help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0821
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ferlin, A.
Right arrow Articles by Foresta, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferlin, A.
Right arrow Articles by Foresta, C.
Related Collections
Right arrow Pediatric Endocrinology
Right arrow Male Endocrinology
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3426-3431
Copyright © 2006 by The Endocrine Society

Changes in Serum Insulin-Like Factor 3 during Normal Male Puberty

Alberto Ferlin, Andrea Garolla, Franco Rigon, Lucia Rasi Caldogno, Andrea Lenzi and Carlo Foresta

Department of Histology, Microbiology and Medical Biotechnologies, Centre for Male Gamete Cryopreservation (A.F., A.G., C.F.), and Department of Pediatrics (F.R., L.R.C.), University of Padova, 35121 Padova, Italy; and Department of Medical Pathophysiology (A.L.), University of Rome "La Sapienza", 00100 Rome, Italy

Address all correspondence and requests for reprints to: Prof. Carlo Foresta, University of Padova, Department of Histology, Microbiology and Medical Biotechnologies, Centre for Male Gamete Cryopreservation, Via Gabelli 63, 35121 Padova, Italy. E-mail: carlo.foresta{at}unipd.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Insulin-like factor 3 (INSL3) is produced by the Leydig cells, and in adults, its secretion is dependent on the state of differentiation of these cells, which, in turn, is dependent on LH. However, the secretion and regulation of INSL3 during puberty is unknown.

Objective: Our objective was to evaluate INSL3 concentrations during normal male puberty and the relation of INSL3 to LH, FSH, and testosterone.

Design and Setting: We conducted a cross-sectional study from January to December 2005 at academic clinics.

Patients: Participating in the study were 75 healthy male subjects aged 9.5–17.5 yr, homogeneously distributed into five pubertal groups of 15 according to Tanner stages.

Main Outcome Measures: We assessed mean testicular volume and LH, FSH, testosterone, and INSL3 concentrations in relation to age and pubertal stage.

Results: We observed an increase of INSL3 and LH levels from Tanner stage 2 to 4, and an increase of FSH from stage 2 to 3. Testosterone levels increased from stage 3 to 4. No differences were seen for all measured hormones between stages 4 and 5. The increase in INSL3 seemed therefore to anticipate the increase in testosterone. However, INSL3 plasma concentrations at pubertal stages 4 and 5 are about one fourth of adult levels, whereas FSH, LH, and testosterone reached adult levels by stage 4. Positive significant correlations were found between INSL3 and LH for all pubertal stages.

Conclusions: This study provides information on the physiological dynamics of INSL3, showing that the serum concentrations of this hormone increased progressively throughout puberty under the differentiating action of LH on Leydig cells. INSL3 is therefore confirmed to represent a marker of Leydig cell differentiation and function. However, a prolonged exposure to LH seems to be necessary to reach INSL3 concentrations of adults. A possible use of INSL3 in puberty disorders is promising.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN-LIKE FACTOR 3 (INSL3), previously known as relaxin-like factor, is a member of the relaxin-insulin hormone family and is a major new circulating hormone in the male. This peptide is produced almost exclusively by the Leydig cells of the testis and affects testicular descent during fetal development by acting on gubernaculum via its specific receptor, leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8) (1, 2, 3, 4). Mutations of INSL3 and/or LGR8 genes have been associated also with human cryptorchidism (5, 6).

In the mouse and rats, Insl3 is highly expressed in the fetal testis but is down-regulated after birth before expression is again up-regulated at puberty (7, 8). Other than the role in testicular descent, recent data suggested additional yet unidentified endocrine and paracrine actions of INSL3 in adults. In fact, INSL3 is expressed also in adult-type Leydig cells (7, 9, 10, 11, 12, 13), and LGR8 is expressed in germ cells of the testis and ovary (12, 14) and in many other tissues, including kidney, muscle, thyroid, pituitary gland, and bone marrow (1, 2, 15). Furthermore, INSL3 is secreted into general circulation in postpubertal males (15, 16, 17, 18, 19). In particular, the availability of a new commercial RIA kit (Phoenix Pharmaceuticals, Belmont, CA) (15) and the development of a semiquantitative time-resolved fluorescence immunoassay (18) recently allowed clarification of many aspects of INSL3 production and regulation in adults (15, 17, 18, 19). These studies showed high INSL3 serum concentrations in the adults (500–1000 pg/ml), demonstrating that this peptide represents a male-specific hormone produced constitutively, once Leydig cells are mature. Its production is dependent on the state of differentiation of the Leydig cells, which in turn is dependent on LH, and INSL3 production is reduced in situations of undifferentiated or altered Leydig cell status. These data have proposed the use of INSL3 as a specific marker of Leydig cell differentiation status, and INSL3 has been suggested to be even more sensitive than testosterone to impaired Leydig cell function (15, 18), even if definitive evidence is lacking.

