Les hypogonadismes hypogonadotrophiques congénitaux masculins, quelles données récentes ?

Congenital hypogonadotropic hypogonadism (CHH) is a very heterogeneous group of disorders resulting from a deficiency of pituitary gonadotropin secretion that is related to defective migration of GnRH neurons or dysfunction of pituitary or hypothalamic system. Gonadotropin deficiency remains a rare cause of hypogonadism; its prevalence is not definitely established and is thought to be about 1/5,000. It is responsible for clinical symptoms that are related to low testosterone levels. The classification of CHH which was previously based on presence of or lack of anosmia has been enriched in the last two decades by the discovery of many genes involved. This allowed a better understanding of CHH and led to new approaches regarding genetic counselling.     

Déficit androgénique lié à l’âge. Que faut-il attendre de l’androgénothérapie?

With the exception of disease or drug-induced changes in Leydig cell function, aging is accompanied by specific changes of androgen status in healthy men. The level of testosterone production decreases in contrast with the rise in plasma protein testosterone binding capacity. Free testosterone, considered to be the biologically active fraction, decreases, leading to tissue androgen deficiency. The resulting clinical picture mimics hypogonadism, including physical and psychological asthenia, decreased libido and sexual behaviour, increased fat mass and decreased lean mass, gynaecomastia, osteoporosis and pro-atherogenic metabolic changes. The cut-off value for plasma testosterone below which androgen deficiency can be considered to be responsible for clinical signs is a key point which determines the therapeutic approach. In the absence of clearly validated data in healthy aging males, this cut-off value has been consensually defined as the mean plasma testosterone levels of men between 30 and 50 years of age minus two standard deviations, corresponding to the zone of hypogonadism in adult males. The association of clinical signs compatible with hypogonadism and reduced total (or preferably bioavailable) plasma testosterone level justifies initiation of hormone replacement therapy after excluding any contraindications (especially prostatic). The aim of this treatment is to reverse the consequences of age-related hypogonadism. Some benefits of this treatment have been clearly demonstrated, such as a decrease of fat mass, and an increase of lean mass and muscle strength. Similarly, bone mineral density increases, particularly in men with the lowest pretreatment plasma testosterone levels. It must be stressed that these changes are observed in truly hypogonadal aging men, but not in aging men with normal plasma testosterone levels. Testosterone replacement therapy can promote the development of gynaecomastia, while dihydrotestosterone tends to reduce gynaecomastia. Finally, androgen replacement therapy appears to improve a hypogonadism-related decrease in libido or sexual behaviour, provided other associated non-endocrine factors have been previously treated. Androgen replacement therapy improves well-being, and physical and psychological asthenia in hypogonadal men. However, this treatment has not been demonstrated to be effective in healthy aging men. Although androgen replacement therapy does not have a negative impact on lipid parameters, its possible cardiovascular protective effects have not yet been demonstrated. In conclusion, androgen replacement therapy, respecting the contraindications, is beneficial in patients of all ages with clearly demonstrated hypogonadism, but has no efficacy on symptoms in other cases.     

Diagnostic et traitement du déficit en androgènes des patients infectés par le virus de l’immunodéficience humaine

Androgen deficiency is frequent among men infected by the human immune deficiency virus (HIV), with an estimated prevalence of between 35% and 50%. Primary testicular damage has been described, either due to the virus itself, opportunistic agents such as CMV,Toxoplasma gondii orMycobacterium avium intracellulare, or less frequently neoplastic invasion by lymphoma or in a context of Kaposi’s sarcoma. However, secondary hypogonadism remains a more frequent cause. Hypogonadotropic hypogonadism can be secondary to opportunistic infections, malnutrition, and sometimes even certain therapeutic agents. Since the introduction of highly active antiretroviral therapies, the prevalence of hypogonadism has substantially decreased. However, it remains a significant clinical problem, particularly among patients suffering from wasting, as androgen deficiency may aggravate the loss of lean body mass observed in the wasting syndrome of HIV patients. Screening for androgen deficiency is therefore indicated in HIV patients suffering from wasting, even in the absence of specific symptoms. Androgen replacement therapy is justified in symptomatic (loss of libido, impotence) and asymptomatic patients with documented hypogonadism. We recommend replacement therapy with testosterone by subcutaneous or intramuscular injection. In the absence of specific symptoms, it should be remembered that testosterone replacement therapy of HIV-infected hypogonadic patients is associated with improvements in body composition and muscle strength, bone densitometry, quality of life and mood. Similar improvements have also been demonstrated in hypogonadic patients with wasting syndrome. Synthetic testosterone analogues such as oxandrolone or nandrolone do not seem to be more powerful than testosterone at replacement doses, and may be associated with more side effects, particularly severe hepatic dysfunction. In contrast, there is no proven benefit of androgen treatment of eugonadic HIV-infected patients, and the treatment of such patients with androgens, even in the presence of wasting, cannot be recommended.     

