Anatomy, Physiology, and Laboratory Evaluation of the Pituitary Gland.

The pituitary gland functions prominently in the control of most endocrine systems in the body. Diverse processes such as metabolism, growth, reproduction, and water balance are tightly regulated by the pituitary in conjunction with the hypothalamus and various downstream endocrine organs. Benign tumors of the pituitary gland are the primary cause of pituitary pathology and can result in inappropriate secretion of pituitary hormones or loss of pituitary function. First-line management of clinically significant tumors often involves surgical resection. Understanding of normal pituitary physiology and basic testing strategies to assess for pituitary dysfunction should be familiar to any skull base surgeon.

60 YEARS OF NEUROENDOCRINOLOGY: The structure of the neuroendocrine hypothalamus: the neuroanatomical legacy of Geoffrey Harris.

In November 1955, Geoffrey Harris published a paper based on the Christian A Herter Lecture he had given earlier that year at Johns Hopkins University in Baltimore, MD, USA. The paper reviewed the contemporary research that was starting to explain how the hypothalamus controlled the pituitary gland. In the process of doing so, Harris introduced a set of properties that helped define the neuroendocrine hypothalamus. They included: i) three criteria that putative releasing factors for adenohypophysial hormones would have to fulfill; ii) an analogy between the representation of body parts in the sensory and motor cortices and the spatial localization of neuroendocrine function in the hypothalamus; and iii) the idea that neuroendocrine neurons are motor neurons and the pituitary stalk functions as a Sherringtonian final common pathway through which the impact of sensory and emotional events on neuroendocrine neurons must pass in order to control pituitary hormone release. Were these properties a sign that the major neuroscientific discoveries that were being made in the early 1950s were beginning to influence neuroendocrinology? This Thematic Review discusses two main points: the context and significance of Harris's Herter Lecture for how our understanding of neuroendocrine anatomy (particularly as it relates to the control of the adenohypophysis) has developed since 1955; and, within this framework, how novel and powerful techniques are currently taking our understanding of the structure of the neuroendocrine hypothalamus to new levels.

Effect of bajijiasu isolated from Morinda officinalis F. C. how on sexual function in male mice and its antioxidant protection of human sperm.

ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, the physiological aspects of human fertility have been seriously influenced by the interactions of genetic and environmental factors. Almost one in 20 males has been affected by male infertility, providing a great challenge and an opportunity to use natural compounds as alternatives to chemical drugs with comprehensive adverse effects. However, ample evidences are scanty to support the physiological mechanisms of natural compounds used to treat male infertility. In traditional Chinese medicine, Morinda officinalis F. C. How is widely used as a herb that invigorates the kidneys and supports yang, the original energy in the human body, to resist diseases and in treating male infertility. In this study, we evaluated whether bajijiasu isolated from the roots of M. officinalis F.C. How is a potential agent for the treatment of male infertility. MATERIALS AND METHOD: In this study, both normal and kidney-yang-deficient mice were administered bajijiasu orally at different concentrations. To determine the pharmacological mechanism of bajijiasu, we observed the sexual behavior and genital organ coefficients, determined their serum hormone levels, analyzed their sperm quality parameters, and examined histopathological sections from them. We also used enzymatic assays to determine the effects of bajijiasu on superoxide dismutase, glutathione peroxidase, and malondialdehyde. Confocal micro-Raman spectroscopy was used to investigate the changes in the DNA of H2O2-damaged human sperm after treatment with bajijiasu in vitro. RESULTS: Our results showed that bajijiasu enhanced the sexual behavior of both normal and kidney-yang-deficient mice. It also markedly increased the testosterone concentrations, reduced the levels of cortisol, improved the quality of the sperm, and counteracted the histopathological impairment induced by hydroxyurea in the kidney-yang-deficient mice. The enzymatic assay and Raman spectra showed that bajijiasu protects the DNA of sperm from damage by H2O2. CONCLUSION: Bajijiasu is a potential androgen-like drug that modulates hormone levels to some extent without producing reproductive-organ lesions, enhances the sexual function of male mice, and protects the DNA of human sperm from H2O2 damage. Thus, bajijiasu is an active ingredient of M. officinalis F.C. How that improves the human reproductive capacity.