The secretion and regulation of INSL3 during puberty in humans is unknown. In this study, we evaluated INSL3 concentrations in 75 normal boys in relation to age, pubertal stages, and LH, FSH, and testosterone levels. With this study, we now have more detailed information on the dynamics of this new testicular hormone.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study was approved by the local ethics committee of the University of Padova and was in accordance with the Helsinki II Declaration. All subjects and their parents were asked for and provided their informed consent.

The study design included 75 healthy male subjects aged 9.5–17.5 yr, homogeneously distributed by their pubertal development into five groups of 15 according to Tanner (20). Pubertal stage assignment was performed by the same two physicians. The subjects were recruited from January to December 2005 among those who came under our observation for clinical assessment of pubertal development and were at the normal stage of pubertal development for their chronological age. The sign for clinical onset of puberty (G2) was considered as testicular volume more than 3 ml. Exclusion criteria were acute and chronic pathologies, in particular uroandrological pathologies such as cryptorchidism, varicocele, orchiepididymitis, and endocrine pathologies as evaluated by normal thyroid hormones and TSH, GH, IGF-I, and cortisol concentrations. None of the recruited subjects was taking medications. Testicular volume was measured using the Prader orchidometer.

Hormone determinations

Serum concentrations of INSL3 in all subjects were measured in duplicate by RIA (Phoenix Pharmaceuticals), as previously reported (15). Intra- and interassay coefficients of variation were less than 5 and 10%, respectively. The lower detection limit of the INSL3 RIA kit, determined by the linear range of the standard curve, was established to be 1 pg/tube (10 pg/ml), and the range of the assay is 1–128 pg/tube (10–1280 pg/ml) (15). LH and FSH were measured by immunoradiometric assay and testosterone by RIA with commercial kits (Adaltis Italia, Bologna, Italy), with detection limits of 0.1 IU/liter, 0.2 IU/liter, and 0.1 nmol/liter, respectively. Inter- and intraassay coefficients of variations were less than 10 and 5% (LH), less than 5 and 5% (FSH), and less than 10 and 10% (testosterone) for our laboratory. Blood samples were obtained in all subjects between 0800 and 0900 h.

Statistical analysis

If a measured hormone concentration was below the limit of detection for the assay, it was expressed as the limit of detection. In general, nonparametric statistics were used because most data did not have a Gaussian distribution. Descriptive data are expressed as median and 95% confidence intervals of the median. The differences in hormone levels between the different pubertal stages were tested with a Wilcoxon’s rank sum test. Correlation coefficients were calculated between INSL3 and FSH, LH, and testosterone by regression. Statistical analysis was performed with the open-source statistical software R (http://cran.r-project.org). P values (two-sided) of <0.05 were regarded as significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The individual serum INSL3, LH, FSH, and testosterone concentrations and the mean testicular volume are shown in relation to age in Fig. 1Go. The median and 95% confidence intervals of the results grouped according to stage of puberty are shown in Table 1Go, whereas the individual results per stage of puberty are shown in Fig. 2Go. The serum levels of LH, FSH, and INSL3, but not of testosterone, significantly increased between stages 1 and 2. All measured hormones then significantly increased between stages 2 and 3 of puberty. LH, INSL3, and testosterone, but not FSH, increased significantly also between stages 3 and 4. No differences were seen for all measured hormones between stages 4 and 5. Therefore, the levels of INSL3 increased progressively throughout puberty in parallel with LH and FSH until stage 4, when INSL3 concentrations seemed to reach a plateau. INSL3 plasma concentrations at pubertal stages 4 and 5 did not reach adult levels (mean levels, 562.3 pg/ml; range, 310.1–908.5 pg/ml) (15), whereas FSH, LH, and testosterone reached adult levels by stage 4.


