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Reference Guide 13500 Linden Ave North Seattle, WA 98133 www.USBioTek.com This information is intended for use by clinicians for educational purposes only. Copyright ©2009 US BioTek Laboratories, Inc. All rights reserved. Comprehensive Urinary Steroid Hormone Profile Reference Guide Background A 24-hour collection is used to measure steroid hormones in urine. Hormone testing is used to identify conditions of deficiencies and excess of which may be assessed against evidence from physical signs, symptoms and past medical history. Hormones are made and released by cells of the endocrine glands. These “chemical messengers” are generally released in short bursts or pulses at various intervals reflecting physical and mental status in addition to circadian variations. A 24-hour urine sample offers the most sensitive means to account for the production and metabolic activity of steroid hormones against the natural variations that we see in a 24-hour period. Steroid hormones are transported by the blood to various target cells on which they have specific effects. The circulating form in the bloodstream is bound almost entirely to various plasma proteins. Urine sampling provides the best indicator of the free or unbound steroid; the biologically active form. Optimal hormone levels in any individual should be within a range that allows them relief from complaints and problems suggestive of a hormone deficiency or excess. The steroid hormones and their metabolites, produced by the adrenal glands and gonads (ovaries and testicles) are the foundation of BioTek’s Comprehensive Urinary Steroid Hormone Profile. The adrenal hormones include cortisol and DHEA. The hormones of the gonads, known as sex hormones, include estrogens, progesterone and testosterone. Steroid hormones are crucial for health and well being. They mediate a wide variety of functions from growth and development, reproduction, anti-inflammatory activity, protection against osteoporosis and certain cancers, to regulation of sexual function and resistance to stress. On a cautionary note, epidemiological data support the role for some steroid hormones in excess or deficiency, in the pathogenesis of certain cancers including that of the breast, uterine endometrium, prostate, testis and ovary. Cancer results from a complex and yet unclear interaction between age, genetic and environmental factors. Tissue biopsy and imaging confirms the diagnosis. Medications affecting steroid hormone levels are diverse and include: estrogens (including birth control pills, hormone replacement therapy), testosterone, corticosteroids, digoxin, thiazides, spironolactone, barbiturates, medicines to treat prostate or breast cancer, and certain anti-seizure drugs. This list is not exhaustive. This guideline is intended as a brief introduction for the clinician. Interpretation of patient results is at the discernment of the clinician in light of a full medical examination and review of current medications. A review of key enzyme systems in steroid hormone metabolism is listed below: 17β-Hydroxysteroid Dehydrogenase (17β-HSD): catalyses the interconversion between highly active 17β-hydroxy and low-activity 17-keto-steroids, thereby regulating the biological activity of the sex steroids. Aromatase: a cytochrome P450 enzyme and the key enzyme for estrogen biosynthesis. Catalyses conversion of androstenedione and testosterone to estrone (E1) and estradiol (E2), respectively. Excess estrogen activity is implicated in hormone-dependent breast cancer, painful endometriosis and fibroids. 11β-Hydroxysteroid Dehydrogenase (11β-HSD): interconverts inactive cortisone and active cortisol. Although bidirectional it primarily functions as a reductase generating active cortisol. 1 5-Reductase (5-R): responsible for the formation of more potent androgens that have been implicated in such conditions as benign prostatic hyperplasia (BPH), male pattern baldness, androgenetic alopecia, hirsutism, acne and polycystic ovarian syndrome. Increased enzyme activity is associated with obesity and insulin resistance in both women and men. The A/E and THF/THF ratios have been suggested to reflect hepatic 5-reductase activity (see below). 