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Circadian variation in plasma prolactin, gonadotropins, and testosterone in diabetic male patients with and without impotence*
FERTILITY AND STERILITY Copyright © 1981 The American Fertility Society
Vol. 35, No.6, June 1981 Printed in U.8A.
CIRCADIAN VARIATION IN PLASMA PROLACTIN, GONADOTROPINS, AND TESTOSTERONE IN DIABETIC MALE PATIENTS WITH AND WITHOUT IMPOTENCE*
ADINA ZEIDLER, M.D.t RONALD GELFAND, M.D. JOSEPH DRAUS, M.Sc. JUDITH K. TAUSCHER, M.Sc. RICHARD T. CHOPP, M.D.:j: Departments of Medicine, Psychiatry, and Urology, University of Southern California School of Medicine, Los Angeles, California 90033
The circadian variation in plasma levels of prolactin, gonadotropins, testosterone, and glucose were studied in 10 young diabetic male patients. Four patients were asymptomatic without sexual dysfunction and six patients had organic impotence. The results of this study indicate that diurnal levels of luteinizing hormone, folliclestimulating hormone, prolactin, and testosterone are similar in diabetic patients with and without impotence. During the nocturnal period, a sleep-related increase in plasma prolactin levels was noted in diabetic patients without impotence. In diabetic patients with impotence, plasma prolactin levels were similar during the diurnal and nocturnal periods. These results further support previous findings that diabetic patients with organic impotence do not have abnormal gonadotropin and testosterone levels. Fertil Steril35:653, 1981
The 24-hour secretory patterns of several anterior pituitary hormones are known to be regulated by the central nervous system and to be sleep-related. 1 Of interest are the secretory diurnal variations of prolactin,2-4 growth hormone,5 and luteinizing hormone. 6 Lack of circadian periodicity of plasma prolactin has been demonstrated in Cushing's disease, hypothalamic tumors,7 and in a group of poorly controlled diabetic patients. 8 The mechanism for the lack of a sleepassociated increase in prolactin levels of patients with diabetes mellitus is unclear, and a possible mechanism of hypothalamic involvement has been considered.
Although there is controversy about whether luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are secreted in a circadian rhythm, 9 testosterone levels have been found to increase during the night in normal adult males. 10 Since the reproductive capacity of men with diabetes mellitus is thought to be impaired,l1 it was of interest to study 24-hour patterns of plasma prolactin (PRL), testosterone, FSH, LH, and plasma glucose in male diabetic patients with and without impotence. PATIENTS AND METHODS
Ten diabetic insulin-treated male patients, age 19 to 36 years, attending the diabetic outpatient clinic at the Los Angeles County-University of Southern California Medical Center, agreed to participate in the study. The patients were in stable diabetic control without clinical or laboratory evidence of ketosis. The patients were free of intercurrent illness, endocrine disease, and liver or kidney disease. Informed consent was obtained
Received October 12, 1980; revised and accepted January 14,1981. *Supported in part by Grant RR-43 from the United States Public Health Service. tReprint requests: Adina Zeidler, M.D., Diabetes Research Laboratory, USC School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. :j:Present address: Department of Urology, New York Medical College, Valhalla, New York.
653
ZEIDLER ET AL.
654
from all subjects. after the patients became familiar with the protocol and accepted the investigation. The patients were admitted to the clinical research center and their usual insulin doses and American Diabetes Association diets were continued. Every patient underwent a complete physi~ cal and neurologic examination. Four of the ten patients had normal libido and potentia, and results of their neurologic examinations were normal. Cystometrography performed on three of these four patients revealed normal sensation during filling, normal bladder volumes, and normal detrusor pressures during attempts to void. These cystometrograms were considered to be within the normal range. All of the other six patients had symptoms of sexual dysfunction manifested by complete impotence (four patients) and decreased ability to maintain erections with a history of retrograde ejaculation (two patients). The detailed neurologic examination revealed lack of ankle reflex with decreased sensation in three patients, and, in one, a lack of knee reflexes as well. The two patients with decreasing ability to maintain erections had normal neurologic examinations. Cystometrograms obtained in this group of six patients demonstrated findings consistent with autonomic bladder dysfunction. This was manifested by decreased sensation during the filling phase, poor detrusor tone during the evacuation or voiding phase, and urinary residuals of 30 to 70 ml, indicating impaired conduction in the afferent and efferent axons of the detrusor muscle.
