Beta-amyloid peptides(1-42) and (1-40) in the cerebrospinal fluid during pregnancy: a prospective observational study.

To evaluate changes in concentrations of selected biomarkers, neurotrophic factors, and growth factors in the cerebrospinal fluid during pregnancy. A prospective observational study was conducted in 32 pregnant women undergoing gynecological and obstetrical surgery under spinal anesthesia in a university hospital. Beta-amyloid(1-42) and beta-amyloid(1-40) peptides, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor were analyzed in cerebrospinal fluid using an enzyme-linked immunosorbent assay. Eight women in second trimester pregnancy who underwent spinal anesthesia for gynecological or obstetrical surgery were compared with 24 matched women in third trimester pregnancies. CSF concentrations of beta-amyloid(1-42) were significantly higher in third trimester pregnancies (p = 0.025). During third trimester, the beta-amyloid ratio correlated with the vascular endothelial growth factor (rs = 0.657; p = 0.008). Higher concentrations of beta-amyloid(1-42) in cerebrospinal fluid of third trimester pregnancies and correlations between the beta-amyloid ratio and the vascular endothelial growth factor support the hypothesis that beta-amyloid peptides are involved in complex adaptive brain alterations during pregnancy.

Cerebrospinal fluid levels of leptin, proopiomelanocortin, and agouti-related protein in human pregnancy: evidence for leptin resistance.

CONTEXT: Leptin suppresses appetite by modulating the expression of hypothalamic neuropeptides including proopiomelanocortin (POMC) and agouti-related peptide (AgRP). Yet during pregnancy, caloric consumption increases despite elevated plasma leptin levels. DESIGN AND PARTICIPANTS: To investigate this paradox, we measured leptin and soluble leptin receptor in plasma and leptin, POMC, and AgRP in cerebrospinal fluid (CSF) from 21 fasting pregnant women before delivery by cesarean section at a university hospital and from 14 fasting nonpregnant women. RESULTS: Prepregnancy body mass index was 24.6 ± 1.1 (SE) vs. 31.3 ± 1.3 at term vs. 26.5 ± 1.6 kg/m(2) in controls. Plasma leptin (32.9 ± 4.6 vs. 16.7 ± 3.0 ng/ml) and soluble leptin receptor (30.9 ± 2.3 vs. 22.1 ± 1.4 ng/ml) levels were significantly higher in pregnant women. However, mean CSF leptin did not differ between the two groups (283 ± 34 vs. 311 ± 32 pg/ml), consistent with a relative decrease in leptin transport into CSF during pregnancy. Accordingly, the CSF/plasma leptin percentage was 1.0 ± 0.01% in pregnant subjects vs. 2.1 ± 0.2% in controls (P < 0.0001). Mean CSF AgRP was significantly higher in pregnant subjects (32.3 ± 2.7 vs. 23.5 ± 2.5 pg/ml; P = 0.03). Mean CSF POMC was not significantly different in pregnant subjects (200 ± 13.6 vs. 229 ± 17.3 fmol/ml; P = 0.190). However, the mean AgRP/POMC ratio was significantly higher among pregnant women (P = 0.003), consistent with an overall decrease in melanocortin tone favoring increased food intake during pregnancy. CONCLUSIONS: These data demonstrate that despite peripheral hyperleptinemia, positive energy balance is achieved during pregnancy by a relative decrease in central leptin concentrations and resistance to leptin's effects on target neuropeptides that regulate energy balance.

Gestation-related reduction in lumbar cerebrospinal fluid volume and dural sac surface area.

