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Transcript
ENDOCRINOLOGY ASSESSMENTS
Urinary Hormone Assessment
Why Test Hormones in the Urine?
Provides an average of fluctuating hormones
Steroid hormone levels naturally fluctuate over the course of a day. Measurement of
hormones in urine collected over several hours provides a stable average of hormone
levels that overcomes the “snapshot” limitation inherent in serum and salivary testing.1
Evaluates hormone utilization
Steroid hormones that are produced primarily in the adrenal cortex, ovaries and testes are
extensively metabolized in various tissues. How they are metabolized influences the ultimate clinical effect of these hormones; this can vary significantly. Measuring their downstream metabolites in the urine can provide us with this critical intracellular information.2
Identifies bioavailable fraction of hormones
The majority of steroid hormones are bound to proteins in the blood that help to maintain
these hormones in a non-active ‘reserve’ form. It is only the tiny, unbound fraction that is
available to act upon the body via cellular hormone receptors. The concentration of binding proteins can vary, making it impossible to predict the bioavailable fraction of hormone
from a measurement of total (bound and unbound) hormone. All hormones measured in
urine represent the unbound, or bioavailable, fraction.
Are there any limitations to urinary
hormone testing?
Abnormal Renal Function
Assessment of any compounds in the urine depends upon normal kidney function.
Therefore, hormones in patients with abnormal renal function should be evaluated via
blood or saliva.
Evaluation of Diurnal Rhythms
Even though averaging hormonal fluctuations in urine offers an advantage, there are
still times when evaluating diurnal rhythms of certain hormones via saliva can provide
valuable information. An example is cortisol, which normally shows a robust output after
waking, with a gradual decline over the remainder of the day. Salivary cortisol testing
(comprising four timed salivary collections over the course of the day) can help reveal
uncharacteristic spikes or drops in cortisol at certain points in the day, or a flattening out
of the diurnal rhythm, a sign of stress-induced maladaptation and dysfunction within the
hypothalamic/pituitary/adrenal (HPA) axis.
Hematuria
Finally, blood in the urine may compromise the accuracy of urinary steroid results, mostly
due to the hormonal content of red blood cells contributing to the total measurement.
INTERPRETIVE
GI U I D E L I N E S
NTERPRETIVE
GUIDELINES
How do I select the most appropriate profile for a patient?
Adrenal steroids
Adrenal steroid evaluation might be considered for patients with dysglycemia (e.g., metabolic syndrome), tissue wasting
disorders or low bone density, chronic fatigue, immune dysfunction, hypo- or hypertension, allergies, menstrual irregularities,
or simply a history of chronic psychological or physiologic stress.
Adrenal assessment is also useful in hypothyroid patients. CRH, which is released from the hypothalamus during stress but also
in response to low cortisol, inhibits TSH secretion and thyroid function. High amounts of glucocorticoids also inhibit TSH secretion. Glucocorticoids and adrenaline render target tissues less sensitive to the effects of thyroid hormone, as well as inhibit the
conversion of T4 to T3. In light of these effects, addressing adrenal imbalances before administering thyroxine makes sense, and
may help improve tolerance of thyroxine in those patients who require it.3
Androgens
Androgen evaluation should be considered for patients experiencing decreased libido or sense of well-being, bone loss,
signs and symptoms of “andropause” in men (e.g., loss of muscle mass, increased adipose, decreased drive), or signs of
hyperandrogenism (e.g., hirsutism, alopecia, acne) or history of PCOS in women.
Estrogens and progesterone
Estrogens and pregnanediol (metabolite of progesterone) levels can help evaluate ovulatory function in pre-menopausal women
with menstrual irregularities and/or infertility, as well as menopausal symptoms in peri- or post-menopausal women. Estrogen
metabolites help assess the risk of breast or prostate cancer, osteoporosis (in postmenopausal women not using HRT), and
autoimmune conditions such as lupus and rheumatoid arthritis.4,5 These markers are also helpful in monitoring patient response
to interventions such as indole-3-carbinol (I3C), diindolylmethane (DIM), and sulforophane.
Comprehensive analysis
Given the close interrelationships of steroid hormones, a broad-spectrum assessment comprising all of these metabolites is
recommended, at least for an initial evaluation. Smaller sub-panels may be employed for follow-up testing to monitor response
to treatments or/or to check levels of previously abnormal results. As mentioned above, collections may be 24 hour collections
or first-morning void.
