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ENDOCRINE ASSESSMENTS Premenopause Why is this test important? This profile provides clinicians with a deeper, more precise understanding of sex steroid metabolism, enabling them to better assess the impact of hormonal imbalances on each woman’s health. It also helps target candidates for hormone replacement therapy (HRT) and provides an easy means of monitoring bio-identical hormone therapy or other interventions along the way.. This comprehensive profile includes measurements of the three major estrogens, two estrogen metabolites that reflect breast cancer risk, two major androgens, progesterone, and sex-hormone binding globulin. What does this test involve? All markers are measured in a single serum specimen. Three versions of the profile are available: premenopausal (specimen collected at peak of luteal phase), menopause, and menopause & HRT (specimen collected 8-10 hours after the last hormone dose). The test report includes commentary and a map of the hormones showing their interrelationships. Due to the diversity of forms and protocols for HRT, the ‘Menopause & HRT’ version of the profile utilizes pre-menopausal follicular reference ranges. What are the consequences of hormonal imbalances? Sex steroids affect a wide array of functions in the body. Imbalances in many of the hormones tested are associated with increased risk of gynecological disorders such as menstrual irregularities, ovarian cysts and uterine fibroids, polycystic ovary syndrome, infertility and spontaneous abortions, and sexual dysfunction. Risk may also be increased for systemic problems such as osteoporosis, heart disease and dyslipidemia, immune weakness, and breast cancer. Identifying clinically significant imbalances can help clinicians to effectively customize treatment and optimize their patients’ health. Additional support materials for this profile are available, including patient brochure and One-Page Test Description. Refer to website www.gdx.net for more educational documents. INTERPRETIVE GI U I D E L I N E S NTERPRETIVE GUIDELINES Progesterone Analyte Progesterone Result Low Suspect • May indicate collection at time other than luteal peak • Luteal phase defect (impaired progesterone production by corpus luteum) • Anovulation* • Chronic stress (steroid precursors shunted toward cortisol production) • Meds: Low progesterone common with oral contraceptives (including recent discontinuation) or ampicillin Consider • Address estrogen imbalances (see E2 and E1 sections of guide) • Address underlying contributors to anovulation or luteal phase defect (see column to left) • Anti-oxidants, especially carotenenoids, if oxidative stress • Support hypothalamic/pituitary/ovarian (HPO) axis, e.g., chasteberry) • Stress management, adrenal support • Check FSH and LH to rule out early menopause • Glandular support for ovary, hypothalamus, pituitary • Address infection or inflammatory condition • Progesterone or pregnenolone supplementation High • Adrenal hyperactivity • Persistent corpus luteum • Progesterone or pregnenolone supplementation • Inhibitors of progesterone metabolism (e.g., ketoconazole, cimetidine, cigarette smoke, or glucocorticoids) • May be seen in some cases of endometriosis, depression-type PMS, or PCOS • Stress management, adrenal support, relaxant herbs, if relevant. • Remove metabolic inhibitors • Address any relevant underlying disorder (see column to left) Result Low Suspect • Hypothyroidism • Hyperinsulinemia • High body mass index • Western-type diet • Low estradiol • Alcohol intake • Hyperprolactinemia • Oral testosterone or high levels of endogenous androgens • Corticosteroids • Meds: Danazol, glucocorticoids, insulin, Norplant, norethindrone acetate (androgenic progestin) Consider • Attention to relevant underlying disorders (e.g., normalize thyroid function, improve insulin sensitivity, reduce body mass index) • SHBG may be increased with isoflavones, dietary