Effects of genistein on stereological and hormonal characteristics of the pituitary somatotrophs in rats.

The hypothalamic-pituitary somatotropic system plays a pivotal role in the regulation of physiological processes and metabolism, which is modulated by gonadal steroids. Considering that genistein belongs to the phytoestrogen family and acts via similar mechanisms to estrogens, the present study was designed to demonstrate whether genistein modulates the morphofunctional characteristic of somatotrophs [growth hormone (GH) cells] in adult rats in comparison with the effects of estradiol. In the study, the orchidectomized adult rats were used as an appropriate model system for testing the effects of this hormone-like substance. Changes in the pituitary somatotrophs were evaluated histologically and stereologically, while GH level was determined biochemically. Using immunolabelling and stereological methods, we showed that orchidectomy (Orx) provoked the decrease of GH cell volume density. After estradiol treatment of Orx rats, the most prominent change concerned the pituitary relative intensity of GH fluorescence and circulating GH level, which were elevated 77 % and 4.7-fold, respectively. Clearly, in contrast to orchidectomy, estradiol treatment enhanced the GH cells activity. Genistein treatment increased pituitary weight and volume, GH cell volume density, the total number of GH cells, and GH blood concentration (1.3-fold) in comparison to the Orx group. Although identical tendencies followed estradiol and genistein administration, the changes observed after genistein treatment were milder compared to estradiol treatment.

Acute inflammation increases pituitary and hypothalamic glycoprotein hormone subunit B5 mRNA expression in association with decreased thyrotrophin receptor mRNA expression in mice.

The biological function of thyrostimulin, consisting of the GPA2 and GPB5 subunit, is currently poorly understood. The recent observation that pro-inflammatory cytokines up-regulate the transcription of GPB5 in vitro suggested a role for thyrostimulin in the nonthyroidal illness syndrome, a state of altered thyroid hormone metabolism occurring during illness. In the present study, we used GPB5 knockout (GPB5(-/-) ) and wild-type (WT) mice to evaluate the role of GPB5 in the pituitary and hypothalamus during acute inflammation induced by lipopolysaccharide (LPS, bacterial endotoxin) administration. We evaluated serum thyroid hormones and mRNA expression of genes involved in thyroid hormone metabolism in the pituitary and in two hypothalamic regions; the periventricular region (PE) and the arcuate nucleus/median eminence region. As expected, LPS administration increased deiodinase type 2 mRNA in the PE, at the same time as decreasing pituitary thyrotrophin (TSH)ß mRNA and serum thyroxine and triiodothyronine both in GPB5(-/-) and WT mice. GPB5 mRNA, but not GPA2 mRNA, markedly increased after LPS in the pituitary (200-fold) and hypothalamus of WT mice. In addition, we found large (>50%) suppression of TSH receptor (TSHR) mRNA in the pituitary and hypothalamus of WT mice but not in GPB5(-/-) mice. In conclusion, our results demonstrate in vivo regulation of central GPB5 transcription during acute illness. The observed differences between GPB5(-/-) and WT mice point to a distinct role for GPB5 in pituitary and hypothalamic TSHR suppression during acute illness.

Effects of laser irradiation of acupuncture points Shenshu on ovariectomized rats.

BACKGROUND AND OBJECTIVE: The effect of laser acupuncture on obesity in postmenopausal women remains unknown. The aim of this study was to investigate the effects of this form of treatment using an animal model. MATERIALS AND METHODS: Seventy-seven female Sprague-Dawley rats were assigned into seven groups: normal control (Normal), sham-operation control (Sham), ovariectomized (OVX) control rats (OVX), OVX rats treated with estrogen (OVX + E), and three groups of ovariectomized rats treated with laser acupuncture (OVX + L). Bilateral ovaries were removed to decrease estrogen levels. After 2 wk, semiconductor laser irradiation was administered to bilateral Shenshu (BL 23) acupoints of rats in the three OVX + L groups at 12, 30, and 60 J/cm(2), respectively. Changes in body weight and pituitary estrogen receptor (ER) mRNA expression were analyzed. Morphological differences in the uterus and pituitary glands were also observed. RESULTS: The OVX group exhibited marked weight gain and a significant decrease in pituitary ERα mRNA expression. Semiconductor laser irradiation at 30 J/cm(2) reduced body weight and increased ERα expression compared with the control, whereas irradiation at 12 or 60 J/cm(2) presented slightly weaker effects. Significant differences in pituitary ERß mRNA were not observed due to lack of optical density data. CONCLUSIONS: The semiconductor laser irradiation of bilateral Shenshu (BL 23) acupoints can exert beneficial effects on OVX rats through reducing body weight and increasing pituitary ERα expression, and 30 J/cm(2) was the most effective dose among those used.

