ENDOCRINE RESEARCH, 20(1), 79-87 (1994)

SUCKLING-INDUCED ATTENUATION OF PLASMA CORTISOL CONCENTRATIONS IN POSTPARTUM LACTATING WOMEN

Janet A. Arnico, MD, Jann M. Johnston, MD, Anthony H. Vagnucci, MD Department of Medicine

University of Pittsburgh School of Medicine (JAA, AHV) and Mercy Hospital of Pittsburgh (JMJ)

Pittsburgh, Pennsylvania 15261

ABSTRACT

The effect of suckling on serum cortisol concentrations was assessed in postpartum lactating women studied during serial breast feeding sessions 1-24 weeks postpartum. The mean 4 SD serum cortisol concentration at 15 min after the start of nursing, 9.8 ? 3.89 pgfdl, was significantly iower, P = 0.001, than prior to the start of nursing, 13.2 f 5.92 pg/dl, The decline in rhe serum cortisol concentratioris in the breast feeding women was not due entirely to the normal metabolism of the hormone or the normal circadian variation in cortisol secretion. These studies complement and expand upon a recent report [3] of a significant decrease in plasma adrenocorticotrophic hormone in breast feeding women studied one week postpartum. The neuroendocrine mechanisms responsible for this effect in women have yet to be defined.

INTRODUCTION

Suckling is associated with alterations in the activity of the hypothalamic-pituitary axis of animals and humans [ 11. The classical example of this phenomenon is the suckling-induced inhibition of gonadotropin releasing hormone (GnRH) release from the hypothalamus of postpartum lactational women and animals which in turn results in low circulating levels of luteinizing hormone (LH) and estradioi [ 11. The neuroendocrine mechanisms which sustain the suckling-induced suppression of GnRH are not understood but may include hormonal, as well as neuronal, inputs. Suckling may also blunt the secretion of other hormones of the hypothalamic- pituitary axis. For example, lactating rats have an attenuated circadian rhythm of corticosterone and a blunted response of corticosterone to stress, compared to non-lactating rats [2], yet the normal feedback relationship of cortisol and adrenocorticotrophic hormone, ACTH, remains intact [2]. A prior report found a significant decline in ACTH concentrations associated with an increase in oxytocin concentrations in the plasma of breast feeding women [3]. We were not aware of this latter study at the time we conducted the present study. Oxytocin, which is released in response to suckling, is known to have inhibitory effects upon ACTH and cortisol secretion in humans [4-51. Some [4-5], but not all investigators [6] . have found that exogenously administered oxytocin inhibits basal and stimulated ACTH and cortisol secretion in men.

79

Copyright 0 1994 by Marcel Dekker, Inc.

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80 AMICO, JOHNSTON, AND VAGNUCCI

A

" 0 3 6 9 1 2 1 5 Time (minutes)

15 5 weeks

8

6

4

2

0

0

6

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0 0 3 6 9 1 2 1 5

Time (minutes)

FIGURE 1

Serum cortisol and oxytocin concentrations prior to and during nursing in 4 postpartum breast feeding women. The mows indicate the initiation of infant suckling. Figure A, Subject 1; Figure B, Subject 2; Figure C, Subject 3; Figure D, Subject 4.

In the present study, we measured cortisol concentrations before and after 15 min of suckling to determine the effect of suckling upon the ACTH-cortisol axis in breast feeding, lactating women. We chose to measure cortisol concentrations in lieu of ACTH because of the greater stability of cortisol in plasma and the fact that cortisol secretion is a direct function of the plasma ACTH level.

METHODS

Six women who were breast feeding their infants were studied on one or more separate occasions (range 1-5 times) 1-24 weeks postpartum. Four women (subjects 1-4, Table I and Figures la-Id) were studied during a single 15 min mid-morning nursing period (between 0900 and 1100 hrs). Two women (subjects 5,6 - Table I) were studied during both a mid-morning

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SUCKLING-INDUCED ATTENUATION

10 B A

0 ,"I 3 4 -

s 2 - K

0 - E

81

10

8 9 weeks 14 weeks

I6

- 4

- 2

. o , 1 1 1 I I I , , , ,

20 weeks = 8 - - 5? 3 6 - 0) rl

Time (minutes)

- 10

- 5

0 6 l 2 15

Time (minutes)

FIGURE 1 Continued

feeding (0900-1 100 hrs) and the next consecutive feeding (1200-1400 hrs) of the same day, Table I. The nursing schedule was on demand by the infant with feedings every 3-4 hrs during the study. Two women bottle feeding their infants were studied as controls, Table 11. Breast feeding women ranged in age from 23 to 40 years with a mean of 28 f 3 years. All delivered vaginally except subjects 3 and 6. Subjects 1 and 5 were primiparous whereas the other women were multiparous. The two nonbreast feeding women were 23 and 33 years of age. had delivered vaginally, were multiparous, and had not previously breast fed.

