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From the Townsend Letter
January 2008

 

Urinary Hormones
by Christa Hinchcliffe, ND and Wendy Ellis, ND

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Life expectancy for women in the United States is 80.1 years; for men, it is 74.8 years.1 As a result, most women will spend more than one-third of their lives in a postmenopausal state and face many health problems associated with reduced levels of endogenous estrogen,2 progesterone, DHEA, and testosterone. Men face similar challenges. Bio-identical hormone replacement therapy (BHRT) can be a safe and effective means to assist women and men at this stage in their lives.

The safety of hormone replacement therapy has been a hot topic of discussion, especially since the 2002 publication of the results of the Women's Health Initiative (WHI). In the WHI, women were using non-bio-identical hormone replacement therapy. Fortunately, the safety of BHRT has been well-researched. BHRT has fewer side effects, especially if used in a cream or gel and applied over the skin or mucous membranes. Some examples of BHRT's benefits include the following:

  • a decrease in cardiovascular risk is shown in multiple studies when estrogen is used transdermal rather than oral,3
  • endometrial hyperplasia is less in low-potency transvaginal estriol or estradiol than with oral estrogen,4
  • the metabolism of estradiol, when used transdermally, has less tendency towards estrogen related cancers due to its end product ratios,5 and
  • if used appropriately, the combination of percutaneous progesterone with percutaneous estradiol can decrease the estradiol-induced proliferation of cyclical epithelial breast tissue; this was shown in vivo prior to breast surgery if applied to normal breast tissue.6

Finally, in another review, the conclusion was made that sex hormones are not oncogenic, but mitogenic.7

BHRT research is mostly lacking two aspects. First, the research is not long-term, and second, few studies are done at the cellular level. We do not know to what extent the mitogenic activity of bio-identical hormones is affecting us at a cellular level, especially if used long-term. To help allay concerns about the safe use of BHRT, we can use careful follow-up testing to monitor not only levels of the steroid hormones, but also their metabolites, relevant enzymes, and hormone ratios.

The most comprehensive and accurate testing method is the 24-hour urine test. Since serum steroid hormone levels naturally fluctuate, sometimes considerably, due to varying half-lives, pulsatile secretion, and (in the case of exogenously applied hormones) time of application, the 24-hour urine collection "averages it all out."

Urine testing is performed with gas chromatography (GC). GC is still unsurpassed in its potential for determining a multitude of steroid metabolites simultaneously in a single steroid profile. Used together with a mass spectrometer (MS) as a detector, this technique ensures the highest specificity in determining steroid metabolites.8,9 Urine testing measures the sum of free and conjugated (sulfated and glucuronidated) hormonal steroids, not the inactive, protein-bound hormones. According to the 1999 edition of Tietz' Textbook of Clinical Chemistry, "Urinary assays are considered to reflect the secretory activity of the endocrine glands."10 The textbook also states that "urinary free cortisol and the measurement of urinary free estradiol, estrone, and testosterone have been shown to provide clinical information that can reflect the production rates of these steroids."10 Moreover, 24-hour urine testing for pregnanediol (progesterone metabolite) is the best biochemical assessment of ovulation based on progesterone production. The most satisfactory alternative is plasma, and the least satisfactory is saliva.11 Lastly, estriol can be more accurately measured in the urine (where estriol is routinely found to be higher than estradiol or estrone). Circulating serum levels of estriol are often found to be quite low, due to its rapid clearance from the body.12

Serum testing is a direct assessment of circulating hormones. Moreover, serum levels have well-established reference ranges. Unfortunately, bio-available and non-protein-bound forms are rarely measured, with the exception of testosterone. Also, serum is only a one-time measurement within a 24-hour period. To be more accurate, two or more blood draws can be taken within a 24-hour period. To evaluate hormone levels via serum, different laboratories use various immunoassays. However, lack of comparability exists with the different immunoassays. Some immunoassays even lack specificity and can have detrimental effects on medical practice. For example, microparticle enzyme immunoassay has errors in estradiol measurements due to interference from unconjugated estriol.13

Saliva testing measures the free, or active, form of steroid hormones via the radioimmunoassay technique. It is a convenient and non-invasive testing method. For example, monthly fluctuations in hormone levels are easily monitored so that follicular, ovulatory, and luteal phases can be determined. Moreover, four separate measurements in one day can help determine the cortisol circadian rhythm.

