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Estrogen: Consequences and Implications of Human Mutations in Synthesis and Action¹

Department of Pediatrics, School of Medicine, University of California–San Francisco, San Francisco, California 94143-0434

Address correspondence and requests for reprints to: M. M. Grumbach, Department of Pediatrics, School of Medicine, University of California–San Francisco, San Francisco, California 94143-0434. E-mail: grumbac{at}itsa.ucsf.edu

	Abstract

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

 
Recent developments have advanced our knowledge of the role of estrogen in the male. Studies of the mutations in CYP19, the gene encoding aromatase, in six females and two males and a mutant estrogen receptor in a man are described. These observations provide illuminating new insights into the critical role of estrogen in the male (as well as female) in the pubertal growth spurt and skeletal maturation, and in the importance of estrogen sufficiency in the accrual and maintenance of bone mass. The weight of evidence supports an effect of androgens on the latter processes, but this effect has not been quantitated.

There is a discordance in the estrogen-deficient male between skeletal growth and skeletal maturation and the accrual of bone mass and density. Estrogen synthesis by the testis is limited before puberty, and estrogen deficiency does not affect the age of pubertal onset. Estrogen deficiency in men leads to hypergonadotropism, macroorchidism, and increased testosterone levels. Estrogen lack has a significant effect on carbohydrate and lipid metabolism, and estrogen resistance was associated with evidence of premature coronary atherosclerosis in a man. These observations have highlighted the role of extraglandular estrogen synthesis and intracrine and paracrine actions.

In the human, in contrast to nonprimate vertebrates, aromatase deficiency and estrogen resistance () does not seem to affect gender identity or psychosexual development. The clinical repercussions of mutations in CYP19 on the fetal-placental unit have highlighted the major role of placental aromatase in the protection of the female fetus from androgen excess, thus preventing androgen-induced pseudohermaphrodism and virilization of the mother. These features are compared with the virilization that occurs in utero in the female spotted hyena.

The novel features of the aromatase deficiency syndrome in the affected female—in the fetus, during childhood, and at puberty—are discussed, including virilization at puberty and development of polycystic ovaries. The severity of the syndrome correlates with the severity of impairment of aromatase formation in expression systems.

Finally, the structural consequences of missense mutations in CYP19 are described in accordance with a model of the structure of human aromatase.

	Introduction

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

 
LONG HELD concepts of the role and effects of estrogen in the male have been challenged by recent discoveries. Historically, the role of estrogen in the development, growth, and function of the human male has been thought to be relatively unimportant and minor. A remarkable change in perspective has recently emerged. Until 1996, only one estrogen receptor (cloned in the mid-1980s) (1, 2) was thought to mediate the effects of estrogen. Furthermore, even though in the human the enzyme (encoded by the CYP19 gene) P450 aromatase—the critical enzyme responsible for the last and irreversible step in estrogen synthesis from androgens—was recognized to be expressed in multiple tissues in the 1990s (3, 4, 5), the significance of estrogen in male physiology had not been appreciated.

New developments have challenged traditional constructs and advanced our understanding of the widespread effects of estrogen in diverse functions in the male, stimulating research ranging from integrative physiology to cell and molecular biology within and outside the reproductive system. Three developments are largely responsible for these advances: 1) description of a man with a null mutation in the ER that caused estrogen unresponsiveness (6) and of men and girls and women (7, 8, 9) with severe estrogen deficiency due to autosomal recessive mutations in the gene encoding aromatase; 2) the concurrent development of mice that lack the estrogen receptor (ERKO mice) (10, 11, 12, 13) or the gene encoding aromatase (ArKO mice) (14); and 3) the discovery of a second widely distributed estrogen receptor, ERß (15, 16, 17, 18, 19, 20, 21), and, most recently, generation of the estrogen receptor ß knockout mouse (ßERKO) (22) (Fig. 1).

View larger version (38K): [in this window] [in a new window]   Figure 1. Human estrogen receptors and ß. The DNA-binding domain (DBD), which contains two zinc fingers, is indicated by C; the hormone-binding domain (HBD) by E which also contains trans-activating function (AF)-2. Domain A/B contains a hormone-independent AF-1, which is distinct in ER and -ß; domain D designates the hinge region (H). The percent homology of estrogen receptor ß (which maps to the q25.1 region of chromosome 6) with (which maps to the long arm of chromosome 14) for the DBD and HBD are indicated. Isoforms have been identified for both receptors; in the 530-amino acid variant of ERß, which represents the full length amino acid sequence, the A/B domain has an additional 53 amino acids (see text). Each of these receptors has distinct, as well as overlapping, cell and tissue patterns of expression. The estrogen receptors are regulated by phosphorylation of both tyrosine and serine residues, a distinctive property among nuclear receptors. The male with estrogen receptor resistance had a homozygous cytosine to thymidine transition at codon 157 in exon 2 (AB domain), resulting in a stop codon (Arg157X).

