Brazilian Journal of Development 50897 ISSN: 2525-8761

Hyperreactio luteinalis in a normal singleton pregnancy: a case report

Hiperreação luteínica em gestação simples normal: relato de caso

DOI:10.34117/bjdv7n5-472 Recebimento dos originais: 07/04/2021 Aceitação para publicação: 03/05/2021

João Eduardo Andrade Tavares de Aguiar Discente do Departamento de Medicina da Universidade Federal de Sergipe – UFS Instituição: Universidade Federal de Sergipe – UFS Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

Alessandra Aleixo Albuquerque Ginecologista e Obstetra pelo Hospital Universitário da Universidade Federal de Sergipe – HU/UFS Instituição: Universidade Federal de Sergipe – UFS Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

Marcos Antônio Lima Carvalho Discente do Departamento de Medicina da Universidade Federal de Sergipe – UFS Instituição: Universidade Federal de Sergipe – UFS Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

Artime Alves Costa Ginecologista e Obstetra no Hospital da Polícia Militar de Sergipe Médico pela Universidade Federal de Sergipe – UFS Instituição: Universidade Federal de Sergipe – UFS Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

Bárbara Rhayane Santos Discente do Departamento de Medicina da Universidade Federal de Sergipe – UFS Instituição: Universidade Federal de Sergipe – UFS Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

Marcella Andrade Tavares de Aguiar Discente de Medicina do Centro Universitário Tiradentes – UNIT/AL Instituição: Centro Universitário Tiradentes – UNIT/AL Endereço: Av. Comendador Gustavo Paiva, 5017 – Cruz das Almas, Maceió–AL, 57038-000 E-mail: [email protected]

Mariana Cunha de Sousa Discente do Departamento de Medicina da Universidade Federal de Sergipe – UFS Instituição: Universidade Federal de Sergipe – UFS

Brazilian Journal of Development, Curitiba, v.7, n.5, p. 50897-50907 may 2021

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Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

Júlia Maria Gonçalves Dias Docente do Departamento de Medicina da Universidade Federal de Sergipe – UFS Doutora em Ciências da Saúde pela Universidade Federal de Sergipe – UFS Universidade Federal de Sergipe – UFS Endereço: Rua Cláudio Batista, s/n – Santo Antônio, Aracaju–SE, 49060-100 E-mail: [email protected]

ABSTRACT Hyperreactio luteinalis (HL) is a very rare and benign condition related to pregnancy, in which there is a massive and functional increase in , occupied by multiple benign theca lutein cysts. It generally does not affect pregnancy course and can be observed and diagnosed incidentally in third trimester. The cysts and, consequently, the ovaries regress spontaneously after delivery due to decrease in hCG. This report describes a case of HL in a 29-year-old primiparous woman with dyspnea, and clinical signs of hyperandrogenism, with the ovaries enlarged on transvaginal ultrasound. The conduct was expectant and, during delivery, a biopsy was performed, which confirmed the diagnosis. The knowledge of benign and self-limited disease defends a conservative treatment and helps in differentiation between HL and other malignant diseases. It is, therefore, essential that obstetricians are familiar with HL to guide the correct management and avoid unnecessary iatrogenic procedures.

Keywords: Ovarian diseases. Ovarian Cysts. Theca cells.

RESUMO A hiperreação luteínica (HL) é uma condição muito rara e benigna relacionada à gravidez, na qual há um aumento maciço e funcional dos ovários, ocupados por múltiplos cistos teca luteínicos benignos. Geralmente não afeta o curso da gravidez e pode ser observada e diagnosticada incidentalmente no terceiro trimestre. Os cistos e, consequentemente, os ovários regridem espontaneamente após o parto por conta da diminuição de hCG. Este relato descreve um caso de HL em primigesta de 29 anos com dispneia, dor pélvica e sinais clínicos de hiperandrogenismo, apresentando os ovários aumentados na ultrassonografia transvaginal. A conduta foi expectante e, durante o parto, foi realizada biópsia, que confirmou o diagnóstico. O conhecimento da doença benigna e autolimitada defende um tratamento conservador e auxilia na diferenciação entre a síndrome e outras doenças malignas. É, portanto, essencial que obstetras estejam familiarizados com a HL para direcionar o correto manejo e evitar desnecessários procedimentos iatrogênicos.

Palavras-chaves: Doenças ovarianas. Cistos Ovarianos. Células tecais.

