Androgen resistance

Androgen resistance causes the androgen insensitivity syndrome in its variant forms and is a paradigm of clinical syndromes associated with hormone resistance. In its complete form, the syndrome causes XY sex reversal and a female phenotype. Partial resistance to androgens is a common cause of ambiguous genitalia of the newborn, but a similar phenotype may result from several other conditions, including defects in testis determination and androgen biosynthesis. The biological actions of androgens are mediated by a single intracellular androgen receptor encoded by a gene on the long arm of the X chromosome. Mutations in this gene result in varying degrees of androgen receptor dysfunction and phenotypes that often show poor concordance with the genotype. Functional characterization and three-dimensional modelling of novel mutant receptors has been informative in understanding the mechanism of androgen action. Management issues in syndromes of androgen insensitivity include decisions on sex assignment, timing of gonadectomy in relation to tumour risk, and genetic and psychological counselling.     

Annual cycles of steroid hormone production, gonad development, and reproductive behavior in the Atlantic stingray

The mating season of the Atlantic stingray (Dasyatis sabina), which begins in August and continues through April, is the longest documented for any elasmobranch fish. Despite this protracted mating period, female stingrays ovulate synchronously at the end of the mating season and there is no evidence for sperm storage by females. Thus, the proximate causal factors and ultimate function of this extended preovulatory mating are unknown. Annual cycles of the gonadal steroids testosterone (T), dihydrotestosterone (DHT), 17beta-estradiol (E2), and progesterone (P4) were measured for 26 months in a wild estuarine population of Atlantic stingrays to test for associations with their reproductive biology, gametogenesis, and sexual behavior. Serum androgen levels in males showed four phases within an annual cycle: (1) androgen suppression between reproductive seasons (April-July), (2) primary androgen increase during the onset of spermatocyte development (August-October), (3) androgen decrease following maximum testis growth and spermatocyte development (November-December), and (4) secondary androgen increase during the peak of sperm maturation (January-March). Increases in male E2 and P4 were correlated with spermatocyte/spermatocyst formation, maximum testis weight, and the primary (but not secondary) androgen surge. We propose that the production of male androgens across the full seven-month preovulatory mating period promotes their aggressive reproductive behavior and drives the protracted mating season of this species. In females, serum T and DHT showed relatively brief increases near ovulation, whereas E2 and P4 showed brief increases near both ovulation and parturition. The increase in female androgens near ovulation may increase female aggression when they are impregnable by courting males and enhance their choice of mates. This estuary sample population shows higher absolute steroid levels and distinct differences in temporal cycles compared to another Florida fresh water lake population, but the cause and significance of these differences are unknown. Experiments are needed to confirm that the aggressive and protracted mating behavior is the result of prolonged male androgen production and to determine whether the sustained preovulatory mating serves some function related to female reproduction.     

Species variation of gonadotropic activity in an in vitro assay measuring androgen formation by carp (Cyprinus carpio) testis with special reference to bioassay of piscine gonadotropins

The objectives of this study were to establish a suitable and validated in vitro bioassay of piscine gonadotropins (GTHs) by using a carp testis androgen production system and to compare the androgenic responses in such an assay to gonadotropins from various vertebrate species. The testes from mature carp with gonadosomatic indices of 8-30% were used. Androgen production was first compared with respect to methods for preparation of the carp testis (sliced, minced, homogenized, and collagenase-dispersed testis preparations). The time course of androgen formation, the effects of xanthine and theophylline, and other factors on androgen production also were investigated. Theophylline was more effective than xanthine in potentiation of gonadotropin-evoked androgen formation by carp testis. The testis preparations were incubated in medium 199 (pH 7.40) containing 2 mM theophylline with shaking at 100 cycles/min at 25 degrees C for 4 hr. Homogenized testis preparations had limited ability for androgen production, while sliced, minced, and minced-collagenase-dispersed testis preparations were highly responsive to gonadotropins for androgen production. The minced testis preparation, utilizing 100 mg/ml incubation medium per vial, was chosen as the standard incubation procedure in this study. The minced testis androgen production assay was highly sensitive to gonadotropins from several piscine species (silver carp, common carp, and salmon), and all these GTHs produced parallel dose-related androgen production curves. Mammalian GTHs were also capable of promoting androgen formation by carp testis, but they were much less potent than were piscine GTHs. Pregnant mares' serum gonadotropin (PMSG) was more effective than human chorionic gonadotropin (hCG) in evoking carp testis androgen production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inactivation of AMPKα1 induces asthenozoospermia and alters spermatozoa morphology

AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, is present in metabolic tissues (muscle and liver) and has been identified as a modulator of the female reproductive functions. However, its function in the testis has not yet been clearly defined. We have investigated the potential role of AMPK in male reproduction by using transgenic mice lacking the activity of AMPK catalytic subunit α1 gene [α1AMPK knockout (KO)]. In the testis, the α1AMPK subunit is expressed in germ cells and also in somatic cells (Sertoli and Leydig cells). α1AMPK KO male mice show a decrease in fertility, despite no clear alteration in the testis morphology or sperm production. However, in α1AMPK(-/-) mice, we demonstrate that spermatozoa have structural abnormalities and are less motile than in control mice. These spermatozoa alterations are associated with a 50% decrease in mitochondrial activity, a 60% decrease in basal oxygen consumption, and morphological defects. The α1AMPK KO male mice had high androgen levels associated with a 5- and 3-fold increase in intratesticular cholesterol and testosterone concentrations, respectively. High concentrations of proteins involved in steroid production (3β-hydroxysteroid dehydrogenase, cytochrome steroid 17 alpha-hydroxylase/17,20 lysate, and steroidogenic acute regulatory protein) were also detected in α1AMPK(-/-) testes. In the pituitary, the LH and FSH concentrations tended to be lower in α1AMPK(-/-) male mice, probably due to the negative feedback of the high testosterone levels. These results suggest that total α1AMPK deficiency in male mice affects androgen production and quality of spermatozoa, leading to a decrease in fertility.     

The marsupial model for male phenotypic development.

In all mammals, androgen formed in the developing testes is responsible for the aspects of male development in which the Wolffian ducts, urogenital sinus and urogenital tubercle are transformed into the epididymis/vas deferens, prostate and penis. That these events take place after birth in the marsupial makes it possible to examine male phenotypic development during pouch life. In the tammar wallaby, Macropus eugenii, the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol (5 alpha-adiol) is formed in the developing testis, is secreted into plasma and has the capacity to virilize female young pouch when administered exogenously. 5 alpha-Adiol is formed by immature testes in many species and appears to act in target tissues once it has been converted to dihydrotestosterone.     

Cardiovascular risks of androgen deprivation therapy

Prostate adenocarcinoma is the most common cancer type in the male sex after skin cancer. Among the several types of treatment for prostate cancer, the androgen deprivation therapy has been highly recommended in patients with metastatic or locally advanced disease, which probably results in increased survival. However, the androgen deprivation is the cause of several adverse effects. Complications such as osteoporosis, sexual dysfunction, gynecomastia, anemia and body composition alterations are well-known effects of the therapy. Recently, a number of metabolic complications have been described, such as increase in the abdominal circumference, insulin resistance, hyperglycemia, diabetes, dyslipidemia and metabolic syndrome, with a consequent increase in the risk of coronary events and cardiovascular mortality in this specific population. This update article presents a literature review carried out at MEDLINE database of all literature published in English from 1966 to June 2009, using the following key words: androgen deprivation therapy, androgen suppression therapy, hormone treatment, prostate cancer, metabolic syndrome and cardiovascular disease, with the objective of analyzing which would be the actual cardiovascular risks of androgen deprivation therapy, also called androgen suppression, in patients with prostate cancer.     

The role of androgens and the androgen receptor in cycling endometrium

Androgens and the androgen receptor (AR) are not only required for male reproductive function, they are also essential for female reproductive physiology. Widely expressed in female reproductive tissues, AR levels fluctuate in a regulated manner in the cycling endometrium. Female androgen production depends on the adrenal glands and expression of key enzymes in the endometrium that facilitate local androgen biosynthesis and conversion. Moreover, levels of circulating androgens, in women of reproductive age, fluctuate in a cycle-dependent manner and a mid-cycle peak is associated with conception. AR and androgen signalling have a decisive role in the differentiation of human endometrial stromal cells into decidual cells. Compelling evidence for androgen signalling in the regulation of endometrial function pertaining to implantation and pregnancy is provided by epidemiological studies demonstrating a strong association between polycystic ovary syndrome, premature ovarian failure or advanced maternal age and adverse pregnancy outcome. Thus, androgen signalling is an essential component of normal endometrial physiology and its perturbation is associated with reproductive failure.     

