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Effect of testosterone administration on serum and urine kallikrein concentrations in female-to-male transsexuals.

Human tissue kallikreins (hKs) (6) comprise a subgroup of 15 homologous secreted serine proteases encoded by a tightly clustered multigene family on the long arm of chromosome 19 (KLK1-KLK15)'. hKs are involved in a wide range of physiological functions and are primarily expressed within the glandular epithelia in many tissues, including the skin, the central and peripheral nervous system, and also in endocrine glands and hormone-dependent tissues such as breast, endometrium, and prostate (1).

In addition to prostate-specific antigen (PSA, hK3), which has important applications as a marker for prostate cancer diagnosis and follow-up, and hK2, an emerging prostate cancer biomarker, many other members of the kallikrein family are also implicated in endocrine-dependent malignancies. All kallikreins studied to date are known to be up- or down-regulated at the mRNA and/or protein level in breast, prostate, ovarian, and testicular cancers (2).

Transcription of the kallikrein genes is modulated by a large number of stimulatory and inhibitory substances, among which sex steroid hormones are the best characterized. Sex steroid hormones affect the initiation and/or progression of endocrine-dependent malignancies, and the role of hKs as cancer biomarkers is only beginning to be understood (3, 4). Studies on the regulation of the kallikrein genes have been performed in vitro mainly with cancer cell lines (5).

Information on the in vivo regulation of hKs by steroid hormones would be useful, but opportunities for in vivo study of the effects of sex steroids on the expression of hKs are rather limited. Transsexuals undergoing cross-sex hormone treatment with high doses of sex steroids provide a relatively unambiguous model, allowing us to study the effects of sex steroids in healthy persons.

In an earlier in vivo study we demonstrated that, in female-to-male transsexuals, concentrations of hK2 and hK3 (PSA) were highly increased in both serum and urine after androgen administration (6). Conversely, antiandrogen plus estrogen administration in male-to-female transsexuals (reducing plasma testosterone values to almost zero) down-regulated concentrations of hK2 and hK3 in serum and urine (7).

Recently developed specific ELISA-type assays of most other kallikreins provided the opportunity to extend our observations on the in vivo hormonal regulation of hK2 and hK3 to other kallikreins. In the present study, we monitored the effects of hormone treatment on serum and urine concentrations of hK2, hK3, hK4, hK5, hK6, hK7, hK8, hK10, hK11, hK13, and hK14 in female-to-male transsexuals receiving high-dose testosterone treatment for 4-12 months.

Materials and Methods

PARTICIPANTS

This single-center, open-label study was approved by the Medical Ethics Committee of the Free University Medical Centre (Amsterdam, The Netherlands). Transsexuals, after careful psychological evaluation, received cross-sex hormone treatment according to the standards of the Harry Benjamin International Gender Dysphoria Association (www.hbigda.org). Participants were included if they were willing to sign informed consent, were able and willing to visit the study center, and had not used exogenous sex hormones before the start of the treatment. These participant data were assessed by questioning the participants and by evaluation of pretreatment hormone concentrations, specifically gonadotropin concentrations, which are suppressed by exogenous sex hormones.

A total of 28 female-to-male transsexuals (mean age 22 years, range 16-37 years) were included in this study. All were treated with 250 mg of testosterone esters (Sustanon[R]; Organon Oss) injected intramuscularly every 2 weeks. Venous blood samples were collected before crosssex treatment and after 4 and 12 months of testosterone administration. Serum samples were stored at -80[degrees]C immediately after collection and until analyzed. At the same time, urine was collected and stored similarly.

HORMONE MEASUREMENTS

For serum 17[beta]-estradiol and testosterone, we performed measurements on commercially available RIAs, and for luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on commercially available immunometric luminescence assays. If values were below the lower limit of detection, the value of this lower limit was used for statistical analysis (for testosterone, 1.0 nmol/L; for LH, 0.3 IU/L; and for FSH, 0.5 IU/L). The body mass index (weight/[height.sup.2]) was also determined (Table 1).

