Recurrent maternal virilisation during pregnancy is extremely unusual. The level of androgenisation in our patient was startling, yet transient. The origin appears to be ovarian but no clear pathology was demonstrable. Several ovarian conditions can result in excessive androgen production in pregnancy. Benign lesions include luteoma and HL. These conditions are associated with large ovarian masses and were originally thought to reflect different ends of a spectrum of pathology resulting from hyper-responsiveness to human chorionic gonadotrophin (hCG). It now appears that they are distinct clinical entities, although distinguishing the two diagnoses can be difficult on clinical or histological grounds.5
Ovarian luteomas are usually solid, multinodular lesions that may be unilateral or bilateral. They occur most commonly in multiparous women of Afro-Caribbean descent and are more common in women with preexisting PCOS. Luteomas can be associated with raised androgens, although they are rarely high enough to cause virilisation and usually regress completely postpartum. There are four reported cases of recurrent luteoma associated with raised androgen concentrations. Two cases presented as ovarian masses with androgenisation as a secondary finding, and three occurred in multiparous women. The first case was of a woman with bilateral ovarian masses noted at two consecutive caesarean sections associated with raised 17-ketosteroid concentrations of 110.7 mg/24 hours (normal range, 6–15).6
The second case was of a multigravida Afro-Caribbean woman who had bilateral luteomas diagnosed at caesarean section in consecutive pregnancies. Urinary 17-ketosteroid values were 230 mg/24 hours, but returned to normal within 10 days after birth.7
The third case was also a multiparous Afro-Caribbean woman who presented during her first pregnancy with a serum testosterone concentration of 40.7 nmol/litre and androstenedione of 21.8 nmol/litre before delivery. Three months postpartum serum testosterone was 3.9 nmol/litre and androstenedione was 11.6 nmol/litre. In this woman, the ovarian mass was noted early in pregnancy and was not present on postpartum ultrasound scanning. An ovarian mass was not found subsequently when androgens were raised during a second pregnancy that was terminated at 12 weeks.8
A fourth case, that of a 26 year old white primigravida woman has been described. She presented during pregnancy with virilisation and raised androgen concentrations (serum testosterone, 23.2 nmol/litre), but with no associated ovarian mass. Testosterone concentrations did not quite return to normal (4.5 nmol/litre) between pregnancies, and the patient suffered with oligomenorrhoea and subfertility, suggestive of PCOS.9
These diagnoses seem unlikely in our patient. She is white, slim, presented as a primigravida, and had no ovarian masses. In addition, her androgen concentrations were much higher than those previously reported.
HL is commonly a cystic, bilateral ovarian condition. It typically occurs in white primigravida women, and is associated with conditions that involve raised hCG values, such as multiple gestation and molar pregnancies. Ovarian hyperstimulation syndrome, which may occur after induction of ovulation with hCG, is thought to be an iatrogenic variant of this condition. HL can occasionally recur in subsequent pregnancies, but raised androgen values and androgenisation are only seen in 15% of cases.1
There is only one case report of recurrent HL associated with raised androgen concentrations.10
Where androgenisation does occur in this condition it is in proportion to the size of the ovarian lesions. Because our patient had no ovarian lesion but extremely high androgen concentrations this diagnosis seems very unlikely.
PCOS may worsen during pregnancy, but in the only reported case associated with recurrent virilisation testosterone concentrations were moderate (18.3 nmol/litre).2
Our patient showed no additional features of PCOS.
“Fetal aromatase deficiency was excluded in our patient by the normal cord androgens, the absence of low maternal oestrogen values, and the normal placental aromatase activity”
FAD is a recently described cause of recurrent virilisation in pregnant women and there is one case report of two affected siblings.11
Aromatase is a cytochrome p450 enzyme normally present in placenta, gonads, brain, adipose tissue, liver, muscle, and hair. It catalyses the conversion of androgens to oestrogens. During pregnancy, large quantities of DHEAS and 16α-DHEAS produced by the fetal and maternal adrenal glands are converted initially to androstenedione and 16α-andostenedione, and thereafter to oestrogens by placental aromatase. This enzyme action may also protect a female fetus from virilisation in conditions of maternal androgen excess, such as congenital adrenal hyperplasia.12
FAD is rare and results from point mutations in the CYP19 gene.13,14
Only about 1% enzyme activity appears necessary to prevent virilisation from increased androgen substrate. Consequently, the abundance of placental aromatase activity demonstrated during the second affected pregnancy suggests that a female infant would not have been virilised at birth. Affected individuals develop skeletal abnormalities related to oestrogen deficiency, and both male and female patients require oestrogen replacement. FAD was excluded in our patient by the normal cord androgens, the absence of low maternal oestrogen values, and the normal placental aromatase activity.
Take home messages
- We report a 28 year old woman with severe virilisation occurring in two successive pregnancies
- Recurrent maternal virilisation is rare—there are only seven previous reports—and this case is unique in its severity
- The differential diagnoses include ovarian disease and fetal aromatase deficiency (FAD)
- FAD was excluded and this case appears to be unique, with an ovarian origin that is not associated with an ovarian mass
- Although we were worried about the risk of fetal virilisation in a female baby, the normal placental aromatase activity and fetal androgen concentrations suggest that a female fetus would not have been affected
Placental sulfatase deficiency may result in raised androgen concentrations in pregnancy, but this enzyme deficiency results in decreased maternal oestrogen values and this was not seen our patient (fig 1). We also reported normal DHEAS concentrations, and these are usually low in sulfatase deficiency. Placental sulfatase deficiency does not lead to increased androgen concentrations of the nature seen in our patient. Furthermore, labour is often delayed in this disorder (both pregnancies were normal term), and there was no evidence of icthyosis, the typical skin lesion seen in sulfatase deficiency, in either infant.
In conclusion, there have been seven previous descriptions of recurrent maternal virilisation in pregnancy. Our patient is unique, however, because of the severity of her androgenisation and the dramatic resolution postnatally. We have excluded a fetal cause and believe that this represents a unique case with an ovarian origin that is not associated with an ovarian mass. We were concerned that if our patient had been pregnant with a female baby there would have been a risk of fetal virilisation; however, the normal placental aromatase activity and fetal androgen concentrations suggest that a female fetus would not have been affected.