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© Dirk Biddle
i) Insulin is secreted by the pancreas in response to eating or to elevated blood sugar. It is deficient in persons with type 1 diabetes and present at insufficient levels in persons with type 2 diabetes. The natural evolution of type 2 diabetes causes insulin levels to fall from high levels to low levels over a course of years. Insulin levels in persons with type 1 and type 2 diabetes may then overlap significantly and thus insulin levels are not very useful in determining type 1 versus type 2 diabetes.
Insulin levels also vary widely from person to person depending upon an individual’s insulin sensitivity (or conversely, their insulin resistance.) Insulin levels also vary widely according to when the last meal occurred. Insulin resistance is a risk factor for coronary disease, thus assessing an individual's insulin resistance may have some value using the HOMA-IR calculation. Insulin levels are also elevated in patients with true hypoglycaemia, however the interpretation of these levels is difficult. Insulin level, when measured by itself at a random time is therefore rarely useful.
ii) C-peptide: This is a fragment cleaved off of the precursor of insulin (pro-insulin) when insulin is manufactured in the pancreas. C-peptide levels usually correlate with the insulin levels, except when people take insulin injections. When a patient is hypoglycaemic, this test may be useful to determine whether high insulin levels are due to excessive pancreatic release of insulin, or from an injection of insulin.
iii) Estradiol is the most commonly measured type of oestrogen. In women its level varies according to age and menstrual cycles. Estradiol levels are also altered when taking birth control pills or oestrogen replacement (hormone replacement therapy - HRT). Oestrogens occur in nature in several forms. In women with active menstrual cycles, the ovaries produce between 70 and 500 micrograms of estradiol daily. This is converted to estrone and to a lesser extent estriol. After menopause, estrone is made in the adrenal glands and is the most active circulating oestrogen.
Oestrogens cause growth and development of female sex organs and maintain female sex characteristics, including underarm and pubic hair and the shape of body and skeleton. Oestrogens also increase secretions from the cervix and stimulate growth of the inner lining of the uterus (endometrium). Oestrogens reduce LDL-cholesterol ("bad" cholesterol) and increase HDL-cholesterol ("good" cholesterol) concentrations in the blood. Oestrogens, when taken alone or in combination with a progestin, have been shown to reduce the risk for hip fracture due to osteoporosis. Oestrogens also increase the liver's ability to manufacture clotting factors.
iv) Prolactin: Men and non-pregnant women will normally have only small amounts of prolactin in their blood. Prolactin is produced in the pituitary and primarily acts to stimulate and maintain breast milk production during pregnancy and after childbirth while the mother is nursing. Thus high prolactin levels (hyperprolactinaemia) are normal in pregnant and lactating women. Prolactin levels quickly decrease when breast feeding is ceased.
There are two types of prolactin (alpha and beta). The alpha variety is linked to lactation while little is known of the function of the beta variety other than it is so far seen to have a benign influence. Only raised alpha prolactin levels are thus deemed to be of any diagnostic value. Unfortunately standard prolactin tests cannot distinguish between the two (1).
High prolactin levels are also seen with: Pituitary tumours (prolactinomas(2)), Anorexia nervosa, Drugs (eg; oestrogen, tricyclic antidepressants, and drugs that block the effect of dopamine - a brain chemical that regulates and inhibits the production of prolactin - such as tranquilizers, some hypertension drugs, and some drugs that are used to treat gastroesophageal reflux). High levels may also be caused by Hypothalamic diseases, Hypothyroidism, Kidney disease, Nipple stimulation (moderate increase), and Polycystic ovary syndrome.
Below normal levels of prolactin are not usually treated but may be indicative of a more general hypopituitarism (decreased pituitary function and decreased hormone production). Low levels may also be caused by drugs such as dopamine, levodopa and ergot alkaloid derivatives.
A test for prolactin is often done a) in woman to determine the cause of an abnormal nipple discharge, an absence of menstrual periods (amenorrhea), or of infertility, or b) in men when a pituitary gland problem is suspected. Also, a prolactin test may be done to evaluate a man's lack of sexual desire or his inability to have an erection (erectile dysfunction), especially if his testosterone levels are abnormally low. Sometimes, abnormal prolactin levels present as idiopathic (i.e., with no discernable cause), often medication in these cases will not be needed, depending on individual symptoms.
Prolactin levels need to be evaluated based on the time of day that they are collected. Levels vary over a 24 hour period - rising during sleep and peaking in the morning. Ideally then your blood sample should be drawn at least 3 hours after waking and preferably after you have been resting quietly for 30 minutes (Prolactin levels also increase during times of physical or emotional stress).
v) Testosterone is the androgenic hormone primarily responsible for normal growth and development of male reproductive organs, including the penis, testicles, scrotum, prostate, and seminal vesicles. Testosterone aslo facilitates the development of secondary male sex characteristics such as musculature, bone mass, fat distribution, hair patterns, laryngeal enlargement and vocal chord thickening. Additionally, normal testosterone levels maintain energy level, healthy mood, fertility and sexual desire (3).
