Testosterone normal or not normal

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Testosterone Normal or not Normal:

Testosterone Normal or not Normal Dr. Hussam El- Mouzi Clinical Pathologist Al Borg Laboratory

Sources of testosterone :

Sources of testosterone 95% of testosterone is produced in the testicles 5 % of testosterone is produced in the adrenal glands. 50% of testosterone is produced in the ovaries 50 % of testosterone is produced in the adrenal glands

Why is testosterone so important:

Why is testosterone so important

Andropause:

Andropause Synonym s Androgen deficiency in aging man (ADAM) Partial androgen deficiency Male menopause Definition The gradual but progressive decline in serum testosterone with aging associated with a cluster of clinical symptoms Muscle atrophy and weakness Osteoporosis Reduced sexual functioning Increased fat mass

Progression of Androgen Deficiency in Aging Males:

Age-related decline begins ~30-40 years of age at approximately ↓ 1.2% per year Average testosterone at age 75 compared to age 25 - Total ↓ 35% - Bioavailable ↓ 50% Progression of Androgen Deficiency in Aging Males McLaughlin SP, Shaban SF, Carson CC. Androgen deficiency in the aging male. In: Kirby RS, ed. Men’s Health. Taylor and Francis; 2004.

So Why Testosterone Decline with Age:

So Why Testosterone Decline with Age ↓ Number Leydig cells ↓ Testosterone secretion ↓ LH signaling to Leydig cells ↓ Testosterone secretion ↑ Increased SHBG ↓ Nonspecific bound fraction of testosterone ↓ Bioavailable testosterone

Prevalence of androgen deficiency in the ageing male:

1/3 of men classified as normal according to their total testosterone levels would be incorrectly labelled Morley et al ., 2002. Prevalence of androgen deficiency in the ageing male

WHAT ARE THE SYMPTOMS OF LOW TESTOSTERONE?:

WHAT ARE THE SYMPTOMS OF LOW TESTOSTERONE ? A lack of energy Low libido (sex drive) Depression Irritability Fatigue Increased blood pressure Loss of muscle Physical height reduction Erections are not "rock hard Sleep disorders

Symptoms of Low Testosterone in Women:

Symptoms of Low Testosterone in Women Anorgasmia or the inability to have orgasms. Lack of interest in sexual activity. Fatigue. Definite loss of muscle strength and mass. Accumulation of fat, especially around the abdomen. Depression. Increased risk of osteoporosis and related bone deterioration. Increased risk of cardiovascular diseases . Vaginal dryness. Painful sexual intercourse. Sudden absence of menstruation. Hot flashes.

MEASURES OF TESTOSTERONE:

MEASURES OF TESTOSTERONE Total Testosterone—all that is produced (3-10ng/ml) equal to 300-1000 ng /dl Free Testosterone—all that is unbound (2-4%) (80-300pg/ dL ) Bioavailable Testosterone— Gold Standard “Free and Loosely/Weakly Bound” 40-50%

Bio-available testosterone (BioT):

Bio-available testosterone ( BioT ) Circulating serum testosterone: SHBG bound T Free T Albumin bound T BioT = Free T + Albumin bound T Slow dissociation half time Fast dissociation half time 50-68% 30-45% 0.5-3%

Scientific interest:

Scientific interest

Advantages of BioT over TotalT:

Advantages of BioT over TotalT SHBG concentrations can vary widely and are related to variables including: diet body mass index insulin concentration age

Advantages of BioT over TotalT:

Advantages of BioT over TotalT bone mineral density sexual function muscle mass development of generalised fragility BioT has been shown to correlate well with clinical parameters such as:

Indications for ordering Bio-T:

Indications for ordering Bio-T Total testosterone and 'free' testosterone assays have been traditionally ordered. Until further knowledge is gained on the assay, these tests should continue to be ordered, along with bioavailable testosterone. Males: - Suspected hypogonadism, as seen in a decline of libido or sexual performance - Infertility - Andropause ("male menopause") - Osteoporosis Females: - Evaluation of hirsutism - Osteoporosis Ferrini RL and Barrett-Connor E: Sex hormones and age. Am J Epidemiol 147(8):750-4, 1998.