Reverse feeding suppresses the activity of the GH axis in rats and induces a preobesogenic state.

Reversed feeding (RF) is known to disrupt hormone rhythmicity and metabolism. Although these effects may be mediated in part by phase inversion of glucocorticoid secretion, the precise mechanism is incompletely characterized. In this study, we demonstrate that acute nocturnal food deprivation in male rats suppressed the amplitude of spontaneous GH secretion during the dark phase by 62% (P < 0.001), without affecting baseline secretion. Prolonged RF, which reduced pituitary weight (by 22%; P < 0.05), also suppressed GH pulse height sufficiently to reduce skeletal growth (by 4-5%; P < 0.01) and terminal liver weight (by 11%; P < 0.001). Despite this suppression of the GH axis, proportionate adiposity was not elevated, probably due to the accompanying 16% reduction in cumulative food intake (P < 0.01). We demonstrate that RF also resulted in phase inversion of core clock gene expression in liver, abdominal white adipose tissue (WAT) and skeletal muscle, without affecting their expression patterns in the suprachiasmatic nucleus. In addition, RF resulted in phase inversion of hepatic peroxisome proliferator-activated receptor γ2 mRNA expression, a 3- to 5-fold elevation in fatty acid synthase mRNA in WAT in both light- and dark-phase samples (P < 0.01) and an elevation in muscle uncoupling protein 3 mRNA expression at the beginning of the light phase (P < 0.01). Consumption of a high-fat diet increased inguinal (by 36%; P < 0.05) and retroperitoneal WAT weight (by 72%; P < 0.01) only in RF-maintained rats, doubling the efficiency of lipid accumulation (P < 0.05). Thus, RF not only desynchronizes central and peripheral circadian clocks, and suppresses nocturnal GH secretion, but induces a preobesogenic state.

HPG-axis hormones during puberty: a study on the association with hypothalamic and pituitary volumes.

OBJECTIVE: During puberty, the hypothalamus-pituitary-gonadal (HPG) axis is activated, leading to increases in luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex steroids (testosterone and estradiol) levels. We aimed to study the association between hypothalamic and pituitary volumes and development of pubertal hormones in healthy pubertal children. METHOD: Hormone levels of LH, FSH, estradiol (measured in urine) and testosterone (measured in saliva) were assessed in 85 healthy children (39 boys, 46 girls) between 10 and 15 years of age. Hypothalamic and pituitary gland volumes were segmented on high resolution structural MRI scans. Since sex hormone production is regulated in a sex-specific manner, associations between hormones, hypothalamus and pituitary were analyzed in boys and girls separately. RESULTS: LH, estradiol and testosterone levels all increased with age in both sexes, whereas FSH level did not. Pituitary volume also increased with age and explained 12%, 10% and 8% of the variance in female estradiol, testosterone and LH levels respectively. Corrected for age, pituitary volume explained 17% of FSH level in girls (not boys). Hypothalamic volume did not change with age and did not significantly explain variance in any hormonal level. DISCUSSION: Our study suggests that a larger pituitary volume is related to higher FSH production, but this association seems independent of pubertal development. The positive association between estradiol, LH and testosterone and pituitary volume is related to age-related pubertal development. With respect to the hypothalamus, we did not find convincing evidence for a larger structure to be involved in elevated hormonal production.

Pituitary adenoma: a radiotherapeutic perspective.

Pituitary adenomas comprise approximately 10% to 20% of all central nervous system neoplasms whereas autopsy series have suggested that the incidence of pituitary adenoma in the general population may approach 25%. Several treatment modalities are used in the treatment of pituitary adenomas, including observation, surgery, medical intervention, and radiotherapy. The treatment modality employed depends greatly on the type of pituitary adenoma and presenting symptoms. This review will discuss the biology of pituitary adenomas and the current management principles for the treatment of prolactinomas, Cushing disease, acromegaly, and nonsecretory adenomas, with an emphasis on the published radiotherapeutic literature.

