Nonpuerperal Lactation and Normal Prolactin Regulation WILLIAM B. MALARKEY Department of Medicine, Division of Endocrinology, Columbus, Ohio 43210
The Ohio State University
Hospitals,
ABSTRACT. Prolactin secretion was evaluated in 11 consecutive patients referred with nonpuerperal lactation who did not have clinical evidence of pituitary tumors. Six patients had normal fasting prolactin (PRL) levels, 13.8 ± 1.8 ng per ml (Group I), and the other 5 women had elevated basal serum PRL concentrations, 182 ± 72 ng per ml (Group II). All Group II patients had amenorrhea; however, 5 of 6 Group I patients had menstrual periods. The 24-h mean serum PRL concentrations were 12.8 ± 1.2 (SEM), 13.3 ± 0.7, and 165 ± 62 ng per ml for the controls and Group I and II, respectively. A pattern of intermittent PRL discharge during the day characterized each group; however, a normal sleep related increase in serum PRL concentration was absent in the Group II patients. Chlorpromazine produced greater than two-fold increases in serum PRL concentrations in the controls and Group I patients; however, this response was absent in Group II. L-Dopa produced appropriate suppres-
sion of serum PRL concentrations in the normals and both patient groups. Normal serum growth hormone, thyroxine, and plasma cortisol characterized each group. Serum estrogen and/or LH and FSH were decreased in 3 of 5 Group II patients; however, the serum concentrations of these hormones were normal in 5 of 6 Group I patients. Short term L-dopa therapy was effective in suppressing lactation in 3 of 5 Group II patients, and it also decreased lactation in the 4 treated Group I patients without significantly altering 24-h mean serum PRL concentrations in the latter group. Conclusion: Hypothalamic-pituitary dysfunction was present in certain patients with nonpuerperal lactation who had elevated 24-h mean PRL concentrations and no PRL release following chlorpromazine and sleep. Frequently, however, nonpuerperal lactation is associated with normal prolactin secretion. (/ Clin Endocrinol Metab 40: 198, 1975)
"IVTONPUERPERAL galactorrhea is as_L \ sociated with a variety of organic and functional hypothalamic-pituitary disorders (1). With the recent development of prolactin (PRL) radioimmunoassay, it has been possible to investigate the hormonal basis for abnormal lactation. Several reports have detailed abnormal PRL regulation in these patients, characterized by elevated fasting PRL concentrations and failure of serum PRL to increase following chlorpromazine or thyroid releasing hormone stimulation (2-4). These same studies have indicated that patients with nonpuerperal lactation may have normal fasting serum PRL levels, which suggests that lactation in these patients may not be due to disordered PRL secretion.
Normal PRL secretion is characterized by pulsatile discharge during the day and a prominent sleep related augmentation in secretion (5,6). Hypersecretion of PRL during the night, therefore, could be missed by only obtaining a fasting sample. Hence, in an attempt to evaluate PRL secretion in patients with nonpuerperal lactation and normal basal PRL concentrations, 24-h profiles of serum PRL concentrations were obtained in 6 of these patients and compared with the PRL secretion of normal subjects and those with hyperprolactinemia.
Received July 18, 1974. This work was supported in part by Clinical Research Grant (RR-34) from the National Institute of Health, GRS Grant (320002) from the College of Medicine, the Ohio State University and the Alex R. MacDonald Memorial Grant for Cancer Research from the American Cancer Society.
