Hirsutism and Hyperandrogenism Associated With Hyperreactio Luteinalis in a Singleton Pregnancy: A Case Report
By Angioni, Stefano Portoghese, Elaine; Milano, Francesca; Melis, Gian Benedetto; Fulghesu, Anna Maria
Abstract The incidence of hyperandrogenism during pregnancy is low, although the incidence of some of the ovarian diseases that can cause it is higher. Hyperreactio luteinalis is a rare benign condition that may mimic ovarian and trophoblastic malignancies. A 23-year-old woman at 20 weeks’ gestational age presenting with severe hirsutism and ovarian masses was treated conservatively and subsequently gave birth to a healthy female neonate. Final diagnosis was hyperreactio luteinalis. Conservative management with close monitoring of patients with hyperreactio luteinalis represents the best approach in such rare cases. Counseling should be provided to reassure the patient as to the transient effects of hyperandrogenism on the mother and the fetus.
Keywords: Hyperreactio luteinalis, maternal hirsutism, pregnancy, adnexal masses
Introduction
Hyperandrogenism and virilization during pregnancy are nearly always the result of conditions arising during pregnancy. The reason for this is that hyperandrogenism in a non-pregnant woman usually results in anovulation and infertility, even if the androgen excess is not clinically evident as hirsutism or virilization. Hyperreactio luteinalis is a rare benign condition characterized by bilateral ovarian enlargement associated with pregnancies characterized by high maternal concentrations of serum human chorionic gonadotropin (hCG) and androgens. Patients may be asymptomatic, with the condition being revealed accidentally at routine pelvic ultrasound or Cesarean section. Symptomatic women may present with abdominal discomfort, dyspnea or abdominal pain as a result of ovarian torsion or hemorrhage [1-3].
Case report
A 23-year-old primigravida was referred to our department at the 20th week of pregnancy complaining of severe hirsutism, localized on the abdomen, face and legs, subsequently evaluated by means of the Ferriman-Gallwey score (score = 21). Ultrasound examination revealed a normal singleton pregnancy with fetus corresponding to amenorrhea; both ovaries however were enlarged (left: 96 mm ? 64 mm ? 70 mm, right: 87 mm ? 68 mm ? 95 mm) with multiple anechoic cysts, the largest having mean diameter of about 3 cm. Serum level of /?-hCG was within the normal range. The patient’s history did not demonstrate any unusual gynecological event over the five years preceding pregnancy.
After a short period the patient was followed on an outpatient basis. Ovarian volume continued to increase gradually without pelvic pain. Evaluation of ss-hCG revealed levels exceeding the normal range, reaching 96 200 mIU/ml at the 27th week (Table I). Androgen levels were significantly increased (Table II) and the volume of the ovaries increased throughout gestation. In spite of the above, fetal development and placenta morphology were normal on ultrasound examination. The patient was distressed by the hirsutism but did not experience abdominal pain. As the risk of complete molar gestation or choriocarcinoma was considered to be extremely remote, the patient was advised to undergo close monitoring of serum /?-hCG with ultrasound monitoring of fetus and ovaries.
Table I. Maternal levels of ss-human chorionic gonadotropin (beta- hCG) during pregnancy and Puerperium.
Table II. Maternal androgen levels during and after pregnancy.
At 34 weeks an ultrasound examination of the abdomen and a chest X-ray were performed. The results of the latter examinations together with blood tests to assess liver function and pregnancy controls did not reveal any abnormal outcome. A series of oncological markers was tested (cancer antigen 125, cancer antigen 19-9, carcinoembryonic antigen, a-fetoprotein) without any abnormal finding.
At the 36th week of gestation informed consent was obtained and the patient underwent elective Cesarean section with delivery of a healthy female (Apgar score 8-9, weight 2.090 kg). During surgery the abdomen was inspected and the ovaries appeared grossly enlarged and polycystic (Figure 1). The mean diameter of the right ovary was 15 cm and the left was 17 cm, with multiple cysts of dimension 3-4 cm full of yellowish fluid. Samples of cystic fluid and multiple biopsies of both ovaries and placenta were sent to the pathologist. The abdomen was explored and no abnormalities were evidenced.
The patient’s immediate postoperative course was unremarkable. Computed tomography scan of the pelvis, abdomen and chest, together with brain magnetic resonance imaging, were all normal. Ovarian volume decreased slowly, reaching normal volume in 2 months. Level of /?-hCG was followed until negative at 2 weeks postpartum. Maternal androgen levels decreased progressively, reaching normal values in 30 days. Hirsutism disappeared in 5 months. Neonatal levels of /?-hCG and androgens were within the normal range. The female neonate showed no signs of virilization. Pathological diagnosis evidenced hyperreactio luteinalis.
Figure 1. Left ovary at Cesarean section.