June 1981
A detailed sexual history was taken from each patient during a psychiatric interview in order to evaluate the possibility of psychogenic impotence. In two-thirds of the patients, the sexual history was substantiated by the spouse or sexual partner. Follow-up interviews were conducted during the next 6 months, once every 4 weeks; no changes in the baseline· findings were demonstrated. Criteria for diagnosing organic impotence were characterized by (1). persistent and/or progressive worsening of sexual dysfunction, irrespective of sexual stimulation (in the absence of any drugs), and (2) an insidious onset of symptoms. 12 After the complete history, physical examination, and .detailed psychiatric consultation, the patients were divided into two groups: group A (n = 4), insulin~treated diabetic patients without impotence, and group B (n = 6), insulin-treated diabetic patients with impotence. On the day of admission to the clinical research center, urine was tested for glucose and ketones four times per day, and blood samples for plasma glucose determinations were obtained at 8:00 A.M., 12:00 noon, and 4:00 P.M. Each patient became familiar with his environment and slept well the first night; the next day, at 7:30 A.M., a 19-9auge butterfly needle was inserted into an antecubital vein which was kept open with a slow intravenous saline drip. Each patient received breakfast and his usual insulin dose. Beginning at 8:00 A.M., a blood sample was obtained every 2 hours 13 for a 24-hour period for determination of plasma PRL, FSH, LH, testosterone, and glucose.
TABLE 1. Clinical Data on the Diabetic Patients Who Participated in the Study for Circadian Variation in Plasma Levels of Prolactin, LH, FSH, Testosterone, and Glucose Patient and group'
Group A 1 2 3 4 Mean ± SEM Group B 5 6
Age
Duration of diabetes
Treatment insulinl24 hrb
Blood urea nitrogen
Blood pressure
yr
yr
units
mg/dl
mmhG
22
3 17 16 8
8 8. 10
120/70 124/78 104/70
15 10.3 ± 1.7
110/70
15 13
130/70 120/70
15
110/80
14
110/70
36 19 21 24 ± 4
11 ± 3
36 36
0.5 1
7
22
12
8
22
8
9 10 Mean ± SEM
32 27 29 ± 3
9 7 6 ± 2
NPH, 35, A.M. NPH, 44, A.M. Lente, 30, A.M. Semilente, 10, A.M. Lente (pork), 40, A.M. NPH, 16, A.M. NPH, 70, A.M. CZI, 15, A.M. NPH, 40, A.M. CZI, 15, A.M. NPH, 22, A.M. NPH, 12, P.M. NPH, 60, A.M. NPH, 37, A.M.
"group A, Asymptomatic diabetic patients; group B, impotent diabetic patients. bNPH, neutral protamine Hagedorn insulin; CZI, crystalline zinc insulin,
19 16 15.3 ± 1
125/80
655
CIRCADIAN VARIATION OF HORMONES IN DIABETIC MALES
Vol. 35, No.6
The sampling during the night was carried out with extreme caution and the patients slept well during the night of the study. The blood was immediately separated and the plasma was stored at - 60° C until assayed. Plasma glucose was determined with a Beckman' glucose analyzer (Beckman Co., Irvine; Calif.). Plasma prolactin levels were determined with a double-antibody radioimmunoassay,14 LH and FSH by the method described by Odell et al.,15, 16 and testosterone by a radioimmunoassay described previously by Kinouchi et aT. 17 Samples from each subject were measured in duplicate in a single assay. Statistical significance was determined with Student's
t-test. 18
__ Group A 0--0
16
E ..... Cl C
12
z
i=
() c( ...J
8
oa:
Group B
*
• p<.05
r
I \1 I )--J 1,\ ',t, )-/1"<',Llj-,-(1 *
1'-.,/i ,/· 1'1..-1
Il.
