Pituitaryadrenal axis

It has been known for a long time that the vital stress-induced hypercortisolism induced by surgery, trauma or sepsis is associated with augmented adrenocorticotropic hormone (ACTH) release, driven presumably by corticotropin-releasing hormone (CRH), cytokines and the noradrenergic system. Concomitantly, circulating aldosterone rises markedly probably under the control of an activated renin-angiotensin system. Hypercortisolism acutely shifts carbohydrate, fat and protein metabolism, so that...

Conclusions

In elderly men, ageing is accompanied by a decrease in objective and subjective physical function, as well as changes in body composition and bone mass. In parallel, important changes in the endocrine system occur. Testosterone administration seems to influence bone mass and perhaps muscle strength, although insufficient evidence exists to confirm that testosterone substitution in the elderly is indicated. Also, oestradiol seems to influence bone mineral density in elderly men. Although DHEA...

Nonendocrine agerelated abnormalities

Although endocrine factors appear to be the major cause of age-related bone loss, there are important non-endocrine factors that also contribute. The level of bone mass present prior to the onset of age-related bone loss is clearly important those persons who have high levels are relatively protected against osteoporosis whereas those with low levels are clearly at a greater risk. As has been long recognized, there are a number of episodic factors that increase bone loss in some, but not other,...

Research in progress

Prospective data from the Vancouver Ovulation and Bone Change Cohort (Prior et al 1996, 1990a) are still being collected as these women become perimenopausal or menopausal. Some of those women continue to keep quantitative basal temperature and Daily Perimenopause Diary (Prior 1999) records, and will potentially provide important comparisons of ovulation and experiences in premenopausal and perimenopausal cycles in relation to subsequent menopause and bone density. As an illustration, one year...

The impact of the HPA axis on human health

Since it is almost impossible to separate the effects of ageing and cumulative stress on the regulation of the HPA axis, it might be of interest to examine how the HPA axis activity is associated with diseases that are characteristic of ageing. This assumes that the insults on the HPA axis of wear and tear are an unavoidable consequence of ageing. Longevity runs in families and 'successful' ageing is likely to have genetic components. Perturbations of the regulation of the HPA axis and...

Mil

< 30 30-39 40-49 50-59 60-69 70-79 80+ Age, years FIG. 5. Changes in sex hormone binding globulin (SHBG) in ageing men. Note the progressive increase in SHBG which binds to approximately 50 of total serum oestrogen or serum testosterone, rendering it largely unavailable to target tissues. The remaining 50 , which is bound to albumin or is free, is bioavailable. Thus, the progressive increases in serum SHBG with ageing are a major reason for the progressive deficiency in bioavailable...

Conclusion

In women, oestrogen deficiency due to the menopause is the major cause of both the early rapid and late slow phases of age-related bone loss. In ageing men, oestrogen deficiency also appears to be the dominant cause and is due to age-related increases in serum SHBG and to impaired gonadal production of sex steroids. The role played by decreases in bioavailable testosterone in bone loss in men is presently unclear. Thus, although other factors contribute, age-related osteoporosis appears to be...

Ageing and lifespan in GHIGFldeficient mice

Several mouse models with GH IGF1 deficiency are available to study the influence of these hormones on ageing and longevity (lifespan). Due to the IGF1 deficiency all homozygous affected mice are dwarfed and they divide as the human models into MPHD including GH (e.g. the Ames dwarf mice and the Snell dwarf mice) and primary IGF1 deficiency (the Laron mouse). These mice first described by Schaible & Gowen (1961) have a mutation in a transcription factor for all anterior pituitary hormones...

Studies in humans

The brain functions involved are those responsible for primitive survival reactions. Studies in non-human primates have shown essentially the same reaction pattern as in rodents (Uno et al 1989). Therefore a similar chain of reaction would also be expected in humans. The situation is, however, more difficult to evaluate in humans, who typically experience a wide variety of external challenges during a long life, with presumably varying vulnerability. Several difficulties are apparent with the...

