1 Obstetric and Gynecology Unit, 2 Pediatric Surgery Unit and 3 Medical Genetics Unit, Department of Obstetric, Gynecologic and Pediatric Sciences and 4 Department of Morphological Sciences and Forensic Medicine, University of Modena and Reggio Emilia, Modena 41100, Italy
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Female pseudohermaphroditism/fetal gender/pregnancy luteoma/prenatal diagnosis/ultrasonography
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
To date, fewer than 200 cases of luteoma in pregnancy have been reported in the literature (Cronjè, 1984; Baxi et al., 1988
; Manganiello et al., 1995
; Choi et al., 2000
). In 25% of cases luteomas are hormonally active, with secretion of androgens, 1050% of mothers with elevated androgen levels are masculinized (Verhoeven et al., 1973
; Cohen et al., 1982
; Cronjè, 1984
) and 6070% of female infants born to masculinized mothers are themselves masculinized to varying degrees (Verhoeven et al., 1973
; Garcia-Bunuel et al., 1975
; Hensleigh and Woodruff, 1978
; Cohen et al., 1982
; Nagamani et al., 1982
; Cronjè, 1984
; Joshi and Dunaif, 1995
; Manganiello et al., 1995
; Choi et al., 2000
).
All reported cases of female pseudohermaphroditism associated with luteoma of pregnancy have been identified post-natally. We present the first case in which a prenatal diagnosis of male phenotype was made at 13 weeks of gestation. This is also the first case described of Prader V masculinization associated with luteoma of pregnancy.
![]() |
Case report |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
A follow-up sonogram was performed at 13 weeks gestation to evaluate the risk of trisomy 21. It revealed a nuchal translucency of 1 mm and a biparietal diameter (BPD) of 23 mm. The patient asked to know the fetal gender. Using a method validated by our group (Mazza et al., 1999,2001
) a cranial notch was seen indicating male fetal gender (Figure 2A
).
|
SRY gene analysis was negative (Figure 3) after a second amniocentesis was performed to provide a rapid fetal sex determination and also to exclude a mistake in the fetal karyotype, maternal cell contamination (MCC) and XX male.
|
During the last three months of pregnancy, the mother developed increased abdominal and lower extremity hair, deepening of the voice and an enlarged clitoris.
At 39 weeks gestation, the patient was admitted with ruptured membranes and fetal distress. She then delivered by caesarean section. Laparotomy revealed bilaterally enlarged maternal ovaries (Figure 4) about 8 cm in diameter, totally replaced by a single mass with a smooth surface. Bilateral resection was performed. On the cut surface, they appeared solid, fleshy and focally haemorrhagic. On microscopic examination, they were entirely composed of round to polygonal cells, with abundant, finely granular, eosinophilic cytoplasm and small nuclei. The cells were arranged in lobules or, occasionally, in pseudoacinar spaces and were separated by thin fibrous septa. No necrotic areas or typical Reinke's crystalloids were identified and, only occasionally, mitotic figures were found (Figure 5
). The diagnosis of luteomas of pregnancy was confirmed.
|
|
At birth, the healthy baby weighed 3250 g, but showed complete masculinization of the external genitalia with the external urethral meatus opening at the apex of the penis and the labioscrotal swellings totally fused to form a scrotum (Figure 6A).
|
Forty days after delivery, feminising genitoplasty was performed and completed at five months of age in the newborn (Figure 6B).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Under normal circumstances, chromosomal sex agrees with phenotypic sex. Occasionally, however, it does not. When the sonographic and cytogenetic findings show that sex is discordant, one should not assume that the cytogenetic sex is more accurate than the sonographic gender assignment.
MCC of amniotic fluid cell cultures is a potential source of error in prenatal diagnosis. The overall frequency of MCC is 0.24%; because MCC would generally not be recognized when the fetal sex is female, the true incidence of MCC is therefore 0.5%. Considerable variability in terms of observed frequency of MCC exists between laboratories. In the majority of cases in which MCC was not detected, only one culture and/or fewer than 20 cells had been examined (Hsu, 1998). In the current report the absence of the SRY gene at second amniocentesis excluded MCC.
Several genital malformations have been diagnosed by prenatal sonography (Mandell et al., 1995). There are several well-recognized disorders that interfere with normal genital development, leading to discrepancies between the anatomy of the external genitalia and the underlying chromosomal constitution. Sex reversal can occur in humans. The incidence of 46,XX karyotype in phenotypic men is approximately one in 20 00024 000 births (De la Chapelle, 1981
). Most 46,XX male patients with normal genitalia are SRY positive; in contrast the great majority of the XX males with genital ambiguity are SRY negative (Ferguson-Smith et al., 1990
). Neverthless, exceptions do occur and Y-negative XX males may exhibit complete masculinization (Vergnaud et al., 1986
; Ramos et al., 1996
; Zenteno et al., 1997
). Recently, 46,XY monozygotic twins with discordant sex phenotype have been described (Somkuti et al., 2000
). Male and female development occurred despite the presence of a common karyotype and despite the presence of the intact SRY conservative motif.