4~~--~----~--~--~----~---+
14
E ..... ;:,
E
10
J:
...J
RESULTS
The clinical data on the patients studied are presented in Table 1. No significant differences between the two groups were noted for age or duration of diabetes. All diabetic patients were stable during the study, with moderate glycosuria and without ketonuria. The circadian patterns of 'plasma PRL, LH, FSH, testosterone, and glucose during the study period are shown in Figure 1. A sleep-related increase was found in PRL concentrations in group A with the highest levels at 2:00 A.M. (12.9 ± 1.5 ng/ml versus 7.9 ± 1 ng/ml; P < 0.05) and 6;00 A.M. (15.2 ± 1.6 ng/ml versus 9 ± 1.1 ng/ml; P < 0.05); however, no sleep-related increase in PRL levels could be demonstrated in diabetic patients with impotence (group B). Plasma LH levels were similar in both groups of patients during the diurnal and nocturnal periods. Plasma FSH levels were comparable in both groups of patients during the study. Plasma testosterone levels increased during the nocturnal period in the asymptomatic diabetic patients (group A) at 2:00 A.M. and 6:00 A.M.; however, there were no significant differences between groups. Plasma glucose levels were increased and similar in both groups of patients during the diurnal period. During the nocturnal period, plasma glucose levels decreased to nearly normal at 4:00 A.M. and 6:00 A.M. No hypoglycemic levels were noted during the study, and plasma glucose levels were comparable in both groups of patients (Fig. 1). DISCUSSION
Our results demonstrate that asymptomatic diabetic male patients without impotence had normal variations of plasma prolactin concentrations
E .... ;:,
5.0
E
3.0
J:
U)
II..
1200
:c.....
~1000 w
z
oa:
w
800
I-
U)
~' 600 U)
W I-
:c....
300
Cl
E 200 Cl Il. 100L-~--~----~--~--~----~---,
0800
1200 1600 2000 2400 0400 0800 TIME
~Ce:;~ +-Nocturnal'"
FIG. 1. Circadian variation in plasma PRL, LH"FSH; testosterone, and glucose (PG) in young diabetic male patients with and without impotence. Data are expressed as means ± standard error of the mean. Group A, asymptomatic diabetic patients; group B, impotent diabetic patients.
during the daytime, but had significantly increased levels during sleep. In contrast, there was no increase in nocturnal prolactin levels in diabetic patients with impotence. These results are
656
ZEIDLER ET AL.
in agreement with a previous study by Drejer et al. 8 which failed to demonstrate an increase in prolactin levels during sleep in five of six poorly controlled insulin-treated diabetic male patients. However, whether those patients had abnormal sexual function was 'not mentioned. The mechanism of lack of nocturnal sleep-related increase in prolactin levels in diabetic patients with impotence is not clear. Increased circulating insulin levels inducing hyperprolactinemia during the nocturnal period in the asymptomatic diabetic patients could be considered; however, both groups of patients had similar plasma glucose levels, and hypoglycemia was not demonstrated. The possibility of altered hypothalamic pituitary function has been proposed to explain the differences in prolactin release in diabetic patients. 8 The release patterns of LH and FSH in insulintreated diabetic male patients have not been previously reported. In normal adult men, the release of gonadotropins has been assessed in certain studies, with no significant circadian variation. 15 Our data demonstrate that LH and FSH in insulin-treated diabetic men are not secreted with a circadian rhythm. These results are in agreement with studies performed in normal male subjects. 9 , 13, 15 Testosterone levels in diabetic men with and without impotence appeared to be normal as demonstrated in our 24-hour sampling. These data confirm previous studies in impotent diabetic male patients when infrequent sampling of testosterone was performed. Our results further support the finding that diabetic male patients with and without impotence have normal basal and diurnal variations of gonadotropin and testosterone levels. However, the lack of a sleep-related nocturnal increase in prolactin levels in this small group of diabetic patients is not readily explainable. It is possible that a change in sleep patterns or an altered hypothalamic-pituitary axis is related to the lack of sleep-related prolactin response in impotent diabetic patients, and additional studies are warranted.
