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Breast Examination does not Elevate Serum Prolactin
FERTILITY AND STERILITY Copyright e 1980 The American Fertility Society
Vol. 33, No.1, January 1980 Printed in U.SA.
BREAST EXAMINATION DOES NOT ELEVATE SERUM PROLACTIN
JOHN JARRELL, M.D.*t STEPHEN FRANKS, M.D. ROBERT McINNES, M.D. KANGE GEMAYEL, M.D. HARVEY GUYDA, M.D. GEORGE H. ARRONET, M.D. FREDERICK NAFTOLIN, M.D. Department of Obstetrics and Gynecology, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada
Serum prolactin and cortisol levels were measured in 24 patients entering the Royal Victoria Hospital infertility center both before and after a thorough physical examination that included a pelvic examination and a search for galactorrhea in both breasts. There was no significant change in the levels of prolactin or cortisol in the group as a whole in those with normal prolactin values and those with high bq,sal prolactin values (P > 0.05). The possible role of stress in the mediation of occasional elevation of basal prolactin values is discussed in relation to the serum cortisol levels. Fertil Steril33:49, 1980
It had been noted at the Royal Victoria Hospital infertility center that the frequency of an elevated initial prolactin sample appeared unusually high. When these patients were subsequently studied, the majority were found to have normal serum prolactin values. It was suggested that the breast or pelvic examination, stress of the occasion, or possibly some other factor might produce this initial elevation of the serum prolactin value. To study this question, both serum prolactin and serum cortisol measurements were obtained before and shortly after physical examinations of patients entering the center for the first time.
The relationship between physical stimulation of the breasts and subsequent changes in serum prolactin levels has been investigated in both puerperal and nonpuerperal women. l , 2 In nonpuerperal women, the response is poorly understood. It has been demonstrated by several investigators that there is a consistent elevation of prolactin levels after such manipulation in normal women,2 whereas others have found that such an increase occurs in only approximately one-third of normal women. 3 These studies suggested the possibility that increases in serum prolactin levels are mediated by a neural reflex present only in some women. Recently it was observed that prolactin levels were often elevated during and after certain procedures of a gynecologic nature, and it was suggested that these elevations were a consequence of stress. 4 Other stress-related parameters were not mentioned, e.g., changes in serum cortisol levels.
MATERIALS AND METHODS
From December 8, 1977, to January 12, 1978, 24 patients admitted to the infertility center at the Royal Victoria Hospital were included in the study. Other than the fact that these patients had been referred for infertility, there was noselection process and all women who were admitted to the center during that period were entered in the protocol. Informed consent was obtained in all cases. The protocol consisted of a complete history followed by a venipuncture for measurement of pro-
Received March 6, 1979; revised June 14, 1979; accepted July 18,1979. *R. S. McLaughlin Fellow, McGill University, 1977-1979. tPresent address and address for reprint requests: John Jarrell, M.D., Department of Obstetrics and Gynecology, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada.
49
JARRELL ET AL.
50
lactin and cortisol levels. A complete physical examination was then performed which included, in each case, an examination for galactorrhea. Ten minutes after the examination, a second blood sample was obtained by venipuncture for measurement of both serum prolactin and cortisol levels. All examinations were carried out between 10 A.M. and 1 P.M. Cortisol levels were measured courtesy of Dr. S. Solomon and Dr. S. Mulay, utilizing a Gammocoat (1251) cortisol radioimmunoassay kit from Clinical Assays, Travenol Laboratories, Cambridge, Mass. 5 Normal values for this technique are 15 to 29 I-Lg/100 ml at 8 A.M. and 5 to 20 I-Lg/lOO ml at 4 P.M. Prolactin values were measured courtesy of Dr. H. Guyda, using standard6 and reagents from the National Institute of Arthritis, Metabolism and Digestive Diseases. The normal range in that laboratory for women in the reproductive age is 0 to 25 ng/ml. Statistical analysis of changes after examination was done with the paired t-test. Breast examinations were carried out in a standardized fashion by four different physicians. After an examination for neoplasia, all four quadrants of each breast were pressed and pressure was directed toward the nipple. The areola was firmly yet gently compressed, an action which caused discomfort in most but not all women. Galactorrhea TABLE 1. Summary of the Clinical Parameters of Each Patient and the Associated Prolactin and Cortisol Values before and after Breast Examination Patient Day of cycle
Cycle length
Galactorrhea
day.
