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Humoral and cellular autoimmune responses

Ease or polyendocrine autoimmune syndrome type 2 (Table 1). On the other hand, patients with polyendocrine autoimmune syndrome type 1 (characterized by adrenal insufficiency, hypoparathyroidism and hypogonadism) have antibodies that react with P450 SCC (cholesterol side-chain cleavage) or, as reported by other authors, another enzyme, the microsomal steroid 17a-hydroxylase (Table 1). It is still uncertain whether these autoantigens are expressed on the surface of adrenal cells or are otherwise accessible to adrenal antibodies in vivo. Finally, IgG preparations from patients with Addisons disease have been reported to cause a dose-dependent decrease of in vitro Cortisol production and or DNA synthesis induced by ACTH in guinea pig adrenal segments maintained in organ culture. The blocking effects occurred irrespective of the presence or absence of adrenal cytoplasmic autoantibodies and were attributed to the production of antibodies against the receptor for ACTH. This hypothesis has...

Individual and Cultural Differences

Adolescents within each sex also differ. Although many intrasexual differences are due to experiential factors, some are due to differences in hormone levels. Individual differences in testosterone level are associated with the strength of libido in adolescents of both sexes (Udry, 1988). Moreover, experience can sometimes affect hormonal levels that alter behavior. Youths who live in violent neighborhoods tend to have higher testosterone levels than those living in peaceful ones, controlling for various factors (Mazur & Booth, 1998). In mammals generally, testosterone rises in competitive situations to mobilize the individual for aggression. Thus living in a dangerous environment can potentiate aggressiveness and competitiveness through a rise in testosterone. Similarly, when men marry, their testosterone levels tend to fall as they withdraw from mating competition, and to rise again if they divorce.

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 (Morley et al 1997) studies have shown that in healthy males mean serum total testosterone (T) levels decrease by about 30 between age 25 and 75, whereas mean serum free T levels decrease by as much as 50 over the same period. The steeper decline of free T levels is explained by an age-associated increase in sexhormone binding globulin (SHBG) binding capacity (Vermeulen & Verdonck 1972). Conflicting results have been reported concerning the question of whether luteinizing hormone (LH)...

Pituitary Gland Abnormalities

Pituitary gland abnormalities are a rare cause for male infertility. In such circumstances, the pituitary gland fails to release hormones necessary to promote sperm production. The pituitary gland in the man produces two important hormones for sexual reproduction luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The primary function of LH is to act on specialized cells within the testicles to manufacture the male hormone testosterone. FSH has the main purpose of stimulating the production of sperm. In most cases of pituitary gland abnormalities, either LH or FSH or both are greatly reduced. This drop in hormones results in lowered testosterone levels and also reduced sperm production.

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

Cross-sectional and longitudinal studies in men showed that serum testosterone declined with ageing (Vermeulen 1991). Even though serum total testosterone may be in the normal range, the free or bioavailable testosterone levels are frequently lower in elderly men (Gray et al 1991, Korenman et al 1990, Baker et al 1976, Harman & Tsitouras 1980). Low testosterone levels in older men are associated with sexual dysfunction, loss of bone, decreased muscle mass and strength, increased body fat, frailty, and poorer quality of life (Swerdloff & Wang 1993). The low circulating serum testosterone levels are usually associated with elevated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in aged men. However, such increases in LH may be inappropriately low compared to those of young men with similar low serum testosterone levels. In search of an animal model to examine the process and mechanisms of reproductive ageing, we and others have defined the BN rat as...

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 in serum LH and FSH after castration in the old, when compared with the young animals provided further evidence for a hypofunctional hypothalamic-pituitary axis (Gruenewald et al 1994). We also showed that the pulsatile secretion of LH was characterized by a shortened pulse interval and reduced areas of the pulses in the old rats. LH pulse amplitude and total area of the LH pulses were also significantly lower in old than in young rats. In contrast, mean serum FSH levels in old rats were...

Adipose Tissue Hormones

Leptin on the hypothalamus is the modulation of the gonadal axis. Low levels of leptin are associated with decreased activity of the gonadal axis, and this explains the relationship between starvation and hypogonadism. After nutritional rescue and weight regain, the levels of leptin in the serum become normal.

