ABSTRACT

In males, estrogens exert pleiotropic effects by acting on several tissue and organs, including the male reproductive system. The action of estrogens is manifest from prenatal life during which the exposure to estrogen excess might influence the development of some structures of the male reproductive tract. Male fertility is under the control of estrogens, especially in rodents. The loss of function of estrogen receptor alpha and/or of the aromatase enzyme leads to infertility in mice. In men, estrogens are able to exert their actions at several levels through the reproductive tract and on several different reproductive cells. However, the regulation of human male reproduction is complex, and the role of estrogens is less clear compared to mice. During fetal and perinatal life, estrogen acts on the central nervous system by modulating the development of some areas within the brain that are committed to controlling male sexual behavior in terms of setting gender identity, sexual orientation development and the evolution of normal adult male sexual behavior. This organizational, central effect of estrogens is of particular significance in other species (especially rodents and rams), but probably less important in men where psychosocial factors become more determining. Other relevant, non-reproductive physiological events, such as bone maturation and mineralization and glucose metabolism, depend on estrogen in men and an increasing body of evidence is disclosing new non-reproductive estrogen function. In this chapter we provide an update of estrogen’s role by reviewing the physiological actions of estrogen on male reproduction and the pathophysiology related to estrogen deficiency and estrogen excess. Phenotypes associated with estrogen deficiency and excess in rodents and in man have shed new light on the mechanisms involved in male reproduction, challenging the perception of the predominant importance of androgens in men. It is now clear that the imbalance between estrogen and androgen in men might affect male reproductive function even in presence of normal circulating androgens. Some uncertainties still remain, especially regarding the impact of abnormal serum estrogen levels on male health, particularly due to the fact that estrogen is not routinely measured in men in clinical practice. Advancements in methods to precisely measure estrogens in men, together with a reduction of their costs, should provide better evidence on this issue and inform clinical practice. In parallel, new basic, genetic, and clinical research is required to improve our knowledge on the role of estrogen in male reproductive function and men’s health in general. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

From an historical perspective, estrogens were identified about 85 years ago and estradiol was identified in 1940, reviewed in (1,2). The first evidence of estrogen production in the male was provided in 1934 by Zondek (3), who documented that male stallions excrete high levels of estrogens in the urine and hypothesized that estrogen production in the male occurs via the intratesticular conversion of androgens into estrogens (1,3,4).

In men, the conversion of androgens into estrogens was first demonstrated a few years later, when an increase in urinary estrogens after the administration of exogenous testosterone was recorded in normal men (5) (Figure 1).

Figur

e 1. Milestones in the advancement of research in the area of estrogens in men. [E₂: 17β-estradiol; ER: estrogen receptor; ERKO: Estrogen Receptor Knock out; ARKO: Aromatase Knock out].

A more detailed demonstration of estrogen production in the human male was provided several years later in 1979 by MacDonald et al. who showed that the aromatization of androgens to estrogens can occur also peripherally in several tissues other than in the testes (2,6).

Prior to the demonstration of estrogen production in males, the effects of estrogen excess on the development of male reproductive organs had been evident since the 1930s (7). Thus, the concept that male tissues are responsive to estrogens was not new, but it was thought that only a great amount of estrogens was able to induce such changes in males (2).

Notwithstanding the large amount of data accumulated in the last eighty years, research in the field of estrogen excess and its role on male reproductive system is still ongoing (8) (Figure 1).

The pioneering studies of Zondek and MacDonald opened the way for an appreciation of the physiological roles of estrogens in the male beyond their effects during embryogenesis (2). Several studies, year after year, provided further data on estrogen’s role in men (9-12), since the first pilot studies on estrogens and male reproductive function (13,14).

The progressive development of immunohistochemical studies and the subsequent progress in the field of molecular biology highlighted the actions of estrogens in the male [for further details see (4)] and opened the way for the creation of estrogen null mice, a useful animal model to study the physiological role of estrogens in vivo (15) (Figure 1).

The detailed characterization of estrogen receptors’ structure and function (15,16) together with the discovery and the characterization of genes involved in estrogens synthesis (17) disclosed the biomolecular mechanisms and related pathways involved in estrogen function and dysfunction. It is now clear that estrogen effects in the male are not confined to reproductive organs but are pleiotropic (18).

In addition, the development of male transgenic mice lacking functional estrogen receptors or the aromatase enzyme (responsible for estrogen biosynthesis) further contributed to advancements in this field (15,16). Finally, the discovery of mutations in both the human estrogen receptor alpha (19) and aromatase (20,21) genes contributed to an understanding of estrogen’s role in human male physiology and pathophysiology (11,12,22-25) (Figure 1).

