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1 Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Houston, Texas 77030, USA2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA3 National Hormone Peptide Program, Harbor-UCLA Medical Center, Torrance, California 90509, USA
(Correspondence should be addressed to D L Hadsell; Email: dhadsell{at}bcm.tmc.edu)
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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Data from a number of experimental models have shown that activation of the JAK/STAT pathway is a direct consequence of PRL or GH stimulation in COS cells expressing the receptors for these hormones (Gouilleux et al. 1995). Studies in our own laboratory have demonstrated that i.v. injection of recombinant murine PRL into the tail vein of a lactating mouse profoundly increases mammary STAT5 phosphorylation within minutes (Hadsell et al. 2007). On the other hand, IGF-I signals through several pathways including the phosphoinositide 3 (PI3)-kinase/Akt and JAK/STAT pathways (Dudek et al. 1997, Gual et al. 1998). Our own studies using i.v. injections of the long-R3 (LR3) analog of IGF-I, a form that has enhanced potency due to an inability to interact with IGF-binding proteins, demonstrated increased phosphorylation of both Akt and STAT5 within the mammary gland within minutes of injection (Lee et al. 2003, Hadsell et al. 2007). Although these observations suggest that both ligands have the capacity to activate short-term signaling events within the mammary tissue of lactating mice, the effects of chronic treatment via s.c. injections have not been studied.
In the mammary gland, the ability of PRL to simulate milk synthesis may be limited by the induction of negative feedback inhibitors such as the suppressors of cytokines signaling (SOCS) genes (Sutherland et al. 2007). The most commonly studied members of this family include SOCS1, SOCS2, and SOCS3, and cytokine-inducible SH2 protein (CIS). In addition to potential effects on PRL signaling, the SOCS genes have also been found to play a feedback-inhibitory role in systems involving GH, IGF-I, and insulin (Ueki et al. 2004, Inaba et al. 2005, LeRoith & Nissley 2005). There may also be other local feedback inhibition mechanisms within the gland that regulate milk production (Knight et al. 1998). Tryptophan hydroxylase 1 (TPH1) is one of the two isozymes, which catalyzes the rate-limiting step in serotonin biosynthesis (Fitzpatrick 1999). In the mammary gland, TPH1 was identified in a suppressive subtractive hybridization screen for genes dependent on PRL (Matsuda et al. 2004). Studies on the role of TPH1 in the mammary gland have led to the suggestion that serotonin produced through the actions of this enzyme in mammary secretory cells acts as a feedback inhibitor of lactation (Matsuda et al. 2004).
The primary goal of these studies was to compare the impact of LR3-IGF-I, recombinant murine PRL, or recombinant murine GH on milk production, and mammary gland development in the mouse during prolonged lactation. A second goal of the study was to determine whether the effects of these hormonal treatments on lactation capacity could be related to changes in mammary cell signaling, and mammary expression of the SOCS, CIS, and TPH1 genes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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All animals were studied in accordance with procedures outlined in the NIH Guide to Care and Use of Experimental Animals. These experiments were approved by the Baylor College of Medicine Animal Care and Use Committee. Mouse dams from the CD-1 strain (Charles River Laboratories, Wilmington, MA, USA) were the experimental unit in all studies. All dams were analyzed in their first lactation and none were concurrently pregnant during the course of these studies. Each dam received a cross-fostered litter of ten 1-day-old pups beginning on day 1 post partum to control for litter size. In addition, litter weights were equalized across all dams. Lactation was prolonged out to 37 days by cross-fostering 7-day-old pups onto each dam every 7 days as previously described (Hadsell et al. 2005, 2006). The relative maternal capacity for milk production was estimated using the weight gain of these independent cross-fostered litters during each of four 7-day periods, days 7–14, 14–21, 21–28, and 28–35. Beginning on day 14 post partum, the dams were given s.c. injections (0.1 ml) of saline or saline containing recombinant LR3-IGF-I (JRH Biosciences, Sigma–Aldrich, www.sigmaaldrich.com/) and recombinant murine GH (National Hormone and Pituitary Program, Torrance, CA, USA) or recombinant murine PRL (National Hormone and Pituitary Program). The number of dams per treatment group was 15, 15, and 10 for saline, LR3, and GH respectively. Injections were administered three times per day at 0800, 1400, and 2000 h respectively. The dose injected was 1.4 and 2.2 mg/kg body weight for LR3 and GH respectively. The ability of PRL to increase lactation capacity was tested in two separate experiments at a dose of either 1 or 4 mg/kg body weight respectively. The number of dams per treatment group was five in the first experiment and ten in the second one. Body composition of the dams was measured on day 36 by scanning each animal once with a PIXImus (Lunar Corp., Madison, WI, USA) dual X-ray absorptiometer as previously described (Nagy & Clair 2000). Mammary glands were harvested on day 37 at 2–4 h following the last injection that was administered at 0800 h. Sampling was timed among the all treatment groups to balance the interval between the last injection and the tissue collection. At the time of harvesting, wet weights were recorded on each of the two no. 4 mammary glands, also known as inguinal glands, located on either side of the ventral midline just slightly anterior to the rear legs. The glands were then either flash-frozen in liquid nitrogen and stored at –80 °C for further analysis or frozen in optimal cutting temperature (OCT)-embedding medium for cryosectioning. Plasma samples were prepared from trunk blood collected at the time of killing.
