use of large volumes of culture fluid\nduring embryo transfer (ET) procedures, difficult\nET, and tubal pathologies ( 12 ,  22 - 24 ).\nThe risk of ovarian pregnancy in patients with\nendometriosis or using IUCDs is controversial ( 3 ,\n 25 ). Unlike tubal pregnancy, the history of pelvic\ninflammatory disease does not increase the risk of\novarian pregnancy ( 2 ,  20 ,  21 ,  26 ).\nPreoperative diagnosis is a challenge to the clinician due to its rarity and lack of typical presenting\nsymptoms or documented risk factors ( 27 ). The\nclinical findings are similar to tubal pregnancy or\nhemorrhagic corpus luteal cyst ( 2 ,  28 ). The most\ncomplaints are abdominal pain and vaginal bleeding ( 3 ,  10 ). The increased vascularity of the ovary\nfacilitates more massive bleeding and hypovalemic shock ( 3 ,  18 ). The asymptomatic patients are\nincidentally discovered during post-  in vitro  fertilization (IVF) monitoring ( 2 ). The ovarian pregnancies could be multiple gestations or heterotopic\ntype ( 2 ,  29 ). There are very few recorded cases\nin which ovarian pregnancy reached viability ( 30 ).\nThe ultrasound features are ovarian enlargement with or without containing a double hyperechogenic ring along with yolk sac, fetal part, or\nfetal heart beat within ovary; fluid collection surrounding the ovary; and an empty uterus ( 2 ,  4 ,  20 ,\n 31 ,  32 ). The sonographic differential diagnosis\nbetween ovarian pregnancy and a ruptured corpus luteal cyst or a hemorrhagic ovarian tumor is\ndifficult ( 2 ,  4 ,  27 ,  33 ). Although definite diagnosis is reached by laparoscopy or laparotomy, some\nof ovarian pregnancies are identifiable by vaginal\nultrasound scanning ( 10 ,  17 ). Ovarian pregnancies can be mistaken for hemorrhagic corpus luteal cysts or pregnancies in the distal part of tube\neven at laparoscopy or laparotomy ( 3 ). Since pregnancy induced tissue destruction and lesser tissue\nis available in conservative surgeries, postoperative diagnosis is also difficult ( 21 ). Therefore, the\nphysicians must exhibit a high degree of suspicion\nfor ovarian pregnancy when managing with pregnancy of unknown location.\nIn recent years, accurate and earlier diagnosis\nhas been performed by the application of vaginal\nultrasound scanning and quantitative hCG measurement ( 1 ,  28 ). So, the management procedures\nof ovarian pregnancy have evolved oopherectomy\nby open surgical procedures and removal of gestational products or ovarian wedge resection by the\nlaparoscopy and/or medical management using intramuscular or local injection of chemotherapeutic\nagents such as methotrexate (50 mg/m2) , hyperosmolar glucose, and prostaglandins, especially in\nyoung patients who have an intact ovarian pregnancy and a desire for future childbearing ( 2 ,  3 ,\n 10 ,  17 ,  20 ,  29 ,  34 - 36 ). Application of these modalities in management of ovarian pregnancy decreases\nmaternal mortality and morbidity rates ( 34 ).\nSerous cyst adenoma is the most common benign epithelial cell tumor of ovary ( 5 ). In some\nretrospective epidemiologic studies, an association has been demonstrated between prolonged\ninfertility/use of ovulation inducing drugs and an\nincreased incidence of ovarian epithelial cell dysplasia and cancer ( 13 - 15 ,  37 - 40 ). The stimulation\nof ovulation and increased levels of estrogen and\nprogesterone explain the potential suspected relationship between the use of fertility medications\nand development of ovarian neoplasia ( 39 )\nIn the other hand, a high frequency of hyperplasia and metaplasia in the ovarian epithelial surface and 2.5-fold increased risk of ovarian cancer\nhave been showed in women with PCOS ( 41 ,  42 ).\nAlthough the contradictory data were reported in\nthe other studies ( 40 ,  43 - 45 ,  46 ), like in a study\nby Brinton, the dosage and number of cycles of\novulation-inducing drugs were not associated with\nelevated risk ( 15 ). This difference is based on different study design, confusing factors such as duration and causes of infertility, parity, as well as\ntype and duration of medical therapy ( 33 ).