Unlike genes for many steroidogenic enzymes, such as CYP17 and CYP21, the large gene (>75 kb) encoding aromatase is expressed in many human tissues (in contrast to the situation in nonprimate vertebrates). The tissue-specific expression of the enzyme is regulated by means of tissue-specific promoters, but the translated protein is the same in all tissues (see Refs. 3, 4, 5) (Fig. 2). These tissues include the placenta and preimplantation blastocyst, the brain, ovary and testis, adipose tissue, fetal liver, muscle, hair follicles, bone, pituitary gland, and the immune system.

View larger version (16K): [in this window] [in a new window]   Figure 2. The structure of the large human CYP19 gene (P450arom) and the mutations that cause aromatase deficiency. The numbered black boxes designate translated exons. The septum in the open box in exon II represents the 3' acceptor splice junction for the untranslated exons. The multiple alternate promoters and the untranslated exons are designated by open boxes. The promoter I.1, which lies more than 40 kb 5' of the translation start site, is responsible for expression of aromatase in the placenta; promoter I.4 is predominant in adipose tissue and the proximal promoter II is the major promoter in the gonads. The distinct P450 arom promoters provide tissue specific expression by alternate splicing with the common 3' acceptor splice junction in exon II; irrespective of the choice of the various promoters, only a single aromatase protein is expressed. The known mutations are shown. X indicates a nonsense (stop) mutation. Three mutations are in the heme binding region (HBR). GT GC + 29aa is a thymidine to cytosine transition at the splice junction between exon VI and intron VI, giving rise to a 29 amino acid insert in aromatase. From Grumbach MM, Conte FA. Disorders of sex differentiation. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams textbook of endocrinology, 9th ed. Philadelphia: W.B. Saunders Co. Ltd., 1998; 1303–1425. Modified from Ref. 9.

View larger version (23K): [in this window] [in a new window]   Figure 3. The complexity of extra-glandular synthesis of estrogen hormones by the conversion of C19 androgens or androgen precursors to aromatic C18 estrogens diagrammatically represented. Intracrine mechanisms (see text) refer, in this instance, to the synthesis in peripheral cells of estradiol from testosterone and other 19-carbon precursors. Testosterone (T) entering the cell from the circulation is converted to dihydrotestosterone (DHT) by 5R (5 reductase 1 or 2), which acts through binding to the androgen receptor (AR). T is converted to E2 (17ß-estradiol) by CYP19, and the E2 binds to either the ER or ERß forming homo- or heterodimers. Intracellular synthesized T, for example, can arise from 4A (androstenedione) and DHEA or DHEAS. The desulfated DHEA is converted to 4A by 3ß-hydroxysteroid dehydrogenase and the 4A is transformed into T by 17ß-hydroxysteroid dehydrogenase (e.g. Type V isoenzyme), which then can be converted to E2; or androstenedione can be converted to estrone and then to E2 by the Type I isoenzyme. Some of the family of 17ß-hydroxysteroid dehydrogenase isoenzymes (e.g. Type II isoenzyme) can convert E2 to estrone, providing an additional mechanism of the regulation of estrogen synthesis and metabolism. The E2 synthesized by intracrine mechanisms can be released to act on a neighboring cell—a paracrine mechanism—through the cell’s estrogen receptors; for example, estradiol synthesized by a mesenchymal cell acting on a neighboring epithelial cell. The E2 also can enter the circulation, an endocrine role. For comparison, an autocrine mechanism is illustrated. IGF-I generated in and released by a peripheral cell can act on the same cell through the cell’s surface IGF-I receptors. Recent studies have emphasized the importance of the autocrine/paracrine role of IGF-I in body growth in contrast to the endocrine role of IGF-I synthesized and released into the circulation by the liver, the major contributor to plasma IGF-I. Mice with a selectively and totally deleted hepatic IGF-I gene have greatly reduced circulating IGF-I, but normal postnatal bone and body growth; these observations challenge the widely held somatomedin hypothesis (198 199 ). Similarly, even though estrogens produced by extraglandular synthesis are a major source of circulating estrogen in the male and the postmenopausal woman, especially, the intracrine and paracrine role of estrogen in its diverse and specialized functions in specific tissues needs to be considered. Endocrine, paracrine, and intracrine estrogen can also act rapidly on cell surface receptors, a nongenomic action.

	Estrogen and Its Effects on Pubertal Growth, Skeletal Maturation, and Bone Accrual

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

 
Estrogen has manifold effects on bone including a critical, but incompletely understood, action in the pubertal growth spurt, in skeletal maturation, and in the arrest of linear growth by fusion of the epiphyseal growth plate, in the accrual of peak bone mass, and in its maintenance and repair. These dynamic actions (including interactions with the GH and insulin-like growth factors (IGF) and their binding proteins, other growth and morphogenic factors, thyroid hormone, vitamin D, retinoids, PTH and PTHRP, cytokines, and their receptors among many factors) involve a variety of complex developmental and homeostatic programs (see Ref. 43).