Figure 1
View larger version (16K):
[in this window]
[in a new window]
  		FIG. 1. Individual serum concentrations of LH, FSH, testosterone (T), and INSL3 and mean testicular volume in 75 healthy boys as a function of age.

 

View this table:
[in this window]
[in a new window]
  		TABLE 1. Median (95% confidence interval) of the median of measurements of age, INSL3, testosterone, LH, FSH, and mean testicular volume at each stage of puberty

 

Figure 2
View larger version (11K):
[in this window]
[in a new window]
  		FIG. 2. Scatter diagram of individual serum concentrations of LH, FSH, testosterone, and INSL3 at each stage of puberty (15 subjects per stage). The median is indicated by solid lines. Significance is indicated when the median is statistically different from the median of the previous stage of puberty. *, P < 0.001; **, P < 0.005; §, P < 0.05. Values for adults (15 ) are reported for comparison.

 
Positive significant correlations were found between INSL3 and LH for all pubertal stages [P < 0.05 in stages 1 (r = 0.52), 2 (r = 0.47), and 3; P < 0.01 in stages 4 (r = 0.80) and 5 (r = 0.57)] (data not shown). Positive significant correlation between INSL3 and LH (P < 0.001) was also observed when all 75 subjects were grouped (Fig. 3Go). A positive significant correlation between INSL3 and testosterone was observed only in stage 3 of puberty (P < 0.05; r = 0.50), whereas positive correlations between INSL3 and FSH were observed in stages 4 (P < 0.05; r = 0.55) and 5 (P < 0.05; r = 0.64) (data not shown).


Figure 3
View larger version (11K):
[in this window]
[in a new window]
  		FIG. 3. Correlation of INSL3 with LH in all subjects (n = 75). The regression line (solid line) and 95% confidence intervals (dotted lines) are indicated. r = 0.92; 95% confidence intervals, 0.87–0.95; P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Animal data initially suggested that the production and secretion of INSL3 from the Leydig cells are dependent on human chorionic gonadotropin (hCG)/LH (7, 12, 13). Recent evidence confirmed these reports also in adult humans: 1) patients with hypogonadotropic hypogonadism have very low INSL3 concentrations, comparable to those found in women (15, 18); 2) treatment of men with hypogonadotropic hypogonadism with hCG produced an increase in INSL3 concentrations (15, 18); and 3) treatment of gonadotropin-suppressed men with hCG induced an increase in INSL3 levels (15, 19). The present study is the first that analyzes INSL3 concentrations during normal puberty and adds evidence for an LH-dependent INSL3 production also during puberty. Furthermore, this study confirms that INSL3 secretion is not affected by testosterone. In conjunction with previous reports on mRNA and protein expression in animal models (7, 8, 13, 21), we have now more detailed information on the physiological dynamics of serum INSL3 and Leydig cell differentiation during puberty. INSL3 concentrations demonstrate a progressive increase throughout puberty that seems to be dependent on the differentiating action of LH on the Leydig cells. Similar to that found in adults (15, 18, 19), serum INSL3 is therefore a marker of Leydig cell differentiation and function. However, in contrast with LH, FSH, and above all testosterone, INSL3 plasma concentrations at the end of puberty did not reach adult levels. A prolonged exposure to LH seems therefore necessary to fully differentiate the Leydig cells. In other words, these data suggest that during puberty, increasing levels of LH fully stimulate steroidogenesis, and thus testosterone secretion to adult levels, whereas the differentiation effect of LH on the Leydig cells, and thus INSL3 secretion, is incomplete at the end of puberty. These data fit well with the current knowledge of the triphasic pattern of Leydig cell development (22). Postnatally, fetal Leydig cells are replaced by a population of neonatal Leydig cells, which remain relatively inactive until puberty. During the first stages of puberty, the pulsatility and increase in LH levels determine the activation of steroidogenesis with the consequent rise in testosterone concentration, and then adult-type Leydig cells completely differentiate (22, 23). It is important to note, however, that the different pattern of secretion of INSL3 and testosterone from the Leydig cells may also be related to the differences between steroid and peptide synthesis and regulation.