Luteinizing hormone release by gonadotropin releasing hormone before and after castration in bulls

The magnitude of gonadotropin releasing hormone (GnRH) induced lutei nizing hormone (LH) release prior to castration, following castration, a nd during testosterone replacement in males, was compared, using 6 9-mon th-old Holstein bulls. Also, the effects of castration and testosterone replacement on patterns of episodic changes in serum LH were studied. Blood samples were collected at hourly intervals for 24 hours prior to castration, at 21 days after castration, and at 23 days postcastration a fter testosterone, 20 mg thrice daily, has been given for 24 hours. Each animal was given GnRH, 40 mcg iv, at 24 hours before castration, at 7 and 14 days after castration, and at 28 days postcastration following 6 days of testosterone treatment. GnRH caused LH release before and after castration. The LH increase was 2.5-fold at 14 days postcastratio n. Testosterone replacement did not reduce the magnitude of LH response to GnRH to precastration levels. The number of episodic increases in serum LH prior to castration averaged 3.7 daily and increased to 6.5 daily at 21 days after castration (p less than .05). The magnitude of increase in LH concentration in these epidsodic events was not affected by castration. Testosterone replacement failed to restore either the average number or change the magniture of LH increase above precastratio n levels. It was shown that LH is normally released episodically in bulls. The peaks of LH release were followed by increased testosterone in serum. Results suggest that LH release in bulls is controlled by gonadic factors other than testosterone.     

Fundamental aspects of hypogonadism in the aging male

With aging in men, serum testosterone levels decline progressively and the prevalence of hypogonadism increases; these changes are associated with alterations in androgen-regulated physiological functions. In young hypogonadal men, similar alterations improve with testosterone replacement. In older men, short-term testosterone treatment trials suggest benefits (eg, on body composition and bone mineral density), without significant adverse effects. Therefore, androgen deficiency may contribute to physiological decline with aging, and testosterone therapy is reasonable for older men with clinical manifestations of androgen deficiency and low testosterone levels. However, the long-term benefits and potential risks (eg, for prostate disease) of testosterone treatment in older men are unknown.     

Metabolism of GnRH in man: influence of estrogens

To clarify the influence of estrogens on the metabolism of gonadotropin-releasing hormone (GnRH), we studied the metabolic clearance rate (MCR) of GnRH (MCRGnRH), and the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and testosterone (total and free fraction) in 9 sexually mature men and 7 women under basal conditions and after treatment with the antiestrogen tamoxifen (2 X 10 mg/day p.o.) for 7 days. In women, the medication was started on day 7 +/- 1 of their menstrual cycles. To calculate the MCR, synthetic GnRH was continuously infused (1.53 micrograms/min) and its serum levels were measured by a radioimmunoassay. During tamoxifen treatment we observed a small but significant decrease in the MCR in men (455 +/- 48 to 357 +/- 46 ml/min/1.86 m2), whereas the known cyclic increase in the MCR in women was blunted (1,769 +/- 147 to 1,558 +/- 119 ml/min/1.86 m2). There was a small but significant increase in LH levels in women (8.3 +/- 2.1 to 11.5 +/- 2.5 mU/ml). LH and testosterone levels in men, and FSH and estradiol levels in both sexes did not change significantly. Conclusion: (1) estrogens regulate the MCRGnRH either directly or by changing gonadotropin levels, but the effect is only slight; (2) an enhanced metabolism of GnRH may contribute to the feedback of estrogens on the secretion of gonadotropins, and (3) the sex-specific difference of the MCR is presumably not caused by estrogens.     