Dr. John Lee was a strong advocate of salivary hormone testing, particularly for monitoring transdermal progesterone. He wrote that transdermal progesterone is highly lipophilic, absorbed through the skin into the fat layer, taken up gradually by red blood cell membranes, and made readily available to all target tissues and saliva.14 However, this may not be completely accurate, as the serum content of progesterone has been shown to be higher than the red blood cell membrane content. In one study, after transdermal application, plasma progesterone and pregnanediol-3-glucuronide (progesterone metabolite) excretion showed small increases, red cell progesterone never exceeded plasma levels, and salivary levels were very high and variable compared to placebo.15 This study also indicates the possibility of false representation of overdose with salivary testing after the use of progesterone cream. Another small study on saliva testing, published in 2003, found variation in results within each laboratory for each participant. The researchers concluded that at-home saliva testing was not reliable.16 However, this needs to be repeated with a larger sample size.

Saliva is a difficult matrix to deal with experimentally.17 The presence of both sex hormone-binding globulin and corticosteroid-binding globulin in uncontaminated saliva casts doubt on the reliability of salivary steroids to accurately reflect circulating free steroid levels.18 Lastly, caution should be exercised in androgen assays, as well as in assays to assess ovarian function. The use of salivary cortisol for measuring endogenous cortisol is the most encouraging.19

As mentioned above, 24-hour urine testing for steroid hormones is extremely valuable, due to the many metabolites that are measured. This is especially true for estrogen and adrenal hormone metabolites. There are more than 20 circulating estrogens in the body; however, estrone, estradiol, and estriol are generally cited as the main players. Estrone and estradiol are potent estrogens, whereas estriol is a relatively weak estrogen. All these values are measured in urine steroid hormone testing, whereas serum testing usually incorporates only estradiol, although estrone can be ordered as well. Urine testing provides free and conjugated values for estrone, estradiol, and estriol, as well as many downstream metabolites for each of these hormones, while serum testing incorporates protein-bound estradiol only.

To further complicate matters, each of these hormone metabolites has actions of its own. Some estrone is metabolized to 4 OH estrone, which may encourage the growth of breast or prostate cancer.20 Yet another metabolite of estrone, 16 alpha OH estrone, is considered an "unsafe" estrogen metabolite, as it is a potent estrogen with uterotopic effects similar to estradiol. This estrogen metabolite forms covalent bonds with amino groups of macromolecules and is genotoxic.21 Estrone is also metabolized to 2 OH estrone, a relatively weak metabolite that may be anti-estrogenic.22 Other metabolites, 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone.23,24 However, 16 alpha OH estrone appears to play an important role in maintaining bone density. As this very brief discussion of estrogen metabolites demonstrates, monitoring how patients metabolize their hormones and what factors may modify hormone metabolization is important. Many patients are taking diindolylmethane (DIM) or indole 3 carbinol (I3C) for "safe" estrogen metabolism. These substances improve the "2/16" ratio, which is known to decrease the risk of breast cancer.25 But not all patients need DIM or I3C, as they may already have a healthy 2/16 ratio, and using these substances may overly decrease the 16 alpha hydroxyestrone fraction, increasing risk for osteoporosis.26

Adrenal hormone values and their metabolites, which are measured in the 24-hour urine test, may point toward significant adrenal dysfunction. Here are some examples:

  • Elevated levels of pregnanetriol indicate congenital adrenal hyperplasia. This is a disorder most often caused by a 21-hydroxlase deficiency and can lead to cortisol and aldosterone deficiencies, as well as progesterone and androgen excess.
  • The cortisol/cortisone should be ~0.7/1. Elevated cortisol/cortisone ratios can be a sign of "Apparent Mineralocorticoid Excess." Elevated ratios are also indicative of licorice excess. Hypertension can occur in either case, as cortisol has an aldosterone-like activity and cortisone does not.
  • The cortisol metabolites tetrahydrocortisone, tetrahydrocortisol, and allo-tetrahydrocortisol account for approximately 50% of daily cortisol biosynthesis.27 If these metabolites add up to 5 mg, then the body is producing about 10 mg of cortisol daily. This is useful in determining adrenal excess or deficiency. In an unpublished study by Patrick N. Friel, BS, at Meridian Valley Labs, all patients who failed the 250mcg ACTH (2/10) stimulation test had low cortisol metabolites in the baseline 24-hour urine.
  • 11-dehydrotetrahydrocorticosterone is an inactive metabolite of corticosterone. Compared to cortisol, corticosterone has approximately one-third the anti-inflammatory action but 15 times the sodium-retaining action.
  • Allo-Tetrahydrocorticosterone and tetrahydrocorticosterone are sensitive markers for monitoring adrenal stress. Both respond to ACTH stimulation with greater "vigor" than even cortisol. Allo-tetrahydrocorticosterone is elevated in young female patients with eating disorders. Levels of tetrahydrocorticosterone are elevated in depressed women, yet significantly decreased in depressed men. Both are useful in evaluating hypoaldosteronism.28,29