The mechanisms involved in the epiphyseal fusion of long bones–the transformation of the cartilaginous growth plate into bone–is mediated in large part by the action of estrogen during puberty. This action includes a program of orderly proliferation, maturation, apoptosis of chondrocytes, proteolysis of the cartilage extracellular matrix, and vascular and osteoblast invasion of the growth plate. Among other factors (44), gelatinase B (45) and vascular endothelial growth factor (VEGF) (46) are essential signals in the ossification process. It is not known whether estrogen has an effect on these important factors in osteogenesis. However, in the mammary gland of the baboon, estradiol stimulated VEGF messenger RNA (47) and estradiol increases VEGF messenger RNA and VEGF protein in the human MCF-7 breast carcinoma line (48). Stimulation by estrogen of VEGF in endothelial cells in bone could provide one explanation for its capacity to increase the rate of epiphyseal fusion. Estradiol-17ß (but not its inactive isomer) also increases protein kinase C activity in chondrocytes from the rat growth plate, apparently involving a nongenomic action (49).

The constancy of bone mass in maturity is maintained by bone remodeling—the critical balance of bone formation and resorption. Resorption of bone by osteoclasts leads to bone formation by mature osteoblasts, the principal effector cells. Although closely linked, these processes are not necessarily regulated by each other, but can occur independently (50). Estrogen (and androgen) affects bone formation, an anabolic effect, and has a well characterized antiresorptive action that involves its action on local cytokine production (51, 52, 53).

In males, constitutional delay in onset of puberty has been advanced as a cause of decreased peak bone mass (54, 55); however, a recent study has disputed this contention (56). On the other hand, sexual infantilism due to hypergonadotropic or hypogonadotropic hypogonadism is associated with decreased peak bone mass. Hypogonadism can also lead to osteoporosis if untreated with estrogen in the female or testosterone in the male; rapid bone loss ensues within 5 yr of castration or the onset of severe hypogonadism. In a long-term study of 72 hypogonadal males, which included serial determinations of volumetric bone mineral density (vBMD) of the lumbar spine, continuous testosterone replacement therapy returned the vBMD into the normal range (57). What mediates this anabolic and antiresorptive effect of testosterone on bone?

Estrogen had been recognized as the major sex steroid in the female, responsible for the pubertal growth spurt, skeletal maturation, and the accrual of bone mass (although some held the view that androgens and androgen precursors secreted by the ovary and adrenal were an important factor in these processes); these effects of estrogen were not thought to be important in the male. At puberty in the female, the increased synthesis and secretion of estrogen by the ovary causes the progressive skeletal maturation that eventually leads to epiphyseal fusion and the termination of linear growth. In the male, on the other hand, received wisdom dictated that testosterone, the corresponding male sex steroid, secreted by the testis was directly responsible for these events during puberty (58) with estrogen having a minor effect, if any.

The reports of a 28-yr-old sexually mature male with tall stature, unfused epiphyses, osteopenia, eunuchoid skeletal proportions, and progressive genu valgum (6) due to an autosomal recessive inherited mutation in the ER (Table 2) and of two adult males with severe estrogen deficiency due to autosomal recessive transmitted mutations in the gene encoding aromatase (9, 59, 60, 61) (Table 2) have changed our thinking. All three men had a normal age of onset of puberty and identical clinical findings despite high or normal testosterone concentrations (Table 3), documenting the critical role in the male of estrogen in skeletal maturation, the accumulation of bone mass, and the pubertal growth spurt. In the two men with aromatase deficiency, but not in the man with estrogen resistance, treatment with estrogen led to rapid skeletal maturation and epiphyseal fusion at the wrist within 6–9 months (59, 60) and a dramatic increase in bone mineralization (61). Fig. 4 shows the growth pattern and bone age and the effect of estrogen treatment in this patient (61). Fig. 5 presents the effect of estrogen treatment on the accrual of bone mass (61).

View this table: [in this window] [in a new window]   Table 2. Comparison of estrogen receptor deficiency (ERKO) and of aromatase deficiency

View this table: [in this window] [in a new window]   Table 3. Plasma hormones in a male with aromatase deficiency or ERKO

View larger version (62K): [in this window] [in a new window]   Figure 4. The linear growth curve (•) and bone age (panels) of the 24-yr-old man with aromatase deficiency whose height was 204.5 cm (+3.7 SD). Note the continued steady growth rate without an apparent pubertal growth spurt, which led to very tall stature and rapid cessation of growth after the institution of estrogen therapy (bar). The X denotes a bone age for the chronological age (dashed line). The open epiphyses at the wrist (left) closed within 6 months of treatment (right). The dark curve is the average normal value for age, and the numerals indicate SD from the mean value (9 61 ). The growth curve and, of interest, height and bone age (data not shown), were almost identical in the man with a nonsense mutation in the estrogen receptor protein (61 ). From Bilezikian JP, Morishima A, Bell J, Grumbach MM. 1998 Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603.