June 1981 REFERENCES 1. PorterJC, Ben-Jonathan N: Neuroendocrine mechanisms involved in biorhythms. In Biorhythms and Human Re-
2.
3. 4.
5. 6.
7.
8.
9.
10.
11.
12. 13.
14.
15.
16.
17. Acknowledgments. We are grateful to Dr. Richard Horton for his helpful advice and to the Nichols Institute, Wilmington, Calif., for their help with the assays. Expert secretarial assistance was provided by Ms. Barbara Adamcik.
18.
production, Edited by MFerin, F Halberg, RM Richart, R Vande Wiele. New York, John Wiley & Sons, 1974, p 607 Sassin JF, Frantz AG, Weitzman ED, Kapen S: Human prolactin: 24-hour pattern with increased release during sleep. Science 177:1205, 1972 Sassin JF, Frantz AG, Kapen S, Weitzman ED: The nocturnal rise of human prolactin is dependent on sleep. J Clin Endocrinol Metab 27:326, 1973 Nokin J, Vekemans M, L'Hermite M, Robyn C: Circadian periodicity of serum prolactin concentration in man. Br Med J 3:561, 1972 Takahashi Y, Kipnis DM, Daughaday WH: Growth hormone secretion during sleep. J Clin Invest 47:2079,1968 Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman ED, Hellman L: Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 287:582, 1972 Kreiger DT, Howanitz PJ, Frantz AG: Absence of nocturnal elevation of plasma prolactin concentrations in Cushing's disease. J Clin Endocrinol Metab 42:260, 1976 Drejer J, Hendriksen C, Nielsen LM, Binder C, Hagan C, Kehlet H: Diurnal variations in plasma prolactin, growth hormone, cortisol and blood glucose in labile diabetes mellitus. Clin Endocrinol (Oxf) 6:57, 1977 Rubin RT, Gouin PR, Kales A, Odell WD: Luteinizing hormone, follicle stimulating hormone, and growth hormone secretion in normal adult men during sleep and dreaming. Psychosom Med 35:309, 1973 Rubin RT, Gouin PR, Lubin A, Roland RE, Pirke KM: Nocturnal increase of plasma testosterone in men: relation to gonadotropins and prolactin. J Clin Endocrinol Metab 40:1027, 1975 Spellacy WM: Carbohydrate metabolism in male infertility and female fertility-control patients. Fertil Steril 27:1132, 1976 Cooper AJ: The causes and management of impotence. Postgrad Med J 48:548, 1972 Swerdloff RS, Odell WD: Some aspects of the control of secretion in LH and FSH in humans. In Gonadotropins, Edited by E Rosemberg. Los Altos Calif, Geron-X, 1968, p 156 Tolis G, Goldstein M, Friesen HG: Functional evaluation of prolactin secretion in patients with hypothalamic pituitary disorders. J Clin Invest 52:783, 1973 Odell WD, Ross GT, Rayford PL: Radioimmunoassay for luteinizing hormone in human plasma or serum: physiological studies. J Clin Invest 46:248, 1967 Odell WD, Parlow AF, Cargille CM, Ross GT: Radioimmunoassay for human follicle stimulating hormone: physiological studies. J Clin Invest 47:2551, 1968 Kinouchi T, Pages L, Horton R: A specific radioimmunoassay for plasma testosterone. J Lab Clin Med 82:309, 1973 Afifi AA, Azen SP: Statistical Analysis: A Computer Oriented Approach. New York, Academic Press, 1972, p 63
Vol. 35, No.6, June 1981 Printed in U.8A.
