Organoids of the female reproductive tract.

Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT-ovaries, fallopian tubes, uterus, cervix and vagina-facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.

Control of anterior pituitary cell excitability by calcium-activated potassium channels.

In anterior pituitary endocrine cells, large (BK), small (SK) and intermediate (IK) conductance calcium activated potassium channels are key determinants in shaping cellular excitability in a cell type- and context-specific manner. Indeed, these channels are targeted by multiple signaling pathways that stimulate or inhibit cellular excitability. BK channels can, paradoxically, both promote electrical bursting as well as terminate bursting and spiking dependent upon intrinsic BK channel properties and proximity to voltage gated calcium channels in somatotrophs, lactotrophs and corticotrophs. In contrast, SK channels are predominantly activated by calcium released from intracellular IP3-sensitive calcium stores and mediate membrane hyperpolarization in cells including gonadotrophs and corticotrophs. IK channels are predominantly expressed in corticotrophs where they limit membrane excitability. A major challenge for the future is to determine the cell-type specific molecular composition of calcium-activated potassium channels and how they control anterior pituitary hormone secretion as well as other calcium-dependent processes.

The somatotropic axis and longevity in mice.

The somatotropic signaling pathway has been implicated in aging and longevity studies in mice and other species. The physiology and lifespans of a variety of mutant mice, both spontaneous and genetically engineered, have contributed to our current understanding of the role of growth hormone and insulin-like growth factor I on aging-related processes. Several other mice discovered to live longer than their wild-type control counterparts also exhibit differences in growth factor levels; however, the complex nature of the phenotypic changes in these animals may also impact lifespan. The somatotropic axis impacts several pathways that dictate insulin sensitivity, nutrient sensing, mitochondrial function, and stress resistance as well as others that are thought to be involved in lifespan regulation.

Somatostatin system: molecular mechanisms regulating anterior pituitary hormones.

The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein-coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland.

[Sarcoidosis: the involvement of anterior pituitary hormones is poorly recognized]. / Sarcoïdose : l'atteinte des hormones à dépendance antéhypophysaire est insuffisamment diagnostiquée.

OBJECTIVE: Hypothalamic-pituitary locations of sarcoidosis are rare. Achieving more systematic hormonal testing could increase the screening of such patients. The objective of this study was to evaluate the impact on the detection of hypothalamic-pituitary sarcoidosis in patients hospitalized for this condition in a lung disease sensibilized department. METHODS: In hormonology department, we collected and analyzed hormonal testing, from the list of patients hospitalized for pulmonary sarcoidosis in 2007-2008. Diabetes insipidus was defined clinically. The case of patients with multiple hormone deficiencies was analyzed for the diagnosis of hypothalamic-pituitary damage. RESULTS: In a cohort of 486 patients, 158 (33%) had a hormonal abnormality. Forty-six of 158 patients (≈30%) had at least one pituitary deficiency or hyperprolactinemia: 31 adrenal insufficiency (isolated for 21), 20 gonadotrop deficiency, 14 hyperprolactinemia, 3 thyreotrop deficiency and a growth hormone deficiency. Among eight patients with association of hyperprolactinemia and hypogonadism, four have a probable diagnosis of hypothalamic-pituitary sarcoidosis, including 3 new cases. DISCUSSION: Despite a selection bias (hospital patients, more severe forms), prevalence of hormonal abnormalities was higher than expected. CONCLUSION: In the condition of this study, hypothalamic-pituitary affected 2.5% of patients with sarcoidosis in pneumologic department (4/158). Hormonal abnormalities were present in one third of hospitalized patients. The most prevalent deficiency found was corticotrope deficiency, secondary to corticosteroid therapy.

The role of hypothalamo-hypophyseal-adrenocortical system hormones in controlling pain sensitivity.