IMMUNOLOGICAL ASSAYS

For all kallikrein measurements in serum and urine, we used ELISA-type immunofluorometric procedures developed in house. Most of these methods have been described and validated in previous publications (8-18). Information on these methods is provided in Table 2. We have tested the cross-reactivity of these ELISA assays against all other kallikreins and have found no crossreactions. The precision of all assays within the dynamic range cited in Table 2 was <10%. These arrays were standardized with recombinant proteins produced in yeast or mammalian expression systems, as previously described (8-18).

STATISTICAL ANALYSIS

Because the distributions of kallikrein concentrations were not gaussian, the nonparametric Wilcoxon signed rank test was used to determine the differences of kallikrein concentrations before and after treatment. For all analyses, a P value of <0.05 was considered statistically significant.

Results

Serum concentrations of 17[beta]-estradiol, testosterone, FSH, and LH, and the body mass index, before and after treatment in the 28 female-to-male transsexuals who were treated with 250 mg of testosterone esters every 2 weeks are summarized in Table 1. After testosterone administration, serum 17(3-estradiol concentrations [mean (SD)] decreased only modestly compared with pretreatment measures [from 177 (16) to 124 (6) pmol/L; P = 0.003]. These estrogens are derived mainly from peripheral aromatization of testosterone rather than from ovarian production and show a correlation with circulating plasma testosterone concentrations (unpublished observation). Serum testosterone concentrations profoundly increased [from 1.9 (0.2) to 30.9 (2.0) nmol/L; P <0.001]. Concentrations of LH and FSH decreased from 5.3 (0.6) to 2.5 (0.5) (P <0.001) and 4.4 (0.2) to 3.0 (0.3) (P = 0.001), respectively. Body mass index increased from 22.6 (0.8) to 24.0 (0.8) (P <0.001). In general, the major endocrine change in these patients was the dramatic increase of serum testosterone.

Serum kallikrein concentrations, before and after 4 months of testosterone treatment, are presented in Table 3. During testosterone administration, serum kallikrein concentrations measured at 4 months were not substantially different from those measured at 12 months. Serum hK2, hK3, hK5, hK6, hK7, hK8, hK10, and hK11 concentrations were significantly (P <0.05) up-regulated by testosterone treatment, with the most profound impact on hK3 and hK2. No statistically significant differences between pre- and posttreatment concentrations were noted for the other serum kallikreins (hK4, hK13, and hK14). We obtained similar data after we used logarithmic transformation to normalize the distributions of each kallikrein concentration.

Urine kallikrein concentrations before and after 4 months of testosterone treatment are presented in Table 4. Urine kallikrein concentrations measured at 4 months were not significantly different from those measured at 12 months. Urine hK2 and hK3 concentrations were significantly up-regulated after testosterone treatment (P <0.001). No statistically significant pre- or posttreatment differences were noted for the other 9 hKs (Table 4). Similar data were obtained after normalization of the distributions of each kallikrein concentration by logarithmic transformation.

Discussion

By measuring changes in serum and urine kallikrein concentrations, we determined the impact that androgens exert on kallikrein gene expression in healthy women of reproductive age. In humans, limited opportunities are available to monitor the effects of profound changes in hormonal milieus on biological variables. Cross-sex hormone treatment of transsexuals provides such an opportunity. Our study may be clinically relevant to women who suffer from hyperandrogenic syndromes, including polycystic ovary syndrome and hirsutism. The participants in this study were female-to-male transsexuals who received testosterone therapy. This treatment led to only minor suppression of plasma estrogen concentrations but profound increases of androgen concentrations. Thus, we attributed the changes in serum and urine hK concentrations mainly to the androgenic stimulation. This hormonal intervention produced a significant up-regulation of serum hK2, hK3, hK5, hK6, hK7, and hK10 concentrations, with the most profound impact on hK2 and hK3. Conversely, in urine, we observed significant up-regulation only of hK2 and hK3, but not of any other hKs.

We previously reported up-regulation of hK2 and hK3 by exogenous androgens in a similar group (6). The up-regulation of hK3 (PSA) by androgens has also been confirmed in other studies. Most of these studies investigated serum and urine PSA concentrations in women with hirsutism or polycystic ovary syndrome, both conditions accompanied in most cases by increased circulating androgen concentrations (19-22). Highly sensitive PSA assays are used to diagnose hyperandrogenic hirsutism (23-24).