1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20 21 22 23 24
25 22 24 13 4 21 6 7 7 20 19 40
28 28 28 29 28 24 28 24 28 28 28
13 25 27 Irregular 14 27 6 28 24 3 21 28 Amenorrhea 19 Irregular 17 Irregular
6 19
30 28
After
nglml
+
+
45
11 Irregular
Prolactin Before
+ +
+
+ +
46 34 36 37 45 28 26 29 19 16 21 21 19 20 15 22 7 23 24 15 9 23 17 18
Cortisol Before
After
JJ.II1100ml
40 30 33 39 43 28 22 22 15 14 51 27 19 17 15 30 6 21 22 15 10
20 16 18
25 8 30 41 15 16 10 12 13 12 13 27 12 17 10
9 12 14 15 6 2 20 10 17
24 29 32 41 9 28 8 10 16 14 26 19 14 18 7 14 21 25 11
6 3 16 8 13
January 1980
-
50
40
E
.......
5
-4
3 3.----:: •
30
c:
40
E
0 0
30, Cl ~
..J
1.
Z
« ..J
4-
4
Cl
i= u
50
0
en
i=
20 It:
20
0
0
U
It: ~
10
•
...
10
•
•
.---_.
PROLACTIN
CORTISOL
FIG. 1. The absence of a response of serum prolactin and cortisol to breast examination is demonstrated. Numbers by each point indicate patients having elevated basal levels of prolactin.
was defined as the expression of a white milky fluid after these manipulations. Patients found to have elevated basal serum prolactin levels were further investigated. When prolactin values were found to be high on repeated samplings, infusions of thyrotropin-releasing factor and sellar polytomography were carried out to assess pituitary function. RESULTS
During the period of the study, 24 patients were evaluated. The relevant data concerning the clinical characteristics of the group and the response of the serum prolactin and cortisol levels to examination are presented in Table 1. Of the 24 patients, 18 had regular cycles, 5 had irregular cycles, and 1 was amenorrheic. Of seven patients found to have galactorrhea, only one had an associated high serum prolactin level. Eight patients were found to have elevated basal prolactin values, and in six the elevation was sustained in the second sample. Over-all, there was no change in the serum prolactin level (23.7 ± 2.0 ng/ml versus 23.8 ± 2.2
BREAST EXAMINATION DOES NOT ELEVATE SERUM PROLACTIN
Vol. 33, No.1
ng/mI) or serum cortisol level (15.4 ± 1.7 jJ.g/100 ml versus 17.1 ± 1.9 jJ.g/100 mI) in response to examination. Of 18 patients with normal basal prolactin levels there was no change in serum prolactin (18.0 ± 1.2 ng/ml versus 19.7 ± 2.5 ng/mD or serum cortisol levels (13.3 ± 1.4 jJ.g/lOO ml versus 14.4 ± 1.6 jJ.g/lOO mI). Similarly, the eight patients with elevated basal prolactin values failed to demonstrate a change in serum prolactin (35.1 ± 2.6 ng/ml versus 32.1 ± 2.8 ng/mI) or cortisol levels (19.6 ± 4.6 jJ.g/100 ml versus 22.6 ± 4.3 jJ.g/100 mI). Only 1 patient of the 24 (patient 11) demonstrated a marked increase in the serum prolactin value and this was associated with an increase in the serum cortisol level from 13 to 26 jJ.g/100 ml. Additional studies were performed on the eight patients with elevated basal prolactin levels. Two patients (patients 1 and 5) were found to have pituitary microadenomas on pituitary polytomography. Four patients (patients 2, 3, 4, and 6) had high prolactin values basally, and all four had either high or rising cortisol levels. Significantly, two of these four women had normal repeat prolactin values and the other two became pregnant within 1 month without medical intervention. The remaining patients (patients 7 and 8) did not show persistently elevated prolactin levels. DISCUSSION
It is apparent from these data that over a 10minute period there is no significant effect of breast, pelvic, or general examination on the serum prolactin level. Of interest, however, is the frequency of basal hyperprolactinemia in this population, which is higher than that generally observed. Although the number of patients is low and substantiation of the conclusions is difficult, it
51
is of interest that four of the eight hyperprolactinemic patients had high or rising serum cortisol values. This finding is in keeping with the hypothesis that stress may provoke a high incidence of hyperprolactinemia in this population and that stress occurs prior to physical examination. This is certainly in keeping with the hypothesis presented by Koninckx4 and Noel et al. 7 but is at variance with the data of Kolodny et al. 2 In order to explore the role of stress more definitively, further studies will require more patients studied for longer periods of time and with more frequent sampling of blood. It will also be important in future to include a group of women who have attended an infertility center for some time as a control population.