BACKGROUND: Facilitation of the spread of neuraxial anesthesia in pregnant women may be attributable in part to compression of the dural sac by the engorged epidural venous plexus. In this study, we used magnetic resonance imaging to examine pregnancy-induced changes in the lumbosacral cerebrospinal fluid (CSF) volume and dural sac surface area. METHODS: Magnetic resonance images of 18 healthy women (mean age 29 yr, mean height 158 cm, and mean weight 58 kg) were obtained to measure lumbosacral CSF volume and dural sac surface area in the nonpregnant and pregnant states (median 36 wk gestation [31-39]) and the paired images were compared. RESULTS: The mean lumbosacral CSF volume and dural sac surface area in the nonpregnant state were 39.6 +/- 5.8 mL and 11.0 +/- 0.8 cm(2), respectively. Pregnancy was associated with compression of the dural sac, resulting in a significantly reduced mean CSF volume (33.2 +/- 6.2 mL) and dural sac surface area (9.9 +/- 1.0 cm(2)) in all subjects (P < 0.001). The mean change in CSF volume and dural sac surface area was 16.7% +/- 0.8% and 10.0% +/- 0.5%, respectively. Gestational week (between 31 and 39 wk) correlated significantly with the reduction in CSF volume (rho = 0.74, P < 0.001) and dural sac surface area (rho = 0.66, P < 0.01). CONCLUSIONS: These findings indicate an association between gestational week (Weeks 31-39) and a reduction in both CSF volume and dural sac surface area. These reductions may, at least in part, explain the facilitation of the spread of intrathecal anesthesia in pregnant women.

Cerebrospinal fluid and serum concentrations of beta-trace protein during pregnancy.

We conducted a prospective observational study among a cohort of 40 term parturients undergoing spinal anaesthesia for elective Caesarean section, to determine the concentration of beta-trace protein in cerebrospinal fluid (CSF) and serum. Serum and CSF samples, taken at the time of dural puncture, were assayed by nephelometry. The mean serum beta-trace protein concentration was 0.39 mg.l(-1) and the mean CSF concentration was 27.9 mg.l(-1), giving a mean ratio of CSF to serum concentration of 76. This ratio is higher than that published for non-pregnant females and for males because of both a higher mean CSF and a lower mean serum beta-trace protein concentration. The concentration correlated positively with both serum creatinine and gestational age. If these concentrations are used to estimate the normal range, we propose that the nephelometric measurement of beta-trace protein might prove a useful diagnostic test for cerebrospinal fluid-cutaneous fistula in parturients.

Changes in cerebrospinal fluid neurochemistry during pregnancy.

BACKGROUND: Little is known about changes in brain function that may occur during pregnancy. Studies in rodents and sheep suggest that several brain neurotransmitter and neurohormonal systems known to modulate anxiety may be altered during pregnancy. METHODS: Cerebrospinal fluid (CSF) and plasma samples were obtained from 21 women (during weeks 38-39 of pregnancy) who were undergoing elective cesarean section and from 22 healthy nonpregnant women. RESULTS: The CSF levels of g-aminobutyric acid (GABA) and 3-methoxy-4-hydroxyphenylglycolwere reduced in pregnant women. There were no changes in CSF glutamate, 5-hydroxyindoleactic acid, and homovanillic acid. There was a large increase in CSF prolactin in pregnant women and also a trend toward an elevation in CSF oxytocin. Levels of prolactin, but not oxytocin, in CSF and plasma were correlated in pregnant women. CONCLUSIONS: These results suggest that pregnancy alters regulation of brain GABA, norepinephrine, and prolactin, which may play a role in changes in vulnerability to anxiety and depression during pregnancy and postpartum. Prolactin circulating in the bloodstream seems to be the major source of CSF prolactin during pregnancy.

Cell-free fetal DNA in the cerebrospinal fluid of women during the peripartum period.

OBJECTIVE: The purpose of this study was to determine whether cell-free fetal DNA is detectable in the cerebrospinal fluid of women during pregnancy and after delivery. STUDY DESIGN: Cerebrospinal fluid was collected from 39 women who underwent an indicated spinal anesthesia procedure. Twenty-six samples were from women who carried at least 1 male fetus, and 13 samples were from women with only a female fetus. DNA was analyzed with the use of real-time polymerase chain reaction for DYS-1 (which represented male fetal DNA) and beta-globin (which represented maternal and fetal DNA). RESULTS: beta-Globin DNA was detected in all cerebrospinal samples. DYS-1 gene sequences were detected in 4 cerebrospinal fluid samples from women who had male fetuses (2 samples were from women who underwent cesarean delivery of singleton pregnancies, 1 sample was from a triplet pregnancy, and 1 sample was from a woman after delivery). No male DNA was detected in the cerebrospinal fluid of women who carried female fetuses. CONCLUSION: Male fetal cells and/or cell-free fetal DNA is detectable in the cerebrospinal fluid of some pregnant women or some women after delivery.

An analysis of excitatory amino acids, nitric oxide, and prostaglandin E2 in the cerebrospinal fluid of pregnant women: the effect on labor pain.

