Recent Progress In Hormone Research[JOURNAL]
Sun
200 papers
Estrogen actions throughout the brain.
McEwen B
Recent Prog Horm Res · 2002 · PMID 12017552 · Publisher ↗
Besides affecting the hypothalamus and other brain areas related to reproduction, ovarian steroids have widespread effects throughout the brain, on serotonin pathways, catecholaminergic neurons, and the basal forebrain c...
Besides affecting the hypothalamus and other brain areas related to reproduction, ovarian steroids have widespread effects throughout the brain, on serotonin pathways, catecholaminergic neurons, and the basal forebrain cholinergic system as well as the hippocampal formation, a brain region involved in spatial and declarative memory. Thus, ovarian steroids have measurable effects on affective state as well as cognition, with implications for dementia. Two actions are discussed in this review; both appear to involve a combination of genomic and nongenomic actions of ovarian hormones. First, regulation of the serotonergic system appears to be linked to the presence of estrogen- and progestin-sensitive neurons in the midbrain raphe as well as possibly nongenomic actions in brain areas to which serotonin neurons project their axons. Second, ovarian hormones regulate synapse turnover in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NMDA) receptors, whereas downregulation of these synapses involves intracellular progestin receptors. A new, rapid method of radioimmunocytochemistry has made possible the demonstration of synapse formation by labeling and quantifying the specific synaptic and dendritic molecules involved. Although NMDA receptor activation is required for synapse formation, inhibitory interneurons may play a pivotal role as they express nuclear estrogen receptor-alpha (ERa). It is also likely that estrogens may locally regulate events at the sites of synaptic contact in the excitatory pyramidal neurons where the synapses form. Indeed, recent ultrastructural data reveal extranuclear ERalpha immunoreactivity within select dendritic spines on hippocampal principal cells, axons, axon terminals, and glial processes. In particular, the presence of ER in dendrites is consistent with a model for synapse formation in which filopodia from dendrites grow out to find new synaptic contacts and estrogens regulate local, post-transcriptional events via second messenger systems.
Reproductive functions of progesterone receptors.
Conneely OM, Mulac-Jericevic B, DeMayo F … +2 more , Lydon JP, O'Malley BW
Recent Prog Horm Res · 2002 · PMID 12017551 · Publisher ↗
The steroid hormone progesterone plays a central role in the reproductive events associated with pregnancy establishment and maintenance. Physiological effects of progesterone are mediated by interaction of the hormone w...
The steroid hormone progesterone plays a central role in the reproductive events associated with pregnancy establishment and maintenance. Physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed as two protein isoforms, PR-A and PR-B. Both proteins arise from the same gene and are members of the nuclear receptor superfamily of transcription factors. Since these two isoforms were identified in the early 1970s, extensive controversy has existed regarding the selective contributions of the individual PR proteins to the physiological functions of progesterone. During the past decade, significant progress has been made in this regard using two complimentary approaches. First, analysis of the structural and functional relationships of each isoform using in vitro systems has generated compelling evidence to support the conclusion that PR-A and PR-B have different transcription activation properties when liganded to progesterone. Second, the advent of gene-targeting approaches to introduce subtle mutations into the mouse genome has facilitated the evaluation of the significance of observations made in vitro in a physiological context. Selective ablation of PR-A and PR-B proteins in mice using these technologies has allowed us to address the spatiotemporal expression and contribution of the individual PR isoforms to the pleiotropic reproductive activities of progesterone. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided proof of concept that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are, indeed, reflected in an ability of the individual isoforms to elicit distinct, physiological responses to progesterone. In PR-A knockout mice, in which the expression of the PR-A isoform is selectively ablated (PRAKO), the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect responses of the mammary gland or thymus to progesterone but instead results in severe abnormalities in ovarian and uterine function, leading to female infertility. These tissue-selective activities of PR-B are due to this isoform's ability to regulate a subset of progesterone-responsive target genes in reproductive tissues rather than to differences in its spatiotemporal expression relative to the PR-A isoform. More recent studies using PR-B knockout (PRBKO) mice have shown that ablation of PR-B does not affect ovarian, uterine, or thymic responses to progesterone but rather results in reduced mammary ductal morphogenesis. Thus, PR-A is both necessary and sufficient to elicit the progesterone-dependent reproductive responses necessary for female fertility, while PR-B is required to elicit normal proliferative responses of the mammary gland to progesterone. This chapter will summarize recent progress in our understanding of the selective contribution of the two PR isoforms to progesterone action.
Aromatase and its inhibitors: significance for breast cancer therapy.