Materials and Methods Five normal women between 22 and 36 yr of age, as well as 11 lactating patients (Tables 1, 2), were admitted to the Clinical Research Center. Six of the lactating patients had normal fasting serum PRL levels (Group I) and 5 had elevated serum PRL concentrations (Group II). Skull X-rays and visual field examinations were normal in each patient. A basic laboratory and endocrine examination was performed which
198
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NONPUERPERAL LACTATION AND PROLACTIN
199
TABLE 1. Patients with galactorrhea and normal serum prolactin concentrations (Group I) Lactation postL-dopa**
Fasting Patient
Age
#1 #2 #3 #4 #5 #6
30 30 25 20 26 20
Mean ± SE
25 ± 2
Duration (yr) 12 3 10
2 4
5 6 ±2
PRL
Menses
Dx
(ng/ml)
regular irregular regular irregular absent regular
Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic
10 12 17 22 10 12
13.8 ± 1.8#
MPrC* (ng/ml) 10 ± 1 14 ± 1 15 ± 2 18 ± 5 9± 1 14 ± 1 13.3 ± 0.7#
, i — — 4 1
* 24 hr mean ± SE prolactin concentration. ** ^ Marked decrease, | slight decrease in easily expressible breast milk. # Mean control fasting level (16.8 ± 1.9), mean control MPrC (12.8 ± 1.2). TABLE 2. Patients with galactorrhea and elevated serum prolactin concentrations (Group II) Duration (yr)
Patient
Age
# 7 # 8
23
4
28 31
#10 #11
22 29
10 12 2 3
Mean ± SE
27 ± 2
5 ±4
#
9 •
Menses
Dx
Absent Absent Absent Absent Absent
Oral contraceptive Idiopathic Idiopathic Chiari-Frommel Oral contraceptive
Basal PRL (ng/ml) 143 96 498 118
56 182 ± 72
MPrC* (ng/ml) 150 ± 69 ± 430 ± 128 ± 49 ± 165 ±
2 4 7 5 1 62
Lactation postL-dopa**
1 —> 4
* 24-hr mean ± SE prolactin concentration. ** il' Marked decrease, | slight decrease, —» no change in easily expressible milk. included normal AM and PM plasma cortisols, a parison t test was used to evaluate the differ24-hr urine for 17-ketosteroids and 17- ence in the 24-h mean PRL concentrations in hydroxysteroids, serum T4, growth hormone the patients before and following L-dopa (GH), electrolytes, calcium and phosphorus. therapy. All patients had hourly blood sampling for 24 h through a heparinized scalp vein needle Results placed in a wrist vein beginning the day , following admission. During this study activity Twenty-four-hour prolactin secretion in was restricted to the patient's room. On succes- normals, Group I, and Group II patients: sive days L-dopa, 0.5 g, was given orally and T h e female controls and Group I patients chlorpromazine, 0.5 mg per kg, was adminis- n a cl similar mean ± SE basal serum PRL tered im with blood sampling at appropriate levels 16.8 ± 1.9 and 13.8 ± 1.8, respecintervals. The specimens were centrifuged and tively. The 24-h mean PRL concentrations the serum was stored at -20 C until assayed for o f the controls and Group I patients were PRL according to the radioimmunoassay almost identical, 12.8 ± 1.2 and 13.3 ± 0.7 method of Sjnha et al. (7). The intra and n g p e r m l > respectively (Table 1). The interassay coefficient or variation of this assay in /-. I.- * u u J i TT • , . . i ., u I l r Group II patients, however, had an eleinor c my laboratory is less than 10%. Serum TLH, FSH . -f n^ u r>r»T i. *.• c „ . i . ,. , n , , vated mean 24-h PRL concentration ot /H>, («), progesterone and estrachol /(9) were also . ,. . , measured by radioimmunoassay on fasting 1 6 5 ± 6 2 n § P e r m l ( T a b l e 2^ T h e P a t t e r n specimens. After discharge L-dopa was given o f P R L secretion was similar in the normal orally to nine patients in gradually increasing a n ^ Group I patients, with intermittent doses up to 2 g daily in an attempt to control the secretion during the day and a prominent galactorrhea and initiate menses. A paired com- nocturnal increase (Fig. 1). The Group II
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JCE & M • 1975 Vol 40 • No 2
MALARKEY
200 IOOO
(7)
(8) (II)
"fc (I - 6 ) Normals
sponses were not significantly different, a Group I patient (#1, Table 1) had an eight-fold increase in serum PRL by 120 min following chlorpromazine. In contrast to the stimulation of serum PRL noted in the normal and Group I patients, the Group II patients failed to significantly increase their serum PRL concentrations following chlorpromazine; the mean basal concentration was 228 ± 73 ng per ml, and the maximally stimulated value was 248 ± 78 ng per ml. L-Dopa, however, produced similar degrees of serum PRL suppression in each group; 49 ± 17, 59 ± 3, and 60 ± 10 percent of baseline concentrations in normals, Group I and Group II, respectively.