Taken together, these data suggest that during both pubertal development and adulthood, testosterone and INSL3 provide different information on the status of the Leydig cells. Testosterone better reflects the steroidogenic activity that is acutely sensitive to LH, whereas INSL3 seems to be uncoupled from this rapid stimulation of steroidogenesis and better reflects the differentiation status of the Leydig cells. This is in accordance with the finding that in adult-type Leydig cells, only testosterone and not INSL3 secretion is acutely responsive to LH and that after long-term treatment with hCG in gonadotropin-suppressed men, INSL3 did not recover to the same degree as testosterone (19, 24). All these data highlight that INSL3 is a more sensitive marker of the status of Leydig cell differentiation and that it is more sensitive to Leydig cell impairment than testosterone.

Although Leydig cell development in humans is quite different from rodents, our findings on INSL3 concentrations during puberty expand the knowledge on this hormone from previous animal data. Insl3 mRNA is first detectable at embryonic d 13.5 in the mouse concomitant with the first determination of the fetal Leydig cell phenotype and increases in expression level to be maximal in the fetal Leydig cells in the immediate perinatal period. This temporal expression is coordinated with the major function of Insl3, which is to stimulate testicular descent by action on the gubernaculum (25, 26). Insl3 is then down-regulated concomitant with the involution of the fetal Leydig cells (7, 21). Insl3 mRNA and protein then increase through puberty in a differentiation-dependent manner concomitant with the establishment of the pituitary-gonadal axis (7). In particular, Insl3 protein increases slowly between d 20 and 30 (corresponding to the mid-end of puberty), initially with a punctuate staining within the Leydig cells. Only after d 30 does the punctuate staining pattern give way to a more homogeneous distribution, similar to that seen in the adult mouse testis (7). Similar results have also been obtained recently in rats (8). INSL3 is therefore a hormone whose production reflects the differentiation status of the Leydig cells in a different way in the fetal and adult-type Leydig cells. Within adult-type Leydig cells, INSL3 is expressed under the differentiation effect of LH, whereas within the fetal Leydig cells, it is expressed in a fashion independent of an active pituitary-gonadal axis.

The dynamics of mouse and rat Insl3 production is therefore very similar to that seen in the present study in humans. Interestingly, treatment of hpg mouse with hCG induced an increase in Insl3 mRNA already by d 3 of treatment but only at 12 d was a punctuate INSL3 immunostaining evident in less than half of the Leydig cells (7). Again, these data are in accordance with the INSL3 concentrations found in our study at the end of puberty, which are at intermediate levels between prepubertal age and adulthood.

In addition to the prenatal, and probably principal, role for INSL3 in testicular descent, postnatally expressed INSL3 has been suggested to exert paracrine (protection of germ cell apoptosis) (12, 14) and endocrine functions (based on the high circulating INSL3 levels and the expression of its receptor LGR8 in various human tissues) (1, 2, 15, 18, 19). The finding of increasing INSL3 production during pubertal development concomitant with the increase in testicular volume and the establishment of a full spermatogenesis further suggests a role for this hormone in the adult testis related to male germ cell development/survival. Furthermore, during adulthood, INSL3 may be used as a marker of the differentiation and functional status of the Leydig cells. Its expression is reduced, for example, when these cells are dedifferentiated to become hyperplastic or neoplastic (27), when they involute in the aging rat (28), when they seasonally dedifferentiate in the roe deer (13), or when they are impaired because of severe testiculopathies in humans (15, 18).

In conclusion, our data provide important data on the dynamics of INSL3 during puberty, showing that, combined with previous animal data, INSL3 is under a stringent developmental control and is up-regulated during puberty under the differentiation action of LH on the Leydig cells. INSL3 has been suggested as a marker of Leydig cell status for clinical conditions associated with decreased testicular function or Leydig cell activity, such as male infertility of testicular origin or hypogonadism. INSL3 is therefore a promising marker also in pubertal disorders, such as premature and delayed puberty.


   Footnotes
 
Disclosure statement: The authors have nothing to disclose.

First Published Online June 27, 2006

Abbreviations: hCG, Human chorionic gonadotropin; INSL3, insulin-like factor 3; LGR8, leucine-rich repeat-containing G protein-coupled receptor 8.

Received April 14, 2006.

