Impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology: functional assessment.

Laboratory mice are used to identify causes of urinary dysfunction including prostate-related mechanisms of lower urinary tract symptoms. Effective use of mice for this purpose requires a clear understanding of molecular, cellular, anatomic, and endocrine contributions to voiding function. Whether the prostate influences baseline voiding function has not been specifically evaluated, in part because most methods that alter prostate mass also change circulating testosterone concentrations. We performed void spot assay and cystometry to establish a multiparameter "baseline" of voiding function in intact male and female 9-wk-old (adult) C57BL/6J mice. We then compared voiding function in intact male mice to that of castrated male mice, male (and female) mice treated with the steroid 5α-reductase inhibitor finasteride, or male mice harboring alleles (Pbsn4cre/+; R26RDta/+) that significantly reduce prostate lobe mass by depleting prostatic luminal epithelial cells. We evaluated aging-related changes in male urinary voiding. We also treated intact male, castrate male, and female mice with exogenous testosterone to determine the influence of androgen on voiding function. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed voiding function from baseline but in a nonuniform manner. Castration feminized some aspects of male urinary physiology (making them more like intact female mice) while exogenous testosterone masculinized some aspects of female urinary physiology (making them more like intact male mice). Our results provide evidence that circulating testosterone is responsible in part for baseline sex differences in C57BL/6J mouse voiding function while prostate lobe mass in young, healthy adult mice has a lesser influence.

Summary of the development the US Environmental Protection Agency's Medaka Extended One Generation Reproduction Test (MEOGRT) using data from 9 multigenerational medaka tests.

In response to various legislative mandates, the US Environmental Protection Agency (USEPA) formed its Endocrine Disruptor Screening Program (EDSP), which in turn, formed the basis of a tiered testing strategy to determine the potential of pesticides, commercial chemicals, and environmental contaminants to disrupt the endocrine system. The first tier of tests is intended to detect the potential for endocrine disruption mediated through estrogen, androgen, or thyroid pathways, whereas the second tier is intended to further characterize the effects on these pathways and to establish a dose-response relationship for adverse effects. One of these tier 2 tests, the Medaka Extended One Generation Reproduction Test (MEOGRT), was developed by the USEPA for the EDSP and, in collaboration with the Japanese Ministry of the Environment, for the Guidelines for the Testing of Chemicals of the Organisation for Economic Co-operation and Development (OECD). The MEOGRT protocol was iteratively modified based on knowledge gained after the successful completion of 9 tests with variations in test protocols. The present study describes both the final MEOGRT protocol that has been published by the USEPA and the OECD, and the iterations that provided valuable insights into nuances of the protocol. The various tests include exposure to 17ß-estradiol, 4-t-octylphenol, o,p'- dichlorodiphenyltrichloroethane, 4-chloro-3-methylphenol, tamoxifen, 17ß-trenbolone, vinclozolin, and prochloraz. Environ Toxicol Chem 2017;36:3387-3403. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Status-Relevant Experiences and Conspicuous Consumption - the Moderating Role of Prenatal Androgen Exposure.

In this paper we study consumers' interest in acquiring and displaying expensive luxury products. Based on recent insights in consumer psychology, which build on developments in evolutionary biology, we consider luxury products as "costly signals": wasteful and costly goods, whose purpose is to communicate one's biological fitness, and social status, to others. In line with previous research, we show that experiences that trigger mate attraction goals (Study 1: Exposure to others in bathing outfit) or status display goals (Study 2: Experiencing a vicarious victory of one's favorite sports team) can increase people's interest in luxury products. However, we demonstrate that some individuals are predictably more responsive to those experiences than others. We used a physiological measure (the proportion of the length of the index finger and ring finger of the right hand, 2D:4D) as a proxy for individual differences in exposure to prenatal androgens (i.e., testosterone). This measure has been related to dominant and competitive behavior later in life. We predict and find that individuals with a low 2D:4D (i.e., high exposure to prenatal androgens) were more responsive to the status-relevant experiences: they became more interested in luxury goods after these experiences. This was not the case for high 2D:4D individuals.

Increased Cross-Gender Identification Independent of Gender Role Behavior in Girls with Congenital Adrenal Hyperplasia: Results from a Standardized Assessment of 4- to 11-Year-Old Children.