Seminiferous tubule androgen receptors in experimental cryptorchidism

As an initial approach to the study of seminiferous tubule androgen receptors in disordered spermatogenesis, cytosol androgen receptors were studied in rats with experimental cryptorchidism. Two weeks after the testis had been repositioned in the abdomen of 6-week-old rats, the animals were hypophysectomized to deplete the testis of androgen, and 1 week later they were killed. Androgen receptor binding was studied in seminiferous tubule cytosol using [3H]methyltrienolone as the radiolabelled probe. The androgen-binding capacity of cryptorchid testis, when expressed as fmol bound/testis, was reduced to 50% of control, in parallel with the decline in testis weight. No change in binding affinity was found. Sucrose density gradient centrifugation using a vertical tube rotor revealed a 9S molybdate-stabilized receptor under low-salt conditions in both cryptorchid and scrotal seminiferous tubule cytosol. Receptor-complex stability studies, analysis by gel filtration and DEAE-cellulose chromatography produced similar results in cryptorchid and scrotal tubules. The mechanism for the reduction in testicular receptor content of an abdominal testis remains to be clarified. The demonstration that testicular androgen receptors can be reduced by cryptorchidism suggests that further studies may indicate the role of receptor binding in testicular function.     

Stromal cells from the rat prostate secrete androgen-regulated factors which modulate Sertoli cell function

Testicular peritubular cells produce paracrine mediators which modulate Sertoli cell function. The production of these mediators (P Mod-S) is controlled by androgens suggesting that mesenchymal-epithelial interactions play an important role in androgen action in the testis. We investigated whether mesenchymal cells from the prostate, another androgen target tissue, produce analogous mediators. To this end rat Sertoli cell cultures were exposed to dialyzed spent media derived from testicular peritubular cells, prostatic stromal cells or footsole fibroblasts. It is demonstrated that the effects of spent media from peritubular cells and stromal cells are nearly identical: they stimulate the production of androgen binding protein and transferrin and they inhibit FSH-inducible aromatase activity. The active principle (or principles) involved is non-dialyzable, heat sensitive and trypsin sensitive. Its production is markedly stimulated by androgens. Fibroblast spent media are inactive. It is concluded that mesenchymal tissue derived from different androgen target tissues may produce identical or similar mediators of androgen action acting on epithelial cells.     

促性腺激素治疗男性低促性腺激素性性功能减退症的疗效评估

目的应用人绒毛膜促性腺激素(hCG)和绝经期妇女尿促性腺激素(HMG)治疗男性低促性腺激素性性腺功能减退症,评价其疗效.方法 64例低促性腺激素性性腺功能减退症患者中Kallmann综合征19例,特发性低促性腺激素型性腺功能低下41例,颅咽管瘤手术后性腺功能低下症4例.33例患者采用hCG 1500 IU肌肉注射,每周2次;31例患者采用hCG 1500 IU + HMG 75 IU联合肌肉注射,每周2次.疗程均6个月以上.结果治疗后所有患者体力改善,体质增强;42例患者出现胡须、阴毛和(或)腋毛.睾丸体积治疗前(3.08±2.44)ml, 治疗后(8.92±5.37)ml(P<0.01);血清卵泡刺激素、黄体生成素和睾酮水平有所提高(P<0.05);6/64患者出现遗精现象,2例有精子生成.以睾丸体积增大为判断疗效的标准,12例无效,52例有效,有效率达81.2%,hCG+HMG组效果明显好于hCG组.结论对男性低促性腺激素性性腺功能减退症患者,用hCG和HMG治疗能促进青春期第二性征发育,体力增加,外生殖器和睾丸进一步发育,并可望部分恢复睾丸产生雄激素和生成精子两项功能,明显优于以往单纯使用或者过早使用雄激素替代的治疗方案.     

Effect of intratesticular administration of gonadotropins on testicular and plasma androgen concentration in the lizard, Uromastix hardwicki

An acute effect of intratesticular injections of varying doses of ovine FSH (NIH-FSH-S12), ovine LH (NIH-LH-S20), and a lizard hypophyseal extract was observed on testicular and plasma androgen concentrations in Uromastix hardwicki. FSH and LH were used in a dose range of 0.25–4.00 ng and the hypophyseal extract was administered at concentrations representing 10–160 μg of fresh pituitary tissue obtained from adult male Uromastix. The test material was injected directly into one testis while the contralateral testis was likewise treated with an equal volume of saline. The control lizards received intratesticular injections of saline on both sides. Testicular and plasma androgen concentrations were measured 3 hr following the injections, using a specific RIA for testosterone. A significant increase in androgen concentration both in the testis and the plasma was obtained with 0.25 ng of FSH and 4.00 ng of LH. Both FSH and LH induced a significant rise in plasma androgen at 1.00 ng, but the increase was markedly greater in the FSH treated lizards. The homologous hypophyseal extract was shown to be active at the minimum dose level used (10 μg). The testosterone content of the uninjected testis in treated lizards was not significantly different from that of the control lizards. It is concluded that the intratesticular route of administration can be used as a sensitive and rapid method for studying in vivo responsiveness of the testis to mammalian and nonmammalian gonadotropins.     

