Hyperreactio luteinalis in association with multiple foetal malformations – a consequence of supra-physiological HCG?

Introduction

Hyperreactio luteinalis (HL) represents enlargement of the ovaries caused by multiple theca-lutein cysts. It arises in relation to abnormally elevated levels of human chorionic gonadotropin (hCG) as seen with multiple gestations, gestational trophoblastic disease (GTD) or chorio-carcinoma [9]. In 1938, Burger et al. described the first case of HL that was not associated with GTD [9]. Since then, sporadic cases have been reported that feature both normal and abnormal pregnancies in both singleton and multiple gestations. Lack of appreciation of HL has led on occasion to inappropriate care and unnecessary interventions [9].

The effects of abnormally high levels of hCG on maternal structures and maternal wellbeing (including hyperemesis and preeclampsia) are reflected in HL, however the impact on foetal development is poorly understood. Here we present a case that describes features of both the maternal and possible foetal consequences of elevated hCG levels.

Case report

A 28-year-old French-Canadian primigravida in a non-consanguineous relationship was referred to our institution after bilaterally enlarged multi-loculated ovaries had been detected at the time of her first routine second trimester ultrasound scan. There was no significant prior medical or family history. She had conceived whilst using a combined oral contraceptive pill and was unsure of the date of her last menstrual period. Estimation of gestational age was based upon her first ultrasound; performed at 15 weeks’ gestation. The sonographic findings were of a singleton male foetus with biometry equivalent to 19 weeks’ gestation. Mildly increased amniotic fluid with a dense appearance was noted. The placenta was markedly enlarged but not hydropic per se with a thickness of 130 mm (Figure 1A and B). No echogenic cystic lesions were noted in the thickened placenta, nor was any chorioangioma or evidence of vesicular molarity detected. Foetal anatomical evaluation identified partial agenesis of the inferior cerebellar vermis (Figure 2), consistent with a variant of Dandy-Walker variant malformation; all other central nervous structures were of normal appearance including a well-visualised corpus callosum. Other findings were of mild retrognathia and bowel hyperechogenicity. The foetal urinary bladder remained distended throughout the scan. A skeletal survey showed bilateral short humeri and femora (below the 5^th centile) and a sandal-gap was also noted. Multiple bilateral maternal ovarian cysts were confirmed with the right ovary measuring 118×80×131 mm and the left 168×114×92 mm; consistent with HL (Figure 1C and D).

Figure 1

Trans-abdominal ultrasound findings in a pregnancy with markedly elevated hCG. (A and B) The appearance of the non-hydropic thick placenta measuring 130 mm in thickness and 94 mm in width, (C) Relation of the enlarged ovary to the cervix and foetal head, (D) Characteristic appearance of an ovary with hyperreactio luteinalis.

Figure 2

Cerebellar vermis partial agenesis by 2D and 3D ultrasound examination. (A) Axial view (B) Coronal view (C) Sagittal view (D) 2D view at the level of the cerebellum.

At that point the patient was counseled regarding diagnostic amniocentesis to exclude foetal aneuploidy and in particular triploidy. Trans-amniotic amniocentesis was performed with sampling revealing amniotic fluid that was heavily stained with old blood, which might be an explanation for the presence of the hyperechogenic bowel.

The serum hCG at 19 weeks of gestation showed an extremely high level at 887,514.0 IU/L. With this high level of hCG and HL, a partial mole was suspected but fluorescence in situ hybridisation (FISH) was normal and the karyotype was subsequently confirmed as 46XY. Although mosaicism and placental mesenchymal dysplasia (PMD) have previously been reported as accounting for some partial moles [6], this was considered unlikely as the placenta demonstrated neither the characteristics of PMD nor any true hydropic or molar changes. The presence of a euploid cell line culture in the karyotype analysis supported these findings. Repeated examination a week later showed the same findings with stable ovarian size. However, she represented shortly after with significant vaginal bleeding and uterine contractions leading to a complete spontaneous abortion at 20 weeks’ gestation.

External examination of the foetal body revealed a well-developed non-macerated male foetus of appropriate weight and size for gestational age with no significant shortening of the limbs identified by external examination only; the bilateral sandal-gap deformity and mild to moderate retrognathia were confirmed. The femur measured 26.9 mm on the babygram corresponding to 19 weeks’ gestation (demise occurred at 20 weeks). Evidence of hypospadias was noted on the immature male genitalia. Internal examination revealed biventricular cardiomegaly, bilateral enlargement of the testicles within the pelvis, partial urethral obstruction with distension of the bladder and ureters, as well as partial absence of the cerebellar vermis (Figure 3A). The testicles measured 1.3×0.7×0.7 cm each, and weighed 271 mg and 315 mg, left and right, respectively (normal for gestational age being 33±11 mg and 32±11 mg, respectively) [5]. On microscopy, the testicular enlargement was found to be caused by marked diffuse Leydig cell hyperplasia (Figure 3B, compare to age-matched control). Gross examination of the placenta revealed a diffusely enlarged and torn, but non-hydropic placenta weighing 311 g (normal for gestational age being 185 g), with retro-placental haematomas over half of its surface, consistent with abruption. Microscopic examination of the placenta demonstrated a range of villous pattern ranging from completely fibrotic large premature villi to smaller mature villi, and prominent but patchy circumferential trophoblastic hyperplasia (Figure 4A), with prominent syncytial knotting. Features of maternal floor infarction and prominent perivillous fibrin deposition were also present. In addition, villous infarction of remote and recent nature and multiple thrombi were found. Immunostaining revealed a markedly increased density of hCG compared to age-matched controls (Figure 4B). Presence of a component of mosaic triploidy was not confirmed by karyotyping of the placental tissue, which found no consistent chromosomal anomalies in 13 metaphases. In addition, FISH revealed no evidence of polyploidy in a selected section with trophoblastic hyperplasia.