Simpson ER, Dowsett M
Recent Prog Horm Res · 2002 · PMID 12017550 · Publisher ↗
Endocrine adjuvant therapy for breast cancer in recent years has focussed primarily on the use of tamoxifen to inhibit the action of estrogen in the breast. The use of aromatase inhibitors has found much less favor due t...
Endocrine adjuvant therapy for breast cancer in recent years has focussed primarily on the use of tamoxifen to inhibit the action of estrogen in the breast. The use of aromatase inhibitors has found much less favor due to poor efficacy and unsustainable side effects. Now, however, the situation is changing rapidly with the introduction of the so-called phase III inhibitors, which display high affinity and specificity towards aromatase. These compounds have been tested in a number of clinical settings and, almost without exception, are proving to be more effective than tamoxifen. They are being approved as first-line therapy for elderly women with advanced disease. In the future, they may well be used not only to treat young, postmenopausal women with early-onset disease but also in the chemoprevention setting. However, since these compounds inhibit the catalytic activity of aromatase, in principle, they will inhibit estrogen biosynthesis in every tissue location of aromatase, leading to fears of bone loss and possibly loss of cognitive function in these younger women. The concept of tissue-specific inhibition of aromatase expression is made possible by the fact that, in postmenopausal women when the ovaries cease to produce estrogen, estrogen functions primarily as a local paracrine and intracrine factor. Furthermore, due to the unique organization of tissue-specific promoters, regulation in each tissue site of expression is controlled by a unique set of regulatory factors. These factors are potential targets for the design of selective aromatase modulators, which could selectively inhibit aromatase expression in breast with the same efficacy as the phase III inhibitors of activity but leave expression in other local sites such as bone and brain untouched.
Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators.
McDonnell DP, Connor CE, Wijayaratne A … +2 more , Chang CY, Norris JD
Recent Prog Horm Res · 2002 · PMID 12017549 · Publisher ↗
The term selective estrogen receptor modulators describes a group of pharmaceuticals that function as estrogen receptor (ER) agonists in some tissues but that oppose estrogen action in others. Although the name for this...
The term selective estrogen receptor modulators describes a group of pharmaceuticals that function as estrogen receptor (ER) agonists in some tissues but that oppose estrogen action in others. Although the name for this class of drugs has been adopted only recently, the concept is not new, as compounds exhibiting tissue-selective ER agonist/antagonist properties have been around for nearly 40 years. What is new is the idea that it may be possible to capitalize on the paradoxical activities of these drugs and develop them as target organ-selective ER agonists for the treatment of osteoporosis and other estrogenopathies. This realization has provided the impetus for research in this area, the progress of which is discussed in this review.
Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma.
Walker CL
Recent Prog Horm Res · 2002 · PMID 12017548 · Publisher ↗
Uterine leiomyomas are the most common gynecologic neoplasm in reproductive-age women. While it is clear that hormonal factors play a prominent role in this disease, how steroid hormones contribute to disease etiology or...
Uterine leiomyomas are the most common gynecologic neoplasm in reproductive-age women. While it is clear that hormonal factors play a prominent role in this disease, how steroid hormones contribute to disease etiology or may be utilized as targets for intervention are currently areas of active scientific investigation. To study the impact of hormones on uterine leiomyomas, the Eker rat has been developed as an in vivolin vitro animal model system for these tumors. Spontaneous leiomyomas arise in intact Eker rats with a high frequency and leiomyoma-derived cell lines from these animals maintain the biochemical and physiological characteristics of the tumors from which they were obtained. Using this animal model system, it has been established that tumor development is absolutely dependent on steroid hormones and that sensitivity/responsiveness to estrogen is enhanced in tumors and tumor-derived cell lines. Modulation of hormonal milieu, such as that which naturally occurs during pregnancy, can effectively inhibit tumor development. The hormone responsiveness of these tumors makes them good candidates for hormonal therapy. Selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene hold promise as potential therapeutic agents for this disease. SERMs inhibit proliferation of leiomyoma-derived cell lines in vitro, repress the growth of these lines in nude mice, and, when administered over a 2- to 4-month course of treatment to Eker rats, reduce tumor incidence by more than 50%. In addition to endogenous hormones, xenoestrogens in our environment (e.g., phytoestrogens, organochlorine pesticides, pharmacologic compounds) are of potential concern with regards to their impact on this disease. These environmental estrogens have been shown to promote the growth of leiomyoma cells in vitro and in vivo. Further elucidation of the role of these and other hormonal and reproductive factors in the development of uterine leiomyoma will be invaluable for increasing our understanding of the etiology of this disease and developing new therapeutic strategies to help to reduce the negative impact of uterine leiomyomas on women's health.