SHBG is the most important in determining the level of testosterone :

SHBG is the most important in determining the level of testosterone Testosterone-bound SHBG is considered biologically inactive It carries a higher percentage of testosterone than either albumin or cortisol -binding globulin It binds testosterone with a much higher affinity than albumin or cortisol -binding globulin 2011 Mount Nittany Medical Center : 1800 East Park Avenue, State College, PA 16803-6797 : ph. (814) 231-7

SHBG is the most important in determining the level of testosterone:

SHBG is the most important in determining the level of testosterone Production regulated by estrogen testosterone balance - Estrogen stimulates SHBG production - Testosterone decreases SHBG synthesis Increased SHBG levels occur in Aging, Hypogonodal men, Hyperthyroidism, Alcoholic liver disease and GH Deficiency Decreased SHBG levels occur in Hypothyroidism, Type 2 Diabetes mellitus, GH excess and Obesity

SHBG is the most important in determining the level of testosterone:

SHBG is the most important in determining the level of testosterone If SHBG ↑ : – Total ‘T’ c/b normal but baT or fT can be low… falsely conclude that AD is absent If SHBG ↓ : – Total ‘T’ c/b low but baT or fT can be normal… falsely conclude that AD is present

SHBG and polycystic ovarian syndrome (PCOS):

SHBG and polycystic ovarian syndrome (PCOS) SHBG is reduced in insulin resistance and actually a very good marker for insulin resistance.Many women with polycystic ovarian syndrome have a high-normal or even a normal total testosterone but have a low SHBG because they have insulin resistance. Therefore, their bioavailable testosterone is often on the high side. On the other hand, birth control pills or other forms of oral estrogen raise the SHBG and would give a higher total testosterone than if the SHBG was normal. These patients often have a normal or low bioavailable testosterone. J Clin Endocrinol Metab. 2005 Jul;90(7):441 9-20

SHBG and Obesity:

SHBG and Obesity Obesity and low testosterone are tightly linked. Obese men are more likely to have low testosterone. Men with very low testosterone are also more likely to become obese. Body fat contains an enzyme called ‘ aromatase ’ that takes your testosterone and converts it into ‘ estradiol ’, which is a primary type of estrogen In parallel, obesity leads to hyperinsulinaemia , which in turn causes a reduction in the hepatic synthesis and circulating levels of sex-hormone-binding globulin (SHBG). So we can say that obesity may cause increase in sex hormone levels but this increase in the level does not promote a rise in SHBG coz the effect is nulled off by high levels of insulin which in turn cause a decrease in production of SHBG in the liver. Pasquali R, Casimirri F, Cantebelli S, Melchionda N, Labate AMM, Fabbri R, Capelli M, Bortoluzzi L 1991 Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism 40:101–104

SHBG and type 2 diabetes:

SHBG and type 2 diabetes Men and women with the lowest blood levels of sex hormone-binding globulin (SHBG) were 10 times more likely to develop type 2 diabetes than those with the highest levels of the protein Research has discovered that sex hormone binding globulin (SHBG) is a reasonably good indicator of insulin resistance. Low levels of SHBG are consistently linked to high levels of insulin in the body. Sustained high levels of insulin are, in turn, associated with the development of the chronic diseases such as high blood pressure, diabetes and coronary heart disease. Studies have shown that men with higher testosterone levels have a lower risk of developing Type 2 DM Pasquali R, Casimirri F, Cantebelli S, Melchionda N, Labate AMM, Fabbri R, Capelli M, Bortoluzzi L 1991 Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism 40:101–104

Free Androgen Index (FAI) (Total Testosterone / SHBG) X 100 :

Free Androgen Index (FAI) ( Total Testosterone / SHBG ) X 100 - Simple ratio of testosterone and SHBG concentrations (commonly called the free androgen index) as an indicator of the free testosterone level. This ratio, which is a useful indicator of an abnormal androgen status, is called the free androgen index (FAI) or, sometimes, the testosterone free index (TFI). - The FAI is often increased in severe acne, male androgenic alopecia (balding), hirsutism , and other conditions in which a normal total testosterone level is found with a low SHBG level. - Many studies have found that the FAI corresponded well with clinical findings but correlated less well with other biochemical usually more useful in serum women than men as most the SHBG in men is bound to testosterone Leo Vankrieken (May 1997). "Testosterone and the Free Androgen Index" (PDF). Diagnostic Products Corporation, Siemens Healthcare . Retrieved 2009-11-01.