It is known that the expression of PSA is mainly regulated by the androgen receptor at the transcriptional level (25). Another study of female-to-male transsexuals found high concentrations of testosterone-up-regulated PSA production, in agreement with our findings (26). PSA concentrations drop significantly after mastectomy, suggesting that breast tissue in women is likely to be the source of androgen up-regulated production of PSA (27,28). However, PSA concentrations after mastectomy remained higher than the PSA concentrations of nonandrogenized women, suggesting other PSA sources in females. PSA has also been detected in endometrial tissues, as well as in several body fluids (breast milk, breast cyst fluid, nipple aspirate fluid, and amniotic fluid) (29-31).

The increased serum concentration of hK2 in response to testosterone administration suggests that hK2 is also under androgenic control, supporting the finding that KLK2 is up-regulated by androgens in prostate and breast cancer cell lines (30,32). The breast also appears to be the main source of hK2 production in females (33). hK2 is secreted in seminal plasma, amniotic fluid, breast milk, and saliva (34). It should be noted that androgens are not the only steroids that could up-regulate PSA and hK2 genes. In vivo and in vitro studies demonstrate upregulation of these genes by progestins (35-37).

Results of tissue-culture studies suggest that hK1-hK4 and hK13-hK15 are mainly up-regulated by androgens, and hK5-hK12 are mainly up-regulated by estrogens (1, 5). In vivo, up-regulation by androgens occurs for hK2 and hK3 and also for hK5, hK6, hK7, hK8, hK10, and hK11.

We observed major changes in urine only for kallikreins hK2 and hK3. Previously, we reported the highly increased expression of hK2 and hK3 in urine of femaleto-male transsexuals receiving testosterone treatment (6). We attributed these changes to production of hK2 and hK3 by the periurethral glands. Apparently, the other studied kallikreins do not seem to be up-regulated by androgens in this tissue.

The serum changes of hK2 and, especially, hK3 in our studied population were much more dramatic than the changes of the other kallikreins (hK5, hK6, hK7, hK8, hK10, and hK11). We attribute this finding to 2 reasons: hK2 and PSA transcription is under direct androgenic control; and these 2 kallikreins are produced only by a small number of tissues, mainly breast tissue, in females. Other kallikreins are produced in a variety of tissues (1). These tissues may contribute significantly to the serum concentration, and they are likely not as sensitive to androgenic stimulation as is female breast tissue. These findings are supported by results of tissue culture studies with breast cancer cell lines in which the androgenic effect on hK2 and hK3 expression is much more pronounced than for the other kallikreins (35-37).

Received January 17, 2006; accepted May 31, 2006.

Previously published online at DOI: 10.1373/clinchem.2006.067041

References

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(12.) Diamandis EP, Scorials A, Fracchioli S, Van Gramberen M, De Bruijn H, Henrik A, et al. Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma. J Clin Oncol 2003;21:1035-43.

(13.) Kishi T, Soosaipillai A, Grass L, Little SP, Johnstone EM, Diamandis EP. Development of an immunofluorometric assay and quantification of human kallikrein 7 in tissue extracts and biological fluids. Clin Chem 2004;50:709-16.

(14.) Kishi T, Grass L, Soosaipillai A, Shimizu-Okabe C, Diamandis EP. Human kallikrein 8: immunoassay development and identification in tissue extracts and biological fluids. Clin Chem 2003;49:87-96.

(15.) Luo LY, Grass L, Howarth DJ, Thibault P, Ong H, Diamandis EP. Immunofluorometric assay of human kallikrein 10 and its identification in biological fluids and tissues. Clin Chem 2001;47:237-46.

(16.) Diamandis EP, Okui A, Mitsui S, Luo LY, Soosaipillai A, Grass L, et al. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. Cancer Res 2002;62:295-300.

(17.) Kapadia C, Chang A, Sotiropoulou G, Yousef GM, Grass L, Soosaipillai A, et al. Human kallikrein 13: production and purification of recombinant protein and monoclonal and polyclonal antibodies, and development of a sensitive and specific immunofluorometric assay. Clin Chem 2003;49:77-86.