Neuroanatomical distribution of MCH in the brain and pituitary of submammalian vertebrates.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that has been initially characterized from a salmon pituitary extract and subsequently identified in various species from all classes of vertebrates. The present review summarizes the current knowledge regarding the neuroanatomical distribution of MCH-immunoreactive neurons in submammalian vertebrates. In all species examined, MCH-immunoreactive perikarya are confined to the hypothalamus, with the exception of the cyclostome Lampetra fluvialis and the lungfish Protopterus annectens, in which additional populations of MCH-immunoreactive cell bodies occur in the telencephalon, and the frogs Rana ridibunda and Rana esculenta which exhibit MCH-positive perikarya in thalamic nuclei. In teleosts, in the frog R. ridibunda and in the L. fluvialis, MCH is present in the classical hypothalamic-neurohypophysial system indicating that the peptide may play the role of a neurohormone. In other groups, MCH-immunoreactive nerve fibers are widely distributed in various brain regions suggesting that, in these species, MCH in the central nervous system may act as a neurotransmitter or/and a neuromodulator rather than a neurohormone.

Age- and hormone-regulation of N-methyl-D-aspartate receptor subunit NR2b in the anteroventral periventricular nucleus of the female rat: implications for reproductive senescence.

Glutamate, acting through its N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the hypothalamus, regulates reproductive neuroendocrine functions via direct and indirect actions upon gonadotrophin-releasing hormone (GnRH) neurones. Previous studies indicate that the NMDA receptor subunit NR2b undergoes changes in protein and gene expression in the hypothalamus in general, and on GnRH neurones in particular, during reproductive ageing. In the present study, we examined whether the NR2b-expressing cell population, both alone and in association with the NR1 subunit (i.e. the latter subunit is necessary for a functional NMDA receptor), is altered as a function of age and / or steroid hormone treatment. Studies focused on the anteroventral periventricular (AVPV) nucleus of the hypothalamus, a region critically involved in the control of reproduction. Young (3-5 months), middle-aged (9-12 months), and aged (approximately 22 months) female rats were ovariectomised and, 1 month later, they were treated sequentially with oestradiol plus progesterone, oestradiol plus vehicle, or vehicle plus vehicle, then perfused. Quantitative stereologic analysis of NR2b-immunoreactive cell numbers in the AVPV showed an age-associated decrease in the density of NR2b-immunoreactive cells, but no effect of hormone treatment. In a second study, immunofluorescent double labelling of NR2b and NR1 was analysed by confocal microscopy of fraction volume, a semi-quantitative measure of fluorescence intensity. No effect of ageing was detected for immunofluorescent NR1 or NR2b alone, whereas the NR2b fraction volume increased in the oestradiol plus vehicle group. With ageing, the fraction volume of the NR2b/NR1-colocalised subunits increased. Together with the stereology results, this suggests that, although fewer cells express the NR2b subunit in the ageing AVPV, a greater percentage of these subunits are co-expressed with NR1. Our results suggest that the subunit composition of NMDA receptors in the AVPV undergo both age- and hormonal-regulation, which may be related to previous observations of changes in functional responses of reproductive neuroendocrine systems to NMDA receptor modulators with ageing.

17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.

Low-voltage-activated (T-type) calcium channels are responsible for burst firing and transmitter release in neurons and are important for exocytosis and hormone secretion in pituitary cells. T-type channels contain an alpha1 subunit, of which there are three subtypes, Cav3.1, -3.2, and -3.3, and each subtype has distinct kinetic characteristics. Although 17beta-estradiol (E2) modulates T-type calcium channel expression and function, little is known about the molecular mechanisms involved. We used real-time PCR quantification of RNA extracted from hypothalamic nuclei and pituitary in vehicle and E2-treated C57BL/6 mice to elucidate E2-mediated regulation of Cav3.1, -3.2, and -3.3 subunits. The three subunits were expressed in both the hypothalamus and the pituitary. E2 treatment increased the mRNA expression of Cav3.1 and -3.2, but not Cav3.3, in the medial preoptic area and the arcuate nucleus. In the pituitary, Cav3.1 was increased with E2 treatment, and Cav3.2 and -3.3 were decreased. To examine whether the classical estrogen receptors (ERs) were involved in the regulation, we used ERalpha- and ERbeta-deficient C57BL/6 mice and explored the effects of E2 on T-type channel subtypes. Indeed, we found that the E2-induced increase in Cav3.1 in the hypothalamus was dependent on ERalpha, whereas the E2 effect on Cav3.2 was dependent on both ERalpha and ERbeta. However, the E2-induced effects in the pituitary were dependent on only the expression of ERalpha. The robust E2 regulation of T-type calcium channels could be an important mechanism by which E2 increases the excitability of hypothalamic neurons and modulates pituitary secretion.