CIRCADIAN VARIATION IN PLASMA PROLACTIN, GONADOTROPINS, AND TESTOSTERONE IN DIABETIC MALE PATIENTS WITH AND WITHOUT IMPOTENCE*
ADINA ZEIDLER, M.D.t RONALD GELFAND, M.D. JOSEPH DRAUS, M.Sc. JUDITH K. TAUSCHER, M.Sc. RICHARD T. CHOPP, M.D.:j: Departments of Medicine, Psychiatry, and Urology, University of Southern California School of Medicine, Los Angeles, California 90033
The circadian variation in plasma levels of prolactin, gonadotropins, testosterone, and glucose were studied in 10 young diabetic male patients. Four patients were asymptomatic without sexual dysfunction and six patients had organic impotence. The results of this study indicate that diurnal levels of luteinizing hormone, folliclestimulating hormone, prolactin, and testosterone are similar in diabetic patients with and without impotence. During the nocturnal period, a sleep-related increase in plasma prolactin levels was noted in diabetic patients without impotence. In diabetic patients with impotence, plasma prolactin levels were similar during the diurnal and nocturnal periods. These results further support previous findings that diabetic patients with organic impotence do not have abnormal gonadotropin and testosterone levels. Fertil Steril35:653, 1981
The 24-hour secretory patterns of several anterior pituitary hormones are known to be regulated by the central nervous system and to be sleep-related. 1 Of interest are the secretory diurnal variations of prolactin,2-4 growth hormone,5 and luteinizing hormone. 6 Lack of circadian periodicity of plasma prolactin has been demonstrated in Cushing's disease, hypothalamic tumors,7 and in a group of poorly controlled diabetic patients. 8 The mechanism for the lack of a sleepassociated increase in prolactin levels of patients with diabetes mellitus is unclear, and a possible mechanism of hypothalamic involvement has been considered.
Although there is controversy about whether luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are secreted in a circadian rhythm, 9 testosterone levels have been found to increase during the night in normal adult males. 10 Since the reproductive capacity of men with diabetes mellitus is thought to be impaired,l1 it was of interest to study 24-hour patterns of plasma prolactin (PRL), testosterone, FSH, LH, and plasma glucose in male diabetic patients with and without impotence. PATIENTS AND METHODS
Ten diabetic insulin-treated male patients, age 19 to 36 years, attending the diabetic outpatient clinic at the Los Angeles County-University of Southern California Medical Center, agreed to participate in the study. The patients were in stable diabetic control without clinical or laboratory evidence of ketosis. The patients were free of intercurrent illness, endocrine disease, and liver or kidney disease. Informed consent was obtained
Received October 12, 1980; revised and accepted January 14,1981. *Supported in part by Grant RR-43 from the United States Public Health Service. tReprint requests: Adina Zeidler, M.D., Diabetes Research Laboratory, USC School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. :j:Present address: Department of Urology, New York Medical College, Valhalla, New York.
653
ZEIDLER ET AL.
654
from all subjects. after the patients became familiar with the protocol and accepted the investigation. The patients were admitted to the clinical research center and their usual insulin doses and American Diabetes Association diets were continued. Every patient underwent a complete physi~ cal and neurologic examination. Four of the ten patients had normal libido and potentia, and results of their neurologic examinations were normal. Cystometrography performed on three of these four patients revealed normal sensation during filling, normal bladder volumes, and normal detrusor pressures during attempts to void. These cystometrograms were considered to be within the normal range. All of the other six patients had symptoms of sexual dysfunction manifested by complete impotence (four patients) and decreased ability to maintain erections with a history of retrograde ejaculation (two patients). The detailed neurologic examination revealed lack of ankle reflex with decreased sensation in three patients, and, in one, a lack of knee reflexes as well. The two patients with decreasing ability to maintain erections had normal neurologic examinations. Cystometrograms obtained in this group of six patients demonstrated findings consistent with autonomic bladder dysfunction. This was manifested by decreased sensation during the filling phase, poor detrusor tone during the evacuation or voiding phase, and urinary residuals of 30 to 70 ml, indicating impaired conduction in the afferent and efferent axons of the detrusor muscle.