UNLABELLED: It is still unclear which neurotransmitters are involved in labor pain. We measured the concentrations of excitatory amino acids, nitric oxide, and prostaglandin E2 in the cerebrospinal fluid (CSF) of pregnant women, particularly in those with labor pain. The patients included in the study consisted of women who underwent cesarean delivery either with labor pain (Labor Pain group, n = 40) or without labor pain (Nonlabor Pain group, n = 58). All patients received spinal anesthesia (intrathecal injection of 10-12 mg of bupivacaine) for the operation, and 2 mL of CSF was collected before bupivacaine injection. Concentrations of aspartate and glutamate (0.50 +/- 0.06 microM and 0.79 +/- 0.10 microM, respectively) were significantly larger in the Labor Pain group than in the Nonlabor Pain group (0.35 +/- 0.03 microM and 0.54 +/- 0.04 microM, P < 0.05). There were no significant differences in the concentrations of nitric oxide and prostaglandin E2 between the groups. A positive correlation was found between CSF concentrations of excitatory amino acids and labor pain. IMPLICATIONS: The excitatory amino acids, aspartate and glutamate, play a role in labor pain. N-methyl-D-aspartate receptor antagonists may be useful for labor pain and postlabor uterine contraction pain relief.

Dissociation of adrenomedullin concentrations in plasma and cerebrospinal fluid in pregnant and non-pregnant women.

Adrenomedullin (AM), a potent vasodilator peptide, has been shown to act within the central nervous system to modulate fluid and electrolyte balance. AM-immunoreactive cells have been found in the anterior pituitary gland and the choroid plexus of humans. In addition, AM activity has been implicated in the regulation of maternal circulation during pregnancy. To determine the relationship between AM concentration in the cerebrospinal fluid (CSF) and plasma, we measured AM levels in CSF and plasma of pregnant (group P, n = 12) and non-pregnant (group NP, n = 10) women scheduled to undergo gynecologic or obstetric surgery. In both groups, the concentration of AM in the plasma exceeded that in the CSF. Plasma AM concentration was significantly higher in pregnant than non-pregnant women (17.3+/-5.8 vs 5.1+/-1.4 pmol/l, mean +/- S.D.; P<0.01), whereas CSF AM concentration did not differ between the two groups (1.3+/-0.9 and 0.9+/-0.4 pmol/l in groups P and NP respectively). No significant correlation was found between AM concentrations in the CSF and plasma. The present findings suggest that AM is present in the CSF and that its concentration in the CSF is regulated independently from that in the plasma.

Elevated cerebrospinal fluid level of substance P and decreased undecapeptidase activity at term pregnancy.

This paper reports a study of substance P and its converting enzyme substance P endopeptidase (SPE) in cerebrospinal fluid (CSF) collected from women at term pregnancy. A method was developed to assess the CSF levels of substance P itself with minimum contribution from prestages or fragments of the undecapetide. The measured activity was compared with that detected in CSF from control, non-pregnant, non-puerperal women. The result indicates a significant increase in substance P-like immunoreactivity at term pregnancy (19.9 +/- 3.9 fmol/ml, n = 10) compared with that of control subjects (12.3 +/- 2.8 fmol/ml, n = 9; P < 0.001). This elevation was suggested to reflect an increased activity in spinal sensory neurons at this stage of pregnancy. The activity of SPE was assessed by measuring the product substance P1-7 by a radioimmunoassay specific for this fragment. It was found that the enzyme activity was significantly decreased in CSF from pregnant women (11.2 +/- 0.71 pmol/h.ml), compared with control samples (18.4 +/- 0.73 pmol/h.ml; P < 0.05). Moreover, a significant negative correlation was found to exist between the level of substance P and the activity of SPE (P < 0.05, r2 = 0.65), suggesting that the enzyme may be involved in a mechanism regulating the level of substance P concentration.

Acid-base state of cerebrospinal fluid during pregnancy and its effect on spread of spinal anaesthesia.

