A New Cause of Female Pseudohermaphroditism: Placental Aromatase Deficiency

Abstract

A description is presented of the first documented case of placental aromatase deficiency. The deficiency caused maternal virilization during pregnancy and pseudohermaphroditism of the female fetus. A 24-yr-old primigravida showed progressive virilization during the third trimester. Urinary excretion of estrogen was less than 14 mumol/day between 35-38 weeks of pregnancy, although nonstress tests showed reactive patterns and serum levels of human placental lactogen were above 460 nmol/L. Maternal serum levels of estrogens were low, and those of androgens were high in the third trimester. A dehydroepiandrosterone sulfate loading test induced a marked increase in maternal serum levels of androgens, whereas no such increase was observed in estrogens. The woman delivered vaginally a live full-term infant who exhibited female pseudohermaphroditism. Cord serum levels of estrogens were extremely low, while those of androgens were high. The aromatase activity of the placenta, determined by the conversion of [7-3H]androstenedione to 17 beta-[7-3H]estradiol and [7-3H]estrone, were less than 0.03 fmol/microgram protein.min (control, 9.6 +/- 2.2 fmol/microgram protein.min). The sulfatase activity of the placenta was 0.63 pmol/microgram protein.min compared to 0.46 +/- 0.16 pmol/microgram protein.min in controls. The rate of aromatization by normal control placentas was the same as that obtained during coincubation of samples of normal placentas and that of the patient. Thus, the presence of aromatase inhibitor in the patient's placenta was excluded.

Embryonic modulation of maternal steroids in European starlings ( Sturnus vulgaris )

“…Because of its role in metabolizing steroids [7,8], the placenta is a vital regulator of the endocrinological 'cross talk' that occurs between mother and foetus [9]. Disruption of steroid metabolism in the placenta can lead to both foetal [10] and maternal abnormalities [11], supporting the idea that the placenta serves as a buffer between the maternal and foetal endocrine environments. Thus, in placental mammals, maternal steroid effects are the result of a dynamic interplay between maternal production and embryonic regulation.…”

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation

“…At birth, these females are characterized by hyperandrogenism and genital ambiguity, ranging from clitoral enlargement to complete labioscrotal fusion [5][6][7].…”

Oestrogen deficiency in men: where are we today?

“…Indeed, until recently no condition of oestrogen insensitivity had been reported, unlike well-documented inactivating mutations of other members of the steroid/ thyroid/retinoid receptor gene superfamily, such as androgen (2), thyroid hormone (3,4) and glucocorticoid hormone receptors (5). Thus, the general acceptance that oestrogens are essential for life worked until the beginning of this decade, when sporadic cases of congenital oestrogen deficiency in humans were reported (6)(7)(8)(9)(10)(11) and a viable line of mutant mice lacking functional ERs was created (12,13). Since then, the idea of a pivotal role of oestrogen for survival has begun to look thin in the light of these new findings, which undoubtedly raise many questions in turn.…”

“…Until now, two different conditions have been identified as possible underlying causes of congenital oestrogen deficiency in humans: (a) oestrogen resistance caused by disruptive mutations of the ER gene (11); and (b) aromatase deficiency due to mutations of the gene encoding aromatase cytochrome P450 (P450arom) (6)(7)(8)(9)(10)(14)(15)(16)(17), the enzyme responsible for aromatization of the A ring of androgens to form the A ring characteristic of oestrogens. Whatever the mechanism, all the tissue-and organ-specific physiological responses triggered by oestrogens are lacking.…”