21-Hydroxylase: a cytochrome P450 enzyme responsible for the synthesis of cortisol and aldosterone. In the extreme case, a defect in this enzyme function results in low glucocorticoid and mineralocorticoid production as seen in congenital adrenal hyperplasia. Estrogens Estrogen may be made in several tissues. Aromatase, widely present throughout the body, catalyzes the rate limiting step in estrogen biosynthesis. The premenopausal ovary contains the highest level of aromatase and is the predominant source of the strongly estrogenic E2 during the premenopausal years. Peripheral adipose tissue and breast tissue also contain aromatase activity. The peripheral conversion of androgens to estrogens accounts for the circulating estrogens found in postmenopausal women and men. Estrone (E1), Estradiol (E2), Estriol (E3) Estrone is not as estrogenic as estradiol. Although higher levels are present in the urine, estradiol is ten times more potent and represents the major biologically active estrogen. Estrone represents the estrogen pool of the body. Estrone and estradiol can interconvert. The end product is E3 which is regarded as the least estrogenic. Estrogens feminize the body. Estrogens (particularly E2) enlarge the breasts, and promote proliferation of the endometrium in the uterus making menstruation possible. Estradiol is responsible for vaginal lubrication and initiating ovulation. The drop in estrogen levels at the end of the menstrual cycle causes the period to begin. The normal menstrual cycle can be divided into 3 distinct phases. The follicular, ovulatory and luteal phases. Follicular Phase Begins with the first day of bleeding to the day before the “LH surge” or ovulation. Development and maturation of a cohort of follicles in the ovaries, of which one will ovulate, occurs at this time. This phase is promoted by follicle stimulating hormone (FSH), from the anterior pituitary. During this time E2 secretion from the ovaries increases slowly, with a concomitant slow but steady fall in FSH and rise in luteinizing hormone (LH). Progesterone levels also begin to increase significantly. E2 peaks the day of the LH surge. Ovulatory Phase Marked by the peak release of LH, “LH surge”, from the anterior pituitary gland. This surge typically lasts about 36-48 hours and is necessary for release of the ovum from the mature follicle. The surge consists of pulsatile bursts of LH from the pituitary. Women with regular menses accompanied by premenstrual breast tenderness, lower abdominal bloating and moodiness are usually ovulatory. An indicator that ovulation occurred in a given cycle is an elevation in urine of the progesterone metabolite, pregnanediol. This is most noted during the luteal phase. 2 Luteal Phase E2 levels fall and progesterone levels continue to increase marking the luteal phase. Progesterone released from the ovary during this time supports the released ovum with levels peaking at about 6-8 days after the LH surge. Typically, the luteal phase lasts about 14 days in the absence of pregnancy and ends with the onset of menstruation. The median menstrual cycle is about 28 days but varies considerably from 18-40 days. Variation typically occurs in the years following the onset of regular menstrual cycles and preceding the peri-menopausal phase when anovulatory cycles are more common. Menopause Cessation of ovarian function is marked by the absence of a menstrual cycle for 12 consecutive months. The postmenopausal ovary and adrenal gland continue to secrete androgens which are converted to estrogens in the periphery (fat cells, skin). This peripheral conversion accounts for most of the circulating estrogen found in postmenopausal women. Estrogen deficiency in women may manifest with1: • Hot flushes followed by chills • Night sweats • Small breasts or breast ptosis • Polymenorrhea, spanomenorrhea • Hypo/Amenorrhea • Spasmodic dysmenorrhea • Vaginal dryness • Vaginal atrophy • Dyspareunia • Vaginal, uterine prolapse Estrogen excess in men may manifest with2: • Obesity • Gynecomastia • Impotence • • • • • • • • Urinary stress incontinence Weight gain Fluid retention, swelling (abdomen, breasts) Persistent fatigue Poor sex drive/libido Osteopenia, osteoporosis Infertility Cardiovascular