To assess the possible relationship between changes in acid-base state of cerebrospinal fluid (CSF) and enhanced spread of spinal anaesthesia during pregnancy, we have measured CSF pH, carbon dioxide tension (PCO2) and HCO3- values in 73 women undergoing spinal anaesthesia with hyperbaric amethocaine 8 mg. Patients were allocated to one of four groups according to gestational period: non-pregnant group (n = 13), first trimester group (8-13 weeks, n = 19), second trimester group (14-26 weeks, n = 11) and third trimester group (27-39 weeks, n = 30). The pH of the CSF was greater in the second and third trimester groups than in the non-pregnant group. CSF PCO2 decreased by 0.53-0.8 kPa throughout pregnancy. CSF HCO3- was decreased throughout pregnancy. Overall, no clinically significant correlation was found between maximum cephalad spread of analgesia and CSF pH, PCO2 or HCO3-. We conclude that pregnancy-induced changes in acid-base state of CSF have little effect on the spread of spinal anaesthesia, although there is a clinically different spread of spinal anaesthesia between non-pregnant and pregnant states.

Density of lumbar cerebrospinal fluid in pregnant and nonpregnant humans.

BACKGROUND: Dextrose-free local anesthetics and opioids, alone and in combinations, are being used increasingly to provide subarachnoid anesthesia and analgesia. These dextrose-free drugs have been described as hypobaric by some and isobaric by others. To accurately classify anesthetics with regard to baricity, the density of cerebrospinal fluid (CSF) must be known. The authors sought to determine the exact density of human CSF, and determine whether CSF density is altered by pregnancy. METHODS: Density measurements accurate to 0.00001 g/ml were made at 37.00 degrees C, using a mechanical oscillation resonance frequency density meter. Cerebrospinal fluid samples were obtained from 44 patients during spinal anesthesia. Five groups were studied: men, and premenopausal, postmenopausal, term pregnant, and postpartum women. RESULTS: Mean CSF densities in men (1.00064 +/- 0.00012 g/ ml), postmenopausal women (1.00070 +/- 0.00018 g/ml), and nonpregnant premenopausal women (1.00049 +/- 0.00004 g/ ml) were significantly greater than in term pregnant (1.00030 +/- 0.00004 g/ml) and postpartum (1.00034 +/- 0.00005 g/ml) women. Cerebrospinal fluid density did not correlate with age. CONCLUSIONS: Mean CSF density varies in different patient subpopulations. Pregnancy and the immediate postpartum period are associated with the lowest CSF densities. In addition, the cutoff values defining hypobaricity (mean CSF density minus three standard deviations) are greater than previously reported. Accurate CSF density values should be used when considering baricity as a mechanism for clinical observations of dextrose-free intrathecal local anesthetics and opioids. Gestational status also should be considered.

Cerebrospinal fluid progesterone in pregnant women.

To assess the possible relationship between an increase in progesterone concentration in cerebrospinal fluid (CSF) and enhancement of spread of spinal anaesthesia, we have measured CSF progesterone concentrations in 134 patients undergoing spinal anaesthesia with hyperbaric amethocaine 8 mg. Patients were allocated to one of five groups according to the gestational period: non-pregnant group (n = 13), first trimester group (8-12 weeks, n = 16), second trimester group (13-24 weeks, n = 18), third trimester group (25-36 weeks, n = 38) and term group (37-41 weeks, n = 49). Progesterone concentration in CSF was higher in the third trimester and term groups than in the non-pregnant, first trimester and second trimester groups. Maximum cephalad spread of analgesia was higher in the second trimester, third trimester and term groups than in the non-pregnant and first trimester groups. Although an increase in CSF progesterone concentration in the second trimester group was similar in magnitude to that observed in the first trimester group, enhanced spread of spinal anaesthesia, comparable in magnitude with that observed in the term group, occurred in the second trimester group. There was no significant correlation between CSF progesterone concentration and spread of spinal anaesthesia in any of the groups. These data suggest that not only a minimum level of progesterone in CSF but also a certain duration of exposure to elevated CSF progesterone concentrations may be necessary for enhancement of spread of spinal anaesthesia, and that values of CSF progesterone concentration do not correlate directly with enhancement of spread of spinal anaesthesia.

Baseline serum and cerebrospinal fluid magnesium levels in normal pregnancy and preeclampsia.