(18.) Borgono CA, Grass L, Soosaipillai A, Yousef GM, Petraki CD, Howarth DH, et al. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res 2003;63:9032-41.

(19.) Negri C, Tosi F, Dorizzi R, Fortunato A, Spiazzi GG, Muggeo M, et al. Antiandrogen drugs lower serum prostate-specific antigen (PSA) levels in hirsute subjects: evidence that serum PSA is a marker of androgen action in women. J Clin Endocrinol Metab 2000;85:81-4.

(20.) Bahceci M, Bilge M, Tuzcu A, Tuzcu S, Bahceci S. Serum prostate specific antigen levels in women with polycystic ovary syndrome and the effect of flutamide+desogestrel/ethinyl estradiol combination. J Endocrinol Invest 2004;27:353-6.

(21.) Yu H, Berkel H. Prostate-specific antigen (PSA) in women. J La State Med Soc 1999;151:209-13.

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(23.) Melegos DN, Yu H, Ashok M, Wang C, Stanczyk F, Diamandis EP. Prostate-specific antigen in female serum, a potential new marker of androgen excess. J Clin Endocrinol Metab 1997;82: 777-80.

(24.) Gullu S, Emral R, Asik M, Cesur M, Tonyukuk V. Diagnostic value of prostatic specific antigen in hirsute women. J Endocrinol Invest 2003;26:1198-202.

(25.) Kim J, Coetzee GA. Prostate specific antigen gene regulation by androgen receptor. J Cell Biochem 2004;93:233-41.

(26.) Goh VH. Breast tissues in transsexual women-a nonprostatic source of androgen up-regulated production of prostate-specific antigen. J Clin Endocrinol Metab 1999;84:313-5.

(27.) Yu H. Clinical implications of prostate-specific antigen in men and women. J Gend Specif Med 2000;53:45-8.

(28.) Sauter ER, Lininger J, Magklara A, Hewett JE, Diamandis EP. Association of kallikrein expression in nipple aspirate fluid with breast cancer risk. Int J Cancer 2004;108:588-91.

(29.) Seliger E, Kaltwasser P, Ropke F. Determination of prostate-specific antigen (PSA) in cytosol of breast tumors and human endometrium: new diagnostic approaches. Zentralbl Gynakol 1998;120:72-5. [German].

(30.) Hsieh ML, Charlesworth MC, Goodmanson M, Zhang S, Seay T, Klee GG, et al. Expression of human prostate-specific glandular kallikrein protein (hK2) expression in the breast cancer cell line T47-D. Cancer Res 1997;57:2651-6.

(31.) Black MH, Diamandis EP. The diagnostic and prognostic utility of prostate-specific antigen for diseases of the breast. Breast Cancer Res Treat 2000;59:1-14.

(32.) Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Young CY, et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 1997;49:857-62.

(33.) Diamandis EP, Yousef GM, Luo LY, Magklara A, Obiezu CV. The new human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol Metab 2000;11:54-60.

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(35.) Zarghami N, Grass L, Diamandis EP. Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer. Br J Cancer 1997;75:579-88.

(36.) Katsaros D, Melegos DN, Diamandis EP. Prostate specific antigen production by breast tumors after induction with oral contraceptives. Clin Biochem 1998;31:285-8.

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(6) Nonstandard abbreviations: hK, kallikrein protein; PSA, prostate-specific antigen; LH, luteinizing hormone; FSH, follicle-stimulating hormone

(7) Human gene: KLK, kallikrein gene.

MARGRITA H. SLAGTER, [1] ANDREAS SCORILAS, [2] LOUIS J.G. GOOREN, [1] WILLEM DE RONDE, [1] ANTONINUS SOOSAIPILLAI, [3] ERIK J. GILTAY, [4] MILTIADIS PALIOURAS, [3, 5] and ELEFTHERIOS P. DIAMANDIS [3, 5] *

[1] Department of Endocrinology, Vrije Universiteit University Medical Centre, Amsterdam, The Netherlands.

[2] Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens, Greece.

[3] Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.