Shideler n3 women 10 cycles

This three-part figure summarizes prospective data on ovulation disturbances during the perimenopause. The top section shows the proportion of three women experiencing three consecutive cycles that are normal (open bar) or showed ovulation disturbances (short luteal phase SLP and or anovulatory in black). MetcalPs data in women with irregular cycles are shown on the left (n 58) and on the right prospective data for 3 4 consecutive cycles in three women (see Fig. 4). The middle portion...

Ageing and the HPA axis

The background provided above is necessary for understanding the potential influence of ageing on the HPA axis and its associated tight network of other neuroendocrine reactions. One may ask whether this system is ageing by what might be called a 'normal' age-related process or if the wear and tear of today's complex, hectic living conditions are involved. As will be seen, it is difficult to separate these two factors. In order to separate out the effects of a 'normal' ageing process from the...

Altered GH neuroregulation in ageing andor hypogonadism

Precisely how ageing and or androgen deficiency impacts the GH IGF1 neuroregulatory unit is not known (Giustina & Veldhuis 1998). However, both animal and human studies make an ensemble perspective essential. For example, clinically, only L-arginine (an agent believed to withdraw SS) combined with (a) GHRH, (b) GHRP or (c) both GHRH and GHRP can normalize GH secretion acutely, when judged against similarly stimulated young adults (Ghigo et al 1990, Khorram et al 1997, Veldhuis & Giustina...

GH and IGF1 versus cogonadotropins

GH and IGF1 can be considered as 'co-gonadotropins', in view of their ability to facilitate LH and or follicle-stimulating hormone (FSH)-stimulated gonadal steroidogenesis in the rat and human (Lin et al 1986, Veldhuis 1996). Clinical studies corroborate a co-gonadotropic action of GH in ovulation induction in hypopituitary, but not eusomatotropic women. Analogously, hypopituitary, but not GH-sufficient, boys and men respond to GH repletion with enhanced human chorionic gonadotropin...

Consequences of the fall in circulating oestradiol

The clinical markers signalling the end of reproductive function in the female are symptoms resulting from loss of ovarian oestradiol secretion. The most striking and characteristic symptom is the hot flush which shows a variable prevalence in different communities, but affects 65 75 of women in developed countries. Broad correlations between circulating oestradiol concentrations and hot flush frequency have been documented in various studies (Guthrie et al 1996). In the Melbourne Women's...

Ageing of the normal brain

Until recently, ageing and senility were considered firm partners. We now know, however, that normal ageing ofthe brain is a process distinct from the degenerative dementias. Early neuropathology studies led to the dogma that up to 40 of neurons inexorably died over the lifespan. That belief was overturned by improved methodology using unbiased stereological techniques (Morrison & Hof 1997). In ageing primates and ageing rodents, rather than a loss of cortical pyramidal cells there is...

Endocrine aspects of healthy ageing in men

Annewieke W. van den Beld and Steven W. J. Lamberts Department of Internal Medicine, Erasmus University Hospital, Rotterdam, The Netherlands A bstract. Frailty is characterized by generalized weakness, impaired mobility and balance and poor endurance. Loss of muscle strength is an important factor in the process of frailty, and is the limiting factor for an individual's chances of living an independent life until death. In men, several hormonal systems show a decline in activity during ageing....

IGF1 and insulin secretion during ageing

The secretion of GH decreases with advancing age, mainly through a decrease in the amplitude of GH pulses (Veldhuis et al 1995). Mean 24 h GH concentrations decline from late puberty into old age (Rudman et al 1981) due to decreased GH production and an increased clearance rate (Iranmanesh et al 1991). The changes in IGF1 levels throughout life appear to mimic those of GH (Ho et al 1987). Accordingly, in a cross-sectional study of healthy adults with similar lean body mass (LBM), the IGF1 blood...