Studies were performed in the Clinical Research Center of the University of Pittsburgh. Temporary indwelling catheters were placed in the ann vein of the mother at least 60 min before the first blood sample. The infants were removed from their mothers for 15 min preceding nursing at which time the infants were weighed. Blood samples, 5 ml, were taken from the mother 15 min and 1 min before nursing and every 3 min during ;I 15 min nursing episode. A fifteen minute sampling time was chosen because this was the average duration of a breast feeding session. The blood was placed in glass tubes that contained sodium heparin and had

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82

- 4

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AMICO, JOHNSTON, AND VAGNUCCI

C 1 week

O' ;J 3 6 9 12 15 l ime (minutes)

10 9 weeks I

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Tlme (minutes)

FIGURE 1 Continued

been pre-chilled on ice. Blood was centrifuged at 3,000 x g at 4°C and the plasma separated from the red blood cells and stored at -20°C until assay. Blood samples drawn at 3 min intervals were measured for oxytocin, whereas the basal and +15 min samples were measured for cortisol concentrations using previously described radioimrnunoassays [7-81. The intra- and inter-assay coefficients of variation for the cortisol assay were 5% (N=38 samples) and 7% (N=121 samples), respectively, and for the oxytocin assay were 5% and lo%, respectively. The sensitivity of the cortisol and oxytocin assays were 0.8 kig/dl and 0.5 pU/m1, respecrively.

STATISTICAL ANALYSIS

A repeated measures analysis of variance was used to analyze the data. The model included two within effects: time (basal and +I5 min) and condition (cortisol and oxytocin). Statistical significance was defined at a level of P 2 0.05.

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SUCKLING-INDUCED ATTENUATION 83

D 25

= 20 P 15

0 -

0

0

1 week 1

I I . , 1 , I

8 weeks

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20 weeks

I I I , , ,

0 3 6 9 1 2 1 5 Time (minutes)

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1 r i " 14 weeks

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-0 0 3 6 9 1 2 1 5

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FIGURE 1 Continued

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84 AMICO, JOHNSTON, AND VAGNUCCI

Weeks Postpartum Basal

2 29.0 5 11.4 9 13.8 15 7.5

9 8.1 14 7.0 20 8.6

1 9.7 9 7.8 18 9.4

1 21.8 4 18.1 8 14.1 14 16.4 20 14.1

4 (A.M.) 8.0 4 (P.M.) 10.0

4 (A.M.) 16.0 4 (P.M.) 20.0

Serum Cortisol Concentrations Before (Basal) and During (+15 min) Breast Feeding in Postpartum Lactational Women.

+15 min (% of Basal)

15.2 (52) 8.0 (70) 6.6 (48) 6.7 (89)

4.5 (55) 6.4 (91) 7.1 (83)

9.7 (100) 5.2 (67) 7.8 (83)

14.7 (67) 13.0 (72) 14.0 (99) 14.8 (90) 11.3 (80)

5.0 (63) 8.0 (80)

12.0 (75) 16.0 (80)

11 Subiect

1

4

5*

6*

Mean f SD 1 (76 f 15) 13.2 k 5.92 9.8 f 3.89

* Studied during consecutive morning and afternoon nursing sessions on the same day. I RESULTS

Basal levels of cortisol in the six women prior to nursing ranged from 7.0 - 29.0 pg/dl, mean f S.D., 13.2 f 5.92 pgjdl, Table I. Levels at 15 min after the start of nursing, when infants were still suckling, were significantly lower, 5.0 - 16.0, mean k S.D., 9.8 f 3.89 uddl, p = 0.001. Individual cortisol responses are shown in the four women studied on multiple occasions during lactation, Figure 1. During each nursing episode the cortisol level was lower after 15 min of suckling vs pre-suckling. In each woman suckling was also associated with an episodic pulsatile increase in plasma oxytocin concentrations, Figure. 1, indicative of effective afferent

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SUCKLING-INDUCED ATTENUATION 85

Week 1 19.5 18.5 (95)

Week 8

stimulation of the milk ejection reflex arc in these women. The mean f S.D. oxytocin prior to initiation of breast feeding was 0.75 k 0.06 pU/ml and at 15 min during suckling, 2.81 f 1.30, p = 0.0039.

11.0 10.0 (90)

In the two women who were studied during consecutive morning and afternoon nursing sessions of the same day (subjects 5 & 6, Table I) the cortisol concentration prior to the start of an afternoon session was higher than at the end of a morning nursing session. During both morning and afternoon nursing sessions serum cortisol concentrations declined during breast feeding. In the breast feeding group as a whole, serum cortisol concentrations declined by about 25% from baseline during 15 min of breast feeding, Table I. In contrast serum cortisol concentrations declined during 15 min of bottle feeding by only 7.5% in two women, one studied at week 1 postpartum and one studied at 8 weeks postpartum, Tnble 11.