Accepted June 20, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, Boettger-Tong HL, Bishop CE, Agoulnik AI 2001 A transgenic insertion causing cryptorchidism in mice. Genesis 30:26–35[CrossRef][Medline]
  2. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ 2002 Activation of orphan receptors by the hormone relaxin. Science 295:671–674[Abstract/Free Full Text]
  3. Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, Bathgate RA, Hsueh AJ 2002 INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem 277:31283–31286[Abstract/Free Full Text]
  4. Bogatcheva NV, Truong A, Feng S, Engel W, Adham IM, Agoulnik AI 2003 GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 17:2639–2646[Abstract/Free Full Text]
  5. Ferlin A, Bogatcheva NV, Gianesello L, Pepe A, Vinanzi C, Agoulnik AI, Foresta C 2006 Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod 12:401–406[Abstract/Free Full Text]
  6. Ferlin A, Simonato M, Bartoloni L, Rizzo G, Bettella A, Dottorini T, Dallapiccola B, Foresta C 2003 The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. J Clin Endocrinol Metab 88:4273–4279[Abstract/Free Full Text]
  7. Balvers M, Spiess AN, Domagalski R, Hunt N, Kilic E, Mukhopadhyay AK, Hanks E, Charlton HM, Ivell R 1998 Relaxin-like factor expression as a marker of differentiation in the mouse testis and ovary. Endocrinology 139:2960–2970[Abstract/Free Full Text]
  8. McKinnell C, Sharpe RM, Mahood K, Hallmark N, Scott H, Ivell R, Staub C, Jegou B, Haag F, Koch-Nolte F, Hartung S 2005 Expression of insulin-like factor 3 (Insl3) protein in the rat testis during fetal and postnatal development and in relation to cryptorchidism induced by in utero exposure to di (n-butyl) phthalate. Endocrinology 146:4536–4544[Abstract/Free Full Text]
  9. Roche PJ, Butkus A, Wintour EM, Tregear G 1996 Structure and expression of Leydig insulin-like peptide mRNA in the sheep. Mol Cell Endocrinol 121:171–177[CrossRef][Medline]
  10. Ivell R, Balvers M, Domagalski R, Ungefroren H, Hunt N, Schulze W 1997 Relaxin-like factor: a highly specific and constitutive new marker for Leydig cells in the human testis. Mol Hum Reprod 3:459–466[Abstract/Free Full Text]
  11. Zimmermann S, Schottler P, Engel W, Adham IM 1997 Mouse Leydig insulin-like (Ley I-L) gene: structure and expression during testis and ovary development. Mol Reprod Dev 47:30–38[CrossRef][Medline]
  12. Kawamura K, Kumagai J, Sudo S, Chun SY, Pisarska M, Morita H, Toppari J, Fu P, Wade JD, Bathgate RA, Hsueh AJ 2004 Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci USA 101:7323–7328[Abstract/Free Full Text]
  13. Hombach-Klonisch S, Schon J, Kehlen A, Blottner S, Klonisch T 2004 Seasonal expression of INSL3 and Lgr8/Insl3 receptor transcripts indicates variable differentiation of Leydig cells in the roe deer testis. Biol Reprod 71:1079–1087[Abstract/Free Full Text]
  14. Anand-Ivell RJ, Relan V, Balvers M, Coiffec-Dorval I, Fritsch M, Bathgate RA, Ivell R 2006 Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis. Biol Reprod 74:945–953[Abstract/Free Full Text]
  15. Foresta C, Bettella A, Vinanzi C, Dabrilli P, Meriggiola MC, Garolla A, Ferlin A 2004 INSL3: a novel circulating hormone of testis origin in humans. J Clin Endocrinol Metab 89:5952–5958[Abstract/Free Full Text]
  16. Bullesbach EE, Rhodes R, Rembiesa B, Schwabe C 1999 The relaxin-like factor is a hormone. Endocrine 10:167–169[CrossRef][Medline]
  17. Ferlin A, Arredi B, Zuccarello D, Garolla A, Selice R, Foresta C, Paracrine and endocrine roles of insulin-like factor 3. J Endocrinol Invest, in press
  18. Bay K, Hartung S, Ivell R, Schumacher M, Jurgensen D, Jorgensen N, Holm M, Skakkebaek NE, Andersson AM 2005 Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metab 90:3410–3418[Abstract/Free Full Text]
  19. Bay K, Matthiesson KL, McLachlan RI, Andersson AM 2006 The effects of gonadotropin suppression and selective replacement on insulin-like factor 3 secretion in normal adult men. J Clin Endocrinol Metab 91:1108–1111[Abstract/Free Full Text]
  20. Tanner JM, Whitehouse RH 1976 Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51:170–179[Abstract/Free Full Text]