Ovarian steroid and gonadotropin concentrations in Group I and Group II. FIG. 1. Twenty-four-hour prolactin profiles of 5 normal All Group I patients had normal serum (o — o) and 10 lactating patients with normal (• — •) estradiol (E ) and gonadotropins (Table 3) 2 and elevated (• —•) basal PRL concentrations. Numwith the exception of patient #5, who had a bers refer to the patients of Table 1 and Table 2 in all figures. Note absence of nocturnal augmentation of low serum E2 and marked elevation in her serum gonadotropins. This patient had PRL secretion in patients # 7 - 1 1 . premature ovarian failure documented by patients, however, had a blunting of sleep an ovarian biopsy revealing bilateral fibrotic ovaries. Serum progesterone concenrelated augmentation in PRL secretion. trations in 2 patients, #1 and #6 (Table 3), Serum prolactin concentrations follow- in the luteal phase of their menstrual cying chlorpromazine and L-dopa. Chlor- cles were compatible with an ovulatory promazine produced an increase in serum episode. Three of the 5 Group II patients PRL concentrations from 12.5 ± 2.0 to a (#7-9, Table 4) examined had low serum maximum of 27.2 ± 5.0 ng per ml and from estrogens and/or serum gonadotropins (Ta12.4 ± 1.0 to a maximum of 46.6 ± 13.0 ng ble 4). Their low serum progesterone per ml in the normal and Group I patients, concentrations were compatible with their respectively. Although these group re- amenorrhea. 8 1
10 12 am—"
2
TABLE 3. Serum gonadotropin and ovarian steroid concentrations in Group I lactating patients with normal serum prolactin levels Patient
Day of cycle
LH (mlU/ml)
FSH (mlU/ml)
E2 (pg/ml)
Progesterone# (ng/ml)
#1 #2 #3 #4
24 6 16 oligomenorrhea amenorrhea 21
10 29 58 34 300* 12.3
5 9 9 14 150*
114 52 155 124 15** 46
7.9 0.8 1.5 1.0 1.0 5.0
#5 #6
5.0
* Increased; ** decreased; # > 5 ng/ml suggests ovulation has occurred.
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201
NONPUERPERAL LACTATION AND PROLACTIN TABLE 4. Serum gonadotropin and ovarian steroid concentrations in Group II lactating patients with elevated serum prolactin levels without apparent pituitary tumors Patient
Day of cycle
LH (mlU/ml)
FSH (mlU/ml)
E2 (pg/ml)
Progesterone# (ng/ml)
# 7 # 8 # 9 #10 #11
amenorrhea amenorrhea amenorrhea amenorrhea amenorrhea
7 7 1** 22 7
5 3**
The Ohio State University
Hospitals,
ABSTRACT. Prolactin secretion was evaluated in 11 consecutive patients referred with nonpuerperal lactation who did not have clinical evidence of pituitary tumors. Six patients had normal fasting prolactin (PRL) levels, 13.8 ± 1.8 ng per ml (Group I), and the other 5 women had elevated basal serum PRL concentrations, 182 ± 72 ng per ml (Group II). All Group II patients had amenorrhea; however, 5 of 6 Group I patients had menstrual periods. The 24-h mean serum PRL concentrations were 12.8 ± 1.2 (SEM), 13.3 ± 0.7, and 165 ± 62 ng per ml for the controls and Group I and II, respectively. A pattern of intermittent PRL discharge during the day characterized each group; however, a normal sleep related increase in serum PRL concentration was absent in the Group II patients. Chlorpromazine produced greater than two-fold increases in serum PRL concentrations in the controls and Group I patients; however, this response was absent in Group II. L-Dopa produced appropriate suppres-
sion of serum PRL concentrations in the normals and both patient groups. Normal serum growth hormone, thyroxine, and plasma cortisol characterized each group. Serum estrogen and/or LH and FSH were decreased in 3 of 5 Group II patients; however, the serum concentrations of these hormones were normal in 5 of 6 Group I patients. Short term L-dopa therapy was effective in suppressing lactation in 3 of 5 Group II patients, and it also decreased lactation in the 4 treated Group I patients without significantly altering 24-h mean serum PRL concentrations in the latter group. Conclusion: Hypothalamic-pituitary dysfunction was present in certain patients with nonpuerperal lactation who had elevated 24-h mean PRL concentrations and no PRL release following chlorpromazine and sleep. Frequently, however, nonpuerperal lactation is associated with normal prolactin secretion. (/ Clin Endocrinol Metab 40: 198, 1975)
"IVTONPUERPERAL galactorrhea is as_L \ sociated with a variety of organic and functional hypothalamic-pituitary disorders (1). With the recent development of prolactin (PRL) radioimmunoassay, it has been possible to investigate the hormonal basis for abnormal lactation. Several reports have detailed abnormal PRL regulation in these patients, characterized by elevated fasting PRL concentrations and failure of serum PRL to increase following chlorpromazine or thyroid releasing hormone stimulation (2-4). These same studies have indicated that patients with nonpuerperal lactation may have normal fasting serum PRL levels, which suggests that lactation in these patients may not be due to disordered PRL secretion.