June 1981
A detailed sexual history was taken from each patient during a psychiatric interview in order to evaluate the possibility of psychogenic impotence. In two-thirds of the patients, the sexual history was substantiated by the spouse or sexual partner. Follow-up interviews were conducted during the next 6 months, once every 4 weeks; no changes in the baseline· findings were demonstrated. Criteria for diagnosing organic impotence were characterized by (1). persistent and/or progressive worsening of sexual dysfunction, irrespective of sexual stimulation (in the absence of any drugs), and (2) an insidious onset of symptoms. 12 After the complete history, physical examination, and .detailed psychiatric consultation, the patients were divided into two groups: group A (n = 4), insulin~treated diabetic patients without impotence, and group B (n = 6), insulin-treated diabetic patients with impotence. On the day of admission to the clinical research center, urine was tested for glucose and ketones four times per day, and blood samples for plasma glucose determinations were obtained at 8:00 A.M., 12:00 noon, and 4:00 P.M. Each patient became familiar with his environment and slept well the first night; the next day, at 7:30 A.M., a 19-9auge butterfly needle was inserted into an antecubital vein which was kept open with a slow intravenous saline drip. Each patient received breakfast and his usual insulin dose. Beginning at 8:00 A.M., a blood sample was obtained every 2 hours 13 for a 24-hour period for determination of plasma PRL, FSH, LH, testosterone, and glucose.
TABLE 1. Clinical Data on the Diabetic Patients Who Participated in the Study for Circadian Variation in Plasma Levels of Prolactin, LH, FSH, Testosterone, and Glucose Patient and group'
Group A 1 2 3 4 Mean ± SEM Group B 5 6
Age
Duration of diabetes
Treatment insulinl24 hrb
Blood urea nitrogen
Blood pressure
yr
yr
units
mg/dl
mmhG
22
3 17 16 8
8 8. 10
120/70 124/78 104/70
15 10.3 ± 1.7
110/70
15 13
130/70 120/70
15
110/80
14
110/70
36 19 21 24 ± 4
11 ± 3
36 36
0.5 1
7
22
12
8
22
8
9 10 Mean ± SEM
32 27 29 ± 3
9 7 6 ± 2
NPH, 35, A.M. NPH, 44, A.M. Lente, 30, A.M. Semilente, 10, A.M. Lente (pork), 40, A.M. NPH, 16, A.M. NPH, 70, A.M. CZI, 15, A.M. NPH, 40, A.M. CZI, 15, A.M. NPH, 22, A.M. NPH, 12, P.M. NPH, 60, A.M. NPH, 37, A.M.
"group A, Asymptomatic diabetic patients; group B, impotent diabetic patients. bNPH, neutral protamine Hagedorn insulin; CZI, crystalline zinc insulin,
19 16 15.3 ± 1
125/80
655
CIRCADIAN VARIATION OF HORMONES IN DIABETIC MALES
Vol. 35, No.6
The sampling during the night was carried out with extreme caution and the patients slept well during the night of the study. The blood was immediately separated and the plasma was stored at - 60° C until assayed. Plasma glucose was determined with a Beckman' glucose analyzer (Beckman Co., Irvine; Calif.). Plasma prolactin levels were determined with a double-antibody radioimmunoassay,14 LH and FSH by the method described by Odell et al.,15, 16 and testosterone by a radioimmunoassay described previously by Kinouchi et aT. 17 Samples from each subject were measured in duplicate in a single assay. Statistical significance was determined with Student's
t-test. 18
__ Group A 0--0
16
E ..... Cl C
12
z
i=
() c( ...J
8
oa:
Group B
*
• p<.05
r
I \1 I )--J 1,\ ',t, )-/1"<',Llj-,-(1 *
1'-.,/i ,/· 1'1..-1
Il.
