Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty?

Puberty is characterized by temporary insulin resistance, which subsides with the completion of pubertal development. This insulin resistance is manifested by lower rates of insulin-stimulated glucose metabolism and compensatory hyperinsulinemia in pubertal compared with prepubertal children. Whether or not pubertal insulin resistance is the result of sex steroids or GH or a combination of both has been investigated in our laboratory. Previously, we demonstrated that T treatment in adolescents with delayed puberty was not associated with the deterioration of insulin action. The present investigation evaluated the effects of 4 months of dihydrotestosterone administration (50 mg im every 2 wk) on body composition, glucose, fat, and protein metabolism, and insulin sensitivity. Ten adolescents with delayed puberty were evaluated before and after 4 months of DHT administration. Body composition was assessed by dual energy x-ray absorptiometry. Insulin-stimulated glucose metabolism was measured during a 3-h hyperinsulinemic (40 mU/m(2).min)-euglycemic clamp procedure. Lipolysis and proteolysis were evaluated by stable isotopes of [(2)H(5)]glycerol and [1-(13)C]leucine. After 4 months of dihydrotestosterone treatment, height, weight, and fat free mass increased and percentage of body fat decreased. IGF-I and nocturnal GH levels did not change. There was no significant change in insulin-stimulated glucose metabolism (57.2 +/- 3.9 vs. 58.3 +/- 3.9 micromol/kg.min). Total body proteolysis and lipolysis did not change. In summary, based on the present and past studies, we conclude that during puberty insulin resistance/hyperinsulinemia is not attributable to gonadal sex steroids in boys.

Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus.

The prevalences of obesity and of non-insulin dependent diabetes mellitus (NIDDM) have increased in the United States population over the past two decades, and thus diabetes prevention has become a major concern of public health agencies such as the National Institutes of Health. Identification of individuals at risk for diabetes is an essential first step in designing and implementing intervention programs. Insulin resistance is the hallmark of the pathophysiology of NIDDM. Subjects with hyperinsulinemia, impaired glucose tolerance, or gestational diabetes are well accepted as being at high risk for diabetes. We propose that the easily identifiable skin lesion, acanthosis nigricans, is common in the major minority groups in the United States and that its presence is a surrogate for laboratory-determined hyperinsulinemia.

Effects of therapy with recombinant human growth hormone on insulin-like growth factor system components and serum levels of biochemical markers of bone formation in children after severe burn injury.

Burn injury in children is associated with low bone formation and long-term bone loss. Because recombinant human GH (rHGH) may accelerate burn wound healing, and because rHGH increases bone formation and density in GH-deficient patients, we studied the short-term effects of rHGH on bone fomation, reflected by osteocalcin and type I procollagen propeptide levels in a randomized, double-blind, placebo-controlled study. Nineteen patients were enrolled and received either rHGH (0.2 mg/kg.day) or an equal volume of saline. Mean burn size and age were not different between the groups, and test substances were given from admission to time of wound healing (mean: 43 +/- 22 days). At wound healing, serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 in the rHGH group rose to mean values of 229% and 187% of the respective means of the placebo group (P < 0.025). Serum osteocalcin concentrations remained below normal in both groups, and type I procollagen propeptide levels achieved a low normal level IGFBR-4 levels were twice that of normal on admission and doubled further at wound healing; IGFBP-5 levels were low on admission but rose to normal at wound healing. We conclude that large doses of rHGH were ineffective in improving disordered bone formation despite increasing serum IGF-1 and IGFBP-3. The rHGH-independent rise in serum levels of the inhibitory binding protein IGFBP-4 suggests a mechanism by which improved bone formation is prevented despite successful elevation of IGF-1 and IGFBP-3 in the burned child.

Hyperinsulinemia and acanthosis nigricans in African Americans.