Testosterone production declines naturally with age. However, testosterone deficiency may result from a disease or damage to the hypothalamus, pituitary gland, or testicles that inhibit hormone secretion and testosterone production (hypogonadism). Depending on age, insufficient testosterone production can lead to abnormalities in muscle and bone development, underdeveloped genitalia, and diminished virility. Studies also have shown that men with obesity, diabetes, or hypertension are more likely to have low testosterone levels.
Women also produce testosterone. Although little is known of its function in the female population it has been linked with libido.
Serum and blood testing is done to determine the availability of testosterone and levels of leutenizing and gonadotropin-releasing hormones in the body. Men with low testosterone in whom normal or high gonadotropin levels are found typically have primary testosterone deficiency, which stems from a problem in the testicles. Secondary and tertiary types, caused by problems of the hypothalamus or pituitary gland, often result in low testosterone and low gonadotropin levels.
Rarely, testicular biopsy is done, usually in cases where sperm is absent from ejaculate despite normal testicle development. Biopsy, which involves using a needle to collect a sample of testicular tissue, may detect a malfunction in sperm production.
vii) Cortisol is a steroid hormone (a glucocorticoid) released from the adrenal cortex in response to adrenocorticotrophic hormone (ACTH – see below). It is involved in glucose synthesis and insulin release and the regulation of blood pressure, immune function and inflammatory response. It also stimulates conversion of proteins to carbohydrates, raises blood sugar levels and promotes glycogen storage in the liver. Cortisol levels are often measured to evaluate pituitary and adrenal function.
Normally, cortisol levels rise and fall during the day, repeating on a 24-hour cycle (diurnal variation). Highest levels are at about 6 to 8 a.m. and lowest levels are at about midnight. Cortisol is also released in higher levels during the body’s “fight or flight” response to stress and is responsible for several stress-related changes in the body. Thus although stress isn’t the only reason that cortisol is secreted into the bloodstream, it has nevertheless been termed “the stress hormone”.
Small increases of cortisol have some positive effects such as a quick burst of energy for survival reasons, for heightened memory functions, a burst of increased immunity, lower sensitivity to pain or to help maintain homeostasis in the body. It has been speculated in that in our current high-stress culture, that the body’s stress response is activated so often, that functioning often doesn’t have a chance to return to normal, producing chronic stress syndrome.
Nevertheless, apart from stress, greater than normal levels of cortisol may indicate an adrenal tumour, Cushing's syndrome, or Ectopic ACTH-producing tumours. Lower than normal levels may indicate Addison's disease or Hypopituitarism. Additional conditions under which the test may be performed include acute adrenal crisis, Ectopic Cushing's syndrome and Pituitary Cushing's (Cushing's disease) (4).
Higher and more prolonged levels of cortisol in the bloodstream (like those associated with chronic stress) have been shown to have negative effects, such as impaired cognitive performance, suppressed thyroid function, blood sugar imbalances (such as hyperglycaemia), decreased bone density, decrease in muscle tissue, higher blood pressure, lowered immunity and inflammatory responses, as well as other health consequences such as increased abdominal fat (which is associated with a greater amount of health problems than fat deposited in other areas of the body). Some of the health problems associated with increased abdominal fat are heart attacks, strokes, the development of , higher levels of ‘bad’ cholesterol (LDL) and lower levels of ‘good’ cholesterol (HDL), which can then lead on to other health problems (5).
Interestingly it is the powerful anti-inflammatory function of cortisol that is harnessed in modern steroidal anti-inflammatory medicines (eg; prednisolone) that are used to treat vasculitis and other inflammatory conditions (see 1.9 Treatment).
viii) Adrenocorticotropic hormone (ACTH, corticotropin) stimulates the adrenal cortex to secrete glucocorticoids such as cortisol (it has little control over the secretion of aldosterone, the other major steroid hormone from the adrenal cortex). This test screens for problems with the pituitary gland or the adrenal glands.
ACTH is secreted from the anterior pituitary in response to corticotropin-releasing hormone from the hypothalamus. Corticotropin-releasing hormone is secreted in response to many types of stress (which makes sense in view of the "stress management" functions of glucocorticoids). Corticotropin-releasing hormone itself is inhibited by glucocorticoids, making it part of a classical negative feedback loop.
Overproduction of ACTH causes overactive adrenal glands and the release of too much cortisol (one form of Cushing's syndrome). A high level of ACTH and a low level of cortisol (or low ACTH and high cortisol levels) could mean a problem with the adrenal glands. Low levels of ACTH and cortisol could mean a problem with the pituitary gland.