Effects of insulin and IGF1 on SMCs

More than a decade ago different publications showed that insulin stimulates SMC proliferation in vitro (Stout 1990). We have observed that in non-cultured cells, SMCs directly taken from the human artery, insulin stimulates collagen secretion. This effect was probably produced by activation of the IGF1 receptors, because addition of insulin receptor-blocking antibodies did not show any inhibition. On the contrary, antibodies blocking IGF1 receptors inhibited the insulin-induced collagen...

Effects of growth hormone and insulinlike growth factor 1 deficiency on ageing and longevity

Endocrinology & Diabetes Research Unit, Schneider Children's Medical Center of Israel and Sackler Faculty of Medicine, Tel Aviv University, Israel Abstract Present knowledge on the effects of growth hormone (GH) insulin-like growth hormone (IGF)1 deficiency on ageing and lifespan are reviewed. Evidence is presented that isolated GH deficiency (IGHD), multiple pituitary hormone deficiencies (MPHD) including GH, as well as primary IGF1 deficiency (GH resistance, Laron syndrome) present signs...

Endocrinology of ageing

In men, several hormonal systems show a gradual decline in activity during ageing, represented by a decrease in their bioactive hormone concentrations. The 'andropause' is characterized by a gradual decline in serum total and bioavailable testosterone, due to a decrease in testicular Leydig cell numbers and in their secretory capacity, as well as by an age-related decrease in episodic and stimulated gonadotropin secretion (Vermeulen 1991). Both cross-sectional (Vermeulen 1991) and longitudinal...

Androgen effects

The 20th century saw dramatic prolongation of life expectancy in developed countries. More people living longer in retirement creates a premium on strategies to promote healthy ageing (meaning, in this context, maintenance of enjoyable and independent living for the longest time with compression of morbidity into the shortest timeframe at the end of life). A focus on gainful coexistence with chronic ailments supplants the eradication of disease. Ameliorating disabilities that accrue during age...

Discussion

Veldhuis This area presents a lot of challenges to me. One of the difficulties I'm having as an endocrinologist with the testosterone theory, is that I don't see this syndrome X (metabolic syndrome) appearing across puberty in boys. At this stage their testosterone goes up 10-30-fold, but they get just mild insulin resistance. This makes me wonder whether insulin resistance is a marker for some other activity in the system. Polycystic ovary syndrome (PCOS) patients (bearing in mind that this is...

The hypothalamic release andor actions of SS in ageing men

Beyondits primary repressive role (above), SS paradoxically maintains somatotrope responsiveness to recurrent stimulation by secretagogues (Baumbach et al 1998, Kraicer et al 1986, Sugihara et al 1989). Specifically, intermittent SS exposure obviates the biochemical down-regulation of GH secretion induced by repeated GHRH and GHRP stimuli (Smith et al 1997). Thus, a critical mechanistic question is whether testosterone depletion limits GH secretion in part by augmenting sustained rather than...

Hypothesis 2 testosterone depletion reduces the potency andor efficacy of GHRHs actions

GHRH stimulates three major responses in somatotropes (i) exocytotic release of stored GH (immediate effect) (ii) de novo GH gene transcription and GH synthesis (acute and short-term actions) and (iii) somatotrope cellular hypertrophy and proliferation (longer-term response) (Giustina & Veldhuis 1998, Mueller et al 1999). Whereas few if any studies show consistently positive regulation of the GHRHergic pathway by oestrogen (Argente et al 1991), in the male rat (non-aromatizable) androgens...

Male reproductive ageing using the Brown Norway rat as a model for man

Christina Wang*, Amiya Sinha Hikim*, Monica Ferrinif, Juan J. Bonavera*, Dolores Vernetf, Andrew Leung*, Yan-He Lue*, Nestor F. Gonzalez-Cadavidf and Ronald S. Swerdloff* Divisions of * Endocrinology and Urology, Departments of Medicine and Surgery, Harbor-UCLA Medical Center and Research and Education Institute, 1000 West Carson Street, Carson, CA 90509, USA Abstract The Brown Norway (BN) rat is an excellent model for male reproductive ageing. We and others have shown that with ageing, the BN...