Effects of immunization against GnRH on gonadotropins, the GH-IGF-I-axis and metabolic parameters in barrows

Surgically castrated male piglets (barrows) reveal an increase in LH and a decrease in GH compared to untreated boars. Boars that were castrated by immunization against gonadotropin releasing hormone (GnRH) have decreased LH but maintain GH. The difference in GH levels between barrows and immunological castrated boars cannot be explained by testicular steroids because they are low in surgical and immunocastrated boars as well. Therefore, differences in GH concentrations might be due to an interaction between GnRH and growth hormone releasing hormone (GRH) in the hypothalamus or the pituitary. This hypothesis was tested with twelve male piglets that had been castrated within 1 week postnatally and fitted with indwelling cephalic vein catheters at 17 weeks of age. They were split into a control group and an immunized group (each n = 6). Vaccination with Improvac® was performed at 18 and 22 weeks of age. Specific radioimmunoassays were used for hormone determinations (GH, LH, FSH, testosterone and IGF-I). Additionally, metabolic responses were evaluated by measuring analytical parameters that characterize protein synthesis and breakdown, and body fat content. The second vaccination led to a rapid decrease of LH below the limit of detection whereas FSH decreased more slowly, over a period of 5 weeks, from 2.2 to 0.5 ng/ml. This level of FSH, which corresponds to boar-specific concentrations, was maintained thereafter. GH decreased with increasing age but was not influenced by vaccination and remained at a low concentration typical for barrows. Similarly, IGF-I was not altered by vaccination. Consequently, metabolic status was not changed by immunization. It is concluded that the difference in GH levels between surgical and immunocastrated boars is not explained by an interaction between GnRH and GRH.     

The evolution of hormonal therapy for prostatic carcinoma

It is well recognized that testosterone has a number of untoward effects on prostatic carcinoma and that castration is associated with significant tumor shrinkage and resolution of symptoms of advanced prostatic carcinoma. Approaches to hormonal therapy have evolved significantly over the last several decades. Initially castration was utilized, which provided effective reduction of testicular androgens, but with adverse psychological factors. The next approach was utilization of diethylstilbestrol, but with significant cardiovascular toxicity in higher doses. The development of the luteinizing hormone-releasing hormone agonists provided an improvement in pharmacologic castration; however, they are associated with a transient testosterone surge and the potential for exacerbation of clinical manifestations of advanced prostate carcinoma (the so-called "testosterone flare"). Recently, gonadotropin-releasing hormone (GnRH) antagonists have been investigated. Abarelix is a pure GnRH antagonist that blocks the anterior pituitary receptor, resulting in prompt and significant reduction not only of luteinizing hormone but also follicle-stimulating hormone. This results in castrate levels of testosterone while avoiding the testosterone surge.     

Regulation of thyroid hormones on the production of testosterone in rats

The effects of a thyroidectomy and thyroxine (T4) replacement on the spontaneous and human chorionic gonadotropin (hCG)-stimulated secretion of testosterone and the production of adenosine 3',5'-cyclic monophosphate (cAMP) in rat testes were studied. Thyroidectomy decreased the basal levels of plasma luteinizing hormone (LH) and testosterone, which delayed the maximal response of testosterone to gonadotropin-releasing hormone (GnRH) and hCG in male rats. T4 replacement in thyroparathyroidectomized (Tx) rats restored the concentrations of plasma LH and testosterone to euthyroid levels. Thyroidectomy decreased the basal release of hypothalamic GnRH, pituitary LH, and testicular testosterone as well as the LH response to GnRH and testosterone response to hCG in vitro. T4 replacement in Tx rats restored the in vitro release of GnRH, GnRH-stimulated LH release as well as hCG-stimulated testosterone release. Administration of T4 in vitro restored the release of testosterone by rat testicular interstitial cells (TICs). The increase of testosterone release in response to forskolin and androstenedione was less in TICs from Tx rats than in that from sham Tx rats. Administration of nifedipine in vitro resulted in a decrease of testosterone release by TICs from sham Tx but not from Tx rats. The basal level of cAMP in TICs was decreased by thyroidectomy. The increased accumulation of cAMP in TICs following administration of forskolin was eliminated in Tx rats. T4 replacement in Tx restored the testosterone response to forskolin. But the testosterone response to androstenedione and the cAMP response to forskolin in TICs was not restored by T4 in Tx rats. These results suggest that the inhibitory effect of a thyroidectomy on the production of testosterone in rat TICs is in part due to: 1) the decreased basal secretion of pituitary LH and its response to GnRH; 2) the decreased response of TICs to gonadotropin; and 3) the diminished production of cAMP, influx of calcium, and activity of 17beta-HSD. T4 may enhance testosterone production by acting directly at the testicular interstitial cells of Tx rats.     

