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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 761-764
Copyright © 1998 by The Endocrine Society

Original Studies

Prolactin Pulsatile Characteristics in Postmenopausal Women1

Laurence Katznelson, Peter N. Riskind, Velia C. Saxe and Anne Klibanski

Neuroendocrine Unit (L.K., V.C.S., A.K.), Department of Neurology (P.N.R.), and the General Clinical Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Laurence Katznelson, M.D., Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BUL457B, Boston, Massachusetts 02114-2696. E-mail: katznelsonl{at}a1.mgh.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Pulsatile PRL secretion undergoes diurnal variation, with maximal PRL release in the evening during sleep in both women and men. However, the impact of the menopause on PRL pulsatile dynamics are largely unknown. To characterize diurnal PRL pulsatile secretion in postmenopausal women, we performed frequent venous sampling over 24 h every 10 min for serum PRL in 7 postmenopausal women (age, 56 ± 4 yr) and in 2 control groups, 8 men (age, 25 ± 8 yr) and 22 cycling women (age, 28 ± 5 yr), at 3 phases of the menstrual cycle. Standard TRH tests (200 µg, iv) were administered at 0900 h after completion of the 24-h sampling, and PRL levels were then obtained at 0, 10, 20, 30, and 60 min in all subjects. PRL pulse characteristics were similar between the postmenopausal women and men. Mean serum PRL levels and PRL pulse frequency were significantly higher in the cycling women than in either postmenopausal women or men over 24 h and during either the day or night periods. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to those during the day in all groups. Pulse amplitude was higher during the night vs. the day in all groups and was highest in the cycling women. PRL responses to TRH administration were greatest in cycling women. These data demonstrate that PRL pulse dynamics are significantly different between postmenopausal women and cycling women, and endogenous estrogen levels may have an important role in this difference. Pulsatile PRL secretion is similar between postmenopausal women and men, suggesting that estrogen levels modulate PRL dynamics across genders.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRL IS secreted in a pulsatile fashion, with maximal PRL release during sleep (1). Although there are multiple inhibitory and stimulatory factors that regulate PRL secretion, gonadal steroids appear to have an important role in modulating PRL secretion and its circadian rhythm. The physiological increases in estrogen levels seen in pregnancy lead to lactotroph hyperplasia and enhanced PRL secretion (2, 3). The finding that estrogen pulses precede PRL pulses suggests further that estrogens regulate pulsatile PRL (4). Additional evidence for an effect of gonadal steroids on PRL secretion includes the finding that basal serum PRL levels are lower in postmenopausal women than in cycling women or are lower in men than in premenopausal women, perhaps reflecting lower endogenous estrogen levels (5).

Development of normative data on PRL pulsations in postmenopausal women is important for understanding the role of estrogen in maintaining PRL secretion. For example, with the widespread use of estrogen agonists/antagonists, such as tamoxifen, the effect of estrogen on pituitary function needs to be defined further (6). Investigations into the effect of postmenopausal status on pulsatile secretion of PRL have been limited with regard to the use of pulse analysis or control groups (1, 5, 7).

To characterize the diurnal pulsatile secretion of PRL in postmenopausal women, it is also necessary to investigate PRL secretory dynamics in estrogen-sufficient subjects and men, a group with relative hypoestrogenemia. Therefore, we performed frequent sampling of PRL in postmenopausal women, cycling women, and men to determine 1) PRL pulsation patterns in postmenopausal women, and 2) the effect of gonadal status and gender on PRL pulsatile secretion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirty-seven subjects were studied. Seven postmenopausal women (mean age, 56 ± 4 yr; range, 51–62 yr) were studied. Menopausal status was confirmed by elevated serum LH and FSH values (>25 mIU/mL) and undetectable serum estradiol levels. None of these women had previously received estrogen replacement. Eight normal men (mean age, 25 ± 8 yr; range, 20–43 yr) were studied. All men had a history of normal sexual and reproductive function and had serum testosterone levels greater than 10.4 nmol/L on at least 2 readings. The mean serum testosterone value was 24.1 ± 8.6 nmol/L (range, 18.2–44.1 nmol/L). Twenty-two premenopausal women with a history of normal menstrual cycles (cycling women; age, 28 ± 5 yr; range, 19–38 yr) were also studied. The age of menarche ranged from 11–16 yr. None of the women had taken oral contraceptives for at least 1 yr before the study. Eight women were studied during the early follicular phase (days 1–7), 10 women were studied during the late follicular phase (days 8–13), and 8 women were studied during the luteal phase (days 21–25). Three of these women were assessed during more than one phase of the menstrual cycle. Luteal phase was confirmed by a serum progesterone level greater than 16 nmol/L. The mean progesterone level in the luteal subjects was 61 ± 12 nmol/L.