Luteinizing hormonetestosterone axis

The low serum testosterone concentrations despite elevated luteinizing hormone (LH) levels documented during the acute stress of surgery or myocardial infarction suggest an immediate stress-induced Leydig cell suppression (Wang et al 1978a,b, Dong et al 1992), the exact cause of which remains obscure. A role for inflammatory cytokines (IL1 and IL2) is possible, as suggested by experimental studies. It may be considered appropriate that the secretion of anabolic androgens be switched off in...

Depression an allostatic disorder with premature mortality

Human depression is a clear example of the allostatic link between chronic stress and reduced longevity. The importance of psychosocial stress for provocation of depressive episodes, for vulnerability to, and for risk of depression has been reviewed by Checkley (1996). Depression is an established outcome of stress, and the ongoing depressive episode itself constitutes a chronic stress. In large, prospective studies of adverse medical outcomes in depression, the customary psychiatric...

Hypothalamicpituitary dysfunction

In addition to a primary testicular failure, the aged BN rat also showed features suggestive of a hypothalamic-pituitary dysfunction. Serum FSH levels were elevated in association with low serum inhibin and decreased spermatogenesis in older rats (Wang et al 1993, Gruenewald et al 1994). In contrast, despite the low serum testosterone levels, serum LH showed no change (Chen et al 1994, Gruenewald et al 1994) or a decrease in aged rats (Wang et al 1993, 1999) (Fig. 1). Moreover, the blunted rise...

Endocrine abnormalities and bone loss in ageing men

Except after orchiectomy, men do not have an equivalent of the rapid phase of bone loss that women experience following menopause. After accounting for the absence of this phase, the patterns of late bone loss and of the increases in serum PTH and bone resorption markers in ageing men are virtually superimposable upon those occurring in women (Riggs et al 1998). In the past, it has been difficult to attribute male bone loss to sex steroid deficiency because men do not have an equivalent of...

Changes in circulating androgens

The significance of changes in androgen secretion is a neglected area of female reproductive ageing. One important study has documented a 50 fall in circulating total and free testosterone concentrations in normal regularly cycling women between the ages of 20 and 40 (Zumoff et al 1995). This has been postulated to reflect declining levels of adrenal androgen precursor secretion. Across the menopausal transition itself, studies from the authors' laboratory indicate that there is no significant...

Overview of the ensemble GHIGF1 axis

The GH IGF1 axis comprises a feedback ensemble controlled jointly by (i) GH-releasing hormone (GHRH) feedforward (ii) somatostatin (SS) inhibition (iii) a GH-releasing oligopeptide (GHRP) signalling pathway and (iv) GH and IGF1 autonegative feedback (Mueller et al 1999, Argente et al 1991, Baumann & Maheshwari 1997, Baumbach et al 1998, Bowers et al 1990, Bowers 1993, Carlsson et al 1990, Frohman & Jansson 1986, Giustina & Veldhuis 1998, Jaffe et al 1993, Kojima et al 1999, Smith et al...

Ageing stress and the brain

Pacific Behavioral Research Foundation, 26386 Carmel Rancho Lane, Suite 202, PO Box 223040, Carmel, CA 93922-3040, USA Abstract. Ageing of the brain is an important factor in overall ageing and mortality, and new insights have clarified the relationship between neuroregulation and ageing. First, neuronal loss in normal ageing is now known to be a minor change. Loss of synapses through dystrophic neuronal change is the hallmark of normal ageing. Second, similar dystrophic changes occur in the...

Fertility

Paternity is well established at the oldest age so the natural history of male fertility is concluded only by death. By contrast, female fertility, terminating naturally at menopause, occupies only half of average adult life expectancy. Despite the enduring fertility potential, fathers older than 50 years are responsible for only *1 of births in developed countries. Communal procreative patterns are determined by the similarity of couple's age and the overwhelming age-restriction of female...