2
Comprehensive Urinary Hormones Interpretive Guidelines
Laboratory Interpretation
Breast & Prostate Cancer Risk Assessment via Estrogen Metabolites
It is not just the amount of total circulating estrogen that impacts breast and prostate cancer risk, but also how that estrogen is
processed. Estrogen can be metabolized in healthy, protective directions, or in unhealthy directions that increase cancer risk.
Urine testing provides the most comprehensive evaluation of estrogen metabolism possible.
Estrone (E1)
Estradiol (E2)
(CYP1A1)
(COMT)
2-MeOE1
2-OHE1
(CYP1B1)
(protective)
16-OHE1
Estriol (E3)
(COMT)
4-OHE1
4-MeOE1
(pro-carcinogenic)
(neutralized)
Healthy Phase 1 metabolism: The enzyme CYP1A1 converts estrone to 2-hydroxyestrone (2-OHE1).
Unhealthy Phase 1 metabolism: CYP3A4 and CYP1B1 convert estrone to 16-hydroxyestrone (16 -OHE1) and
4-hydroxyestrone (4-OHE1), respectively.
Healthy Phase 2 metabolism: COMT (methylation enzyme) neutralizes 4-OHE1 to 4-methoxyestrone (4-MeOE1). COMT also
converts 2-OHE1 to its most protective form, 2-methoxyestrone (2-MeOE1).6
2-Hydroxyestrone (FMV urine)
2.01
2-Methoxyestrone (FMV urine)
<dl
16α-Hydroxyestrone (FMV urine)
9.36
4-Hydroxyestrone (FMV urine)
2.89
4-Methoxyestrone (FMV urine)
2-Hydroxyestrone/16α-Hydroxyestrone Ratio (FMV urine)
2-Methoxyestrone/2-Hydroxyestrone Ratio (FMV urine)
2.10
0.21
<dl
4-Methoxyestrone/4-Hydroxyestrone Ratio (FMV urine)
LOWER RISK of breast or prostate cancer is
associated with:
• Higher 2-OHE1
• Higher 2-OHE1/16-OHE1 ratio
• Higher 2-MeOE1/2-OHE1 ratio
• Higher 4-MeOE1/4-OHE1 ratio
0.73
HIGHER RISK of breast or prostate cancer is
associated with:
• Higher 16-OHE1
• Higher 4-OHE1
• Lower 2-OHE1/16-OHE1 ratio7,8,9(also associated with RA
and lupus)10,11
• Lower 2-MeOE1/2-OHE1 ratio
• Lower 4-MeOE1/4-OHE1 ratio
Comprehensive Urinary Hormones Interpretive Guidelines
3
TREATMENT OPTIONS to improve estrogen metabolism:
Lower 2-OHE1 and/or 2-OHE1/16-OHE1 ratio,
or higher 4-OHE1 ?
• Increase intake of cruciferous vegetables.
• Consider broccoli derivatives such as:
- indole-3-carbinol (I3C) – (150 mg 2-3 X day)
- diindolylmethane (DIM) – (120 mg 1-2 X day)
- sulforaphane – (30 mg/day)
• Rule out hypothyroidism, toxicity (e.g., pesticides, polycyclic
aromatic hydrocarbons, PCBs).
Lower 2-MeOE1/2-OHE1 and/or 4-MeOE1/4-OHE1
ratios ?
• Provide nutritional support for methylation:
- Ensure adequate protein and/or assimilation of protein
- Ensure adequate magnesium, B2, B6, B12, folic acid,
serine
- Consider betaine (trimethylglycine, or TMG) –
(500 mg 2-3 X day)
HRT and Hormone Balance Assessment
Bio-identical hormones are fully represented in a urinary hormone evaluation, including their downstream metabolites.
Because urinary hormones offer the best reflection of how the body is processing exogenous hormones, steroid measurement
in the urine helps ensure that the therapy is having the desired effect.
NOTE: Oral contraceptives and other synthetic hormones, such as medroxyprogesterone acetate (e.g., Provera®) are not
reflected in any laboratory assay, including urine. Conjugated equine estrogens (e.g., Premarin®) are only partially represented,
although the balance of their estrone metabolites may help shed light on breast cancer risk.
NOTE: Urinary hormones are available as 24-hour collections or First-Morning Void (FMV), which reflects nocturnal levels of
hormones. Because of the variability of HRT delivery systems and their pharmacokinetics, it may be easier to obtain a reliable
‘average’ by using the 24-hour collection rather than a First-Morning Void in HRT-supplemented individuals.
ESTROGENS (estradiol, estrone, estriol, and estrogen metabolites) in the urine reflect circulating levels as well as tissue
metabolism. As a result of metabolism, serum estradiol is largely represented as estrone (glucuronide) in the urine.12
Estrogen metabolism is discussed above.