Overview of the ensemble GHIGF1 axis

GHRH is an established primary agonist driving the biosynthesis and pulsatile secretion of GH in all mammalian species (Giustina & Veldhuis 1998). Conversely, somatostatin (SS) is a dominant inhibitory signal, which antagonizes the exocytotic secretion of GH, but not its biosynthesis or storage (Hofland & Lamberts 1996). GHRPs are potent and selective oligopeptidyl GH secretagogues (Bowers et al 1984), mimicked by certain non-peptidyl agonists and exemplified endogenously by a 3Ser-octanoylated 28-amino acid GHRP-like ligand (Smith et al 1997, Howard et al 1996, Kojima et al 1999, Mueller et al 1999). The foregoing trilogy of neuropeptidyl regulators controls GH secretion via topographically and biochemically distinct receptors and secondary signalling molecules (Barinaga et al 1985, Giustina & Veldhuis 1998, Mayo 1992, Mueller et al 1999). These diverse, but uniquely interactive, features create (a) cooperative mechanisms of biological control, and (b) multiple vulnerable...

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

Based on the foregoing physiology, and testosterone's ability to rescue hypo-somatotropism in older men (Gentili et al 2000), we postulate that testosterone can (a) enhance endogenous GHRH secretion and or (b) facilitate somatotrope responsiveness to GHRH. To this end, we are carrying out clinical experiments to drive the GHRHergic signalling pathway in older men while simultaneously fixing inputs by SS and GHRP before and after testosterone supplementation.

The hypothalamic release andor actions of SS in ageing men

Fourfold stimulation by short-term (3 week) parenteral testosterone supplementation of (i) GH secretory burst mass (ii) 24 h rhythmic GH release (iii) GH ApEn (irregularity measure) and (iv) serum IGF1 concentrations in older men FIG. 6. Fourfold stimulation by short-term (3 week) parenteral testosterone supplementation of (i) GH secretory burst mass (ii) 24 h rhythmic GH release (iii) GH ApEn (irregularity measure) and (iv) serum IGF1 concentrations in older men aromatizable and non-aromatizable androgens in the rodent (Giustina & Veldhuis 1998, Mueller et al 1999, Chihara et al 1981, Frohman 1996). Indeed, diethylstilbestrol administration to young men and the normal preovulatory milieu in young women enhance GH release stimulated by secretagogues that putatively withdraw SSergic restraint (Frantz & Rabkin 1965). Given such divergent clinical data, it will be crucial to clarify how testosterone deficiency modulates SSergic signalling in the human.

Early Diagnosis Of Hemochromatosis Phenotyping Vs Genotyping

Early diagnosis of hemochromatosis permits treatment of iron overload and thereby prevents premature death due to hepatic cirrhosis (and primary liver cancer) and diabetes mellitus complications.1-1,2-1 Preventing iron overload may also reduce the frequency or severity of arthropathy, hypogonadotrophic hypogonadism and other endocrinopathic disorders, and cardiac abnormalities. 1,2

If a normal vagina or uterus are not obviously present

A low or normal serum FSH concentration suggests functional hypothalamic amenorrhea, congenital GnRH deficiency, or other disorders of the hypothalamic-pituitary axis. Cranial MR imaging is indicated in most cases of hypogonadotropic hypogonadism to evaluate hypothalamic or pituitary disease. Cranial MRI is recommended for all women with primary hypogonadotropic hypogonadism, visual field defects, or headaches.

Normal or low serum gonadotropin concentrations and all other tests normal

This result is one of the most common outcomes of laboratory testing in women with amenorrhea. Women with hypothalamic amenorrhea (caused by marked exercise or weight loss to more than 10 percent below the expected weight) have normal to low serum FSH values. Cranial MRl is indicated in all women without an a clear explanation for hypogonadotropic hypogonadism and in most women who have visual field defects or headaches. No further testing is required if the onset of amenorrhea is recent or is easily explained (eg, weight loss, excessive exercise) and there are no symptoms suggestive of other disease.

Neuroendocrine Syndromes

Prader-Willi syndrome is a neuroendocrine disorder with chromosomal abnormalities (characterized by deletion of the proximal part of the long arm of chromosome 15 among other abnormalities) first described by Prader, Labhart, and Willi in 1956.40 The diagnostic features are those of obesity, short stature, and developmental delay, with the child presenting with profound muscular hypotonia, swallowing difficulties, and hypogonadism. A single case has been reported of a 10-day-old neonate with bilateral SDH of the posterior falx with associated extradural hemorrhage, which was hypothesized to be caused by a genetically related abnormality of homeostasis, although the specific homeostatic abnormality was not stated.41 The infant had been delivered by cesarean section following breech presentation, although these delivery related mechanisms were excluded as the cause of the SDH.