Neuroimaging in posttraumatic hypopituitarism.

Posttraumatic hypopituitarism is the failure of the hypothalamic-pituitary axis secondary to traumatic brain injury. It can clinically present as decreased muscle mass, concentration, libido, and fertility. It can also present as increased fatigue, depression, and cognitive deficits. In addition, electrolyte abnormalities such as hyponatremia can occur in hypopituitarism. As a result of heightened awareness of posttraumatic hypopituitarism, it is a phenomenon that is becoming more commonly diagnosed. Posttraumatic hypopituitarism is a diagnosis based on clinical evaluation, laboratory testing, and neuroimaging. Of the radiological techniques, magnetic resonance imaging is the preferred technique to image the pituitary gland. This article contains coronal and sagittal magnetic resonance imaging of the posterior fossa, illustrating the normal hypothalamus and pituitary gland as well as adjacent structures. The sequential enhancement pattern of the normal pituitary gland is consistent with its vascular supply. A colored illustration was created to display the vascular supply to the hypothalamus, pituitary stalk, and pituitary gland.

Thyrotrophin in the pars tuberalis triggers photoperiodic response.

Molecular mechanisms regulating animal seasonal breeding in response to changing photoperiod are not well understood. Rapid induction of gene expression of thyroid-hormone-activating enzyme (type 2 deiodinase, DIO2) in the mediobasal hypothalamus (MBH) of the Japanese quail (Coturnix japonica) is the earliest event yet recorded in the photoperiodic signal transduction pathway. Here we show cascades of gene expression in the quail MBH associated with the initiation of photoinduced secretion of luteinizing hormone. We identified two waves of gene expression. The first was initiated about 14 h after dawn of the first long day and included increased thyrotrophin (TSH) beta-subunit expression in the pars tuberalis; the second occurred approximately 4 h later and included increased expression of DIO2. Intracerebroventricular (ICV) administration of TSH to short-day quail stimulated gonadal growth and expression of DIO2 which was shown to be mediated through a TSH receptor-cyclic AMP (cAMP) signalling pathway. Increased TSH in the pars tuberalis therefore seems to trigger long-day photoinduced seasonal breeding.

Effect of Achyranthes aspera L. on fetal abortion, uterine and pituitary weights, serum lipids and hormones.

BACKGROUND: The practice of traditional medicine for the control of fertility in rural Ethiopia is based on folk use of numerous antifertility herbs and Achyranthes aspera is one of these used for this purpose. Many plants are known to possess anti-fertility effect through their action on hypothlamo-pituitary-gonadal axis or direct hormonal effects on reproductive organs resulting in inhibition of ovarian steroidogenesis. OBJECTIVES: The present study focused to investigate the effect of methanolic leaves extract of Achyranthes aspera L. on some indicators for anti-fertility activities such as abortifacient, estrogenesity, pituitary weight, and ovarian hormone level and lipids profile in female rats, in attempt to validate the traditional claim. METHODS: The abortifacient effect of the methanolic extract of the leaves of Achyranthes aspera was determined by counting the dead fetuses in vivo. Effect on estrogenesity was assessed by taking the ratio of the uterine weight to body weight. The ratio of the pituitary weight to body weight was also calculated. The effect of the extract on the level of ovarian hormones and lipid profile was evaluated using electrochemiluminescence immunoassay. RESULTS: The extract showed significant (p<0.05) abortifacient activity and increased pituitary and uterine wet weights in ovarectimized rats. The extract, however, did not significantly influence serum concentration of the ovarian hormones and various lipids except lowering HDL at doses tested. CONCLUSION: The methanolic leaves extract of Achyranthes aspera possesses anti-fertility activity, which might be exploited to prevent unwanted pregnancy and control the ever-increasing population explosion.