[4] Geestelijke Gezondheidszorg Delfland, Institute of Mental Health, Delft, The Netherlands.

[5] Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.

* Address correspondence to this author at: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario, Canada M5G 1X5, Fax 416-586-8628; e-mail ediamandis@mtsinai.on.ca.
Table 1. Age, body mass index, and hormonal data before and after 4
months of testosterone administration in 25 female-to-male transsexuals

Variable Mean (SE) Median Range P value (a)

Age, years 26.0 (1.2) 24.0 16.4-37.0
Body mass index,
kg/[m.sup.2]
 Before treatment 22.6 (0.8) 22.2 16.6-32.4
 After treatment 24.0 (0.8) 23.0 18.6-35.1 <0.001
Testosterone, nmol/L
 Before treatment 1.9 (0.2) 1.8 1.0-3.7
 After treatment 30.9 (2.0) 30.0 13.0-49.0 <0.001
17 [beta]-estradiol,
pmol/L
 Before treatment 177 (16) 162 83-399
 After treatment 124 (6) 124 67-201 0.003
Luteinizing hormone,
IU/L
 Before treatment 5.3 (0.6) 4.5 1.9-16.0
 After treatment 2.5 (0.5) 1.8 0.30-9.1 0.001
Follicle-stimulating
hormone, IU/L
 Before treatment 4.4 (0.2) 4.2 2.6-6.3
 After treatment 3.0 (0.3) 3.0 0.50-5.0 0.001

If hormone concentrations declined below the lower limit of detection,
the value of that lower limit was used in the analysis (for
testosterone, 1.0 nmol/L; for LH, 0.3 IU/L; and for FSH, 0.5 IU/L).

(a) Calculated by Wilcoxon signed rank test.

Table 2. ELISA assays used in the present study

 Coating/ Dynamic Detection
 Detection Range, Limit,
Kallikrein Antibody ng/L ng/L Reference

hK2 mono/mono 2000 6 (8)
hK3 mono/mono 2000 1 (9)
hK4 mono/poly 20 000 100 (10)
hK5 mono/mono 25 000 100 (11)
hK6 mono/mono 50 000 100 (12)
hK7 mono/mono 20 000 200 (13)
hK8 mono/mono 20 000 200 (14)
hK10 mono/mono 20 000 50 (15)
hK11 mono/mono 50 000 100 (16)
hK13 mono/mono 20 000 50 (17)
hK14 mono/poly 20 000 100 (18)

Mono, monoclonal mouse antibody; poly, polyclonal rabbit antibody.

Table 3. Serum kallikrein concentrations before and after testosterone
administration for 4 months in female-to-male transsexuals

 Mean (SE), Median,
Kallikrein, ng/L ng/L ng/L Range

hK2
 Before treatment, n = 25 0.7 (0.2) 0 0-4
 After treatment, n = 23 1.5 (0.5) 1 0-10

hK3
 Before treatment, n = 25 2.3 (0.7) 1 0-16
 After treatment, n = 23 20 (4) 16 4-83

hK4b
 Before treatment, n = 25 0 0 <100
 After treatment, n = 23 0 0 <100

hK5 171 (14)
 Before treatment, n = 25 207 (14) 153 80-369
 After treatment, n = 23 204 107-366

hK6
 Before treatment, n = 25 3,160 (129) 2998 1882-4498
 After treatment, n = 22 3,686 (143) 3635 2668-5200

hK7
 Before treatment, n = 25 4,209 (729) 3360 16-18 964
 After treatment, n = 23 5,444 (913) 4548 702-23 796

hK8
 Before treatment, n = 25 985 (276) 614 186-7164
 After treatment, n = 23 1,334 (408) 906 306-9956

hK10
 Before treatment, n = 25 870 (80) 754 448-2460
 After treatment, n = 23 1,094 (129) 1052 368-3568

hK11
 Before treatment, n = 24 322 (32) 300 103-773
 After treatment, n = 23 376 (35) 337 89-545

hK13
 Before treatment, n = 25 10 (6) 0 0-165
 After treatment, n = 23 15 (11) 1 0-270

hK14
 Before treatment, n = 25 412 (39) 376 126-838
 After treatment, n = 23 434 (37) 449 00-773