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 change in the circulating concentrations of total testosterone, whilst there is a fall in sex hormone binding globulin and an increase in free androgen index (Burger et al 2000b). Studies from other investigators suggest that there may be a further increase in circulating androgen levels in the late 50s and 60s (Laughlin 2000). The precise consequences of these changes in androgen for womens' health in general are unknown. On the other hand, loss of androgen as may occur following ovariectomy...

Obesity Associated with Recognized Medical Condition

Chromosomal abnormalities are more frequent causes of a predisposition to obesity. Prader-Willi syndrome, due to deletion or uniparental disomy of part of the long arm of chromosome 15, is associated with characteristic facies, small hands and feet with tapering fingers, hypogonadism, early hypotonia, difficulty feeding, and initially failure to thrive. From the second year of life many of these children show voracious appetite, progressive obesity, and negative behavior (stealing food and refusing to follow a diet). Many also commonly have psychodevelopmental problems with moderate mental retardation that exacerbates the difficulties maintaining normal weight for height and age. Gross obesity commonly leads to early death associated with hypoventilation (Pickwickian syndrome) and or complications of type 2 diabetes mellitus.

Luteinizing hormonetestosterone axis

As critical illness becomes prolonged, hypogonadotropic hypogonadism ensues (Vogel et al 1985, Woolf et al 1985). Circulating levels of testosterone become extremely low, often undetectable in men whereas oestradiol concentrations are reduced to a lesser degree, thereby increasing the oestradiol testosterone molar ratio. The progressive decline in serum gonadotropin levels, however, appears to lag behind the rapid decline in serum testosterone. In men with PCI, a high LH pulse frequency with an abnormally low LH pulse amplitude is seen and this has been interpreted as an impaired LH response to very low circulating testosterone levels (Van den Berghe et al 1994b). Endogenous dopamine, opiates IL1, and the 'relatively spared' oestradiol level may be involved in the pathogenesis of the gonadotropin deficiency. Androgen treatment in men affected by prolonged critical illness failed to induce conclusive clinical benefit (Tweedle et al 1972). An alternative approach with exogenous...

Other polyendocrine autoimmunity syndromes

The POEMS syndrome is a rare form of plasma cell dyscrasia with polyneuropathy, organomegaly (liver and or spleen), endocrinopathy (hypogonadism, hypothyroidism or diabetes mellitus), monoclonal gammopathy and skin changes, these features giving rise to the acronym. It is likely that the POEMS syndrome represents a variant of osteosclerotic myeloma. The endocrine dysfunction may be caused by specific autoantibodies but this remains unproven.

Clinical Features

Normal fetal position, and difficult delivery. The hypotonia is evident in the newborn period, accompanied by poor sucking and failure to thrive. Hypogonadism resulting in cryptorchidism and scrotal hypoplasia in males and labial hypoplasia in females are also seen in the newborn period.

Prader Willie Syndrome

Prader-Willie syndrome (PWS) occurs evenly across both gender and ethnic lines. Approximately 1 individual in 10,000-15,000 births is impacted. PWS is caused by a microdeletion of chromosomal matter on chromosome 15. One unique feature of PWS is that genes are expressed in a divergent manner depending on whether one inherited them from one's mother or one's father. Physical manifestations include failure to thrive (early in development), characteristic facial features (e.g., narrow nasal bridge, downturnedmouth, almond-shaped eyes, and thin upper lip), hypotonia, hypogonadism, later insatiable appetite and resulting obesity, and a specific behavioral phenotype.

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 menopause, and because serum total testosterone levels decrease only marginally with age except for a small subset of elderly men who develop clinical hypogonadism. However, in the last 5 years, thinking on this issue has undergone a sea change. First, in population studies, we (Khosla et al 1998) and others have shown that although levels of serum total testosterone and oestrogen decrease only slightly in men with ageing, there are major decreases in biologically available levels of both sex...

Spironolactone Induced Gynecomastia

Subsequently, in patients who develop gynecomastia, blood testosterone levels decrease and blood estradiol levels increase. These changes come about by increases in metabolic clearance rate of testosterone as well as an increase in peripheral conversion to estradiol. Consequently, excessive stimulation of breast tissue as a result of an imbalance between estrogen and testosterone in the body leads to increased ductal proliferation and tender breast enlargement in males. Discontinuation of the drug results in slow reversal of this process sometimes requiring several months for complete normalization of breast size.