Nowadays, notwithstanding this long history of studies, reviewed in (26-28), the role of estrogens in the physiology of the male reproductive tract is still not fully understood. The presence of estrogens in the human testis is well documented (29,30), and there is clear evidence that estrogens exert a wide range of biological effects in both men and women (10,12,18,24,25,31).

PHYSIOLOGY

Estrogen Biosynthesis in Males

The term estrogen refers to any substance, natural or synthetic, able to interact with the estrogen receptor (ER) (32,33). 17β-estradiol (estradiol) is the prevalent endogenous estrogen form in mammals, although many of its metabolites could be detected with several degrees of estrogenic activity (34). In humans, the three major endogenous estrogens are estrone (E1), estradiol (E2), and estriol (E3) (33) (Figure 2). In males, estrogens mainly derive from circulating androgens. The key step in estrogen biosynthesis is the aromatization of the C19 androgens, testosterone and androstenedione, to form estradiol and estrone, respectively (32). This step is under the control of the aromatase enzyme (32,35) (Figure 2).

Figure 2.

Biochemical pathway of testosterone conversion into estrogen.

However, a wide number of other endogenous products belongs to the category of estrogenic compounds, such as 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, Δ4-androstenedione, Δ5-androstenediol, 3α-androstanediol (3α-Adiol), 3β-androstanediol (3β-Adiol), 2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone and 16α-hydroxyestrone (33). In particular, dihydrotestosterone (DHT), an androgenic metabolite of testosterone that is synthesized by the enzyme 5 alpha reductase, can be metabolized into 3 β-Adiol, an intermediate metabolite with estrogenic activity (32,36). All these molecules differ in terms of ER affinity (33). Various exogenous substances also show estrogenic activity, such as bisphenol A, metalloestrogens, phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol) and mycoestrogens (e.g., zeranol) (37). These exogenous estrogens can influence human physiology via environmental exposure or ingestion, however the real impact in vivo as well as critical thresholds and cumulative amount of exposure remain to be fully elucidated (38).

The aromatase enzyme is a P450 mono-oxygenase enzyme complex (17) present in the smooth endoplasmic reticulum, which acts through three consecutive hydroxylation reactions, with the final reaction being the aromatization of the A ring of androgens (17,34) (Figure 2). This enzymatic complex is composed of a ubiquitous and non-specific NADPH-cytochrome P450 reductase, together with the regulated form of cytochrome P450 aromatase (17,29). The latter is highly specific for androgens (39,40). The conversion of androgens into estrogens takes place mainly in the testes, adipose tissue and muscle tissue, even though other male tissues are also involved to a lesser extent (17,34,35) (Figure 2).

The P450 aromatase enzyme is encoded by the CYP19A1 gene: a gene of 123 kb of length, which consists of at least 16 exons and is located on the long arm of chromosome 15 in the q21.2 region in humans (9,17,34) (Figure 3). This gene belongs to the cytochrome P450 superfamily, similar to other enzymes involved in steroidogenesis (32).

Figure 3.

Schematic representation of the human aromatase (CYP19) gene. [Red bars: first exons associated with upstream alternative, tissue-specific promoters; yellow bars: coding exons; black bar: heme-binding region].

Circulating estrogens are mainly reversibly bound to sex hormone binding globulin (SHBG), a β-globulin, and, to a lesser degree, to albumin (41). The amount of circulating free estradiol depends on several factors, of which the concentrations of albumin and SHBG are the most important (41). Serum free estradiol may be calculated by a complicated formula using total estradiol, SHBG, and albumin levels or may be measured by means of equilibrium dialysis or centrifugal ultrafiltration methodology; both, however, are too time consuming and expensive to be employed in routine clinical practice (41). When calculating free estradiol, the reliability of the value of total serum estradiol should be considered, since assays commonly used for estradiol in clinical laboratories have poor accuracy when measuring the low serum estrogen characteristic in males (42-44).

Estrogen Actions in Males

Estrogen action is mediated by interaction with specific nuclear estrogen receptors (ERs), which are ligand-inducible transcription factors regulating the expression of target genes after hormone binding (10,34,45). Two subtypes of ERs have been described: estrogen receptor α (ERα) and the more recently discovered estrogen receptor β (ERβ) (34,45). These two ER subtypes show different ligand specificity and transcriptional activity, and mediate the classical, direct, ligand-dependent pathway involving estrogen response elements in the promoters of targets genes and protein-protein interactions with several transcription factors (45). These two different ERs have different transcriptional activity (46). In particular, ERβ shows a weaker transcriptional activity compared to ERα (45). This difference is due to the presence of different ERβ isoforms, which can modulate estrogen signaling using different pathways and lead to different impacts on the regulation of target genes (45,46). In addition, it should be remarked that the co-expression of both ERα and ERβ in the same cell determines a complex cross-talk finally resulting in the antagonistic effect exerted by ERβ on ERα-dependent transcription (45,46). Thus, the presence/absence of ER subtypes together with their cross-talk determines a cell’s ability to respond to different ligands as well as the regulation of transcription of different target genes (45).

