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Hyperreactio luteinalis (HL) and spontaneous ovarian hyperstimulation syndrome (OHSS) are both rare conditions during pregnancy. The clinical presentation of HL and OHSS are comparable and both should be differentiated from ovarian carcinoma. We present a case of a 32-year-old woman who was initially seen with markedly enlarged multicystic ovaries and ascites in the 13th week of a spontaneously conceived pregnancy. Ultrasonographic follow-up and magnetic resonance imaging of the ovaries were employed in order to avoid exploratory laparotomy and rule out ovarian carcinoma. The patient received supportive therapy and delivered a healthy child at term. The increasing use of ultrasonography may lead to more frequent findings of multicystic ovaries in spontaneously conceived pregnancies. Making the distinction between HL and spontaneous OHSS in these cases may be difficult though clinically irrelevant as the approach to treatment is similar in both. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.
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- Case report
A 32-year-old woman, gravida 4 para 2, was referred to our clinic at 13 weeks' gestation following a routine ultrasound scan that revealed bilateral large ovarian cysts. Apart from mild bronchial asthma, her medical, gynecological and surgical histories were unremarkable. She had been on oral contraceptives for a year prior to conception, and denied using drugs for ovulation induction. Her pertinent history included two normal, spontaneously conceived pregnancies, two term vaginal deliveries of normal weight babies and a first-trimester spontaneous miscarriage. Early in her fourth pregnancy a transvaginal ultrasonogram disclosed an intrauterine gestational sac containing an embryo with a crown–rump length of 24 mm, corresponding to 9 + 4 weeks' gestation. Enlarged ovaries were not detected at that scan.
The patient's complaints were nausea and abdominal tightness. On examination the abdomen was distended and diffusely tender with no signs of peritoneal irritation. No evidence of thyroid disease or hyperandrogenism was noted. Pelvic examination disclosed a firm and closed cervix and a uterus whose size was consistent with 13 weeks' gestation. Our ultrasound scan confirmed a viable intrauterine pregnancy with normally developing fetus, bilaterally enlarged multicystic ovaries (10.3 × 10.1 × 7.0 cm right, 9.0 × 8.5 × 7.7 cm left) with ‘spoke wheel’ appearance (Figure 1) and mild ascites. Color and pulsed Doppler studies disclosed normal uterine and ovarian vessels. Resistance index, pulsatility index and systolic/diastolic flow ratio measured at the ovarian artery were 0.53, 0.92 and 3.14, respectively. Laboratory tests revealed normal concentrations of hemoglobin, hematocrit, white cells, platelets, creatinine and blood urea nitrogen; creatinine clearance was 107 cc/min, albumin concentration was at the lower limit of normal at 3.4 g/dL. Thyroid stimulating hormone (TSH) was low, free triiodothyronine and free thyroxine were normal. The beta subunit of human chorionic gonadotropin (beta-hCG) was elevated (Table 1). Total testosterone and androstenedione levels were at the upper normal limits for pregnancy (Table 1). Blood vasculoendothelial growth factor (VEGF) was below 5 ng/ml and blood interleukin-6 was negative. A chest radiograph did not detect pleural effusion. Magnetic resonance imaging (MRI) was performed to rule out ovarian malignancy and showed bilateral symmetrical multicystic enlargement of the ovaries. The cystic wall was neither thickened nor enhanced. A diagnosis of benign ovarian enlargement was confirmed. During the next 2 months her clinical condition was stable, and the level of beta-hCG and ovarian volume decreased gradually (Table 1). At 23 weeks the patient was admitted to the hospital with uterine contractions and mild vaginal bleeding. A diagnosis of partial placental abruption was made based on clinical presentation, physical examination and sonographic identification of placental location. Coagulation parameters PT (prothrombin time) and aPTT (activated partial thromboplastin time) were normal. Both transvaginal and abdominal sonographic studies at this stage failed to identify the ovaries. The symptoms resolved without treatment and the patient was discharged 4 days later. She delivered a 3000-g healthy female newborn at term. The infant showed no signs of virilization. The ultrasound appearance of the mother's ovaries was entirely normal 4 months after delivery.
Table 1. Summary of clinical parameters of the patient presented during pregnancy
|Parameter||13 weeks||14 weeks||17 weeks||24 weeks||29 weeks||34 weeks|
|Ovary dimensions (cm)|
|Right||10.3 × 10.1 × 7.0||8.8 × 8.2 × 4.0||7.7 × 4.0 × 3.6|| |
|Left||9.0 × 8.5 × 7.7||8.1 × 5.7 × 5.6||6.6 × 4.2 × 2.2|| |
|Beta-hCG (IU/L)||137 100|| ||67 270||29 650||44 446||54 393|
|TSH (mIU/L)||0.17|| || ||1.07|| || |
|Thyroxine, free T4 (ng/dL)||2|| |
|Triidothyronine, free T3 (ng/dL)||0.45|| |
|Testosterone (µg/L)||3|| |
|Androstenedione (µg/L)||4.5|| |
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- Case report
This case is one of few reports of ovarian hyperstimulation-like syndrome occurring in a spontaneously conceived pregnancy, which was closely monitored and managed expectantly throughout complete gestation. Without any iatrogenic induction of ovulation, the differential diagnosis was spontaneous OHSS vs. HL. In both conditions the bilateral cluster of giant simple or hemorrhagic luteinized ovarian cysts with minimal stroma are seen, giving a ‘spoke wheel’ appearance. Although invariably present in severe OHSS, ascites of varying severity may be recognized in both. OHSS is almost exclusively associated with ovulation induction with exogenous gonadotropins2. However, OHSS can rarely occur with a spontaneous ovulatory cycle, especially in multiple gestation3, hypothyroidism4, molar pregnancy5, in subjects with hyperandrogenism and polycystic ovary syndrome6 as well as in normal singleton pregnancy7. Typically, iatrogenic OHSS is diagnosed immediately following conception2, but the time of diagnosis is more variable with spontaneously occurring OHSS.