Estrone (24hr urine)
67.12
Estradiol (24hr urine)
6.95
Estriol (24hr urine)
<dl
Reference ranges are gender-specific and related to either menstrual status (24 hr) or age (FMV).
Estrone:
Phase
Follicular
Midcycle
Luteal
Menopausal
Male
4
Reference Range
3.60-57.60 mcg/24 hr
24.00-156.00 mcg/24
10.80-72.00 mcg/24 hr
0.30-7.90 mcg/24 hr
3.00-28.50 mcg/24 hr
Comprehensive Urinary Hormones Interpretive Guidelines
PROGESTERONE is metabolized into numerous downstream compounds, but most immediately into pregnanediol and
pregnanetriol. Urine levels of these metabolites tend to correlate with levels of serum progesterone, thus may be used to
assess status of the hormone.13
Pregnanediol (24hr urine)
Pregnanetriol (24hr urine)
0.31
0.51
ANDROGENS such as DHEA, testosterone, and androstenedione tend to be extensively metabolized into downstream androgen compounds. As a result, the levels of testosterone along with “Total 17-ketosteroids” (DHEA plus metabolites) should be used
to assess androgen status and/or efficacy of androgen replacement.
17-Ketosteroids, Total* (24hr urine)
10.51
Total 17-ketosteroids include the following:
DHEA (24hr urine)
<dl
Androsterone (24hr urine)
2.56
Etiocholanolone (24hr urine)
2.38
11-Keto-androsterone (24hr urine)
<dl
11-Keto-etiocholanolone (24hr urine)
11-Hydroxy-androsterone (24hr urine)
11-Hydroxy-etiocholanolone (24hr urine)
0.70
3.36
1.40
Lower level of Total 17-Ketosteroids may be
associated with:
• Acute or chronic stress
(check Total 17-Hydroxy-corticosteroids)
• Aging, DHEA deficiency
• Excessive conversion of androgens to estrogens
(see “Aromatase activity” below)
• High estrogen level or estrogen replacement including oral
contraceptives (can increase sex-hormone binding globulin,
which reduces the amount of bioavailable androgens)
• Smoking, chronic alcohol ingestion
• Diabetes mellitus
• Ketoconazole, metformin, troglitazone
Higher level of Total 17-Ketosteroids may be
associated with:
• DHEA, androstenedione, or testosterone supplementation
• High protein- or high calorie diet
• PCOS (especially with obesity) and/or hirsutism and/or acne
• Low sex-hormone binding globulin
(e.g., from hyperinsulinemia or hypothyroidism)
• Aromatase inhibitors
• Congenital adrenal hyperplasia
• Tumors of adrenals, ovaries, or testes
TREATMENT OPTIONS to increase
Total 17-Ketosteroids:
• Improve insulin sensitivity.
• Correct thyroid imbalances.
TREATMENT OPTIONS to decrease
Total 17-Ketosteroids:
• Stress management (see section for
Total 17-Hydroxy-corticosteroids)
• Increase dietary protein.
• Address aromatase imbalances.
• Consider supplementation with DHEA (15-100 mg/day)
or other androgens.
Comprehensive Urinary Hormones Interpretive Guidelines
5
AROMATASE ACTIVITY:
The enzyme aromatase converts androgens to estrogens. If enzyme activity is excessive, then administration of testosterone or
DHEA may mostly serve to increase levels of estrogen.
HIGHER aromatase activity is suggested by:
• Lower Total 17-ketosteroids along with higher estrogens
TREATMENT OPTIONS to reduce aromatase:
• Weight loss (greater aromatase activity in adipose)
• Reduce stress and/or inflammation.
• Improve insulin sensitivity.
• Natural aromatase inhibitors:
- Chrysin (1-3 gms/day, oral; 100-300 mg/day transdermal))
- Green tea and/or green tea extract (500 mg 1-3 X day)
- Epilobium (250 mg 1-2 X day)
- Flaxseed (5-10 gms/day)
- Stinging nettles (300 mg 1-2 X day, freeze-dried leaf)
- Vitamin C (500 mg 1-2 X day)
• Pharmaceutical aromatase inhibitors:
-Anastrozole (Arimidex®) (1 mg/day)
-Exemestane (Aromasin®) (25 mg/day)
-Letrozole (Femara®) (2.5 mg/day)
5-ALPHA-REDUCTASE ACTIVITY:
The enzyme 5-alpha reductase converts testosterone to dihydrotestosterone (DHT), a potent androgen associated with
male-pattern baldness, acne, hirsutism, polycystic ovarian syndrome, prostate hypertrophy and cancer risk. Alternatively,
testosterone can be metabolized by 5-beta reductase to an inactive metabolite.