ERα in humans is encoded by the ESR1 gene located on the long arm of chromosome 6, while the ESR2 gene encodes ERβ and is located on band q22-24 of human chromosome 14 (45,46). The two ER proteins have a high degree of homology at the amino acid level (45) (Figure 4).

Figure 4.

Estrogen receptor gene structure showing the 9 exons (lower panel), cDNA domains (indicating exons), and protein structures of both ERα and ERβ (upper panels: colored boxes denote the different functional domains of the protein).

ERs are nuclear receptors in which structurally and functionally distinct domains are recognized. Estrogens bind the COOH-terminal multifunctional ligand-binding domain (LBD), whereas the DNA-binding domain recognizes and binds DNA (45,46). The NH2-terminal domain, the most variable domain, is involved in the transcriptional activation (45). This domain recruits a range of coregulatory protein complexes to the DNA-bound receptor (45). The two ER forms share a high degree of sequence homology except in their NH2-terminal domains. This specificity accounts for different transcriptional effects on different target genes (45,46). The ER genomic pathway begins with the binding of estrogen to ER (45). This interaction induces conformational changes in the ER, allowing receptor dimerization and subsequent nuclear translocation prior to binding to estrogen response elements or to other regulatory sites within target genes (45,46). Thereafter, the availability of several coregulatory proteins influences the transcriptional response to estrogen (45,46).

While it is clear that estrogens regulate transcription via nuclear interaction with their receptors, a non-genomic action of estrogens has been also demonstrated, suggesting a different molecular mechanism involved in some estrogen actions (34,45-48). In vitro studies show a very short latency time between the administration of estrogens and the appearance of its biological effects. These actions seem to be mediated by a cell-surface G protein-coupled receptor, known as GPR30, that does not act through a transcriptional mechanism (34,47,48). Rapid effects of estrogens result from the actions of specific receptors localized most often to the plasma membrane; in particular it seems that a monomeric portion of the ERα is translocated from the nucleus to the plasma membrane (47,48).

Recently, immunohistochemical analysis of murine tissues reported the presence of GPR30 in the male reproductive tract, including testes, epididymis, vas deferens, seminal vesicles and prostate (49). Furthermore, a rapid response to estradiol suggests that non-genomic estrogen actions are involved also in human spermatozoa (50,51). The different intracellular pathways of estrogen action are summarized in Table 1.

Table 1.

Characteristics of Estrogen Actions and Related Biomolecular Pathways

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Estrogen Actions	Receptors	Mechanism/Pathway	Final effect	Features
Genomic (Nuclear actions)	ERα	Transcriptional: nuclear interaction with estrogen-responsive elements	Modulation of estrogen target gene expression	Slow effects (minutes or hours)
	ERβ	Transcriptional: nuclear interaction with estrogen-responsive elements	Modulation of estrogen target gene expression	Slow effects (minutes or hours)
Non-genomic (cell membranes actions)	Estrogen receptors on cells membrane (GPR30)	Cells membrane changes	Changes in ionic transport through cell surface	Rapid effects (seconds)

[ERα: estrogen receptor alpha; ERβ: estrogen receptor beta].

Aromatase enzyme and ERs are widely expressed in the male reproductive tract both in animals and humans (52,53), implying that estrogen biosynthesis occurs at this site and that both locally produced and circulating estrogens may interact with ERs in an intracrine/paracrine and/or endocrine fashion (34). Today, it is clear that not only testicular somatic cells, but also germ cells constitute a source of estrogens in human (29,54). Thus, the concept of a key role for estrogen in the male reproductive tract is strongly supported by the ability of the male reproductive structures to produce and respond to estrogens (26,52). In men, the aromatase enzyme and ERs are expressed in several tissues including those involved in male reproduction. The distribution and expression of aromatase and ERs described below concerns the male reproductive organs.