While reports showing a link between prenatal androgen exposure and human gender role behavior are consistent and the effects are robust, associations to gender identity or cross-gender identification are less clear. The aim of the current study was to investigate potential cross-gender identification in girls exposed prenatally to high concentrations of androgens due to classical congenital adrenal hyperplasia (CAH). Assessment included two standardized measures and a short parent interview assessing frequency of behavioral features of cross-gender identification as conceptualized in Part A of the diagnostic criteria for gender identity disorder (GID) in the DSM-IV-TR. Next, because existing measures may have conflated gender role behavior with gender identity and because the distinction is potentially informative, we factor analyzed items from the measures which included both gender identity and gender role items to establish the independence of the two constructs. Participants were 43 girls and 38 boys with CAH and 41 unaffected female and 31 unaffected male relatives, aged 4- to 11-years. Girls with CAH had more cross-gender responses than female controls on all three measures of cross-gender identification as well as on a composite measure of gender identity independent of gender role behavior. Furthermore, parent report indicated that 5/39 (12.8 %) of the girls with CAH exhibited cross-gender behavior in all five behavioral domains which comprise the cross-gender identification component of GID compared to 0/105 (0.0 %) of the children in the other three groups combined. These data suggest that girls exposed to high concentrations of androgens prenatally are more likely to show cross-gender identification than girls without CAH or boys with and without CAH. Our findings suggest that prenatal androgen exposure could play a role in gender identity development in healthy children, and may be relevant to gender assignment in cases of prenatal hormone disruption, including, in particular, cases of severely virilized 46, XX CAH.

Androgen changes and flexible rutting behaviour in male giraffes.

The social organization of giraffes (Giraffa camelopardalis) imposes a high-cost reproductive strategy on bulls, which adopt a 'roving male' tactic. Our observations on wild giraffes confirm that bulls indeed have unsynchronized rut-like periods, not unlike another tropical megaherbivore, the elephant, but on a much shorter timescale. We found profound changes in male sexual and social activities at the scale of about two weeks. This so far undescribed rutting behaviour is closely correlated with changes in androgen concentrations and appears to be driven by them. The short time scale of the changes in sexual and social activity may explain why dominance and reproductive status in male giraffe in the field seem to be unstable.

Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society.

BACKGROUND: Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age. METHODS: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism. RESULTS: The prevalence of hirsutism is ~10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention. CONCLUSIONS: Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism but also the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutism is, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint.

Second-to-fourth digit ratio predicts success among high-frequency financial traders.

Prenatal androgens have important organizing effects on brain development and future behavior. The second-to-fourth digit length ratio (2D:4D) has been proposed as a marker of these prenatal androgen effects, a relatively longer fourth finger indicating higher prenatal androgen exposure. 2D:4D has been shown to predict success in highly competitive sports. Yet, little is known about the effects of prenatal androgens on an economically influential class of competitive risk taking-trading in the financial world. Here, we report the findings of a study conducted in the City of London in which we sampled 2D:4D from a group of male traders engaged in what is variously called "noise" or "high-frequency" trading. We found that 2D:4D predicted the traders' long-term profitability as well as the number of years they remained in the business. 2D:4D also predicted the sensitivity of their profitability to increases both in circulating testosterone and in market volatility. Our results suggest that prenatal androgens increase risk preferences and promote more rapid visuomotor scanning and physical reflexes. The success and longevity of traders exposed to high levels of prenatal androgens further suggests that financial markets may select for biological traits rather than rational expectations.

[Anaesthesia for patients with adrenal gland diseases]. / Anästhesie bei Erkrankungen der Nebennierenrinde--Effizientes Risikomanagement von der Prämedikation bis zum Aufwachraum.