fiber, flaxseed High • Hyperthyroidism • Thyroxine therapy • Significant weight loss • Smoking • Caffeine • High fiber diet • Oral estrogens or high levels of endogenous estrogens • Oral contraceptives • Meds: tamoxifen, carbamazepine, clomiphene, anti-convulsants, phenytoin, and rifampin • Normalize thyroid function, if relevant • DHEA supplementation may reduce SHBG, at least in postmenopausal women Binding Proteins Analyte Sex-Hormone Binding Globulin (SHBG) 2 Androgens Analyte DHEA-S (Dehydroepiandrosterone sulfate) Result Low Suspect: • Chronic stress (adrenal fatigue or shunting of precursors to cortisol production) • Aging • Hypocholesterolemia • Inflammation (TNF activity) • Smoking • Meds: ketoconazole and anti-epileptics Low DHEAS may be associated with depression, high body mass index, impaired immunity, dyslipidemia, reduced insulin sensitivity, reduced bone mass, and chronic conditions such as rheumatoid arthritis, lupus, chronic fatigue, and cardiovascular disease High • Observed in PCOS (greater DHEA response to ACTH) • Insulin resistance with hirsutism • Acute stress • Adrenal hyperplasia or Cushing’s syndrome • Hyperprolactinemia • DHEA supplementation • Meds: clomiphene Consider: • Stress management • Adrenal support: Nutrition (e.g., vitamin C, pantothenic acid, B6, zinc, magnesium) Herbal adrenal adaptogens (Siberian or Panax ginseng, ashwaganda, etc. Avoid licorice when cortisol is high) Adrenal glandular • Anti-inflammatory measures, if relevant • DHEA supplementation • Stress management, if relevant • Address PCOS and/or hyperinsulinism (e.g., weight reduction, exercise, reduce carbohydrates and hydrogenated fats, chromium, zinc, magnesium, alpha lipoic acid, fish oils, meds such as metformin or pioglitizone) High DHEAS may result in testosterone excess in women Analyte Testosterone (total) Result Low Suspect: Ovarian or adrenal insufficiency (see DHEAS level) • High aromatase activity (expect higher E2), e.g., alcohol; glucocorticoids, inflammation, glycerrhiza; hypothalamic or pituitary insufficiency (also expect low estrogens, thyroid, and adrenals); inflammatory conditions (TNF inhibits production of its precursor, DHEA) • Meds: ketoconazole, fluconazole, digoxin, danazol, glucocorticoids, nafarelin, spironolactone, thioridazine, phenothiazines, troglitazone, oral contraceptives, THC, or licorice (suppressed production) Consider: • Support hypothalamic/pituitary/ovarian (HPO) axis, e.g., chasteberry, adrenal adaptogen herbs • Ovarian glandular • Glandular supplementation (e.g., hypothalamus, pituitary, adrenal) • Address infection or inflammatory condition (TNF reduced by fish oils, nettle leaf, green tea, ginkgo biloba, N-acetyl cysteine, and Eleuthrococcus, abdominal fat reduction) • Rule out aromatase stimulation • Consider aromatase inhibitors IF E2 and E1 are high (e.g., chrysin, flavonoids, phytoestrogens, flaxseed, procyanidins in grape seed and red wine, progesterone (inhibits cortisol-induced aromatase induction), non-steroidal aromatase inhibitors, e.g., anastrozole (Arimidex) • Testosterone or DHEA supplementation (also reduces SHBG, thus increasing bioavailable testosterone) • Testosterone-enhancing herbs (e.g., Siberian or Korean ginseng, ashwaganda, Tribulus terrestris, horny goat weed) High • Ovarian (primarily) or adrenal hyperactivity (refer to DHEAS) • May be related to PCOS and/or insulin resistance • Abdominal obesity • DHEA supplementation • Aromatase inhibition (e.g., smoking, chrysin, flavonoids, ketoconazole, oxidative stress) • Address PCOS and/or insulin resistance (e.g., weight reduction, exercise, reduce carbohydrates and hydrogenated fats, chromium, zinc, magnesium, alpha lipoic acid, fish oils, medications such as metformin or pioglitizone) Continued on next page 3 Analyte Testosterone (total), cont’d Result High, cont’d Suspect • Meds: barbiturates, cimetidine, clomiphene, estrogens, rifampin, phenytoin • Gonadotropin stimulation of ovary in perimenopause (may lead to spikes in testosterone) • Associated with celiac disease in men (low 5- reductase); not known if also applies to women Consider • D-chiro-inositol (for PCOS) • Oral contraceptives suppress ovarian (primarily) Considerand adrenal androgen production • Rule out testosterone-raising drugs or aromatase inhibition • Aromatase may be enhanced by boron, vitamin D3, diindolylmethane (DIM), licorice • Consider reducing dietary protein or fat, increasing exercise • Increase SHBG to reduce bioavailable testosterone (e.g., isoflavones, dietary fiber, flaxseed, oral estrogens) Analyte Free Androgen Index (FAI) Result Low Suspect Note: Refer to individual levels of SHBG and Total Testosterone for most appropriate interpretation Consider Note: Refer to individual levels of SHBG and Total Testosterone to determine most appropriate target(s) for intervention • Low total testosterone • High SHBG • Meds: antiepileptics, DES, digoxin, spironolactone, phenothiazines, ketoconazole, THC, SHBG-inducing meds High Note: Refer to individual levels of SHBG and Total Testosterone for most appropriate interpretation • High total testosterone • Low SHBG • Meds: barbiturates, clomiphene, danazol, SHBG-reducing meds Estrogens Analyte Estradiol (E2) and Estrone (E1) 4 Result Low Suspect (E2 most significant) • Low body mass index (BMI) • Strenuous exercise (may lead to anovulation and less peripheral production of estrogen) • Chronic stress (precursors shunted to production of stress hormone or inhibitory HPA feedback loops) • Hypothalamic or pituitary insufficiency • Chronic inflammation (see comment for low DHEAS) • Decreased conversion from androgens (check for high testosterone) (e.g., smoking, chrysin, flavonoids, ketoconazole) • Meds: ketoconazole, oral contraceptives (including recent use), cimetidine, megestrol (anti-neoplastic agent) Consider • Support hypothalamic/pituitary/ovarian (HPO) axis, e.g., chasteberry, adrenal adaptogen herbs • Glandular supplementation (e.g., ovary, hypothalamus, pituitary, adrenal) • Stress management, adrenal support (see comments for DHEAS) • Increase BMI, if relevant • If testosterone is elevated, rule out aromatase inhibition (e.g., smoking, chrysin, flavonoids, ketoconazole). Aromatase activity enhanced with boron, vitamin D3 diindolylmethane (DIM), licorice • Broad-spectrum nutrition • Common herbs with estrogen-like activity include red clover, fennel, sage, hops, black cohosh, licorice, panax ginseng, fennel, anise High • Decreased hepatic clearance of estrogen • High intestinal beta-glucuronidase activity (increased reuptake of estrogen) • High BMI • Hypothyroidism • Adrenal insufficiency (stimulatory HPA feedback loops) • Promote hepatic clearance (e.g., lipotropic factors, liver botanicals, broad-spectrum nutrition) • Check stool for beta glucuronidase activity • Reduce excess weight Continued on next page Analyte Estradiol (E2) and Estrone (E1), cont’d Result High, cont’d Suspect • Smoking (higher E2 levels) • Meds: clomiphene, tamoxifen, digoxin (for E1) • Inflammation (cytokines increase conversion of E1 to E2) • Estrogen or androgen supplementation High E2 may be associated with PMS (esp. featuring anxiety or water retention; progesterone may be low), breast tenderness, irritability, dysmenorrhea, increased risk of endometrial hyperplasia and CA (if not balanced by progesterone), increased breast density and breast CA risk, ovarian cysts, uterine fibroids, and menometrorrhagia Analyte Estriol (E3) Result Low Suspect • Reduced conversion from 16 -hydroxyestrone (check level) • Meds: ampicillin, penicillin, aspirin, probenecid, thyroxine, albuterol (although most effects seen only in pregnancy) Consider • Increase exercise • Increase dietary fiber (reduces enterohepatic reuptake of estrogen) • Stress management, adrenal support • If testosterone is low, aromatase activity can be reduced with chrysin, flavonoids, phytoestrogens (esp. genestein), flaxseed (enterolactone), procyanidins