Minireview: sex differentiation.

Mammalian sex differentiation is a hormone-dependent process in the male following the determination of a testis from the indifferent gonad through a cascade of genetic events. Female sex differentiation is not dependent on ovarian hormones, yet there is evidence that members of the Wnt family of developmental signaling molecules play a role in Müllerian duct development and in suppressing Leydig cell differentiation in the ovary. The testis induces male sex differentiation (including testis descent) through a time-dependent production of optimal concentrations of anti-Müllerian hormone, insulin-like factor(s) and androgens. Observations in several human syndromes of disordered fetal sex development corroborate findings in murine embryo studies, although there are exceptions in some gene knockout models. The ubiquitously expressed AR interacts in a ligand-dependent manner with coregulators to control the expression of androgen-responsive genes. Preliminary studies suggest the possibility of hormone resistance syndromes associated with coregulator dysfunction. Polymorphic variants in genes controlling androgen synthesis and action may modulate androgenic effects on sex differentiation.     

Androgens and Androgen Receptors as Determinants of Vascular Sex Differences Across the Lifespan

Androgens, including testosterone and its more potent metabolite dihydrotestosterone, exert multiple actions in the body. Physiologically, they play a critical role in male sex development. In addition, they influence vascular function, including arterial vasodilation and mediation of myogenic tone. Androgens are produced from 9 weeks' gestation in the human fetal testis, as well as in small amounts by the adrenal glands. Serum concentrations vary according to age and sex. The vasculature is a target for direct actions of androgens, which bind to various sex hormone receptors expressed in endothelial and vascular smooth muscle cells. Androgens exert both vasoprotective and vasoinjurious effects, depending on multiple factors including sex-specific effects of androgens, heterogeneity of the vascular endothelium, differential expression of androgen and sex hormone receptors in endothelial and vascular smooth muscle cells, and the chronicity of androgen administration. Long-term administration of androgens induces vasoconstriction and influences endothelial permeability, whereas acute administration may have opposite effects. At the cellular level, androgens stimulate endothelial cell production of nitric oxide and inhibit proinflammatory signalling pathways, inducing vasorelaxation and vasoprotection. However, androgens also activate endothelial production of vasoconstrictors and stimulate recruitment of endothelial progenitor cells. In humans, both androgen deficiency and androgen excess are associated with increased cardiovascular morbidity and mortality. This review discusses how androgens modulate vascular sex differences across the lifespan by considering the actions and production of androgens in both sexes and describes how cardiovascular risk is altered as levels of androgens change with aging.     

Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome

CONTEXT: The clinical and biological features of Sertoli cell and Leydig cell dysfunction are usually investigated when characterizing disorders of sex development in 46,XY individuals: This allows gonadal dysgenesis, a defective development of the gonad, to be distinguished from defects restricted to androgen synthesis or sensitivity. In humans, mutations in steroidogenic factor-1 (SF-1), one of the critical factors involved in testis development, have been reported to cause gonadal dysgenesis with or without adrenal failure in 46,XY individuals. OBJECTIVE: We report a SF-1 mutation that caused ambiguous genitalia associated with strikingly different hormonal phenotypes in two affected 46,XY children from the same family. METHODS: Hormonal evaluation included testosterone (T), anti-Mullerian hormone (AMH), inhibin B, FSH, and LH measurements during the first weeks of life, a period when physiological activation of the gonadotropin-gonadal system occurs. Direct DNA sequencing of the coding sequence of the SF-1 and the androgen receptor (AR) genes was performed. RESULTS: Both 46,XY children had ambiguous genitalia with no Mullerian structures and no adrenal insufficiency. The older child showed normal elevation of T (up to 7.6 nmol/liter, 2.2 ng/ml), AMH (504 pmol/liter, 70.6 ng/ml), inhibin B (245 pg/ml), FSH, and LH during the first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome. The AR sequence was, however, normal. In the second child, T, AMH, and inhibin B were low, suggesting gonadal dysgenesis. In both children and their mother, a c.536delC frameshift mutation in the SF-1 gene was found. This mutation terminates translation at position 295, removing the ligand-binding domain and the activation function 2 (AF-2) domain, a critical domain for SF-1 transactivating activity. CONCLUSIONS: The usual markers of testis dysgenesis may be normal in 46,XY individuals with SF-1 mutation. Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene.     