Possible indicators of higher 5-reductase activity include:
• Higher androstanediol
• Higher androsterone
• Lower etiocholanolone
• Lower E:A (5:5) ratio
• THF:a-THF ratio
TREATMENT OPTIONS to reduce 5-reductase:
• Reduce carbohydrate intake.
• Herbal 5 reductase inhibitors:
- Saw palmetto (160 mg 2 X day, extract)
- Pygeum (50-150 mg/day)
- Stinging nettle nettles (300 mg 1-2 X day, freeze-dried leaf)
• Flaxseed (5-10 gms/day)
• Soy isoflavones (20-80 mg day)
• Green tea and/or green tea extract (500 mg 1-3 X day)
• Quercetin (200-400 mg 1-3 X day)
• Progesterone
• Pharmaceutical 5-reductase inhibitors:
- Finasteride (Proscar® – 5 mg/day; Propecia® – 1 mg/day)
- Dutasteride (Avodart®) (0.5 mg/day)
6
Comprehensive Urinary Hormones Interpretive Guidelines
Adrenal Stress Assessment & Anabolic/Catabolic Balance
Adrenal Stress:
Stress increases cortisol production, which can be life-saving in the short term. Chronic stress, however, can lead to cortisolinduced immune suppression, hyperglycemia, insulin resistance, central obesity, hypertension, memory impairment, hyperlipidemia, and/or altered thyroid function.14,15,16 Low cortisol production and/or HPA axis impairment, including low diurnal variation
in cortisol secretion, may follow chronic over-activation of the axis by chronic stress, leading to fatigue and other problems.17
Greater than 95% of cortisol is metabolized before excretion.18 Urinary “Total hydroxy-corticosteroids” (17-OHCS) account for
more than 50% of cortisol’s metabolic byproducts, thus can be used along with cortisol to help gauge overall glucocorticoid
production and metabolism.
Cortisol:
Cortisol, Free (24hr urine)*
60
17-Hydroxy-corticosteroids, Total* (24hr urine)
38.58
Total 17-hydroxy-corticosteroids include the following:
Pregnanetriol (24hr urine)
2.38
allo-Tetrahydrocortisol, a-THF (24hr urine)
Tetrahydrodeoxycortisol (24hr urine)
Tetrahydrocortisone, THE (24hr urine)
Tetrahydrocortisol, THF (24hr urine)
9.89
0.64
22.33
9.66
NOTE: Cortisol is not included in the Total 17-OHCS for two reasons: 1) Cortisol and the 17-OHCS are prepared and measured
differently; and 2) all research examining 17-OHCS has utilized the GC-MS method only, thus excluding cortisol.
Lower urinary cortisol along with lower
Total 17-hydroxy-corticosteroids suggests:
• Low cortisol production, as in adrenal insufficiency
(e.g., chronic stress, fibromyalgia, chronic fatigue syndrome,
or Addison’s disease) or congenital adrenal hyperplasia
(metabolic enzyme deficiency)
or
• Suppression of endogenous cortisol production from
exogenous glucocorticoids such as Prednisone19
or
• Pituitary insufficiency
Higher urinary cortisol along with higher
Total 17-hydroxy-corticosteroids suggests:
• High cortisol production (e.g., severe stress, strenuous
exercise, anorexia nervosa, or Cushing’s disease)
or
• Normal or low cortisol production, along with increased
clearance and metabolism of cortisol (e.g., obesity20 or
chronic stress)*
*NOTE: Urinary cortisol reflects both the production and the excretion of cortisol. Therefore, it is highly recommended to also
check serum a.m. cortisol or timed salivary collections throughout the day to help identify patients with low baseline levels and/or
impaired HPA axis function (flattened curve).
Comprehensive Urinary Hormones Interpretive Guidelines
7
TREATMENT OPTIONS for adrenal excess (confirmed by elevated salivary
or serum cortisol):
• Stress management (adequate sleep, meditation, yoga, or other stress-reducing activities; avoidance of overscheduling
and negative thinking, etc; breathe, move, laugh)
• Minimize stimulants such as caffeine, ephedra, yerba mate.
• Identify and address sources of physiologic stress (e.g., inflammatory conditions, allergies, reactive hypoglycemia,
dysbiosis/leaky gut, or infection).