Androgen supplementation and prostate cancer risk: strategies for pretherapy assessment and monitoring

Since in men androgen levels decrease with age and result in symptoms of hypogonadism, the use of testosterone supplementation to treat symptoms resulting from hypogonadism is increasing. One potential complication of this treatment is the possibility of an increased risk of prostate cancer. Although most authorities agree that androgen is involved in the exacerbation of existing carcinoma of the prostate, the action of androgens on the carcinogenic process is not well understood. Attempts to demonstrate a correlation between hormone levels and prostate cancer have yielded inconsistent results. No clear evidence exists that androgen supplementation to restore physiologic levels produces any deleterious effects on the prostate. It is highly doubtful that when testosterone therapy is administered to middle-aged or older men, any potential prostate cancer promotion effect will be clinically manifested in the absence of already established cancer. It is, however, imperative that existing or developing prostate cancer be ruled out before initiation and during androgen replacement therapy. As with any therapeutic regimen, careful monitoring of the patient receiving treatment is recommended and constitutes good medical care.     

Effects of testosterone on hormonal content and calcium-dependent basal secretion in female rat pituitary cells

In vivo and in vitro effects of elevated androgens on agonist-induced gonadotropin secretion have been addressed previously. Here we investigated the effects of testosterone on hormonal content and basal (in the absence of agonists) hormone release in pituitary lactotrophs, somatotrophs and gonadotrophs from female rats. Furthermore we tested the hypothesis that testosterone action is dependent on the pattern of spontaneous and Bay K 8644 (a L-type calcium channel agonist) -induced calcium signalling. Mixed anterior pituitary cells were cultured in steroid containing or depleted media, and testosterone (1pM to 10nM) was added for 48h. Cells were studied for their spontaneous and Bay K 8644-induced calcium signalling pattern and total hormone levels (release and hormonal content). In lactotrophs, somatotrophs and gonadotrophs testosterone did not affect the pattern of spontaneous calcium signalling. Bay K 8644-induced calcium signalling and hormone release were not affected by testosterone. In both steroid-depleted and -containing medium, testosterone inhibited prolactin (PRL), luteinizing hormone (LH) and growth hormone (GH) cellular content and release in a dose-dependent manner, with IC(50)s in a sub-nanomolar concentration range. These results indicate that testosterone inhibits basal hormone release from lactotrophs, somatotrophs and gonadotrophs without affecting intracellular calcium signalling. This action of testosterone is not dependent on the presence of other steroid hormones.     

Effect of dexamethasone on secretion of luteinizing hormone and testosterone in the boar

Eight adult, Yorkshire-Landrace crossbred boars were used to evaluate the effects of the synthetic glucocorticoid, dexamethasone (DXM) on the secretion of luteinizing hormone (LH) and testosterone. Four treatments of 4 d each were administered: 1) 2 ml i.m. of 0.9% (w/v) NaCl solution (control); 2) DXM (2 ml i.m. as a dose of 50 mug/kg body weight, every 12 h); 3) DXM plus gonadotropin releasing hormone (GnRH; 50 mug in 1 ml i.m. every 6 h); 4) 2 ml NaCl solution i.m. plus a single dose of 50 mug i.v. GnRH. Blood samples were collected twice daily from an indwelling jugular vein catheter for 3 d and at 15 min intervals for 12 h on the fourth day. DXM treatment resulted in lower (P M0.01) testosterone values in samples collected twice daily. More frequent sampling on Day 4 revealed that DXM reduced (P<0.01) the number of pulsatile increases of LH in plasma, although the individual mean pulse areas did not fiffer between the NaCl- and DXM-treated groups. This was associated with a decreased pulse frequency of testosterone (P<0.05). GnRH plus DXM treatment caused a significant elevation (P<0.05) in mean values as well as in the mean pulse area and in the total of the individual pulse areas of LH. Pulse area and mean concentrations of testosterone were also increased (P<0.01) when GnRH was given concurrently with DXM. Comparison of a single injection of GnRH when NaCl was being administered (Treatment 4) to one of the injections of GnRH (Day 4, 0800 h, Treatment 3) revealed a subsequently greater (P<0.01) pulse area in LH above base-line during DXM treatment (7.67 +/- 1.17 ng/ml) than during the NaCl (4.17 +/- 0.73 ng/ml) treatment period. This was reflected in a greater (P<0.01) pulse increase of testosterone following the LH pulse in boars treated with DXM. It is concluded that DXM treatment in the boar can reduce the pulse frequency of LH secretion, presumably by affecting GnRH secretion, but it has less effect directly on pituitary LH synthesis and release.     

Familial hypogonadotropic hypogonadism with alopecia.