Hormonal changes in the menopause transition.
Burger HG, Dudley EC, Robertson DM … +1 more , Dennerstein L
Recent Prog Horm Res · 2002 · PMID 12017547 · Publisher ↗
The menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is heralded by the menopausal transition, a period when the endocrine, biological, and clinical features...
The menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is heralded by the menopausal transition, a period when the endocrine, biological, and clinical features of approaching menopause begin. A common initial marker is the onset of menstrual irregularity. The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the ovary, the most striking of which is a profound decline in follicle numbers. Follicle-stimulating hormone (FSH) is an established indirect marker of follicular activity. In studies of groups of women, its concentration, particularly in the early follicular phase of the menstrual cycle, begins to increase some years before there are any clinical indications of approaching menopause. The rise in FSH is the result of declining levels of inhibin B (INH-B), a dimeric protein that reflects the fall in ovarian follicle numbers, with or without any change in the ability of the lining granulosa cells to secrete INH-B. Estradiol levels remain relatively unchanged or tend to rise with age until the onset of the transition and are usually well preserved until the late perimenopause, presumably in response to the elevated FSH levels. During the transition, hormone levels frequently vary markedly - hence, measures of FSH and estradiol are unreliable guides to menopausal status. Concentrations of testosterone have been reported to fall by about 50% during reproductive life, between the ages of 20 and 40. They change little during the transition and, after menopause, may even rise. Dehydroepiandrosterone (DHEA) and DHEAS, its sulphate, on the other hand, decline with age, without any specific influence of the menopause. Symptoms of the menopause can be interpreted as resulting primarily from the profound fall in estradiol, occurring over a 3- to 4-year period around final menses, a fall that presumably contributes importantly to the beginning, in the late perimenopause, of loss of bone mineral density.
Neuroendocrine modulation and repercussions of female reproductive aging.
Wise PM, Smith MJ, Dubal DB … +5 more , Wilson ME, Rau SW, Cashion AB, Böttner M, Rosewell KL
Recent Prog Horm Res · 2002 · PMID 12017546 · Publisher ↗
The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormo...
The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women. Recently, it has become clear that estrogens act on more than just the hypothalamus, pituitary, ovary, and other reproductive organs. In fact, they play roles in a wide variety of nonreproductive functions. With the increasing life span of humans from approximately 50 to 80 years and the relatively fixed age of the menopause, a larger number of women will spend over one third of their lives in the postmenopausal state. It is not surprising that interest has increased in factors that govern the timing of the menopause and the repercussions of the lack of estrogen on multiple aspects of women's health. We have used animal models to better understand the complex interactions between the ovary and the brain that lead to the menopause and the repercussions of the hypoestrogenic state. Our results show that when rats reach middle age, the patterns and synchrony of multiple neurochemical events that are critical to the preovulatory gonadotropin-releasing hormone (GnRH) surge undergo subtle changes. The precision of rhythmic pattern of neurotransmitter dynamics depends on the presence of estradiol. Responsiveness to this hormone decreases in middle-aged rats. The lack of precision in the coordination in the output of neural signals leads to a delay and attenuation of the luteinizing hormone surge, which lead to irregular estrous cyclicity and, ultimately, to the cessation of reproductive cycles. We also have examined the impact of the lack of estrogen on the vulnerability of the brain to injury. Our work establishes that the absence of estradiol increases the extent of cell death after stroke-like injury and that treatment with low physiological levels of estradiol are profoundly neuroprotective. We have begun to explore the cellular and molecular mechanisms that underlie this novel nonreproductive action of estrogens. In summary, our studies show that age-related changes in the ability of estradiol to coordinate the neuroendocrine events that lead to regular preovulatory GnRH surges contribute to the onset of irregular estrous cycles and eventually to acyclicity. Furthermore, we have shown that the lack of estradiol increases the vulnerability of the brain to injury and neurodegeneration.
Transcription factors underlying the development and endocrine functions of the placenta.
Cross JC, Anson-Cartwright L, Scott IC
Recent Prog Horm Res · 2002 · PMID 12017545 · Publisher ↗
The placenta has been the subject of extensive basic research efforts in two distinct fields. The developmental biology of placenta has been studied because it is the first organ to develop during embryogenesis and becau...
