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Hypogonadism

This is defined as inadequate gonadal function, manifested by defects in game-togenesis and or secretion of gonadal hormones. The manifestations vary according to the sex of the subject, and whether the onset is pre- or post-pubertal. The features of pre-pubertal hypogonadism are those of pubertal delay, while the features of post-pubertal hypogonadism are often more subtle. Mechanisms of hypogonadism These can be categorised as Primary or hypergonadotrophic hypogonadism due to ovarian or testicular failure, with lack of sex steroid production by the gonads Secondary or hypogonadotrophic hypogonadism, due to either failure of the hypothalamic GnRH pulse generator, or to pituitary failure to secrete gonadotrophins

Olfactory Disturbances Dysosmia

Cirrhosis And Cerebral Edema

Unilateral anosmia may be caused by a tumor (meningioma). Korsakoff syndrome can render the patient unable to identify odors. Viral infections (influenza), heavy smoking, and toxic substances can damage the olfactory epithelium trauma (disruption of olfactory nerves, frontal hemorrhage), tumors, meningitis, or radiotherapy may damage the olfactory pathway. Parkinson disease, multiple sclerosis, Kallmann syndrome (congenital anosmia with hypogonadism), meningoen-cephalocele, albinism, hepatic cirrhosis, and renal failure can also cause olfactory disturbances.

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 MRI 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.

Effects of Estrogen on Risk Factors for Diabetes

Another characteristic of postmenopausal women is androgenicity associated with low SHBG levels, which is also considered an important risk factor for insulin resistance and type 2 diabetes (120). In the Rancho Bernardo Study, SHBG was found to be inversely correlated with type 2 diabetes and impaired glucose tolerance (IGT) in postmenopausal women (130). In this regard, Andersson and associates (131) also reported that low SHBG levels were associated with type 2 diabetes in both men and women. Furthermore, they also reported that serum testosterone levels were positively correlated with the degree of insulin resistance in women. Estrogen, in contrast to androgens may increase SHBG levels. These increases in SHBG were associated with improved glucose homeostasis (132). In this context, it is also interesting that the incidence of diabetes is higher in men than in women until women reach menopause (133).

Genetic Disease Models

As summarized in Table 2, disturbance of GnRH causes hypogonadism in Kallmann's syndrome by affecting the Kal-X gene, but GnRH is also affected in the Prader-Lahart-Willi syndrome and idiopathic hypogonadotrophic hypogonadism. Tumors, infiltrations, trauma, irradiation, ischemia, and surgery may cause hypothalamic or pituitary dysfunction.1,2 Isolated FSH deficiency is found with the Pasqualini syndrome. Table 2 Differential diagnosis of hypogonadotropic and hypergonadotropic hypogonadism Hypogonadotropic hypogonadism (HH) Idiopathic hypogonadotropic hypogonadism (IHH) Kallmann syndrome Adult-onset IHH Fertile eunuch syndrome Adrenal hypoplasia congenita Genetic defects of the gonadotropin subunits HH associated with other pituitary hormone deficiencies HH associated with obesity Prader-Willi syndrome Laurence-Moon-Biedl syndrome Hypergonadotropic hypogonadism Table 3 Laboratory testing of hypogonadism hypogonadism disease disease

New Research Areas

Large, long-term clinical trials are needed in males over the age of 50 years to determine the benefits and risks of androgen replacement therapy. These studies could determine if cardiovascular risk, prostate cancer, frailty, fractures, osteoporosis, cognitive function, and life expectancy are influenced by androgen replacement therapy. A critical area of uncertainty is what testosterone concentration is needed to provide adequate androgenic effects. This is an important question because it relates to the concentration of testosterone where benefits might or might not be expected. Should free, bioavailable, or total testosterone concentrations be used

Selective Androgen Receptor Modulators

The development of selective androgen receptor modulators (SARMs) that have anabolic effects on the muscle but that do not have adverse effects on the prostate and cardiovascular system has been of considerable interest for the treatment of older men with testosterone deficiency.51-54 The nonsteroidal SARMs differ from testosterone in that they are not converted to active metabolites, such as estradiol and DHT, but they act as agonists in muscle and bone and only partial agonists in prostate and seminal vesicles. More favorable pharmacokinetics and androgen receptor specificity of nonsteroidal SARMs compared to testosterone provide promise for unique pharmacological interactions with the androgen receptor and actions that may allow more specific indications for their clinical use. The proposed mechanisms to explain the tissue selectivity of SARMs as nuclear receptor modulators include ligand binding specific conformational changes in the ligand-binding domain and modulation of surface...