Enzyme activity, pre-determined by genetics or influenced exogenously by medications or supplements, can play a very important role in determining hormone safety in individuals. We are often hearing about supplements and medications for improving clinical conditions such as weight loss and hair loss, for improving estrogen metabolism, and for aiding post-cancer treatment (aromasin, tamoxifen). By altering metabolic pathways and up- or downregulating enzyme activity, what are we affecting on a cellular level?

Urine testing not only measures the activity of specific enzymes, but also gives information about downstream metabolites that are influenced by various endogenous hormones. By measuring downstream metabolites, we can better determine the enzyme activity associated with each hormone. For example, if a patient is taking saw palmetto, we can determine the effectiveness of the medication by seeing a shift in the testosterone metabolized down the 5 beta DHT pathway vs. the 5 alpha DHT pathway. Women who suffer from PCOS very frequently have an upregulation in the 5 alpha reductase pathway – which is seen as an increase in the downstream metabolites driven by this enzyme. This is pertinent information and may help guide your diagnosis of this condition.

Urine testing additionally determines activity of 11 beta hydroxysteroid dehydrogenase (11 b HSD), an enzyme with two isoenzymes (I and II) and bidirectional activity. The isoenzyme, 11 b HSD1, facilitates the regeneration of active cortisol and corticosterone (both 11 hydroxy glucocorticoids) from their inactive forms, cortisone and 11 dehydrocorticosterone by oxidoreductase (11 b reductase) action.30 The reverse reaction facilitating inactivation of cortisol to cortisone is affected by the 11 b HSD2 enzyme through 11 b dehydrogenation.31

Leptin-resistant Zucker obese rats have impaired 11 b HSD1 in the liver with increased activity in the omental adipose tissue.32 Dysregulation of 11b HSD1 in human obesity has been recognized and appears to be tissue-specific. An increase in BMI is associated with impaired 11b HSD1 activity, the degree of impairment correlating with visceral fat mass.33 This downregulation of 11 b HSD1 activity in the obese could be protective against development of insulin resistance. Like the genetically obese Leptin-resistant Zucker rats, obese humans also demonstrate impairment of hepatic 11 b HSD1 activity, resulting in decreased reactivation of corticosteroids, while 11 b HSD1 activity in subcutaneous abdominal adipose tissue is increased.34,35 This increase in 11 b HSD1 in adipose tissue might explain the proliferation of fat tissue and adverse metabolic effects in obesity. Growth hormone replacement in growth hormone-deficient patients results in reduction of body fat along with lowered ratio of cortisol to cortisone in keeping with 11 b HSD1 inhibition.36 With the increase in insulin resistance in the population, it is useful to have this added information via urine testing when addressing the approach to treatment.

In women, 24-hour urine testing sometimes finds lower levels of estriol than the sum of estrone and estradiol, which many population-based studies have shown to be associated with increased breast cancer risk. Administration of Lugol's iodine (six to eight drops daily and tapered according to response) most frequently increases estriol and diminishes estrone and estradiol.37 Urine testing can also help explain failure of BHRT to relieve menopausal symptoms. In this circumstance, much higher than anticipated levels of all estrogens are frequently found in the urine, a situation termed "hyperexcretion" or "failure of hormone retention." Treatment with physiologic-dose (300-600 micrograms) of cobalt chloride almost always corrects this situation, gradually reducing urinary estrogen excretion towards normal, while menopausal symptoms gradually fade.37

Hormone Use in Clinical Practice with Urine Testing – Two Case Studies
Seventy-two-year-old Frank came in to the office with complaints of muscle weakness, lack of stamina, and erectile dysfunction. Among various supplements, he was taking 100 mg of pregnenolone. Pregnenolone is considered the "mother of all steroids," as it is at the top of the steroid hormone tree and may be converted to anything downstream (cortisol, estrogen, testosterone, DHEA, etc.).