Mammary gland development
Epithelial content of the mammary tissue and alveolar luminal area was determined by segmentation analysis of images captured from hematoxylin- and eosin-stained mammary tissue sections. For each specimen, ten digital images were captured from randomly chosen fields using a Spot RT CCD (Diagnostic Instruments, Sterling Heights, MI, USA). Images were then coded to prevent investigator bias in the processing and analysis. For the measurement of percent epithelial area, the images manually processed using pixel selection tools within Adobe Photoshop 5.0 (Adobe Systems). This processing consisted of selection of the stromal elements within each image followed by pseudo-coloring to produce a binary image consisting of stromal and epithelial compartments. For the measurement of alveolar area, the major and minor axes of an ellipse, which would approximate each alveolus, were manually drawn onto the alveoli within each image. Images containing these drawn axes were then converted to binary images. The resulting binary images were then analyzed using Image Pro 5.1 (Media Cybernetics, Silver Spring, MD, USA). For epithelial area, the pixel area occupied by epithelium in each image was directly measured and expressed as a percentage of the entire image. For luminal area, the major and minor axes for each ellipse were measured in pixels and then converted to micrometers. Luminal areas were then calculated using the formula for an ellipse, 
(L/2+W/2), where L is the major axis and W is the minor axis.
Hormone measurements
The plasma concentrations of both human and murine IGF-I were measured using ELISA-based assays. The hIGF-I assay was a non-extraction IGF-I ELISA (Diagnostic Systems Laboratories, Inc., Webster, TX, USA) with a sensitivity of 20 ng/ml and an intra-assay coefficient of variation of 5–9%. Murine IGF-I was measured using a rat/mouse-specific immunoenzymometric assay (Immunodiagnostic Systems, Inc., Fountain Hills, AZ, USA) with a sensitivity of 82 ng/ml and an intra-assay coefficient of variation of 5–7%. Plasma progesterone was measured using a commercially available RIA (Diagnostic Systems Laboratory). This assay had a sensitivity of 0.1 ng/ml using 25 µl plasma, and reported intra- and inter-assay coefficients of variations of 5.6 and 3.3% respectively. For the analysis of plasma PRL and GH, the samples were shipped on dry ice to the National Hormone and Pituitary Program. The intra-assay coefficients of variation for these assays were 4.2 and 4.4% respectively. The RIA immunoreagents are distributed to researchers on request by the National Institute of Diabetes and Digestive and Kidney Diseases, National Hormone and Pituitary Program.
Western blotting
Total tissue protein extracts of mammary tissue were prepared from 50 mg tissue and western blotting was conducted as previously described (Hadsell et al. 2003). Briefly, blots were prepared using PROTRAN nitrocellulose (Schleicher & Schuell, Keene, NH, USA). Detection was based on enhanced chemiluminescence using SuperSignal West Pico Chemiluminescent Substrate (Pierce, Rockford, IL, USA), an HRP-conjugated donkey anti-rabbit at a dilution of 1:2000 (Amersham Biosciences), and BioMax MR film (Kodak). Phospho-Akt was measured using an antibody (1:1000 dilution) to phospho-Ser473 that reacts with all three Akt isoforms (Cell Signaling Technology, Beverly, MA, USA). Phospho-ERK1/2 was measured using an antibody (1:1000 dilution) that detects dual phosphorylation of Thr202 and Tyr204 (Cell Signaling Technology). Phosphorylation of STAT5 was detected using an antibody (1:1000 dilution) to phospho-Tyr694 and total STAT5 (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Phosphorylation of STAT3 was analyzed using an antibody (1:1000 dilution) to phospho-Tyr705 and total STAT3 (Cell Signaling Technology). Total amounts of each of Akt1 and ERK1/2 were also measured by western blotting as previously described (Hadsell et al. 2001). Equality of protein loading ensured by running all samples on parallel gels that were subsequently stained with Coomassie blue. Densitometry data were acquired from the fluorograms using Scion Image (Scion Corporation, Frederick, MA, USA). All densitometry data were corrected for variations in loading using densitometry data obtained from the Coomassie-stained gels.