Normal PRL secretion is characterized by pulsatile discharge during the day and a prominent sleep related augmentation in secretion (5,6). Hypersecretion of PRL during the night, therefore, could be missed by only obtaining a fasting sample. Hence, in an attempt to evaluate PRL secretion in patients with nonpuerperal lactation and normal basal PRL concentrations, 24-h profiles of serum PRL concentrations were obtained in 6 of these patients and compared with the PRL secretion of normal subjects and those with hyperprolactinemia.
Received July 18, 1974. This work was supported in part by Clinical Research Grant (RR-34) from the National Institute of Health, GRS Grant (320002) from the College of Medicine, the Ohio State University and the Alex R. MacDonald Memorial Grant for Cancer Research from the American Cancer Society.
Materials and Methods Five normal women between 22 and 36 yr of age, as well as 11 lactating patients (Tables 1, 2), were admitted to the Clinical Research Center. Six of the lactating patients had normal fasting serum PRL levels (Group I) and 5 had elevated serum PRL concentrations (Group II). Skull X-rays and visual field examinations were normal in each patient. A basic laboratory and endocrine examination was performed which
198
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NONPUERPERAL LACTATION AND PROLACTIN
199
TABLE 1. Patients with galactorrhea and normal serum prolactin concentrations (Group I) Lactation postL-dopa**
Fasting Patient
Age
#1 #2 #3 #4 #5 #6
30 30 25 20 26 20
Mean ± SE
25 ± 2
Duration (yr) 12 3 10
2 4
5 6 ±2
PRL
Menses
Dx
(ng/ml)
regular irregular regular irregular absent regular
Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic Idiopathic
10 12 17 22 10 12
13.8 ± 1.8#
MPrC* (ng/ml) 10 ± 1 14 ± 1 15 ± 2 18 ± 5 9± 1 14 ± 1 13.3 ± 0.7#
, i — — 4 1
* 24 hr mean ± SE prolactin concentration. ** ^ Marked decrease, | slight decrease in easily expressible breast milk. # Mean control fasting level (16.8 ± 1.9), mean control MPrC (12.8 ± 1.2). TABLE 2. Patients with galactorrhea and elevated serum prolactin concentrations (Group II) Duration (yr)
Patient
Age
# 7 # 8
23
4
28 31
#10 #11
22 29
10 12 2 3
Mean ± SE
27 ± 2
5 ±4
#
9 •
Menses
Dx
Absent Absent Absent Absent Absent
Oral contraceptive Idiopathic Idiopathic Chiari-Frommel Oral contraceptive
Basal PRL (ng/ml) 143 96 498 118
56 182 ± 72
MPrC* (ng/ml) 150 ± 69 ± 430 ± 128 ± 49 ± 165 ±
2 4 7 5 1 62
Lactation postL-dopa**
1 —> 4
* 24-hr mean ± SE prolactin concentration. ** il' Marked decrease, | slight decrease, —» no change in easily expressible milk. included normal AM and PM plasma cortisols, a parison t test was used to evaluate the differ24-hr urine for 17-ketosteroids and 17- ence in the 24-h mean PRL concentrations in hydroxysteroids, serum T4, growth hormone the patients before and following L-dopa (GH), electrolytes, calcium and phosphorus. therapy. All patients had hourly blood sampling for 24 h through a heparinized scalp vein needle Results placed in a wrist vein beginning the day , following admission. During this study activity Twenty-four-hour prolactin secretion in was restricted to the patient's room. On succes- normals, Group I, and Group II patients: sive days L-dopa, 0.5 g, was given orally and T h e female controls and Group I patients chlorpromazine, 0.5 mg per kg, was adminis- n a cl similar mean ± SE basal serum PRL tered im with blood sampling at appropriate levels 16.8 ± 1.9 and 13.8 ± 1.8, respecintervals. The specimens were centrifuged and tively. The 24-h mean PRL concentrations the serum was stored at -20 C until assayed for o f the controls and Group I patients were PRL according to the radioimmunoassay almost identical, 12.8 ± 1.2 and 13.3 ± 0.7 method of Sjnha et al. (7). The intra and n g p e r m l > respectively (Table 1). The interassay coefficient or variation of this assay in /-. I.