In one family several male and female members had hypogonadism and frontoparietal alopecia, whereas other members with normal sexual development had normal scalp hair. Clinical and laboratory evaluation of three affected young men (two brothers and their cousin) revealed that the hypogonadism was the result of decreased serum concentrations of follicle stimulating and luteinizing hormones. There was no evidence of a deficiency of any other pituitary hormone. Long-term treatment of the three patients with human chorionic gonadotropin resulted in an increase in the serum testosterone concentration, the appearance of male secondary sex characteristics and an increase in the size of the external genitalia.     

Growth hormone - hormone replacement for the somatopause?

Twenty-four-hour growth hormone (GH) secretion reaches a peak at around puberty and by the age of 21 has begun to decrease. Thereafter the fall in GH secretion is progressive such that by the age of 60 most adults have total 24-hour secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland. Patterns of GH secretion are similar to those in younger people but GH pulses are markedly reduced in amplitude. Sleep and exercise remain the major stimuli for GH secretion. The fall in GH secretion seen with ageing coincides with changes in body composition and lipid metabolism that are similar to those seen in adults with GH deficiency. In elderly subjects, although GH secretion is markedly reduced, remaining GH secretion correlates closely with body composition (particularly with lean body mass and inversely with central abdominal fat). Pioneering studies carried out by Rudman showed that GH administration to elderly subjects with low insulin-like growth factor-I levels resulted in reversal of many of the changes associated with GH deficiency, namely an increase in lean body mass and bone mineral density and a reduction in body fat and plasma cholesterol. These changes were remarkably similar to those shown a year earlier in adults with GH deficiency given GH replacement. Subsequent studies of GH replacement in elderly adults have confirmed Rudman's initial observations but have been dominated by side effects which have led to a high number of dropouts. It is now clear that the elderly are very sensitive to GH and the doses used need to be very low, increased very slowly and tailored to the individual needs of each patient. Using this more cautious approach, recent studies have been very positive. A series of papers from Blackman's group, presented at the US endocrine meeting in San Diego in 1999, investigated the effects of GH with or without testosterone supplements (in men) and oestrogen supplements (in women). Their results showed positive effects of GH on lean body mass, central fat, low-density lipoprotein cholesterol and aerobic capacity. In many instances there was a positive interaction between GH and hormone replacement with testosterone and oestrogen, but it appeared that GH showed the most potent anabolic effects. Clearly more studies are needed before GH replacement for the elderly becomes established. Safety issues will require close scrutiny, but the data available so far are sufficiently positive to undertake large multicentre, placebo-controlled trials, particularly looking at endpoints associated with prevention of frailty and loss of independence.     

Effect of a potent gonadotropin releasing hormone antagonist on pulsatile testosterone and gonadotropin secretion in the male nonhuman primate

A potent gonadotropin releasing hormone (GnRH) antagonist [Ac-delta 3Pro1, pFDPhe2, DTrp3,6]-GnRH was given to adult male monkeys to determine the acute effect on pulsatile testosterone and gonadotropin secretion. Blood was drawn at 30 min intervals over 54 h without anesthesia using a mobile vest and tether assembly to support an indwelling catheter. After a 6 h control period, 0.1, 1.0, 2.0, 4.0 mg GnRH antagonist/kg bw in 1 ml corn oil sc, was given to intact adult male monkeys. The highest dose of GnRH antagonist decreased circulating testosterone within 6 h and for approximately 24-36 h duration. These data demonstrate that this GnRH antagonist can reduce serum testosterone both acutely and for intervals greater than 24 h and that the effective dose in intact animals is several-fold (up to 20 times) greater than in castrate animals.     

Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism

GnRH is the central regulator of reproductive function responding to central nervous system cues to control gonadotropin synthesis and secretion. GnRH neurons originate in the olfactory placode and migrate to the forebrain, in which they are found in a scattered distribution. Congenital idiopathic hypogonadotropic hypogonadism (CIHH) has been associated with mutations or deletions in a number of genes that participate in the development of GnRH neurons and expression of GnRH. Despite the critical role of GnRH in mammalian reproduction, a comprehensive understanding of the developmental factors that are responsible for regulating the establishment of mature GnRH neurons and the expression of GnRH is lacking. orthodenticle homeobox 2 (OTX2), a homeodomain protein required for the formation of the forebrain, has been shown to be expressed in GnRH neurons, up-regulated during GnRH neuronal development, and responsible for increased GnRH promoter activity in GnRH neuronal cell lines. Interestingly, mutations in Otx2 have been associated with human hypogonadotropic hypogonadism, but the mechanism by which Otx2 mutations cause CIHH is unknown. Here we show that deletion of Otx2 in GnRH neurons results in a significant decrease in GnRH neurons in the hypothalamus, a delay in pubertal onset, abnormal estrous cyclicity, and infertility. Taken together, these data provide in vivo evidence that Otx2 is critical for GnRH expression and reproductive competence.     