Masculinization of external genitalia by androgens in a 46,XX fetus is another possible explanation for discordant phenotypic and cytogenetic sex. Female embryos have the same androgen receptor system in the urogenital tract as male embryos (George and Noble, 1984); therefore, administration of androgens at the appropriate time during embryogenesis causes profound masculinization of the female offspring (Schultz and Wilson, 1974
). In humans, clinical findings are classified as Prader IV (Prader, 1986
) and for Prader V the external genitalia look completely male. The internal genitalia are, however, not masculinized and Wolffian duct remnants are normal.
Although congenital adrenal hyperplasia is the most common cause of masculinization in a female fetus, masculinization as a consequence of a maternal hormone-producing tumour is becoming a more frequently recognized clinical entity (Novak et al., 1970; Vehoeven et al., 1973).
Luteoma of pregnancy must be presumed in pregnant women with ovarian mass and discrepancy between fetal karyotype and external genitalia. Luteoma of pregnancy represents a specific puzzling clinicopathological entity. Recognition of this entity is important so that unnecessary oophorectomy, with concomitant risk to both the patient and the fetus, is avoided. The sonographic features of luteoma of pregnancy have been described as that of a solid mass, with either single or multiple nodes and can be unilateral or bilateral (Choi et al., 2000). Because of the solid nature of the mass, it is impossible to differentiate luteomas from other solid ovarian neoplasms, such as luteinized thecoma, granulosa cell tumour or Leydig cell tumour, based on imaging characteristics alone. Bilaterality and multinodularity are more common in luteomas than in these other tumours.
Only 65% of masculinized mothers, however, deliver masculinized female infants (Rice et al., 1969; Joshi and Dunaif, 1995
). Even when concentrations of free testosterone are increased in a masculinized mother, some protective mechanisms appear to prevent fetal masculinization. Placental aromatization of androgens and the protective buffering effect of the high concentrations of estrogens found in the fetal blood might be responsible for the protection of the fetus against masculinization (Hensleigh et al., 1975
).
Variables including the duration and timing of embryo-fetal androgen exposure, a deficit of protective factors and fetal organ sensitivity can also influence the degree of fetal masculinization. A case with a mutation in the P-450 aromatase gene led to female pseudohermaphroditism that reached Prader V stage (Ludwig et al., 1998). In the present case the early onset androgenic stimulation may have been responsible for the complete fetal masculinization.
In conclusion, to the best of our knowledge, all cases of female pseudohermaphroditism associated with luteoma of pregnancy reported so far have been Prader types IIII; the current case is the first with a total masculinization of external genitalia in a girl (Prader type V) and it is the first case in which prenatal diagnosis of the male phenotype was done at 13 weeks of gestation.
Families can benefit from prenatal identification of this pathology and several aspects, such as post-natal medical care, birth registration, gender assignment and timing of surgery, can be planned.
![]() |
Notes |
---|
Submitted on June 7, 2001; resubmitted on September 7, 2001
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Choi, J.R., Levine, D. and Finberg, H. (2000) Luteoma of pregnancy: sonographic findings in two cases. J. Ultrasound Med., 19, 877881.
Cohen., D.A., Daughaday, W.H. and Weldon, V.W. (1982) Fetal and maternal virilization associated with pregnancy. Am. J. Dis. Child., 136, 353356.[Abstract]
Cronjè, H.S. (1984) Luteoma of pregnancy. SA. Med. J., 66, 5960.
De la Chapelle, A. (1981) The etiology of maleness in XX men. Hum. Genet., 58, 105116.[ISI][Medline]
Ferguson-Smith, M.A., Cooke, A., Affara, N.A., Boyd, E. and Tolmie, J.L. (1990) Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination. Hum. Genet., 84, 198202.[ISI][Medline]
Garcia-Bunuel, R., Berek, J.S. and Woodruff, J.D. (1975) Luteoma of pregnancy. Obstet. Gynecol. 45, 407413.[Abstract]
George, F.W. and Noble, J.F. (1984) Androgen receptors are similar in fetal and adult rabbits. Endocrinol., 115, 14511458.[Abstract]
Hensleigh, P.A. and Woodruff, J.D. (1978) Differential maternalfetal response to androgenizing luteoma or hyperrreactio luteinalis. Obstet. Gynecol. Surv., 33, 262271.[Medline]
Hensleigh, P.A., Carter, R.P. and Gratjan, H.E., Jr (1975) Fetal protection against masculinization with hyperreactio luteinalis and virilization. J. Clin. Endocrinol. Metab., 40, 816823.[Abstract]
Hsu, L.Y.F. (1998) Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In Milunsky, A. (ed) Genetic Disorders and The Fetus. The Johns Hopkins University Press, Baltimore, USA, 179248.
