Rare manifestation of hyperreactio luteinalis: when both the mother and baby girl are virilised
- 1 Paediatrics & Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
- 2 Obstetric and Gynaecology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
- 3 Paediatrics & Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong, Hong Kong
- Correspondence to Dr Wing Shan Queenie See; wsqsee@gmail.com
Abstract
Hyperreactio luteinalis is a benign, pregnancy-related condition with cystic enlargement of the ovaries and elevated androgen. However, only one-third of patients manifest as maternal virilisation and rarely does it cause fetal virilisation. Here, we report a virilised baby girl born to a virilised mother because of hyperreactio luteinalis. This case illustrates our management to maternal and fetal virilisation.
Background
Neonatal virilisation is a frequently encountered paediatric condition which warrants assessment and investigation. In female newborns presenting with virilisation, it is important to assess the mother as well. If maternal virilisation is also present, the list of differential diagnoses would be completely different. Herein, we report a case of hyperreactio luteinalis causing both maternal and fetal virilisation.
Case presentation
A baby was born at 32 weeks of gestation with a birth weight of 1.59 kg. The mother was a primigravida female in her 40s. She had complex medical history. She had poorly controlled type 2 diabetes mellitus requiring insulin infusion during her pregnancy, as well as chronic hypertension with nephropathy and maculopathy, a history of hyperthyroidism, ischaemic stroke on aspirin and polycystic ovarian syndrome (PCOS). Antenatal fetal scan at 23 weeks of gestation showed ambiguous genitalia with clitoromegaly. The mother was also found to have bilateral adnexal multi-septated cysts, which were not present in the prepregnant pelvic ultrasound scans. The mother declined both non-invasive prenatal testing to determine the fetal gender and amniocentesis for fetal chromosomal microarray testing. She developed pre-eclampsia at 32 weeks requiring an emergency lower segment caesarean section. A biopsy of the adnexal mass was performed at the same time (figure 1).
Bilateral adnexal multi-separated cysts of the mother during caesarean section.
At birth, the baby was noted to have prominent labial minora and clitoromegaly. The clitoris was measured 0.9 cm×0.6 cm. The anogenital distance was 0.9 cm. No gonad was palpable. There was no labial fusion, rugae nor hyperpigmentation. The anus was patent and other systemic examinations were unremarkable. The mother was also noted to be virilised with clitoromegaly with excessive hair growth over her chin, thigh and pubic region, which had worsened during pregnancy.
Investigations
The karyotype of the baby showed 46XX. Electrolytes, blood glucose and newborn screening for congenital adrenal hyperplasia (CAH) were unremarkable with normal 17a-OH progesterone. Testosterone was elevated to 4.6 nmol/L (reference: 0.35–0.7 nmol/L). Dehydroepiandrosterone (DHEAS) was slightly elevated to 17.2 µmol/L (reference: 2.9–16.5 µmol/L). Pelvis ultrasound showed normal uterus and cervix with no gross mass lesion. Bilateral adrenal glands appeared normal.
Mother’s blood test during pregnancy showed elevated testosterone 27 nmol/L (reference: 0.7–2.8 nmol/L) and normal DHEAS 3 µmol/L (reference: 1.7–9.2 µmol/L) (figure 2). Histology of the mother’s adnexal mass showed fibrous stroma lined by luteinised cells with abundant eosinophilic granular cytoplasm and enlarged hyperchromatic nuclei, in keeping with hyperreactio luteinalis.
Serial maternal testosterone level. Source: Wing Shan Queenie See.
Approach to baby girl with virilisation. Source: Wing Shan Queenie See.
Differential diagnosis
In view of maternal virilisation with high testosterone, normal DHEAS and bilateral maternal adnexal mass during pregnancy, the differential diagnoses of fetal virilisation would include pregnancy luteoma or hyperreactio luteinalis or rarely androgen-secreting ovarian tumour. Cytochrome P450 oxidoreductase deficiency caused by mutations in POR gene could also cause both fetal and maternal virilisation but this could not explain the maternal adnexal mass and the absence of skeletal features in the baby. CAH was also excluded based on the biochemical picture and it would not be able to explain the maternal features.
Treatment
After performing extensive literature search, it was concluded that the baby was most likely suffering from hyperreactio luteinalis, which is a benign pregnancy-related condition. Thus conservative treatment was adopted for both the mother and the baby.
Outcome and follow-up
The baby and mother’s androgens levels were serially monitored. The baby’s DHEAS level gradually normalised and her testosterone level also dropped from 27 nmol/L to 2.1 nmol/L in 1 month. Mother’s testosterone also fell from 29 nmol/L post partum to 0.54 nmol/L in 1 month.
Discussion
We reported a case of maternal and fetal virilisation with high testosterone, normal DHEAS and maternal bilateral adnexal masses, which resolved post partum. The histology showed maternal corpus luteal cysts, concluding the diagnosis of hyperreactio luteinalis.