View larger version (42K): [in this window] [in a new window]   Figure 5. The dramatic change in bone density during estrogen therapy in the man with CYP19 deficiency. The initial daily dose of 0.3 mg of conjugated estrogens was gradually increased during the first 12 months to 0.75 mg daily, his present dose (see text). On this dosage, the accrual of bone density continued after growth ceased (within 6 months) and increased to within the normal range for adult young men without inducing gynecomastia, impotence, or excessive weight gain. Following baseline studies, bone density was measured at 12, 30, and 36 months (vertical lines) (61 ). Modified from Bilezikian JP, Morishima A, Bell J, Grumbach MM. 1998 Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603.

Pubertal growth spurt

Despite normal or increased (the aromatase-deficient men) plasma concentrations of testosterone, none of the men had an apparent pubertal growth spurt (Fig. 4). Whereas the evidence provided by examination of their growth curves is not definitive because of gaps in measurement, the data suggest continued steady, slow growth throughout adolescence and the 3rd decade without a "pubertal inflection" or epiphyseal fusion. The delay in skeletal maturation with continued growth leads to eunuchoid skeletal proportions (9). These observations strongly support an essential role for estrogen in the pubertal growth spurt in the male.

Not only does a rise in estradiol concentration correlate with the earlier onset of the pubertal growth spurt in normal girls, but in boys sampled longitudinally before and during puberty, the rise in the estradiol levels as measured by an ultrasensitive bioassay correlated with peak height velocity which occurred, as expected, about 3 yr after pubertal onset (62). Of note, the plasma estradiol concentrations during peak height velocity are similar in boys and girls (about 3–4 pg/mL) and correlate not only with testosterone levels in boys, but with bone age as well.

Additional critical support is provided by the pattern of growth in 46,XY phenotypic females with the complete androgen insensitivity or resistance (CAIS) syndrome. These women have a pubertal growth spurt despite resistance to the action of testosterone owing to a mutation or deletion of the androgen receptor. In the study by Zachmann et al. (63), the adult height of CAIS patients was 172.3 ± 4.1 cm SD, 10 cm greater than normal women (162.2 ± 6.0 cm SD), but 2.4 cm less than normal men (174.7 ± 6.7 cm SD). The greater mean height of CAIS than normal women may be related in these 46,XY individuals, in part, to Y-specific growth genes outside of the pseudoautosomal region on the short arm of the Y chromosome. The age of peak height velocity and the pattern of skeletal maturation and epiphyseal fusion were comparable to normal females. Zachmann et al. (63) advanced these observations as evidence for the importance of estrogen alone in the female pubertal growth, as opposed to the role of ovarian or adrenal androgens. This study indicated that despite high testosterone concentrations in the presence of physiologically ineffective testosterone action, the pubertal growth in these XY women is attributable to estrogen secreted by the testis and arising from extragonadal conversion of androgens to estrogens (the latter occurs independent of the androgen receptor). Similarly, for example, the autosomal dominant aromatase excess syndrome in prepubertal age boys, in addition to gynecomastia, is associated with an increased rate of growth and skeletal maturation despite a prepubertal concentration of plasma testosterone (64, 65, 66, 67). Comparable observations have been reported in boys below age 6 with the Peutz-Jeghers syndrome and estrogen-secreting testicular tumors (68, 69, 70).

Other subtle and suggestive, but not definitive, clues to the effect of estrogen on growth and skeletal maturation in the male are listed in Table 4. The low plasma concentrations of estradiol during peak height velocity suggest a potent effect of circulating estradiol on linear growth, but at least two other factors need to be considered in the process: the local aromatization of androgen in bone and the effect with pubertal onset of increased GH secretion and IGF-I generation (reviewed in Refs. 70, 71). Even though GH secretion increases 2- to 3-fold during puberty, a normal pubertal growth spurt can occur without increasing the dose (per kg) of rhGH therapy in children with severe GH deficiency (58, 72).

Bone maturation and the accrual of bone mass during puberty

Aromatase is expressed widely in human and rodent bone, including in osteoblasts (73, 74, 75, 76, 77, 78, 79), chondrocytes of articular cartilage and bone adipocytes (73). Both estrogen receptors, and ß, are expressed in human bone; ER is expressed in osteoblasts (80, 81, 82) and in human osteoclasts (52) (although the latter remains controversial; Refs. 82, 83), and ERß is expressed in osteoblasts, but less so than ER (84). ER is expressed in resting, proliferative, and hypertrophic human growth plate chondrocytes (82); in contrast, ERß was identified only in hypertrophic epiphyseal chondrocytes (41, 85).

With the onset of puberty there is a rapid increase in bone mass (86, 87, 88, 89, 90, 91), which correlates with bone age. The rate of bone mass accrual approaches a peak in girls by 16 yr, about 3 yr after menarche, and in boys by about 17 yr; the rate then decreases, reaching a plateau in the 3rd decade. For example, white girls attained 94% of volumetric bone density by age 17 yr; in contrast, white boys attained only 86% of volumetric bone density by 17 yr of age (90). Bone acquisition during childhood and through puberty is a major determinant of peak bone mass, which is influenced by genetic and a variety of other factors, as well as hormones. In both sexes, this peak occurs after peak height velocity; hence, the attainment of peak bone mass lags behind the increase in linear growth.