Klinefelter Syndrome

Physical manifestations of KS result in impairment of normal genital and sexual development. Although persons with KS enter puberty at the typical age, inadequate testosterone levels prevent normal pub-ertal progress. Hypogonadism is present with a slowed development of or lack of secondary sexual characteristics. In addition, KS leads to smaller than normal testes that often contribute to infertility. Cognitive abilities range from mild mental retardation to above-average intelligence. In general, persons with KS have deficits in verbal abilities, whereas nonverbal abilities are typically in the average range. Behaviorally, individuals with KS may be reserved, withdrawn, and immature, and they are at risk for having poor peer relationships. Self-esteem problems also have been described. In contrast, they also have been described as being easygoing, underactive, compliant, and, consequently, well liked by teachers.

Peripheral Nervous System

Usually, sympathetic and parasympathetic divisions act separately and at times cooperatively. Sweat glands and blood vessels in the limbs have only sympathetic innervation the pupil and bladder are dominated by parasympathetic fibers. Certain disparate domains see both divisions working together in never-ending modulation (with neurohormonal assistance) of cardiac rhythmicity and intermittent assistance in male sexual function (erection is mediated mainly by parasympathetic fibers but ejaculation by sympathetic

Cannabis and the cannabinoids

There are conflicting reports on the effects of chronic high doses of THC on human sexual function, but there is some evidence that spermatogenesis and testosterone levels are decreased. In women, a single cannabis cigarette can suppress release of luteinizing hormone, so that lack of ovulation frequently occurs in women who abuse this drug. Lowered birth weight and increased chances of malformations have also been reported in the offspring of women who abuse THC during pregnancy. It is also possible that in utero exposure to this drug causes behavioural abnormalities in childhood.

Epidemiology And Classification Of Dm1

In the classical form, which is the most common, symptoms become evident between the second and the fourth decade of life, showing a slow progression over time (table 36.1). The key feature of the disease is myotonia, which is characterised by delayed relaxation after muscular contraction (fig 36.1A,B) progressive muscular weakness (dystrophy) and wasting are also typical findings facial, axial, semi-distal, and distal compartments are predominantly involved. DM1 is, however, a multisystem disorder indeed, affected patients can manifest abnormalities of other organs and systems including the eye (cataract), the endocrine system (diabetes, thyroid dysfunction, hypogonadism), the central nervous system (cognitive impairment, mental retardation, attention disorders), the gastrointestinal system (dysphagia, constipation, gallbladder stones, pseudoobstruction), and the heart (table 36.2).

Testicular dysfunction

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 with age (Fig. 1). Intratesticular testosterone and inhibin concentrations were not lower, and in fact appeared to be higher in testes that showed marked regression, because of the loss of seminiferous tubule content in the testis (Wang et al 1993,1999). The decrease in serum testosterone was due to decreased Leydig cell secretory capacity as demonstrated by Zirkin et al (1993), Zirkin & Chen (2000) and Chen et al (1994, 1996). The Leydig cell dysfunction resulted from reductions in the levels...

Individual Variation In Laterality

For example, relative performance on tests of verbal and visuospatial ability are related to handedness, but the relationship appears complex and is moderated by sex and by overall reasoning ability. There is also evidence that extreme intellectual precocity, especially for mathematical reasoning, is related to advanced development of the right hemisphere relative to the left, perhaps as a result of increased testosterone levels during fetal development. It also appears that some forms of dyslexia (impaired acquisition of reading) are related to subtle abnormalities within the language areas of the left hemisphere, perhaps leading to an overreliance on the less efficient mechanisms of the right hemisphere. Considerable additional work is needed, however, to substantiate these relationships and to discover the precise mechanisms that might account for them.

Alcohol

Consuming alcohol of more than one or two drinks per day can affect the quality and quantity of sperm, lower testosterone levels, and contribute to impotence. A 1996 research study from Finland showed that moderate alcohol consumption can kill off some sperm-producing cells within the testicles and also may cause abnormal sperm shapes. A normally shaped sperm should resemble a streamlined tadpole with an oval head and long tail. Abnormally shaped sperm vary in appearance and may have two tails, a tapered head, a crooked kinky shape, or an unusually large or small head. Any of these abnormalities make it so that the sperm is unable to penetrate the surface of the egg and therefore unable to successfully fertilize the egg. Men who partake in heavy alcohol consumption that is, more than six drinks per day are more likely to suffer from low sperm count, poor sperm motility, and abnormal sperm shape.