• Address causes of persistent cortisol activation or production:
- Excess adipose, especially abdominal / high insulin / metabolic syndrome21
- Hypothyroidism22
- Inflammation23
• Adequate intake of vitamin C, magnesium, zinc, B vitamins; consider additional B6 (100 mg 1-2 X day) and pantothenic acid
(500 mg 2-3 X day)
• Phosphatidylserine to calm HPA axis activation and prevent neuronal cortisol toxicity24 (300-800 mg/day)
• Calmative herbal agents such as passiflora, hypericum, valerian, scutellaria, magnolia bark, hops (consult companies for
product dosing recommendations)
• Calmative nutritional agents such as GABA (250 mg 1-3 X day), L-theanine (100 mg 3-4 X day)
• Herbal “adaptogenic” herbs such as eleutherococcus (Siberian ginseng), ashwagandha, astragalus, schizandra, rhodiola
(consult companies for product dosing recommendations)
• Rule out licorice ingestion (prevents cortisol breakdown).25
• DHEA to balance cortisol (check Total 17-ketosteroids) and/or plant sterols/sterolins (reduces cortisol, balances
cortisol/DHEA ratio).26
TREATMENT OPTIONS for adrenal insufficiency (confirmed by low salivary
or serum cortisol):
• Stress management (adequate sleep, meditation, yoga, or other stress-reducing activities; minimize over-scheduling,
negative thinking, etc.)
• Address sources of chronic physiologic stress (e.g., inflammatory conditions, allergies, reactive hypoglycemia,
dysbiosis/leaky gut, infection).
• Gentle exercise
• Minimize intake of sweets and simple carbohydrates.
• Adequate intake of vitamin C, magnesium, zinc, B vitamins; consider additional B6 (100 mg 1-2 X day)
and pantothenic acid (500 mg 2-3 X day)
• Herbal “adaptogenic” herbs such as eleutherococcus (Siberian ginseng), Panax ginseng, ashwagandha, astragalus, s
chizandra, rhodiola, licorice (consult companies for product dosing recommendations)
• Bovine glandular supplements (e.g., adrenal, hypothalamus, pituitary), adrenal cortical extract, or low-dose hydrocortisone
(e.g., 5 mg 4 X day), only after low cortisol has been confirmed by salivary and/or serum cortisol; always balance with DHEA)
(Consult companies for product dosing recommendations.)
Anabolic/Catabolic Balance
Persistent catabolic effects of cortisol are most damaging when not balanced by anabolic hormones such as
dehydroepiandrosterone (DHEA), important in functions such as immunity, reproduction (via its conversion to downstream
sex steroids), cardiovascular health, bone density, and memory.
This anabolic/catabolic balance – or the balance of ‘growth and healing’ versus ‘wear and tear’ in the body – can be
assessed by comparing total 17-hydroxycorticosteroids with total 17-ketosteroids in the urine.
Anabolic/Catabolic Balance (24hr urine)
8
0.27
Comprehensive Urinary Hormones Interpretive Guidelines
A low Anabolic/Catabolic balance may be associated with:
• A metabolic shift in which the production of stress hormone is favored over the production of androgens and
downstream estrogens
• Aging
• Deficient growth hormone
• Chronic stress or glucocorticoid therapy
• Excessive exercise
• Acute or chronic illness, reduced ability to recover from illness or injury
• Increased risk of developing disease, poorer prognosis in patients with illness27,28
TREATMENT OPTIONS to increase Anabolic/Catabolic Balance:
• Refer to appropriate Treatment Options for adrenal excess (high Total 17-hydroxy-corticosteroids) or low Total 17-ketosteroids,
depending on which imbalance is contributing to the low ratio.
A high Anabolic/Catabolic balance may be associated with:
• Excessive androgen therapy or a metabolic shift in which androgen production is favored over cortisol production
• Possible polycystic ovarian syndrome and/or hirsutism
• Congenital adrenal hyperplasia (enzyme deficiencies)
• Adrenal tumors
• Extreme athleticism
TREATMENT OPTIONS to decrease Anabolic/Catabolic Balance:
• Refer to appropriate Treatment Options for adrenal insufficiency (low Total 17-hydroxy-corticosteroids) or high Total 17-ketosteroids, depending on which imbalance is contributing to the high ratio.
Comprehensive Urinary Hormones Interpretive Guidelines
9
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Comprehensive Urinary Hormones Interpretive Guidelines
© 2008 Genova Diagnostics
11
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.
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Asheville, NC 28801
828.253.0621
www.GDX.net
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