The men with estrogen deficiency or estrogen resistance have severe osteopenia as quantified by dual-energy x-ray absorptiometry scans and an increased rate of bone turnover, as evidenced by the markers of osteoblastic and osteoclastic activity (Table 5). Treatment with high doses of estrogen had no effect on growth, the skeleton, or classic estrogen end organs in the man with the null mutation of the estrogen receptor (6). In contrast, a relatively low dose of conjugated estrogen (0.3 mg/day gradually increased to 0.75 mg/day over 12 months) had a dramatic positive effect on biological markers of bone metabolism, bone mass and maturation, as well as other sites of estrogen action (see below), without evoking gynecomastia (59, 61). Epiphyseal fusion at the wrist was rapid in both men with severe aromatase deficiency (59, 60, 61). In the patient described by Morishima et al. (9) (who had fused proximal femoral epiphyses but not ossification of the iliac apophyses), epiphyseal fusion occurred by the 6th month of estrogen treatment and, as a consequence, linear growth ceased (Fig. 4), but bone mineral accrual continued (Fig. 5) (61). Within 3 years of initiating estrogen therapy, the markers of bone turnover gradually approached normal values (Table 6). The excretion of urinary calcium fell, and bone mass increased dramatically. Bone mass in the lumbar spine had increased by 20.7%, in the femoral neck by 15.7%, and in the distal radius by 12.9% (61). In this estrogen-treated aromatase-deficient man, all but the radial site was at the mean value for normal young men (Fig. 5).

View this table: [in this window] [in a new window]   Table 5. Markers of bone homeostasis in men with aromatase deficiency or deficiency in estrogen receptor

The two girls with aromatase deficiency (one a sibling of the affected man) we studied during adolescence had a delayed bone age despite increased circulating androgens and virilization at puberty (8, 9). Estrogen therapy induced a pubertal growth spurt and epiphyseal fusion in both girls. A female child with a null mutation in the P450 arom gene (CYP19) had densitometric evidence of osteopenia of the lumber spine at age 3 4/12 yr that improved after 50 days of low-dose estrogen therapy (96).

Thus, in both males and females the lack of estrogen leads to a dissociation between skeletal growth and skeletal maturation and the accrual of bone density and mass.

Prepubertal estrogens may be important in the sex difference in the rate of skeletal maturation. A bone age of 13 yr in boys is equivalent in the standard gender-specific estimates of skeletal age to that of an 11-yr-old girl; the bone maturation of girls in childhood is about 20% more advanced than that of boys. The nature of this difference had not been understood. Whereas RIA were sufficiently sensitive and specific to quantitate the low testosterone levels in prepubertal boys (97, 98), the method of estimating low (pg/mL) amounts of serum estradiol (99), despite many reports to the contrary, was not sufficiently sensitive and specific to detect prepubertal levels in girls, much less in boys even after solvent extraction and thin-layer chromatography (100). Although a prepubertal sex difference in plasma estradiol concentrations was suspected, the hypothesis remained speculative until Klein et al. (101) developed an ultrasensitive recombinant cell bioassay for serum estradiol (detection limit 0.02 pg/mL). With this assay, prepubertal girls (age 7.5 ± 2.1 yr SD) had a mean concentration of serum estradiol of 0.6 ± 0.6 pg/mL, whereas the level in prepubertal boys was 0.08 ± 0.2 pg/mL; no correlation with age or body mass index was found. This more than 7-fold difference was proposed to explicate the more advanced skeletal maturation of prepubertal girls compared with boys (101). Moreover, aromatase activity was not detected or present at a low level in the Leydig cells of prepubertal boys (102, 103), nor was aromatase detected in the human fetal testis at 16–18 weeks of gestation (69). Aromatase is not well expressed in the testis until LH rises at the time of male puberty (102, 103, 104). Furthermore, the total aromatase activity of adipose tissue and other extraglandular tissues is low in childhood (64, 105). Accordingly, in the male, circulating estrogen and intracrine and paracrine estrogen becomes important in growth and skeletal maturation during puberty, but not at its onset.

These observations indicate that estrogen has an essential role in the pubertal growth spurt, skeletal maturation, and the accrual of a normal peak bone mass in males as well as females and may have an effect on the prepubertal accretion of bone mineral in the female. New therapeutic approaches—the use of nonsteroidal third generation aromatase inhibitors (e.g. letrozole, anastrozole) and ER antagonists, including SERM—to control growth and skeletal maturation in disorders of growth and puberty by suppression of estrogen synthesis or action are suggested by the critical role of estrogen in these processes (Table 7). The use of these pharmacological agents in the male should not delay or affect the appearance of male secondary sex characteristics. Furthermore, they suggest that in the human ER, but not ERß, is the principal estrogen receptor that mediates the action of estrogen on bone mass accrual and epiphyseal fusion. Additional support is indicated by the bone findings, still preliminary, in the ERKO (11, 106) and ArKO mouse (Simpson, E.R., personal communication), but there are important species differences. Table 8 summarizes the effect of estrogen in the male and female on pubertal growth and bone.