Difficulty in measuring testosterone :

Difficulty in measuring testosterone Samples should be collected before 10:00 a.m Peak at the morning and decline to reach the lowest level in the night The secretion of testosterone is regulated by GnRH secretions from the brain which in turn is affected by seasonal changes. This means that testosterone levels can fluctuate dramatically (up to 1 ng /ml) in as little as fifteen minutes Ann Clin Biochem 2006;43:196-199 doi:10.1258/000456306776865034© 2006 Association for Clinical Biochemistry

Difficulty in measuring testosterone:

Difficulty in measuring testosterone Over the course of a day the levels can vary by as much as 50%. a single blood test is unlikely to yield an accurate picture If total level are in the "low normal" range, less than 3 ng /ml levels should be monitored. If levels are below normal, less than 2.5 ng /ml, your physician may recommend replacement therapy . Ann Clin Biochem 2006;43:196-199 doi:10.1258/000456306776865034© 2006 Association for Clinical Biochemistry

Laboratory workout before HRT:

Laboratory workout before HRT Total Testosterone Bioavailable Testosterone (AKA “Free and Loosely Bound”) Free Testosterone (if Bioavailable T is unavailable) SHBG LH FSH Prolactin Cortisol Thyroid Panel CBC Comprehensive Metabolic Panel Lipid Profile PSA (age dependent) IGF-1, IGFBP-3 (if HGH therapy is being considered) 2009 HRC Medical Center

INDIVIDUAL ASSAYS EXPLAINED :

INDIVIDUAL ASSAYS EXPLAINED TOTAL TESTOSTERONE when Total T is at low-normal levels. Total T is important for titration of HRT, but its relevance is reduced in older men, by virtue of their increased serum concentrations of SHBG (and therefore lowered Bioavailable Testosterone) BIOAVAILABLE TESTOSTERONE This is the actual amount the body has available for use, If Bio T is not readily available, Free T may be a second choice substitute, as Bio T and Free T serum concentrations are usually well correlated. Bioavailable Testosterone is the gold standard for serum androgen evaluation .

INDIVIDUAL ASSAYS EXPLAINED:

INDIVIDUAL ASSAYS EXPLAINED Luteinizing Hormone (LH) LH has a half-life of only minutes. When you combine this fact with the absolute pulsatile nature of its pituitary release, care must be taken to avoid placing too much weight upon a single draw. Most important reason to assay the gonadotrophins is to differentiate between primary and secondary ( hypogonadotropic ) hypogonadism. Follicle Stimulating Hormone (FSH) The hours long half-life and less pulsatile production of FSH makes it a better marker for gonadotropin production. It is less an acute phase reactant to varying serum androgen and estrogen levels than LH. Greatly elevated FSH levels could signal a gonadotrophin -secreting pituitary tumor.

INDIVIDUAL ASSAYS EXPLAINED:

INDIVIDUAL ASSAYS EXPLAINED PROLACTIN 5% of hypogonadotrophic hypogonadism is associated with hyperprolactinemia . Greatly elevated hyperprolactinemia , or hyperprolactinemia plus a Total Testosterone less than 1.5ng/ mL , equals a trip to an Endocrinologist for a pituitary MRI. CORTISOL Elevated levels can cause secondary ( hypogonadotropic ) hypogonadism. THYROID PANEL Even subclinical hypothyroidism mimics hypogonadism in several of its effects.

INDIVIDUAL ASSAYS EXPLAINED:

INDIVIDUAL ASSAYS EXPLAINED CBC Above 18.0/55.0 TRT is withheld, and therapeutic phlebotomy recommended. CMP - Baseline for sodium (which may elevate initially secondary to androgen supplementation) - LFT’s, as elevations may occurs secondary to androgen supplementation - BUN/ creatinine ratio as marker for hormonal hemo -concentration PSA At the initiation of TRT in older men, when serum androgen levels are rapidly rising, PSA may, too

An approach for the diagnostic evaluation of adult men suspected of having androgen deficiency :

An approach for the diagnostic evaluation of adult men suspected of having androgen deficiency <200ng/dl In elderly BMJ Publishing Group Limited 2011

Conclusion:

Conclusion Bio-T and F-T must be ordered in combination with T-T for androgenic activity evaluation . Bio-T is the gold standard with F-T for the evaluation of androgenic activity mainly in low normal and low T-T results Conditions affecting SHBG dramatically affect testosterone measurement . Aging decrease the level of testosterone . Difficulty in measuring testosterone

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