ROLE OF ESTROGENS IN MALE REPRODUCTION

Regulation of Gonadotropin Feedback

The regulation of gonadotropin feedback is an important and well-documented action of estrogen in males. While testosterone has been classically considered the key hormone for the control of gonadotropin feedback in the male, a role for estrogens was recently clarified in studies performed in normal and GnRH-deficient men. We now know that ERs are expressed both in the hypothalamus and the pituitary. In particular, GnRH neurons express ERβ but not ERα (179,180), thus the inhibitory effects of estrogens on these cells is mediated through other neuromediators (e.g. kisspeptin, neurokinin B) released by other neurons expressing also the ERα (181). ERs, especially ERα are expressed in gonadotropes cells (182).

The response of the hypothalamic-pituitary-gonadal axis to androgens is confirmed by the administration of dihydrotestosterone (DHT), which is able to partially decrease LH and FSH with a concomitant reduction in serum testosterone and estradiol (183). However, the discovery of men with congenital estrogen deficiency has provided further evidence for a relationship between estrogens and gonadotropin secretion also in men (22). In fact, serum gonadotropins are high in all adult patients with aromatase deficiency, notwithstanding normal to increased serum testosterone levels (135), thus implying that estrogens are also important for the regulation of circulating gonadotropins levels in men.

The effects of estrogens on gonadotropin secretion have been investigated in GnRH-deficient men whose gonadotropin secretion was normalized by pulsatile GnRH administration. Moreover, in order to determine the precise role of sex steroids on the hypothalamo-pituitary-testicular axis, several studies characterized by the administration of testosterone, testosterone plus testolactone (an aromatase inhibitor), or estradiol have been performed (184,185). Testosterone alone induced a significant decrease in mean basal LH and FSH levels as well as of LH pulse amplitude, demonstrating a direct suppressive effect on the pituitary of testosterone and its metabolites. In general, mean LH levels and LH pulse frequency are suppressed to a greater extent in normal control subjects under testosterone administration, suggesting the involvement of a hypothalamic site of action of testosterone (or its metabolites) in suppressing GnRH secretion. In order to discriminate the impact of testosterone from its aromatized products, both groups of subjects were treated with testosterone plus testolactone. The addition of this aromatase inhibitor completely inhibited the testosterone effect on gonadotropin secretion both in normal and GnRH-deficient men, thus leading to a significant increase in mean LH levels in both groups. The latter was greater in normal men who received testolactone alone than in normal men who received testosterone plus testolactone, thus confirming a direct effect of androgens on gonadotropin secretion in normal men. On the basis of the results of these studies, it is clear that the aromatization of testosterone to estradiol is, at least in part, required for normal gonadotropin feedback at the pituitary level (185). In fact, when the same experimental model was applied using estradiol administration instead of testolactone, mean LH and FSH levels as well as LH pulse amplitude decreased significantly during the treatment (184). These studies have demonstrated an important direct inhibitory effect of estradiol on gonadotropin secretion in both GnRH-deficient and normal men (184,185) and support the concept that, at least in part, the inhibitory effect on gonadotropin secretion is mediated by the conversion of testosterone to estradiol (4,186). Accordingly, the administration of the aromatase inhibitor letrozole to healthy adult males is able to suppress aromatase activity and serum estradiol levels leading to an increase of gonadotropins (187). Only the restoration of normal circulating estrogens, by means of transdermal estrogen administration, normalized gonadotropin secretion in this setting (187). In contrast, it seems that the 5α-reduction of testosterone to DHT does not play a very important role in pituitary secretion of gonadotropins (188); DHT, in fact, slightly decreases LH and FSH only after long-term administration (183).

All these studies suggest possible estrogen action at the level of hypothalamus. In order to clarify the role of estrogen on the feedback regulation of gonadotropin secretion at hypothalamic level, Hayes et al. (189) conducted a study involving men affected by idiopathic hypogonadotropic hypogonadism (IHH), whose gonadotropin secretion was normalized by long-term pulsatile GnRH therapy, followed by treatment with the aromatase inhibitor anastrozole. They observed that the inhibition of estradiol synthesis led to an increase in mean gonadotropin levels that was greater in normal subjects than in IIH men, suggesting a hypothalamic involvement. The rise in mean LH concentrations in normal subjects due to anastrozole was due to increased LH pulse frequency and amplitude. The authors concluded that estrogen acts at the hypothalamic level by decreasing GnRH pulse frequency and pituitary responsiveness to GnRH (189). Subsequently, the same group (190) demonstrated that the administration of estradiol in normal subjects, whose endogenous testosterone and estradiol synthesis was inhibited through the use of ketoconazole, reduced mean LH levels by lowering LH pulse frequency, but not amplitude. These authors went on to report that the sex steroid component to FSH negative feedback was not androgenic but rather was mediated by estradiol effects on the frequency of GnRH stimulation (190,191).