4~~--~----~--~--~----~---+
14
E ..... ;:,
E
10
J:
...J
RESULTS
The clinical data on the patients studied are presented in Table 1. No significant differences between the two groups were noted for age or duration of diabetes. All diabetic patients were stable during the study, with moderate glycosuria and without ketonuria. The circadian patterns of 'plasma PRL, LH, FSH, testosterone, and glucose during the study period are shown in Figure 1. A sleep-related increase was found in PRL concentrations in group A with the highest levels at 2:00 A.M. (12.9 ± 1.5 ng/ml versus 7.9 ± 1 ng/ml; P < 0.05) and 6;00 A.M. (15.2 ± 1.6 ng/ml versus 9 ± 1.1 ng/ml; P < 0.05); however, no sleep-related increase in PRL levels could be demonstrated in diabetic patients with impotence (group B). Plasma LH levels were similar in both groups of patients during the diurnal and nocturnal periods. Plasma FSH levels were comparable in both groups of patients during the study. Plasma testosterone levels increased during the nocturnal period in the asymptomatic diabetic patients (group A) at 2:00 A.M. and 6:00 A.M.; however, there were no significant differences between groups. Plasma glucose levels were increased and similar in both groups of patients during the diurnal period. During the nocturnal period, plasma glucose levels decreased to nearly normal at 4:00 A.M. and 6:00 A.M. No hypoglycemic levels were noted during the study, and plasma glucose levels were comparable in both groups of patients (Fig. 1). DISCUSSION
Our results demonstrate that asymptomatic diabetic male patients without impotence had normal variations of plasma prolactin concentrations
E .... ;:,
5.0
E
3.0
J:
U)
II..
1200
:c.....
~1000 w
z
oa:
w
800
I-
U)
~' 600 U)
W I-
:c....
300
Cl
E 200 Cl Il. 100L-~--~----~--~--~----~---,
0800
1200 1600 2000 2400 0400 0800 TIME
~Ce:;~ +-Nocturnal'"
FIG. 1. Circadian variation in plasma PRL, LH"FSH; testosterone, and glucose (PG) in young diabetic male patients with and without impotence. Data are expressed as means ± standard error of the mean. Group A, asymptomatic diabetic patients; group B, impotent diabetic patients.
during the daytime, but had significantly increased levels during sleep. In contrast, there was no increase in nocturnal prolactin levels in diabetic patients with impotence. These results are
656
ZEIDLER ET AL.
in agreement with a previous study by Drejer et al. 8 which failed to demonstrate an increase in prolactin levels during sleep in five of six poorly controlled insulin-treated diabetic male patients. However, whether those patients had abnormal sexual function was 'not mentioned. The mechanism of lack of nocturnal sleep-related increase in prolactin levels in diabetic patients with impotence is not clear. Increased circulating insulin levels inducing hyperprolactinemia during the nocturnal period in the asymptomatic diabetic patients could be considered; however, both groups of patients had similar plasma glucose levels, and hypoglycemia was not demonstrated. The possibility of altered hypothalamic pituitary function has been proposed to explain the differences in prolactin release in diabetic patients. 8 The release patterns of LH and FSH in insulintreated diabetic male patients have not been previously reported. In normal adult men, the release of gonadotropins has been assessed in certain studies, with no significant circadian variation. 15 Our data demonstrate that LH and FSH in insulin-treated diabetic men are not secreted with a circadian rhythm. These results are in agreement with studies performed in normal male subjects. 9 , 13, 15 Testosterone levels in diabetic men with and without impotence appeared to be normal as demonstrated in our 24-hour sampling. These data confirm previous studies in impotent diabetic male patients when infrequent sampling of testosterone was performed. Our results further support the finding that diabetic male patients with and without impotence have normal basal and diurnal variations of gonadotropin and testosterone levels. However, the lack of a sleep-related nocturnal increase in prolactin levels in this small group of diabetic patients is not readily explainable. It is possible that a change in sleep patterns or an altered hypothalamic-pituitary axis is related to the lack of sleep-related prolactin response in impotent diabetic patients, and additional studies are warranted.