Figure 3

Bilaterally enlarged testes, partial urethral obstruction, and partial absence of vermis, in a foetus with elevated maternal hCG. (A) Gross findings. The testes (short arrows) are abdominally located and grossly enlarged. As well, the bladder is distended and ureters (arrowheads) appear tortuous and widened. Inset: In the hindbrain, there is partial absence of vermis, with exposure of the 4^th ventricle (arrow) (B) Microscopic findings. There is diffuse Leydig cell hypertrophy within the testes (left), compared to age-matched control (right) (H+E, 200× original magnification).

Figure 4

Micrographs of placenta with elevated hCG and comparisons with age matched control. (A) There is circumferential prominence of the trophoblastic layer (left) compared to age-matched control (right) (H+E stain, 200× original magnification). (B) There is higher expression of hCG, and thickening of the trophoblastic layer (left) compared to age matched control (right) as demonstrated by hCG immunostain (200× original magnification). Inset fragment of identical control tissue placed on the two immunohistochemistry slides to control for differences in staining due to external factors.

Postpartum follow-up showed gradual spontaneous resolution of the HL. The level of hCG dropped markedly immediately postpartum to 191,230 IU/L and was 1475.0 IU/L 3 weeks later. By the fifth week, the hormonal levels were at <0.5 IU/L.

Discussion

HL is a rare finding in normal pregnancies. As most women presenting with HL are young, it is of paramount importance to recognise this benign entity and include it among the differential diagnoses of complex ovarian cystic changes to avoid performing unnecessary radical surgery as has previously been described in such cases [9].

It is suggested that the etiology may in part be caused by an underlying predisposition of the ovaries, resulting in an exaggerated sensitivity of the ovaries to gonadotropins (e.g., polycystic ovary syndrome) [2]. Sonographic features of HL include enlarged ovaries consisting of multiple theca-lutein cysts of various sizes. The thin walls of neighbouring large cysts have a specific appearance in 2D sonography, the so-called “spoke wheel” sign (Figure 1C). The stroma between cysts is markedly compressed and has physiological vasculature. These findings are the key features of the diagnosis. Previous reports have demonstrated a clear association between this ovarian pathology and abnormally high levels of hCG. This case has two unusual findings in the context of HL: foetal malformations including a Dandy-Walker malformation and testicular hypertrophy. It is possible that the findings observed in this case represent an as yet undescribed syndrome, but it is rather speculated here that these may be the consequences of the supra-physiological levels of hCG associated with HL in this case. The detailed pathological examinations of the foetus and placenta offer a novel insight into the possible consequences of very elevated hCG, with no previous reports of similar findings. Microscopic examination of the bilaterally enlarged foetal testicles showed Leydig cell hyperplasia, most likely a response to the gonadotropic effects of elevated hCG. Two cases of female foetal virilisation [4, 8] have been described in the literature but no examinations of a male foetus or foetal testicular hyperplasia have been reported. The Dandy-Walker malformation might be a co-incidental finding in our case, but given the rarity of these two entities and existing data suggesting a possible increased rate of congenital malformations with hCG treatment [3], it is possible that this and perhaps other findings such as the retrognathia may also be caused by the supra-physiological hCG levels. The possible mechanisms at play here are however not known.

Existing data suggest that hCG treatment is not associated with congenital anomalies [3], however, given the supra-physiological levels observed here, which are very much higher than therapeutic doses, the association especially with the anomalies noted in the urogenital system is a plausible theory.

The hypospadias and associated partial urethral obstruction we believe is likely to be caused by an increase in progesterone production by the hyper-stimulated maternal theca-lutein cells. Progesterone is a substrate for 5-alpha reductase and acts as a competitive inhibitor of testosterone to dihyrotestosterone conversion; the latter being required for the development of the external male genitalia. It has previously been observed that a five-fold increase in the risk of hypospadias exists in males born through in vitro fertilisation (IVF) who have been exposed to exogenous progesterone [7].

The cardiac hypertrophy observed in the foetus in the absence of any obstructive lesion is likely to be secondary to the increased systemic resistance of the enlarged placental mass and the increased cardiac output required to perfuse this.

The increased width of trophoblastic tissue in this case remains unexplained; the increase in the mass of trophoblastic tissue is the likely source of the elevated hCG levels, consistent with its increased hCG expression (Figure 4B). In the literature, the width of trophoblastic tissue from 4 to 20 weeks has been correlated with hCG levels, and the rapidly rising hCG level seen between 3–4 and 9–10 weeks of gestational age coincides with the proliferation of trophoblastic villi. Conversely, declining hCG levels are associated with a relative reduction in the mass of the trophoblastic tissue [1].

HL is a rare and benign entity as far as maternal health is concerned and its appropriate identification may avoid women undergoing unnecessary surgery. The characteristic finding is of multiple theca-lutein cysts caused by either elevated hCG levels or an exaggerated maternal response to normal hCG levels. In cases where the levels are elevated in the absence of a foetal aneuploidy, the possible teratogenic effects of hCG should be considered and a detailed foetal evaluation is essential. Although poor outcomes are typically observed in cases with elevated hCG levels, this finding does not preclude the possibility of a normal outcome.