Compared with the US white, non-Hispanic population, the African-American population has a nearly two-fold higher prevalence of noninsulin-dependent diabetes mellitus (NIDDM). Obesity, which usually precedes NIDDM, is associated with the skin lesion acanthosis nigricans in African Americans. This study was undertaken to determine what the relationship of acanthosis nigricans was to hyperinsulinemia, a major risk factor for NIDDM. Eighty-nine African-American subjects with acanthosis nigricans and 25 others without the skin lesion were evaluated using oral glucose tolerance testing and responsiveness to insulin. Noninsulin-dependent diabetes mellitus was present in 19 of the subjects with acanthosis nigricans. The prevalence of NIDDM in this group increased with increasing age, reaching 50% among those in their 40s. Fasting plasma insulin concentration was in direct proportion to the severity of the acanthosis nigricans involvement of the neck. These data suggest that among African Americans, this skin lesion is a marker for hyperinsulinemia and insulin resistance. Furthermore, the presence of acanthosis nigricans identifies a subset with a much higher prevalence of NIDDM than is present in African Americans in the general population.

Androgen regulation of growth hormone binding protein.

Male puberty is associated with elevated plasma concentrations of growth hormone (GH) and insulin-like growth factor-I (IGF-I), as well as accelerated linear growth. These effects can be reproduced by administration of testosterone (T). To further elucidate the mechanisms underlying pubertal growth, we treated 14 boys with delayed puberty and short stature with either T (n = 7) or 5alpha-dihydrotestosterone (DHT) (n = 7) and compared the effect on plasma concentrations of GH, IGF-I, and GH binding protein (GHBP). Before treatment and after either three or four doses of T enanthate or DHT heptanoate, mean 12-hour GH concentration (8 AM to 8 PM) and plasma IGF-I, T, DHT, and GHBP levels were measured, and height velocity (HV) was measured over this interval. T treatment resulted in an increase of mean GH from 3.3 to 12.0 microg/L (P < .005) and of IGF-I from 22.3 to 45.4 nmol/L (P < .01). During treatment, HV was 11.0 +/- 1.1 cm/yr, consistent with normal pubertal growth, and plasma T was 22.5 +/- 5.3 nmol/L. GHBP decreased in this group from 937 to 521 pmol/L (P < .025). DHT treatment resulted in a small decrease of mean GH from 4.3 to 2.9 microg/L (P < .025) and of IGF-I from 29.4 to 27.2 nmol/L (nonsignificant [NS]). During treatment, HV was 9.3 +/- 1.1, not significantly different from the HV obtained with T treatment, and plasma DHT was 24.2 nmol/L at 1 week and 29.2 at 2 weeks postinjection. Likewise, there was a decrease in GHBP from 928 to 698 pmol/L (P < .025). The decline in GHBP with T treatment was apparently due to an androgen receptor-dependent mechanism, since the same effect was seen during treatment with the nonaromatizable androgen, DHT. This effect is opposite to the normal chronological trend upward for GHBP, which occurs from infancy into midpuberty. Factors determining the upward trend are not known, but are evidently independent of the plasma concentration of sex hormones and GH. The increase in IGF-I in response to T treatment despite a moderate decline in GHBP (and possibly GH receptor) levels is most likely due to the large increase in GH, which may override a modest decrease in GHBP/GH receptor.

The effects of testosterone and dihydrotestosterone on hypothalamic regulation of growth hormone secretion.

Testosterone (T) administration to pubertal boys increases spontaneous GH secretion. It is not known whether this occurs via pituitary or hypothalamic mechanisms. We evaluated the GH secretion of 12 boys, aged 13.67 +/- 0.37 yr (mean +/- SE), diagnosed with constitutional delay in growth and adolescence. The evaluation was made both before and after 3 months of treatment with T or the nonaromatizable androgen, 5 alpha-dihydrotetosterone. Serum for determination of spontaneous GH secretion was sampled every 20 min for 24 h. Pituitary responsiveness was assessed by the administration of GHRH with sampling of GH at intervals for the next 2 h. This was also done with pyridostigmine (PDS) pretreatment to assess the effects of somatostatin. The dose of androgen used was 80 mg/m2 month. All tests were then repeated during treatment. Spontaneous GH secretion was analyzed by the Cluster method. The response to GHRH was measured as the area under the curve. Somatostatin effects were quantified as the difference in responsiveness between the two GHRH tests performed at each admission: one without prior PDS administration and one in which somatostatin was blocked by PDS. Treatment with T increased mean spontaneous GH secretion from 2.25 +/- 0.34 micrograms/L before treatment to 6.77 +/- 0.69 micrograms/L (mean +/- SE; P < 0.001) and mean spontaneous peak height from 5.62 +/- 1.05 to 17.21 +/- 1.52 micrograms/L (mean +/- SE; P < 0.001). No significant differences between pretreatment and treatment evaluations for any spontaneous GH secretory parameters were seen in 5 alpha-dihydrotestosterone-treated patients, except that maximum peak height was decreased after treatment (P < 0.02). In T treated patients, the GHRH stimulation tests without prior PDS administration changed from 84.14 +/- 34.54 total micrograms/L before to 102.3 +/- 35.82 total micrograms/L (mean +/- SE; P = NS) after androgen treatment. PDS pretreatment produced an increase in responsiveness to GHRH over the test without PDS pretreatment. This increase was 127.03 +/- 35.68 total micrograms/L before T treatment; after T treatment, this increase was 78.38 +/- 57.6 total micrograms/L (mean +/- SE; P = NS). T treatment, via an estrogen-dependent mechanism, caused increased GH pulse amplitude, thereby increasing the mean serum GH concentration. This increase was not the result of increased pituitary responsiveness or decreased somatostatin tone. This indicates that T exerted its effect on GH via increased GHRH pulse amplitude.