in grape seed and red wine, progesterone (inhibits cortisolinduced aromatase induction) • Stimulate SHBG, if low (Note: will lower bioavailable testosterone) • Phytoestrogens (e.g., soy isoflavones) act as weak antagonists to estrogen when levels are high • Consider progesterone supplementation, to balance (refer to progesterone value) Consider Note: Any intervention should be based on levels of 16 -hydroxyestrone (refer to ‘Estrogen Metabolism’) and the other estrogens Low E3 results in higher net estrogen activity in body (if E1 and/or E2 are higher) High • Generally results in lower net estrogen activity in body (competitive antagonist to E1 and E2) • Enhanced conversion from 16 -OHE1 (protective effect on breast CA risk); OR associated with high level of 16 -OHE1 (increased breast CA risk)— Refer to level of 16 -OHE1 Estrogen Metabolism Analyte 2:16 -Hydroxyestrone Ratio Result Low Suspect Low 2:16 -OHE1 ratio suggests shunting of estrogen metabolism to the more potent 16 -OHE1 and/or 4-OHE1 (check level of 16 -OHE1) • Increased net estrogen activity in body • Increased risk of breast cancer • Rheumatoid arthritis • Lupus (SLE) • Greater bone mass, although possibly less likely to show increases in BMD with HRT Note: The above risks are modified when E1 and E2 trend low • Pesticide exposure • Hypothyroidism • Obesity • High fat, low fiber diet • Omega-6 fatty acids • Alcohol consumption • Meds: oral contraceptives Consider Note: Decision to modify ratio should be based on patient’s respective risks for breast cancer (high estrogen) and osteoporosis (low estrogen) To increase ratio: • Cruciferous vegetables (e.g., broccoli, cabbage, cauliflower) • Indole 3-carbinol (I3C) or diindolylmethane (DIM) • Flaxseed (lignans) • Soy isoflavones (genestein, daidzein) • Fish oils (omega-3 fatty acids) • Reduce dietary fat • Rosemary, kudzu, turmeric Note: It is recommended for follow-up testing to use same specimen type as used in this test (blood versus urine) Continued on next page 5 Analyte 2:16 -Hydroxyestrone Ratio, cont’d Result High Suspect • High 2:16 -OHE1 ratio suggests shunting of estrogen metabolism away from the more potent 16 OHE1 and/or 4-OHE1 (check level of 16 -OHE1) • Decreased net estrogen activity in body • Decreased risk of breast cancer • Studies on bone density are mixed: High ratio (along with low estrogens) may correlate with increased risk of osteoporosis. However, 2OHE1 stimulates osteoblasts, and women with higher 2:16 ratio appear to gain more bone with HRT. Note: The above risks are modified when E1 and E2 trend high Consider To reduce ratio: • Apiaceous vegetables (e.g., carrots, parsnips, celery, dill, parsley) • Reduce intake of cruciferous vegetables, soy, flax Note: It is recommended for follow-up testing to use same specimen type as used in this test (blood versus urine) • High intake of cruciferous vegetables, soy, flax • High coffee consumption • Regular alcohol consumption • Smoking • Meds: Prozac™, thyroxine Add-on Markers Analyte Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) Analyte Androstenedione 6 Result Low Suspect • Excess estrogen or testosterone (provides negative feedback to anterior pituitary) • Deficient progesterone (pre-menopausally) • Glucocorticoid excess • Excessive exercise • Hyperprolactinemia (may suppress GnRH via a dopamine-related mechanism) • Hypothyroidism (TRH-induced prolactin secretion) • Possible PCOS (if low FSH along with high LH) • Deficient hypothalamic secretion of GnRH (including anorexia nervosa or genetic disorders) • Pituitary insufficiency • Congenital adrenal hyperplasia • Radiation or trauma to pituitary • Critical illness (transitory suppression) • Prolonged administration of anabolic steroids • Autoimmune damage to hypothalamus or pituitary • Meds: Oral contraceptives, estrogens, phenothiazines Consider • Identify and correct underlying cause (see column to left) • Refer to estrogen levels and suggested interventions • Refer to