Acute Marijuana Toxicity

Physiological effects Dose-related tachycardia, blood pressure remains stable, increased appetite, dry (cotton) mouth, conjunctival injection, reduced intra-ocular pressure, bronchodilation, weakness, muscle tremors, urinary retention, low testosterone levels impotence. Psychological effects Dose-related euphoria, relaxation, sensory alterations. Preexisting psychopathology may predispose to transient, acute psychotic reactions with paranoid delusions and hallucinations.

Gonadotrophin releasing hormone

It is secreted by hypothalamic neurons in the arcuate nucleus and the orga-num vasculosum lamina terminalis. The neurons responsible arise as precursor peripheral sensory neurons of the nasal epithelium, from the medial olfactory placode, and migrate into the hypothalamus. Failure of migration of the neurons is associated with Kallman's syndrome of hypogonadotrophic hypogonadism and anosmia. The neurons do not have any axonal connections with other neuronal networks. Their axons are directed into the median eminence, where they are apposed to the hypophyseal portal vessels.

Olfactory Placode Derivatives

The olfactory placode also forms neuroendocrine cells that migrate along the olfactory nerve into the forebrain and dien-cephalon. These neurons produce gonadotropin-releasing hormone (GnRH) and form the terminal nerve-septo-preoptic GnRH system (reviewed in Dubois et al., 2002). This system regulates gonadotropin release from the adenohypophysis (anterior pituitary), another placodal derivative (section Overview of Cranial Ectodermal Placodes). Hence, the olfactory placode is not only essential for olfaction, but also for reproduction. This is seen clinically in Kallmann's syndrome, in which olfactory axons and GnRH neurons fail to migrate into the brain, resulting in anosmia and sterility (hypogonadism) (reviewed in MacColl et al., 2002). An early-stage fate-map in zebrafish, however, challenges the olfactory placode origin of GnRH neurons, suggesting that terminal nerve GnRH neurons originate from the neural crest, and hypothalamic GnRH neurons from the hypophyseal placode...

Hormones and Aging Hope Springs Eternal

Serum levels of total and bioavailable testosterone gradually decrease with age in men and are associated with changes in cognition. Cher-rier and coinvestigators (2001) examined the relationship between exogenous testosterone administration and cognitive abilities in a population of healthy older men. The investigators raised the circulating total testosterone in the treatment group an average of 130 from baseline at week 3 and 116 at week 6. Because of aromatization of testosterone, estradiol increased an average of 77 at week 3 and 73 at week 6 in the treatment group. Significant improvements in cognition were observed for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) in older men treated with testosterone compared with their baseline evaluation and the performance of the placebo group. Although no one has investigated if hormonal treatment with testosterone can restore the age-related decrease of...

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

Weight reduction also decreases androgen levels and restores ovulation in women with PCOS (202). Most of the studies suggest a significant reduction in total testosterone and a significant increase in SHBG, positively affecting the free testosterone levels. This effect is probably as a result of the improvement in hyperinsulinemia that directly affects ovarian androgen production. Metformin (1500 mg), when administered daily for 4-8 weeks in obese women with PCOS, resulted in a decrease in insulin and free testosterone levels (210). Metformin at the above dose improved insulin sensitivity, decreased serum LH and increased serum follicle-stimulating hormone and SHBG (211). Higher plasma insulin, lower serum androstenedione and less severe menstrual abnormalities are baseline predictors of

Clinical Trial Issues

Most clinical trials with testosterone replacement treatment have been done in postpubertal males with hypogonadism from various causes. With few exceptions, they have been open-label double-blind studies would be a challenge, although preferable. Total testosterone concentrations have generally been used for the diagnosis of androgen deficiency and for adequacy of replacement testosterone therapy. Free or bioavailable testosterone concentrations may provide a better basis for diagnosis of deficiency and for adequate replacement therapy. Intrinsic potency, bioavailability, and rate of clearance from the circulation are determinants of the biological actions of androgens. A 5 mg delivery dose of a patch or gel system or 200 mg of either testosterone enanthate or cypionate intramuscularly (IM) every 2 weeks is administered for androgen replacement therapy in males with hypogonadism. If IM testosterone enanthate or cypionate is used, an injection of 100 mg produces a better pattern of...

Sexual Desire and Aging

Male Steriod Facies

Hormone levels play a role in men's sexual expression, and changes in hormone levels may account for some of the age-related changes in sexuality. Testosterone is the key hormone that regulates sexual response in men and has some effect in women. Testosterone is produced by the adrenal glands, testicles, and ovaries. Women produce less than a tenth of the amount produced by men. Testosterone levels in men are highest in the morning right after waking and decrease throughout the day, so blood tests for testosterone are taken before 9 00 am for accuracy. After a rise during adolescence, testosterone production declines throughout life in men. Much less is known about age-related production of testosterone in women.

Alcohol Induced Sexual Dysfunction

Chronic male alcoholics, even without liver dysfunction, commonly demonstrate primary hypogonadism, as evidenced by decreased sperm count and motility, and altered sperm morphology. Increases in luteinizing hormone and a decrease in the free androgen index were reported in noncirrhotic males and related to lifetime quantity of ethanol intake (Villalta et al., 1977).

A Uterus absent

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.

Stress Management

Muscles tighten as stress starts, often causing intense headaches, backaches, and gastrointestinal problems. Stress also can cause testosterone levels to decrease and blood vessels in the penis to constrict, often resulting in erection problems. The rush of hormones caused by a stressful situation can bring on an asthma attack in a person with a history of asthma. Stress also draws the blood supply away from the abdominal area and encourages overproduction of acids in the digestive system, often leading to indigestion and other gastrointestinal problems. Other problems related to stress include insomnia and irritability.

Sex Hormones

Although the biological basis of sex differences in the brain's structure and function has not been entirely elucidated, there are at least two reasons that the brains of men and women might be different, size and laterality of cognitive processes. These two reasons, however, are not entirely independent. As I mentioned earlier, men's brains are larger than women's brains and there are more neurons. Although these differences are at least in part developmental, it is unknown whether these differences between men's and women's brains are induced by differences in hormonal exposure during development, are related to genetic differences independent of the hormonal influence, or are a combination of both. Men's and women's brains from the fetus to old age are exposed to different sex hormones, and hormones might influence thought patterns, moods, and behavior, both during development and after maturation. As mentioned previously, one of the major differences between the brains of men and...

Androstenedione

However, clinical studies do not support its claimed benefits. Androstenedione does not increase muscle strength or muscle size. Androstenedione does not appear to increase testosterone levels on a long-term basis. It does increase estrogen levels, which may increase the risk of conditions and cancers that are sensitive to this hormone, including endometriosis, uterine fibroids, and cancers of the breast, uterus, ovaries, and prostate. Androstenedione decreases levels of HDL, the good form of cholesterol, and may thereby increase the risk of heart disease and stroke. Multiple other possible side effects may occur with androstenedione.

Treatment Strategies

If hypogonadism is identified as the underlying cause of fatigue, exogenous testosterone or synthetic anabolic steroids may be administered (Dufour et al., 2005). However, patients receiving this treatment are susceptible to anabolic and androgenic effects such as increased heart rate, increased blood pressure, and hirsutism. Testosterone therapy may take the form of injections, pills, patches, gels, or creams. This treatment has been shown to have a beneficial effect on not only fatigue but also sexual interest, appetite, wasting, energy levels, and even concomitant depression. It Anemia Hypogonadism Adrenal insufficiency Hypothyroidism Infections Malnutrition Depression Inactivity

Endocrine System

Alcohol interferes with gonadal function even in the absence of cirrhosis by inhibiting normal testicular, pituitary, and hypothalamic function. Testicular atrophy, low testosterone levels, decreased beard growth, diminished sperm count, and a loss of libido result. However, testicular atrophy does not occur in all male alcoholics but is associated with alcohol dehydrogenase polymorphism in the testes, as reflected by the genetic variant of an increased frequency of the ADH21 allele (Yanauchi et al., 2001).

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