disease • • • Benign prostate hypertrophy Myocardial infarction Testosterone treatments Note: As a man gains body fat, his aromatase enzyme becomes more active converting more androstenedione and testosterone to estrogen, creating an estrogen-to-testosterone imbalance. Estriol Quotient (EQ) = E3/E1+E2 The ratio of estriol (E3), to the sum of estrone (E1) and estradiol (E2), known as the estriol quotient (EQ), is believed to reflect the degree of “estrogenicity”.3 These 3 classical estrogens differ in estrogenic potency. E3 is classified as a short-acting “weak estrogen” compared to E1 and E2 due to its lower affinity for the estrogen receptors and its higher clearance rate. A higher EQ is therefore believed to be favorable. Low EQs have been found in postmenopausal women with breast cancer and premenopausal women with fibrocystic breast disease.4 In pregnancy, E3 is an indicator of fetal well-being and closely reflects fetal adrenal activity. E3 has also been shown to increase significantly prior to the onset of normal labor.5 During the normal menstrual cycle, E1 and E2 are lower during the early follicular (day 2) and late luteal (day 26) phase compared to E3. The EQ may be elevated during these time periods reflecting this proportionate drop in E1 and E2.6 3 Estrogen Metabolites The inactivation and clearance of estrogens involves several specific P450 enzymes of which are abundant in the liver but also found in most cells. Phase I of this process involves hydroxylation; the first step in making the compounds more water soluble for their elimination. Phase II involves the conjugation to methyl, sulfate and glucuronide groups. Among the estrogen metabolites formed during this process, some are highly estrogenic whereas some are not. Genetic polymorphisms of the cytochrome P450 enzymes, affecting the transformation of the estrogens have and continue to be identified as playing an integral role in hormone-sensitive cancer etiology.7 2-Hydroxyestrone (2-OHE1)/ 16-Hydroxyestrone (16-OHE1) Ratio 2- and 16-hydroxyestrone are metabolites of the parent estrogenic hormones; estradiol (E2) and estrone (E1). These parent compounds are readily interconverted in the body by the enzyme 17β-hydroxysteroid dehydrogenase, 17β-HSD. The ratio of 2- to 16-hydroxyestrone has been utilized in research studies as a risk assessment tool for breast cancer, prostate cancer and other hormone-sensitive diseases. A positive association between breast cancer risk, for example, and persistently elevated blood levels of estrogens has been consistently found in many studies.8,9,10,11 Estrogens are a proliferative stimulus to breast tissue, increasing the number of cell divisions and, by inference the mutation rate. The hydroxylation of estrogen at the C-16, or carbon-16 position, produces the biologically strong 16-OHE1 metabolite. This metabolite demonstrates significant proliferative or stimulatory activity on human cancer cell lines.12,13,14 Hydroxylation at the C-2 position, on the other hand, yields the biologically weaker estrogen metabolite, 2-OHE1. This metabolite exerts anti-proliferative properties on human cancer cells with little to no estrogenic activity.15 A low urine 2:16-OHE1 ratio indicates preferential metabolism via the 16-hydroxylation pathway to yield 16-OHE1. Abnormal estrogen metabolism with increased 16-OHE1 activity compared to 2-OHE1 has been associated with proliferative thyroid disease16, prostate cancer17, knee osteoarthritis in middle aged women18, and autoimmune disease including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in women and men.19 Interestingly, the abnormal pattern of estrogen metabolism favoring 16-hydroxylation seems to be independent of sex and gonadal steroid production. One study found total serum concentrations of E2 to be well within physiologic range in both sexes affected by RA and SLE.20 Another study found no difference in concentrations of E2 in breast cancer tissue among pre- and postmenopausal women despite the fact that the plasma levels decrease by 90% after menopause.21 It is understood that estrogen and its metabolic products may be synthesised de novo in the target tissue. The enzyme aromatase converts upstream androgen precursors (testosterone, androstenedione) to the estrogens. Following menopause, for example, this becomes the primary source of estrogens; the conversion of androgens to estrogens by the enzyme aromatase in adipose tissue. This conversion is thought to be dependent on the inflammatory state of the target tissue and is up regulated in inflamed loci. Increased tissue aromatase activity is induced by locally produced inflammatory cytokines (TNF-α, IL-1, and IL-6). This is strongly suggestive of a common theme to disease; one of chronic inflammation and inflammation-dependent reactions.22 Although the optimal level for the ratio is not known, an increase in the ratio of 2-hydroxyestrone relative to 16-hydroxyestrone is considered to be protective23, or an indicator of favorable estrogen metabolism. Currently there are no published human data on the effects of very high ratios or what can be considered reasonable upper limits. 4 4-Hydroxyestrone (4-OHE1) 4-hydroxyestrogens are carcinogenic estrogen metabolites with relative binding affinities for estrogen receptors equal to or greater than the parent E1 and E2 compounds. 4-hydroxylation activity has been identified in breast tissue, ovary, adrenal gland, uterus and elsewhere. Further metabolism yields quinone/semiquinone intermediates capable of generating free radicals able to cause oxidative damage to lipids, proteins and DNA.24 2-Methyoxyestrone (2-ME1), 4-Methoxyestrone (4-ME1) 2- and 4-hydroxylated estrogen metabolites may be converted to corresponding methoxyestrogens during Phase II of estrogen detoxification. Methylation, via the enzyme catechol-O-methyltransferase (COMT), inactivates their estrogenic potential and blocks their ability to undergo oxidation to reactive quinone/semiquinone metabolites that can participate in the generation of free radicals. Polymorphisms are associated with a low activity form of COMT. These Phase II metabolites may be converted back to their hydroxylated estrogens by glucuronidase. A balance among the methoxylated and hydroxylated estrogen metabolites is likely required to maintain homeostasis.25 DHEA 17β-HSD Androstenedione 17β-HSD Aromatase 16α-OHE1 Estrogenic Genotoxic P450 2-OHE1 Conjugates Methoxystrogens, Glucuronides, Sulfates Protective COMT Excretion 17β-HSD Estradiol (E2) P450 4-OHE1 COMT Conjugates 2-, 4- Methoxyestrogens Inactive Estrogens Testosterone Aromatase Estrone (E1) P450 Androstenediol Semi Q Quinones Oxidative Damage GSH Transferase Inactive Estrogen Excretion Progesterone & Metabolites Progesterone (P), Pregnanediol (P2) Progesterone (P), is the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the adrenal cortex, gonads and other tissues. P is involved in normal breast development, the proliferative changes that occur during the menstrual cycle, pregnancy and lactation. In breast tissue, P is converted to several metabolites, some of which are believed to stimulate or inhibit cell proliferation and tumorigenesis. In vitro studies show elevated P 5α-reductase activity with higher 5α- reduced P metabolites, in breast tumor tissue compared to normal breast tissue.26 Produced by the ovaries during the luteal phase of the menstrual cycle, the role of progesterone in the premenopausal female is to support the ovum and prepare the uterus for implantation of the fertilized egg. To determine if ovulation occurred in a given cycle, an elevation in the urinary metabolite of progesterone, pregnanediol (P2), will be seen in the luteal phase with peak levels occurring about 6-8 days after the LH surge. However, the quality of ovulation is evaluated by an endometrial biopsy. 5 Progesterone deficiency (= estrogen excess) may manifest with27: • Premenstrual breast swelling and • Dysmenorrhea tenderness • Endometriosis • Premenstrual abdominal bloating • Ovarian cysts • Premenstrual irritability, anxiety, • Uterine fibroids tension • Infertility • Cystic breasts • Breast & endometrial cancer • Mastalgia • Menorrhagia In men, progesterone is predominantly secreted by the adrenal glands; levels of which decline with age, but may be comparable to young adult women in the follicular phase, during ¾ of their lifetime. Progesterone is believed to play a favorable role in reducing E2 and DHT levels; speeding the conversion