The placenta has been the subject of extensive basic research efforts in two distinct fields. The developmental biology of placenta has been studied because it is the first organ to develop during embryogenesis and because a number of different gene mutations in mice result in embryonic lethality due to placental defects. The trophoblast cell lineage is relatively simple such that only two major, terminally differentiated cell types appear: an "invasive trophoblast" cell subtype such as extravillous cytotrophoblast cells in humans and trophoblast giant cells in mice, and a "transport trophoblast" cell subtype that is a syncytium (syncytiotrophoblast) in humans and mice. These two cell types also have been the focus of endocrinologists because they are the source of major placental hormones. Understanding the transcriptional regulation of placental hormone genes has given insights into the control of specificity of gene expression. Because most placental hormones are produced by very specific trophoblast cell subtypes, the transcriptional details promise to give insights into cell-subtype specification. The fields of developmental biology and molecular endocrinology appear to be meeting on this common ground with the recent discovery of key transcription factors. Specifically, the basic helix-loop-helix (bHLH) transcription factor Hand1 is essential for differentiation of trophoblast giant cells in mice and also regulates the promoter for the giant cell-specific hormone, placental lactogen I gene (Pl1). In contrast, formation of syncytiotrophoblast cells in mice is controlled by a distinct genetic pathway that is governed by the Gcm1 transcription factor, a homologue of the Drosophila glial cells missing gene. Human GCM I has been shown to regulate the activity of the placental-specific enhancer of the aromatase gene (CYP19), which is specifically expressed in syncytiotrophoblast. Together, these findings imply that some key transcription factors have the dual functions of controlling both critical cell fate decisions in the trophoblast cell lineage and later the transcription of cell subtype-specific genes unrelated to development.
Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization.
Richards JS, Russell DL, Ochsner S … +5 more , Hsieh M, Doyle KH, Falender AE, Lo YK, Sharma SC
Recent Prog Horm Res · 2002 · PMID 12017544 · Publisher ↗
The interactions of peptide and steroid hormone signaling cascades in the ovary are critical for follicular growth, ovulation, and luteinization. Although the pituitary gonadotropins follicle-stimulating hormone (FSH) an...
The interactions of peptide and steroid hormone signaling cascades in the ovary are critical for follicular growth, ovulation, and luteinization. Although the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play key regulatory roles, their actions are also dependent on other peptide signaling pathways, including those stimulated by insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta) family members (e.g., inhibin, activin, growth differentiation factor-9, bone morphogenic proteins), fibroblast growth factor, and Wnts (via Frizzled receptors). Each of these factors is expressed and acts in a cell-specific manner at defined stages of follicular growth. IGF-1, estrogen, and FSH comprise one major regulatory system. The Wnt/Frizzled pathways define other aspects relating to ovarian embryogenesis and possibly ovulation and luteinization. Likewise, the steroid receptors as well as orphan nuclear receptors and their ligands impact ovarian cell function. The importance of these multiple signaling cascades has been documented by targeted deletion of specific genes. For example, mice null for the LH-induced genes progesterone receptor (PR) and cyclo-oxygenase-2 (COX-2) fail to ovulate. Whereas PR appears to regulate the induction of novel proteases, COX-2 appears to regulate cumulus expansion. This review summarizes some new aspects of peptide and steroid hormone signaling in the rodent ovary.
Steroidogenic factor 1: an essential mediator of endocrine development.
Parker KL, Rice DA, Lala DS … +9 more , Ikeda Y, Luo X, Wong M, Bakke M, Zhao L, Frigeri C, Hanley NA, Stallings N, Schimmer BP
Recent Prog Horm Res · 2002 · PMID 12017543 · Publisher ↗
The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP and officially designated NR5A1) has emerged as an essential regulator of endocrine development and function. Initially identified as a tissue-s...
The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP and officially designated NR5A1) has emerged as an essential regulator of endocrine development and function. Initially identified as a tissue-specific transcriptional regulator of the cytochrome P450 steroid hydroxylases, SF-1 has considerably broader roles, as evidenced from studies in knockout mice lacking SF-1. The SF-1-knockout mice lacked adrenal glands and gonads and therefore died from adrenal insufficiency within the first week after birth. In addition, SF-1 knockout mice exhibited male-to-female sex reversal of their internal and external genitalia, impaired expression of multiple markers of pituitary gonadotropes, and agenesis of the ventromedial hypothalamic nucleus (VMH). These studies delineated essential roles of SF-I in regulating endocrine differentiation and function at multiple levels, particularly with respect to reproduction. This chapter will review the experiments that established SF-1 as a pivotal, global determinant of endocrine differentiation and function. We next discuss recent insights into the mechanisms controlling the expression and function of SF-1 as well as the current status of research aimed at delineating its roles in specific tissues. Finally, we highlight areas where additional studies are needed to expand our understanding of SF-1 action.