Acknowledgments. The authors wish to acknowledge the assistance of Dr. Bernard Robaire and Dr. George Tolis in the preparation of the manuscript, and the assistance of Dr. E. Hamilton, Dr. V. Senikas, Dr. N. Brassard, and Mrs. S. Fernandez. REFERENCES 1. 'llysonJE, Hwang P, Guyda H, Friesen H: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14, 1972 2. Kolodny RC, Jacobs LS, Daughaday WH: Mammary stimulation causes prolactin secretion in non-lactating women. Nature 238:284, 1972 3. Frantz AG: Prolactin. N Engl J Med 298:201, 1978 4. Konickx P: Stress hyperprolactinemia in clinical practice. Lancet 1:273, 1978 5. Technical Bulletin 6012279: Clinical Assays. Travenol Laboratories, Cambridge, Mass, January 22,1979 6. Hwang P, Guyda H, Friesen H: A radioimmunoassay for human prolactin. Proc Nat! Acad Sci USA 68:1902,1971 7. Noel GL, Suh HK, Stone JG, Frantz AG: Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 35:840, 1972
Vol. 33, No.1, January 1980 Printed in U.SA.
BREAST EXAMINATION DOES NOT ELEVATE SERUM PROLACTIN
JOHN JARRELL, M.D.*t STEPHEN FRANKS, M.D. ROBERT McINNES, M.D. KANGE GEMAYEL, M.D. HARVEY GUYDA, M.D. GEORGE H. ARRONET, M.D. FREDERICK NAFTOLIN, M.D. Department of Obstetrics and Gynecology, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada
Serum prolactin and cortisol levels were measured in 24 patients entering the Royal Victoria Hospital infertility center both before and after a thorough physical examination that included a pelvic examination and a search for galactorrhea in both breasts. There was no significant change in the levels of prolactin or cortisol in the group as a whole in those with normal prolactin values and those with high bq,sal prolactin values (P > 0.05). The possible role of stress in the mediation of occasional elevation of basal prolactin values is discussed in relation to the serum cortisol levels. Fertil Steril33:49, 1980
It had been noted at the Royal Victoria Hospital infertility center that the frequency of an elevated initial prolactin sample appeared unusually high. When these patients were subsequently studied, the majority were found to have normal serum prolactin values. It was suggested that the breast or pelvic examination, stress of the occasion, or possibly some other factor might produce this initial elevation of the serum prolactin value. To study this question, both serum prolactin and serum cortisol measurements were obtained before and shortly after physical examinations of patients entering the center for the first time.
The relationship between physical stimulation of the breasts and subsequent changes in serum prolactin levels has been investigated in both puerperal and nonpuerperal women. l , 2 In nonpuerperal women, the response is poorly understood. It has been demonstrated by several investigators that there is a consistent elevation of prolactin levels after such manipulation in normal women,2 whereas others have found that such an increase occurs in only approximately one-third of normal women. 3 These studies suggested the possibility that increases in serum prolactin levels are mediated by a neural reflex present only in some women. Recently it was observed that prolactin levels were often elevated during and after certain procedures of a gynecologic nature, and it was suggested that these elevations were a consequence of stress. 4 Other stress-related parameters were not mentioned, e.g., changes in serum cortisol levels.