Endocrine abnormalities and bone loss in women

This phase begins at menopause, can be prevented by oestrogen replacement, and almost certainly results from the cessation of ovarian function. Oestrogen acts through high affinity oestrogen receptors in osteoblasts and osteoclasts to restrain bone turnover, and when this restraint is lost at menopause, overall bone turnover increases and resorption increases more than formation. In addition, the increased activity of osteoclasts and their prolonged lifespan lead to trabecular plate perforation...

Atherogenity of insulin

Clinical studies have demonstrated that those processes linked to hyperinsulinaemia, such as type 2 diabetes or obesity, show a higher mortality due to coronary or cerebral atherosclerosis (Pyorala et al 1985). Furthermore, experimental results show that insulin acts on the vascular wall, either producing hypertension and endothelial changes, or influencing the smooth muscle cells (SMCs) to proliferate. It is well known that endothelial lesions and SMC proliferation are basic steps of...

The agedependent pressor effect of water

While individual patients with orthostatic hypotension due to autonomic failure had described improvement in upright blood pressure and functional capacity following ingestion of water, there was limited support for this concept based on current understanding of human physiology. We examined the effect of oral ingestion of water in patients with two forms of autonomic failure, pure autonomic failure (PAF) and multiple system atrophy (MSA) (Jordan et al 1999, 2000a,b). PAF and MSA patients often...

Glucose tolerance glucose utilization and insulin secretion in ageing

Muller*, Josephine M. Egan*, Reubin Andres*, Johannes Veldhuisf and Graydon S. Meneilly Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, *Laboratory of Clinical Physiology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore 21224, MD, University of Virginia, Division of Endocrinology and Metabolism, Charlottesville, VA 22908, USA, and Department of Medicine, University of...

The incretin effect in ageing and in type 2 diabetes

Incretin is the umbrella term to cover the multiple gut factors (now known to be hormones) which augment insulin response above that which can be attributed to glucose alone. This insulinotropic effect has been demonstrated by matching the time course of the plasma glucose excursion following an OGTT with both an i.v. infusion of glucose (Perley & Kipnis 1967) and during a hyperglycaemic clamp. In the hyperglycaemic clamp, plasma glucose was increased to * 11 mmol l for 2 h on two different...

Testicular dysfunction

Epididymal Growth

Reproductive ageing in the BN rat is characterized by low serum testosterone levels (Zirkin et al 1993, Wang et al 1993, 1999). Low serum testosterone levels are also a hallmark of the ageing male demonstrated in both cross-sectional and longitudinal studies (Vermeulen 1991, Gray et al 1991). We studied serum testosterone levels and sperm concentration in 6, 9, 12, 15, 18 and 31 month-old BN rats. Beginning at 15 months, plasma testosterone and inhibin levels both showed a progressive decline...

The concept of frailty and successful ageing

Age-related disability is characterized by generalized weakness, impaired mobility, impaired balance and poor endurance. This state is also called 'frailty' and is defined as a syndrome of multi-system reduction in physiological capacity as a result of which an older person's function may be severely compromised by minor environmental challenges, giving rise to the condition 'unstable disability' (Campbell & Buchner 1997). The increase in heterogeneity with age makes research findings more...

Clinical consequences of the decline in activity of the hormonal systems

Testosterone has long been known for its anabolic effects (Brodsky et al 1996). Muscle weakness, anaemia, lowered bone mass, and mood disturbances rapidly normalize in mid-adult hypogonadal men during T replacement therapy. Since the decrease in serum T concentrations occurs in parallel with the decrease in muscle mass, strength and bone mass, it has been suggested that these are causatively related. Several cross-sectional and longitudinal studies have demonstrated relationships in older men...

Fpg

Diabetic by FPG + GTT Diabetic by FPG Diabetics missed if no GTT FIG. 3. Distributions for diagnosis of diabetes (D) made from FPG (5 7.0 mmol l x-axis) and from two-hour plasma glucose level following OGTT (511.1 mmol l y-axis) in the BLSA population. We summarized 25 reports of studies that have computed the prevalence of diabetes in a population when both fasting glucose and the glucose tolerance test (GTT) were used (the WHO recommendation) in contrast to the prevalence when only the...