Androgen-stimulated pubertal growth: the effects of testosterone and dihydrotestosterone on growth hormone and insulin-like growth factor-I in the treatment of short stature and delayed puberty.

The purpose of this study was to investigate the roles of androgenic and estrogenic mechanisms in the stimulation of structural growth and plasma GH in male puberty. To resolve these two possible mechanisms, we compared the effect of two androgens in the treatment of constitutional delay in growth and adolescence: an aromatizable androgen, testosterone (T), and a nonaromatizable androgen, dihydrotestosterone (DHT). Nine adolescent males, Tanner stage 1 or 2, were studied before and during treatment with T enanthate (group A) or DHT heptanoate (group B). After 2.5 months of treatment, the height velocity (HV) was 12.6 +/- 2.8 cm/yr (n = 3) in group A and 8.9 +/- 1.7 cm/yr (n = 6) in group B, both within the range of peak HV for pubertal males. In group A, the integrated concentration of GH (ICGH) increased from 3.12 +/- 0.90 to 13.67 +/- 6.0 micrograms/L (P < 0.05), and plasma insulin-like growth factor-I (IGFI) increased from 126.7 +/- 2.5 to 350.3 +/- 20.3 micrograms/L (P < 0.01); plasma T increased from 0.8 +/- 0.5 to 33.8 +/- 11.0 nmol/L (P < 0.001), and the LH response to LHRH decreased from 27.6 +/- 10.7 to 5.9 +/- 2.5 IU/L (P = NS). In group B, ICGH decreased from 4.32 +/- 0.61 to 2.39 +/- 0.42 (P < 0.025), and IGF-I decreased from 218.3 +/- 39.2 to 184.0 +/- 15.8 (P = NS). Plasma T increased from 2.0 +/- 0.5 to 2.7 +/- 0.8 (P = NS), and the LH response to LHRH decreased from 45.7 +/- 14.5 to 10.7 +/- 5.8 (P < 0.05). To further evaluate the mechanism of the effect of DHT on plasma GH, seven male subjects with adolescent gynecomastia were treated with DHT heptanoate, and their responses were studied at 1 week and 3.5 months. ICGH decreased in conjunction with a decrease in the integrated T concentration (r = -0.77; P < 0.001) and to a slight degree with decreasing plasma estradiol (r = -0.39; P < 0.2). Plasma IGF-I did not show a significant change in the subjects with gynecomastia. Thus, the increase in GH at puberty in males appears to be due to an estrogen-dependent mechanism. The suppressive effect of DHT on GH secretion may be due to either suppression of estradiol production or a direct effect. Acceleration of HV into the peak pubertal range by DHT without an increase in plasma GH suggests that an increase in GH is not necessary for the pubertal growth spurt.

High-density lipoprotein response to 5-alpha-dihydrotestosterone and testosterone in Macaca fascicularis: a hormone-responsive primate model for the study of atherosclerosis.