Molecular defects of the androgen receptor.
McPhaul MJ
Recent Prog Horm Res · 2002 · PMID 12017542 · Publisher ↗
Mutations in the androgen receptor (AR) gene cause a range of phenotypic abnormalities of male sexual development. At one end of the spectrum are individuals with complete androgen insensitivity (complete testicular femi...
Mutations in the androgen receptor (AR) gene cause a range of phenotypic abnormalities of male sexual development. At one end of the spectrum are individuals with complete androgen insensitivity (complete testicular feminization) who exhibit normal breast development and female external genitalia. At the other extreme are individuals with male phenotypes that are characterized by either subtle undervirilization or infertility. Studies in a number of different laboratories have identified mutations of the AR gene in subjects with androgen resistance syndromes. Defects that interrupt the AR open-reading frame have been traced to a number of distinct types of genetic alterations, have been identified in widely separated segments of the AR gene, and are invariably associated with the phenotype of complete androgen insensitivity. By contrast, mutations that cause single amino acid substitutions within the AR are localized to the DNA- or ligand-binding domains of the receptor protein and have been associated with the full range of androgen-resistant phenotypes. Regardless of the nature of the mutation, functional studies and assays of AR abundance suggest that the phenotypic abnormalities that result from mutation of the AR are the result of the impairment of receptor function, decreases in receptor concentration, or both.
Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man.
McLachlan RI, O'Donnell L, Meachem SJ … +4 more , Stanton PG, de Kretser DM, Pratis K, Robertson DM
Recent Prog Horm Res · 2002 · PMID 12017541 · Publisher ↗
A detailed understanding of the hormonal regulation of spermatogenesis is required for the informed assessment and management of male fertility and, conversely, for the development of safe and reversible male hormonal co...
A detailed understanding of the hormonal regulation of spermatogenesis is required for the informed assessment and management of male fertility and, conversely, for the development of safe and reversible male hormonal contraception. An approach to the study of these issues is outlined based on the use of well-defined in vivo models of gonadotropin/androgen deprivation and replacement, the quantitative assessment of germ cell number using stereological techniques, and the directed study of specific steps in spermatogenesis shown to be hormone dependent. Drawing together data from rat, monkey, and human models, we identify differences between species and formulate an overview of the hormonal regulation of spermatogenesis. There is good evidence for both separate and synergistic roles for both testosterone and follicle-stimulating hormone (FSH) in achieving quantitatively normal spermatogenesis. Based on relatively selective withdrawal and replacement studies, FSH has key roles in the progression of type A to B spermatogonia and, in synergy with testosterone, in regulating germ cell viability. Testosterone is an absolute requirement for spermatogenesis. In rats, it has been shown to promote the adhesion of round spermatids to Sertoli cells, without which they are sloughed from the epithelium and spermatid elongation fails. The release of mature elongated spermatids from the testis (spermiation) is also under FSH/testosterone control in rats. Data from monkeys and men treated with steroidal contraceptives indicate that impairment of spermiation is a key to achieving azoospermia. The contribution of 5alpha-reduced androgens in the testis to the regulation of spermatogenesis is also relevant, as 5alpha-reduced androgens are maintained during gonadotropin suppression and may act to maintain low levels of germ cell development. These concepts are also discussed in the context of male hormonal contraceptive development.
The expression of the follicle-stimulating hormone receptor in spermatogenesis.
Heckert LL, Griswold MD
Recent Prog Horm Res · 2002 · PMID 12017540 · Full text
Results from experiments using mouse models suggest that the role of follicle-stimulating hormone (FSH) in spermatogenesis is the regulation of Sertoli cell proliferation and, ultimately, the size and spermatogenic capac...
Results from experiments using mouse models suggest that the role of follicle-stimulating hormone (FSH) in spermatogenesis is the regulation of Sertoli cell proliferation and, ultimately, the size and spermatogenic capacity of the testis. The regulation of the expression of the FSH receptor (FSHR) gene is very cell specific and plays an initial role in the ultimate response of the Sertoli cells to FSH. The extreme cell specificity and the importance of the FSH response to spermatogenesis have led to an extensive characterization of the promoter of the FSHR gene. Several widely expressed transcription factors - including USF 1 and 2, GATA-1, and SF-1 and potential elements such as an E2F site and an Inr region - have been shown to contribute to the maximal transcription of the transfected FSHR gene. However, these experiments have failed to provide clues as to the cell-specific expression of the FSHR gene. In both cell transfections and in transgenic mice, the promoter can direct expression of transgenes promiscuously. The rodent FSHR promoter contains conserved CpG dinucleotides that were shown to be methylated in nonexpressing cells and tissue but unmethylated in Sertoli cells. The methylated CpG sites could interfere with the binding of general transcription factors and/or lead to a repressive chromatin structure in the nonexpressing cells. While yet-undiscovered cell-specific factors may play a role in the expression of the FSHR gene, repression and activation of local chromatin structure are likely to be involved.