MATERIALS AND METHODS
From December 8, 1977, to January 12, 1978, 24 patients admitted to the infertility center at the Royal Victoria Hospital were included in the study. Other than the fact that these patients had been referred for infertility, there was noselection process and all women who were admitted to the center during that period were entered in the protocol. Informed consent was obtained in all cases. The protocol consisted of a complete history followed by a venipuncture for measurement of pro-
Received March 6, 1979; revised June 14, 1979; accepted July 18,1979. *R. S. McLaughlin Fellow, McGill University, 1977-1979. tPresent address and address for reprint requests: John Jarrell, M.D., Department of Obstetrics and Gynecology, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada.
49
JARRELL ET AL.
50
lactin and cortisol levels. A complete physical examination was then performed which included, in each case, an examination for galactorrhea. Ten minutes after the examination, a second blood sample was obtained by venipuncture for measurement of both serum prolactin and cortisol levels. All examinations were carried out between 10 A.M. and 1 P.M. Cortisol levels were measured courtesy of Dr. S. Solomon and Dr. S. Mulay, utilizing a Gammocoat (1251) cortisol radioimmunoassay kit from Clinical Assays, Travenol Laboratories, Cambridge, Mass. 5 Normal values for this technique are 15 to 29 I-Lg/100 ml at 8 A.M. and 5 to 20 I-Lg/lOO ml at 4 P.M. Prolactin values were measured courtesy of Dr. H. Guyda, using standard6 and reagents from the National Institute of Arthritis, Metabolism and Digestive Diseases. The normal range in that laboratory for women in the reproductive age is 0 to 25 ng/ml. Statistical analysis of changes after examination was done with the paired t-test. Breast examinations were carried out in a standardized fashion by four different physicians. After an examination for neoplasia, all four quadrants of each breast were pressed and pressure was directed toward the nipple. The areola was firmly yet gently compressed, an action which caused discomfort in most but not all women. Galactorrhea TABLE 1. Summary of the Clinical Parameters of Each Patient and the Associated Prolactin and Cortisol Values before and after Breast Examination Patient Day of cycle
Cycle length
Galactorrhea
day.
1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20 21 22 23 24
25 22 24 13 4 21 6 7 7 20 19 40
28 28 28 29 28 24 28 24 28 28 28
13 25 27 Irregular 14 27 6 28 24 3 21 28 Amenorrhea 19 Irregular 17 Irregular
6 19
30 28
After
nglml
+
+
45
11 Irregular
Prolactin Before
+ +
+
+ +
46 34 36 37 45 28 26 29 19 16 21 21 19 20 15 22 7 23 24 15 9 23 17 18
Cortisol Before
After
JJ.II1100ml
40 30 33 39 43 28 22 22 15 14 51 27 19 17 15 30 6 21 22 15 10
20 16 18
25 8 30 41 15 16 10 12 13 12 13 27 12 17 10
9 12 14 15 6 2 20 10 17
24 29 32 41 9 28 8 10 16 14 26 19 14 18 7 14 21 25 11
6 3 16 8 13
January 1980
-
50
40
E
.......
5
-4
3 3.----:: •
30
c:
40
E
0 0
30, Cl ~
..J
1.
Z
« ..J
4-
4
Cl
i= u
50
0
en
i=
20 It:
20
0
0
U
It: ~
10
•
...
10
•
•
.---_.