The present review addresses analysis of data demonstrating the role of the hypothalamo-hypophyseal-adrenocortical axis (HHACA) in controlling pain sensitivity. Experiments on rats have demonstrated the analgesic effects of exogenous hormones of all components of the HHACA - corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids - in the same models, and have also shown that the opioid and non-opioid mechanisms contribute to the development of the analgesia induced by these hormones. Endogenous glucocorticoids are involved in the development of analgesia mediated by non-opioid mechanisms. Along with the non-opioid mechanisms associated with endogenous glucocorticoids, the analgesic effect of ACTH can be mediated by the opioid mechanism. Unlike the situation with ACTH, the analgesic effect of CRH is mediated exclusively by non-opioid mechanisms, one of which is associated with HHACA hormones, while the other, appearing only on systemic administration, is not associated with these hormones. The actions of glucocorticoids on pain are mediated by neurons in the central gray matter of the midbrain.

Retention of genes involved in the adenohypophysis-mediated endocrine system in early vertebrates.

The adenohypophysis of vertebrates receives peptide hormones from the hypothalamus and secretes hormones that regulate diverse physiologic processes in peripheral organs. The adenohypophysis-mediated endocrine system is widely conserved across vertebrates but not invertebrates. Phylogenetic analysis indicates that the emergence of this system coincided with two rounds of whole-genome duplication (2R-WGD) in early vertebrates, but direct evidence linking these events has been unavailable. We detected all human paralogons (series of paralogous regions) formed in early vertebrates as traces of 2R-WGD, and examined the relationship between 2R-WGD and the evolution of genes essential to the adenohypophysis-mediated endocrine system. Regarding genes encoding transcription factors (TFs) involved in the terminal differentiation into hormone-secreting cells in adenohypophyseal development, we showed that most pairs of these genes and their paralogs were part of paralogons. In addition, our analysis also indicated that most of the paralog pairs in families of adenohypophyseal hormones and their receptors were part of paralogons. These results suggest that 2R-WGD played an important role in generating genes encoding adenohypophyseal TFs, hormones, and their receptors for increasing the diversification of hormone repertoire in the adenohypophysis-mediated endocrine system of vertebrates.

Hypopituitarism: clinical features, diagnosis, and management.

Hypopituitarism is characterized by loss of function of the anterior pituitary gland. It is a rare condition that can present at any age and is caused by pathology of the hypothalamic-pituitary axis or one of many gene mutations. The symptoms and signs of hypopituitarism may evolve over several years and be nonspecific or related to the effects of the underlying disease process or to hormone deficiencies. Investigation of patients requires a combination of basal hormone levels and dynamic function tests; management requires regular monitoring. The goal of physicians managing patients who have hypopituitarism is to improve their health and long-term outcome.

Normal physiology of hypothalamic pituitary regulation.

The anterior pituitary is a complex heterogeneous gland that exerts a central role in the integration of several regulatory systems. Its six key hormones affect peripheral glands or target tissues and are essential for reproduction, growth and development, metabolism, adaptation to external environmental changes, and stress. Each of the pituitary hormones is regulated by the central nervous system through neuroendocrine pathways involving the hypothalamus, by feedback effects from peripheral target gland hormones, and by intrapituitary mechanisms. The hormones are secreted in a pulsatile manner, which is distinct for each hormone and reflects the influence of its individual neuroendocrine control mechanisms.

Electrotonic coupling in the anterior pituitary of a teleost fish.

The anterior pituitary of teleost fish contains a variety of endocrine cells, which, under control from the hypothalamus, release trophic hormones and thereby play a major role in reproduction, social behavior, and growth. In fish, hypothalamic fibers directly innervate the pituitary. The hypothalamic hormones released from these fibers bind to membrane receptors on pituitary cells, triggering action potentials, a rise in cytosolic calcium, and exocytosis. It is unclear whether these activities are confined to the stimulated cell or propagate to adjacent cells. We addressed this issue using whole cell and perforated patch-clamp techniques in a novel, hypothalamo-pituitary slice preparation from the tilapia fish (Oreochromis niloticus). Pituitary cells at rest generated occasional spontaneous spikes and sharp depolarizations of lower amplitude. The latter probably represented spikes in neighboring, electrotonically coupled cells. The presence of electrotonic communication, probably mediated by gap junctions, was also supported by the finding that Lucifer Yellow diffuses between cells. To quantify this connectivity, we performed simultaneous recording from pairs of adjacent cells. Thirty-three percent of the cells exhibited strong reciprocal coupling. Coupling coefficients ranged between 0.18 and 0.31, and coupling resistances ranged between 16 and 39 GOhm. The electrical junctions were effective low pass filters, attenuating action potentials much more than low frequency waveforms. We conclude that electrical activities of anterior pituitary cells in teleost fish are synchronized by coupling through gap junctions. Regulation of this coupling may play a critical role in determining complex patterns of pituitary hormone secretion.

Neuropeptides in anterior pituitary development.

Recent studies using biotechnological methods have achieved significant advances in our knowledge of molecular mechanisms underlying pituitary gland development and the differentiation of pituitary cytotypes. A large number of neuropeptides have been reported in the adult pituitary gland as well as in the central and peripheral nervous system. The early presence of neuropeptides during pituitary development is reviewed here. Neuromedin U (NmU), galanin and the polypeptide 7B2 have been localised to different endocrine cells of the gland. Their expression seems to be manifold even though it is temporally and spatially regulated. There is now firm immunocytochemical evidence that neuropeptides are present during morphogenesis of the pituitary and can be present simultaneously with all pituitary hormones.

Adipokinin, a proopiomelanocortin-derived lipid-mobilizing anterior pituitary hormone.

Hormonal control of lipid metabolism during prolonged fasting is unclear. The involvement of the classical, lipid-mobilizing hormone from the anterior pituitary, i.e., beta-lipotropin (beta-LPH), is suspect. It and adrenocorticotropin (ACTH) are formed concurrently in the pituitary during the processing of the prohormone, proopiomelanocortin (POMC), and are secreted together. During prolonged fasting the control of metabolism requires minimal participation by ACTH and maximal lipid-mobilizing activity which is inconsistent with the present concept of ACTH and beta-LPH secretion. Hypothetically, the needed control can be satisfied by the alteration of the accepted processing of POMC so as to form beta-LPH and a new lipid-mobilizing hormone which also has modest ACTH-like activity. It is proposed that this hormone be named 'adipokinin'. An analog of this proposed hormone appears to have been isolated previously from porcine pituitaries.

Corticotrophs and peptides.

Corticotrophs were long thought to be a static, homogeneous population of cells that respond positively to hypothalamic stimulation, are inhibited by glucocorticoid feedback and secrete a single biologically active peptide, ACTH(1-39). Our current understanding is that this is an oversimplification and corticotrophs are a dynamic and more complex group of cells. The biosynthetic precursors of ACTH and other cleavage products of proopiomelanocortin (POMC) have been found to be secreted by anterior pituitary cells, to circulate and to have biological activity. POMC and the biosynthetic intermediate, pro-ACTH, exert activity antagonistic to ACTH(1-39) on glucocorticoid secretion by adrenal cells, and other derivatives of POMC are mitogenic to adrenocortical cells. In terms of responses to hypothalamic and peripheral factors, corticotrophs are functionally heterogeneous. This is reflected in the sensitivity of individual subtypes of corticotrophs to CRH, vasopressin and glucocorticoids. There is a functional plasticity amongst the various types of corticotrophs. During gestation, in fetal sheep, changes occur in the overall ACTH-secretory responses to CRH relative to vasopressin, the proportions of total corticotrophs that respond to the respective peptides and the average secretory response of individual cells. Corticotrophs also respond to locally produced pituitary factors. Local actions of leukaemia inhibitory factor are demonstrated by the effects of immunoneutralization of the peptide in pituitary cells. Urocortin and preproTRH(178-199) are locally produced peptides with potent stimulatory and inhibitory actions on corticotrophs, respectively. The specific roles of these peptides are under investigation.

Anterior pituitary hormones, stress, and immune system homeostasis.

An extensive, and controversial, literature concluding that prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid hormones are critical immunoregulatory factors has accumulated. However, recent studies of mice deficient in the production of these hormones or expression of their receptors indicate that there are only a few instances in which these hormones are required for lymphocyte development or antigen responsiveness. Instead, a case is made that their primary role is to counteract the effects of negative immunoregulatory factors, such as glucocorticoids, which are produced when the organism is subjected to major stressors. The immunoprotective actions of PRL, GH, IGF-I, and/or thyroid hormones in these instances may ensure immune system homeostasis and reduce the susceptibility to stress-induced disease. These immuno-enhancing effects could be exploited clinically in instances where the immune system is depressed due to illness or various treatment regimens.

Mechanisms controlling the function and life span of the corpus luteum.

The primary function of the corpus luteum is secretion of the hormone progesterone, which is required for maintenance of normal pregnancy in mammals. The corpus luteum develops from residual follicular granulosal and thecal cells after ovulation. Luteinizing hormone (LH) from the anterior pituitary is important for normal development and function of the corpus luteum in most mammals, although growth hormone, prolactin, and estradiol also play a role in several species. The mature corpus luteum is composed of at least two steroidogenic cell types based on morphological and biochemical criteria and on the follicular source of origin. Small luteal cells appear to be of thecal cell origin and respond to LH with increased secretion of progesterone. LH directly stimulates the secretion of progesterone from small luteal cells via activation of the protein kinase A second messenger pathway. Large luteal cells are of granulosal cell origin and contain receptors for PGF(2alpha) and appear to mediate the luteolytic actions of this hormone. If pregnancy does not occur, the corpus luteum must regress to allow follicular growth and ovulation and the reproductive cycle begins again. Luteal regression is initiated by PGF(2alpha) of uterine origin in most subprimate species. The role played by PGF(2alpha) in primates remains controversial. In primates, if PGF(2alpha) plays a role in luteolysis, it appears to be of ovarian origin. The antisteroidogenic effects of PGF(2alpha) appear to be mediated by the protein kinase C second messenger pathway, whereas loss of luteal cells appears to follow an influx of calcium, activation of endonucleases, and an apoptotic form of cell death. If the female becomes pregnant, continued secretion of progesterone from the corpus luteum is required to provide an appropriate uterine environment for maintenance of pregnancy. The mechanisms whereby the pregnant uterus signals the corpus luteum that a conceptus is present varies from secretion of a chorionic gonadotropin (primates and equids), to secretion of an antiluteolytic factor (domestic ruminants), and to a neuroendocrine reflex arc that modifies the secretory patterns of hormones from the anterior pituitary (most rodents).

Glycoprotein hormone structure-function and analog design.

Human chorionic gonadotropin (hCG), luteinizing hormone, follicle-stimulating hormone (FSH), and thyrotropin (TSH) are hormones that share a common alpha subunit but differ in their beta subunits. Recombinant DNA techniques, valuable tools for structure-function analyses, provide an approach for designing therapeutic analogs. FSH is used clinically to stimulate the ovarian follicles for in vitro fertilization and to initiate follicular maturation in women with infertility problems. The CG beta subunit contains a carboxy-terminal extension (CTP) with four serine O-linked oligosaccharides, which is important for the long half-life of hCG. A clinical problem of FSH is its relatively short half-life in circulation. Fusing CTP to the FSH beta coding sequence increased the in vivo potency of the resulting FSH dimer over three-fold. Analogs of the other hormones containing CTP also increase their biologic half-life. Subunit assembly is vital to the function of these hormones. To address whether alpha and beta subunits can be synthesized as one chain and also maintain biological activity, a chimera comprised of the hCG beta subunit genetically fused to the alpha subunit was constructed. The resulting polypeptide was efficiently secreted and displayed an increased biologic activity in vitro and in vivo. Similarly, the single-chain form of FSH also retained in vivo activity. Since subunit dissociation inactivates the activity of the heterodimer, single-chain analogs should have longer biological half-lives. These analogs represent suitable substrates for engineering potent and stable agonists and antagonists.

Effects of pituitary hormones on the prostate.

BACKGROUND: Although essential, androgens alone are not sufficient to induce normal growth and functionality of the prostate. Nonandrogenic hormones must also be involved in the proliferation of the prostate cancer cells which do not respond to antiandrogenic therapy and which thus become androgen-independent. Prolactin, but also growth hormone and luteinizing hormone, are potentially able to act on both normal and abnormal prostatic cells. METHODS: In this review we summarize data from the literature concerning the physiological and pathological implications of prolactin, growth hormone, and luteinizing hormone on the prostate. RESULTS: In rodent prostates, prolactin and growth hormone can induce a variety of effects independently of androgens (e.g., transactivation of certain genes, or synthesis of the major secretion products). Moreover, hyperprolactinemia is responsible for inflammation and dysplasia of the gland, while growth hormone promotes the development of prostate tumors in vivo in the mouse and rat. Growth hormone acts on the gland directly, through prostatic growth hormone receptors, and/or indirectly via the stimulation of insulin-like growth factor-I (IGF-I) synthesis in the liver. Luteinizing hormone receptor is expressed in rat and human prostates. Luteinizing hormone increases the amount of various transcripts in the rat prostate through an androgen-independent pathway. CONCLUSIONS: Prolactin, growth hormone, and luteinizing hormone, alone or synergistically with androgens, play physiologically significant roles in the normal prostate. The involvement of these hormones in the development of benign prostatic hyperplasia and prostatic carcinoma is an issue that needs to be addressed.

Cell and molecular biology of the pars tuberalis of the pituitary.

The pars tuberalis of the adenohypophysis is mainly composed of a special type of endocrine cells, pars tuberalis-specific cells, lining the primary capillary plexus of the hypophysial portal system. Dense expression of melatonin receptors and marked changes in morphological appearance, production pattern, and secretory activity during annual cycle show that these cells are highly sensitive to changes in photoperiod. This leads to the hypothesis that the pars tuberalis is involved in the transmission of photoperiodic stimuli to endocrine targets. Several investigations support the theory that pars tuberalis-specific cells are multipotential cells exerting a modulatory influence on the secretory activity of the pars distalis. Specifically, there is accumulating evidence that seasonal modulation of prolactin secretion, independent of hypothalamic input, is due to melatonin-regulated activity of pars tuberalis-specific cells. The exact nature of secretory products and their effects within neuroendocrine regulation, however, remain rather enigmatic. Accordingly, molecular mechanisms regulating gene expression under the influence of photoperiod, respectively, circulating melatonin levels are still incomplete. Recent cloning of melatonin receptor genes and new data on intracellular signal transduction will probably lead to new insights on melatonin action and pars tuberalis-specific cell physiology.

GH transcription factors.

The pituitary transcription factor Pit-1 is expressed during the later differentiation stages of anterior pituitary development and Pit-1 mutations have been identified as the cause of a combined pituitary hormone deficiency (CPHD) for GH, prolactin and TSH. Mutations within the human Pit-1 gene can either impair the DNA binding of this transcription factor, or while leaving DNA binding capabilities unimpaired, decrease its function within the transactivation complex. Approximately half of all patients with this phenotype do not show any defect within the Pit-1 gene. Prop-1, a recently discovered transcription factor of anterior pituitary development, seemed a likely candidate for such mutations. Prop-1 mutations, however, have been found so far to induce a combined pituitary hormone deficiency for GH, prolactin, TSH and gonadotropins. We describe here a group of patients with isolated and combined pituitary hormone deficiencies who were screened for Pit-1 and Prop-1 mutations to characterize the phenotypic spectrum of defects within these two genes.