Discussion

Bjorntorp I didn't have time to show that in the stressed men. Particularly in the small subset of 'burned out' men I referred to, testosterone levels are lowered. The hyperandrogenicity problem is probably a separate female issue. There is a sort of chicken and egg discussion about which comes first, the changes in the androgens or the changes in the oestrogens. But when we give androgens in moderate amounts to female rats, they become highly insulin resistant. When investigators have given androgens to women there is one US study (Lovejoy et al 1996) and one Dutch study on transsexuals (Elbers et al 1997) they also become insulin resistant. I believe that when you give testosterone, these things happen.

Androgen effects

Like most steroids and drugs, testosterone binds with varying affinity to circulating proteins notably SHBG and albumin. It is often stated or assumed that various measures of 'free' testosterone are superior markers of androgen supply to, and or net effects upon, androgen sensitive tissues than measurement of total testosterone, the gold standard for biochemical confirmation of androgen deficiency. The so-called 'free hormone' hypothesis has a long and tortuous history (Edwards & Ekins 1988, Pardridge 1988, Mendel 1989). Regarding testosterone, claims of superiority for derived testosterone assays are based exclusively on theoretical arguments without clinical validation yet even in theory, freer movement of unbound testosterone into tissues would be just as likely a priori to result in faster metabolic inactivation as enhanced biological effects on target tissues. Derived testosterone assays include direct measurement of free (non-protein-bound) testosterone by equilibrium...

Chromosome Disorders

Klinefelter's syndrome is a sex chromosome abnormality that occurs in 1 of 600 males, with a karyotype of 47. Individuals with Klinefelter's syndrome possess an extra X chromosome XXY. Clinical characteristics are variable and include some learning and developmental disabilities, hypogonadism, small testes, and gynecomastia occuring in puberty. The condition can be managed by administering testosterone supplements beginning in adolescence. As with some other sex chromosome abnormalities, adults with Klinefelter's syndrome are usually infertile. hypogonadism underdeveloped testes or ovaries

Dnmt2 Dnmt3a

Adult testes had severe hypogonadism. Females showed a maternal-effect lethal in that heterozygous progeny of homozygous females died before midgestation. Maternal methylation imprints were markedly disrupted, while genome-wide methylation patterns were normal.

Reproductive System

Hormonal Complications Males Obese men have elevated levels of plasma estrone and estradiol that correlate with the degree of obesity. Plasma total testosterone and free testosterone (the biologically active moiety) are reduced in obese men, and the reductions correlate negatively with the degree of obesity. The reduced levels of free and total testosterone are not generally accompanied by hypogo-nadism or a decrease in libido, potency, or sperm count in obese men. Free and total plasma testosterone levels normalize upon significant weight reduction. Also, estrogen levels are normalized if individuals attain normal weight but not if the weight loss is modest and significant obesity persists.

Deer And Elk Antlers

Antler growth begins when blood testosterone concentrations increase, just as greatly reduced testosterone levels trigger antler shedding. Length of daylight influences changes in testosterone level. Elk antlers in mature bulls begin to regrow as soon as they are shed in February or March.

Cushings Syndrome

Repeat surgery on the pituitary can be performed. After successful resection of a recurrent or persistent adenoma, remission rates in the range of 70-75 can occur. Diabetes insipidus, cerebrospinal fluid rhinorrhea, low-grade meningitis, hypothy-roidism, and hypogonadism are the more common complications. Radiation therapy with adjunctive adrenolytic drugs is also an important second- line therapy. Doses in the range of 45-54 Gy are used. The timing of repeat surgery or radiation therapy is usually based on symptom return, am plasma cortisol levels, 24 urine free cortisol, and low dose dexamethasone suppression testing.

Prader Willi Syndrome

Prader-Willi syndrome is a condition characterized by mental retardation, hypotonia, hypogonadism, and obesity. It is a sporadic multisystem disorder with an incidence of 1 in 10,000. It is due to a chromosomal deletion on the 15th chromosome. Presentation in infancy is of poor suck, hypotonia, developmental delay, and early failure to thrive. During childhood, the poor eating habits change to hyperphagia and obesity, which becomes a major problem for health and life. Consequences of obesity include somnolence, hypoventilation, cor pulmonale, and non-insulin-dependent diabetes mellitus. Associated problems are scoliosis, strabismus, and inability to vomit. Occasional problems may include decreased sensitivity to pain, seizure disorder, short stature, skin picking, easy bruisability, fractures from minor trauma, and acanthosis nigricans.

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