Male germ cell gene expression.
Eddy EM
Recent Prog Horm Res · 2002 · PMID 12017539 · Publisher ↗
Formation of the male gamete occurs in sequential mitotic, meiotic, and postmeiotic phases. Many germ cell-specific transcripts are produced during this process. Their expression is developmentally regulated and stage sp...
Formation of the male gamete occurs in sequential mitotic, meiotic, and postmeiotic phases. Many germ cell-specific transcripts are produced during this process. Their expression is developmentally regulated and stage specific. Some of these transcripts are product of genes that are male germ cell-specific homologs of genes expressed in somatic cells, while some are expressed from unique genes unlike any others in the genome. Others are alternate transcripts derived from the same gene as transcripts in somatic cells but differing from them in size and/or overall sequence. They are generated during gene expression by using promoters and transcription factors that activate transcription at different start sites upstream or downstream of the usual site, by incorporation of alternate exons, by germ cell-specific splicing events, and by using alternate initiation sites for polyadenylation. Male germ cell development consists of an assortment of unique processes, including meiosis, genetic recombination, haploid gene expression, formation of the acrosome and flagellum, and remodeling and condensation of the chromatin. These processes are intricate, highly ordered, and require novel gene products and a precise and well-coordinated program of gene expression to occur. The regulation of gene expression in male germ cells occurs at three levels: intrinsic, interactive, and extrinsic. A highly conserved genetic program "intrinsic" to germ cells determines the sequence of events that underlies germ cell development. This has been underscored by recent studies showing that meiosis involves many genes that have been conserved during evolution from yeast to man. During meiosis and other processes unique to germ cells, the intrinsic program determines which genes are utilized and when they are expressed. In the postmeiotic phase, it coordinates the expression of genes whose products are responsible for constructing the sperm. The process of spermatogenesis occurs in overlapping waves, with cohorts of germ cells developing in synchrony. The intrinsic program operating within a particular germ cell requires information from and provides information to neighboring cells to achieve this coordination. Sertoli cells are crucial for this "interactive" process as well as for providing essential support for germ cell proliferation and progression through the phases of development. The interactive level of regulation is dependent on "extrinsic" influences, primarily testosterone and follicle-stimulating hormone (FSH). Studies during the last 4 years have established that FSH is not essential for germ cell development but instead serves an important supportive role for this process. While testosterone is essential for maintenance of spermatogenesis, it acts on Sertoli cells and peritubular cells and has indirect effects on germ cells. The extrinsic and interactive processes are extremely important for establishing and maintaining an optimum environment within which gametogenesis occurs. Nevertheless, an intrinsic evolutionarily conserved genetic program regulates male germ cell gene expression and development.
Cellular and molecular pathways regulating mammalian sex determination.
Tilmann C, Capel B
Recent Prog Horm Res · 2002 · PMID 12017538 · Publisher ↗
In mammals, sex is determined by the presence or absence of a single gene on the Y chromosome, Sry. Sry, a member of the high mobility group family of transcription factors, is required to initiate male-specific pathways...
In mammals, sex is determined by the presence or absence of a single gene on the Y chromosome, Sry. Sry, a member of the high mobility group family of transcription factors, is required to initiate male-specific pathways and repress female-specific pathways. Expression of Sry in the gonad, beginning at 10.5 days postcoitum, leads to the differentiation of the somatic supporting cell precursors as Sertoli cells. These cells direct the other cells of the gonad into their respective lineages. Currently, no direct targets of Sry are known. A number of cellular pathways initiated by Sry are required for testis development. These include the proliferation of pre-Sertoli cells and commitment to the Sertoli lineage, migration of cells from the adjacent mesonephros, and formation of a male-specific vasculature. Work is underway to identify genes controlling these processes. These genes will then be linked to Sry.
Genetic determinants of type 2 diabetes.
Froguel P, Velho G
Recent Prog Horm Res · 2001 · PMID 11237227 · Publisher ↗
Hyperglycemia of type 2 diabetes mellitus (T2DM) results from a complex interplay of genetic and environmental factors that influence a number of intermediate traits (e.g., beta-cell mass, insulin secretion, insulin acti...