	Androgens, Growth, and Bone Mass Accrual

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

It is important to emphasize that establishing a role for estrogen does not exclude a direct effect of androgen on bone in the male (but one less important than traditionally thought). Quite likely, the direct effect of testosterone (not mediated by conversion to estradiol) is small with reference to pubertal growth and epiphyseal fusion. However, the effect of estrogen treatment on bone mass accrual in the aromatase deficient males occurred in the presence of normal or increased testosterone concentrations. A significant body of evidence supports a direct role for androgen on bone mass and in the sexual dimorphic features of the skeleton (107, 108, 109, 110, 111). The human androgen receptor is present in a variety of bone cells, including osteoblasts (112), osteoclasts (108, 113), osteocytes (114), and hypertrophic growth plate chondrocytes (114). The androgen receptor is expressed in periosteal bone (114) as well as cancellous bone. That androgens have a significant role in bone mass accrual is supported by evidence reviewed by Hofbauer and Khosla, (111) Orwoll (107), and Kasperk et al. (109) in the human and, for example, by Vanderschueren et al. (115, 116, 117, 118, 119) and Lea and Flanagan (120) in the rat and by Maor et al. (121) in the mouse. In many studies in the rodent, aromatizable androgens (e.g. testosterone, androstenedione) were used and not dihydrotesterone or synthetic androgens that are not substrates for aromatase, and they confound interpretation of the direct action of androgen on bone (111). However, 5-dihydrotestosterone and some synthetic androgens can increase the rate of growth, and, synthetic androgens, the rate of skeletal maturation of children, without increasing circulating GH or IGF-I concentrations.

Furthermore, the decline in bone mass in elderly men correlates better with free estradiol concentrations than with free testosterone levels (122, 123). Men have greater cortical bone width and, as would be predicted from their taller size and higher bone mass, testosterone probably stimulates the periosteal growth of cortical bone (124). Of interest, women with ovarian hyperandrogenism have high BMD (125). Moreover, estrogen treatment of male to female transsexuals increases BMD and markers of bone remodeling (126, 127).

As a counterpart to the action of estrogen in the male on pubertal growth and the skeleton, one can turn to the CAIS in the 46,XY phenotypic female who is unresponsive to androgens because of a deletion or null mutation in the X-linked gene encoding the androgen receptor. In these women, the testes secrete estradiol (99) and testosterone, and aromatase activity in the testis and in peripheral tissues is intact. As mentioned earlier, these women have a pubertal growth spurt and fuse their epiphyses in the absence of androgen action. The effect of this mutation on bone mass accrual and bone turnover is smaller, but many confounding factors, including castration in childhood or adolescence and the location of the testes, complicate the interpretation of this phenomenon. Estrogen production, at least in some individuals with CAIS, although greater than that in the normal young male adult (99, 128), is less than the estimated mean estrogen production during the normal menstrual cycle. While both volumetric and areal bone density are reduced in CAIS, biochemical markers of bone turnover are normal (129, 130, 131). The skeletal mass in these women is similar to that of normal women (130). Nor do these patients seem to have an increased risk of fractures (129). These observations, however, suggest that the production of estrogen by both the testis and peripheral tissues is sufficient to induce a pubertal growth spurt, epiphyseal fusion, and near normal accrual of bone mass for normal women. Parenthetically the androgen-resistant male rat, analogous to the human with partial androgen resistance, has reduced bone remodeling and size, but not decreased bone density (115, 116, 117).

In summary, the conventional belief that the human male skeleton accrues greater bone mass than that of the female because of the direct action of testosterone alone seems no longer tenable. Estrogen has an essential role in attaining optimal peak bone mass in the male. Nevertheless, androgen seems to have a direct but unquantitated effect on the skeleton that has not been distinguished unambiguously from the putative skeletal effects of genes on the human Y chromosome, nor from the observation that most of the sex differences and the age-related changes at the end of puberty are attributable to differences in skeletal dimensions than to bone density.

	The Testis and Ovary and the Regulation of Gonadotropins

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

 
In the man with severe aromatase deficiency whom we studied, circulating levels of testicular androgens and of FSH and LH were elevated (9). In the man reported by Carani et al. (60), whose CYP19 mutation was associated with a lesser degree of aromatase deficiency, the serum gonadotropins were slightly increased, but the testosterone level was normal. In the estrogen-resistant man (6), testosterone concentrations were normal, but estradiol and estrone levels were more than twice the upper value for the normal range, and gonadotropin concentrations were increased.