Gene expression analysis
RNA was isolated from a piece of the no. 4 mammary gland using Trizol reagent (Invitrogen). The isolated RNA was quantitated using a NanoDrop spectrophotometer. Taqman Gene Expression Assays (Applied Biosystems, Inc., Foster City, CA, USA) were used to quantitate mRNA for SOCS1 (Mm00782550_s1), SOCS2 (Mm00850544_g1), SOCS3 (Mm00545913_s1), CIS (Mm00515488_m1), and TPH1 (Mm00493794_ml) by quantitative RT-PCR. The 18S rRNA (X03205.1
[GenBank]
) was quantitated in each sample as a loading control. All of the Taqman assays used in this study were validated by the manufacturer over a six log dilution range and have efficiencies of 100±10%. The intra-assay coefficients for variation for the assays ranged from 7.1 to 10.7%. Reverse transcription was performed on 10 ng RNA using Taqman reverse transcription reagents. The reaction mixture was 10 ng RNA, 1x RT buffer, 5.5 mM magnesium chloride, 2.5 µM random hexamers, 4 units RNase inhibitor, and 31.25 units MultiScribe reverse transcriptase. Reactions were incubated in an MJ Research PTC-200 Peltier Thermal Cycler (Bio-Rad Laboratories). The conditions were 10 min at 25 °C, 1 h at 37 °C, and 5 min at 95 °C. The reactions were placed in a well of a MicroAmp optical 96-well reaction plate (Applied Biosystems) and mixed with a 40 µl PCR mix containing 1x Taqman Universal PCR MasterMix and 1x Taqman Gene Expression Assay. Q-PCR was performed in a 7900 Fast Real-Time PCR System (Applied Biosystems). The reactions were incubated at 50 °C for 2 min, then at 95 °C for 10 min. The reactions were then cycled 40 times at 95 °C for 15 s and at 60 °C for 1 min. 
Ct was calculated from the Ct values of the gene of interest and the sample's 18S rRNA content. Fold changes in the mRNA levels were calculated in relation to the saline controls as previously described (Livak & Schmittgen 2001).
Data analysis
Litter weight gain data were analyzed in three ways. First, the repeated measures procedure of SPSS (version 12.01 for Windows; SPSS Inc, Chicago, IL, USA) was used to compare weekly weight gain of each cross-fostered litter. The model for this analysis used injection (LR3 versus GH versus saline) as the fixed variable, day post partum as a repeated measure within each dam, and litter gain during the pretreatment week as a covariate. Second, the same repeated measures procedure was used to compare the second derivative of weekly litter gain for each of the 3 weeks that the injections were administered. Finally, total weight gain of the cross-fostered litters for the entire 3-week period was compared using a one-way ANOVA. The model for this analysis used injection as a fixed variable and litter gain during the pretreatment week as a covariate. Maternal body weight data were analyzed using a repeated measures analysis. The model for this analysis used injection as a fixed variable, day post partum as a repeated measure within each dam, and maternal bodyweight during the pretreatment week as a covariate. Data for body composition, mammary weight, epithelial area, plasma IGF-I, plasma progesterone, western blotting, and real-time qRT-PCR were analyzed using a one-way ANOVA. Specific treatment group comparisons were then done using a one-way ANOVA by predefined contrasts between the saline-injected group and each of the other three treatment groups. All the data are presented as means±S.E.M. Differences were considered statistically significant at P
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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The first experiment to determine the ability of exogenous PRL to enhance lactation persistence used a dose that was shown to be biologically effective in previously published studies with both rats and mice (Noel & Woodside 1993, Capuco et al. 1999). In this initial experiment, an s.c. daily dose of 1 mg/kg of murine PRL failed to increase lactation performance (Fig. 1A) and had no impact on maternal body weight (Fig. 1C). This dose of PRL also failed to increase maternal plasma PRL (157±63 and 94±38 ng/ml for saline- and PRL-injected dams respectively). On the basis of this study, a second PRL experiment was conducted using a dose that was 4 mg/kg per day. In this second study, circulating maternal PRL concentrations were elevated (P<0.05) in the PRL-injected group (32±9 and 1400±588 ng/ml in saline- and PRL-injected dams respectively), but lactation capacity was still similar to that of saline-injected dams (Fig. 1B). Maternal body weight, however, was higher (P<0.05) in dams receiving PRL at 4 mg/kg per day than that of dams receiving saline (Fig. 1D). Interestingly, the high dose of PRL injected in the second experiment also decreased (P<0.05) maternal circulating concentrations of both progesterone and IGF-I. For progesterone, the concentrations were reduced in PRL-injected dams to 10% of that found in the saline-injected controls (2±1 and 21±4 ng/ml respectively). Maternal circulating IGF-I concentrations in PRL-injected dams were reduced to 77% of that found in the saline-injected group (399±45 and 515±27 ng/ml respectively).
