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.     

Steroid hormones and the cardiovascular system: direct actions of estradiol, progesterone, testosterone, gluco- and mineralcorticoids, and soltriol [vitamin D] on central nervous regulatory and peripheral tissues

Knowledge of steroid hormone sites of action and related effects in cardiovascular and neural regulatory tissues is reviewed. Evidence for nuclear receptor sites is derived mainly from autoradiographic studies with relatively intact tissues and some biochemical studies with tissue homogenates. In the heart and in the walls of blood vessels, estradiol, dihydrotestosterone, corticosterone, aldosterone, dexamethasone, and soltriol (vitamin D) show nuclear binding. In the brain and spinal cord, neuronal regions associated with cardiovascular regulation contain nuclear receptors in specific patterns for each steroid hormones, including progesterone and soltriol. These data indicate that all steroid hormones exert direct actions on the cardiovascular system at its different levels of organization, thus enabling adjustment to the changing demands during reproduction (gonadal steroids), stress (adrenal steroids), and solar seasons (vitamin D-soltriol).     

Steroid hormones and the cardiovascular system: Direct actions of estradiol,progesterone, testosterone,gluco- and mineralcorticoids,and soltriol [vitamin D] on central nervous regulatory and peripheral tissues

Summary Knowledge of steroid hormone sites of action and related effects in cardiovascular and neural regulatory tissues is reviewed. Evidence for nuclear receptor sites is derived mainly from autoradiographic studies with relatively intact tissues and some biochemical studies with tissue homogenates.In the heart and in the walls of blood vessels, estradiol, dihydrotestosterone, corticosterone, aldosterone, dexamethasone, and soltriol (vitamin D) show nuclear binding. In the brain and spinal cord, neuronal regions associated with cardiovascular regulation contain nuclear receptors in specific patterns for each steroid hormones, including progesterone and soltriol. These data indicate that all steroid hormones exert direct actions on the cardiovascular system at its different levels of organization, thus enabling adjustment to the changing demands during reproduction (gonadal steroids), stress (adrenal steroids), and solar seasons (vitamin D-soltriol).     

Steroid hormones enhanced sister-chromatid exchange in cultured CHO cells

The influence of steroid hormones on the induction of sister-chromatid exchange (SCE) in cultured CHO cells was studied. It was observed that estradiol-17 beta, estriol, estrone and ethynyl estradiol treatments enhanced SCE rates compared to the controls. Overall, these compounds produced a dose response effect. The importance of a detailed study on the long-term genetic effects of steroids on mammalian cells is emphasized.     

The role of the CCN family of proteins in female reproduction

The CCN family of proteins consists of six high homologous matricellular proteins which act predominantly by binding to heparin sulphate proteoglycan and a variety of integrins. Interestingly, CCN proteins are regulated by ovarian steroid hormones and are able to adapt to changes in oxygen concentration, which is a necessary condition for successful implantation. CCN1 is involved in processes of angiogenesis within reproductive systems, thereby potentially contributing to diseases such as endometriosis and disturbed angiogenesis in the placenta and fetus. In the ovary, CCN2 is the key factor for follicular development, ovulation and corpora luteal luteolysis, and its deletion leads to fertility defects. CCN1, CCN2 and CCN3 seem to be regulators for human trophoblast proliferation and migration, but with CCN2 acting as a counterweight. Alterations in the expression of these three proteins could contribute to the shallow invasion properties observed in preeclampsia. Little is known about the role of CCN4–6 in the reproductive organs. The ability of CCN1, CCN2 and CCN3 to interact with numerous receptors enables them to adapt their biological function rapidly to the continuous remodelling of the reproductive organs and in the development of the placenta. The CCN proteins mediate their specific cell physiological function through the receptor type of their binding partner followed by a defined signalling cascade. Because of their partly overlapping expression patterns, they could act in a concert synergistically or in an opposite way within the reproductive organs. Imbalances in their expression levels are correlated to different human reproductive diseases, such as endometriosis and preeclampsia.     

Effect of testosterone on the hypothalamic-pituitary-gonadal axis of pinealectomized and pineal-intact male rats.

Previous studies indicate that steroid hormones alter pineal biochemistry, and it has been suggested that at least part of the negative feedback effect of steroid hormones on pituitary gonadotropin release may be mediated by the pineal gland. In this study, pinealectomy did not alter the inhibitory effect of testosterone on neuroendocine-gonadal activity in the male rat, suggesting that the pineal gland does not mediate the response of the rat hypothalamic-pituitary axis to testosterone.     