Severe subfertility in mice with androgen receptor inactivation in sex accessory organs but not in testis

Androgen action on sex accessory organs influences rodent fertility, but the mechanisms remain unclear and investigation is difficult without the ability to restrict androgen action in specific tissues. We used Cre-LoxP technology to generate male mice with prostate epithelial-specific androgen receptor deficiency (denoted PEARKO). In addition to prostate, these males have reduced androgen action due to tissue-selective androgen receptor inactivation in seminal vesicle, epididymis, and vas deferens, whereas the testis is unaffected. We find that fertility of PEARKO males was severely reduced, compared with littermates with prominent defects in copulatory plug formation, which were smaller, softer, and more friable than controls. Despite normal testis sperm production, sperm numbers were reduced in caput but increased in cauda epididymis, suggesting alterations in sperm epididymal transit kinetics associated with increased rate of spontaneous acrosome reaction and abnormal flagellar morphology in PEARKO cauda epididymal sperm. Whereas the quantitative in vitro fertilizing ability of PEARKO epididymal sperm was normal, fewer fertilized oocytes were flushed from the oviducts of females after natural mating with PEARKO males. These data show that sperm formed in mice with impaired androgen action restricted to accessory glands and epididymis are quantitatively normal in number and in vitro fertilizing function but that severe in vivo subfertility reflects other functions related to sperm transport and survival in female reproductive tract that determine fertility in vivo.     

Hypogonadotropic hypogonadism in nephrotic rats: increased sensitivity to negative feedback effects of testosterone

Pituitary-testicular function was examined in adult male rats with aminonucleoside-induced nephrotic syndrome as a model for similar disease in humans. Nephrotic rats developed androgen deficiency, as manifested by decreased prostate and seminal vesicle weights, lower serum total and free testosterone levels, and reduced testosterone release from testes incubated in vitro. Despite hypoandrogenism, the weight and histologic appearance of the testes (light microscopy) were not affected in nephrotic rats. This androgen deficiency seemed to be a consequence of decreased gonadotropin output rather than primary testicular failure, since both pituitary gonadotropin content and serum gonadotropin levels (basally and after luteinizing hormone releasing factor; LHRH) were reduced in nephrotic rats. In addition, the percentage increase in testosterone release by testes incubated in vitro after addition of exogenous gonadotropin was similar in nephrotic and control groups. However, gonadotropin output in nephrotic rats was not impaired in the absence of testis, since no reduction was seen in either post-castration serum gonadotropin levels in vivo or gonadotropin release from pituitaries incubated in vitro. This presumed inhibitory effect of the testis on gonadotropin output in nephrotic rats was confirmed directly by demonstrating an increased sensitivity to testosterone-mediated suppression of gonadotropins in castrate animals in vivo. The presence or absence of albumin also seemed to modulate the suppressive effect of testosterone on gonadotropin output from normal pituitaries incubated in vitro. We conclude that nephrotic male rats develop hypogonadotropic hypogonadism secondary to an increase in sensitivity of the pituitary to the negative feedback effects of testosterone.     

Sex determination: a 'window' of DAX1 activity.

Traditionally, DAX1 was considered an 'anti-testis' gene because DAX1 duplications in XY individuals cause male-to-female sex reversal: dosage-sensitive sex reversal (DSS). In DSS, two active DAX1 genes on one X chromosome can abrogate testis formation. By contrast, mutations and deletions of DAX1 cause adrenal hypoplasia congenita (AHC). Although AHC patients develop testes, gonadal defects include disorganized testis cords and hypogonadotropic hypogonadism, which is not completely restored with gonadotropin or androgen therapy. Recent evidence of XY sex reversal in Dax1-deficient mice strongly supports a role for Dax1 as a 'pro-testis' gene. Therefore, perhaps DAX1/Dax1 acts within a 'window' of activity, outside of which testis formation does not occur. Here, we discuss the function and possible mechanisms of DAX1 action in male gonadogenesis.     

Complete androgen insensitivity Pathophysiology, diagnosis, and management.

The syndrome of complete androgen insensitivity is an X-linked inherited disorder resulting in marked inhibition of androgen action. The following case illustrates a subject with complete androgen insensitivity who, despite being a genetic and gonadal male, presents as a phenotypic female with primary amenorrhea, normal breast development, and lack of axillary and pubic hair. The diagnosis, pathophysiology, and management of the condition are discussed, as well as recently identified abnormalities in the androgen-receptor gene. The partial forms of androgen insensitivity are also included in the discussion.