Magnetic resonance imaging of the hypothalamus-pituitary unit in childrensuspected of hypopituitarism: who, how and when toinvestigate.

The magnetic resonance (MR) identification of pituitary hyperintensity in the posterior part of the sella has been the most striking recent finding contributing to the diagnosis of "idiopathic" and permanent GH deficiency (GHD). Moreover, advancements in DNA technology have shed new light on the study of the genetic causes of hypopituitarism. Abnormalities in two genes, the GH-N encoding the GH and the GHRH receptor (GHRH-R), have been identified, while mutations in five other gene-encoding transcription factors such as Pit-1, Prop-1, Hesx-1, Lhx-3 and Lhx-4 involved in anterior pituitary development, have also been described. MR imaging shows marked differences in pituitary morphology indicating different GHD etiologies and different prognoses. Ectopic posterior pituitary is a specific marker of permanent GHD. These patients do not have Pit-1, Prop-1, or Lhx-3 mutations and should be carefully monitored for evolving pituitary hormone defects, though they do not require GH re-evaluation in adulthood; selected cases may have Hesx-1 or Lhx-4 mutations. MR evidence of normal or small anterior pituitary gland, enlarged empty sella, pituitary hyperplasia and/or intrasellar or suprasellar mass when associated with combined pituitary hormone deficiency call for molecular analysis of Pit-1, Prop-1, Hesx-1, or Lhx-3. Limitation of neck rotation and Chiari-I malformation may suggest Lhx-3 or Lhx-4 mutations (exceedingly rare). In "idiopathic" isolated GHD, evidence of normal anterior or small anterior pituitary size with normal location of posterior pituitary and normal connection between the hypothalamus and pituitary gland is suggestive of "transitory" or false positive GHD; patients with such characteristics should be re-evaluated well before reaching adult height. In selected cases, anterior pituitary height that is 2 SD below age-adjusted normal pituitary height could be suggestive of GHRH-R gene defect; it is worth pointing out that normal pituitary MR together with severe GHD has been observed, though rarely, in subjects with a genetic origin of GHD.

Re-evaluation of the afferent connections of the pituitary in the weakly electric fish Apteronotus leptorhynchus: an in vitro tract-tracing study.

The pituitary plays a key role in the interaction between the brain and the endocrine system. We re-examined the afferent connections of the pituitary in the weakly electric fish Apteronotus leptorhynchus using the in vitro application of dextran-tetramethylrhodamine to the pituitary. The resultant retrograde labeling was analyzed. Application of the tracer to the rostral part, but not the caudal part, of the pituitary labels hypothalamic cells in the anterior division of the periventricular nucleus, the suprachiasmatic nucleus, and the nucleus tuberis lateralis pars anterior. Application of the tracer to either the rostral or caudal parts of the pituitary labels hypothalamic cells in the posterior division of the periventricular nucleus (RPPp), the nucleus hypothalamus caudalis (Hc), the nucleus hypothalamus anterioris, the ventral hypothalamic nucleus, and the central nucleus of the inferior lobe. Furthermore, cells in the rostral two-thirds of the brainstem reticular formation (RF) project to the entire rostrocaudal extent of the pituitary. The largest projections to the pituitary are from Hc, PPp, and RF. Of the cells in Hc that project to the pituitary, almost all (96%) are small and the remainder are medium-sized. Of the cells in PPp that project to the pituitary, about half are small or medium-sized (44% and 56%, respectively). In Hc and PPp, about one-third to one-half of the cells that project to the pituitary are markedly elongated. The cells in RF that project to the pituitary are small (4%), medium-sized (89%), or large (7%) and about four-fifths of these cells are markedly elongated. With regard to the RF projections, the pituitary may receive copies of motor instructions and sensory information supplied by collaterals of the descending and ascending projection systems of RF cells. Thus, the ongoing motor activity of the animal and the ensuing sensory feedback from this activity could directly influence the pituitary.