Pituitary Responsiveness Research Articles

High-dose recombinant LH add-back strategy using high-dose GnRH antagonist is an innovative protocol compared with standard GnRH antagonist

High daily doses of gonadotrophin-releasing hormone (GnRH) antagonists during the follicular phase of ovarian stimulation were associated with low implantation rates. To test if this occurred because of profound pituitary suppression, the pituitary response was suppressed with a high-dose GnRH antagonist and recombinant LH (rLH) was added back to correct the implantation rate. An open-label, randomized, controlled, prospective clinical study in 60 patients undergoing IVF was performed. GnRH antagonist was initiated on day 6 of stimulation (2 mg/day) together with 375 IU rLH, and maintained until the day of HCG administration. Controls received 0.25 mg/day GnRH antagonist. Fluctuating LH concentrations were present on days 3 and 6 in both groups. This strong fluctuation continued on day 8 and on the day of HCG administration in the control (low-dose) group, where 30% of patients had LH concentrations <1 IU/1 on the HCG day. The study (high-dose) group showed stable LH concentrations on day 8 and on the HCG day, with no LH surges. No clinical differences were found between groups. The LH add-back strategy (375 IU/day) rescued the adverse effects that high doses of GnRH imposed on implantation. These results suggest that rLH should be considered during ovarian stimulation with GnRH antagonist.

Functional characterization of the hypothalamic–pituitary–adrenal axis of the Wistar Audiogenic Rat (WAR) strain

The Wistar Audiogenic Rat (WAR) strain is a genetic model of sound-induced reflex epilepsy which was selected starting from audiogenic seizures susceptible Wistar rats. Wistar resistant rats were used as WAR's control in this study. In the acute situation, audiogenic seizures (AS) in WARs mimic tonic–clonic seizures and, in the chronic protocol, mimic temporal lobe epilepsy. AS have been shown to evoke neuroendocrine responses; however, the hypothalamic–pituitary–adrenal activity in the WAR has not been established. The aim of this study was to evaluate the hypothalamic–pituitary–adrenal axis (HPA) responses to exogenous ACTH stimulation (8ng/rat), fifteen minute restraint stress and circadian variation (8am and 8pm) under rest conditions in these animals through plasma measurements of ACTH and corticosterone concentrations. We also measured the body weight from birth to the 9th week of life and determined adrenal gland weight. We found that WARs are smaller than Wistar and presented a higher adrenal gland weight with a higher level of corticosterone release after intravenous ACTH injection. They also showed altered HPA axis circadian rhythms and responses to restraint stress. Our data indicate that, despite the lower body weight, WARs have increased adrenal gland weight associated with enhanced pituitary and adrenal responsiveness after HPA axis stimulation. Thus, we propose WARs as a model to study stress–epilepsy interactions and epilepsy–neuropsychiatry comorbidities.

The Effect of Short-Term Nutritional Supplementation and Body Condition on the Pituitary and Ovarian Responses of Anoestrous Ewes to the “Ram Effect”

The Effect of Short-Term Nutritional Supplementation and Body Condition on the Pituitary and Ovarian Responses of Anoestrous Ewes to the “Ram Effect”

A Yogurt of the Future as an Anxiety Treatment

Over the past few years, research in rodents has revealed the existence of a “microbiota–gut–brain axis,” through which microbial actions are mediated through vagal afferent nerves to affect functional bowel disorders, hypothalamic–pituitary–adrenal axis stress responses, and anxiety behaviors. Now, researchers from two laboratories using slightly different …

Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood

There are well-recognized sex differences in many pituitary endocrine axes, usually thought to be generated by gonadal steroid imprinting of the neuroendocrine hypothalamus. However, the recognition that growth hormone (GH) cells are arranged in functionally organized networks raises the possibility that the responses of the network are different in males and females. We studied this by directly monitoring the calcium responses to an identical GH-releasing hormone (GHRH) stimulus in populations of individual GH cells in slices taken from male and female murine GH-eGFP pituitary glands. We found that the GH cell network responses are sexually dimorphic, with a higher proportion of responding cells in males than in females, correlated with greater GH release from male slices. Repetitive waves of calcium spiking activity were triggered by GHRH in some males, but were never observed in females. This was not due to a permanent difference in the network architecture between male and female mice; rather, the sex difference in the proportions of GH cells responding to GHRH were switched by postpubertal gonadectomy and reversed with hormone replacements, suggesting that the network responses are dynamically regulated in adulthood by gonadal steroids. Thus, the pituitary gland contributes to the sexually dimorphic patterns of GH secretion that play an important role in differences in growth and metabolism between the sexes.