For many years another important unresolved issue has been the relative role of circulating vs. locally produced estrogens in the control of gonadotropin secretion. Now we know that the effects of circulating estrogen are more relevant than that of locally produced, at both the hypothalamic and pituitary level (187) (Figure 5). Accordingly, the administration of both the aromatase inhibitor letrozole and estradiol at different dosages showed that serum testosterone and gonadotropins were inversely related to circulating estradiol, depending on the dose of exogenous estradiol (187). The serum estradiol required to obtain the same levels of gonadotropins were not different compared to that at baseline, suggesting that aromatase inhibition and the blockade of locally produced estrogens are less important than previously thought (187). In the same year, our group reached the same conclusions using a different approach. In men with aromatase deficiency, we demonstrated that circulating rather than locally produced estrogens are the main inhibitors of LH secretion (157). This implies that the role of locally produced estradiol on gonadotropin feedback at hypothalamic and pituitary levels is relatively modest in vivo (Figure 5). However, the role of locally produced estrogens has been poorly investigated since evaluating the effects of locally produced estrogens in vivo is challenging (186).

Data available in the literature demonstrate that (i) circulating estrogens are involved in gonadotropin suppression both at pituitary (187) and hypothalamic level (157,190), and (ii) estrogen effects on hypothalamus are independent from central aromatization, but requires adequate amounts of circulating estrogens in normal healthy men (187), in men with IHH (190,191), and in men with aromatase deficiency (157).

The effects of estrogen on gonadotropin secretion at the pituitary level operate from early- to mid-puberty (186,192,193) into old age in men (194). The administration of an aromatase inhibitor (anastrozole 1 mg daily for 10 weeks) to young men aged 15-22 years (192) resulted in a 50% decrease in serum estradiol concentrations, an increase in testosterone concentrations and an increase in both LH and FSH values during the study protocol. These hormonal parameters were restored after the discontinuation of anastrozole treatment (192). In addition, the administration of letrozole increased serum LH levels, LH pulse frequency and amplitude and the response of LH to GnRH administration in boys during early and mid-pubertal phases, confirming that estrogens act at the pituitary level during early phases of puberty (193), the role of estrogens in infancy and at the beginning of puberty remaining less known (186). The same mechanism continues to operate during adulthood and early senescence (195), as shown in fifteen eugonadal men, aged 65 years treated with 2 mg anastrozole for 9 weeks, in which serum FSH and LH levels increased significantly, in spite of an increase in serum testosterone levels (194). Similar results were replicated by using letrozole in older men (173). For these reasons, the use of aromatase inhibitors as blockers of the negative feedback on gonadotropin has been tested as a possible strategy useful for the treatment of late-onset male hypogonadism (196). The rationale was that increasing endogenous serum testosterone through the inhibition of the rate of conversion of testosterone into estradiol led to the consequent LH and FSH increase (196). After the first encouraging results (197-199), this kind of treatment seems to be not effective, especially on large-scale clinical trials and for long periods of time (195,196,200,201).

Figure 5.

Sex steroid control of gonadotropin secretion after recent advances: estrogens, but not androgens, are the main regulator of gonadotropins and the action of circulating estradiol prevails with respect to that of locally produced estradiol. [T: testosterone; DHT: dihydrotestosterone; E2: estradiol; GnRH: gonadotropin releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone].

Previous data suggest that estradiol may modulate GnRH receptor number and function at hypothalamic-pituitary level (202), since ERs were detected in GnRH secreting neurons (203). Moreover, both genomic and non-genomic estrogen actions seems to be involved in the regulation of the gonadotropin feedback in males (203,204), although the precise mechanism remains unclear (205). Nevertheless, it is now well established that androgens need to be converted to estrogens in order to ensure the integrity of the gonadotropin feedback mechanism in men, testosterone itself having a lesser role than previously thought (Figure 5), and circulating estrogen, rather than locally produced estrogen, having a major role at the hypothalamic pituitary level (157,187,191).