A decrease in high-density lipoprotein cholesterol (HDL-C), a major risk factor for coronary artery disease, occurs during puberty in males. Previous studies have shown this decrease with testosterone (T) therapy for adolescent males, but the mechanism of this effect is unknown and has not been studied in a non-human primate. Two adult male monkeys (Macaca fascicularis) were studied to determine simultaneous changes in plasma androgens and HDL-C during the phases precastration (Ci); postcastration (Cx); Cx and T therapy; Cx and dihydrotestosterone (DHT) therapy; and T and 5-alpha-reductase inhibitor therapy (4-MA). After castration, the HDL-C concentrations increased significantly in both animals (monkey A, 57.0 +/- 1.8 mg/dL SE to 66.6 +/- 2.2, P less than .005; monkey B, 62.9 +/- 1.6 to 80.2 +/- 1.7, P less than .001). T-propionate treatment produced a significant decrease in HDL-C (monkey A, 48.0 +/- 5.0, P less than .01; monkey B, 43.5 +/- 0.5, P less than .001), which was similar to HDL-C reductions seen when treated with a nonaromatizeable androgen, DHT-propionate (monkey A, 47.5 +/- 1.5, P less than .005; monkey B, 44.5 +/- 3.5, P less than .001). T and the 5-alpha-reductase inhibitor therapy did not increase HDL-C from the levels with T therapy alone (monkey A, 55.7 +/- 1.9, NS; monkey B, 57.3 +/- 0.3, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Inappropriate adrenal androgen secretion with once-a-day corticosteroid therapy for congenital adrenal hyperplasia.

To determine whether cortisone acetate given as a single daily dose would be as effective as the same amount divided into three doses in suppressing adrenal androgen secretion in congenital adrenal hyperplasia, we studied three patients with the salt-losing variety, who were judged to have been adequately treated during the previous year. Each patient was receiving cortisone acetate, 20.6 to 22.6 mg/m2 body surface area per day, divided into three doses, and 9 alpha-fluorohydrocortisone, 0.05 to 0.1 mg/day. Their spontaneous and adrenocorticotropic hormone-stimulated blood concentrations of 17 alpha-hydroxyprogesterone, androstenedione, and testosterone were measured initially and were normal. Cortisone acetate was then given once a day in the same total daily dose. After 3 months, plasma adrenocorticotropic hormone concentration was increased in all three patients, and in two of them the plasma levels of 17 alpha-hydroxyprogesterone and androstenedione were also increased. In the third patient, after 7 months of once-daily therapy, plasma levels of 17 alpha-hydroxyprogesterone and androstenedione were increased. We conclude that a physiologic replacement dosage of cortisone acetate given once daily is not effective in controlling excessive adrenal androgen secretion in congenital adrenal hyperplasia.

Dihydrotestosterone heptanoate: synthesis, pharmacokinetics, and effects on hypothalamic-pituitary-testicular function.

Dihydrotestosterone heptanoate (DHT-hp), a seven-carbon fatty acid ester of DHT, was synthesized, and its pharmacokinetics and effects on hypothalamic-pituitary-testicular function were determined in men and pubertal boys. Plasma DHT levels markedly increased 24 h after im injection of DHT-hp, reached their peak during the first week, and fell to baseline levels after 4-6 weeks. An estimated 43-55% of DHT-hp was converted to DHT 4-6 weeks after injection. Plasma testosterone, estradiol, LH, and FSH levels decreased by 4 days after DHT-hp injection, were lowest during the second week, and returned to baseline values after 4-6 weeks. The LH and FSH responses to GnRH were diminished by chronic administration of DHT-hp to pubertal boys at 3-week intervals for 15 weeks. The affinity of DHT-hp was 100 times less than the affinity of DHT for the human androgen receptor, and no affinity for the estrogen receptor in breast tissue could be demonstrated. Since DHT is a nonaromatizable androgen, and neither DHT nor DHT-hp binds readily to the estrogen receptor, suppression of LH and FSH secretion by this drug probably occurs via an androgen-dependent mechanism. Receptor binding and pharmacokinetic data indicate that unesterified DHT is the active principle. DHT-hp is a useful derivative of DHT, since prompt, predictable, and sustained rises in DHT occur after its administration.

Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence. Correlation with plasma testosterone levels.