Joshi, R. and Dunaif, A. (1995) Ovarian disorders of pregnancy. Endocrinol. Metab. Clin. N. Am., 24, 153169.[ISI][Medline]
Ludwig, M., Beck, A., Wickert, L., Bolkenius, U., Tittel, B., Hinke, L.K. and Bidlingmaier, F. (1998) Female pseudohermaphroditism associated with a novel homozygous G-to-A (V370-to-M) substitution in the P450 aromatase gene. J. Ped. Endocrinol. Metab., 11, 657664.[ISI][Medline]
Malinak, L.R. and Miller, G.V. (1965) Bilateral multicentric ovarian luteomas of pregnancy associated with masculinization of a female infant. Am. J. Obstet. Gynec., 91, 251259.[ISI][Medline]
Mandell, J., Bromley, B., Craig, A.P. and Benacerraf, B.R. (1995) Pre-natal sonographic detection of genital malformations. J. Urol., 153, 19941996.[ISI][Medline]
Manganiello, P.D., Adams, L.V., Harris, R.D. and Ornvold, K. (1995) Virilization during pregnancy with spontaneus resolution postpartum: a case report and review of the English literature. Obstet. Gynecol. Surv., 50, 404410.[Medline]
Mazza, V., Contu, G., Falcinelli, C., Battafarano, S., Cagnacci, A., Vito, G., Forabosco, A. and Volpe, A. (1999) Biometrical threshold of biparietal diameter for certain fetal sex assignment by ultrasound. Ultrasound Obstet. Gynecol.,13, 308311.[ISI][Medline]
Mazza, V., Falcinelli, C., Paganelli, S., Contu, G., Mantuano, S.M., Battafarano, S.D., Forabosco, A. and Volpe, A. (2001) Sonographic early fetal gender assignment: a longitudinal study in pregnancies after in-vitro fertilization. Ultrasound Obstet. Gynecol., 17, 513516.[ISI][Medline]
Nagamani, M., Gomez, L. and Garza, J. (1982) In-vivo studies in luteoma of pregnancy. Obstet. Gynecol., 59, 105S110S.[Medline]
Novak, D.J., Lauchlan, S.C., McCawley, J.C. and Faiman, C. (1970) Virilization during pregnancy. Am. J. Med., 49, 281290.[ISI][Medline]
Prader, A. (1986) Disorders of Sexual Differentiation (Intersexuality). In Labhart, A. (ed) Clinical Endocrinology Theory and Practice, Springer-Verlag, 715747.
Ramos, E.S., Moreira-Filho, C.A., Llorach-Velludo, M.A., Tucci, S. Jr, Duarte, M.H., Araujo, A.G. and Martelli, L. (1996) SRY-negative true hermaphrodites and an XX male in two generations of the same family. Hum. Genet., 5, 598598.
Rice, B.F., Barclay, D.L. and Sternberg, W.H. (1969) Luteoma of pregnancy: steroidogenic and morphologic considerations. Am. J. Obstet. Gynecol., 104, 871878.[ISI][Medline]
Schultz, F.M. and Wilson, J.D. (1974) Virilization of the wolffian duct in the rat fetus by various androgens. Endocrinol., 94, 979986.[ISI][Medline]
Somkuti, S.G., Wachtel, S.S., Schinfeld, J.S., Jackson, L., Tharapel, A.T. and DiGeorge, A.M. (2000) 46,XY monozygotic twins with discordant sex phenotype. Fertil. Steril., 74, 12541256.[ISI][Medline]
Sternberg, W.H. (1963) Non functioning ovarian neoplasms. In The Ovary. International Academy of Pathology monograph. Baltimore, The Williams & Wilkins Co.
Vergnaud, G., Page, D.C., Simmler, M.C., Brown, L., Rouyer, F., Noel, B., Botstein, D., de la Chapelle, A. and Weissenbach, J. (1986) A deletion map of the human Y chromosome based on DNA hybridization. Am. J. Hum. Genet., 38, 109124.[ISI][Medline]
Verhoeven, A.T., Mastboom, J.L., Van Leusden, H.A. and van der Velden, W.H. (1973) Virilization in pregnancy co-existing with an (ovarian) mucinous cystoadenoma: A case report and review of virilizing ovarian tumors in pregnancy. Obstet. Gynecol. Surv., 28, 597622.[Medline]
Zenteno, J.C., Lopez, M., Vera, C., Mendez, J.P. and Kofman-Alvaro, S. (1997) Two SRY-negative male brothers without genital ambiguity. Hum. Genet. 100, 606610.[ISI][Medline]
accepted on October 24, 2001.