Hyperglycemia of type 2 diabetes mellitus (T2DM) results from a complex interplay of genetic and environmental factors that influence a number of intermediate traits (e.g., beta-cell mass, insulin secretion, insulin action, fat distribution, obesity). The primary biochemical events leading to diabetes are still unknown in most cases. Although several monogenic forms of diabetes have been identified, T2DM seems to be a polygenic disorder in the majority of cases. T2DM is probably also multigenic, meaning that many different combinations of gene defects may exist among diabetic patients. Significant results were obtained in the identification of the genetic determinants of monogenic forms of diabetes with young age of onset. However, despite the evidence for a strong genetic background, little of the genetic risk factors for the more-common forms of polygenic T2DM are known to date. The goal of this chapter is to summarize and discuss the significant results of recent literature on the genetics of both the monogenic and polygenic forms of T2DM.
Genetics of type 1A diabetes.
Redondo MJ, Fain PR, Eisenbarth GS
Recent Prog Horm Res · 2001 · PMID 11237226 · Publisher ↗
Type 1A diabetes is an autoimmune disease with genetic and environmental factors contributing to its etiology. Twin studies, family studies, and animal models have helped to elucidate the genetics of autoimmune diabetes....
Type 1A diabetes is an autoimmune disease with genetic and environmental factors contributing to its etiology. Twin studies, family studies, and animal models have helped to elucidate the genetics of autoimmune diabetes. Most of the genetic susceptibility is accounted for by human leukocyte antigen (HLA) alleles. The most-common susceptibility haplotypes are DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201. Less-common haplotypes such as DQA1*0401-DQB1*0402 and DQA1*0101-DQB1*0501 are associated with high risk for diabetes; however, large study populations are needed to analyze their effect. The DQA1*0102-DQB1*0602 haplotype is associated with diabetes resistance. DR molecules, such as DRB1*1401, confer protection from diabetes. Monozygotic twins of patients with type 1A diabetes have a diabetes risk higher than that for HLA-identical ordinary siblings, suggesting that non-HLA genes contribute to diabetes risk. Polymorphisms in the regulatory region of the insulin gene (designated IDDM2), polymorphisms in cytotoxic T lymphocyte antigen-4 (CTLA-4) gene (IDDM12), and other genes are likely to contribute to diabetes risk and susceptibility in some individuals. In selected families, major diabetogenes (e.g., IDDM17, autoimmune regulator gene (AIRE)) are likely to be of importance. Other factors--either noninherited genes (i.e., somatic mutations and T-cell receptor or immunoglobulin rearrangements) or environment--may have a role in progression to diabetes. This is suggested by the finding that the risk for monozygotic twins of patients with type 1A diabetes is not 100 percent. Studying the genetics of type 1A diabetes will allow us to better define this disease, to improve our ability to identify individuals at risk, and to predict the risk of associated disorders.
Of mice and men: K(ATP) channels and insulin secretion.
Aguilar-Bryan L, Bryan J, Nakazaki M
Recent Prog Horm Res · 2001 · PMID 11237225 · Publisher ↗
K(ATP) channels are a unique, small family of potassium (K+)-selective ion channels assembled from four inward rectifier pore-forming subunits, K(IR)6.x, paired with four sulfonylurea receptors (SURs), members of the ade...
K(ATP) channels are a unique, small family of potassium (K+)-selective ion channels assembled from four inward rectifier pore-forming subunits, K(IR)6.x, paired with four sulfonylurea receptors (SURs), members of the adenosine triphosphate (ATP)-binding cassette superfamily. The activity of these channels can be regulated by metabolically driven changes in the ratio of adenosine diphosphate (ADP) to ATP, providing a means to couple membrane electrical activity with metabolism. In pancreatic beta cells in the islets of Langerhans, K(ATP) channels are part of an ionic mechanism that couples glucose metabolism to insulin secretion. This chapter 1) briefly describes the properties of K(ATP) channels; 2) discusses data on a genetically recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI), caused by loss of beta-cell K(ATP) channel activity; and 3) compares the severe impairment of glucose homeostasis that characterizes the human phenotype with the near-normal phenotype observed in K(ATP) channel null mice.
Mechanisms of inhibin signal transduction.
Bernard DJ, Chapman SC, Woodruff TK
Recent Prog Horm Res · 2001 · PMID 11237224 · Publisher ↗
Inhibin was first identified as a gonadal hormone that potently inhibits pituitary follicle-stimulating hormone (FSH) synthesis and secretion. Although the notion of a nonsteroidal, gonadally derived inhibitory substance...
Inhibin was first identified as a gonadal hormone that potently inhibits pituitary follicle-stimulating hormone (FSH) synthesis and secretion. Although the notion of a nonsteroidal, gonadally derived inhibitory substance was realized in the early 1930s (McCullagh, 1932), identification of the hormone was not accomplished until more than 50 years later. At that time, inhibin was purified from bovine and porcine follicular fluid and was shown to be produced in two forms through dimeric assembly of an alpha subunit (18 kDa) and one of two closely related beta subunits (betaA and betaB, approximately 14 kDa) (Ling et al., 1985; Miyamoto et al., 1985; Rivier et al., 1985; Robertson et al., 1985). Dimers of alpha and betaA and alpha and betaB subunits form inhibin A and inhibin B, respectively. In the process of purifying inhibin, two groups also identified homo- and heterodimers of the inhibin beta subunits (Ling et al., 1986; Vale et al., 1986). These hormones, the activins, were shown to potently stimulate FSH secretion from primary pituitary cultures and are now known to play important roles in growth and development (Woodruff, 1998; Pangas and Woodruff, 2000). Inhibins and activins are considered members of the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors, based on a pattern of conserved cysteine residues in the alpha and beta subunits, similar to other ligands in the family. Identification of the subunit proteins led to the cloning of their cDNAs and subsequently to their chromosomal mapping in several species (Mason et al, 1985,1986; Forage et al., 1986; Mayo et al., 1986; Esch et al., 1987; Woodruff et al., 1987; Barton et al., 1989; Hiendleder et al., 2000). Three additional activin-related beta subunits (betaC and betaE in mammals and betaD in Xenopus laevis) also have been identified but do not appear to play a role in FSH regulation (Hotten et al., 1995; Oda et al., 1995; Fang et al., 1996, 1997; Loveland et al., 1996; Schmitt el al., 1996; O'Bryan et al., 2000; Lau et al., 2000). To date, only one alpha subunit has been reported. The inhibin subunits are expressed in various tissues (Meunier et al., 1988a, 1988b) but the gonads are clearly the primary source of circulating inhibins (Woodruff et al., 1996). While inhibins act in a paracrine role in some tissues (Hsueh et al., 1987), their best-understood roles are as endocrine regulators of pituitary FSH. Activins also were purified from follicular fluid but because circulating activin levels generally are low, most actions of the hormones are likely to be paracrine in nature (Woodruff, 1998). Several reviews in the past decade have clearly and thoroughly addressed the characterization and regulation of the inhibins and activins and their roles in reproductive function (Vale et al., 1988; Ying, 1988; Woodruff and Mayo, 1990; Mayo, 1994; Woodruff and Mather, 1995). In this chapter, we focus our attention on more-recent developments in inhibin research. First, we discuss differential regulation of inhibin isoforms. Specifically, we describe patterns of inhibin A and B secretion in the context of the female reproductive cycle. Second, we review molecular mechanisms of inhibin subunit regulation. Third, while inhibins are best known for their role in pituitary FSH regulation, other functions of the ligands are becoming better understood. We review the animal and human literature addressing the possible role of inhibins in gonadal cancers. While we know "what" inhibins do in various contexts, we have a very limited understanding of "how" the ligands have their effects on target cells. Recently, candidate inhibin receptor molecules have been identified (Draper et al., 1998; Hertan et al., 1999; Lewis et al., 2000; Chung et al., 2000). Next, we detail our current understanding of inhibin signal transduction. Finally, in light of the data reviewed here, we pose questions and outline future directions for inhibin research. While this review is concerned primarily with expression and function of inhibin, activin function and mechanisms of action are described where necessary to shed light on inhibin function. Several reviews of activin's role in reproductive and other processes can be found elsewhere (Woodruff, 1998; Pangas and Woodruff, 2000).
Leptin controls bone formation through a hypothalamic relay.
Karsenty G
Recent Prog Horm Res · 2001 · PMID 11237223 · Publisher ↗
Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight,...
Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight, and reproduction are controlled by identical endocrine pathways. We used mouse genetics as a tool to translate these clinical observations into a molecular hypothesis. The ob/ob and db/db mice were valuable models, since two of the three functions thought to be co-regulated are affected in these mice: they are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis of the mechanism leading to this high bone mass revealed that it was due to an increase of bone formation. All data collected indicate that, in vivo, leptin does not act directly on osteoblasts but rather through a central pathway following binding to its specific receptors located on hypothalamic nuclei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstream of the hypothalamus is unknown but current experiments are attempting to identify it.
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