Effect of LPS on Reproductive System at the Level of the Pituitary of Anestrous Ewes

In our research we focused our attention on the effect of the immune stress induced by bacterial endotoxin-lipopolysaccharide (LPS) on the hypothalamic-pituitary-gonadal axis (HPG) at the pituitary level. We examined the effect of intravenous (i.v.) LPS injection on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release from the anterior pituitary gland (AP) in anestrous ewes. The effect of endotoxin on prolactin and cortisol circulating levels was also determined. We also researched the effect of immune challenge on the previously mentioned pituitary hormones and their receptors genes expression in the AP. Our results demonstrate that i.v. LPS injection decreased the plasma concentration of LH (23%; p < 0.05) and stimulates cortisol (245%; p < 0.05) and prolactin (60%; p < 0.05) release but has no significant effect on the FSH release assayed during 6 h after LPS treatment in comparison with the control levels. The LPS administration affected the genes expression of gonadotropins' β-subunits, prolactin and their receptors in the AP. Endotoxin injection significantly decreased the LHβ and LH receptor (LHR) gene expression (60%, 64%; p < 0.01 respectively), increased the amount of mRNA encoding FSHβ, FSH receptor (FSHR) (124%, 0.05; 166%, p < 0.01; respectively), prolactin and prolactin receptor (PRLR) (50%, 47%, p < 0.01; respectively). The presented, results suggest that immune stress is a powerful modulator of the HPG axis at the pituitary level. The changes in LH secretion could be an effect of the processes occurring in the hypothalamus. However, the direct effect of immune mediators, prolactin, cortisol and other components of the hypothalamic pituitary-adrenal (HPA) axis on the activity of gonadotropes has to be considered as well. Those molecules could affect LH synthesis directly through a modulation at all stages of LHβ secretion as well as indirectly influencing the GnRHR expression and leading to reduced pituitary responsiveness to GnRH stimulation.

PPARG Regulates Gonadotropin-Releasing Hormone Signaling in LbetaT2 Cells In Vitro and Pituitary Gonadotroph Function In Vivo in Mice1

Peroxisome proliferators-activated receptor gamma (PPARG) ligands improve insulin sensitivity in type 2 diabetes and polycystic ovarian syndrome (PCOS). Despite clinical studies showing normalization of pituitary responsiveness to gonadotropin-releasing hormone (GnRH) in patients with PCOS, the precise role of PPARG in regulating the hypothalamic-pituitary-gonadal axis remains unclear. In the present study, we tested the hypothesis that the PPARG agonist rosiglitazone has a direct effect on the pituitary. In mouse LbetaT2 immortalized gonadotrophs, rosiglitazone treatment inhibited GnRH stimulation of the stress kinases p38MAPK and MAPKs/JNKs, but did not alter activation of ERKs, both in the presence and absence of activin. Furthermore, p38MAPK signaling was critical for both Lhb and Fshb promoter activity, and rosiglitazone suppressed the GnRH-mediated induction of Lhb and Fshb mRNA. Depletion of PPARG using a lentivirally encoded short hairpin RNA abolishes the effect of rosiglitazone to suppress activation of JNKs and induction of the transcription factors EGR1 and FOS as well as the gonadotropin genes Lhb and Fshb. Lastly, we show conditional knockout of Pparg in pituitary gonadotrophs caused an increase in luteinizing hormone levels in female mice, a decrease in follicle-stimulating hormone in male mice, and a fertility defect characterized by reduced litter size. Taken together, our data support a direct role for PPARG in modulating pituitary function in vitro and in vivo.