of E2 to the less potent E1, and competitively blocking the conversion of T to DHT, respectively. Elevated E2 and a DHT/T ratio may result from progesterone deficiency. Progesterone is also believed to play an important role in sperm motility.28 Progesterone deficiency (=estrogen and DHT excess) in men may manifest with: • Gynecomastia • Cardiovascular disease • Benign prostate hypertrophy • Increased sex drive/libido (due to excess DHT vs.T) • Male pattern baldness • Cancer of the prostate Since progesterone is the major precursor of the adrenal hormones (cortisol and aldosterone), and androgens (androstenedione and testosterone), progesterone deficiency may be accompanied by deficiencies of these hormones in both women and men. 17-Hydroxysteroids (Glucocorticoids) Pregnanetriol (P3) A metabolite of 17-hydroxyprogesterone, normally produced in small quantities by the adrenal glands and gonads. Elevated levels of P3 in addition to P2 are associated with a deficiency in the enzyme 21-hydroxylase in congenital adrenal hyperplasia. Hirsute women may show elevated urine levels of P3 suggesting an adrenal abnormality probably in the 21-hydroxyulation of P.29 Cortisol, Cortisone Allo-Tetrahydrocortisol (-THF), Tetrahydrocortisone (THE), Tetrahydrocortisol (THF) Cortisol represents the principle circulating glucocorticoid secreted under the control of the hypothalamo-pituitary-adrenal (HPA) axis. The role of cortisol in the body includes; the regulation of carbohydrate and amino acid metabolism, maintenance of blood pressure, modulation of catecholamine discharge, the stress and inflammatory response. Blood cortisol levels are highest in the morning (6-8 a.m.) and lowest in late afternoon/evening. Melatonin and growth hormone are secreted at night to reduce cortisol levels and allow sleep. Cortisol deficiency or adrenal fatigue may manifest with30: • Poor resistance to stress (physical, • mental, emotional) • Inadequate food absorption • • Hypoglycemia • Acute hair loss • • Anxiety, irritability • Sweating feet and hands Excessive/chronic inflammation (arthritis, chronic fatigue syndrome, fibromyalgia) Increase in susceptibility to many infections Brownish skin folds (due to excess ACTH release on weak adrenals) More than 90% of circulating cortisol is protein bound. The free fraction is the biologically active form. About 50% of the glucocorticoids secreted in a day are released in the urine as THF, α-THF and THE.31 6 THF and THF are the two main metabolites of cortisol. THE is the main metabolite of cortisone. A defect in the interconversion of the biologically active cortisol into inactive cortisone is reflected by a reduced level of urinary cortisone metabolites compared to cortisol metabolites. This is calculated using the ratio below. This ratio is used as an index of 11β-hydroxysteroid dehydrogenase, 11β-HSD, activity: THF + THF / THE A ratio of approximately 1 is considered normal.32 11β-HSD activity is important in controlling the overall equilibrium of local glucocorticoid levels and maintaining a constant balance between cortisol and cortisone in “glucocorticoid target tissues” (liver, gonads, adipose tissue, brain). Tissue-specific changes of 11β-HSD activity have been shown in obesity with decreased activity in liver and increased activity in adipose tissue. Enhanced conversion of cortisone to cortisol in the adipose tissue of the abdomen plays a role in the pathogenesis of central obesity. Cortisol is essential for adipocyte differentiation (increase in fat cell size). Waist (an indicator of central obesity) has been shown to be positively correlated with the THF + THF / THE ratio indicating increased 11β-HSD with increasing central fat distribution.33 The ratio of THF/THF is an indicator of 5-reductase vs. 5β-reductase activity. An elevated ratio reflects preferential 5-reductase activity. This ratio, combined with anthropometric data, may be used as an index of insulin sensitivity in women with polycystic ovarian syndrome (PCOS), the most common endocrine disorder in women of reproductive age. PCOS is associated with hypercortisolism, hyperandrogenism and hyperinsulinemia. Insulin and androgens enhance 5reduction.34 Mineralocorticoids Tetrahydrocorticosterone (THB), Tetrahydro-11-dehydrocorticosterone (THA) Mineralocorticoids are produced by the adrenal cortex and are involved in the reabsorption of sodium with an associated reabsorption of water and secretion of potassium. Aldosterone is the principle mineralocorticoid produced. Elevated mineralocorticoids may result in hypertension and edema due to excess sodium and water retention. The potassium loss may cause muscle weakness. Low mineralocorticoid production is associated with Addison’s disease. Glucocorticoids circulate at levels 100 times that of mineralocorticoids with similar affinity for the mineralocorticoid receptors in target tissues. The 11β-HSD enzyme, responsible for the conversion of cortisol to inactive cortisone protects the mineralocorticoid receptors from cortisol intoxication. As seen with the glucocorticoid metabolites mentioned above, the sum of the urinary tetra-hydroderivatives of mineralocorticoids may be used as an indirect index of their production.35 Two major urinary metabolites of the mineralocorticoid corticosterone are tetrahydrocorticosterone 7 (THB) and tetrahydro-11-dehydrocorticosterone (THA) in addition to aldosterone. Corticosterone itself has low glucocorticoid and mineralocorticoid potency. THB and THA excretion has been shown to be elevated in hypertensive patients. This may be of particular importance in combination with mildly deficient 11β-HSD enzyme activity.36,37 Increased excretion of mineralocorticoid metabolites in addition to that of glucocorticoids has been shown in PCOS women, primarily due to increased peripheral 5α-reducatase activity.38 17-Ketosteroids (17-KS) - Androgens These are primarily the adrenal androgens. In women and children, the adrenal gland is the predominant source. In men about one-third are of gonadal origin. The main precursors of these 17-KS are dehydroepiandrosterone (DHEA), the mandatory precursor of both male and female sex hormones, and its sulfate, DHEAS. 17-KS are elevated in Cushing’s syndrome, adrenal hyperplasias (congenital is rare), some adrenal tumors, ovarian and testicular cancer, PCOS, pregnancy and obesity. Virilization is very often secondary to hypersecretion of adrenal androgens. Decreased 17-KS levels are found in adrenal insufficiency, Addison’s disease, hypopituitarism, myxedema, nephrosis and anorexia nervosa. Deficiencies are also associated with decreased axillary and pubic hair, aging, erectile dysfunction and low sexual satisfaction/desire in women and men. Aromatase converts androgen to estrogen. High enzyme activity is suggested by low total 17-KS along with high estrone (E1) and estradiol (E2). Medications that may increase 17-KS: • Antibiotics • Dexamethasone • • Spironolactone Phenothiazines Medications that may decrease 17-KS: • Birth control pills • Estrogens • • Prolonged use of Salicylates Thiazide diuretics Androsterone (A), Etiocholanolone (E); A/E Ratio Derived primarily from both adrenal androgens and testosterone, these two stereoisomers represent the principle 17-ketosteriods and the final end products in the androgen degradation pathway. When considered in conjunction with testosterone (T) excretion, these 17-KS reflect alterations in androgen activity. A is a product of the enzyme 5-reductase. E is a product of the enzyme 5β-reductase. 5-reductase activity is up-regulated by androgens. The ratio of A/E is used as an index of 5-reductase activity. This enzyme also converts T to dihydrotestosterone (DHT) and is important in determining the magnitude of the androgen stimulus in some tissues. This ratio, combined with anthropometric data, may be used as an index of insulin sensitivity in women with PCOS, the most common endocrine disorder in women of reproductive age.39 Increased 5-R activity may manifest with: • Polycystic ovarian syndrome (PCOS) • Acne • Hirsutism • Androgenetic alopecia • • • Virilization Male pattern baldness Benign prostatic hyperplasia (BPH) The ratio of -THF/THF is regarded as a more representative index of 5-reductase activity (see above). 