June 1981 REFERENCES 1. PorterJC, Ben-Jonathan N: Neuroendocrine mechanisms involved in biorhythms. In Biorhythms and Human Re-
2.
3. 4.
5. 6.
7.
8.
9.
10.
11.
12. 13.
14.
15.
16.
17. Acknowledgments. We are grateful to Dr. Richard Horton for his helpful advice and to the Nichols Institute, Wilmington, Calif., for their help with the assays. Expert secretarial assistance was provided by Ms. Barbara Adamcik.
18.
production, Edited by MFerin, F Halberg, RM Richart, R Vande Wiele. New York, John Wiley & Sons, 1974, p 607 Sassin JF, Frantz AG, Weitzman ED, Kapen S: Human prolactin: 24-hour pattern with increased release during sleep. Science 177:1205, 1972 Sassin JF, Frantz AG, Kapen S, Weitzman ED: The nocturnal rise of human prolactin is dependent on sleep. J Clin Endocrinol Metab 27:326, 1973 Nokin J, Vekemans M, L'Hermite M, Robyn C: Circadian periodicity of serum prolactin concentration in man. Br Med J 3:561, 1972 Takahashi Y, Kipnis DM, Daughaday WH: Growth hormone secretion during sleep. J Clin Invest 47:2079,1968 Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman ED, Hellman L: Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 287:582, 1972 Kreiger DT, Howanitz PJ, Frantz AG: Absence of nocturnal elevation of plasma prolactin concentrations in Cushing's disease. J Clin Endocrinol Metab 42:260, 1976 Drejer J, Hendriksen C, Nielsen LM, Binder C, Hagan C, Kehlet H: Diurnal variations in plasma prolactin, growth hormone, cortisol and blood glucose in labile diabetes mellitus. Clin Endocrinol (Oxf) 6:57, 1977 Rubin RT, Gouin PR, Kales A, Odell WD: Luteinizing hormone, follicle stimulating hormone, and growth hormone secretion in normal adult men during sleep and dreaming. Psychosom Med 35:309, 1973 Rubin RT, Gouin PR, Lubin A, Roland RE, Pirke KM: Nocturnal increase of plasma testosterone in men: relation to gonadotropins and prolactin. J Clin Endocrinol Metab 40:1027, 1975 Spellacy WM: Carbohydrate metabolism in male infertility and female fertility-control patients. Fertil Steril 27:1132, 1976 Cooper AJ: The causes and management of impotence. Postgrad Med J 48:548, 1972 Swerdloff RS, Odell WD: Some aspects of the control of secretion in LH and FSH in humans. In Gonadotropins, Edited by E Rosemberg. Los Altos Calif, Geron-X, 1968, p 156 Tolis G, Goldstein M, Friesen HG: Functional evaluation of prolactin secretion in patients with hypothalamic pituitary disorders. J Clin Invest 52:783, 1973 Odell WD, Ross GT, Rayford PL: Radioimmunoassay for luteinizing hormone in human plasma or serum: physiological studies. J Clin Invest 46:248, 1967 Odell WD, Parlow AF, Cargille CM, Ross GT: Radioimmunoassay for human follicle stimulating hormone: physiological studies. J Clin Invest 47:2551, 1968 Kinouchi T, Pages L, Horton R: A specific radioimmunoassay for plasma testosterone. J Lab Clin Med 82:309, 1973 Afifi AA, Azen SP: Statistical Analysis: A Computer Oriented Approach. New York, Academic Press, 1972, p 63