Cognitive deficits in relation to personality type and hypothalamic‐pituitary‐adrenal (HPA) axis dysfunction in women with stress‐related exhaustion

Exhaustion caused by long-term work-related stress may cause cognitive dysfunction. We explored factors that may link chronic stress and cognitive impairment. Personality, psychiatric screening, and behavior were assessed by self-reporting measures in 20 female patients (mean age 39.3 years; range 26-53) with a preliminary diagnosis of stress-related exhaustion and in 16 healthy matched controls. Cognitive performance was investigated with a detailed neuropsychological test battery. Cortisol axis function was assessed by urinary and saliva collections of cortisol, dexamethasone suppression, Synacthen response, and corticotropin-releasing hormone (CRH) tests. Proinflammatory cytokines were measured. Hippocampal volumes were estimated by magnetic resonance imaging. Multivariate and univariate statistical methods were used to explore putative differences between groups and factors linked to cognitive impairment. Cognitive function clearly differed between groups, with decreased attention and visuospatial memory in the patient group, suggesting frontal cortex/medial temporal cortex-network dysfunction. Increased harm avoidance and persistence was present among patients, with lowered self-directedness linked to lower quality of life, increased anxious and depressive tendencies, and experiences of psychosocial stress. Attention was decreased with concomitantly impaired visuospatial memory. The pituitary (adrenocorticotropic hormone, ACTH) response to CRH was decreased in patients, with an increased cortisol/ACTH response to CRH. However, cortisol production rates, diurnal or dexamethasone-suppressed saliva cortisol levels, and the cortisol response to Synacthen were unaltered. Hippocampal volumes did not differ between groups. These findings suggest that cognitive dysfunction in stress-related exhaustion is linked to distinct personality traits, low quality of life, and a decreased ACTH response to CRH.

Estrogen Negative Feedback on Gonadotropin Secretion: Evidence for a Direct Pituitary Effect in Women

Previous animal and human studies using low-dose estrogen have demonstrated estrogen negative feedback on gonadotropin secretion through gonadotropin-releasing hormone (GnRH) release at the level of the hypothalamus in women. Whether low-dose estrogen also exerts a direct negative feedback at the level of the pituitary is unclear due to insufficient data. In a recent study, a decrease was found in pituitary responsiveness to GnRH with aging in women. Studies in human beings aimed to establish a direct pituitary site of estrogen negative feedback and investigate the interaction of estrogen, and aging in the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) feedback loop have been hampered by the inability thus far to isolate the pituitary response from endogenous hypothalamic input. This study tested the hypothesis that estrogen has a direct negative feedback effect at the pituitary and also investigated whether this effect would vary with aging. Isolation of pituitary responsiveness from hypothalamic and ovarian input was achieved through blockade of the GnRH receptor using the NAL-GLU GnRH antagonist, followed by graded doses of GnRH before and after 1 month of estrogen administration. The participants were healthy postmenopausal women aged 48 to 56 years (n = 8) or 70 to 75 years (n = 8). After estrogen administration, there was a significant decrease in the LH (P = 0.01) and FSH (P = 0.0001) responses to GnRH in all study subjects. There was also a decrease in the ratio of FSH to LH amplitudes in response to GnRH (P = 0.04). The inhibitory effect of estrogen on FSH responses was significantly diminished with aging (P = 0.02). In contrast to FSH, LH responses were not significantly affected by aging (P = 0.4). These findings demonstrate that estrogen has a direct inhibitory effect on pituitary responsiveness to GnRH in women. This estrogen negative feedback diminishes with aging. FSH but not LH responses are inhibited by estrogen.

Octreotide administration, under particular temporal conditions, enhances the responses of growth hormone to growth hormone-releasing hormone in normal subjects

Somatostatin not only inhibits basal and GHRH-stimulated GH secretion but might also enhance pituitary GH responsivity to GHRH under different temporal conditions. We investigated whether octreotide, a long-acting somatostatin analogue, has any positive actions on GHRH-induced GH release in normal human subjects. The study consisted of three protocols. At 0800 hours, after fasting overnight, all subjects received 1 microgram/kg GHRH i.v. bolus at 0 minutes. In each protocol, either octreotide (200 micrograms s.c.) or placebo were given respectively 8, 12, or 16 hours prior to GHRH challenge. Three groups of eight normal volunteers (four female and four male in each group), aged 18-35 years, were randomly assigned to each protocol. Growth hormone was measured by IRMA. Samples for GH assay were taken at -30 and 0 minutes and then at 15-minute intervals up to 120 minutes. When placebo or octreotide were administered 8 hours before GHRH, peak GH levels were respectively (mean +/- SE, mU/l) 56.2 +/- 16.6 and 60.8 +/- 11.4 (NS). Also, when placebo or the somatostatin analogue were administered 16 hours prior to GHRH, peak GH levels were comparable (61.0 +/- 7.4 vs 58.8 +/- 7.4, NS). However, in the group receiving placebo or octreotide 12 hours prior to GHRH, the GH responses to GHRH were clearly enhanced by octreotide administration (peak GH levels, mU/l, 55.6 +/- 21.6 vs 104.0 +/- 17.4, P < 0.02). This enhancement of GH responses was observed in all subjects. Octreotide administration did not affect GH responses to GHRH when given either 8 or 16 hours prior to GHRH. However, octreotide enhanced GHRH-induced GH release when administered 12 hours prior to GHRH. It thus appears that, under particular temporal conditions, octreotide may act positively on GH secretion in man.