8 Androstenedione Produced in the adrenal glands, ovaries and testes, androstenedione carries little intrinsic androgenic activity but is readily converted to both active androgens (testosterone) and estrogens. This may result in androgenic or estrogenic effects of excess. Androgen excess may manifest with: • Acne beyond puberty • Hirsutism • Male pattern baldness • Voice deepening • Weight gain • Loss of female body contour • Altered menstrual cycling/infertility Estrogen excess may manifest with: • Gynecomastia • Testicular atrophy • Impotency • Altered menstrual cycling • Endometrial hyperplasia • • • • • • • Fatigue/mood swings Increased libido in women Clitoromegaly Testicular atrophy Edema Liver disease/cancer Reduced HDL-C • Risk of uterine, breast & prostate cancer Blood clotting Glucose intolerance Hypertriglyceridemia • • • Androstanediol Androstanediol is the most abundant male androgen metabolite. Its levels reflect the degree of androgen activity; a high level reflects a high conversion rate down the androgen pathway from DHEA to testosterone to DHT in target tissues.40 Androstanediol is a breakdown product of DHT and may be used as a marker of androgen activity in peripheral tissues such as the skin; levels of which may be associated with hirsutism in women. Hirsutism reflects increased 5-reudctase activity which produces DHT (highly active form of testosterone) leading to the stimulation of hair growth in areas that are typically without hair. In women, up to 80% of androstanediol is formed from adrenal precursors. In men, the gonadal contribution is greater.41 Elevated androstanediol has been associated with acne in both sexes. Testosterone (T), Dihydrotestosterone (DHT) Testosterone, the major natural androgen sustains bone density and strength, lean body tissue, muscle size, muscle strength, erythropoiesis, energy, cognitive function, mood, and sexual function in men and women. Produced largely by the Leydig cells of the testes in response to LH from the anterior pituitary, testosterone is also made in smaller amounts by the adrenal glands in both men and women and ovaries in women. In women, about half of T comes from conversion of DHEA and androstenedione in fat and skin, the other half comes from the ovaries and adrenals in response to pituitary LH, and adrenocorticotropic hormone (ACTH), respectively. Testosterone synthesis includes several intermediates including DHEA and androstenedione. Testosterone is converted in the target tissues to the potent metabolite dihydrotestosterone DHT, by the enzyme 5-reductase. The androgenic potency of DHT is three fold higher than T. DHT exhibits trophic effects on the prostate gland, and mediates androgenic alopecia. Testosterone levels exhibit circadian variation with levels highest in the early morning. This circadian variation diminishes with age along with the response of the Leydig cells to pituitary release of LH. From the age of 30 onwards, total serum testosterone levels decline 1%/year. 9 Men aged 70-80 average levels that are ½ to ⅔ that of men in their 20’s. This age-related decline in free bioavailable testosterone is often described as andropause, the male “counterpart” to menopause. This decline may be associated with age-related muscle loss, loss of libido, osteopenia and cognitive decline. Testosterone deficiency in men may manifest with42: • Infertility due to low sperm count • Decreased sex drive/libido • Erectile dysfunction • Lack of mental firmness and assertiveness • Reduced muscle mass, strength and tone • • • • • • Prostate hypertrophy Dysuria, nocturia Hot flushes followed by chills Cardiovascular disease Osteoporosis Cancer of the prostate Elevated levels of testosterone in men may manifest with: Cancer of the testicles or adrenal glands Testosterone deficiency in women may manifest with43: • Decreased sex drive/libido • • Dyspareunia • Lack of mental firmness and assertiveness • • Diminished motivation • • Persistent fatigue • Reduced muscle mass, strength and tone • Cardiovascular disease • Osteoporosis Loss of ovarian function/oophorectomy (levels of T and precursor androstenedione may decline by 50%) Addison’s disease Corticosteroids, birth control pills, oral estrogens used for hormone replacement therapy (oral estrogens increase sex hormone binding globulin (SHBG), which in turn reduces free T and E2) Elevated levels of testosterone in women may manifest with: Cancer of the ovaries or adrenal glands Elevated levels