Twenty-four-hour urine testing via GC/MS determined his testosterone levels to be on the very low end of normal, with the estrone fraction three times as high as the testosterone values, at a level consistent with most premenopausal females. Estradiol was within normal limits. The pregnenolone was discontinued, and testosterone was given. Three months later, the gentleman returned with improved stamina and muscle strength and had improvements in erectile function. Urine studies confirmed a decrease in estrone and an increase in testosterone values.

Fifteen-year-old Melissa came into the office with complaints of severe PMS, weight gain, heavy menses, hirsutism, and acne. Twenty-four-hour urine collection indicated estrogens and progesterone within normal limits, with a very elevated DHEA and free testosterone fraction. The 11 beta HSD1 enzyme activity was increased, and the 5 alpha reductase enzyme was also increased. The patient was put on strict dietary recommendations for insulin resistance and given saw palmetto, 160 mg per day. The 5 alpha reductase enzyme activity was reduced, as well as 5 alpha DHT on follow-up studies, and the patient noted a remarkable improvement in acne, as well as hirsutism.

The safety of bio-identical hormone replacement therapy is continually evolving. Fortunately, there are many studies to assist our understanding of their positive nature and alleviate worry over side effects. However, the extent of how the steroid hormones affect the body on a cellular level is not completely known. Apprehension over the practice of BHRT can be lessened with adequate and comprehensive testing methods, such as with the 24-hour urinalysis. The 24-hour urinalysis measures the active form of steroid hormones, their metabolites, enzymes, and ratios by GCMS method, a gold standard in the hormone-testing industry. This information is extremely beneficial in aiding our diagnosis and decisions on the use of appropriate hormone protocols.