In addition, our patient has macroorchidism (he did not consent to provide a semen sample before estrogen treatment). The infertile man reported by Carani et al. (60) had small testes and oligospermia with immotile on semen analysis, but he had a brother with a normal CYP19 gene who also was infertile and had azoospermia. The familial occurrence of infertility in this pedigree limits an interpretation of the influence of estrogen deficiency on spermatogenesis. The estrogen-resistant man had normal-sized testes and a normal sperm count with a sperm viability of 18% (normal >50%). However, the male ERKO mouse becomes infertile due, at least in part, to an interruption of fluid resorption by the efferent ductules of the epididymis, which leads to dilatation and disruption of the seminiferous tubules (132), whereas the ßERKO male mouse is fertile but less so than the wild type mouse (22). The male ArKO, initially fertile, develops progressive infertility associated with impaired spermatogenesis and a reduction in spermatids (133). In the human male, in contrast to the rodent, the data are insufficient at present to allow an assessment of the action of estrogen on spermatogenesis and fertility.

Treatment with estrogen in the men with aromatase deficiency reduced the elevated gonadotropin values into the normal range; in our patient estrogen treatment decreased the high testosterone and dihydrotestosterone concentrations into the male range and the enlarged testes reduced to normal (9, 61) (Table 9).

View larger version (21K): [in this window] [in a new window]   Figure 6. The male hypothalamic-pituitary gonadotropin-testis axis in the light of observations in aromatase deficiency and defective estrogen receptor. The observations suggest that estradiol has a significant role in the regulation of FSH and LH. The plasma estradiol arises from the testes and from aromatization of 19-carbon steroids in extra-glandular tissues; in addition, intracrine and autocrine/paracrine roles of locally synthesized estradiol in the pituitary gland and hypothalamus can affect FSH and LH secretion. Accordingly, estradiol, testosterone, and inhibin all play a part in the regulation of gonadotropin secretion in males.

	Carbohydrate and Lipid Metabolism and the Cardiovascular System

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

View this table: [in this window] [in a new window]   Table 10. Glucose and lipid metabolism in men with C19 deficiency or estrogen receptor deficiency

The effect of estrogen on carbohydrate metabolism is unclear; estrogen deficiency is associated with impaired glucose tolerance (138, 139). However, the normal or elevated testosterone concentration acting in the absence of estrogen synthesis or estrogen action by the estrogen receptor may play a role in this phenomenon.

In summary, men with defective estrogen synthesis or action (ERR) have a propensity for insulin resistance and dyslipidemia.

Estrogen has a cardioprotective effect (140, 141). This seems to be mediated by two different mechanisms: its effect on serum lipids (142, 143, 144, 145) and its direct action on human vascular endothelial and smooth muscle cells and cardiac myocytes and fibroblasts (reviewed in Refs. 146); both estrogen receptors and ß are present in these cardiovascular cells and are widely expressed in the cardiovascular system (147, 148, 149, 150, 151, 152, 153, 154). In addition, there are rapid nongenomic actions of estrogen on the vascular system (153, 155, 156) and local estrogen synthesis by aromatase in cardiovascular tissue (157). The man with a null mutation of the estrogen receptor had an intact rapid (within 5 min) brachial vasodilatory response to sublingual estradiol and an increase in brachial artery flow velocity (a nongenomic action involving calcium-activated potassium channels in vascular smooth muscle cells), but lacked endothelium-dependent vasodilation mediated by endothelial nitric oxide generation (159), a nongenomic effect on endothelial cells which may be mediated by a cell membrane estrogen receptor encoded by the same transcript as the nuclear receptor (29). By electron-beam computed tomography scan, early coronary artery calcification indicated the presence of coronary atherosclerosis despite a low concentration of serum LDL-cholesterol (159) (Table 12). These observations, although limited to one well-studied patient, are consistent with the importance of estrogen and estrogen receptor on cardiovascular function and protection from cardiovascular disease.

View this table: [in this window] [in a new window]   Table 12. Cardiovascular function in the estrogen receptor -deficient man at age 31 yr

	Psychosexual Development and the Central Nervous System (CNS)

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

Estrogen receptors and aromatase activity are present in many regions of the CNS and coexist in some neurons (171), and different effects of estrogen on neuronal and glial cell growth and function and cerebral blood flow are mediated by genomic and nongenomic mechanisms (18, 169, 172, 173, 174, 175, 176, 177). For example, estrogen-replacement therapy in postmenopausal women may have a putative neuroprotective effect (161, 178) and reduce the risk or delay the onset of Alzheimer’s disease (179) (reviewed in Ref. 161). Estrogen decreases the generation of Alzheimer ß-amyloid peptides on neuronal cells in vitro (180) and may improve short-term memory in postmenopausal women (181).

In women, the menopause and adrenopause reduce the availability of 19-carbon steroid substrates for peripheral conversion to estrogen and, accordingly, reduce local estrogen formation and action by paracrine, autocrine, and intracrine mechanisms. In men, 19-carbon precursors of estrogen, mainly of testicular origin (testosterone and androstenedione), gradually decline with age but, nevertheless, are available throughout the aging process for local conversion to estrogen and may provide a mechanism for a persistent neuroprotective effect of estrogen on the CNS. Indeed, this analogy extends to bone; there is a 5-fold greater risk of fracture in the subsequent life of 50-yr-old women as compared with 50-yr-old men.

