Sex Steroid Signaling Research Articles

Role of Endocytosis in Cellular Uptake of Sex Steroids

Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.

Dynamic profiling of estrogen receptor and epidermal growth factor signaling in the uteri of genistein- and estrogen-treated rats

The pharmacokinetics and time course actions of the soy isoflavone, genistein, and estradiol benzoate (EB) on sex steroid and growth factor signaling were compared in the rat uterus. Following one s.c. injection of 500 mg genistein/kg BW or 500 μg EB/kg BW, AUC for genistein was 20171.8 ng h/ml and was 15.7 ng h/ml for estradiol-17-β. Estrogen receptor-α (ER-α) decreased within 2 h of genistein or EB treatment, returning to basal levels within 24 and 48 h, respectively. In response to genistein and EB, progesterone receptors (PRs) A and B increased between 16 and 24 h, with a significant increase at 24 and 48 h. Epidermal growth factor receptor (EGFR) expression peaked 16 h after genistein or EB treatment, inversely correlating with extracellular regulating kinase (ERK) phosphorylation. These effects were inhibited by antiestrogen pretreatment, demonstrating a requirement for ER. At 16 h, uterine weight, epithelial cell height, and cell proliferation increased. While EGFR levels increased, phosphorylated EGFR was not altered. Reduced phosphorylation of downstream kinases corresponded with decreased stromal phosphorylated-ERK (P-ERK) immunolabeling, suggesting signal attenuation. Dynamic profiling of sex steroid receptors and EGF signaling molecules suggest a similar mechanism of action for genistein and EB in the uterus, albeit at approximately 1000-fold concentration.

Alzheimer?s disease: the impact of age-related changes in reproductive hormones

Receptors for hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function are expressed throughout the brain, and in particular the limbic system. The most studied of these hormones, the sex steroids, contain receptors throughout the brain, and numerous estrogenic, progestrogenic and androgenic effects have been reported in the brain related to development, maintenance and cognitive functions. Although less studied, receptors for gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and activins also are found throughout the limbic system on a number of cell types, and they too transduce signals from circulating hormones as demonstrated by their multiple effects on the growth, development, maintenance and function of the brain. This review highlights the point that because of the feedback loops within the HPG axis, it is difficult to ascribe structural and functional changes during development, adulthood and senescence to a single HPG hormone, since a change in the concentration of any hormone in the axis will modulate hormone concentrations and/or receptor expression patterns for all other members of the axis. The most studied of these situations is the change in serum and neuronal concentrations of HPG hormones associated with menopause/andropause. Dysregulation of the HPG axis at this time results in increases in the concentrations of serum GnRH, gonadotropins and activins, decreases in the serum concentrations of sex steroid and inhibin, and increases in GnRH and LH receptor expression. Such changes would result in significantly altered neuronal signaling, with the final result being that there is i.e. increased neuronal GnRH, LH and activin signaling, but decreased sex steroid signaling. Therefore, loss of cognitive function during senescence, typically ascribed to sex steroids, may also result from increased signaling via GnRH, LH or activin receptors. Future studies will be required to differentiate which hormones of the HPG axis regulate/maintain cognitive function. This introductory review highlights the importance of the identification of HPG hormone neuronal receptors and the potential of serum HPG hormones to transduce signals to regulate brain structure and function during development and adult life.

Dysregulation of the Hypothalamic-Pituitary-Gonadal Axis with Menopause and Andropause Promotes Neurodegenerative Senescence