Notes
1. National Vital Statistics Reports. June 28, 2006; 54 (19); Deaths: Preliminary Data for 2004. Available at: www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_19.pdf. (871KB .pdf) Accessed October 5 2007.
2. Gleason CE, Carlsson CM, Johnson S, Atwood C, Asthana S. Clinical pharmacology and differential cognitive efficacy of estrogen preparations. Ann N Y Acad Sci. 2005;1052:93-115. Review.
3. Eilertsen AL, Hoibraaten E, Os I, Andersen TO, Sandvik L, Sandset PM. The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis. Maturitas. 2005;52(2):111-8.
Lacut K, Oger E, Le Gal G, Blouch MT, Abgrall JF, Kerlan V, Scarabin PY, Mottier D; SARAH Investigators. Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein. Thromb Haemost. 2003;90(1):124-31.
Post MS, Christella M, Thomassen LG, van der Mooren MJ, van Baal WM, Rosing J, Kenemans P, Stehouwer CD. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol. 2003;23(6):1116-21. Epub 2003 May 1.
Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V, Collet M, Abgrall JF, Aiach M, Scarabin PY, Mottier D; SARAH Investigators. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol. 2003;23(9):1671-6. Epub 2003 Jul 17.
De Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administraion. J Clin endocriol Metab. 1986;62(3): 536-41.
Basdevant A, De Lignieres B, Guy-Grad B. Differential lipemic and hormone responses to oral and parenteral 17B-estradiol in postmenopausl women. Am J Obstet Gynecol 1983;147:77-81.
Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997;17(11): 3071-8.
Vongpatanasin W, Tuncel M, Mansour Y, Arbique D, Victor RG. Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation. 2001;103(24):2903-8.
4. Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergstrom R, Correia N, Persson I. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. 1999;353(9167):1824-8
5. Lippert TH, Seeger H, Mueck AO. Estradiol metabolism during oral and transdermal estradiol replacement therapy in postmenopausal women. Horm Metab Res. 1998;30(9):598-600.
Friel PN, Hinchcliffe C, Wright JV. Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone. Altern Med Rev. 2005;10(1):36-41.
6. Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de Lignieres B. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998;69(5):963-9.
7. Wren BG. Do female sex hormones initiate breast cancer? A review of the evidence. Climacteric 2004;7:120-128
8. Ranke MB, ed: Diagnostics of Endocrine Function in Children and Adolescents. Basel (Switzerland): S. Karger AG; 2003, 427-449.
9. Wudy SA, Hartmann MF.Gas chromatography-mass spectrometry profiling of steroids in times of molecular biology. Horm Metab Res. 2004;36(6):415-22
10. Burtis C, Tietz N, Ashwood E. Tietz Textbook of Clinical Chemistry, 3rd Edition W.B. Saunders Co; 1999:1533.
11. Metcalf MG, Evans JJ, Mackenzie JA. Indices of ovulation: comparison of plasma and salivary levels of progesterone with urinary pregnanediol. J Endocrinol. 1984;100(1):75-80.
12. Henderson B, et.al. Hormones, Genes, and Cancer. London: Oxford University Press; 2001: 25.
13. Cao Z, Swift TA, West CA, Rosano TG, Rej R. Immunoassay of estradiol: unanticipated suppression by unconjugated estriol. Clin Chem. 2004;50(1):160-5
14. Lee JR. Topical progesterone. Menopause. 2003;10(4):374.
15. Lewis JG, McGill H, Patton VM, Elder PA.Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women Maturitas. 2002;41(1):1-6.
16. Hagen J, Gott N, Miller DR. Reliability of Saliva Hormone Tests. Journal of the American Pharmacists Association. 2003;43(6):724 - 726.
17. Kalfas S, Rundegren J. Biological qualities of saliva sterilized by filtration or ethylene oxide treatment. Oral Microbiol Immuno. 1991;6:182-6.
18. Chu FW, Ekins RP. Detection of corticosteroid binding globulin in parotid fluids: evidence for the presence of both protein-bound and non-protein-bound (free) steroids in uncontaminated saliva. Acta Endocrinol (Copenh). 1988;119:56-60.
Hammond GL, Langley MS. Identification and measurement of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in human saliva. Acta Endocrinol (Copenh). 1986;112:603-8.
19. Lewis JG. Steroid Analysis in Saliva: An Overview. Clin Biochem Rev. 2006; 27(3):139-146.
20. Markushin Y, Gaikwad N, Zhang H, Kapke P, et al. Potential biomarker for early risk assessment of prostate cancer. Prostate. 2006;66(14):1565-71.
21. Bradlow HL, Davis DL, Lin G, Sepkovic D, Tiwari R. Effects of pesticides on the ratio of 16 alpha/2-hydroxyestrone: a biologic marker of breast cancer risk. Environ Health Perspect. 1995;103(Suppl 7):147-150.
22. Lord RS, Bongiovanni B, Bralley JA. Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Altern Med Rev. 2002;7(2):112-29.
23. Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL. Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992;84(8):634-638.
24. Jernström H, Klug TL, Sepkovic DW, Bradlow HL, Narod SA. Predictors of the plasma ratio of 2-hydroxyestrone to 16{alpha}-hydroxyestrone among pre-menopausal, nulliparous women from four ethnic groups. Carcinogenesis. 2003;24(5):991-1005.
25. Kabat GC, O'Leary ES, Gammon MD, et al. Estrogen metabolism and breast cancer. Epidemiology. 2006;17(1):80-8.
26. Lim SK, Won YJ, Lee JH, et al. Altered hydroxylation of estrogen in patients with postmenopausal osteopenia.. J Clin Endocrinol Metab. 1997;82(4):1001-6.
27. Burtis CA, Ashwood ER, Tietz NW. Tietz Textbook of Clinical Chemistry. 3rd ed. Philadelphia, PA: W.B. Saunders Company; 1999.
28. Poor V, Biro I, Bufa A, et al. Urinary steroids in young women with eating disorders. J Biochem Biophys Methods. 2004;61(1-2):199-205.
29. Poór V, Juricskay S, Gáti A, Osváth P, Tényi T. Urinary steroid metabolites and 11beta-hydroxysteroid dehydrogenase activity in patients with unipolar recurrent major depression. J Affect Disord. 2004;81:55-9.
30. Seckl JR, Walker BR. Minireview: 11ß-Hydroxysteroid Dehydrogenase Type 1 – A Tissue-Specific Amplifier of Glucocorticoid Action. Endocrinology. 2001;142(4):1371-6.
31. Ibid.
32. Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology. 2000;141(2):560-3.
33. Valsamakis G, Anwar A, Tomlinson JW, et al. 11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89(9):4755-61.
34. Stewart PM, Boulton A, Kumar S, Clark PM, Shackleton CH. Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab. 1999;84(3):1022-7.
35. Rask E, Olsson T, Söderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001;86(3):1418-21.
36. Weaver JU, Thaventhiran L, Noonan K, et al. The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults. Clin Endocrinol (Oxf). 1994;41(5):639-48.
37. Wright, JV. Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice. Ann NY Acad Sci. 2005;1057:506-524.

 

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