PROLACTIN
CORTISOL
FIG. 1. The absence of a response of serum prolactin and cortisol to breast examination is demonstrated. Numbers by each point indicate patients having elevated basal levels of prolactin.
was defined as the expression of a white milky fluid after these manipulations. Patients found to have elevated basal serum prolactin levels were further investigated. When prolactin values were found to be high on repeated samplings, infusions of thyrotropin-releasing factor and sellar polytomography were carried out to assess pituitary function. RESULTS
During the period of the study, 24 patients were evaluated. The relevant data concerning the clinical characteristics of the group and the response of the serum prolactin and cortisol levels to examination are presented in Table 1. Of the 24 patients, 18 had regular cycles, 5 had irregular cycles, and 1 was amenorrheic. Of seven patients found to have galactorrhea, only one had an associated high serum prolactin level. Eight patients were found to have elevated basal prolactin values, and in six the elevation was sustained in the second sample. Over-all, there was no change in the serum prolactin level (23.7 ± 2.0 ng/ml versus 23.8 ± 2.2
BREAST EXAMINATION DOES NOT ELEVATE SERUM PROLACTIN
Vol. 33, No.1
ng/mI) or serum cortisol level (15.4 ± 1.7 jJ.g/100 ml versus 17.1 ± 1.9 jJ.g/100 mI) in response to examination. Of 18 patients with normal basal prolactin levels there was no change in serum prolactin (18.0 ± 1.2 ng/ml versus 19.7 ± 2.5 ng/mD or serum cortisol levels (13.3 ± 1.4 jJ.g/lOO ml versus 14.4 ± 1.6 jJ.g/lOO mI). Similarly, the eight patients with elevated basal prolactin values failed to demonstrate a change in serum prolactin (35.1 ± 2.6 ng/ml versus 32.1 ± 2.8 ng/mI) or cortisol levels (19.6 ± 4.6 jJ.g/100 ml versus 22.6 ± 4.3 jJ.g/100 mI). Only 1 patient of the 24 (patient 11) demonstrated a marked increase in the serum prolactin value and this was associated with an increase in the serum cortisol level from 13 to 26 jJ.g/100 ml. Additional studies were performed on the eight patients with elevated basal prolactin levels. Two patients (patients 1 and 5) were found to have pituitary microadenomas on pituitary polytomography. Four patients (patients 2, 3, 4, and 6) had high prolactin values basally, and all four had either high or rising cortisol levels. Significantly, two of these four women had normal repeat prolactin values and the other two became pregnant within 1 month without medical intervention. The remaining patients (patients 7 and 8) did not show persistently elevated prolactin levels. DISCUSSION
It is apparent from these data that over a 10minute period there is no significant effect of breast, pelvic, or general examination on the serum prolactin level. Of interest, however, is the frequency of basal hyperprolactinemia in this population, which is higher than that generally observed. Although the number of patients is low and substantiation of the conclusions is difficult, it
51
is of interest that four of the eight hyperprolactinemic patients had high or rising serum cortisol values. This finding is in keeping with the hypothesis that stress may provoke a high incidence of hyperprolactinemia in this population and that stress occurs prior to physical examination. This is certainly in keeping with the hypothesis presented by Koninckx4 and Noel et al. 7 but is at variance with the data of Kolodny et al. 2 In order to explore the role of stress more definitively, further studies will require more patients studied for longer periods of time and with more frequent sampling of blood. It will also be important in future to include a group of women who have attended an infertility center for some time as a control population.
Acknowledgments. The authors wish to acknowledge the assistance of Dr. Bernard Robaire and Dr. George Tolis in the preparation of the manuscript, and the assistance of Dr. E. Hamilton, Dr. V. Senikas, Dr. N. Brassard, and Mrs. S. Fernandez. REFERENCES 1. 'llysonJE, Hwang P, Guyda H, Friesen H: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14, 1972 2. Kolodny RC, Jacobs LS, Daughaday WH: Mammary stimulation causes prolactin secretion in non-lactating women. Nature 238:284, 1972 3. Frantz AG: Prolactin. N Engl J Med 298:201, 1978 4. Konickx P: Stress hyperprolactinemia in clinical practice. Lancet 1:273, 1978 5. Technical Bulletin 6012279: Clinical Assays. Travenol Laboratories, Cambridge, Mass, January 22,1979 6. Hwang P, Guyda H, Friesen H: A radioimmunoassay for human prolactin. Proc Nat! Acad Sci USA 68:1902,1971 7. Noel GL, Suh HK, Stone JG, Frantz AG: Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 35:840, 1972