Senescence is characterized neurologically by a decline in cognitive function, which we propose is the result of degenerative processes initiated by the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis with menopause and andropause. Compelling epidemiologic evidence to support this assertion includes the increased prevalence of Alzheimer disease (AD) in women, the correlation of serum HPG hormones with disease and the decreased incidence, and delay in the onset of AD following hormone replacement therapy. Dysregulation of the axis at this time leads to alterations in the concentrations of all serum HPG hormones (decreased neuronal sex steroid signaling, but increased neuronal gonadotropin releasing hormone, luteinizing hormone, and activin signaling). Hormones of the HPG axis, receptors for which are present in the adult brain, are important regulators of cell proliferation and differentiation during growth and development. Based on this, we propose that dysregulated HPG hormone signaling with menopause/andropause leads to the abortive reentry of differentiated neurons into the cell cycle via a process we term "dyosis." Interestingly, the major biochemical and neuropathologic changes reported for the AD brain also are intimately associated with neuron division: altered AbetaPP metabolism, Abeta deposition, tau phosphorylation, mitochondrial alterations, chromosomal replication, synapse loss, and death of differentiated neurons. Recent evidence supports the premise that AD-related biochemical changes are likely the combined result of increased mitotic signaling by gonadotropins and GnRH, decreased differentiative and neuroprotective signaling via sex steroids, and increased differentiative signaling via activins. This results in a hormonal milieu that is permissive of cell cycle reentry but does not allow completion of metaphase. Partial resetting of the axis following administration of normal endogenous sex steroids delays the onset and decreases the incidence of AD. Ideally, supplementation with HPG hormones should mimic closely the serum concentrations of all HPG hormones in reproductive men and cycling women to prevent dyotic signaling and attempted neuron division.

Alzheimer?s disease: the impact of age-related changes in reproductive hormones

Receptors for hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function are expressed throughout the brain, and in particular the limbic system. The most studied of these hormones, the sex steroids, contain receptors throughout the brain, and numerous estrogenic, progestrogenic and androgenic effects have been reported in the brain related to development, maintenance and cognitive functions. Although less studied, receptors for gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and activins also are found throughout the limbic system on a number of cell types, and they too transduce signals from circulating hormones as demonstrated by their multiple effects on the growth, development, maintenance and function of the brain. This review highlights the point that because of the feedback loops within the HPG axis, it is difficult to ascribe structural and functional changes during development, adulthood and senescence to a single HPG hormone, since a change in the concentration of any hormone in the axis will modulate hormone concentrations and/or receptor expression patterns for all other members of the axis. The most studied of these situations is the change in serum and neuronal concentrations of HPG hormones associated with menopause/andropause. Dysregulation of the HPG axis at this time results in increases in the concentrations of serum GnRH, gonadotropins and activins, decreases in the serum concentrations of sex steroid and inhibin, and increases in GnRH and LH receptor expression. Such changes would result in significantly altered neuronal signaling, with the final result being that there is i.e. increased neuronal GnRH, LH and activin signaling, but decreased sex steroid signaling. Therefore, loss of cognitive function during senescence, typically ascribed to sex steroids, may also result from increased signaling via GnRH, LH or activin receptors. Future studies will be required to differentiate which hormones of the HPG axis regulate/maintain cognitive function. This introductory review highlights the importance of the identification of HPG hormone neuronal receptors and the potential of serum HPG hormones to transduce signals to regulate brain structure and function during development and adult life.

The Gonadotropin Connection in Alzheimer's Disease

Although not traditionally thought of as regulators of neuronal function, the hypothalamic-pituitary-gonadal (HPG) hormones luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and activins possess neuronal receptors. These receptors are found throughout the limbic system on a number of different cell types, and, like reproductive tissues, the expression of these receptors is regulated by hormonal feedback loops. These hormones and their receptors regulate structure and a diverse range of functions in the brain. Therefore, it is not surprising that the dysregulation of the HPG axis with menopause and andropause (leading to elevated LH, GnRH, and activin signaling but decreased sex steroid signaling) might promote alterations in both the structure and function of neuronal cells. To date, most evidence has accumulated for a role of LH in promoting neurodegenerative changes. LH is known to cross the blood-brain barrier, receptors for LH are most concentrated in the hippocampus, that region of the brain most vulnerable to Alzheimer's disease (AD) and LH is significantly elevated in both the serum and the pyramidal neurons of AD subjects. LH promotes the amyloidogenic processing of the amyloid-beta precursor protein in vitro, and the antigonadotropin leuprolide acetate decreases amyloid generation in mice. Moreover, leuprolide acetate improves the cognitive performance and decreases amyloid-beta deposition in aged transgenic mice carrying the Swedish AbetaPP mutation. Therefore, the elevation of LH with the dysregulation of the HPG axis at menopause and andropause is a physiologically relevant signal that could promote neurodegeneration. Epidemiological support for a role of LH/GnRH in AD is evidenced by a reduction in neurodegenerative disease among prostate cancer patients a group known to GnRH agonists. Clinical trials are underway for the treatment of AD using GnRH analogs and should provide further insights into the gonadotropin connection in AD.