Serum insulin-like growth factor I levels in growth hormone-deficient adults: influence of sex steroids

Measurement of serum insulin-like growth factor I (IGF-I) concentrations remains the single most important tool in the evaluation of growth hormone (GH) replacement in GH-deficient adults, and the therapeutic goal is to maintain the level within the age-adjusted normal range. In healthy adults, IGF-I levels do not differ between males and females, whereas spontaneous GH secretion is approximately twofold higher in females. Untreated GH-deficient women exhibit lower IGF-I levels compared with men, and the increase in serum IGF-I during GH replacement is also significantly less. Put together, these data suggest resistance to GH in women, which in healthy individuals is compensated for by increased GH secretion. Administration of oral oestrogen in healthy post-menopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GH deficiency lowers IGF-I concentrations and increases the amount of GH necessary to obtain IGF-I target levels during treatment. These data clearly suggest that hepatic suppression of IGF-I production by oestrogen subserves the gender difference in GH sensitivity, but it is also likely that sex steroids may interact with the GH/IGF axis at further levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-I production, and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-I production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in adult women with hypopituitarism merits consideration.     

Selective estrogen receptor modulators to prevent treatment-related osteoporosis

The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Consistent with this observation, GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. GnRH agonists markedly decrease serum levels of both testosterone and estrogen. Estrogens play a central role in homeostasis of the normal male skeleton, and the available evidence suggests that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects of GnRH agonists. The central role of estrogens in male bone metabolism provides a strong rationale to evaluate selective estrogen receptor modulators for prevention of treatment-related osteoporosis in men with prostate cancer. Preliminary evidence suggests that both raloxifene and toremifene increase bone mineral density in GnRH agonist-treated men. An ongoing pivotal study will evaluate the effects of toremifene on fractures and other complications of GnRH agonists in men with prostate cancer.     

Modulation of growth hormone, luteinizing hormone, and testosterone secretion by excitatory amino acids in boars

Ketamine hydrochloride, an n-methyl-d-aspartate (NMDA) receptor antagonist was used in an experiment that tested the hypothesis that fasting-induced increases in growth hormone (GH) secretion is mediated by excitatory amino acid (EAA) neurotransmission in boars. The effects of the drug on circulating concentrations of luteinizing hormone (LH) and testosterone were also evaluated. Blood was sampled at 15-min intervals for 8 h from 12 boars fitted with jugular vein catheters. At Hours 4 and 6, fasted boars (feed was withdrawn 48 h before the start of blood sampling) received i.m. injections of ketamine (19.9 mg/kg body weight; n=4) or .9% saline (n=4). Boars allowed feed on an ad libitum basis (n=4) received i.v. injections of n-methyl-d,l-aspartate (NMA; 2.5 mg/kg body weight), an NMDA receptor agonist, at Hours 4 and 6. Secretion of GH increased after NMA injections but was unaffected by treatment with ketamine or saline. Circulating concentrations of LH and testosterone were increased by injections of ketamine but were unaffected by injections of NMA or saline. Our results suggest that NMA is a potent GH secretagogue, but do not support the hypothesis that EAA neurotransmission drives the increased GH secretion displayed in fasted boars. Our finding that ketamine increased LH and testosterone release supports the notion that EAA have inhibitory effects on gonadotropin secretion in acutely fasted swine.     

The somatopause: to treat or not to treat?

There is much evidence that some aspects of ageing are similar to those observed in selective hormone deficiencies during adulthood. Replacement therapy in hypogonadism and/or growth hormone (GH) deficiency in adulthood is very successful in reversing the related clinical symptomatology. However, preliminary studies of GH treatment in the normal elderly have been largely disappointing: an increase in muscle mass is only accompanied by improved muscle strength if exercise is also increased during this period. No real benefit of GH therapy, additional to that of exercise, has been reported. Epidemiological studies indicate a relationship between high-normal insulin-like growth factor-I levels and cancer development. No definitive answers can presently be given regarding the safety of long-term GH therapy in otherwise healthy individuals during the somatopause.