Allostasis allostatic load and ageing

Another shift in the neuroregulatory perspective is the proposal that ageing is related to lifetime stress, under the concepts of allostasis and allostatic load. Sterling & Eyer (1988) introduced the term allostasis to explain morbidity and mortality associated with chronic stress, especially social stress in human populations. They defined allostasis as 'maintaining stability through change'. The boundaries between allostasis and related constructs such as homeostasis, adaptation and...

The effect of insulin and IGF1 on the cytoskeleton in relation to SMC migration

Actin Cytoskeleton And Insulin

The cytoskeleton is a complex network of protein filaments extending throughout the cytoplasm that is involved in a range of cell processes. Of the three main 10 min after insulin 10 imin after insulin + diltiazem FIG. 2. Insulin-induced F-actin reorganization near the membrane of human vascular smooth muscle cells showing a ruffling which does not appear when Ca2+ channels of these cells are blocked by diltiazem. The results are similar in the case of IGF1 (unpublished). 10 min after insulin...

Sexuality

Since antiquity, history and literature are replete with references to the waning of male virility, in all its ambiguities, with age. The seemingly inexhaustible repertoire of remedies to stave it off testifies to the ubiquity of this human fixation. In particular, the decline in male sexuality in old age, being both emblematic and problematic, it is not surprising that aphrodisiacs are among the most ancient and ubiquitous of folk remedies. The modern educated layman, however, having lost...

The ageing female reproductive axis II ovulatory changes with perimenopause

Female Reproductive Axis

Division of Endocrinology and Metabolism, University of British Columbia, Vancouver Hospital andHealth Sciences Centre, Vancouver, BC, Canada V5Z 1C6 A bstract. Perimenopause, a complex physiological transition for midlife women, begins with changes in experiences many years before cycles become irregular, oestradiol levels decrease or follicle-stimulating hormone levels increase. Erratic and average higher oestradiol levels as well as shorter luteal phase lengths and lower progesterone levels...

Mechanisms of conjoint failure of the somatotropic and gonadal axes in ageing men

Mulligan and C. Y. Bowers Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202, Endocrine Section, Salem Veterans Affairs Medical Center, Salem, Virginia 24153, Geriatrics and Extended Care Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249, and Department of Medicine SL53, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA Abstract. Endogenous growth hormone...

References

Alexandersen P, Haarbo J, Christiansen C 1996 The relationship of natural androgens to coronary heart disease in male a review. Atherosclerosis 125 1 13 Anderson BA 1975 Male age and fertility results from Ireland prior to 1911. Population Index 41 561 567 Ayta IA, McKinlay JB, Krane RJ 1999 The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 84 50 56 Brawley OW, Parnes H 2000 Prostate cancer prevention trials in the USA....

Stress and the function of the hypothalamicpituitaryadrenal axis

The hypothalamic pituitary adrenal HPA axis regulates the secretion of cortisol. The net result of the output of cortisol from the adrenals is dependent on central stimulatory events and feedback inhibitory mechanisms. The central regulation takes the shape of a diurnal rhythm, which in humans consists of high activity in the early morning hours and low activity in the afternoon evening. This basic pattern is changed by the experience of a variety of factors which are often grouped together...

Henry G Burger Emma Dudley Pam Mamers David Robertson

Nigel Groome and Lorraine Dennerstein The ageing female reproductive axis I 161 Discussion 167 Jerilynn C. Prior The ageing female reproductive axis II ovulatory changes with perimenopause 172 Discussion 186 Holger Leitolf, Jens Behrends and Georg Brabant The thyroid axis in ageing 193 Discussion 201 Greet Van den Berghe and Stephen M. Shalet Critical illness as a model of hypothalamic ageing 205 Discussion 216 Dariush Elahi, Denis C. Muller, Josephine M. Egan, Reubin Andres, Johannes Veldhuis...