In a complementary way, our knowledge on the role of estrogens in gonadotropin feedback has been enhanced through studies of men with congenital estrogen deficiency. The description of a man lacking a functional ERα (19) revealed a remarkable hormonal pattern consisting of normal serum testosterone, high estradiol and estrone levels, but increased serum FSH and LH concentrations; the serum testosterone remained in the normal range because of increased aromatization of testosterone to estradiol (Table 6). Other important information about estrogen’s role in the human male came from the discovery of naturally occurring mutations in the aromatase gene. To date, of the sixteen different cases of human male aromatase deficiency that have been described, all were discovered to be aromatase-deficient as adults, except one who was diagnosed as a child (137,141) and another one who was diagnosed at 15 months of age (145) (Table 6). Eight out of fourteen adult patients with aromatase deficiency had increased basal FSH concentrations (20,21,135,138-140,144,150-152,154), two had serum FSH in the upper normal range (143,144), and the remaining four had normal FSH (144,146-148). The subject diagnosed during childhood had normal FSH in infancy (137) and high to normal FSH levels at puberty (141). The unique patient diagnosed early at 15 months had normal serum T, LH, and FSH (145). LH was normal in all aromatase adult patients (138-140,144,146,147,150-152), except for one subject with elevated serum LH (20,136) and two subjects with high to normal LH levels (21,143,154) (Table 6). Serum testosterone concentrations were generally normal or high-to-normal except for the first case described with elevated serum levels (20,136), and two other aromatase-deficient men with testosterone slightly above the normal range (138,139). Conversely, another man with aromatase deficiency presented with low to normal serum testosterone levels (150,156). In all sixteen patients estradiol concentrations were undetectable (20,136-149). (Table 6). The detection of increased gonadotropin levels despite normal-to-increased serum testosterone levels, in these men, further highlights the key role for estrogen in regulating circulating gonadotropins in men (155,157), In normal men with pharmacologically induced sex steroid deprivation, estradiol but not testosterone, was able to restore normal FSH serum levels (191). Due to the concomitant impairment of the patient's spermatogenesis, complete normalization of serum FSH was not achieved in all aromatase-deficient men during estradiol treatment, even in the presence of physiological levels of circulating estradiol (135), only supraphysiological levels of estrogens were able to normalize FSH (21,135,154,155).

A detailed study of the effects of different doses of transdermal estradiol on pituitary function in two men with congenital aromatase deficiency demonstrated that estrogens might control not only basal secretion of gonadotropins but also their responsiveness to GnRH administration (138,155,157). In these studies, estrogen administration to three male patients with aromatase deficiency caused a decrease in both basal and GnRH-stimulated LH, FSH and α-subunit secretion with a dose-dependent response to GnRH administration (138,155,157). In 2006, Rochira et al. (157), demonstrated that estrogen’s effects on LH secretion are exerted both at pituitary and hypothalamic level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulse amplitude, and the reduction of the frequency of LH pulses respectively, during estrogen treatment to normalize estradiol serum levels in two aromatase-deficient men. In normal physiology, these data provide evidence that the negative feedback effects of circulating estrogens is more important than estrogen locally produced at the hypothalamic level (157). As previously explained, these data confirm data from healthy men (186).

Notwithstanding recent advances in the study of estrogen’s role in males, some difficulties remain when data from men with congenital estrogen deficiency are interpreted, particularly if phenotype heterogeneity is considered (161,186). No abnormalities were found in either gonadotropin secretion or in testis position and size in the patient with congenital aromatase deficiency diagnosed in childhood (137), unlike female newborns (206). For these reasons, the role of estrogens in the hypothalamo-pituitary-testicular axis should become relevant in a later stage of life than infancy in men. Furthermore, the smaller than expected increase in FSH levels (given the prevailing serum testosterone levels and impaired spermatogenesis) in two estrogen-deficient men (157), suggests a possible role of estrogens in priming and maturation of hypothalamus-pituitary-gonadal axis in men (155,156). Thus, the control of gonadotropin feedback exerted by sex steroids during early infancy and childhood remains a matter of debate in the human male (186).

In conclusion, estrogens are the main sex steroids involved in the control of gonadotropin secretion in men, testosterone having a minor but determinant role as demonstrated by evidence coming from complete androgen insensitivity (CAIS) syndrome in which serum LH is above normal as a consequence of androgen resistance notwithstanding elevated circulating estradiol (207).

