Aromatase Deficiency and Estrogen Resistance: From Molecular Genetics to Clinic

, Departments of Obstetrics & Gynecology and Molecular Genetics, Division of Reproductive Endocrinology, University of Illinois at Chicago, Chicago, Illinois.

Semin Reprod Med. 2000;18(1) 

In This Article

Abstract and Introduction


Our knowledge of the physiologic roles of estrogen in women and men has been advanced by recent descriptions of mutations disrupting estrogen biosynthesis and action. Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19 gene. It gives rise to ambiguous genitalia in 46,XX individuals. At puberty, affected girls have hypergonadotropic hypogonadism, fail to develop secondary sexual characteristics, and exhibit progressive virilization. The affected 46,XY individuals have normal male sexual differentiation and pubertal maturation. These men are extremely tall and have eunuchoid proportions with continued linear growth into adulthood, lack of epiphyseal closure, and osteoporosis due to estrogen deficiency. Although estrogen was shown to be essential for normal sperm production and function in mice, its role in fertility is not clear in men. Thus far, one estrogen-resistant human, a man with a mutant estrogen receptor-gene, has been described. His clinical presentation was similar to that of aromatase-deficient men.


Scientific developments within the past 10 years have advanced our knowledge of the role of estrogen in humans. Consequences of mutations in the CYP19 (aromatase P450) gene in six females and three males and a mutant estrogen receptor-gene in a man are discussed in this article. Until early 1990s, aromatase deficiency had been considered incompatible with life. Since the first description in 1991 of a Japanese newborn girl with an aromatase P450 (P450arom) gene defect, [1,2] there have been several reports in the world literature describing aromatase deficiency. Thus far, three (Japanese, French, and German) newborn girls,[1,3,4] one Swiss newborn boy, [5] one 4-year-old Swiss girl, [6] one

American adolescent girl, [7] two American adult siblings -- a woman and a man, [8] and an Italian adult man [9] with P450arom gene defects have been described in detail. Very convincingly, estrogen biosynthesis in all these patients was virtually absent, giving rise to a number of anticipated as well as unexpected symptoms. As a result, we now know that aromatase deficiency is an autosomal recessive condition manifest in 46,XX fetuses by female pseudohermaphroditism and, in the case of adult men, tall stature with eunuchoid proportions due to unfused epiphyses. In fact, the essential role of estrogen as a determinant of height and bone mass was understood only after the description of an estrogen-resistant [10] and two aromatase-deficient men. [8,9] In the majority of aromatase-deficient patients, transient maternal virilization during preg-nancy was documented. In fact, maternal virilization during the pregnancy was the only clue that led to the genetic diagnosis of aromatase deficiency in one asymptomatic newborn boy. [5] The spotted hyena [11] may constitute a natural animal model to explain some but not all of the mechanisms giving rise to genital ambiguity in newborn girls who are affected by aromatase deficiency. Moreover, studying female patients with aromatase deficiency may provide new insights into the pathophysiology of polycystic ovary disease. Finally, studying aromatase-deficient men [8,9] confirmed and extended the conclusions drawn from study of an estrogen-resistant man [10] regarding the role of estrogen action in men.

The physiologic roles of estrogens in women include development of secondary sexual characteristics, regulation of gonadotropin secretion for ovulation, preparation of tissues for progesterone response, maintenance of bone mass, regulation of lipoprotein synthesis, prevention of urogenital atrophy, and possibly regulation of insulin responsiveness [12] and maintenance of cognitive function. However, the important physiologic roles of estrogens in men were largely unanticipated until estrogen was found to be necessary for fusion of epiphyses and prevention of bone loss. Estrogens also appear to play a role in glucose metabolism; as indicated earlier, Smith et al [10] described an extremely tall man with estrogen resistance who had incomplete epiphyseal closure with a history of continued linear growth into adulthood, osteoporosis, and glucose intolerance. This condition was caused by a homozygous point mutation in the estrogen receptor gene. Thus far, estrogen receptor deficiency in a woman has not been described; features of aromatase deficiency, however, have provided new insights into the physiologic role of estrogens in the human body.

The human placenta develops from trophectoderm of the blastocyst and is genetically fetal tissue. Among mammalian placentae, the human placenta is uniquely capable of efficiently aromatizing massive amounts of C19 steroids into estrogens. Pregnant women at or near term have a daily production of 70 µmol (20 mg) of estradiol and 300-450 µmol (80-120 mg) of estriol. [13] During the third trimester of gestation, it is common to detect maternal serum estradiol levels above 100,000 pmol/L (27,000 pg/mL) and estriol levels above 55,000 pmol/L. The physiologic role of this massive placental estrogen production during preg-nancy is not understood. However, when the aromatization capacity of the placenta was exceeded by the overproduction of C19 steroids of maternal origin (e.g., by luteomas) during early pregnancy, [14] virilization of the female fetus and the mother was noted. By contrast, serum estradiol (1053-1900 pmol/L or 287-518 pg/mL) or estriol (134-2200 pmol/L or 37-608 pg/mL) levels in the third trimester were extremely low in the pregnant mothers of the infants with aromatase deficiency. [1,6] Placental tissue from such a newborn with aromatase deficiency failed to convert C19 precursors into estrogens. [1,2] As a result, the androgen and estrogen precursor dehydroepiandrosterone sulfate (DHEAS) derived primarily from the fetal adrenal is converted in placenta to androstenedione and testosterone. Thus, both the female fetus and mother become virilized. Severe genital ambiguity noted in the female fetuses[1,3,4,6,7,8] implies exposure of external genitalia to testosterone and dihydrotestosterone much earlier than the 12th week of gestation. [15]