Digoxin and ouabain increase the synthesis of cholesterol in human liver cells

Digoxin and ouabain are steroid drugs that inhibit the Na⁺/K⁺-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells. Received 10 January 2009; received after revision 11 February 2009; accepted 6 March 2009     

Steroid hormones enhanced sister-chromatid exchange in cultured CHO cells

Summary The influence of steroid hormones on the induction of sister-chromatid exchange (SCE) in cultured CHO cells was studied. It was observed that estradiol-17 , estriol, estrone and ethynyl estradiol treatments enhanced SCE rates compared to the controls. Overall, these compounds produced a dose response effect. The importance of a detailed study on the long-term genetic effects of steroids on mammalian cells is emphasized.This work was supported by NIH-Minority Biomedical Research Support Program (MBRS), Grant No. RR 08124-11. The author is thankful for the technical assistance provided by NIH-MBRS student, Hoang Duong.     

Secificity of mouse endocervical cell response progesterone: presence of receptors]

The mouse cervical cell response to progesterone, corticosterone, and androgens was studied in vitro and comparatively by grafts on males. Contrary to the exocervical cells which responded more or less to the three steroid hormones, the endocervical cells responded exclusively to progesterone even in an estrogen free system. This result suggests the existence in the mouse endocervical cells of specific receptors to progesterone and indicates that the squamons cells of the uterine cervix have a different response to steroid hormones depending on where these cells are located.     

Effect of testosterone on the hypothalamic-pituitary-gonadal axis of pinealectomized and pineal-intact male rats

Summary Previous studies indicate that steroid hormones alter pineal biochemistry, and it has been suggested that at least part of the negative feedback effect of steroid hormones on pituitary gonadotropin release may be mediated by the pineal gland. In this study, pinealectomy did not alter the inhibitory effect of testosterone on neuroendocrine-gonadal activity in the male rat, suggesting that the pineal gland does not mediate the response of the rat hypothalamic-pituitary axis to testosterone.We wish to thank Susan H. Losee, Brigitte G. Mann and John Georgeson for excellent technical assistance. This investigation was supported by NSF grant SER 77-03836 and a grant from the University of Wisconsin-Parkside Committee on Research to E.P.W. and by NIH grant HD-09885 and NSF grant PCM 76-09955 to F.W.T.     

Regulation of B and T cell development by anterior pituitary hormones

Hormones produced by the anterior pituitary gland have been implicated in the regulation of primary lymphocyte development. In order to identify endocrine factors involved in that process, several strains of mice with genetic defects resulting in a selective impairment in the production of one or more anterior pituitary-derived hormones have been analysed. This study has resulted in the classification of endocrine hormones into the following four categories (i) hormones such as prolactin with no apparent effects on primary lymphopoiesis; (ii) anabolic hormones such as growth hormone and insulin-like growth factor-I whose stimulatory effects on primary lymphopoiesis are non-lineage-specific and related to their actions as systemic mediators of growth and/or differentiation; (iii) hormones such as thyroid hormones that have an obligate role in primary B lymphopoiesis; and (iv) hormones such as oestrogens that act as negative regulators of lymphopoiesis.     

Demonstration of high affinity binding of estradiol in adrenal cortex tissue]

Evidence is presented demonstrating the presence of a high affinity (Ka10(8)M-1), limited capacity (3-4 pmoles/mg protein) estradiol binder in the soluble fraction of the Bovine, Rat and Human adrenal cortex. The binding appears specific to the estrogen structure whereas C19 and C21 steroids do not bind. Upon sucrose density gradient centrifugation, the estradiol binder sedimented at 9 S at low ionic strength and was shifted to 4.5 S in the presence of 0.5 M KCl. This demonstration of a receptor-like moiety for estradiol in the adrenal cortex lends biochemical support to previous observations suggesting that adrenal cortex functions may be modulated by a direct effect of gonadal steroid hormones.     

Chemical properties of alcohols and their protein binding sites

Alcohols affect a wide array of biological processes including protein folding, neurotransmission and immune responses. It is becoming clear that many of these effects are mediated by direct binding to proteins such as neurotransmitter receptors and signaling molecules. This review summarizes the unique chemical properties of alcohols which contribute to their biological effects. It is concluded that alcohols act mainly as hydrogen bond donors whose binding to the polypeptide chain is stabilized by hydrophobic interactions. The electronegativity of the O atom may also play a role in stabilizing contacts with the protein. Properties of alcohol binding sites have been derived from X-ray crystal structures of alcohol-protein complexes and from mutagenesis studies of ion channels and enzymes that bind alcohols. Common amino acid sequences and structural features are shared among the protein segments that are involved in alcohol binding. The alcohol binding site is thought to consist of a hydrogen bond acceptor in a turn or loop region that is often situated at the N-terminal end of an alpha-helix. The methylene chain of the alcohol molecule appears to be accommodated by a hydrophobic groove formed by two or more structural elements, frequently a turn and an alpha-helix. Binding at these sites may alter the local protein structure or displace bound solvent molecules and perturb the function of key proteins.     