OTHER NON-REPRODUCTIVE PHYSIOLOGICAL ESTROGEN ACTIONS IN MEN

Estrogens and the Male Bone

There is increasing evidence suggesting that circulating estrogens plays a key role in bone health in men, as in women (286). The relative contribution of androgen versus estrogens in the regulation of the male skeleton, however, is complex and relatively unclear (287). Some estrogen actions on male bone, such as bone maturation and the acceleration of growth arrest, are now well defined (286,288). The important role of estrogen in bone metabolism in men has been characterized in the last 15 years by means of the description of rare case reports of estrogen-deficient men (135,152) and by several epidemiological studies (289,290). All patients with congenital estrogen deficiency due to estrogen resistance (19,133,134) or aromatase deficiency (20,136-149). have unfused epiphyses in adulthood and fail to reach their closure and complete bone maturation (11,18,25,130,286). Estrogen replacement therapy led to skeletal maturation and improvement of bone mineral density in all aromatase-deficient men described so far (11,135,144) in a dose-dependent way (147,154) while testosterone treatment did not (21,22,159). During puberty and late adolescence, epiphyseal closure, growth arrest, the achievement of peak bone mass, and final bone maturation are mainly under the control of estrogens and all these processes do not progress in the case of severe estrogen deficiency leading to tall stature and osteoporosis (21,22,135,286). The eunuchoid body proportions of the skeleton typical of hypogonadal men are the effect of estrogen deficiency during late adolescence and of the disproportional growth between long bones and the appendicular skeleton (11,286). During adulthood, both normal circulating estradiol and testosterone are required for maintaining bone mineral density in aromatase-deficient men (136,159,160) as well as in the general male population (132,286,287,289-292). Estrogen action on bone seems to be possible only when circulating estradiol is above a threshold between approximately 15 and 25 pg/mL (55-92 pmol/L) (286,289). This mechanism has been suggested both for growth arrest and bone maturation (152) and for bone mineral density (BMD) (132,289,292) and suggest that circulating estrogens above this threshold are required for optimal skeletal maturation and mineralization in men (130,286). Relative estrogen deficiency, rather than testosterone deficiency, is responsible for bone loss in hypogonadal men as clearly demonstrated when using different doses of exogenous testosterone alone or in combination with a potent aromatase inhibitor in men treated with GnRH analogues (293). In this study, BMD decreased and indices of bone resorption increased only in the group of men treated with both testosterone and anastrozole independently from the dose of exogenous testosterone administered to men with pharmacologically-induced hypogonadism (293). Furthermore, this study confirms that serum estradiol below 10 pg/mL is particularly harmful for bone health (293).

Similarly, in men with prostate cancer, estrogen deficiency induced by Androgen Deprivation Therapy (ADT) is the main factor involved in bone loss, increase of bone fragility, and the occurrence of osteoporotic fractures since serum estradiol falls below 5 pg/mL in men receiving ADT (294-296) similar to what happens in women taking antiestrogens for breast cancer (132,292,297). Accordingly, new strategies for the treatment of prostate cancer by using blockers of the androgen receptor and exogenous estradiol are being investigated in order to mitigate the risk of bone fractures and other side effects of ADT (224,295,296). In particular, transdermal estradiol resulted effective in preventing bone loss compared to LHRH analogue in men with prostate cancer (298).

Figure 6.

Genetically determined factors influencing the amount of serum estrogens in men starting from a determined amount of circulating serum T. [SNPs: single-nucleotide polymorphisms; T: testosterone; DHT: dihydrotestosterone; E₂: estradiol; GnRH: gonadotropin releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone].

Except for rare cases of congenital estrogen deficiency (162), clinical experimental models of estrogen deficiency (199,285,293), and ADT (295,296), the most common condition in men is relative estrogen deficiency induced by hypogonadism and low serum levels of T, the precursor for estrogen production (Figure 1) (131,290,299,300). Relative estrogen deficiency may occur in hypogonadal men (299,300) especially in those with a less functioning aromatase enzyme (290,301), whose function is mainly under genetic determination (Figure 6) (131,132,292). The association between some polymorphisms of both ERα (302,303) and aromatase (304,305) genes and low bone mineral density (BMD) have clearly pointed out that the estrogen pathway is crucial for bone health in men confirming epidemiological and clinical data. These data have been recently confirmed by studies based on genome-wide association studies. These studies provided evidence on the role of aromatase enzyme in relative estrogen deficiency occurring in men with hypogonadism and its impact on BMD (Figure 6). Accordingly, a genome-wide association study demonstrated how some genetic variants of the aromatase enzyme are correlated with circulating serum E2 and BMD and that genetically determined values of circulating estradiol are linked to BMD by estimating that every 1 pg/mL of serum E2 corresponds to a genetically determined increase of BMD of 0.048 standard deviation (306). These results have been recently replicated by another GWAS study (307). Similarly, serum estradiol but not testosterone was identified as a causal factor in bone osteoporotic fractures in 175,583 men studied using a Mendelian randomization approach (308). Thus, the lower the serum estradiol the greater the extent of bone loss in hypogonadal men, the decrease of serum T exerting a direct, minor role (131,132,157,292,293). As a matter of fact, in male to female transexuals, high serum E2 induced by estrogen therapy maintains and increases bone mass despite low serum T (309,310). The degree or relative estrogen deficiency in hypogonadal men depends on several factors, including aromatase functioning (Figure 6).