All subjects had normal histories, physical examinations, and renal and thyroid function tests. The study was approved by the subcommittee on human studies at the Massachusetts General Hospital, and written informed consent was obtained from all subjects.

Experimental protocol

Subjects were admitted to the Clinical Research Center at Massachusetts General Hospital at 0800 h for placement of an iv catheter. Beginning at 0900 h, venous samples were obtained every 10 min for 24 h. Time of sleep was recorded after visual inspection by a research nurse. After completion of the 24-h sampling, subjects received TRH (200 µg, iv), and blood samples for PRL determination were obtained 0, 10, 20, 30, and 60 min after TRH administration. Serum samples were stored at -20 C and assayed in bulk at study completion.

All subjects were given a diet of 30% protein, 30% fat, and 40% carbohydrates during the admission. Meals were given at 0830, 1200, and 1800 h. Smoking and caffeine were not permitted. Subjects were allowed to ambulate ad libitum.

Hormone assays

Serum testosterone was measured by RIA (ICN Biomedical, Carson, CA). This assay has a detection limit of 0.3 nmol/L, and an intraassay coefficient of variation of 11%. Serum progesterone, PRL, LH, and FSH were determined by previously described methods (8). All PRL samples for an individual patient were determined in the same assay to avoid interassay variation.

Pulse detection

Pulses were detected by means of the Pulsar program, using a conservative assay coefficient of variation of 13% and cut-off criteria identical to those reported in a previous analysis of PRL pulsatility (9).

Statistics

Data were analyzed by a one- or two-way ANOVA, with repeated measures as appropriate. Multiple comparisons were performed using Scheffe’s test. PRL pulse analysis was performed over the 24-h period or during the day (0800–1950 h) vs. the night (2000–0750 h).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
As shown in Tables 1Go and 2Go and Fig. 1Go, mean serum PRL levels and PRL pulse frequency during the day and night were significantly higher in the cycling women than in either postmenopausal women or men. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to the day in all groups (see Fig. 1Go). Postmenopausal women and men had similar mean serum PRL levels and PRL pulse frequency over 24 h and during the day and night periods. Representative profiles of pulsatile PRL release in relationship to sleep for a postmenopausal woman, a man, and a cycling woman are shown in Fig. 2Go.


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  		Table 1. Mean PRL levels (nanograms per mL)

 

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  		Table 2. PRL pulse frequency

 


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  		Figure 1. Profiles of pulsatile PRL release in postmenopausal women, men, and cycling women. Serum PRL values were determined at 10-min intervals for 24 h. Mean serum PRL concentrations ±1 SD are demonstrated for each group.

 


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  		Figure 2. Profiles of pulsatile PRL release in relation to sleep in a representative postmenopausal woman (a), man (b), and cycling woman (c). Serum PRL values were determined at 10-min intervals for 24 h. The black bar refers to the period of sleep.

 
PRL pulse amplitude was significantly higher in cycling women than in postmenopausal women and men (see Table 3Go). Men and postmenopausal women had similar pulse amplitude values. PRL pulse amplitude was greater during the night than during the day for all groups (P < 0.02). The mean PRL pulse duration was significantly shorter in cycling women compared to those in the other groups, as shown in Table 3Go. Cycling women had a higher proportion of very brief pulses compared to men, but had a lower proportion of very long pulses compared to postmenopausal women (data not shown). Mean pulse duration was similar for both the men and postmenopausal women. There was no diurnal variation in pulse duration.


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  		Table 3. PRL pulse amplitude and duration

 
Maximal spontaneous serum PRL levels during the 24-h period were significantly higher in cycling women than in either postmenopausal women or men (see Table 4Go). Maximal spontaneous serum PRL levels were similar in postmenopausal women and men.


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  		Table 4. Maximal PRL levels (nanograms per mL)

 
Responses to TRH administration are shown in Table 5Go. There were significant differences between men and cycling women for absolute PRL increment (P = 0.004, by ANOVA and Scheffe’s test) after TRH administration.


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  		Table 5. Response to TRH administration

 
Mean serum PRL levels, PRL pulse number, and pulse duration were similar in the early follicular, late follicular, and luteal phases. Mean serum PRL levels and PRL pulse number were higher at night vs. day during each phase (P < 0.003 and P < 0.05, respectively). PRL pulse amplitude was significantly higher in the early follicular compared to the late follicular women (P < 0.04).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We investigated PRL pulse characteristics in postmenopausal women, cycling women, and men. In all three groups, we found that PRL was secreted in a circadian rhythm with regard to mean PRL levels, pulse amplitude, and pulse frequency. PRL secretory characteristics in the postmenopausal women were similar to those in adult men rather than those in cycling women. These data demonstrate that PRL undergoes pulsatile secretion in postmenopausal women in a circadian rhythm similar to that in men, but lower than that in estrogen-sufficient, cycling women.