HL is believed to be an exaggerated ovarian luteinization due to hyperstimulation by or hypersensitivity to hCG. Historically, the diagnosis was often made incidentally and later in pregnancy. Extra-ovarian symptoms included maternal virilization in about 25% of patients and occasionally ascites. Consisting of multiple theca lutein cysts, HL may accompany conditions with elevated placental hCG, such as multiple pregnancies, hydatidiform mole or gestational trophoblastic disease8, but more than half of the reports occurred with normal singleton pregnancies9. Endogenous hCG is secreted by the trophoblast starting 7–8 days after fertilization. In normal singleton pregnancy hCG concentration in the maternal serum reaches a peak level of 100 000 IU/L between 8–10 weeks of gestation, and declines to 40 000 IU/L from 20 weeks until delivery10. In the case presented, beta-hCG levels detected were about twice the norm at the end of the first trimester (Table 1) and could serve as the trigger to either spontaneous OHSS or HL.
Both conditions share underlying risk factors, comparable clinical presentation, indistinguishable sonographic appearance of the ovaries and non-surgical expectant management, and can be viewed as entities in continuum1, 11. The ‘spoke wheel’ sign of large simple thin-walled cysts, along with intensely compressed stroma with physiological vasculature, is regarded as a key sign of both diagnoses. Nonetheless, some disparities between spontaneous OHSS and HL do exist; HL may occur unilaterally and its clinical course is more indolent. Some complications that accompany each entity are derivatives of a dissimilar clinical course. Severe life-threatening OHSS entails dramatic fluid shifts prompting hypovolemia and thrombosis12, while HL runs a less acute course, which may be more prone to misdiagnosis of an ovarian tumor and unnecessary oophorectomy9. Along this line, although hyperandrogenism with polycystic ovary syndrome is a well-known risk factor for spontaneous OHSS6, virilization is rare. In HL however, virilization is seen in 25% of patients and hyperandrogenism is even more frequent. Probably the more indolent course of HL allows the changes in secondary sexual characteristics to develop over time1. Other rare complications such as ovarian torsion and labor dystocia may be common to all ovary-expanding conditions.
Many putative mediators have been cited as inducers of ovarian hyperstimulation including VEGF, various cytokines, prostaglandins, histamine, estrogen, prolactin and renin. To assist in the differential diagnosis we measured VEGF, as one of the main factors responsible for OHSS development5, 13. VEGF was also shown to be triggered by hCG in vitro and in vivo. However, the blood level of VEGF does not always parallel the clinical course of OHSS5. Therefore, the finding of low serum VEGF concentration when hCG levels were maximal does not fully rule out the diagnosis of OHSS, nor serve as a distinguishing feature between OHSS and HL.
The possibility of ovarian cancer should be taken into consideration in cases of rapid ovarian growth9. However, the bilaterality and exaggerated but regular ovarian morphology reveals this to be a functional derangement. The exclusion of the diagnosis of ovarian cancer was made by ultrasonography and MRI that revealed the classic ‘spoke wheel’ appearance that is characteristic of theca lutein cysts without solid components. MRI has been suggested as the preferred method for imaging enlarged ovaries14. However, in this case MRI added no further information to the data drawn from a simple ultrasonogram. Color Doppler studies of the ovarian vessels excluded pathological flow parameters. Serum CA125 tends to be elevated in pregnancy, therefore, its measurement could not serve as a discriminator between benign conditions versus ovarian malignancy1. The reduction in ovarian volume and the resolution of ascites, along with gradual symptomatic relief, observed during careful clinical and ultrasonic follow-up, contributed to the decision for close observational management.
In conclusion, (i) spontaneous OHSS and HL are related entities that share risk factors, symptoms, and presumably pathogenesis; (ii) both diagnoses should be managed conservatively after ovarian malignancy is ruled out; (iii) serial ultrasonographic scans may be the preferable method of follow-up of ovarian multicystic appearance during pregnancy; and (iv) with the expanding use of ultrasonography in pregnancy, multicystic ovarian enlargement is expected to be encountered more frequently. Consideration of entities such as HL and spontaneous OHSS prevent unnecessary surgical intervention.