OBJECTIVE: To determine whether baseline cerebrospinal fluid magnesium levels in preeclampsia differ from those in normal pregnancy, and to ascertain whether pre-treatment cerebrospinal fluid magnesium levels correlate with serum levels, which would suggest a baseline alteration in the blood-brain barrier in preeclampsia. METHODS: When spinal analgesia or anesthesia was administered for delivery, serum and cerebrospinal fluid magnesium levels were determined in 20 normal gravidas and 20 preeclamptic women not treated with magnesium sulfate. Data were analyzed by two-sided Student t test and regression analysis. RESULTS: Mean (+/- standard deviation) cerebrospinal fluid magnesium level for preeclamptic patients was 2.23 +/- 0.09 mEq/L, which was not significantly different from controls. Regression analysis revealed no significant correlation between cerebrospinal fluid and serum magnesium levels for either normal or preeclamptic gravidas. CONCLUSION: During the third trimester, there is no difference in baseline, pre-treatment cerebrospinal fluid magnesium levels in preeclamptic patients compared to normal subjects, and no correlation between cerebrospinal fluid and serum magnesium over the range of baseline values.

Penicillin levels following the administration of benzathine penicillin G in pregnancy.

OBJECTIVE: To investigate the distribution of penicillin in the maternal-placental-fetal unit at term gestation. METHODS: Twenty-five healthy gravidas at 38-39 weeks' gestation scheduled for elective repeat cesarean delivery under spinal anesthesia received benzathine penicillin G, 2.4 million units intramuscularly (IM) preoperatively. Ten women delivered 1 day after injection, five delivered 2-3 days after, and ten delivered 7 days after. We collected maternal serum and cerebrospinal fluid, amniotic fluid (AF), and cord serum at delivery. Penicillin levels were measured using a validated agar disc diffusion method (sensitivity 0.006 micrograms/mL) with Micrococcus lutea as the test organism. RESULTS: There was no significant difference in mean penicillin levels at day 1, day 2-3, or day 7 for maternal serum, maternal cerebrospinal fluid, cord serum, or AF. The mean (+/- standard error) penicillin concentration (range 0.005-0.59 micrograms/mL) in maternal serum declined from 0.14 +/- 0.04 micrograms/mL 1 day after injection to 0.08 +/- 0.06 micrograms/mL 7 days after injection. The proportion of patients with a penicillin concentration at or above 0.018 micrograms/mL in the maternal serum declined significantly from day 1 to day 7 (P = .03). Overall, nine of 25 women (36%) had serum penicillin levels that were less than 0.018 micrograms/mL. CONCLUSION: A wide range of penicillin levels were observed in gravidas at term in the maternal serum, cerebrospinal fluid, umbilical cord serum, and AF within 1 week after 2.4 million units of benzathine penicillin G IM. We speculate that altered pharmacokinetics may affect the efficacy of this drug for prevention of congenital syphilis in the near-term gestation.

Catecholamine concentrations in venous plasma and cerebrospinal fluid in normal and complicated pregnancy.

The concentrations of adrenaline and noradrenaline were determined in venous plasma and cerebrospinal fluid (CSF) of 41 pregnant women at term scheduled for elective or 'hot' caesarean section and in 7 healthy non-pregnant women scheduled for elective surgery. Group 1: 10 pregnant women at term with a normal history of their pregnancy; group 2: like group 1, but in active labour for more than 4 h; group 3: 10 pregnant women with insulin-dependent diabetes mellitus with or without slightly elevated arterial blood pressure; group 4: 11 women with pre-eclampsia gravis; group 5: 7 healthy non-pregnant women of fertile age. The highest values of mean arterial blood pressure and of venous plasma noradrenaline were found in the pre-eclamptic group 4, mean arterial blood pressure and plasma noradrenaline levels correlated to each other. However, concentrations of noradrenaline in CSF in group 4 did not differ significantly from the other groups. It is speculated that a different origin of hypertension may be the reason for the normal noradrenaline concentrations in CSF. This finding is in contrast to earlier findings in which noradrenaline levels in CSF were elevated in patients with essential hypertension.

Effect of pregnancy and pain on cerebrospinal fluid immunoreactive enkephalins and norepinephrine in healthy humans.