Perioperative management of patients with adrenal gland diseases requires detailed information on the individual endocrine status and the potential complications. Typical signs of primary hyperaldosteronism (Conn's syndrome) comprise arterial hypertension, hypokalaemia and metabolic alkalosis. In such cases preoperative treatment with spironolactone is highly recommended. In patients with hypercortisolism (Cushing's syndrome) the following concomitant disorders must be considered particularly: arterial hypertension, osteoporosis, vulnerable skin, diabetes mellitus, and increased risk for infection and thromboembolism. In all patients with proven or suspected adrenocortical insufficiency (i.e. Addison's disease, after removal of a cortisol producing tumour or as the result of long-term therapy with glucocorticoids) consequent perioperative supplementation of hydrocortisone is mandatory. In patients with phaeochromcytoma hypertensive crisis and tachyarrhythmias may occur intraoperatively resulting from massive catecholamine release. Thus, preoperative treatment with the beta-antagonist phenoxybenzamine is obligatory. In contrast, nitroprusside is the substance of choice for intraoperative control of blood pressure. beta-blocking agents may be used in phaeochromocytoma but only under sufficient beta-blockade. Removal of a malignant tumour of the adrenal gland may induce massive haemorrhage, and thus anaesthetic management has to be modified.

Regulating of growth hormone sensitivity by sex steroids: implications for therapy.

Growth hormone (GH) is an important regulator of body composition, reducing body fat by stimulating fat oxidation and enhancing lean body mass by stimulating protein accretion. The emergence of differences in body composition between the sexes during puberty suggests sex steroids modulate the action of GH. Work from our laboratory have investigated the influence of estrogens and androgens on the metabolic actions of GH in human adults. The liver is an important site of physiological interaction as it is a sex steroid responsive organ and a major target of GH action. Estrogen, when administered orally impairs the GH-regulated endocrine and metabolic function of the liver via a first-pass effect. It reduces circulating IGF-I, fat oxidation and protein synthesis, contributing to a loss of lean and a gain of fat mass. These effects occur in normal and in GH-deficient women and are avoided by transdermal administration of physiological doses of estrogen. In contrast, studies in hypopituitary men indicate that testosterone enhances the metabolic effects of GH. Testosterone alone stimulates fat oxidation and protein synthesis, both of which are enhanced by GH. Studies in GH deficiency adults have consistently reported women to be less sensitive to GH than men. In summary, estrogens and androgens exert divergent effects on the action of GH. The results provide an explanation for sexual dimorphism in body composition in adults and the gender-related response to GH replacement in hypopituitary subjects. In the management of hypopituitarism, estrogens should be administered by the parenteral route in women and testosterone be replaced in men to optimize the benefits of GH replacement.

Androgen insufficiency in women.

Androgens are directly secreted by the ovaries and adrenals in women, and androgen precursors from these glands are converted in a variety of peripheral tissues into androgens. The major androgen in women is testosterone, and its action in target tissues can be mediated through the androgen receptor or through the estrogen receptor after aromatization to estradiol. Low sexual desire that causes personal distress (or hypoactive sexual desire disorder [HSDD]) is the most common form of female sexual dysfunction, and androgen insufficiency is one cause of this problem. In addition to a low libido, the clinical construct of the female androgen insufficiency syndrome includes the presence of persistent, unexplained fatigue and a decreased sense of well-being. Although there is conflicting information about the relationship between serum testosterone concentrations and sexual desire, multiple randomized, double-blind, placebo-controlled treatment trials have demonstrated that testosterone improves libido significantly more than placebo. Doses that provide physiologic to slightly supraphysiologic serum free or bioavailable testosterone concentrations are safe and associated with only mild androgenic side effects of acne and hirsutism. Oral, but not parenteral or transdermal, testosterone may decrease high-density lipoprotein cholesterol. At present, no testosterone preparation has been approved by the FDA for the treatment of low sexual desire (HSDD), so all such therapy is considered to be off-label use at this time.

New strategies for the medical treatment of prostate cancer.

Androgen is a major growth factor in the normal prostate and determines the overall number of prostate cells. Metastatic prostate cancer, while initially responsive to androgen ablation, eventually becomes hormone-refractory and resistant to many treatments. Unfortunately, there are very few agents in the preclinical stage with a seemingly promising future for hormone-refractory prostate cancer (HRPC) that are actually taken through the complete drug development process, including US Food and Drug Administration approval. Many novel strategies under investigation for treating HRPC target metastatic prostate cancer cells that are neither androgen-dependent nor in the proliferative state. Examples of therapies that target this so-called "Achilles' heel" of HRPC include immune therapy, gene therapy, angiogenesis inhibition, and activation of programmed cell death. Unique properties of HRPC allow for the development of novel treatments that target prostate-specific antigen (PSA), human glandular kallikrein-2, or prostate-specific membrane antigen. An inactive prodrug with a thapsigargin analogue, a sesquiterpene lactone from the plant Thapsia garganica, is currently under investigation specifically for the targeted therapy of HRPC. Preclinical data suggest the PSA-targeting abilities of this novel therapy are associated with a nearly complete cessation of tumour growth with minimal toxicity.