 P
Kallikrein, ng/L value (a)

hK2
 Before treatment, n = 25 0.013
 After treatment, n = 23

hK3
 Before treatment, n = 25 <0.001
 After treatment, n = 23

hK4b
 Before treatment, n = 25
 After treatment, n = 23

hK5
 Before treatment, n = 25 <0.001
 After treatment, n = 23

hK6
 Before treatment, n = 25 0.001
 After treatment, n = 22

hK7
 Before treatment, n = 25 <0.001
 After treatment, n = 23

hK8
 Before treatment, n = 25 <0.001
 After treatment, n = 23

hK10
 Before treatment, n = 25 0.001
 After treatment, n = 23

hK11
 Before treatment, n = 24 0.003
 After treatment, n = 23

hK13
 Before treatment, n = 25 0.28
 After treatment, n = 23

hK14
 Before treatment, n = 25 0.078
 After treatment, n = 23

(a) Calculated by Wilcoxon signed rank test.

(b) No detectable concentrations in any sample.

Table 4. Urinary kallikrein concentrations before and after
testosterone administration for 4 months in female-to-male
transsexuals

 Mean
Kallikrein, ng/L [+ or -] SE (a) Median Range

hK2
 Before treatment, n = 28 0.14 (0.0) 0 0-2
 After treatment, n = 23 4.2 (1.0) 3 0-17

hK3
 Before treatment, n = 28 5.4 (2.6) 1 0-64
 After treatment, n = 23 1604 (453) 539 22-7734

hK4
 Before treatment, n = 28 2405 (160) 2302 552-4637
 After treatment, n = 23 2273.9 (203) 2429 627-3616

hK5
 Before treatment, n = 28 254 (60) 130 20-1436
 After treatment, n = 23 435 (180) 89 0.00-3374

hK6
 Before treatment, n = 28 1205 (424) 352 35-8788
 After treatment, n = 23 894 (315) 243 28-6172.0

hK7
 Before treatment, n = 25 3239 (743) 1376 229-16 262
 After treatment, n = 21 3440 (1,016) 1772 214-17 738

hK8
 Before treatment, n = 28 523 (132) 224 31-3122
 After treatment, n = 23 615 (146) 265 53-2439

hK10
 Before treatment, n = 28 920 (429) 377 0-12 231
 After treatment, n = 23 617 (208) 232 0-4182

hK11
 Before treatment, n = 28 2008 (493) 705 76-12 159
 After treatment, n = 23 1334 (418) 748 73-9160

hK13
 Before treatment, n = 28 3460 (1,024) 1305 82-22 561
 After treatment, n = 23 2458 (804) 991 25-16 246

hK14
 Before treatment, n = 28 482 (73) 380 84-2170
 After treatment, n = 23 585 (144) 371 73-3302

Kallikrein, ng/L P value (a)

hK2
 Before treatment, n = 28 <0.0001
 After treatment, n = 23

hK3
 Before treatment, n = 28 <0.0001
 After treatment, n = 23

hK4
 Before treatment, n = 28 0.51
 After treatment, n = 23

hK5
 Before treatment, n = 28 0.79
 After treatment, n = 23

hK6
 Before treatment, n = 28 0.67
 After treatment, n = 23

hK7
 Before treatment, n = 25 0.62
 After treatment, n = 21

hK8
 Before treatment, n = 28 0.10
 After treatment, n = 23

hK10
 Before treatment, n = 28 0.73
 After treatment, n = 23

hK11
 Before treatment, n = 28 0.24
 After treatment, n = 23

hK13
 Before treatment, n = 28 0.49
 After treatment, n = 23

hK14
 Before treatment, n = 28 0.84
 After treatment, n = 23

(a) Calculated by Wilcoxon signed rank test.
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Title Annotation:Endocrinology and Metabolism
Author:Slagter, Margrita H.; Scorilas, Andreas; Gooren, Louis J.G.; de Ronde, Willem; Soosaipillai, Antonin
Publication:Clinical Chemistry
Date:Aug 1, 2006
Words:4171
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