prolactin level and suggested interventions • Evaluate thyroid function High • Low estrogen or testosterone • Primary ovarian insufficiency (premature ovarian failure or onset of menopause) • Hyperinsulinemia (increases LH); may cause hyperandrogenism • Congenital disorders (e.g., Turner Syndrome) • Pituitary adenoma (FSH high, LH normal) • Meds: L-dopa, clomiphene, ketoconazol • Identify and correct underlying cause (see column to left) • Refer to estrogen level and suggested intervention • Rule out hyperinsulinemia (high LH) Result Low Suspect • Ovarian or adrenal insufficiency (see DHEAS level) • Hypothalamic or pituitary insufficiency (also expect low estrogens, thyroid, and adrenals) • High aromatase activity (expect higher estrone); e.g., alcohol, glucocorticoids Consider • Identify and correct underlying cause (see column to left) Continued on next page Analyte Androstenedione, cont’d Analyte Prolactin Result Low, cont’d Suspect • Inflammatory conditions (TNF inhibits production of its precursor, DHEA) • Hyperprolactinemia (stimulates adrenal androgen production) • Meds: carbamazepine, ketoconazole, Norplant™ High • Ovarian or adrenal hyperactivity (refer to DHEAS level) • DHEA supplementation • Aromatase inhibition (e.g., smoking, chrysin, flavonoids, ketoconazole, oxidative stress) • Licorice (inhibits conversion of androstenedione to testosterone) • Meds: clomiphene, metyrapone, cimetidine, DHEA Result Low Suspect • Hyperthyroidism (prolactin inhibited by T3) • Prolonged dopamine infusion • Sheehan syndrome (post-partum pituitary necrosis) • Pituitary tumor, or treatment of tumor • Head injury • Infection (e.g., histoplasmosis, TB) • Infiltrative diseases (e.g., hemochromatosis, sarcoidosis) • Bulimia • Inborn error • Meds: ergot derivatives, L-dopa, bromocriptine, calcinonin, rifampin, valproic acid, tamoxifen High • Excess estrogen • Pregnancy or post-partum • Primary hypothyroidism • Alcoholic cirrhosis • Celiac disease (active) • Hypoglycemia • PCOS • Insulin resistance • Chest trauma or surgery • Pituitary tumor (micro- or macroadenoma) • Anti-prolactin antibodies (prolactin/IgG complex; symptoms may be minimal) • Intracranial tumors • Meds: cimetidine, cocaine, estrogens, oral contraceptives, haloperidol, methadone, phenothiazines, tricyclic antidepressants, MAO inhibitors, metoclopramide, reserpine, danazol, phenytoin, verapamil, opiates Consider • Identify and correct underlying cause (see column to left) • Evaluate for PCOS (refer to levels of testosterone, LH, and DHEA; if levels high, check insulin Consider • Identify and correct underlying cause (see column to left) • Normalize thyroid, if high • Remove prolactin-suppressing medications • Identify and correct underlying cause (see column to left) • Pregnancy test, if relevant • Refer to estrogen levels and suggested interventions • Normalize thyroid, if low • Evaluate adrenal function • Rule out celiac disease, remove gluten if positive • Improve insulin sensitivity • Remove prolactin-inducing medications • IgG Anti-prolactin antibodies • MRI, if suspect tumor • L-tyrosine? (dopamine inhibits prolactin) • Vitamin B6 • Progesterone (inhibits prolactin in vitro) • Dopamine agonists (e.g., bromocriptine, pergolide, quinagolide) • Ergoline derivatives (e.g., cabergoline) • Surgery (large tumors causing visual field deficit) 7 This information is for the sole use of a licensed health care practitioner and is for educational purposes only. It is not meant for use as diagnostic information. All claims submitted to Medicare/Medicaid for Genova Diagnostics laboratory services must be for tests that are medically necessary. “Medically necessary” is defined as a test or procedure that is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Consequently, tests performed for screening purposes will not be reimbursed by the Medicare program. 63 Zillicoa Street Asheville, NC 28801 800 522.4762 www.GDX.net © 2008 Genova Diagnostics e,ig,HormHealth_Pre,071408