\nIn some cohort studies, ovulation-inducing\ndrugs were related to an elevated risk of border\nline serous tumors ( 13 ,  40 ,  47 ). However, there is\na possible association between prolonged use of\nclomiphene citrate and invasive epithelial ovarian\ntumors ( 40 ). This relationship should be pointed\nout with caution. The confounding influence of infertility and nulliparity should be kept in mind. Additionally, the other authors did not confirm these\ndata in case-control studies ( 13 ,  15 ,  42 ,  48 ,  49 ).\nFertility experts frequently use metformin, an\ninsulin-sensitizing agent, as an ovulation-inducing\nmedication in PCOS ( 50 ,  51 ). Although its connection with ectopic gestation is reported ( 52 ), its\nassociation with serous cyst adenoma is undetermined. Some studies showed metformin use has\nbeen associated with a significant decrease in risk\nof prostate, pancreas, and breast cancer ( 53 ,  54 );\nhowever, its molecular effect on ovarian tissue,\nand also, its effect on the risk of ovarian tumors\nremain undetermined ( 50 ). Although superovulation and increased serum levels of ovarian steroid\nhormones are the suspected pathogenesis of raising incidence of epithelial cell tumors following\ninduction ovulation, superovulation is very rare\nevent after metformin use ( 51 ); furthermore, estrdiol and progesterone serum levels are near the\nphysiologic levels in cycles after being induced by\nthis agent ( 50 ).\nHowever, to the best of our knowledge, this\nstudy is the first case report of coexistence of an\novarian pregnancy and a serous cyst adenoma\nin the same ovary following ovulation induction\nwith metformin. Review of the literature showed\nonly a few reports presenting the coincidence of\na serous cyst adenoma with an ectopic pregnancy.\nThey have been cases involving tubal or abdominal pregnancy coinciding with serous cyst adenoma ( 52 ,  55 ,  56 ). Vazquez et al. ( 55 ) reported tubal\npregnancy and ovarian serous cyst adenoma in a\n40-year-old patient. The pregnancy was happened\nafter induction of ovulation by clomiphene citrate.\nPricop et al. ( 56 ) presented a case with abdominal\npregnancy and serous cyst adenoma. Werlin et al.\n( 52 ) reported a coincidence of tubal pregnancy\nwith a serous cyst adenoma in the same fallopian\ntube following induction ovulation with metformin, letrozol, and low-dose gonadotropin. After review of literature, we did not find original study\nor documented case report about relationship between the use of metformin and ovarian tumors.\nIn our case, the presenting signs and symptoms\nwere severe abdominal pain with vaginal spotting,\nelevated β-hCG, ovarian mass and empty uterus.\nShe fulfilled the criteria for ovarian pregnancy, as\nby Spiegelberg’s outlines. She had a concurrent benign serous cyst adenoma in the same ovary. Our\npatient was previously labeled with PCOS. Pregnancy happened following induction of ovulation\nwith metformin. In term of risk factors, infertility\nand the use of ovulation inducing drugs might be\nthe possible predisposing factors for the ovarian\npregnancy. The relationship between metformin\nand serous cyst adenoma is not clear.\n\nOvarian pregnancy is uncommon entity, which is difficult to diagnose. The microinvasive surgical\nprocedures and medical managements are effective therapeutic options in the treatment of unruptured ovarian pregnancies, especially in young patients. Although the current findings are not strong\nto support a link between fertility drugs and ovarian cancer, it seems to be an association between\nreduced fertility and increased neoplasia risk.\nCareful inspection of the ovaries at surgery indicated the high risk of ovarian tumors for patients\nwith long-standing history of infertility or fertility\nagents use in order to exclude the presence of a\nneoplasm. Moreover, further prospective, multicenter, and long follow-up studies considering all\nconfounding factors are necessary to improve our\nability for diagnosis and treatment of ovarian pregnancy, and to determine the patho-physiological\nmechanisms underlying the possible link between\ninfertility or the use of ovulation inducing drugs\nand ovarian tumors.","source_license":"CC-BY-4.0","license_restricted":false}