Estrogens in insects

Summary Insects representing 5 different orders contain androgen and estrogen-like substances as determined by radioimmunoassay. Estradiol and estriol have been identified by gas chromatography-mass spectrometry. The presence of these steroids in insects suggests that the vertebrate sex hormones have an ancient evolutionary history.We thank Ms Mary Ann Seifert of the Campus Chemical Instrumentation Center of The Ohio State University, Mr John Powell of the Department of Obstetrics and Gynecology, Ms Florence Kraft and Mr Charles Palmer Jr for their technical assistance.From September 1982 to August 1983, Dr Mechoulam was Distinguished Visiting Professor of the Ohio State University, supported in part by the Graduate School.     

Glucocorticoids in T cell apoptosis and function

Glucocorticoids (GCs) are a class of steroid hormones which regulate a variety of essential biological functions. The profound anti-inflammatory and immunosuppressive activity of synthetic GCs, combined with their power to induce lymphocyte apoptosis place them among the most commonly prescribed drugs worldwide. Endogenous GCs also exert a wide range of immunomodulatory activities, including the control of T cell homeostasis. Most, if not all of these effects are mediated through the glucocorticoid receptor, a member of the nuclear receptor superfamily. However, the signaling pathways and their cell type specificity remain poorly defined. In this review, we summarize our present knowledge on GC action, the mechanisms employed to induce apoptosis and the currently discussed models of how they may participate in thymocyte development. Although our knowledge in this field has substantially increased during recent years, we are still far from a comprehensive picture of the role that GCs play in T lymphocytes. Received 20 August 2005; received after revision 27 September 2005; accepted 10 October 2005     

Cholesterol homeostasis and function in neurons of the central nervous system

Cholesterol is a multifaceted molecule. First, it serves as an essential membrane component, as a cofactor for signaling molecules and as a precursor for steroid hormones; second, its synthesis, intercellular transport and intracellular distribution present a logistic tour de force requiring hundreds of cellular components, and third, it plays a crucial role in major human diseases. Despite intense research on this molecule, its metabolism in the central nervous system and its role in neuronal development and function are not well understood. Here I summarize recent results and hypotheses about how neurons maintain their cholesterol level and how cholesterol influences the establishment and maintenance of synaptic connections.     

Synthesis and metabolism of vertebrate-type steroids by tissues of insects: a critical evaluation

This review covers the synthesis and the metabolism of vertebrate-type steroids (progesterone, testosterone, estradiol, corticosteroids) by insect tissues and discusses the significance of the reactions for insect physiology. Biosynthesis of vertebrate-type steroids from cholesterol hitherto has been demonstrated in only two insect species, i.e. the water beetle Acilius sulcatus (Coleoptera) and the tobacco hornworm Manduca sexta (Lepidoptera). In Acilius, steroid synthesis is associated with exosecretion (chemical defense). Nothing, however, is known about a physiological role of the C21 steroid conjugate present in ovaries and eggs of Manduca. No synthesis of vertebrate-type steroids was observed in any other insect investigated to date. Most metabolic conversions of steroids by insects concerned oxidoreduction of oxygen groups (hydroxysteroid dehydrogenase activity) and (polar and apolar) conjugate formation. All important enzymatic steps involved in synthesis and catabolism, as known from studies with tissues of vertebrates, were not, or hardly observed. The conclusion is drawn that typical vertebrate-type (C21, C19 and C18) steroids probably do not act as physiologically active substances in insects.     

Cl<Superscript>–</Superscript> affects the function of the GABA cotransporter rGAT1 but preserves the mutal relationship between transient and transport currents

The effects of reducing external Cl- on the electrophysiological properties of the Na+/Cl(-)-dependent GABA transporter rGAT1 expressed in Xenopus oocytes were investigated. In agreement with a recently proposed kinetic scheme, the effects of Cl- are complex but preserve the mutual relationship that links the transport-associated current, I(tr), measured in saturating GABA concentration, and the transient current, I(pre), recorded in the absence of GABA following a voltage step from the holding potential Vh to V. In particular, I(tr) (V) - I(tr) (Vh) = r integral I(pre) (V) dt, where r is the relaxation rate of I(pre) at the same membrane potential and Cl- concentration. The model also predicts a relationship between charge relaxation rate and apparent affinity for GABA, which is also verified in the presence of lowered Na+ or Cl- concentrations. In these conditions, the binding rate of GABA to the transporter is increased. All these effects are consistent with the hypothesis that interaction of the organic substrate with rGAT1 induces a conversion from a capacitive to a conductive mode of operation without strongly altering either the amount or the rate of charge movement.     

Chromatographic conditions in the expression of corticosteroid receptor specificity.

It is shown that cytosol preparations bound with various concentrations of a steroid are necessary to reveal physicochemically distinct, heterogeneous and polymorphic receptors present in the hormone specific target organ, that these cannot be fully appreciated in one-shot experiments at suboptimal steroids levels, and that they escape detection by equilibrium binding and Scatchard analysis alone.