Discussion
The incidence of hyperandrogenism during pregnancy is low, although the incidence of some of the ovarian diseases that can cause it is higher [4]. The possibility of androgen excess usually arises when a pregnant woman presents with the rapid onset of masculinization. Affected women may have a variety of symptoms including hirsutism (at times requiring shaving), acne, temporal balding, clitoromegaly, and deepening of the voice. The two most common causes of gestational hyperandrogenism are luteomas and hyperreactio luteinalis. Pregnancy luteomas are benign, solid, multinodular tumours at times manifested through ovarian enlargement and maternal virilization. Originally luteomas and hyperreactio luteinalis were considered as representing the spectrum of one disease with both a solid and a cystic variant, although this view has since been challenged [5] . The etiology of hyperreactio luteinalis and the normal range of /?-hCG associated with this condition are as yet unknown. It has been proposed that the condition may be manifested as an exaggerated ovarian response to / ?-hCG leading to the formation of theca lutein cysts [3] . Furthermore, in 30-50% of cases the latter may be associated with gestational trophoblastic disease [3]. Indeed, hCG-producing gynecological malignancies may derive from either ovarian or trophoblastic tissue. The average incidence of ovarian tumors in pregnancy is 1 in 1000. The majority of masses are mature teratomas (45%) or cystadenomas (34%) [6]. The incidence of ovarian malignancies ranges from 1 in 8000 to 1 in 20 000 deliveries. Gestational trophoblastic neoplasia occurs more commonly, with incidence ranging between 0.26 and 2.1 per 1000 pregnancies [7]. Ovarian malignancies which produce hCG and androgens are limited to germ cell tumors. Of all germ cell tumors, dysgerminoma is the most frequent malignant type encountered in the pregnant patient, accounting for 45% of all malignancies in pregnancy [I]. Other germ cell malignancies which may produce hCG are ovarian choriocarcinoma, mixed germ cell, embryonal and polyembyoma. Overall germ cell malignancies are known to be associated with pregnancy in only a small number of cases. Patients suspected as being affected by these malignancies will often present dubious findings on ultrasound evaluation.
Ovarian masses present in hyperreactio luteinalis may likewise appear suggestive for malignancy on imaging studies [8]. Moreover, hyperreactio luteinalis may mimic ovarian hyperstimulation syndrome (OHSS). Patients with OHSS usually have a history of induction of ovulation although the condition may on rare occasions occur spontaneously [9,10].
Approximately 30 cases of hyperreactio luteinalis occurring in normal singleton pregnancies [1,11-23] are reported in the literature. The discovery of hyperreactio luteinalis may take place at any time during gestation. The majority of cases (54%) are noted in the third trimester, 16% in the peripartum period, and 16% in the first trimester. More than 37% of cases are discovered at the time of Cesarean section. Extraovarian symptoms including virilization (14-25%) and ascites (4%) may be manifested [5].
This rare condition should be taken into account when high ss- hCG levels, ovarian enlargement and hirsutism are manifested during pregnancy. Our case developed the hyperandrogenism and hirsutism described in 15% of all cases of hyperreactio luteinalis. This was the main symptom. The possibility of virilization of a female fetus exposed to high androgen levels during pregnancy is questionable. During normal pregnancy the increase of testosterone and androstenedione levels does not lead to virilization probably due to high levels of estradiol, progesterone and sex hormone-binding globulin that may interfere with the biological activity of androgens [23] . It remains to be clarified whether a female fetus would be protected even in the case of extremely high androgen levels. In the ten previously described cases of hyperandrogenism and hirsutism and/or virilization of the mother, the single female neonates showed no signs of virilization [9,10,17]. A similar occurrence was observed in our case, with a healthy female neonate showing no sign of exposure to high levels of maternal androgens. Nevertheless, followup lasting until the time of adolescence may be advisable. Our case showed elevated hCG levels in the second and third trimester of gestation that subsequendy dropped significantly 24 h after delivery, reaching 450 mIU/ml after 1 week and zero after 2 weeks. In retrospect, the elevated levels of hCG combined with the abnormal masses noted at ultrasound led to the performance of multiple procedures with potentially significant morbidity. The combination of serial hCG titers and judicious use of imaging studies to evaluate the progress of the pregnancy over time, as well as to monitor the progression or regression of ovarian masses, may potentially allow such procedures to be avoided. In conclusion, our case provides further support for conservative management of the condition once the possibility of ovarian and trophoblast malignancies has been ruled out. The mere presence or absence of symptoms is in no way suggestive of malignancy, as nearly 30% of ovarian cancers in pregnancy are asymptomatic. In the presence of suspected hyperreactio luteinalis associated with hirsutism and/or virilization, counseling should be provided in order to reassure patients. Indeed, both our experience and reports published in the literature underline the receding of maternal symptoms after a few months and no deleterious effects on neonates.
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STEFANO ANGIONI, ELAINE PORTOGHESE, FRANCESCA MILANO, GIAN BENEDETTO MEUS, & ANNA MARIA FULGHESU
Division of Gynecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal-Fetal Medicine, and Imaging, University of Cagliari, Cagliari, Italy
(Received 4 November 2006; revised 5 January 2007; accepted 9 January 2007)
Correspondence: S. Angioni, Division of Gynecology, Obstetrics and Pathophysiology of Human Reproduction, Department of Surgery, Maternal-Fetal Medicine, and Imaging, University of Cagliari, via Ospedale, 1-09124 Cagliari, Italy. Tel: +39070652797. Fax: +39070668575. E-mail: sangioni@yahoo.it
Copyright Taylor & Francis Ltd. May 2007
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