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Because GH, LR3, and PRL all had the capacity to alter maternal body weight, DEXA analysis was used to determine whether maternal body composition was changed by these treatments as well. Maternal lean body mass (Lean) and total bone area (Area) were higher (P<0.0001) in LR3- and GH-treated dams than those in saline-injected dams (Table 1). Bone mineral content was higher (P<0.05) in LR3-treated dams than that in PRL-injected dams while percent body fat was lower (P<0.05) in GH-treated dams than that in saline-injected dams.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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Numerous studies have examined the impact of PRL, GH, and IGF-I on milk production in lactating cows, goats, and rats respectively (Tucker 1974, Flint et al. 1984, 1994, Plaut et al. 1987, Davis et al. 1989, Prosser et al. 1990, Flint & Gardner 1994). Only a few studies have examined the impact of these hormones on lactation in the mouse (Nandi 1958a,b, Capuco et al. 1999, Hadsell et al. 2005). The data presented in this paper are the first to compare the effects of these three hormones on milk production, mammary cell signaling, and mammary gene expression during prolonged lactation in the mouse.
All the three hormones in this study had effects on maternal physiology, mammary cell signaling, or mammary gene expression. The PRL-injected dams exhibited increased body weight and altered circulating concentrations of both progesterone and IGF-I. The increased maternal body weight was probably a result of increased food intake since previous studies have demonstrated that PRL is orexigenic in rats (Byatt et al. 1993, Noel & Woodside 1993, Woodside 2007). Surprisingly, neither the expression of SOCS3 nor the phosphorylation of STAT5 was increased in the mammary glands of PRL-injected dams. Our own previous work on PRL signaling has shown that the recombinant murine PRL used in the present study is capable of inducing mammary STAT5 phosphorylation when administered intravenously to lactating mice (Hadsell et al. 2007). In addition, others have demonstrated that exogenous GH and PRL increased the expression of SOCS3 in the mammary tissue of virgin mice (Le Provost et al. 2005). In lactating rats, however, SOCS gene expression was induced by exogenous PRL only after 48 h of separation from their litters, suggesting that milk removal impacts the regulation of SOCS gene expression by PRL or other cytokines (Tam et al. 2001). In addition, differences in the route of administration, the duration of treatment, and the timing of sample collection may have impacted our ability to detect changes in STAT5 phosphorylation and induction of SOCS gene expression. Regardless, an effect of PRL on milk production might still have been detected if it were present.
The effects of PRL on milk production in normal lactating rats as well as in dairy cows have been largely negative with the exception of one study on prolonged lactation (Flint et al. 1984). Both PRL and GH have been demonstrated to support lactogenesis in hypophysectomized mice (Nandi 1958a,b) and both factors also stimulate milk production in lactating rats that have been treated with anti-GH antiserum and bromocryptine (Flint & Gardner 1994). In addition, GH or PRL can increase lactation capacity in conjunction with thyroxine in hypothyroid lactating mice (Capuco et al. 1999). In dairy cows and goats, GH, but not PRL, has been shown to increase milk production (Plaut et al. 1987, Jacquemet & Prigge 1990, van Amburgh et al. 1997). In addition, short-term infusions of IGF-I have been found to increase milk synthesis in goats (Prosser et al. 1990). Our mouse data are consistent with the conclusion that milk production in normal lactating mice during prolonged lactation, as in cows and rats, is largely unresponsive to exogenous PRL. Our data are also consistent with the possibility that milk production may be more responsive to GH in mice than that in rats despite the fact that in both species PRL and GH elicit similar changes in maternal physiology that may not have been directly linked to milk production (Thatcher & Tucker 1970).