High levels of ACTH can also be caused by emotional or physical stress (such as recent surgery or severe pain) or may indicate Addison's disease, Cushing's disease, or a tumour that is producing ACTH.
Abnormally low levels of ACTH can indicate damage to the pituitary gland caused by factors such as surgery, radiation, stroke, head injury, or a tumour. It can also indicate overactive adrenal glands due to a tumour that is producing cortisol. This is known as Cushing's syndrome.
Both ACTH and cortisol levels vary throughout the day. ACTH is normally highest in the early morning (between 6 a.m. and 8 a.m.) and lowest in the evening (between 6 p.m. and 11 p.m.). Cortisol levels are frequently measured at the same time as ACTH. Further, because ACTH is released in bursts, its levels in the blood can vary from minute to minute. Interpretation of the test results is difficult and often therefore requires the skill of an endocrinologist.
NOTE: The adrenal cortex is a factory for producing steroid hormones. Like all steroids, adrenal corticosteroids are synthesized from cholesterol through a series of enzyme-mediated transformations. In total, at least two to three dozen different steroids are synthesized and secreted. Nevertheless three broad classes of steroidal hormones are of importance: the catecholamines (eg; epinepherine and norepinepherine), the mineralocorticoids (eg; aldosterone) and the Glucocorticoids (eg; cortisol) plus some sex steroids (eg; androgen).
It is the goal of the RPNVC to be able to present explanations for as many of these steroid hormones as possible (other than the ones described in these pages). To that end this website will be continually updated – not only in this section but also within other sections of interest – and visitors are advised to check for updates regularly.
ix) Free thyroxine (FT4, Free tetriodothyronine) and Free triiodothyronine (FT3): The thyroid gland secretes three hormones: a) Thyroxine (T4) is the major hormone secreted by the follicular cells of the thyroid gland. T4 is involved in controlling the rate of metabolic processes in the body and influencing physical development. 99.97% of the T4 circulating in the blood is bound to transport proteins such as Thyroxine-binding globulin (TBG), and to a lesser extent Thyroid-binding pre-albumin (TBPA - this protein is also responsible for the transport of retinol, so now has the preferred name of transthyretin - TTR) and Albumin, b) Triiodothyronine (T3) is 3-4 times more potent than T4. Only 15% of the total normal T3 concentration is directly secreted by the thyroid follicular cells. 99.7% of the secreted T3 is bound to the same proteins as T4 and c) Calcitonin is also secreted by the -cells of the thyroid gland. Its function is totally unrelated to the other thyroid hormones, since it is involved in calcium homoeostasis.
The thyroid hormones, are tyrosine-based hormones produced by the thyroid gland. An important component in their synthesis is iodine (see below). As noted, the major form of thyroid hormone in the blood is thyroxine (T4). This is converted to active T3 thyronamines within cells by deiodinases. T3 thyronamines are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a).
The thyronines (T4) act on the body to increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline). The thyroid hormones are essential to the proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.
The thyronamines (T3 > T1a, T0a) function via an unknown mechanism to inhibit neuronal activity and thus they play an important role in the hibernation cycles of mammals. One effect of administering the thyronamines is a severe drop in body temperature.
When thyroid hormones are protein-bound, they are not active, so the amount of free (not bound to protein) T3/T4 is what is important. As mentioned above, only a very small fraction of the circulating thyroid hormones are free - FT4 0.03% and FT3 0.3%. This free fraction is biologically active, hence measuring concentrations of free thyroid hormones is of great diagnostic value. These values are referred to as fT4 and fT3. For this reason, measuring total thyroxine in the blood can be misleading.
Another critical diagnostic tool is the amount of thyroid-stimulating hormone (THS) that is present.
x) Thyroid stimulating hormone (Thyrotropin or TSH) is a hormone, synthesised and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland. TSH levels are tested in patients suspected of thyroid disease. Higher than normal levels of TSH may indicate congenital hypothyroidism (cretinism), hypothyroidism or thyroid hormone resistance. Lower than normal (suppressed) levels of TSH may indicate hyperthyroidism.
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1 CAUTION: If your health professional is planning medication for an idiopathic raised prolactin level, make sure he has determined if the test has shown raised alpha or raised beta levels. Raised beta levels are benign and need no medication. Further, idiopathic raised alpha levels should only be medicated if symptoms cause discomfort (such as lactation without pregnancy) or more rarely, in anticipation of a planned pregnancy.
2 As prolactinomas are often small, your doctor may also order an MRI (magnetic resonance imaging), both to try and locate the tumour within the pituitary gland and to assess both the size of the tumour and of the pituitary (which often enlarges).
3 http://www.urologychannel.com/testosteronedeficiency/diagnosis.shtml
4 http://www.nlm.nih.gov/medlineplus/ency/article/003693.htm