A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate (100, 200, and 200 mg/mo, respectively, for three months). Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels (-12.0 mg/dL [-0.30 mmol/L]) during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant (not necessarily directly causal) of plasma HDL-C levels during pubertal development.

Studies of molecular species of the human androgen receptor (AR): comparison of the physicochemical properties of the [3H]methyltrienolone-AR complex formed in cytosol to the complex produced in intact genital skin fibroblasts.

Two forms of the human genital skin fibroblast (GSF) androgen receptor (AR) complexed with [3H]17 alpha-methyltrienolone were compared: 1) the intact complex formed in cytosol at 4 C (broken cell or B/C complex); and 2) the complex formed in the whole cell at 37 C (W/C complex). The intact form of the B/C complex was distinguished from partly degraded forms by the gel filtration profile in 0.5 M KCl. The W/C complex was considered to represent the transformed state of the receptor. The W/C complex had a smaller molecular radius than the B/C complex by gel filtration (Kav = 0.26-0.28 vs. 0.11-0.18). By low salt density gradient centrifugation, the B/C complex sedimented at 8.8S and the W/C complex at 6.6S. However, in 0.5 M KCl, each sedimented at 5.1S, and they were homogeneous, indicating that the monomeric forms differed markedly in molecular radius, but by only about 20,000 daltons in calculated mol wt (134,500 vs. 114,300 daltons). The complexes were separated from DNA, desalted, and compared by chromatography on DEAE-Sephacel and hydroxylapatite (HAP). The B/C complex bound readily to both column matrices and eluted from each as a sharp homogeneous peak: from DEAE at 172-190 mM KCl and from HAP at 123 mM phosphate. The W/C complex, however, was heterogeneous. One component did not bind to DEAE, and one eluted at 22-40 mM KCl. The W/C complex eluted from HAP as a peak at 42 mM, with a shoulder at 102 mM phosphate. Thus, transformation of the human genital skin fibroblast androgen receptor involves a major decrease in molecular radius and loss of negative charge with a possible loss of a 20,000-dalton macromolecular component.

Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate.

Four boys with persistent pubertal gynecomastia were given intramuscular dihydrotestosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradiol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period. Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.

Cytosol androgen receptor (AR) in human skin fibroblasts: characterization of the binding reaction and differentiation from androgen binding molecules of lower affinity.

Androgen binding was studied in cytosol of human fibroblasts at 4 degrees C. When 5 alpha-dihydrotestosterone (DHT) was the ligand, a curvilinear Scatchard plot was seen, which was resolved into two components: I the androgen receptor (AR), Kd = 0.12-0.44 nM, and II a low affinity species, Kd = 6.3-28 nM. The same cytosol demonstrated only type I binding for 3H-methyltrienolone (MTr), Kd = 0.10-0.40 nM. The AR, i.e., 3H-MTr binding activity, eluted at 440,000 d by gel filtration chromatography in pre-labeling and post-labeling experiments. When the ligand was 3H-DHT, binding activity in the 10,000-45,000 d range was seen in addition to AR. Thus, saturable nonreceptor steroid binding was seen for DHT but not for MTr. The latter is the preferred ligand for the study of the AR in this system.

Abnormality of intracellular 5 alpha-dihydrotestosterone binding in simple hypospadias: studies on equilibrium steroid binding in sonicates of genital skin fibroblasts.

A method was developed for the measurement of the binding of [3H]5 alpha-dihydrotestosterone, [3H]DHT and other steroids at equilibrium with intracellular androgen receptor of genital skin fibroblasts. This method utilized 0.2 M Na2MoO4 to stabilize the receptor and Sephadex G-25 chromatography to eliminate steroid metabolism. This binding protein showed the expected limited capacity, high affinity, and specificity of an androgen receptor. Using this method, penile skin cultures from 26 infants with simple hypospadias (HS) were compared with 18 controls. The [3H]DHT binding capacity (Bmax) was 10.1 +/- 1.3 (+/- SE) fmol/mg protein for controls and 6.1 +/- 1.7 for HS. The two populations were significantly different by Mann-Whitney test (P less than 0.001). Equilibrium dissociation constant was similar for both groups. Surprisingly, there was no correlation between Bmax and the severity of the anatomic defect. Bmax was below the values seen in HS for two of three infants with male pseudohermaphroditism. In complete androgen insensitivity, DHT binding was unmeasurable. A subgroup exists in HS with an abnormality of intracellular androgen receptors. The lack of correlation between severity of hypospadias and Bmax suggests that additional factors, such as differences in physicochemical properties of the receptor or factors present in utero, contribute to the development of HS.