Ovarian reserve in young women with low birth weight and normal puberty: a pilot case–control study

Aim. Studies indicate that women born small for gestational age (SGA) have impaired ovarian function. The origin of this ovarian dysfunction is still debatable. The aim of this study was to compare ovarian ageing between girls born appropriate for gestational age (AGA) and SGA. Therefore, we measured Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), E2, Anti-Müllerian hormone (AMH) levels and the pituitary response to endogenous Gonadotropin-releasing hormone (GnRH) in adolescent girls born SGA and AGA.Methods. A case–controlled pilot study consisting of seven SGA women (birth weight <10th percentile AGA) and 13 AGA women with regular menstrual cycles, age 19.9 (±0.42). Early follicular FSH, LH, Oestradiol (E2) and AMH levels were measured. After baseline samples, 100 μg GnRH was administered intravenously and at 30, 60 and 90 min blood samples were taken to measure gonadotropin levels and to compute the response to endogenous GnRH.Results. Mean follicular phase LH, FSH, E2 and AMH levels did not significantly differ between young women born SGA and AGA. Furthermore, the response to endogenous GnRH showed no significant differences either.Conclusions. We concluded against extension of this pilot study. Based on our observations it seems unlikely that limited ovarian reserve is a predominated problem in adolescent SGA.

The effectiveness of vasopressin as an ACTH secretagogue in cattle differs with temperament

By using the temperament selection criterion of exit velocity (EV), cattle typically exhibiting hypercortisolism and a blunted response to exogenous corticotrophin-releasing hormone (CRH) can be identified via individual behavioral responses to handling. To further characterize hypothalamic–pituitary–adrenal (HPA) axis dysfunction associated with bovine temperament, the present study compared pituitary and adrenal activity, following stimulation with exogenous vasopressin (VP), in steers with an excitable or calm temperament. Serial blood samples were collected via indwelling jugular cannula for 6 h preceding and 6 h following administration of a VP bolus. Plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol were quantified by RIA to determine pituitary and adrenal responsiveness within temperament groups. Cortisol concentrations in excitable steers during the pre-challenge period revealed an increased initial adrenal reactivity to interactions with humans. Subsequent acclimation to the experimental surroundings yielded greater baseline cortisol concentrations in the cattle with an excitable temperament. Pituitary stimulation with VP resulted in a greater ACTH output from the excitable compared to the calm animals. The data presented herein provide additional evidence that HPA axis function in cattle of an excitable temperament may be akin to a state of chronic stress. The bovine temperament model may be of further use to both decipher mechanisms associated with HPA dysfunction and to elucidate physiological phenotypes or pathologies that have parallels in other species.

Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus.