DISCUSSION

Suckling was associated with a prompt decline in the plasma cortisol concentration of each lactating woman in this study. This acute change in plasma cortisol is not readily explained by a change in either the plasma volume or the concentration of cortisol binding globulin, neither of which would be expected to change that rapidly. The decline in serum cortisol concentrations in lactating women is not simply due to the normal circadian variation of this hormone [8,9], since in the two breast feeding women studied during consecutive morning and afternoon sessions of the same day, the baseline cortisol concentration prior to the start of the afternoon session did not continue the downslope of the mid-morning values. In fact, the plasma cortisol concentration prior to the start of the afternoon nursing session was higher than at the completion of the morning nursing session, Table I. The average decline in serum cortisol concentrations during nursing sessions was 25%, which was greater than would be predicted from the known half-life of serum cortisol, which is approximately 65 min [ 9 ] . Based upon a half-life of 65 inin, the decline in serum cortisol from baseline should be no greater than 11.5% in 15 min. Moreover, the decline in cortisol concentrations in non-breast-feeding women at cornparnble stages of lactation was = 5% at 15 min. Thus the decline in cortisol concentrations seen in the postpartum state was not due to an altered half-life or metabolic clearance rate.

Whether the suckling-induced change in cortisol concentration is occurring at the level of the adrenal gland, the pituitary gland, or the hypothalamus, was not determined in this study.

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86 AMICO, JOHNSTON, AND VAGNUCCI

Stimulation of cortisol secretion is a direct function of the plasma ACTH level and i s the only action of ACTH of established biological importance. Therefore a change in the cortisol concentration likely reflects a change in ACTH secretion, however a direct action of suckling upon adrenal gland secretion can not be excluded. Relevant to the observations in the present paper is the recent report which found a significant decline in plasma ACTH concentrations and a downward, but non-significant trend, in serum cortisol concentrations in seven women studied one week postpartum during breast-feeding [3]. The significant decrease in serum ACTH concentrations correlated with the time of peak secretion of oxytocin in these women [3],

We monitored oxytocin concentrations during nursing episodes in the present study as a peripheral marker of activation of the milk-ejection reflex [lo]. In each woman, infant suckling promoted episodic oxytocin release. Because oxytocin has been previously reported to modulate ACTH and cortisol concentrations [3,4,5] we can not exclude an effect of oxytocin upon cortisol suppression. On the other hand, a change in the cortisol concentration may be mediated by the suckling stimulus, independent of oxytocin. Our data confirm and expand Chiodera’s findings [3] in that we found statistically significant attenuation in serum cortisol concentrations and these changes in cortisol were found not only in the first week but up to 6 months postpmum.

What adaptive purpose the change in cortisol concentrations subserves in lactation is not known. We speculate that the suckling-induced decline in cortisol may have evolved to protect the infant from high ambient cortisol concentrations of the mother. The postpartum period is characterized by inordinate time demands upon the mother, constant disruption of the normal sleep/wake cycle, and the responsibility of caring for a newborn. Such stresses may activate the hypothalamic-pituitary-adrenal axis of the mother and give rise to elevated semm cortisol concentrations. Since cortisol can pass to the infant via breast milk, high concentrations of cortisol could potentially have deleterious effects upon the infant 111,121. Thus, suckling- induced inhibition of cortisol may have evolved as an adaptive mechanism to protect the infant. At present the mechanism of the attenuation in cortisol concentrations during suckling in breast feeding women remains unknown. To determine the physiological significance of these findings will require use of an experimental animal model.

ACKNOWLEDGMENTS

These studies were supported inpart by funds from the Department of Veterans Affairs (JAA) and NIH Grant RR-0056 for the Clinical Research Center of the University of Pittsburgh. Janet A. Amico is recipient of a Clinical Investigator Award, Career Development Program of the Department of Veterans Affairs. We acknowledge Janine Janosky, Ph.D. for the statistical analysis of the data, Jann McWilliams, R.N., and the staff of the Clinical Research Center for assistance with the clinical studies, and Mrs. Marge Altvater, Mrs. Michele Dobransky and Ms. Kathleen Poland for typing the manuscript. Please address correspondence to Janet A. Amico, M.D; Division of Endocrinology and Metabolism; E l 140 Biomedical Science Tower; University of Pittsburgh School of Medicine: Pittsburgh, PA 15261.

References

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2, Lightman SL, Young WS. 1989 Lactation inhibits stress-mediated secretion of corticosterone and oxytocin and hypothalamic accumulation of corticotrophin-releasing factor and enkephalin messenger ribonucleic acids. Endocrinology 124:2358-2364.

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SUCKLING-INDUCED ATTENUATION 87

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