Serum and intratumoural GH and IGF-I concentrations: Prognostic factors in the outcome of canine mammary cancer

The biological implication of the growth hormone/insulin like growth factor-I (GH/IGF-I) axis in canine mammary tumours (CMT) has been recently demonstrated, however its clinical and prognostic implications are unknown. Our aim was to investigate its prognostic significance.Hormonal determinations were done by enzyme immunoassays techniques validated for canine species in serum and tumour tissue from 32 bitches with CMT and in serum and normal mammary tissue from 10 controls. Serum and tissular GH and IGF-I concentrations were significantly higher in the case of malignant tumour compared with benign and controls. GH and IGF-I elevated concentrations were significantly associated with tumour relapse and/or metastases during follow-up and in dogs with reduced survival times; however these parameters were not independent prognostic factors in multivariate analysis. This association demonstrates a link between high serum and intratumoural GH and IGF-I concentrations and a worse prognosis and opens the possibility to new anticancer endocrine therapies in dogs.     

Influence of nutritional deprivation on insulin-like growth factor I, somatotropin, and metabolic hormones in swine

Although growth hormone (GH) is a primary stimulus for the synthesis of insulin-like growth factor I (IGF-I), other factors such as nutritional status, insulin, and thyroid hormones are important modulators of circulating IGF-I levels. Thus, the effects of feed restriction and subsequent refeeding on plasma levels of IGF-I, GH, insulin, and thyroid hormones were studied in swine. Despite an elevation in plasma GH levels after 48 h of feed restriction, circulating IGF-I levels were decreased by 53% (P less than .05). Plasma triiodothyronine (T3) and insulin were lower (P less than .05) within 24 h after the feed restriction began, whereas thyroxine (T4) did not decrease until 48 h after removal of feed. Blood glucose levels remained unchanged throughout the experiment. Refeeding after the 48-h fast was associated with a decline (P less than .05) in circulating GH levels within 2 h, concomitant with an elevation (P less than .05) in plasma insulin and T3. Refeeding fasted pigs was associated with an increase (P less than .05) in plasma IGF-I; however, levels still had not returned to prefast concentrations within 24 h after refeeding. These data indicate that the GH-IGF-I axis becomes uncoupled during nutritional restriction in swine and that inadequate nutrient supply may limit the expression of the anabolic effects of GH.     

Effects of food intake and food withholding on plasma ghrelin concentrations in healthy dogs

OBJECTIVE: To investigate the physiologic endocrine effects of food intake and food withholding via measurement of the circulating concentrations of acylated ghrelin, growth hormone (GH), insulin-like growth factor-I (IGF-I), glucose, and insulin when food was administered at the usual time, after 1 day's withholding, after 3 days' withholding and after refeeding the next day in healthy Beagles. ANIMALS: 9 healthy Beagles. PROCEDURES: Blood samples were collected from 8:30 AM to 5 PM from Beagles when food was administered as usual at 10 AM, after 1 day's withholding, after 3 days' withholding, and after refeeding at 10 AM the next day. RESULTS: Overall mean plasma ghrelin concentrations were significantly lower when food was administered than after food withholding. Overall mean plasma GH and IGF-I concentrations did not differ significantly among the 4 periods. Circulating overall mean glucose and insulin concentrations were significantly higher after refeeding, compared with the 3 other periods. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, food withholding and food intake were associated with higher and lower circulating ghrelin concentrations, respectively, suggesting that, in dogs, ghrelin participates in the control of feeding behavior and energy homeostasis. Changes in plasma ghrelin concentrations were not associated with similar changes in plasma GH concentrations, whereas insulin and glucose concentrations appeared to change reciprocally with the ghrelin concentrations.     

Selection for growth rate or against back fat thickness in pigs is associated with changes in growth hormone axis plasma protein concentration and mRNA level.

Selection for increased growth rate or decreased back fat thickness results in concomitant changes in endocrine and metabolic status. Growth hormone (GH) changes in blood plasma concentration related to selection for growth rate and fat deposition were reported in pigs. The molecular mechanisms regulating selection-induced changes in GH plasma concentration remain largely unknown. We investigated selection-associated changes in GH axis parameters in 2 pig lines selected for increased growth rate (F-line), or decreased back fat thickness (L-line), respectively. First, we investigated selection-associated changes in GH pulse parameters. In both selection lines we found each generation a declining GH peak maximum concentration and area under the GH curve. GH pulse width was not associated with generation number. In both lines generation number was associated with a declined pulse interval, indicating that the number of pulses per day increased on average with 1 pulse per 24 h per generation. Second, plasma concentration of GH axis related Insulin-like growth factor-I (IGF-I) and insulin were investigated. Plasma IGF-I concentration was not associated with generation number in the F-line. Mean plasma insulin concentration declined each generation in both lines. Third, we investigated changes in GH and Pit-1 mRNA levels. In both selection lines GH and Pit-1 mRNA levels increased approximately 50% each generation. The high SD of the GH mRNA levels in both lines may suggest that the GH mRNA levels are pulsatile in vivo. We postulate a molecular mechanism that may explain how selection is associated with increased GH mRNA levels and GH pulse numbers, while lowering GH release per pulse.     

Role of progestin-induced mammary-derived growth hormone in the pathogenesis of cystic endometrial hyperplasia in the bitch

Endogenous progesterone and synthetic progestins may induce hypersecretion of growth hormone (GH) of mammary origin, hyperplastic ductular changes in the mammary gland, and the development of cystic endometrial hyperplasia (CEH) in dogs. It was investigated whether progestin-induced mammary GH plays a role in the pathogenesis of CEH in the bitch. During 1 year, bitches with surgically excised mammary glands and healthy control bitches received medroxyprogesterone acetate (MPA). Before and after MPA treatment, uterine and mammary tissues were collected for histological, immunohistochemical, and RT-PCR examination. After MPA administration, the mammary tissue in the control dogs had differentiated into lobulo-alveolar structures and CEH was present in all uteri of both dog groups. In the MPA-exposed mammary tissue of the control dogs, GH could only be demonstrated immunohistochemically in proliferating epithelium. After treatment with MPA the dogs of both groups had immunohistochemically demonstrable GH in the cytoplasm of hyperplastic glandular uterine epithelial cells. RT-PCR analysis of the mammary gland tissue after MPA administration demonstrated a significant higher GH gene, and lower GHR gene expression than before treatment. In the uterus, the expression of the gene encoding for GH was significantly increased in the mastectomized dogs, whereas in the control dogs the expression of the gene encoding for insulin-like growth factor-I had significantly increased with MPA administration. MPA treatment significantly down regulated PR gene expression in the uterus in both dog groups. These results indicate that progestin-induced GH of mammary origin is not an essential component in the development of CEH in the bitch.     

Abundance of message for insulin-like growth factors-I and -II and for receptors for growth hormone,insulin-like growth factors-I and -II,and insulin in the intestine and liver of pre- and full-term calves

The somatotropic axis and insulin are involved in pre- and postnatal development. In pre- and full-term calves (GrP0 and GrN0; born after 277 and 290 d of pregnancy, respectively) and in preterm calves on d 8 of life after being fed for 7 d (GrP8), we studied whether there are differences in the abundance of messenger RNA (mRNA) of IGF-I and IGF-II and of receptors for GH, IGF-I, IGF-II, and insulin among different intestinal sites (duodenum, jejunum, ileum, and colon) and whether there are ontogenetic differences during the perinatal period in intestine and liver. Intestinal site differences (P < 0.05) existed in mRNA levels of IGF-I and IGF-II and receptors for GH, IGF-I, IGF-II, and insulin. Abundance of mRNA of IGF-I and -II and of receptors for IGF-I and GH was highest (P < 0.05) in the colon, abundance of the receptor for IGF-II was comparably high in the colon and ileum, and that of the receptor for insulin was similarly high in colon, ileum, and jejunum. Among GrP0, GrN0, and GrP8 groups, there were differences (P < 0.05) in mRNA levels of IGF-I and IGF-II and of receptors for GH, IGF-I, IGF-II and insulin. Abundance of mRNA of IGF-I and IGF-II and of receptors for GH, IGF-I, IGF-II and insulin was highest (P < 0.05) in GrP0 calves immediately after birth and was primarily seen in the ileum. In liver, the mRNA levels differed (P < 0.05) among groups for IGF-II and receptors for IGF-I, IGF-II, and insulin, and were highest (P < 0.05) for IGF-II in GrP0, for receptors of IGF-I in GrN0, and were higher (P < 0.05) in GrP0 than GrP8 for receptors of IGF-II. In conclusion, mRNA levels of IGF-I and IGF-II and of receptors for GH, IGF-I, IGF-II, and insulin were different at different intestinal sites and in intestine and liver and changed during the perinatal period.     

Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly

BACKGROUND: Serum insulin-like growth factor-I (IGF-I) has been used in place of serum growth hormone quantification for identifying acromegaly in diabetic cats. The utility of IGF-I as a screening test for acromegaly has not been critically evaluated. This retrospective study was performed to evaluate the usefulness of serum IGF-I concentration for identifying acromegaly. HYPOTHESIS: Serum IGF-I is a useful screening test for acromegaly in diabetic cats. ANIMALS: A review was made of the medical records of 74 diabetic cats that had serum IGF-I quantified. The diabetes was classified as well controlled (15 cats), poorly controlled because of problems with the insulin treatment regimen, concurrent disease, or both (40), or poorly controlled with clinical findings consistent with acromegaly (19). METHODS: A review of medical records was made. RESULTS: Serum IGF-I concentration was significantly (P < .0001) increased in acromegalic diabetic cats, compared with well-controlled and poorly controlled diabetic cats. Sensitivity and specificity for serum IGF-I concentration were 84% (95%/ confidence interval [CI] = 60.4-96.6%) and 92% (95% CI = 81.3-97.2%), respectively. There was no significant correlation between serum IGF-I concentration and duration of insulin treatment (r = 0.23, P = .089), insulin dosage (r = 0.14, P = .30), age (r = 0.16, P = .12), and pituitary volume (r = 0.40, P = .11), but a modest correlation was found between serum IGF-I concentration and body weight (r = 0.48, P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Results support the use of serum IGF-I concentration as a screening test for acromegaly in diabetic cats that have clinical findings supportive of the disease.     

Growth hormone and mammary development.

Classic studies in rodents conducted in the 1950s showed that growth hormone (GH) is essential for mammary development both in the pubertal phase and during pregnancy. Since then, a considerable number of experiments have been carried out in ruminants to investigate the role of GH for regulation of normal mammary development and to examine the possibility of enhancing mammary growth by administration of GH. The available evidence demonstrates that GH treatment stimulates mammary growth before puberty, but the data do not convincingly support the idea that the effect is translated into increased milk yield. GH treatment during late pregnancy seems to stimulate both mammary growth and milk yield during lactation. The limited data concerning the effect of GH on mammary growth during lactation indicate that mammary growth is unaffected by GH treatment in early lactation, whereas GH seems to increase the amount of mammary parenchyma in mid-lactation. The mechanism of action of GH remains a puzzle, but the effect of exogenous GH most likely involves insulin-like growth factor-I (IGF-I). Full understanding of the role of endogenous GH for regulation of normal mammary development requires more knowledge about the interaction between GH and IGF-I and the interplay between the GH-IGF-I axis and locally produced factors, including receptors, binding proteins, and growth factors.     

Metabolic adaptations associated with irreversible glucose loss are different to those observed during under-nutrition

In this study the hypothesis that irreversible glucose loss results in an 'uncoupling' of the somatotrophic axis (increasing plasma GH levels and decreasing plasma IGF-I) was tested. During periods of negative energy balance the somatotrophic axis respond by increasing plasma GH and decreasing plasma IGF-I levels. In turn, elevated GH repartitions nutrient by increasing lipolysis and protein synthesis, and decreases protein degradation. Irreversible glucose loss was induced using sub-cutaneous injections of phloridizin. Seven non-lactating cows were treated with 8g/day phloridizin (PHZ) and seven control animals (CTRL, 0g/day), while being restricted to a diet of 80% maintenance. PHZ treatment increased urinary glucose excretion (P<0.001), resulting in hypoglycemia (P<0.001). As a response to this glucose loss, the PHZ treated animals had elevated plasma NEFA (P<0.005) and BHBA (P<0.001) levels. Average plasma insulin concentrations were not altered with PHZ treatment (P=0.059). Plasma GH was not different between the two groups (P>0.1), whereas plasma IGF-I levels decreased significantly (P<0.001) with PHZ treatment. The decline in plasma IGF-I concentrations was mirrored by a decrease in the abundance of hepatic IGF-I mRNA (P=0.005), in addition the abundance of hepatic mRNA for both growth hormone receptors (GHR(tot) and GHR(1A)) was also decreased (P<0.05). Therefore, the irreversible glucose loss resulted in a partial 'uncoupling' of the somatotrophic axis, as no increase in plasma GH levels occurred although plasma IGF-I levels, hepatic IGF-I mRNA declined, and the abundance of liver GH receptor mRNA declined.     

Immunohistochemical expression of progesterone receptors, growth hormone and insulin growth factor-I in feline fibroadenomatous change

The immunohistochemical expression, tissue-specific and cell-specific distribution patterns of progesterone receptors (PR), growth hormone (GH) and insulin growth factor-I (IGF-I) have been studied in 22 cases of feline fibroadenomatous change (FFAC). PR and GH were detected in all cases and were distributed homogeneously throughout the lesion, while IGF-I was detected in 77% of the cases at the site of ductal budding. The simultaneous expression of PR, GH and IGF-I was detected in epithelial cells in 14 of 22 cases while PR and GH expression only was detected in epithelial cells in 11 cases. Cases that expressed GH and IGF-I without PR expression in the stroma were the most numerous. Double immunohistochemical staining showed the co-localisation of PR and GH in a subset of ductal epithelial cells located between basal/myoepithelial and luminal cells (probably undifferentiated stem cells). These results suggest that ligand-activated progesterone receptors may induce the local synthesis of GH which in turn may exert its proliferative action directly and also indirectly through the production of other growth factors, such as IGF-I, in an autocrine/paracrine manner.     

Prognostic factors associated with survival two years after surgery in dogs with malignant mammary tumors: 79 cases (1998-2002)

OBJECTIVE: To identify prognostic factors for female dogs that have undergone surgical removal of malignant mammary tumors. DESIGN: Retrospective case series. ANIMALS: 79 female dogs with malignant mammary tumors. PROCEDURE: Information obtained from the medical records included breed, age, sex, tumor size (maximum diameter), number and location of affected mammary glands, time between tumor identification and surgical removal, radiographic evidence of distant metastasis, surgical procedure, ovariohysterectomy (OHE) status, histologic classification of the tumor, and survival time. RESULTS: Results of univariate analyses indicated that clinical stage, tumor size, OHE status, metastasis to adjacent lymph nodes or distant sites, and histologic classification of the tumor were significantly associated with survival 2 years after surgery. Tumors > or = 5 cm in diameter and tumors that had been identified > 6 months before surgery were more likely to metastasize to adjacent lymph nodes. Ovariohysterectomy was more beneficial in dogs with complex carcinomas than in dogs with simple carcinomas. In multivariate analyses, clinical stage, tumor size, and OHE status were significantly associated with survival 2 years after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that tumor stage, tumor size, and OHE status were significant prognostic factors associated with survival 2 years after surgery in dogs with malignant mammary tumors. Further, either dogs with tumors > or = 5 cm in diameter or dogs with tumors present for > 6 months prior to surgery had a higher risk of having lymph node metastases.     

Pregnancy-related diabetes mellitus in two dogs

CASE SUMMARIES: Two cases of diabetes mellitus occurring in bitches in association with pregnancy are reported. In the first case, a bitch with suspected acromegaly developed diabetes mellitus within 2 weeks of the due date. Despite insulin therapy, euglycaemia was not achieved. Two live, small pups were delivered by elective Caesarean section but died within 2 days. Signs consistent with acromegaly resolved but diabetes mellitus was permanent in the bitch. In the second case, diabetic ketosis with severe gastrointestinal disease was diagnosed 2 days after Caesarean section was performed due to dystocia. The pups delivered all died within 5 days. The bitch recovered fully from diabetes mellitus within 2 weeks and has remained euglycaemic without insulin for a period of at least 18 months. CLINICAL RELEVANCE: These two cases demonstrate that diabetes mellitus can occur in association with pregnancy in dogs, that diabetic ketosis can occur during transient diabetes mellitus in dogs, and suggest that acromegaly may occur during pregnancy-related dioestrus in dogs. The scarcity of previous reports of this nature, however, suggests that such cases are unusual. Lack of prompt resolution of hyperglycaemia may result in secondary diabetes mellitus becoming permanent. Management should focus on immediate insulin therapy or ovariohysterectomy to minimise this risk. Even mild hyperglycaemia should not be ignored during pregnancy. The insulin antagonistic effects of pregnancy, stressful illness, surgery and dystocia can be enough to result in diabetic ketosis in the absence of permanent insulin deficiency. Maternal hyperglycaemia may contribute to adverse fetal outcomes in dogs but further study is required regarding the nature of the risk.     

Pregnancy-related diabetes mellitus in two dogs

CASE SUMMARIES: Two cases of diabetes mellitus occurring in bitches in association with pregnancy are reported. In the first case, a bitch with suspected acromegaly developed diabetes mellitus within 2 weeks of the due date. Despite insulin therapy, euglycaemia was not achieved. Tw o live, small pups were delivered by elective Caesarean section but died within 2 days. Signs consistent with acromegaly resolved but diabetes mellitus was permanent in the bitch. In the second case, diabetic ketosis with severe gastrointestinal disease was diagnosed 2 days after Caesarean section was performed due to dystocia. The pups delivered all died within 5 days. The bitch recovered fully from diabetes mellitus within 2 weeks and has remained euglycaemic without insulin for a period of at least 18 months.

CLINICAL RELEVANCE: These two cases demonstrate that diabetes mellitus can occur in association with pregnancy in dogs, that diabetic ketosis can occur during transient diabetes mellitus in dogs, and suggest that acromegaly may occur during pregnancy-related dioestrus in dogs. The scarcity of previous reports of this nature, however, suggests that such cases are unusual.

Lack of prompt resolution of hyperglycaemia may result in secondary diabetes mellitus becoming permanent. Management should focus on immediate insulin therapy or ovariohysterectomy to minimise this risk. Even mild hyperglycaemia should not be ignored during pregnancy. The insulin antagonistic effects of pregnancy, stressful illness, surgery and dystocia can be enough to result in diabetic ketosis in the absence of permanent insulin deficiency. Maternal hyperglycaemia may contribute to adverse fetal outcomes in dogs but further study is required regarding the nature of the risk.     

High body weight gain and reduced bovine mammary growth: physiological basis and implications for milk yield potential

Available evidence concerning the relationship between growth rate, mammary growth and milk yield in heifers leads to these conclusions: 1) Increased growth rate due to high feeding level before puberty onset can lead to reduced pubertal mammary growth and reduced milk yield potential. 2) Increased growth rate due to high feeding level after puberty and during pregnancy have no effect on mammary growth and milk yield. 3) Higher body weight gain due to higher genetic potential for growth is positively related to milk yield. The negative effect of high feeding level before puberty occurs in all breeds, but the level of feeding causing reduced yield varies. Variation in responses between experiments suggests that feeding regimes that support high growth rates without negative effect on yield can be developed. A breakthrough most likely will originate from increased knowledge of the physiological relationship between nutrition and mammary development. Our investigations suggest that blood growth hormone (GH) is important for mammary development, and that the negative effect of high feeding level on mammary development may be due to reduced blood GH. GH, however, does not bind to mammary tissue. Experiments with exogenous GH suggest that GH acts on mammary tissue via IGF-I, but IGF-I is increased by high feeding level - not decreased as GH. This paradoxical relationship cannot be explained by changes in circulating IGF binding proteins. However, the sensitivity of mammary tissue to IGF-I is reduced by high feeding level, probably due to the action of locally produced binding proteins and/or growth factors.     

Evaluation of circulating IGF-I and IGFBP-3 as biomarkers for tumors in dogs

BackgroundSerum-based parameters are considered non-invasive biomarkers for cancer detection. In human studies, insulin-like growth factor-I and II (IGF-I and IGF-II) and insulin-like growth factor binding protein-3 (IGFBP-3) are useful as diagnostic or prognostic markers and potential therapeutic targets.ObjectivesThis study examined the diagnostic utility of circulating IGF-I, IGF-II, and IGFBP-3 levels in healthy dogs and dogs with tumors.MethodsThe serum concentrations of these biomarkers in 86 dogs with tumors were compared with those in 30 healthy dogs using an enzyme-linked immunosorbent assay (ELISA).ResultsThe ELISA results showed no difference between healthy dogs and dogs with tumors in the serum IGF-II concentrations. On the other hand, there was a significant difference in the circulating IGF-I and IGFBP-3 levels between healthy dogs and dogs with tumors. The concentrations of serum IGF-I (median [interquartile range], 103.4 [59.5–175] ng/mL) in dogs with epithelial tumors were higher than those (58.4 ng/mL [43.5–79.9]) in healthy dogs. Thus, the concentrations of serum IGFBP-3 (43.4 ng/mL [33.2–57.2]) in dogs with malignant mesenchymal tumors were lower than those (60.8 ng/mL [47.6–70.5]) in healthy dogs.ConclusionsThe serum IGF-I and IGFBP-3 levels can be used as diagnostic biomarkers in dogs with tumors.     

Growth hormone excess and the effect of octreotide in cats with diabetes mellitus

In this prospective study 16 cats with diabetes mellitus were examined for concurrent acromegaly by measuring plasma growth hormone (GH) and insulin-like growth factor-I concentrations, and magnetic resonance imaging (MRI) of the pituitary fossa. Additionally, the effects of octreotide administration on the plasma concentrations of glucose, GH, α-melanocyte-stimulating hormone (α-MSH), adrenocorticotrophic hormone (ACTH), and cortisol were measured.Five cats were diagnosed with hypersomatotropism. The pituitary was enlarged in these 5 cats and in 2 other cats. Six cats that required a maximum lente insulin dosage ≥1.5 IU/kg body weight per injection had pituitary enlargement and 5 of these cats had acromegaly. Plasma concentrations of GH, ACTH, and cortisol decreased significantly after single intravenous administration of the somatostatin analogue octreotide in the acromegalic cats. The effect on GH concentrations was more pronounced in some of the acromegalic cats than in others. In the non-acromegalic cats only ACTH concentrations decreased significantly. In both groups plasma glucose concentrations increased slightly but significantly, whereas α-MSH concentrations were not significantly affected.In conclusion, the incidence of hypersomatotropism with concomitant pituitary enlargement appears to be high among diabetic cats with severe insulin resistance. Some of these cats responded to octreotide administration with a pronounced decrease in the plasma GH concentration, which suggests that octreotide administration could be used as a pre-entry test for treatment with somatostatin analogues.     

Cardiac changes induced by excess exogenous growth hormone in juvenile miniature poodles

The transient elevated plasma growth hormone (GH) levels that occur at a young age in giant breed dogs may have consequences in adult life. The aim of this study was to investigate whether excess juvenile GH has consequences for cardiac function and morphology. To simulate the naturally occurring juvenile hypersomatotropism in giant breed dogs, elevated plasma GH and insulin-like growth factor-I (IGF-I) concentrations were induced in six miniature poodles (GH dogs) by daily administration of supraphysiological doses of GH starting at 12 weeks of age. Eight miniature poodles of the same age that received vehicle only served as controls. Cardiac anatomy and function were evaluated by echocardiography. After euthanasia at 21 weeks of age, the hearts were examined for weight, myocyte dimensions and collagen fraction. The hearts of the GH dogs had larger atria (+22%), a thicker left ventricular wall (+21%), greater weight (+84%), and their cardiomyocytes were 15% longer, 25% thicker, and 92% greater in volume than those of control dogs. The mean collagen fraction was also higher in the GH dogs (5.6%) than in the controls (3.1%). In conclusion, excess GH in juvenile miniature poodles resulted in myocardial hypertrophy and increased collagen content. These findings are consistent with observations in acromegalic human patients and in rats treated with GH.     

Growth hormone suppresses the expression of IGFBP-5, and promotes the IGF-I-induced phosphorylation of Akt in bovine mammary epithelial cells

Growth hormone (GH) plays a specific role to inhibit apoptosis in the bovine mammary gland through the insulin-like growth factor (IGF)-I system, however, the mechanism of GH action is poorly understood. In this study, we show that GH dramatically inhibits the expression of IGFBP-5, and GH along with IGF-I enhanced the phosphorylation of Akt through the reduction of IGF binding protein (IGFBP)-5. To determine how GH affects Akt through IGF-I in bovine mammary epithelial cells (BMECs), we examined the phosphorylation of Akt in GH treated BMECs and found that IGF-I induced phosphorylation of Akt was significantly enhanced by the treatment with GH. We demonstrated that GH reduces mRNA and protein expression of IGFBP-5 in BMECs, but it does not affect the expression of IGFBP-3. To determine that the enhanced effect of the Akt phosphorylation by the treatment of GH is due to the inhibition of the expression of IGFBP-5, we examined the effect of IGFBP-3 and -5 on the phosphorylation of Akt through IGF-I in the GH-treated BMECs. The phosphorylation of Akt was inhibited in a dose-dependent manner when IGFBP-5 was added at varying concentrations and was also inhibited in the presence of IGFBP-3. The results of this study suggest that GH plays an important role on mammary gland involution in bovine mammary epithelial cells.     

Clinical, pathological and immunohistochemical study of feline mammary fibroepithelial hyperplasia following a single injection of depot medroxyprogesterone acetate

Feline mammary fibroepithelial hyperplasia (FMFH) following a single injection of depot medroxyprogesterone acetate (MPA) was observed in eight intact young queens. The repository compound is marketed as a veterinary product by a local pharmaceutical company with an indication for contraception in cats. The drug was administered according to the recommended doses and injection frequencies. Serum hormone assays performed immediately before neutering and 3 weeks after neutering detected persistently high levels of progesterone suggesting that depot MPA was still exerting its influence. No corpora lutea were found in those cases ruling out ovaries as the main site of progesterone. Immunohistochemistry performed on the hyperplastic mammary glands detected progesterone receptors in the nuclei of ductal cells, and growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the cytoplasm of ductal epithelium. Overdosing should be considered here as the animals received at least 10 mg/kg of depot MPA in a single injection. Progestin-induced local synthesis of GH and IGF-I in mammary epithelial cells is suggested as one of the pathogenic mechanisms involved in the development of FMFH.     

Oestradiol enhances plasma growth hormone and insulin-like growth factor-I concentrations and increased the expression of their receptors mRNAs in the liver of ovariectomized cows

Many metabolic hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and insulin affect ovarian functions. However, whether ovarian steroid hormones affect metabolic hormones in cattle remains unknown. This study aimed to determine the effect of sex steroids on the plasma profiles of GH, IGF-I and insulin and their receptors in the liver and adipose tissues of dairy cows. Ovariectomized cows (n = 14) were randomly divided into four groups: control group (n = 3) was treated with saline on Day 0; oestradiol (E2) group (n = 3), with saline and 1 mg oestradiol benzoate (EB) on Day 0 and 5, respectively; progesterone (P4) group (n = 4) with two CIDRs (Pfizer Inc., Tokyo, Japan) from Day 0; and E2 + P4 group (n = 4) with two CIDRs on Day 0 that were removed on Day 6 and were immediately injected with 1 mg EB. The animals were euthanized after the experiment, and liver and adipose tissues samples were quantitatively analysed using real-time PCR for the expression of mRNA for the GH (GHR), IGF-I (IGFR-I) and insulin (IR) receptor mRNAs. Oestradiol benzoate significantly increased the number of peaks (p < 0.05), pulse amplitude (p < 0.05) and area under the curve (AUC; p < 0.01) for plasma GH; moreover, it increased plasma IGF-I concentration (p < 0.05), but it had no effect on the plasma insulin profile. P4 significantly decreased the AUC (p < 0.01), compared with the control group, whereas it did not affect the number of peaks and the amplitude of GH pulses. P4 + E2 did not affect the GH pulse profile. E2 increased the mRNA expression of GHR, IGFR-I and IR in the liver (p < 0.05), whereas both P4 and E2 + P4 did not change their expressions. Our results provide evidence that the metabolic and reproductive endocrine axes may regulate each other to ensure optimal reproductive and metabolic function.