The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer

The purpose of this review is to discuss the epidemiologic literature on the association of sex steroid hormones and components of their signaling and metabolic pathways with prostate cancer and to describe data evaluating racial variation in sex steroid hormone pathways as a possible explanation for the notably higher risk of prostate cancer in African-American men compared to white or Asian men. Although sex steroid hormones likely contribute to the growth and progression of prostate cancer, associations between hormones and prostate cancer risk across the range of normal levels have been difficult to reliably demonstrate epidemiologically. Methodologic issues no doubt have made the detection of these associations difficult. Of particular importance are (1) the inadequacy of measuring circulating hormones in middle age as a surrogate for the exposure in the target cells in the prostate at the relevant time in life and (2) the current inability to integrate across components of the sex steroid hormone signaling pathway to fully capture target cell androgenic and estrogenic stimulation. Although the approach of evaluating polymorphisms in genes involved in sex steroid hormone signaling or metabolism as a way to minimize some of the issues in the direct measurement of hormones is logical, the findings among these studies are somewhat difficult to reconcile as well. The problems of the changing case mix due to screening for elevated PSA, small sample sizes increasing the likelihood of false negative and false positive results, the controls and their allele frequencies not being representative of the population at risk, and lack of knowledge of the functional consequence of a polymorphism in relation to other polymorphisms in that gene or without consideration of other genes involved in the same pathway may be contributory. The primary result of the Prostate Cancer Prevention Trial confirms that intraprostatic dihydrotestosterone levels in the normal range indeed do contribute to the growth of prostate adenocarcinoma. However, the secondary result of higher-grade disease in cases in the finasteride arm coupled with clinical studies showing higher grade disease in non-metastatic cases with lower serum androgens, if not a pathological artifact or detection bias in the finasteride arm, possibly suggests a complex relationship between androgens and the growth versus differentiation of a prostate tumor. Finally, racial variation in components of the sex steroid hormone pathway do appear to exist, but whether the extent of the variation is adequately great such that it accounts for some of the substantial differences in prostate cancer incidence among blacks, whites, and Asians is unclear.

New perspectives on growth factor-sex steroid interaction in the prostate

Many organs respond to both sex steroids and growth factors. Regulation of these pathways is integral to cell–cell communications during development and aberrant changes cause disease pathogenesis. Traditionally, paracrine and endocrine actions of growth factors and steroid hormones are considered independently. Recently, new data indicated that activin/TGFβ and sex steroid signalling are linked; explicitly, that the pathways cross-talk intracellularly. Here we present new perspectives on these interactions, using examples predominantly from the prostate, as it is a well-characterised organ in this context. While this information provides insight to the potential mechanisms behind these interactions, it also presents a new challenge; the action of any of these factors cannot be considered exclusively without considering the impact on the other biological pathways.

Expression of sex steroid receptor genes and comodulation with retinoid signaling in normal human uroepithelial cells and bladder cancer cell lines

The expression of sex steroid receptor genes in human uroepithelial cells (UEC) and their role in bladder carcinogenesis is unknown. Expression of androgen receptor (hAR), estrogen receptor (hER), and vitamin d3 receptor (hVDR3) genes in normal human stromal cells (SC) and UEC, six bladder cancer cell lines, and two SV-40-immortalized cell lines (SVC) was determined by reverse transcriptase polymerase chain reaction (RT-PCR). Functionality was assessed indirectly by relative RT-PCR, which identified comodulation of mRNA expression between retinoic acid and sex steroid receptor genes. UEC and SC expressed hAR and hER mRNA constitutively at low levels, but only positive controls expressed hVDR3. Every cancer cell line and the SVC showed aberrant expression. Treatment of cells with all- trans-retinoic acid up-regulated hAR and hER expression, whereas treatment with sex steroids up-regulated retinoic acid receptor expression. Cell proliferation was not affected by sex steroids or by their inhibitors. Sex steroid signaling pathways are functional in UEC and appear to be altered during bladder tumorigenesis. The sex steroid receptors may play a role in normal differentiation.