Sexual differentiation in three unconventional mammals: spotted hyenas, elephants and tammar wallabies.

The present review explores sexual differentiation in three non-conventional species: the spotted hyena, the elephant and the tammar wallaby, selected because of the natural challenges they present for contemporary understanding of sexual differentiation. According to the prevailing view of mammalian sexual differentiation, originally proposed by Alfred Jost, secretion of androgen and anti-Mullerian hormone (AMH) by the fetal testes during critical stages of development accounts for the full range of sexually dimorphic urogenital traits observed at birth. Jost's concept was subsequently expanded to encompass sexual differentiation of the brain and behavior. Although the central focus of this review involves urogenital development, we assume that the novel mechanisms described in this article have potentially significant implications for sexual differentiation of brain and behavior, a transposition with precedent in the history of this field. Contrary to the "specific" requirements of Jost's formulation, female spotted hyenas and elephants initially develop male-type external genitalia prior to gonadal differentiation. In addition, the administration of anti-androgens to pregnant female spotted hyenas does not prevent the formation of a scrotum, pseudoscrotum, penis or penile clitoris in the offspring of treated females, although it is not yet clear whether the creation of masculine genitalia involves other steroids or whether there is a genetic mechanism bypassing a hormonal mediator. Wallabies, where sexual differentiation occurs in the pouch after birth, provide the most conclusive evidence for direct genetic control of sexual dimorphism, with the scrotum developing only in males and the pouch and mammary glands only in females, before differentiation of the gonads. The development of the pouch and mammary gland in females and the scrotum in males is controlled by genes on the X chromosome. In keeping with the "expanded" version of Jost's formulation, secretion of androgens by the fetal testes provides the best current account of a broad array of sex differences in reproductive morphology and endocrinology of the spotted hyena, and androgens are essential for development of the prostate and penis of the wallaby. But the essential circulating androgen in the male wallaby is 5alpha androstanediol, locally converted in target tissues to DHT, while in the pregnant female hyena, androstenedione, secreted by the maternal ovary, is converted by the placenta to testosterone (and estradiol) and transferred to the developing fetus. Testicular testosterone certainly seems to be responsible for the behavioral phenomenon of musth in male elephants. Both spotted hyenas and elephants display matrilineal social organization, and, in both species, female genital morphology requires feminine cooperation for successful copulation. We conclude that not all aspects of sexual differentiation have been delegated to testicular hormones in these mammals. In addition, we suggest that research on urogenital development in these non-traditional species directs attention to processes that may well be operating during the sexual differentiation of morphology and behavior in more common laboratory mammals, albeit in less dramatic fashion.

Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating.

Among all extant mammals, only the female spotted hyena (Crocuta crocuta) mates and gives birth through the tip of a peniform clitoris. Clitoral morphology is modulated by foetal exposure to endogenous, maternal androgens. First births through this organ are prolonged and remarkably difficult, often causing death in neonates. Additionally, mating poses a mechanical challenge for males, as they must reach an anterior position on the female's abdomen and then achieve entry at the site of the retracted clitoris. Here, we report that interfering with the actions of androgens prenatally permanently modifies hyena urogenital anatomy, facilitating subsequent parturition in nulliparous females who, thereby, produce live cubs. By contrast, comparable, permanent anatomical changes in males probably preclude reproduction, as exposure to prenatal anti-androgens produces a penis that is too short and has the wrong shape necessary for insertion during copulation. These data demonstrate that the reproductive costs of clitoral delivery result from exposure of the female foetus to naturally circulating androgens. Moreover, the same androgens that render an extremely unusual and laborious process even more reproductively costly in the female are apparently essential to the male's physical ability to reproduce with a normally masculinized female.

Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man.

The effects on reproductive tract development in male rats, of neonatal exposure to potent (reference) oestrogens, diethylstilboestrol (DES) and ethinyl oestradiol (EE), with those of two environmental oestrogens, octylphenol and hisphenol A were systematically compared. Other treatments, such as administration of a gonadotrophin-releasing hormone antagonist (GnRHa) or the anti-oestrogen tamoxifen or the anti-androgen flutamide, were used to aid interpretation of the pathways involved. All treatments were administered in the neonatal period before onset of puberty. The cellular sites of expression of androgen receptors (AR) and of oestrogen receptor-alpha (ERalpha) and ERbeta were also established throughout development of the reproductive system. The main findings were as follows: (i) all cell types that express AR also express one or both ERs at all stages of development; (ii) Sertoli cell expression of ERbeta occurs considerably earlier in development than does expression of AR; (iii) most germ cells, including fetal gonocytes, express ERbeta but not AR; (iv) treatment with high, but not low, doses of potent oestrogens such as DES and EE, induces widespread structural and cellular abnormalities of the testis and reproductive tract before puberty; (v) the latter changes are associated with loss of immunoexpression of AR in all affected tissues and a reduction in Leydig cell volume per testis; (vi) none of the effects in (iv) and (v) can be duplicated by treating with high-dose octylphenol or bisphenol A; (vi) none of the reproductive tract changes in (iv) and (v) can be induced by simply suppressing androgen production (GnRHa treatment) or action (flutamide treatment); and (vii) the adverse changes induced by high-dose DES (iv and v) can be largely prevented by co-administration of testosterone. Thus, it is suggested that many of the adverse changes to the testis and reproductive tract induced by exposure to oestrogens result from a combination of high oestrogen and low androgen action. High oestrogen action or low androgen action on their own are unable to induce the same changes.

[Cryptorchism--assessment from an andrologic viewpoint]. / Kryptorchismus--eine Betrachtung aus andrologischer Sicht.

This report deals with the pathology, diagnosis and therapy of cryptorchidism from the andrological point of view. Hypothalamic-pituitary gonadal failure and a reduced transformation of gonocytes are the key factors in fertility disorders. The aim of all well-timed therapy must be to improve the fertility potential of the sexually mature male. At present, the determination through biopsy of the fertility index during orchiopexy offers the only possibility of prospective diagnosis in this respect. In the future, it will be necessary to have a standardized procedure in order to guarantee the long-term effect of correctly timed orchiopexy on fertility.

Androgens and sexuality.

A review of the literature reveals that the endocrine determinants of female sexuality are complex and difficult to characterize. In adolescent males, free testosterone directly affects sexual motivation, with social factors exerting little or no effect. In adolescent girls, by contrast, societal and peer pressure play a pivotal role in the appearance of certain sexual behaviors. Throughout a woman's life, hormonal and psychosocial factors are critical influences. It is possible that cyclic patterns of testosterone are less important for female sexual behavior than the "tonic" effect of overall testosterone levels. Although the estrogen dependence of the vaginal epithelium--important for postmenopausal women--has been clearly established, the role of other hormonal factors and treatments, particularly those involving androgens, in human female sexual behavior remains enigmatic. The search for an understanding of these relationships is not merely an interesting academic exercise but is necessary to determine what role, if any, androgens may play in the treatment of sexual dysfunction during the female reproductive years.

PIP: The strong association between testosterone, pubertal development, and libido observed in adolescent males does not appear in females. Rather, the sexuality of adolescent females seems to be affected to a larger extent by peer group interactions and psychosocial issues. Controlled studies of the effects of androgen administration as well as correlation studies focusing on circulating levels of androgens and female sexual behavior have produced divergent findings and are limited by a failure to measure biologically active testosterone. Generally, pooled data indicate that female sexual interest is highest shortly after, shortly before, or during menstruation. Other studies suggest that cyclic patterns of testosterone are less relevant to female sexuality than the "tonic" effect of overall testosterone levels. Oral contraceptive users have substantially lower levels of free testosterone than nonusers, yet there is no evidence that this change is linked with reduced sexual interest or activity. It is important that future research in this area take into account the confounding effects of psychosocial factors.