Human genetics indicate that kisspeptin and neurokinin B (NKB) signaling are necessary for generating pulsatile LH release and therefore for initiation of puberty and maintaining gonadal function. In the present study, male monkeys were employed to examine 1) whether activation of the NKB receptor (NK3R) is associated with GnRH release, and 2) hypothalamic localization of these peptides using immunofluorescence histochemistry. Agonadal juveniles, in which pituitary responsiveness to GnRH was heightened by GnRH priming, were employed to indirectly examine GnRH-releasing actions of NK3R and kisspeptin receptor agonists by tracking LH after their i.v. injection. Castrated adults were used for immunohistochemistry. Single i.v. injections of NKB or senktide (an NK3R agonist) elicited robust LH discharges that were abolished by GnRH receptor antagonism (acyline) confirming the ligands' hypothalamic action. Intermittent infusion of senktide (1-min pulse every hour for 4 h), in contrast to that of kisspeptin, failed to sustain pulsatile GnRH release. Repetitive senktide injections did not compromise the GnRH-releasing action of kisspeptin. NKB and kisspeptin were colocalized in perikarya of the arcuate nucleus and in axonal projections to the median eminence, confirming earlier findings in sheep. These results are consistent with the human genetics, and indicate that although brief activation of NK3R stimulates GnRH release, repetitive stimulation of this pathway, in contrast to that of kisspeptin receptor, fails to sustain pulsatile GnRH release. In addition, the data provide a platform for future elucidation of the interactions between NKB and kisspeptin that are required for generating pulsatile GnRH release in primates.

Hypothalamic Pituitary Adrenal Axis Responses to Low‐Intensity Stressors are Reduced After Voluntary Wheel Running in Rats

Regular physical exercise is beneficial for both physical and mental health. By contrast, stress is associated with deleterious effects on health and there is growing evidence that regular physical exercise counteracts some of the effects of stress. However, most previous studies have suggested that prior exercise does not alter the acute hypothalamic pituitary adrenal (HPA) axis responses to stress. The present series of studies provides evidence that in rats, 6 weeks (but not 1 or 3 weeks) of voluntary wheel running reduces the HPA axis responses to lower-intensity stressors such as an i.p. saline injection, exposure to a novel environment or exposure to moderate intensity noise, but not to more intense stressors such as predator odour exposure or restraint. Daily exercise does not appear to be necessary for the reduction in HPA axis responses, with intermittent access (24 h out of each 72-h period) to a running wheel for 6 weeks, resulting in similar decrements in adrenocorticotrophic hormone and corticosterone release in response to 85 dBA noise exposure. Data from in situ hybridisation for c-fos mRNA are consistent with the hypothesis that voluntary exercise results in a decrease in HPA axis responsiveness to a low-intensity stressor at a central level, with no changes in primary sensory processing. Together, these data suggest that 6 weeks of daily or intermittent exercise constrains the HPA axis response to mild, but not more intense stressors, and that this regulation may be mediated at a central level beyond the primary sensory input.

Effects of housing and short-term transportation on hormone and lymphocyte receptor concentrations in beef cattle

The experiment was designed to evaluate the effects of housing system and short-term transportation on the pituitary and adrenal response and on blood progesterone concentrations of beef cattle. Since the use of steroid hormones in farm animals has been banned in the EU (Council Directive 96/22/EC), it seems important to study the possible modifications in serum progesterone concentrations induced by stress in cattle. Thirty-two, 6 months old male Piedmontese beef cattle (16 reared in a littered loose house, Group A, and 16 housed in a littered tying stall barn, Group B) were blood sampled at T1 (6 months old), T2 (12 months old), T3 (18 months old, before transportation to the slaughterhouse) and T4 (after transportation to the slaughterhouse) in order to measure hormonal concentrations and lymphocyte glucocorticoid (GR) and β-adrenergic (β-AR) receptor concentrations. Circulating hormone concentrations were measured using commercial radioimmunoassay kits, whereas lymphocyte receptor density was determined through binding assays. In beef cattle housed in tie stall barn a significant increase in serum cortisol concentration was observed at T3, whereas there was no effect of the housing system on blood progesterone concentrations. Short-term transportation caused a significant increase in blood cortisol and catecholamine concentrations in both groups, whereas lymphocyte GR and β-AR significantly decreased in Group A. Our data confirm the activation of the hypothalamic–pituitary–adrenal axis and the catecholaminergic system in short-term transportation and suggest that the stress-induced increase in circulating progesterone concentrations does not exceed the limit established by pending legislation.

Sex‐ and age‐specific effects of nutrition in early gestation and early postnatal life on hypothalamo‐pituitary‐adrenal axis and sympathoadrenal function in adult sheep

The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n = 22; UC, n = 19) or were undernourished (CU, n = 17; UU, n = 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 microg kg(1)) plus arginine vasopressin (AVP) (0.1 microg kg(1)). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and sympathoadrenal function. With altered glucose tolerance previously reported in this model, this may have long-term detrimental effects on metabolic homeostasis and cardiovascular function.