of T or DHEAS may reveal PCOS (PCOS may be characterized by irregular periods, anovulation, adult acne, increased waist-to-hip ratio, hirsutism and male pattern hair loss (from excess DHT production), deepening voice, ovaries enlarged by cysts, insulin resistance/insulin elevations). Women with PCOS have an androgenic shift in hormone balance with increased T and cortisol levels and lowered estrogen.44 10 1 Hertoghe, Thierry. (2006). The Hormone Handbook. United Kingdom: International Medical Publications. Hertoghe, op. cit. Zumoff, B., Fishman, J., Bradlow, H.L., et al. (1975). Hormone profiles in hormone-dependent cancers. Cancer Research, 35, 3365-3373. 4 Bagli, N.P., Shah, P.N., Mistry, S.S. (1980). The estriol quotient in fibrocystic disease, a high-risk group of breast cancer. Indian J. Cancer, 17(4), 201-204. 5 Goodwin, T.M. (1999). A role for estriol in human labor, term and preterm. Am. J. Obstet. Gynecol., 180(1). 6 Wright, J.V., Schliesman, B., Robinson, L. (1999). Comparative measurements of serum estriol, estradiol, and estrone in non-pregnant, premenopausal women: a preliminary investigation. Alt. Med. Rev., 4(4), 266-270. 7 Tworoger, S.S., Chubak, J., Aiello, E.J., et al. (2004). Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. Canc Epid Biomarkers & Prevention, 13:94-101. 8 Eliassen, A.H., Missmer, S.A., Tworoger, S.S., et al. (2006). Endogenous steroid hormone concentrations and risk of breast cancer: does the association vary by a woman’s predicted breast cancer risk? J Clin Oncol, 24:1823-1830. 9 Kaaks, R., Rinaldi, S., Key, T.J., et al. (2005). Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer, 12:1071-1082. 10 Missmer, S.A., Eliassen, A.H., Barbieri, R.L., Hankinson, S.E. (2004). Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst, 96:1856-1865. 11 Endogenous hormones and breast cancer collaborative group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst, 2002; 94:606-16. 12 Yager, J.D., Davidson, N.E. (2006). Estrogen carcinogenesis in breast cancer. N Eng J Med, 354:270-282. 13 Lottering, M.L., Haag, M., Seegers, J.C. (1992). Effects of 17b-estradiol metabolites on cell cycle events in MCF-7 cells. Cancer Res, 52:5926-5932. 14 Lippert, C., Seeger, H., Mueck, A.O. (2003). The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells. Life Sciences, 72:877-883. 15 Lippert, C., Seeger, H., Mueck, A.O. (2003). The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells. Life Sciences, 72:877-883. 16 Chan, E.K., Sepkovic, D.W., Bowne, H.J.Y., et al. (2006). A hormonal association between estrogen metabolism and proliferative thyroid disease. Otolaryngology-Head and Neck Surgery, 134, 893-900. 17 Muti, P., Westerlind, K., Wu, T., et al. (2002). 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Washington: The Institute for Functional Medicine, Inc. 2 3 11 5β-R Tetrahydrocorticosterone THB THF THA 5α-R: 5α-Reductase 5β-R: 5β-Reductase HSD: Hydroxysteroid dehydrogenase 17β-HSD: 17β-Hydroxysteroid dehydrogenase 11β-HSD: 11β-Hydroxysteroid dehydrogenase 11β-OH: 11β-Hydroxylase AR: Aromatase COMT: Catechol-O-Methyltransferase 21-OH: 21-Hydroxylase Enzyme Abbreviations: 5α-R Cortisol 11β-OH 5β-R Cortisone THE α-THF 5β-R 5α-R Androstenedione HSD DHEA E3 4-OHE1 16α-OHE1 P450 COMT 2-OHE1 © US BioTek Laboratories 4-ME1 4-Methoxyestrone/estradiol Sulfation/Glucuronidation 2-ME1 2-Methoxyestrone/estradiol Sulfation/Glucuronidation/ Methylation COMT 2-Hydroxyestrone/estradiol 17β-HSD Androstanediol HSD E2 AR 17β-Estradiol T DHT 5α-R Testosterone HSD Androstenediol Dihydrotestosterone 17β-HSD 17β-HSD 4-Hydroxyestrone/estradiol A Androsterone HSD 16α-Hydroxyestrone/estradiol Estriol E1 Estrone E Etiocholanolone HSD AR 17β-HSD 17β-HSD 5β-Androstanedione 5α-Androstanedione P3 DHEAS Dehydroepiandrosterone Pregnanetriol Tetrahydrocortisone 11β-HSD 11-Deoxycortisol 21-OH Tetrahydrocortisol Allo-Tetrahydrocortisol Corticosterone 11β-OH THS HSD 17α-Hydroxyprogesterone Tetrahydro-11-dehydrocorticosterone Aldosterone P2 Pregnanediol 17-Hydroxypregnenolone Tetrahydrodeoxycortisol 11-Deoxycorticosterone 21-OH P Progesterone HSD Pregnenolone 18-Hydroxycorticosterone Cholesterol Metabolism of Select Steroid Hormones 13500 Linden Ave North Seattle, WA 98133 www.usbiotek.com