- * u u J i TT • , . . i ., u I l r Group II patients, however, had an eleinor c my laboratory is less than 10%. Serum TLH, FSH . -f n^ u r>r»T i. *.• c „ . i . ,. , n , , vated mean 24-h PRL concentration ot /H>, («), progesterone and estrachol /(9) were also . ,. . , measured by radioimmunoassay on fasting 1 6 5 ± 6 2 n § P e r m l ( T a b l e 2^ T h e P a t t e r n specimens. After discharge L-dopa was given o f P R L secretion was similar in the normal orally to nine patients in gradually increasing a n ^ Group I patients, with intermittent doses up to 2 g daily in an attempt to control the secretion during the day and a prominent galactorrhea and initiate menses. A paired com- nocturnal increase (Fig. 1). The Group II
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JCE & M • 1975 Vol 40 • No 2
MALARKEY
200 IOOO
(7)
(8) (II)
"fc (I - 6 ) Normals
sponses were not significantly different, a Group I patient (#1, Table 1) had an eight-fold increase in serum PRL by 120 min following chlorpromazine. In contrast to the stimulation of serum PRL noted in the normal and Group I patients, the Group II patients failed to significantly increase their serum PRL concentrations following chlorpromazine; the mean basal concentration was 228 ± 73 ng per ml, and the maximally stimulated value was 248 ± 78 ng per ml. L-Dopa, however, produced similar degrees of serum PRL suppression in each group; 49 ± 17, 59 ± 3, and 60 ± 10 percent of baseline concentrations in normals, Group I and Group II, respectively.
Ovarian steroid and gonadotropin concentrations in Group I and Group II. FIG. 1. Twenty-four-hour prolactin profiles of 5 normal All Group I patients had normal serum (o — o) and 10 lactating patients with normal (• — •) estradiol (E ) and gonadotropins (Table 3) 2 and elevated (• —•) basal PRL concentrations. Numwith the exception of patient #5, who had a bers refer to the patients of Table 1 and Table 2 in all figures. Note absence of nocturnal augmentation of low serum E2 and marked elevation in her serum gonadotropins. This patient had PRL secretion in patients # 7 - 1 1 . premature ovarian failure documented by patients, however, had a blunting of sleep an ovarian biopsy revealing bilateral fibrotic ovaries. Serum progesterone concenrelated augmentation in PRL secretion. trations in 2 patients, #1 and #6 (Table 3), Serum prolactin concentrations follow- in the luteal phase of their menstrual cying chlorpromazine and L-dopa. Chlor- cles were compatible with an ovulatory promazine produced an increase in serum episode. Three of the 5 Group II patients PRL concentrations from 12.5 ± 2.0 to a (#7-9, Table 4) examined had low serum maximum of 27.2 ± 5.0 ng per ml and from estrogens and/or serum gonadotropins (Ta12.4 ± 1.0 to a maximum of 46.6 ± 13.0 ng ble 4). Their low serum progesterone per ml in the normal and Group I patients, concentrations were compatible with their respectively. Although these group re- amenorrhea. 8 1
10 12 am—"
2
TABLE 3. Serum gonadotropin and ovarian steroid concentrations in Group I lactating patients with normal serum prolactin levels Patient
Day of cycle
LH (mlU/ml)
FSH (mlU/ml)
E2 (pg/ml)
Progesterone# (ng/ml)
#1 #2 #3 #4
24 6 16 oligomenorrhea amenorrhea 21
10 29 58 34 300* 12.3
5 9 9 14 150*
114 52 155 124 15** 46
7.9 0.8 1.5 1.0 1.0 5.0
#5 #6
5.0
* Increased; ** decreased; # > 5 ng/ml suggests ovulation has occurred.
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201
NONPUERPERAL LACTATION AND PROLACTIN TABLE 4. Serum gonadotropin and ovarian steroid concentrations in Group II lactating patients with elevated serum prolactin levels without apparent pituitary tumors Patient
Day of cycle
LH (mlU/ml)
FSH (mlU/ml)
E2 (pg/ml)
Progesterone# (ng/ml)
# 7 # 8 # 9 #10 #11
amenorrhea amenorrhea amenorrhea amenorrhea amenorrhea
7 7 1** 22 7
5 3**