Hyperreactio luteinalis is a benign, pregnancy-related cystic enlargement of the ovaries that is frequently associated with hydatidiform mole, trophoblastic disease or choriocarcinoma.1 The presentation can be variable. Patients may be diagnosed incidentally by antenatal ultrasound or during caesarean section. They may also present with virilisation, abdominal discomfort, or even acute abdomen due to ovarian torsion or rupture. The exact aetiology of hyperreactio luteinalis is not known but it was proposed to be related to ovarian stimulation by human chorionic gonadotropin.1 2 Most (66%) occurred in primiparity. A majority of them also had a number of comorbidities, including PCOS (6.9%)3 and thyroid problems (12%).4 Even though most affected mothers had elevated androgen levels (84%), only 30% of them had maternal virilisation5 and it is rarely associated with fetal virilisation (3.5%).1 The previously reported case of maternal and fetal virilisation in hyperreactio luteinalis was a 24-year-old pregnant woman who presented with virilisation during pregnancy.6 Ultrasonography showed bilateral enlarged multi-cystic ovaries and her serum androgen was elevated. She suffered from pre-eclampsia at 38 weeks of gestation. A caesarean section and diagnostic ovarian biopsies were performed and confirmed the diagnosis of hyperreactio luteinalis. Our case and the above reported case shared the same presentation of virilisation, followed by pre-eclampsia. This supports previous studies on the androgen role in placental development.
Regarding the low percentage of fetal virilisation compared with the relatively high maternal virilisation rate in hyperreactio luteinalis, it may be related to the timing of androgen exposure and other protective mechanisms.7 8 For instance, if androgen exposure occurred after 12 weeks of gestation, there will be no labial fusion. Therefore, the fetal virilisation without labial fusion observed in our case probably reflected that the androgen exposure was likely after 12 weeks of gestation. Other protective mechanisms would include an increase in maternal sex hormone binding globulin, progesterone competing for androgen binding sites and the conversion of maternal androgen to oestrogen via the placental cytochrome P450 aromatase enzyme, thus reducing the bioavailability of androgen.
In order to evaluate virilisation during pregnancy, assessment of both the mother and the fetus are crucial. The underlying aetiology would depend on whether the mother, the fetus, or both were virilised. For instance, causes for maternal virilisation alone would include (box 1): luteoma, theca-lutein cysts, exogenous androgen administration, placental aromatase deficiency, Sertoli-Leydig cell tumour, adrenal tumour or other ovarian tumours. These conditions could be differentiated from hyperreactio luteinalis by serum androgen levels and the typical ultrasonographic ‘spoke-wheel’ appearance of the ovary in hyperreactio luteinalis,1 and, rarely, the presence of fetal virilisation, if the fetus is a female.
Differential diagnoses of pregnant mother with virilisation
Cause of gestation hyperandrogenism
Luteoma
Theca-lutein cysts
Hyperreactio luteinalis
Exogenous androgen administration
Placental aromatase deficiency
Sertoli-Leydig cell tumour
Other ovarian tumour
Metastatic tumour to ovaries
Adrenal tumours
When both the mother and the female fetus are virilised, the possible causes would include transplacental transfer of maternal androgen due to pregnancy luteoma, hyperreactio luteinalis or androgen-secreting ovarian tumour. Despite the fact that there are mechanisms to protect the fetus, aromatase does not inactivate dihydrotestosterone and theoretically virilisation of the baby can occur when maternal androgen level is too high.9 On the other hand, fetal cytochrome P450 oxidoreductase deficiency could result in both maternal and female fetal virilisation. This is a disorder of steroidogenesis and is associated with cortisol deficiency, altered sex steroid synthesis, ambiguous genitalia, skeletal malformations and maternal virilisation. Maternal virilisation typically resolves after delivery but glucocorticoid replacement therapy for the baby is necessary.10
In conclusion, we described a case of maternal and fetal virilisation due to hyperreactio luteinalis. It is a benign condition which would spontaneously resolve after delivery. It is important to differentiate this condition from other causes of maternal (box 1) and fetal virilisation (figure 3) during pregnancy, to avoid unnecessary intervention, treatment and anxiety.
Learning points
This case illustrated a rare manifestation-fetal virilisation in hyperreactio luteinalis.
-
Hyperreactio luteinalis is a benign condition during pregnancy which resolves after delivery of the baby.
-
A conservative approach should be adopted for hyperreactio luteinalis.
-
It is important to delineate the underlying cause of virilisation during pregnancy and manage accordingly.
-
Correct identification of hyperreactio luteinalis could reduce unnecessary investigations and anxiety to the mother.
Ethics statements
Patient consent for publication
Footnotes
-
Contributors WSQS was involved in the assessment, investigation and management of patient, literature review and drafting the original manuscript. TYMS was involved in the assessment, investigation and management of patient, review and editing of the manuscript. W-KGP was involved in the assessment, investigation and management of patient, review and editing of the manuscript. JY-lT was involved in the assessment, investigation and management of patient, review and editing of the manuscript.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
-
Competing interests None declared.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer