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.

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 aldosterone secretion by the pituitary gland.

In the rat, the pituitary gland is essential for the stimulation of aldosterone secretion by sodium depletion. Hypophysectomy abolishes the response to sodium depletion, whereas whole pituitary gland injections partially restore it. The response cannot be restored by injections of either adrenocorticotropin or growth hormone, nor by adrenocorticotropin plus thyroxin. The pituitary gland must secrete a hormone or possibly several hormones which are necessary for the adrenal gland to respond to sodium depletion.

Induction of pituitary lactotrope differentiation by luteinizing hormone alpha subunit.

Addition of gonadotropin releasing hormone to cultures of fetal rat pituitary induced differentiation of lactotropes as revealed by immunocytochemistry. Antiserum to luteinizing hormone (LH) (recognizing native LH), but not antiserum to LH-beta (recognizing both native LH and its beta subunit), inhibited this induction. Further addition of highly purified LH-alpha subunit in culture medium also induced lactotrope differentiation. Thus, the alpha subunit may have a specific biological activity of its own with probable practical use in clinical investigations.

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.

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.

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.

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.

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.

Response of a pregnancy-dependent mouse mammary tumor to hormones.

A transplantable, pregnancy-dependent, mouse mammary tumor line (TPDMT-4) showed a pregnancy-dependent growth in DDD breeders. The tumors grew during pregnancy, regressed rapidly after parturition, and reached ascending peaks in subsequent pregnancies. Growth without regression occurred in animals with pituitary isografts (PI), but not after the hosts were ovariectomized. The effects of ovariectomy was negated by sc injections of both 17beta-estradiol (E) and progesterone (P), but single injections of E or P did not abolish the effect of the ovariectomy. The tumors also grew in virgins given sc implants of E and P or deoxycorticosterone acetate (DCA) pellets. Adrenalectomy had no influence on the tumor growth in PI-bearing animals, but DCA injections stimulated secretion production by both tumor cells and normal mammary cells. The hormonal conditions that produced tumor growth caused in the host mammary glands the full lobulo-alveolar development seen in mid- to late-pregnant animals. In the hosts without tumor growth, the mammary glands had small clusters of acini at most. The tumors were classified as type A morphologically. Our results suggest that the growth of TPDMT-4, like that of normal mammary glands, is controlled by prolactin, E, and P.

Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins.

The carcinogen-induced rat mammary carcinoma model, developed a quarter of a century ago by Dr. Charles Brenton Huggins, is today the standard laboratory animal model in the study of human breast cancer. This model has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability, organ site specificity, tumors of ductal origin, tumors of predominantly carcinomatous histopathological characteristics, tumors of varying growth factor and/or hormone responsiveness, and the potential to examine tumor initiation and promotion processes. Since the development of this model, an extensive literature describing the biological behavior and responsiveness of these tumors has been provided. The purpose of this communication is to condense, summarize, and integrate this vast literature into a single review with the intent on facilitating information acquisition and conceptualism by both the new and the established experimental oncologist. In addition, and equally important, this communication is a tribute to Dr. Huggins, whose pioneering efforts in the development of this model and whose scientific contributions and dedication to the oncological sciences in general have made an important and lasting impact on us all.

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.

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.

Neurohypophyseal hormone regulation of endothelin secretion from rabbit endometrial cells in primary culture.

Immunoreactive endothelin-1 (IR-ET-1) was detected in the cultured medium from endometrial but not myometrial cells of rabbits in primary culture using a specific radioimmuno assay (RIA). Similar results were obtained with a radioreceptor assay using myometrial membranes. In a reverse-phase HPLC synthetic ET-1 and IR-ET-1 of the extract medium from endometrial cells revealed essentially the same elution profiles, as determined by RIA. Two selective agonists of oxytocin (OT) or V1 vasopressin (VP) receptors produced, respectively, a 6- and 2-fold increase of IR-ET-1 release from endometrial cells. These effects were completely reversed by the addition of two specific antagonists of OT and V1 VP receptors. Our results indicate that ET-1 is produced and released in the culture medium of rabbit endometrial cells in primary culture. The release of ET-1 is under receptor-specific control by neurohypophyseal hormones.

Anterior pituitary hormonal regulation of testicular gonadotropin-releasing hormone receptors.

Testicular GnRH receptors are increased 2-fold 1 day after hypophysectomy and remain elevated for up to 6 days. Consequently, the present study was undertaken to determine which pituitary hormone(s) regulated testicular GnRH receptors. Adult male rats were hypophysectomized and injected sc every 8 h for 2 days with LH, FSH, GH, PRL, estradiol, testosterone, 5 alpha-dihydrotestosterone, and vehicle (controls), beginning within 5 h of surgery. The animals were decapitated on the third day after hypophysectomy, the testes were excised, and interstitial tissue was teased from seminiferous tubules before storage at -70 C until assayed. The analog D-Ala6-des-Gly10-GnRH ethylamide was used to assess GnRH receptors on 10,800 X g-membrane fractions of interstitial tissue. The administration of GH, PRL, and FSH at concentrations which maintained LH receptors in adult or immature hypophysectomized rats did not prevent the increase in GnRH receptors, whereas LH replacement prevented the rise in GnRH analog binding in a dose related manner. LH also reduced preexisting posthypophysectomy increases in GnRH receptor concentrations. Injections of estradiol (5 micrograms/day) partially inhibited the posthypophysectomy increase in GnRH receptors, whereas the androgens 5 alpha-dihydrotestosterone and testosterone were ineffective. These results indicate that LH can regulate testicular GnRH receptors. Since GnRH directly inhibits testosterone secretion, inhibition of testicular GnRH receptors by LH may be one of the mechanisms by which LH replacement enhances testosterone production after hypophysectomy.

Interrelations of dietary and hormonal effects in aging.

A model system is proposed which suggests that aging involves a genetically programmed process encoded within specific regions of the central nervous system and is characterized by a gradual ascendency of inhibitory over excitatory influences. The resulting neural suppression reduces tonic stimulation to the hypothalamus-pituitary-endocrine axis, the autonomic nervous system and the spinal cord, and promotes the secretion of inactive pituitary hormone, the involution of the somatic musculature (smooth, cardiac and striated) and the compromise of secretomotor function. Experimental observation from nutritional restriction studies which include the prolongation of the life-span and delays in reproductive and homeostatic aging, degenerative coat changes and the appearance of neoplasia, are considered from the perspective of this hypothesis.

Chronic neuroendocrinological sequelae of radiation therapy.

A variety of neuroendocrine disturbances are observed following treatment with external radiation therapy when the hypothalamic-pituitary axis (HPA) is included in the treatment field. Radiation-induced abnormalities are generally dose dependent and may develop many years after irradiation. Growth hormone deficiency and premature sexual development can occur following doses as low as 18 Gy fractionated radiation and are the most common neuroendocrine problems noted in children. Deficiency of gonadotropins, thyroid stimulating hormone, and adrenocorticotropin are seen primarily in individuals treated with > 40 Gy HPA irradiation. Hyperprolactinemia can be seen following high-dose radiotherapy (> 40 Gy), especially among young women. Most neuroendocrine disturbances that develop as a result of HPA irradiation are treatable; patients at risk require long-term endocrine follow-up.

The endocrinology of obesity.

Numerous endocrine alterations are associated with obesity (Table 1). The majority of the alterations are secondary to obesity and must be considered simply associated and potentially in the pathogenesis of the complications of obesity. The discovery of new endocrine peptides such as leptin that signal body fat content will increase our understanding of the regulation of body fat content. As a result, therapies will most certainly be developed that are directly targeted at the alterations in endocrine function.

Identification of MIF as a new pituitary hormone and macrophage cytokine and its role in endotoxic shock.

The protein mediator described originally as macrophage migration inhibitory factor has been "rediscovered" to be both a novel pituitary hormone and a pro-inflammatory, macrophage-derived cytokine. MIF plays a pivotal role in the host response to endotoxic shock and appears to serve as a pituitary "stress" hormone that regulates systemic inflammatory responses.

Pituitary regulation of Leydig cell function in the adult male rat.

The effects of hypophysectomy on serum testosterone, 125I-labelled hCG binding to testicular membranes and on testicular responsiveness were studied in adult rats. Serum testosterone decreased rapidly over the first 6 h after hypophysectomy. LH receptors were determined (pmol/testis) by measuring the specific binding of 125I-labelled hCG in membrane preparations of testes of rats hypophysectomized 1, 2, 3, 6, 9, or 15 days earlier. Hypophysectomy did not result in a decrease in 125I-labelled hCG binding on day 1 but this had decreased to 40% of that in intact controls by day 2. A gradual decline was found between days 2 and 6 at which time hCG binding had decreased to 15%. No further decrease occurred between days 6 and 15. Scatchard analysis indicated that the decline in hCG binding was due to a decreaffinity. FSH, testosterone, dihydrotestosterone, and oestradiol were unable to prevent the decline in hCG binding. Although serum testosterone, testicular testosterone content, and 125I-labelled hCG binding decreased rapidly after hypophysectomy, testicular responsiveness to LH was biphasic. The intraperitoneal administration of 25 microgram LH 2 h before decapitation increased testosterone in the circulation to a greater extent extent in animals hypophysectomized for 1 day than in intact controls while hCG binding affinities and capacities had not changed. Two or three days after hypophysectomy testicular responsiveness to LH was similar to that of intact controls even though hCG binding in hypophysectomized animals had decreased to 40 and 28% of intact controls respectively. It is concluded that (1) the testis is dependent on anterior pituitary hormones for maintenance of testicular LH receptors and testosterone secretion, (2) FSH, testosterone, dihydrotestosterone, or oestradiol cannot prevent the decline in testicular LH receptors resulting from hypophysectomy, and (3) steroidogenic capacity of the testis persists significantly longer than the hCG binding capacity of the testis.