Endogenous spinal opioid or noradrenergic system activation may increase pain threshold during pregnancy and following a painful stress. Variation in spinal antinociceptive activity is also postulated to explain in part the large variability in postoperative opioid analgesic requirements. In this study, spinal noradrenergic and opioid activity, as reflected by the CSF concentrations of norepinephrine and immunoreactive enkephalins (total enkephalin-containing peptides), was determined in 58 women prior to surgery. The CSF concentration of these substances did not differ between pregnant and non-pregnant women. CSF norepinephrine tended to be greater in pregnant women who had experienced painful labor than in those who had not (1240 +/- 300 vs. 570 +/- 160 pmol/l; P = 0.056) and these women self-administered less morphine following cesarean section than those without labor pain (64 +/- 4 vs. 86 +/- 7 mg/24 h; P less than 0.01). However, CSF concentration of norepinephrine or immunoreactive enkephalins did not correlate with postoperative morphine use. These results suggest that spinal immunoreactive enkephalin and noradrenergic activity are not increased during pregnancy. However, pain may activate spinal noradrenergic pathways affecting pain sensation.

Effect of decreased cerebrospinal fluid proteins on the spread of local anaesthetic drugs in pregnancy.

Cerebrospinal fluid (CSF) and plasma protein concentrations were determined in 60 ASA-I female patients, 30 non-pregnant women, who were to undergo lower abdominal or lower limb surgery (group I, controls) and 30 pregnant women at term, who were posted for lower segment caesarean section (group II). All patients received spinal analgesia. Time of onset of analgesia and level of analgesia achieved were compared in two groups. A significant fall (16.6%) was noted in the plasma proteins in pregnant (6.10 +/- 0.6 g/dl) women as compared to non-pregnant patients (7.30 +/- 0.44 g/dl; P less than 0.01). CSF proteins also showed a significant fall (43.2%) in pregnant (25.80 +/- 5.52 mg/dl), as compared to non-pregnant women (45.43 +/- 7.66 mg/dl; P less than 0.001). Dose of local anaesthetic drug required was significantly less (44%) in pregnant (3.21 +/- 0.29 mg/segment) as compared to non-pregnant women (5.73 +/- 0.74 mg/segment; P less than 0.01). Time of onset of block was significantly less in pregnant than in non-pregnant patients after the injection of drug (2.86 +/- 0.42 sec and 3.41 +/- 0.43 sec respectively; P less than 0.01). No correlation was found between plasma proteins and CSF proteins. CSF protein concentration also did not correlate with dose of local anaesthetic drug, or with time of onset of block. It is suggested that fall in CSF protein concentration may be another contributory factor in the reduced dose requirement of local anaesthetic drug for subarachnoid block during pregnancy.

Immunoreactive beta-casomorphin-8 in cerebrospinal fluid from pregnant and lactating women: correlation with plasma levels.

We measured plasma and cerebrospinal fluid (CSF) beta-casomorphin-8, a product of beta-casein hydrolysis which has opioid activity, by RIA in women during late pregnancy and lactation and in nonpregnant nonpuerperal women. Before RIA, the samples were acidified and extracted by reverse phase silica gel chromatography, which removed most of the beta-casein. Lactating women had a significantly higher mean plasma beta-casomorphin-8 concentration (2.66 nmol/L; n = 8) than women in late pregnancy (0.82 nmol/L; n = 8) and nonpregnant women (0.32 nmol/L; n = 5). The CSF beta-casomorphin-8 concentration also was significantly higher in lactating women (mean, 0.35 nmol/L; n = 8) than during late pregnancy (0.22 nmol/L; n = 8) or in nonpregnant women (0.15 nmol/L; n = 5). A positive correlation was found between plasma and CSF beta-casomorphin-8 levels in the entire study group. The milk beta-casomorphin-8 concentration, measured in five puerperal women, averaged 19.8 nmol/L. Thus, there is a decreasing concentration gradient between milk and plasma and between plasma and CSF. Chromatographic analysis revealed mol wt heterogeneity of the RIA-active material. In CSF at least three different components were detected, two of mol wt around 900-2,000 and one of approximately 12,000. One of the low mol wt components coeluted in several chromatographic systems with synthetic beta-casomorphin-8 (mol wt, 900). Such a component was not found in milk or plasma, in which the major activity was due to larger sized peptides. The major peaks in milk were around 1,500-2,000 and 12,000 mol wt, corresponding to the larger peaks in CSF. The results suggest that fragments of the milk protein beta-casein may cross the breast parenchyma-blood barrier into plasma and subsequently penetrate the blood-brain barrier to reach the central nervous system. Thus, mammary tissue may assume endocrine function during galactopoiesis, and beta-casein could be considered a prohormone.