  21. Spiess AN, Balvers M, Tena-Sempere M, Huhtaniemi I, Parry L, Ivell R 1999 Structure and expression of the rat relaxin-like factor (RLF) gene. Mol Reprod Dev 54:319–325[CrossRef][Medline]
  22. Prince FP 2001 The triphasic nature of Leydig cell development in humans, and comments on nomenclature. J Endocrinol 168:213–216[Abstract]
  23. Chemes HE 1996 Leydig cell development in humans. In: Payne AH, Hardy MP, Russell LD, eds. The Leydig cell. Vienna, IL: Cache River Press; 175–202
  24. Sadeghian H, Anand-Ivell R, Balvers M, Relan V, Ivell R 2005 Constitutive regulation of the Insl3 gene in rat Leydig cells. Mol Cell Endocrinol 241:10–20[CrossRef][Medline]
  25. Zimmermann S, Steding G, Emmen JM, Brinkmann AO, Nayernia K, Holstein AF, Engel W, Adham IM 1999 Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 13:681–691[Abstract/Free Full Text]
  26. Nef S, Parada LF 1999 Cryptorchidism in mice mutant for Insl3. Nat Genet 22:295–299[CrossRef][Medline]
  27. Klonisch T, Ivell R, Balvers M, Kliesch S, Fischer B, Bergmann M, Steger K 1999 Expression of relaxin-like factor is down-regulated in human testicular Leydig cell neoplasia. Mol Hum Reprod 5:104–108[Abstract/Free Full Text]
  28. Paust HJ, Wessels J, Ivell R, Mukhopadhyay AK 2002 The expression of the RLF/INSL3 gene is reduced in Leydig cells of the aging rat testis. Exp Gerontol 37:1461–1467[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Hum Reprod UpdateHome page
R. Ivell and R. Anand-Ivell
Biology of insulin-like factor 3 in human reproduction
Hum. Reprod. Update, July 1, 2009; 15(4): 463 - 476.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Sports. Med.Home page
C Baldari, L Di Luigi, G P Emerenziani, M C Gallotta, P Sgro, and L Guidetti
Is explosive performance influenced by androgen concentrations in young male soccer players?
Br. J. Sports Med., March 1, 2009; 43(3): 191 - 194.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Bay, A. S. Cohen, F. S. Jorgensen, C. Jorgensen, A. M. Lind, N. E. Skakkebaek, and A.-M. Andersson
Insulin-Like Factor 3 Levels in Second-Trimester Amniotic Fluid
J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4048 - 4051.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
E. Lague and J. J. Tremblay
Antagonistic Effects of Testosterone and the Endocrine Disruptor Mono-(2-Ethylhexyl) Phthalate on INSL3 Transcription in Leydig Cells
Endocrinology, September 1, 2008; 149(9): 4688 - 4694.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
C. Foresta, D. Zuccarello, A. Garolla, and A. Ferlin
Role of Hormones, Genes, and Environment in Human Cryptorchidism
Endocr. Rev., August 1, 2008; 29(5): 560 - 580.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Bay, H. E. Virtanen, S. Hartung, R. Ivell, K. M. Main, N. E. Skakkebaek, A.-M. Andersson, The Nordic Cryptorchidism Study Group, and J. Toppari
Insulin-Like Factor 3 Levels in Cord Blood and Serum from Children: Effects of Age, Postnatal Hypothalamic-Pituitary-Gonadal Axis Activation, and Cryptorchidism
J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 4020 - 4027.
[Abstract] [Full Text] [PDF]

Home page
 J AndrolHome page
J. K. Amory, S. T. Page, B. D. Anawalt, A. D. Coviello, A. M. Matsumoto, and W. J. Bremner
Elevated End-of-Treatment Serum INSL3 Is Associated With Failure to Completely Suppress Spermatogenesis in Men Receiving Male Hormonal Contraception
J Androl, July 1, 2007; 28(4): 548 - 554.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Gambineri, L. Patton, R. De Iasio, F. Palladoro, U. Pagotto, and R. Pasquali
Insulin-Like Factor 3: A New Circulating Hormone Related to Luteinizing Hormone-Dependent Ovarian Hyperandrogenism in the Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2066 - 2073.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ferlin, A.
Right arrow Articles by Foresta, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferlin, A.
Right arrow Articles by Foresta, C.
Related Collections
Right arrow Pediatric Endocrinology
Right arrow Male Endocrinology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals