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Overexpression of des(1-3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation.

During prolonged lactation, the mammary gland gradually loses the capacity to produce milk. In agricultural species, this decline can be slowed by administration of exogenous growth hormone (GH), which is believed to act through insulin-like growth factor 1 (IGF1). Our previous work demonstrated delayed natural mammary gland involution in des(1-3)IGF1-overexpressing transgenic mice (Tg[Wap-des{1-3}IGF1]8266 Jmr), hereafter referred to as WAP-DES mice. The present study tested the hypothesis that overexpressed des(1-3)IGF1 would delay the loss of milk production during prolonged lactation. Accordingly, we examined lactational performance in WAP-DES mice by artificially prolonging lactation with continual litter cross-fostering. Over time, lactational capacity and mammary development declined in both WAP-DES and control mice. However, the rate of decline was 40% slower in WAP-DES mice. Mammary cell apoptosis increased by 3-fold in both groups during prolonged lactation but was not different between genotypes. Plasma concentrations of murine IGF1 were decreased in WAP-DES mice, while those of the transgenic human IGF1 were elevated during prolonged lactation. Phosphorylation of the mammary IGF1 receptor was increased in the WAP-DES mice, but only during prolonged lactation. Plasma prolactin decreased with prolonged lactation in nontransgenic mice but remained high in WAP-DES mice. The WAP-DES mice maintained a higher body mass and a greater lean body mass during prolonged lactation. These data support the conclusion that overexpressed des(1-3)IGF1 enhanced milk synthesis and mammary development during prolonged lactation through localized and direct activation of the mammary gland IGF1 receptor and through systemic effects on prolactin secretion and possibly nutrient balance.

Animals↗

Duration of diestrous period and secretion of progestins during prolonged lactation in the rat.

The duration of the diestrous period in vaginal smears and the levels of progestins in ovarian venous blood were investigated in rats whose lactation period was prolonged by replacing pups at appropriate intervals. In prolonged lactating rats, the first diestrous period after the pospartum ovulation (21.7 +/- 0.8 days) was similar to that occurring in normal lactating rats. Subsequently proestrous or estrous vaginal smears reappeared at intervals during prolonged lactation. A total of 19 rats were studied during this period of prolonged lactation and 44 diestrous periods were observed. Forty-eight % of these periods ranged in length from 11 to 16 days (mean of 12.7). Very short diestrous periods lasting less than 3 days were observed 25% of the time. Diestrous periods lasting more than 17 days were observed only infrequently (7%). Progesterone concentration in the ovarian vein during the 2nd diestrous period reached a peak 4 days after the 1st estrus and the level was maintained until 11 days after the 1st estrus. The level of 20alpha-hydroxypregn-4-en-3-one remained fairly constant throughout the 2nd diestrous period.

Animals↗

Changes in secretory cell turnover, and mitochondrial oxidative damage in the mouse mammary gland during a single prolonged lactation cycle suggest the possibility of accelerated cellular aging.

Milk synthesis by the mammary gland declines during prolonged lactation despite the continued suckling stimulus and complete removal of mammary secretions. Although this process has been hypothesized to result from cellular aging there has been no reported analysis of aging markers in the lactating mammary gland. The goal of these studies was to relate lactation performance in the mouse during a single prolonged lactation cycle to changes in mammary development and mitochondrial oxidative damage. During an artificially prolonged lactation cycle, the capacity of the dams to support litter growth decreased over time. This decrease was associated with decreased mammary epithelial content. Cell proliferation, along with the percentage of mammary progenitor cells, was high during early lactation, but low during prolonged lactation. Apoptosis increased during prolonged lactation. Oxidative damage to mitochondrial DNA increased during the early postpartum period and remained elevated through the end of the cycle. In contrast oxidative damage to mitochondrial protein was high during early lactation and decreased through mid lactation to increase again with prolonged lactation. The results suggest that a single prolonged lactation cycle may replicate on an accelerated basis some of the changes that occur with a lifetime of aging in organs possessing more stable cell populations.

Animals↗

Changes in body weight, milk production, food and water consumptions and vaginal smears in rats during prolonged lactation.

Concurrent observations were made in the rat on the changes in the milk production, body and organ weight, food and water consumptions and in the ovarian function in two separate series of experiments in which the period of lactation was prolonged to 60 and 45 days, respectively, by replacing suckling pups by younger ones. In most of the variable examined, marked changes occured between day 20 and 30 of lactation, that is, at the stage correspondong to the end of the normal lactation period. Milk production rate during prolonged lactation expressed by daily gain in weight of litters decreased to 60% of the level before day 20, and was associated with a great reduction of nucleic acid contents of the mammary gland. Definite decreases in weight of the anterior pituitary and the adrenal glands were observed. The food intake remained constant from day 15 of lactation onwards, therefore, the feed efficiency for milk production declined gradually during the period of normal lactatation remaining at a low level thereafter.. After the first recurrence of vaginal estrus which also occured between day 20 and 30, the replacement of litters was followed by the appearance of estrus, whereas replacement before day 15 did not affect the ovarian function. In addtition to these changes, a depressing effect of estrus on the milk production was observed.

Adrenal Glands↗

Fat and energy contents of expressed human breast milk in prolonged lactation.

OBJECTIVE: To estimate fat and energy contents of human milk during prolonged lactation. METHODS: Thirty-four mothers, of term, healthy, growing children, who had been lactating for >1 year (12-39 months) were recruited. Control subjects were 27 mothers, of term infants, who had been lactating for 2 to 6 months. Fat contents of the milk samples were estimated as creamatocrit (CMT) levels. Energy contents of the milk were measured with a bomb calorimeter. RESULTS: The groups did not differ in terms of maternal height and diet, infant birth weight, gestational age, or breastfeeding frequency. They differed significantly in terms of maternal age, maternal weight, and BMI. The mean CMT levels were 7.36 +/- 2.65% in the short-duration group and 10.65 +/- 5.07% in the long-lactation group. The mean energy contents were 3103.7 +/- 863.2 kJ/L in the short-duration group and 3683.2 +/- 1032.2 kJ/L in the long-duration group. The mean CMT levels and mean energy contents were correlated significantly with the duration of lactation (R2 = 0.22 and R2 = 0.23, respectively). In multivariate regression analysis, CMT levels (or energy contents) were not influenced by maternal age, diet, BMI, or number of daily feedings but remained significantly influenced by the duration of lactation. CONCLUSIONS: Human milk expressed by mothers who have been lactating for >1 year has significantly increased fat and energy contents, compared with milk expressed by women who have been lactating for shorter periods. During prolonged lactation, the fat energy contribution of breast milk to the infant diet might be significant.

Breast Feeding↗

Mammary nucleic acids and pituitary prolactin secretion during prolonged lactation in mice.

Lactation was prolonged until 61 days by repeated renewal of litters every week after day 12 in primiparous C3H/He strain mice. On days 12, 19, 40, and 61 of lactation, litters were removed for 5 h and after 1 h of resuckling the synthesis of DNA and RNA in the mammary gland was estimated by the incorporation of (3H)thymidine and (14C)uridine into mammary DNA and RNA in vitro respectively. Mammary nucleic acid content and pituitary and plasma levels of prolactin were also assayed. Nulliparous mice were similarly treated on day 19 of pregnancy. The percentage gain in litter weight per week was highest between days 5 and 12 of lactation, declined until days 26-33 and became steady thereafter. Mammary DNA synthesis was extremely high on day 19 of pregnancy, decreased on day 12 of lactation to less than one-fifteenth of that on day 19 of pregnancy and increased linearly therafter. Changes in mammary DNA content were not so marked, but DNA content was high on days 12 and 19 of lactation. RNA synthesis was highest on day 19 of pregnancy, abruptly decreased on days 12 and 19 of lactation and increased again with the advance of lactation. Mammary RNA content, RNA:DNA and 14C:3H ratios increased from day 19 of pregnancy to days 12-19 of lactation and decreased on days 40 and 61. While the pituitary levels of prolactin were almost constant during lactation, they were significantly higher than those on day 19 of pregnancy. There were only slight differences in plasma prolactin levels at any stage.

Animals↗

Factors related to duration of postpartum amenorrhoea among USA women with prolonged lactation.

Duration of postpartum amenorrhoea (PPA) was compared among women who breast-fed for > or = 6 months (breast-feeding group) or < or = 3 months (formula-feeding group) and was found to be significantly shorter among the latter. Associations between maternal factors and duration of PPA were examined. Within the formula-feeding group, the only variable associated with duration of PPA was duration of breast-feeding. Among breast-feeding mothers who resumed menstruation after 3 months postpartum, duration of PPA was positively associated with parity and negatively associated with maternal body mass index (BMI) at 3 months postpartum. Among breast-feeding mothers who resumed menstruation after 6 months, duration of PPA was positively associated with parity, pregnancy weight gain, number of night feeds and milk volume at 6 months, and negatively associated with maternal age and BMI at 6 months postpartum. These results indicate that maternal anthropometric status is related to duration of PPA, even in a relatively well-nourished population of lactating women.

Adult↗

Breast-milk calcium concentrations during prolonged lactation in British and rural Gambian mothers.

Detailed investigation of breast-milk calcium concentrations during 2 years of lactation have been conducted in Cambridge, UK, and rural Gambia. Mature milk concentrations remained steady for 3 months but declined during months 4-12 by over 25% (p less than 0.001). The pattern was identical in both communities despite differences in breast-feeding practices. Calcium concentrations were not related to feed frequency or breast-milk sodium concentrations, suggesting that breast involution is not responsible for the decrease after 3 months. Breast-milk calcium concentrations were characteristic of the individual, varied twofold between mothers and were independent of maternal age, parity and milk output. Gambian breast-milk contained 19% less calcium than Cambridge milk, throughout lactation (p less than 0.001). The extent to which this reflected the lower calcium intakes of Gambian mothers is unknown. Further studies are required to determine factors regulating breast-milk calcium secretion.

Breast Feeding↗

Zinc in breast milk during prolonged lactation: comparison between the UK and the Gambia.

A total of 580 breast milk samples were collected from 56 lactating women living in a rural village community in The Gambia, West Africa, and 92 samples were obtained from 57 lactating women living in Cambridge, England. Total zinc content of each sample was measured by atomic absorption spectrometry, and pooled samples of the Gambian breast milks, representing successive periods of lactation, were fractionated into fat, whey and insoluble casein fractions, to examine zinc distribution. The two sets of milks both exhibited a dramatic decline in total zinc concentrations with increasing duration of lactation, in common with previous studies. However, the UK milks unexpectedly had lower zinc contents at all stages than the Gambian milks. Milk zinc levels were not significantly related to either maternal age or parity in the Gambian women. The proportion of zinc found in the sedimentable fraction remained nearly constant with increasing duration of lactation, but the proportion found in the fat fraction increased and the proportion in the whey fraction declined. These observations are potentially relevant for estimations of milk zinc availability and the fulfillment of zinc requirements by infants, and hence for infant feeding practices.

Adolescent↗

Role of the nutritional status of the litter and length and frequency of mother-litter contact bouts in prolonging lactational diestrus in rats.

Food restricting lactating rat dams over the first 2 weeks of lactation results in a prolongation of the period of lactational diestrus. Such food restriction has not only a direct effect on the dam but also the pups are undernourished, and the pattern of dam-litter contact is also changed. In a series of studies, we investigated the effects of nursing undernourished pups and the change in dam-litter interaction on the prolongation of lactational diestrus. While nursing undernourished pups in the last 2 weeks of lactation is sufficient to extend lactational diestrus in ad lib-fed dams nursing well-nourished pups in the last 2 weeks of lactation is not necessary for the prolongation of lactational diestrus seen in food-restricted dams. Further, neither nursing underfed pups nor increased nest time in the first 2 weeks postpartum are necessary factors for the prolongation of lactational diestrus in food-restricted dams.

Animals↗

Prolactin level after prolonged lactation: contraceptive evaluation.

A study was conducted to evaluate serum prolactin during lactation among 60 mothers with prolonged breastfeeding for 2 years. Patients were classified into 3 groups with 20 in each: lactating for less than 6 months, lactating for 6-12 months, and lactating for 12-24 months. There was hyperprolactinemia during lactation and serum prolactin levels decreased as lactation progressed. After long lactation (over a year), 10 of 20 women were amenorrheic and 10 were menstruating; 6 of the menstruating women were ovulating and 4 nonovulating. Prolonged lactation was found to be relatively successful for family spacing.

Amenorrhea↗

Prolonged lactation reduces ovarian cancer risk in Chinese women.

To investigate the effect of lactation on the risk of ovarian cancer for Chinese women, a case-control study was conducted in Hangzhou, capital of Zhejiang province, China. Cases were 275 patients with histologically confirmed epithelial ovarian cancer. Controls were 623 women without neoplasm. All participants were parous women who had given at least one live birth and had been residents of Zhejiang province for at least 10 years. Information was collected using a validated and reliable questionnaire on total months of lactation, number of children breastfed, and average duration of lactation per child. Multivariate logistic regression models were used to assess the association between ovarian cancer risk and lactation variables, accounting for age, locality, full-term pregnancy, oral contraceptive use and family history of the cancer. The adjusted odds ratios were 0.51 (95% confidence interval (CI) 0.3-0.9) and 0.44 (95% CI 0.2-0.9) respectively for women with over 12 months of lactation and at least three children breastfed, compared with those with 4 months or less lactation and one child breastfed. The corresponding dose-response relationships were also significant (P<0.05). Therefore, prolonged lactation could reduce the risk of ovarian cancer for Chinese women.

Adult↗

Prolonged lactational infertility in adolescent rhesus monkeys.

The present study examined the effects of first pregnancy and nursing behavior on postpartum infertility in seasonally breeding rhesus monkeys to assess whether prolonged lactational infertility observed in adolescent mothers is due to a particular pattern of nursing or to decrements in body growth rates. After a successful first pregnancy, a significant percentage of the lactating adolescent mothers (57.1%; n = 8) failed to exhibit an ovulation with normal luteal phase during the subsequent breeding season. In contrast, the remaining lactating adolescents (42.9%, n = 6) and all of the adult mothers (100%, n = 6) exhibited ovulations with a normal luteal phase. Age alone was not the critical variable, since all nonlactating adolescents exhibited ovulations with normal luteal phase parameters in the subsequent breeding season. The luteal phase abnormalities exhibited by the subset of lactating adolescent females were characterized by an inadequate luteal phase (ILP) and by significantly lower serum levels of progesterone, estradiol, and bioactive luteinizing hormone. The occurrence of these ILP ovulations was associated with more frequent nursing bouts prior to ovulation and during the subsequent luteal phase. In contrast, nursing patterns for adult females who had ovulations with normal luteal phases were more similar to those of the infertile lactating adolescents exhibiting significantly longer and more frequent nursing bouts, suggesting that fully adult females may be less sensitive to the inhibitory aspects of a suckling stimulus. Differences in luteal phase function among lactating adolescents were not related to differential rates of ponderal or skeletal growth. A still-developing neuroendocrine system may thus render a significant proportion of adolescent females more sensitive to suckling-induced suppression of gonadotropin secretion.

Animals↗

Breast-milk amylase activity in English and Gambian mothers: effects of prolonged lactation, maternal parity, and individual variations.

Breast milk contains an amylase that may contribute to carbohydrate digestion in infants. The aim of our study was to determine whether mothers differ in their breast-milk amylase activity and whether the activity is maintained during prolonged lactation. This was investigated by measuring breast-milk amylase activity by hydrolysis of maltotetraose in 63 English mothers of parity 1-5 and 107 Gambian mothers of parity 1-12 who were at various stages of lactation (0.5-27 mo). Amylase was present in all samples and showed a great range of activity from 0.08 to 3.53 IU/mL. Amylase activities did not vary during a feed nor over 24 h, and each mother had a characteristic level of activity in her milk. Amylase activity was higher in the 1st trimester of lactation, and decreased by 35% (p less than 0.001) to a plateau at 6-27 mo. Gambian mothers of very high parity (parity 11-12) had 54% of the activity of primiparous mothers (p less than 0.001), after adjustment for stage of lactation. Using community data on milk volume, the estimated breast-milk amylase intake by breast-fed children was on the order of 800-1000 IU/24 h in the 1st trimester and 400 IU/24 h in the 2nd year of lactation. Individual measurements emphasized the great differences in this intake among children of the same age. Our study showed that breast milk is an important source of amylase both in developed and developing countries, but there are large variations in intake among children.

Adult↗

Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit.

BACKGROUND: Failure of arterial serum lactate to achieve normal levels has been associated with an increased mortality among medical and trauma patients. At our institution the ability of the patient to normalize arterial serum lactate has been utilized as an end point of resuscitation. In this study, we examine the correlation between length of time to lactate normalization and mortality. METHODS: The charts of 95 consecutive surgical intensive care unit (SICU) patients requiring hemodynamic monitoring or therapy were reviewed retrospectively. Hemodynamic, demographic, and laboratory data were recorded. Patients were stratified by lactate normalization time, and a subgroup analysis of survivors and nonsurvivors was performed by univariate and multivariate analysis. RESULTS: Patients not achieving a normal lactate level sustained a 100% hospital mortality rate. Those clearing between 48 and 96 hours sustained a 42.5% mortality rate. Patients normalizing in 24 to 48 hours had a 13.3% mortality rate, and those clearing in less than 24 hours had a mortality rate of 3.9%. Subgroup analysis by survival revealed differences in time to lactate clearance, initial blood pressure, and initial lactate on univariate analysis. On multivariate analysis only time of lactate clearance was found to differ. CONCLUSIONS: Prolongation of lactate clearance is associated with increasing mortality. Failure of a patient to normalize lactate is associated with 100% mortality. Measurement of arterial serum lactate is a simple and effective predictor of outcome and end point of therapy.

APACHE↗

Prolactin secretion during prolonged lactational amenorrhoea.

Basal serum prolactin levels were elevated up to 66 weeks postpartum in lactating amenorrhoeic women. The serum prolactin level in fully breast-feeding women was significantly higher than in women who were partially breast-feeding. The mean basal serum prolactin level in menstruating, lactating women was significantly higher than the mean level in women who had weaned and had normal menstrual cycles. The rise in prolactin due to suckling was seen up to 66 weeks postpartum. The marked variability and lack of reproducibility of individual suckling responses may obscure the importance of prolactin secretion in the postpartum period. Nevertheless, this study confirms that prolactin secretion is increased in women with prolonged lactational amenorrhoea.

Amenorrhea↗

The response of plasma prolactin to suckling during normal and prolonged lactation in the rat.

In dams which had been kept isolated from pups for 8-10 h, the magnitude of the suckling-induced prolactin rise in the plasma was studied in relation to intensity of suckling stimulus and lactational age of the mother. At midlactation the response of prolactin evoked by suckling was enhanced as litter size increased. Suckling of 2 pups induced a greater prolactin rise in dams adjusted to 2 pups than in dams adjusted to 8 pups. Suckling of 8 pups caused a greater prolactin rise in dams which had been adjusted to an 8-pup litter, than in rats with a 2-pup litter. At late and prolonged lactation the rise of prolactin in the plasma induced by the suckling stimulus of 8 pups was significantly lower than at midlactation. Injection of perphenazine after a period of suckling induced a moderate increase of plasma prolactin in dams at midlactation, and a similar increase in dams at late lactation and at day 42 of lactation. It is concluded that in the first half of lactation the number of pups, i.e. the intensity of the suckling stimulus, is an important factor in determining the magnitude of the prolactin response to suckling. The lower response of plasma prolactin to suckling in late lactation is neither caused by a decrease in suckling stimulus from the pups nor by an increase in prolactin clearance; it is probably due to a gradual reduction in prolactin synthesizing and releasing capacity of the pituitary, brought on by a desensitization of the neural or neuroendocrine system to suckling stimuli as lactation proceeds.

Animals↗