1 INTRODUCTION Hyperreactio luteinalis (HL) is a very rare and benign condition related to pregnancy, in which there is a massive, functional and bilateral enlargement of ovaries,

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43 may. 2021 Brazilian Journal of Development 50899 ISSN: 2525-8761 occupied by multiple benign theca lutein cysts1-3. About 100 cases of HL have been reported in literature, with the majority of cases in multiparous patients, with multiple pregnancies, with gestational trophoblastic disease or undergoing treatment1,4. This condition is very rare in a single spontaneous pregnancy5-6. HL is a gestational syndrome that generally does not affect pregnancy course and can be observed and diagnosed incidentally in third trimester2,7. In most cases, there are no symptoms, but it can lead to nausea and vomiting, lower abdominal pain, loss of appetite, electrolyte disorders, ascites and signs of virilization (such as hirsutism and clitoromegaly)2. Although etiology is still unknown, it is believed the cysts' formation is associated with high serum level of human chorionic gonadotropin (hCG) or with increased ovarian sensitivity to hCG, causing increased production of ovarian androgens1. In this study, we report a primigravid patient with spontaneous bilateral ovarian enlargement during a normal singleton pregnancy, in which the diagnosis of HL was made in an obstetrics service in Sergipe.

2 CASE DESCRIPTION A 29-year-old primiparous patient, with no comorbidities, clinical, gynecological or surgical history, started normal prenatal single gestation with 10 weeks in a private service in Aracaju, Sergipe. The patient reported symptoms of dyspnoea and pelvic pain and she had clinical signs of hyperandrogenism, such as hirsutism, acne and alopecia. On transvaginal ultrasound (USG TVS), at 24 weeks, a solid cystic mass was observed in left , with 89 cm3 (Figure 1), and an MRI was requested, which confirmed the presence of a multi- sept cystic mass. β-hCG was requested, resulting in 1084.13 mIU/mL. The conduct, after a literary review, was expectant, waiting for the moment of delivery to perform a biopsy.

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Figure 1. Transvaginal ultrasound of left ovary, with 89 cm3, showing a multi-sept cystic mass in a pregnant woman at 24 weeks of gestation

In obstetric ultrasonography with doppler, at 37 weeks, the mass reached 366 cm3, with numerous regular, thick and vascularized septa, in addition to showing another cyst in right ovary, with the same characteristics of the left, of 430 cm3. Previously, two other obstetric ultrasounds, performed at 33 and 34 weeks, demonstrated ovaries with the same characteristics. The 33-week ultrasound presented a left ovary with 247cm3 (Figure 2) and a right ovary with 262cm3 (Figure 3), and the 34-week ultrasound showed a left ovary with 284cm3 and a right ovary 299cm3.

Figure 2. Transvaginal ultrasound of left ovary, 262 cm3, with multi-sept cystic mass in a pregnant woman at 33 weeks of gestation.

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Figure 3. Transvaginal ultrasound of right ovary, 247 cm3, with multi-sept cystic mass in a pregnant woman at 33 weeks of gestation.

There was no anticipation of delivery, and a cesarean section was performed at 40 weeks of gestation, associated with oophoroplasty for biopsy (Figures 4 e 5), in August 2017. The result showed in both ovaries luteinized follicular cysts, with hemorrhagic corpus lutein on the left. In September 2017, USG TVS was performed, which showed a reduction in volumes to 211cm3 and 247cm3 in right and left ovaries, respectively, followed by monitoring and USG TVS. In March 2019, another USG TVS showed ovaries with volumes 21.7cm3 to the right and 21.5cm3 to the left.

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Figure 4. Left ovary during cesarean delivery.

Figure 5. Oophoroplastia with wedge resection of left ovary during cesarean delivery.

3 DISCUSSION HL, also called theca lutein cyst, is a self-limited syndrome, with bilateral enlargement of ovaries, and is associated with theca lutein cysts and increased hCG levels, which is secreted by the trophoblast in first trimester, with a peak in the 9th week

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43 may. 2021 Brazilian Journal of Development 50903 ISSN: 2525-8761 of gestation (highest average level of 100,000 IU/L)2,8. Estradiol and prolactin are suspected to play a role in the pathogenesis or maintenance of the disease9. In the present case, hCG levels were not abnormally high. The "spoke-wheel" appearance of ovaries on imaging studies represents the formation of theca lutein cysts10. Other characteristic findings of imaging techniques are physiological flow in Doppler velocimetry, absence of solid components, deformed contour and multiple cysts of about 1-3cm7,11-12. Before imaging exams, enlarged ovaries were identified only in symptomatic patients, undergoing surgical intervention, or during cesarean delivery. Currently, with contemporary imaging methods, early detection of HL by non-surgical procedures is possible. However, unnecessary surgical operations are still frequently performed7. Although there are reports in literature of HL in simple single pregnancies, as in this case, the syndrome appears to be related to gestational trophoblastic disease and multiple pregnancies2,5. Other risk factors are: Rh sensitization, twin-to-twin transfusion syndrome, hydrops fetalis, molar pregnancy, choriocarcinoma, polycystic ovaries, gestational diabetes, ovulation induction, clomiphene therapy, decreased beta-hCG clearance due to renal dysfunction3. Hypothyroidism, polycystic ovary syndrome (PCOS), follicle-stimulating hormone/luteinizing hormone (FSH/LH) mutation and gonadotropin-secreting adenoma can also lead to HL3. Pelvic masses, with detection of enlarged ovaries, present a problem of differential diagnosis, mainly due to the mimicry of malignant character13. HL, ovarian hyperstimulation syndrome (OHSS) and ovarian cancer must be considered. Cancer should be considered, especially in cases of elevated cancer markers, such as CA-1251. OHSS is a serious complication characterized by a bilateral multicystic ovarian enlargement that occurs at the beginning of first trimester and which has the common cause of iatrogenic ovarian induction, with exogenous gonadotropins (used in infertility treatment)1-2,8. Unlike HL, termination of pregnancy is sometimes inevitable in patients with OHSS, as it may present more severe symptoms that impair the pregnancy course, such as massive ascites, hemoconcentration and other acute fluid imbalances1-2,8. This similarity between HL and SHEO can be explained by the fact that the mutation in FSH/LH receptor causes hypersensitivity to hCG14. The symptoms are usually asymptomatic, but they can occur with nausea and vomiting, lower abdominal pain, loss of appetite, hydroelectrolytic disorder, ascites, dyspnoea and signs of virilization2-3. Nausea and vomiting are correlated with high

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43 may. 2021 Brazilian Journal of Development 50904 ISSN: 2525-8761 serum hCG levels15. In the case of our patient, she presented dyspnea and pelvic pain, in addition to clinical signs of hyperandrogenism, such as hirsutism, acne and alopecia. Hyperandrogenism is characteristic of HL due to significant increase in serum levels of total testosterone and androstenedione16. Since during pregnancy the production of sex hormone-binding globulin increases, reducing the clinical manifestations of hyperandrogenism, these virilization signs are rare in HL, occurring in only 15 to 30% of the affected pregnant women3,11,17. Considering spontaneous postpartum regression and benignity, management must be conservative and expectant1, just like our patient's. There are reports of patients with regression still during the gestational period or with complete resolution of the condition after 12 months, especially in cases associated with gestational trophoblastic disease11. In addition to observation, HL does not need any treatment unless complications occur, such as , cyst rupture, pelvic entrapment or hemorrhage2-3. In these conditions, as well as in case of suspected malignancy, surgical interventions are necessary1. There are reports in literature of other complications, such as thyroid dysfunction [the alpha subunit of hCG is similar to thyroid stimulating hormone (TSH)], hyperemesis gravidarum, hyperandrogenism, preeclampsia/eclampsia, HELLP syndrome (hemolysis, increase in liver enzymes and thrombocytopenia), premature birth, intrauterine growth restriction, placental insufficiency and delayed lactation2,11,16. Some of these complications can be explained by the high concentrations of hCG, which can contribute to the development of coagulation changes and predispose to thromboembolic complications11. However, no complications were identified in the case of the patient in our study. It is important to note the condition mimics malignancy and the possibility of cancer can lead to unnecessary intervention, such as cystectomies and oophorectomies, resulting in iatrogenesis, especially infertility5. To avoid iatrogenic management, an expectant approach with regular evaluation of ovarian cysts is recommended, including accurate and careful imaging, hormonal profile and tumor biomarkers measurement (such as CA125, carcinoembryonic antigen -CEA-, alpha-fetoprotein and CA 19-9) to rule out malignancy1,18,13. HL manifests itself, unlike cancer, with high levels of hCG, normal levels of tumor biomarkers and multicystic ovarian lesions without internal mass

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43 may. 2021 Brazilian Journal of Development 50905 ISSN: 2525-8761 on ultrasound and magnetic resonance imaging1,4. Unfortunately, this patient's hormones and biomarkers were not measured. Tumor biomarker CA125, despite being commonly used to assist in the suspicion of ovarian malignancy, has low specificity and sensitivity in discrimination of benignity and malignancy of pelvic masses1. To exclude malignancy, it is important to perform a biopsy or wedge resection with a frozen section to avoid unnecessary surgical excisions and conserve ovarian tissue5,11. In the case of this patient, a wedge resection of the ovaries was performed during cesarean section. On the other hand, it is worth mentioning HL does not contraindicate vaginal delivery11. In case of need for surgical intervention, attention should be paid to risks of mortality to the fetus during anesthesia and surgery, such as teratogenic or lethal drug effects (transient hypotension, with consequent fetal hypoxia, caused by anesthesia process); and premature uterine contraction with contraction of uterine vessels due to surgical manipulation, which would lead to fetal death1. Finally, after delivery, high concentrations of androgens and hCG can promote delayed lactation and low production of breast milk11. In addition, it is important to advise pregnancies on low risk of recurrence in a future pregnancy19.

4 FINAL CONSIDERATIONS Although HL is extremely rare in normal pregnancies, the knowledge of benign and self-limited disease defends a conservative treatment and helps in differentiation between the syndrome and other malignancies. It is, therefore, essential that obstetricians are familiar with HL to guide the correct management and avoid unnecessary iatrogenic procedures.

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