EFFECTS OF ESTROGEN EXCESS

CLINICAL IMPLICATIONS OF ESTROGENS IN MALES

FUTURE DIRECTIONS

Notwithstanding consistent advancements in the comprehension of estrogen role in men the pathophysiology of estrogens in males remains not fully explored and further studies are advocated. Preliminary data suggest that the decline in serum estradiol is associated with all-cause mortality in community-dwelling older men, but further investigations are needed to prove this relationship (422). In addition, the knowledge of the role of estrogen-related genetic determinants in male pathophysiology is still in its infancy. In recent years some research based on genome-wide association studies (GWAS) have provided new insights to this field (76,306-308,423). GWAS are useful in examining unexplored areas concerning physiological and pathological actions and related genetic determinants (Figure 6). Concerning estrogens in men a recent GWAS allowed disclosing more details on the association between low serum estradiol and increased adiposity and showed that higher estradiol levels were associated with lower adiposity (423). Thus, GWAS are promising for disclosing new important aspects related to estrogen pathophysiology in men and for improving the knowledge of genetic determinants of estrogens in health and disease. Advancement in the comprehension of individual genetically determined estrogen actions (Figure 6) together with the diffusion of LC-MS/MS in clinical laboratories allowing precise measurement of estrogens in men will pave the way to better tailor the management and therapy of both estrogen deficiency and excess in the human male.

CONCLUSIONS

Sex steroids account for sexual dimorphism because they are responsible for the establishment of primary and secondary sexual characteristics, which are under the control of androgens and estrogens in male and female, respectively. Advances in the understanding of the role of estrogens in animal and human models suggest a role for this sex steroid in the reproductive function of both sexes. The fact that both estrogen excess and estrogen deficiency influence male sexual development, testis function, the hypothalamic-pituitary-testis axis, spermatogenesis and ultimately male fertility, highlight the biological importance of estrogen action in males. Thus, estrogens, not only androgens, are responsible for some crucial physiological functions in men like fertility, reproduction, and bone health. In particular, the balance of serum estradiol to testosterone ratio is likely crucial for maintaining all these functions, thus suggesting that the homeostatic equilibrium between estrogens and androgens is important for the correct functioning of several physiological systems in men (11,22,34,121,158,172,381). From an evolutionary perspective, this relevance of estrogen actions in males provides an example of the parsimony operating in biological events that are crucial for the evolution of the human species such as growth and reproduction (Figure 7).

This chapter has addressed the reproductive effects of estrogens in males but there are emerging roles for estrogens in non-reproductive tissues. In particular, even though testosterone has traditionally been considered the sex hormone involved in bone maturation and growth arrest in men the key role of estrogens on growth has recently been revealed.

Figure 7.

Direct and indirect (estrogen mediated) testosterone actions. [DHT: dihydrotestosterone, AR: androgen receptor; ERs: estrogen receptors].

A major area of uncertainty is the possible role of estrogen in boys before puberty. It is known that low levels of circulating estradiol are detected in infancy when using ultrasensitive assays, but their significance is not known (130).

Several lines of evidence support the view that estrogens are required for, and in part mediate, androgen actions on several tissues and organs in men (Figure 7). The progress made in the last thirty years in this field have clarified the importance of estrogen in men but leaves some issues still unsolved. In particular, estrogen actions on bone and on gonadotropin secretion are now well characterized and part of the estrogen action on spermatogenesis is known, but further evidence is needed to clarify several aspects still under debate.

ACKNOWLEDGMENTS

We are indebted to Kenneth Korach S. (National Institutes of Health, Research Triangle Park, NC, United States), Evan Simpson (Hudson Institute of Medical Research, Clayton, Australia), Laura Maffei (Buenos Aires, Argentina) for their collaboration with our group in this research field.

A special thanks to Marco Faustini-Fustini (Ospedale Bellaria, Bologna, Italy), Antonio Balestrieri (Ospedale Bufalini, Cesena, Italy), Antonio R.M. Granata (University of Modena and Reggio Emilia), Elisa Pignatti (University of Modena and Reggio Emilia), Fabio Lanfranco (University of Turin, Italy), and Paolo Beck-Peccoz (Univesity of Milan, Italy) for fruitful discussion and collaboration in the research area of estrogen role in the human male.

We are grateful to Bruno Madeo, MD, PhD, Chiara Diazzi, MD, PhD Lucia Zirilli, MD, PhD Daniele Santi MD, PhD (University of Modena and Reggio Emilia) for their contribution in revising some parts of the previous version of this chapter (November 24, 2016).

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