This is the first investigation that details PRL pulse characteristics in postmenopausal women and demonstrates differences in pulsatile secretion of PRL in the night compared to the day. In a previous study in five postmenopausal women, a circadian rhythm in PRL secretion was demonstrated after measurement of PRL at 1-h intervals (10). However, further analysis of pulse characteristics was not performed in their study. Previous studies of postmenopausal women have not included estrogen-sufficient cycling women or men for comparison. Our data serve as an important control database for further investigations regarding pathological states such as PRL-secreting pituitary tumors in postmenopausal women (6).

We found that postmenopausal women had different pulse characteristics, including lower pulse amplitude, frequency, and pulse duration during the day and night phases, compared to those in cycling women. One possible explanation for the difference between postmenopausal women and cycling women is an effect of estrogen on PRL secretion. Estradiol pulses precede PRL pulses by approximately 2 h, suggesting that rising levels of estradiol facilitate the secretion of PRL (4). Further evidence for a role of estrogen in regulating PRL secretion comes from studies involving the administration of estradiol to postmenopausal women (11). Chang et al. (10) performed hourly PRL sampling in five postmenopausal women before and after administration of 50 µg/day ethinyl estradiol for 4 weeks. In this study, estrogen administration resulted in an augmentation of PRL secretion in a diurnal rhythm. Therefore, although detailed pulse analysis was not performed, this study is consistent with a stimulatory effect of estrogen on the secretion of PRL. Veldhuis et al. (12) found that estrogen administration resulted in a significant increase in pulse amplitude without a change in pulse frequency in postmenopausal women. Consistent with these results, cycling women in our study had higher mean PRL levels and pulse amplitudes compared to postmenopausal women. These data support the hypothesis that estrogens play an important physiological role in modulating PRL secretion. In contrast to Veldhuis et al. (12), we also found group differences in PRL pulse frequency, suggesting altered hypothalamic regulation. Sleep quality, duration, and onset are determinants of PRL release, and, although a formal assessment of sleep cycles was not performed, it is possible that differences in sleep patterns may have contributed to the results in this study (1). In addition, age-related alterations in the regulation of PRL secretion may contribute to the observed group differences (7, 13).

Consistent with previous reports in men, we found that PRL was secreted in a pulsatile, diurnal pattern, with higher pulse amplitude and pulse frequency at night (14, 15). In contrast to a prior study in 12 young men, our data also suggest that PRL pulse frequency is higher at night (15). The reasons behind this difference are unclear.

Administration of TRH resulted in a greater absolute increment in PRL secretion in cycling women compared to men. There was a tendency for less TRH-induced PRL release in postmenopausal women compared to cycling women, but this difference was not significant. Although serum PRL levels are elevated in the setting of primary hypothyroidism (16), the role of TRH in the physiological regulation of PRL is unclear. Estrogens may augment the effect of hypothalamic peptides, such as TRH, on PRL secretion (17). In postmenopausal women, exogenous estrogens were shown in one study to enhance the PRL response to TRH (18), but not in another (19). Circulating estradiol levels may directly or via effects on hypothalamic factors modulate PRL pulsatility and contribute to the differences seen between genders and between postmenopausal and cycling women. Our data also suggest that there may be less PRL reserve in men and postmenopausal women than in cycling women.

We did not demonstrate a change in mean PRL levels across the menstrual cycle. Our data are consistent with those from previous studies (20, 21), but contrast with others that have shown an increase in PRL levels during the periovulatory and luteal phases of the menstrual cycle (22, 23). Differences between data from previous studies and the present results may be due to the fact that we performed PRL sampling more frequently than in other studies. However, our study may be limited by the fact that subjects were not studied prospectively across a menstrual cycle, and therefore, there may not have been sufficient power to demonstrate a significant change across the menstrual cycle. Nevertheless, it is unlikely that dramatic changes in PRL levels are present across the menstrual cycle.

We investigated PRL secretion in postmenopausal women and demonstrated the presence of a circadian rhythm in mean PRL levels, PRL pulse amplitude, and pulse frequency. These values were similar to those in younger men and lower than those in cycling, estrogen-sufficient women. These data suggest that estrogens play a critical role in the regulation of PRL in both women and men. Further studies are necessary to determine other mechanisms that underlie the differential regulation of PRL pulsatile secretion associated with gender and age.


   Footnotes
 
1 This work was supported by Grant MO1-RR-01066. Back

Received September 16, 1997.

Revised December 2, 1997.