Table 13 compares and contrasts the salient features of estrogen receptor -resistance and estrogen deficiency in the male.

View this table: [in this window] [in a new window]   Table 13. Comparison of clinical features in men with CYP19 deficiency and estrogen receptor resistance

	Mutations in CYP19 in the Female and Placental Aromatase

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

View larger version (24K): [in this window] [in a new window]   Figure 7. The placental synthesis of testosterone and 18-carbon steroids from 19-carbon precursors in the CYP19-deficient fetoplacental unit. The placenta lacks the gene encoding CYP17 and hence is unable to convert 21-carbon steroids to 19-carbon steroids. The black box indicates the consequences of CYP19 deficiency on the placental synthesis of estrogens; the enzymatic block leads to the overproduction of testosterone and androstenedione. 3ß-HSD, 3ß-hydroxysteroid dehydrogenase 2; 17-ßHSOR, 17ß-hydroxysteroid dehydrogenase 3; DHT, dihydrotestosterone; 4A, androstenedione; E1, estrone; E2, estradiol; E3, estrone. (Reproduced with permission from Conte et al., J Clin Endocrinol Metab 1994; 78:1287–1292.)

View larger version (27K): [in this window] [in a new window]   Figure 8. The pattern of plasma unconjugated estrogens throughout normal gestation. (Note the log scale for plasma concentration; gestational age has been calculated from the last menstrual flow). Estriol is an indirect indicator of the synthesis of DHEA and 16OH DHEA and their sulfates by the fetal adrenal cortex and liver and of the capacity for aromatization of 19-carbon steroids by the placenta. Plasma estriol was first detected at 0.05 ng/mL at 9 weeks gestational age and increased dramatically over the next 7 weeks (shown by • and thick curve). This is a time in gestation when the fetal adrenal undergoes rapid growth and when placental aromatase activity increases. (Modified from Buster JE. Estrogen metabolism. In: Speroff L, Simpson JL, eds. Reproductive endocrinology, infertility, and genetics, Vol V of Gynecology and obstetrics. Hagerstown, MD: Harper and Row, 1980; 1–11.)

The findings in the aromatase-deficient patients and the estrogen-resistant man suggest that estrogen synthesis or action through the estrogen -receptor in the blastocyst, fetus, and fetal portion of the placenta is not essential for normal embryonic and fetal development (8, 9) (Table 18).

	Structural Consequences of CYP19 Mutations

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

View larger version (47K): [in this window] [in a new window]   Figure 9. Structural consequences of human aromatase mutations. A, A tracing of the backbone atoms for a human aromatase model (193 ). The heme ring is shown in red, and the location of bound substrate is indicated by the black arrow. B, Amino acid substitution mutations described in patients with aromatase deficiency. This is a coned-down view of the substrate binding site of panel A viewed more from above and to the left of substrate as depicted in panel A. The heme, still shown in red, serves to orient the viewer. The majority of the protein is shown in yellow as a tracing of the backbone atoms only, whereas all atoms of the mutated residues arginine 365 (R365), valine 370 (V375), arginine 375 (R375), arginine 435 (R435), and cysteine 437 (C437) are shown in cyan. Note the proximity (black dots) between arginine 435 (positive charge) and the carboxyllic acid group of the heme (negative charge).

	Epilogue

Top Abstract Introduction Estrogen and Its Effects... Androgens, Growth, and Bone... The Testis and Ovary... Carbohydrate and Lipid... Psychosexual Development and the... Mutations in CYP19 in... Structural Consequences of CYP19... Epilogue References

 
Human mutations, through their clinical repercussions, can have a profound effect on our understanding of complex biologic systems. This concept is well illustrated by the rare mutations that impair estrogen synthesis or action. Table 19 lists conventional wisdom before the detection of mutations in human CYP19 and in estrogen receptor and the challenge to these constructs that have originated from the study of patients with these genetic errors.

View this table: [in this window] [in a new window]   Table 19. Conventional wisdom: prearom deficiency and deficiency of ER

View this table: [in this window] [in a new window]   Table 19A. New insights: post-arom deficiency and deficiency of ER

	Acknowledgments

The coordinates for the aromatase model were kindly provided by Dr. Sandra Graham (University of Texas Southwestern Medical School); the images were generated at the University of California–San Francicso Computer Graphics Lab.

	Footnotes

 
¹ This work was supported in part by NIH Grants P41-RP01081 and M01RR01271, Pediatric Clinical Research Center, and NIH Clinical Investigator Award DK02387 (to R.J.A.). This presentation is dedicated to the memory of Akira Morishima, M.D., among the first fellows in M.M.G.’s laboratory, and a friend and colleague for over 4 decades.

Received September 3, 1999.

Revised October 12, 1999.

Accepted October 12, 1999.

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