The impact of exogenous GH and LR3 on maternal physiology in this study was evident in a number of the endpoints examined. Both GH and LR3 increased maternal body weight. However, unlike PRL, these increases probably occurred through a different mechanism since they were associated with alterations in body composition. The body weight and composition effects in LR3-injected dams were similar to those previously observed during prolonged lactation in the WAP-DES mice (Hadsell et al. 2005). The results are also consistent with the reported ability of IGF-I to improve nitrogen retention in female rats (Tomas et al. 1993). Along with the effects on body composition, however, the fact that milk production was increased in three independent mouse studies suggests that IGF-I, like GH, may be more effective at stimulating milk production in mice than in rats (Flint et al. 1992, 1994, Su & Cheng 2004, Hadsell et al. 2005).
An important point to remember is that both LR3 and des(1–3)IGF-I are known to be more potent than wild-type, endogenous, IGF-I since they do not interact with IGF-binding proteins (Clemmons et al. 1992, Oh et al. 1993). From the standpoint of interactions with the type-I IGF receptor, des(1–3)IGF-I and wild-type IGF-I are equivalent, while LR3 has somewhat reduced affinity (Ballard et al. 1986, 1987, Bagley et al. 1989). The impact of this reduced affinity appears minimal from a biological standpoint since LR3 maintains greater potency than wild-type IGF-I in both in vitro and in vivo assays (Ballard et al. 1986, Tomas et al. 1993). Therefore, although endogenous IGF-I was elevated in the GH-injected dams, this elevation would be expected to have less of a biological effect than that found in the WAP-DES transgenic dams or the LR3-injected dams. Clearly, the LR3 impacted the gland since both Akt phosphorylation and SOCS3 gene expression were elevated. However, the milk production response to LR3 might have been greater if circulating concentrations were as high as those originally observed with the WAP-DES mice (Hadsell et al. 2005). In addition, the comparison of mammary cell signaling and gene expression between the LR3- and the GH-injected dams suggests the possibility that the impact of GH on milk production may be mediated through additional factors that are independent of IGF-I action. This point was evident from the fact that both SOCS1 and TPH1 gene expression were altered in mammary tissue of GH-injected mice, but not affected in LR3-injected dams. In addition, while SOCS3 might have also been expected to increase in mammary tissue of both the LR3- and GH-injected dams, it was only altered in response to LR3 (Adams et al. 1998, Yadav et al. 2005).
Among the most interesting aspects of the GH effects were the impact on mammary expression of the gene for TPH1. In the mammary gland, TPH1 controls the synthesis of serotonin, a factor that regulates the ability of PRL to support mammary gland development and milk synthesis (Matsuda et al. 2004). Targeted mutation of the TPH1 gene in mice inhibits mammary involution (Matsuda et al. 2004). The expression of TPH1 is inducible both by PRL and teat sealing, a treatment that inhibits activation of STAT5 and causes mammary gland involution (Matsuda et al. 2004). The expression of TPH1 is also increased in the mammary tissue of lactating mice that are subjected to an interval nursing protocol that maintains lactation, but decreases the frequency of milk removal (Hadsell et al. unpublished data 2007). These observations, coupled with the fact that mammary expression of TPH1 was decreased in the GH-injected dams, suggest that some of the potential lactation-enhancing effects of GH may be mediated through decreased synthesis of mammary serotonin.
In summary, administration of exogenous GH, LR3–IGF-I, and PRL has significant effects on maternal physiology, mammary gland signaling, and mammary gene expression, yet only recombinant murine GH and LR3 were capable of enhancing lactation capacity in the litter cross-fostered mouse during prolonged lactation. A potential mechanism for the ability of GH to increase lactation capacity may lie in its ability to repress the expression of TPH1 within the mammary gland. This potential mechanism, and its regulation by the frequency of milk removal, will be the subject of future studies in both mice and dairy cows.
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Declaration of Interest |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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Funding |
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Acknowledgements |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of InterestReferences |
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Received in final form 19 March 2008
Accepted 8 April 2008
Made available online as an Accepted Preprint 8 April 2008
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) and saline-injected (
) dams. (C and D) Maternal body was also compared between the two groups within each experiment. Each symbol represents the mean±S.E.M. for five dams each in (A and C) and ten dams each in (B and D). The asterisk indicates a statistically significant (P
) LR3- (
) or GH-injected (
), percent epithelia (
), and lumen area (
) among mammary tissue harvested at 37 days post partum in saline-, LR3-, or GH-injected dam. Each symbol represents the mean±S.E.M. for 20, 15, and 10 dams in the saline, LR3, and GH treatment groups respectively. The asterisks indicate a statistically significant (P
