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

Conclusions from Studies of Aromatase-Deficient Humans

First, aromatase deficiency is not a universally lethal defect as was once believed. This pertains because two homozygous siblings were conceived. [8] Fetal estrogens are not necessary for successful implantation or embryonic or fetal development. Whether or not maternally derived estrogen can substitute is not known at this time. On the other hand, aromatase expression in human placenta appears to be necessary for the clearance of DHEAS from fetal and maternal adrenals by conversion into estrogens. Otherwise, placental sulfatase, 3 beta-hydroxysteroid dehydrogenase delta4-5-isomerase, and 17 beta-hydroxysteroid dehydrogenase have the capacity to convert this precursor into testosterone. This results in enough testosterone production to create severe virilization of female external genitalia in early embryonic life.

The role of estrogen in the sex steroid-gonadotropin feedback mechanism is clarified by the observations in patients with aromatase deficiency. For example, serum gonadotropins were markedly elevated during the first few years of life of aromatase-deficient girls, emphasizing the negative feedback role of ovarian estrogen during this period. Persistently elevated gonadotropins and large ovarian cysts were documented between ages 2 and 4 in the Swiss girl, suggesting an important role of estrogen, albeit in very low serum levels, in maintaining the gonadostat. [6] In aromatase-deficient men, elevated concentrations of serum FSH and LH despite the strikingly high testosterone level support an important negative feedback role of estrogen either of peripheral origin or synthesized locally in the brain from C19 steroid precursors or from both sources in the regulation of FSH and LH.[27,28] In fact, levels of serum gonadotropins and testosterone decreased after low-dose estrogen replacement in an aromatase-deficient man. [9]

The chronically elevated levels of gonadotropins in the absence of estrogen in aromatase-deficient girls gave rise to formation of multiple large ovarian cysts that resolved with estrogen replacement therapy. [6,7,8] An ovarian biopsy result for one of the aromatase-deficient girls at puberty was reported to be consistent with the polycystic ovary syndrome. [8] Comparable histologic features were found in the ovaries of alpha-ERKO mice. [4] Ovaries of ArKO or alpha-ERKO adult mice showed multiple cystic follicles but no evidence of ovulation. Thus, estrogen action appears to be necessary for normal cyclic follicular development by way of regulating gonadotropin secretion. Aromatase deficiency or estrogen resistance, however, does not prevent un-controlled follicular growth, which seems to be mediated primarily by gonadotropins. Although not yet described, gene defects that cause milder degrees of aromatase deficiency or estrogen resistance may be common and may be manifest as the polycystic ovary syndrome (e.g., anovulation, multicystic ovaries, and insulin resistance).

The possible impact of lack of estrogen representation in the brain on psychosexual development of both women and men with aromatase deficiency was considered by two groups of authors[7,8,29] Thus far, no evidence is available to suggest gender identity problems in these patients. [29] It appears that estrogen deficiency may decrease the libido of these men. [29]

The striking effects of the lack of estrogen on bone maturation and turnover were demonstrated in the two extremely tall and aromatase-deficient men with eunuchoid proportions and are similar to those described in the estrogen-resistant man. [8,9,10] Epiphyseal fusion and maintenance of bone mass appear to be two obvious but until now unrecognized consequences of estrogen action in men. Estrogens have been shown to exert their effects on osteoblasts and osteoclasts through regulation of cytokine expression in the bone.[30,31] It is remarkable that the low plasma concentrations of estrogen that are ordinarily found in normal men may be sufficient to suppress the expression of osteoporotic cytokines in the bone. The physiologic role of local production of estrogen within bone cells is not yet known. A synergistic role of testosterone at levels found in adult men in this antiresorptive action of estrogen is likely. Bone density was increased in one aromatase-deficient man upon estrogen administration, and, similarly, insulin resistance improved. [32] This is consistent with the similar decrease in basal insulin levels in postmenopausal women treated with transdermal estradiol. [12] On the other hand, the estrogen-resistant man [10] showed biochemical evidence of both insulin resistance and glucose intolerance that did not respond to very high doses of estrogen, as expected. Although the mechanism of insulin resistance in aromatase deficiency [8] is not known, it is not likely to be caused by elevated testosterone because the estrogen-resistant man [10] had a much more severe degree of insulin resistance despite normal serum testosterone. As already noted, the possible association of aromatase deficiency with abnormal testicular size and low sperm count and motility has not yet been resolved. Normal sperm count but low motility noted in the estrogen-resistant man [10] suggests male infertility as another symptom associated with deficient estrogen action. It is not yet clear whether the severe oligoasthenospermia found in an aromatase-deficient man was due to estrogen deficiency or other genetic factors. [9]

Another crucial role of estrogens in men has been demonstrated to be the regulation of lipoprotein synthesis. [33] Aromatase inhibitor treatment of normal men decreased serum HDL cholesterol levels. [33] The abnormally low HDL/LDL cholesterol ratio in an aromatase-deficient man [8] emphasizes this critical role of estrogen action in men, which is the prevention of cardiovascular disease. In fact, this abnormal lipid profile was partially reversed by estrogen replacement in another aromatase-deficient man. [9]

Finally, one can envision mutations in the CYP19 (P450arom) gene causing milder degrees of aromatase deficiency analogous to other steroidogenic P450 defects, for example, late-onset 21-hydroxy-lase deficiency. These may give rise to a host of symptoms with varying degrees of severity, such as the polycystic ovary syndrome and incomplete pubertal development in women and infertility, insulin resistance, tallness with eunuchoid proportions, and tendency to develop cardiovascular dis-ease in both men and women. As another twist, because tissue-specific expression of the CYP19 gene is regulated in part by use of tissue-specific promoters, [6] mutations in any of these promoter regions or splice junctions may result in loss of estrogen formation in one organ only, for example, placenta, ovary, brain, or adipose tissue. Analysis of such cases would provide insight into the relative role of estrogens produced in each of these sites.