Accepted December 9, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Waldstreicher J, Duffy JF, Brown EN, Rogacz S, Allan JS, Czeisler CA. 1996 Gender differences in the temporal organization of prolactin (PRL) secretion: evidence for a sleep-independent circadian rhythm of circulating PRL levels–a clinical research center study. J Clin Endocrinol Metab. 81:1483–1487.[Abstract]
  2. Tyson JE, Hwang P, Guyda H, Friesen HG. 1972 Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol. 113:14–20.[Medline]
  3. Scheithauer BW, Sano T, Kovacs KT, Young Jr WF, Ryan N, Randall RV. 1990 The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc. 65:461–474.[Medline]
  4. Juneja HS, Karanth S, Dutt A, Parte P, Meherjee P. 1991 Diurnal variations and temporal coupling of bioactive and immunoactive luteinizing hormone, prolactin, testosterone and 17ß-estradiol in adult men. Horm Res. 35:89–94.[CrossRef][Medline]
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  6. Fornander T, Rutqvist LE, Wilking N, Carlstrom K, Von Schoultz B. 1993 Oestrogenic effects of adjuvant tamoxifen in postmenopausal breast cancer. Eur J Cancer. 29A:497–500.
  7. Greenspan SL, Klibanski A, Rowe JW, Elahi D. 1990 Age alters pulsatile prolactin release: influence of dopaminergic inhibition. Am J Physiol. 258:E799–E804.
  8. Filicori M, Butler JP, Crowley WF. 1984 Neuroendocrine regulation of the corpus luteum in the human. J Clin Invest. 73:1638–1647.
  9. Veldhuis JD, Johnson ML. 1986 Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. Am J Physiol. 250:E486–E493.
  10. Chang RJ, Davidson BJ, Carlson HE, Judd HL. 1982 Circadian pattern of prolactin secretion in postmenopausal women receiving estrogen with or without progestin. Am J Obtet Gynecol. 144:402–407.[Medline]
  11. Robyn C, Vekemans M. 1976 Influence of low dose oestrogen on circulating prolactin. LH and FSH levels in post-menopausal women. Acta Endocrinol (Copenh). 83:9–14.[Abstract/Free Full Text]
  12. Veldhuis JD, Evans WS, Stumpf PG. 1989 Mechanisms that subserve estradiol’s induction of increased prolactin concentrations: evidence of amplitude modulation of spontaneous prolactin secretory bursts. Am J Obtet Gynecol. 161:1149–1158.[Medline]
  13. Sassin JF, Frantz AG, Weitzman ED, Kapen S. 1972 Human prolactin: 24-hour pattern with increased release during sleep. Science. 177:1205–1207.[Abstract/Free Full Text]
  14. Sowers JR, Viosca SP, Windsor C, Korenman SG. 1983 Influence of dopaminergic mechanisms on 24-hour secretory patterns of prolactin, luteinizing hormone and testosterone in recumbent men. J Endocrinol Invest. 6:9–15.[Medline]
  15. Veldhuis JD, Johnson ML. 1988 Operating characteristics of the hypothalamo-pituitary-gonadal axis in men: circadian, ultradian, and pulsatile release of prolactin and its temporal coupling with luteinizing hormone. J Clin Endocrinol Metab. 67:116–123.[Abstract]
  16. Honbo KS, van Herle AJ, Kellett KA. 1978 Serum prolactin levels in untreated primary hypothyroidism. Am J Med. 64:782–787.[CrossRef][Medline]
  17. Couzinet B, Dorey F, Schaison G. 1989 Effects of vasoactive intestinal polypeptide, TRH, and dopamine on prolactin secretion in estrogen-primed postmenopausal women. Acta Endocrinol (Copenh). 121:235–240.[Abstract/Free Full Text]
  18. Joseph PJ, Couzinet B, Brailly S, Rigaud C, Raynaud JP, Schaison G. 1986 Interactions of oestradiol benzoate and promegestone upon basal and TRH-induced prolactin secretion in postmenopausal women. Clin Endocrinol (Oxf). 24:497–503.[Medline]
  19. Erfurth EM, Ericsson UB. 1992 The role of estrogen in the TSH and prolactin responses to thyrotropin-releasing hormone in postmenopausal as compared to premenopausal women. Horm Metab Res. 24:528–531.[Medline]
  20. Clifton DK, Aksel S, Bremner WJ, Steiner RA, Soules MR. 1988 Statistical evaluation of coincident prolactin and luteinizing hormone pulses during the normal menstrual cycle. J Clin Endocrinol Metab. 67:832–838.[Abstract]
  21. Ehara Y, Siler T, VandenBerg G, Sinha YN, Yen SS. 1973 Circulating prolactin levels during the menstrual cycle: episodic release and diurnal variation. Am J Obstet Gynecol. 117:962–970.[Medline]
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