Renal hypoprostaglandism, hypertension, and type IV renal tubular acidosis reversed by furosemide.

A 13-year-old white girl with severe hypertension and type IV renal tubular acidosis had decreased renal chloride clearance and exaggerated sodium chloride reabsorption by the ascending limb of Henle during hypotonic saline diuresis. Urinary prostaglandin E2 excretion was markedly diminished and often undetectable (0 to 37 ng/24 h). Treatment with oral furosemide completely reversed the hypertension and hyperkalemic acidosis, and effected a 20-fold rise in urinary prostaglandin E2. Sodium chloride reabsorption by the thick ascending limb of Henle decreased from 93.5% to 79.3%. Renal hypoprostaglandism may have a pathogenic role in this syndrome by enhancing chloride reabsorption in the ascending limb of Henle leading to extracellular fluid volume expansion, hypertension, and suppression of the renin-angiotensin-aldosterone axis. The therapeutic effects of furosemide may be partially mediated by enhancing the biosynthesis of renal prostaglandins or inhibiting their breakdown.

Cortisol and its possible role in regulation of sodium and potassium in human milk.

Cortisol (F), Na, and K were measured in human milk samples taken every 4 h during 28 24-h cycles in 19 subjects. F in milk, measured by radioimmunoassay of unchromatographed extracts, demonstrated a circadian variation similar to that of plasma F and was dexamethasone-suppressible. Values ranged from 220 +/- 41 (SE) ng/dl at 2300 h to 1,214 +/- 210 at 0700 h. When milk extracts were chromatographed, a similar circadian variation was seen, and F ranged from 87 +/- 27 (SE) ng/dl at 2300 h to 784 +/- 164 at 700 h. The morning values of F exceeded previous estimates of corticosteroid binding capacity in milk, indicating the possibility of significant levels of unbound F. The subjects were divided into three groups according to time postpartum: I, 3.5-6 wk; II, 8-18 wk, and III, 20-32 wk. In milk, normalized values of F (unchromatographed) and electrolytes (x/means) were compared, with x the value at time t and means the mean value for a 24-h cycle. A significant circadian variation was seen in milk for (x/means)Na, (x/means)K, (x/means)Na/K, and x/means)F. Correlation of (x/means)F with (x/means)Na 4 h later was negative in all three groups (r = -0.36 to -0.56, P less than 0.10-0.001) as was (x/means)F vs. (x/means)Na/K (r = -0.33 to -0.61, P less than 0.10-0.001); (x/means)F vs. (x/means)K 4 h later was positive (r = 0.38 to 0.52, P less than 0.05-0.001). Dexamethasone administration caused a significant decrease in milk means Na and an increase in meansK in all five subjects (P less than 0.01). Thus, milk Na and K concentrations appeared regulated by adrenal corticosteroids.

Diurnal and longitudinal variations in human milk sodium and potassium: implication for nutrition and physiology.

Human milk sodium ([Nal]) and potassium ([K)] concentrations were measured every 4 h for 24 h in 28 subjects 3.5 to 32 wk postpartum. A diurnal variation in milk Na was seen, which was reciprocal to K. Significant negative correlations between Na and K were seen in these periods: 3.5 to 6; 8 to 18, 20 to 32 wk postpartum (p less than 0.01 for each). The mean 24 h milk sodium concentrations (x(Na)) decreased between 3.5 and 18 wk postpartum (p less than 0.005 by paired t test). Changes in mean potassium (-XK) were not statistically significant. Diet apparently does not affect milk Na. Administration of a low Na diet: 10.8 +/- .9 (SD) mEq Na/day and 60 to 100 mEq K/day for 2 days did not change x(Na). But urinary Na decreased 7-fold as aldosterone increased 5-fold. No significant correlation was seen between 24 h Na excretion in urine and x(Na) in milk (n = 51). A significant positive correlation was seen between urinary K and -XK in milk (r = 0.36), p less than 0.001).