Injury Severity Differentially Alters Sensitivity to Dexamethasone after Traumatic Brain Injury

We have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths, to produce either moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 microg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation.

Developmental changes in pituitary function during the prepubertal period in female rats.

To observe the functional changes occurring in the pituitary gland during the prepubertal period in the female rat, pituitary responsiveness to synthetic Gn-RH and changes in serum gonadotropins and estradiol were examined between 10–35 days of age. Serum LH, FSH and estradiol were elevated during the early infantile period, and then declined gradually as the animal approached maturity. Significant increases in serum LH levels were observed 15 minutes after intraperitoneal administration of synthetic Gn-RH (100ng/100g BW) at all ages studied, although a slightly reduced LH release occurred in response to Gn-RH between days 20–30. The pituitary FSH response to Gn-RH was highest on day 10, followed by a general downward trend, and increased again on day 35. Gonadotropin responses to Gn-RH were found to be almost completely suppressed in the rats ovariectomized at 10 postnatal days. However, pretreatment with estradiol benzoate (EB) following ovariectomy produced a significant increase of LH and FSH release in response to Gn-RH. Progesterone, administered in combination with EB, showed no further influence on the sensitivity of the pituitary to Gn-RH. These results suggest that ovarian steroids, especially estrogen, may play an important role in the maturing processes of the pituitary function during the prepubertal phase.

Prolactin response to suckling in a group of fully breast feeding women during the early postpartum period.

Prolactin response to suckling was studied in a group of fully breast feeding women (N = 58) between 4-6 weeks postpartum. Basal, suckling stimulated and the increment of prolactin showed wide individual variations. Basal prolactin concentrations varied from 140 to 4,600 mIU/l, suckling stimulated prolactin from 400 to 5,600 mIU/l and the increment of prolactin from 40 to 4,160 mIU/l. Basal (p = 0.0395) and suckling stimulated (p = 0.0423) prolactin concentrations significantly increased as the number of night breast feeds increased and the suckling stimulated (p = 0.0218) prolactin concentrations significantly increased as the number of breast feeds/24 h increased. However, the magnitude of the rise in prolactin in response to suckling was not dependent on basal prolactin concentration. Basal, suckling stimulated or the increment of prolactin were not significantly different between subjects having different breast feeding frequencies, when the subjects were grouped according to the number of breast feeds. These differences may be due to the large individual variation in prolactin concentrations seen in women having similar breast feeding frequencies which may arise from individual variations in hypothalamic--pituitary response to suckling.

Age and the Thyrotropin Response to Hypothyroxinemia

Some studies suggest altered pituitary functioning and TSH production with aging. Our objective was to test the hypothesis that less TSH production occurs despite comparable hypothyroxinemia with advancing age. We retrospectively studied adult outpatients of all ages with confirmed hypothyroidism and documented their TSH and free T4 concentrations. Two populations of 112 patients were subdivided into four age groups: 1) patients newly diagnosed with primary hypothyroidism and 2) thyroid cancer patients undergoing l-T4 withdrawal in preparation for diagnostic or therapeutic radioiodine. The relationship between paired free T-4 and TSH concentrations and patient age was studied. With spontaneous hypothyroidism, the mean TSH concentration decreased nonsignificantly in each ascending age group with comparable free T4 (FT4) concentrations (<35 yr, 69 mIU/liter; 35-49 yr, 49 mIU/liter; 50-64 yr, 43 mIU/liter; >64 yr, 29 mIU/liter). With iatrogenic hypothyroidism, the mean TSH concentration decreased significantly in each ascending age group (<35 yr, 156 mIU/liter; 35-49 yr, 115 mIU/liter; 50-64 yr, 74 mIU/liter; >64 yr, 46 mIU/liter; P<0.001) despite similar FT4 concentrations. The relationship between the log-transformed TSH and FT4 was significantly and inversely affected by age in multivariate analyses in both spontaneous hypothyroidism (P=0.0005) and in iatrogenic hypothyroidism (P<0.0001). Age modifies the pituitary set point or response to comparably reduced free T4 concentrations, resulting in lesser serum TSH elevation in older individuals. This phenomenon occurs with both spontaneous and iatrogenic hypothyroidism. This may be an adaptive response in normal aging or a pathological alteration of pituitary function with age.