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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2677
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 5 1655-1661
Copyright © 2008 by The Endocrine Society

24-Hour Serum Levels of Growth Hormone, Prolactin, and Cortisol in Pre- and Postmenopausal Women: The Effect of Combined Estrogen and Progestin Treatment

Nea Kalleinen, Päivi Polo-Kantola, Kerttu Irjala, Tarja Porkka-Heiskanen, Tero Vahlberg, Arho Virkki and Olli Polo

Sleep Research Unit (N.K., P.P.-K., A.V., O.P.), Department of Physiology, and Departments of Biostatistics (T.V.) and Mathematics (A.V.), University of Turku, FIN-20520, Turku, Finland; Department of Obstetrics and Gynecology (P.P-K.), Turku University Central Hospital, FIN-20520, Turku, Finland; Mehiläinen Oy (K.I.), FIN-20520 Turku, Finland; Department of Physiology (T.P.-H.), University of Helsinki, FIN-00014 Helsinki, Finland; and Department of Pulmonary Diseases (O.P.), Tampere University Hospital, FIN-33521 Tampere, Finland

Address all correspondence and requests for reprints to: Nea Kalleinen, Sleep Research Unit, Dentalia, Lemminkäisenkatu 2, FIN-20520 Turku, Finland. E-mail: nea.kalleinen{at}utu.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: Our objective was to study the 24-h profiles of GH, prolactin (PRL), and cortisol concentrations in older postmenopausal and middle-aged premenopausal women, before and after estrogen-progestin treatment (EPT).

Design: The study was a randomized, placebo-controlled, double-blind trial. GH, PRL, and cortisol were sampled every 20 min for 24 h in 18 postmenopausal (aged 58–70 yr) and 17 premenopausal (aged 45–51 yr) women before and after 6 months of EPT.

Results: The mean 24-h GH (1.0 vs. 1.8 mU/liter, P = 0.033) and PRL (6.8 vs. 10.0 ng/ml, P = 0.009) concentrations were lower in postmenopausal than in premenopausal women. After EPT, the postmenopausal GH and PRL did not differ from premenopausal baseline levels. Postmenopausal mean 24-h GH (P < 0.001) and PRL (P = 0.002), daytime GH (P < 0.001) and nighttime PRL (P = 0.004) were higher during EPT compared with placebo. Cortisol levels did not differ. Premenopausal mean nighttime PRL (P = 0.026) and cortisol (P = 0.018) were higher during EPT compared with placebo. Postmenopausal PRL and premenopausal GH and PRL concentrations were higher at night than during the day. EPT did not alter this pattern.

Conclusions: Menopause was associated with decreased 24-h levels of GH and PRL, which were reversible with EPT. In contrast, cortisol levels were not affected by menopause or EPT. In middle-aged premenopausal women, the studied effects of EPT were limited to nighttime increases of PRL and cortisol.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
In addition to direct effects of the female sex hormones on their target organs, many of their effects are indirect, mediated through other hormones. Some of the actions of the sex hormones are considered to counteract aging until menopause occurs. Because GH, prolactin (PRL), and cortisol are affected by aging (1, 2, 3), changes in their secretions across menopause and during menopausal hormone therapy (HT) are of interest.

GH secretion is pulsatile with maximal secretion occurring at night shortly after sleep onset (2). Total GH secretion and its sleep-associated release progressively decline with aging (1, 2, 4, 5). Women have higher levels of GH than men of the same age, but this difference disappears after menopause (1, 6). Age-related GH decrease may account for some of the undesirable changes in body composition, such as decrease in protein synthesis and muscle mass, turnover of bone, and increase in fat mass, because GH treatment restores, at least partially, these changes (1).

PRL concentration is minimal around noon, and major elevation occurs soon after sleep onset (2). This circadian and sleep-dependent pattern of PRL secretion is maintained, but the levels decrease with increasing age (2, 7). PRL levels are higher in conditions with high estrogen concentrations such as in young women, especially during pregnancy (8). In men and postmenopausal women, the diurnal PRL levels are low (7).

Cortisol secretion has a circadian pattern, with the highest levels in the morning and the lowest in the evening (2). This pattern is not markedly affected with aging, but the levels tend to increase (2, 3, 9). Postmenopausal women have higher cortisol levels than premenopausal women (10), but the effect of age has not been excluded. Although cortisol is essential in response to acute stress, chronic elevation of cortisol is detrimental (11, 12).

HT is used to alleviate climacteric symptoms in peri- and postmenopausal women and is also effective in controlling early symptoms in premenopausal women. Unopposed estrogen treatment (ET) or estrogen combined with progestin [estrogen-progestin treatment (EPT)] is administrated either orally or transdermally in a continuous or cyclic pattern. Previous studies on the effects of HT on GH, PRL, and cortisol levels have used various formulas and routes of administration and produced conflicting results. We measured the 24-h serum profiles of these hormones in pre- and postmenopausal women before and after oral EPT, the most commonly used form of HT. Our hypothesis was that there are menopause- rather than age-related changes in these hormone profiles, which can be demonstrated by their reversibility on EPT.


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

The study subjects comprised 35 healthy women recruited from the Turku city area, Finland. All women gave written informed consent. The study had the approval of the Ethical Committee of Turku University Hospital. Seventeen women were premenopausal (age range 45–51 yr), verified with low serum FSH (<23 IU/ml) and ongoing menstrual cycle. The 18 postmenopausal women (age range 58–70 yr) had chronic amenorrhea. Exclusion criteria were screened, and the study protocol was explained in an interview. Physical examination included gynecological examination and transvaginal ultrasound. Subjects with a neurological, cardiovascular (apart from treated hypertension), endocrinological (apart from treated hyperlipidemia), or mental disease; malignancies; abuse of alcohol or medications; and smoking and excessive consumption of caffeine were excluded. The use of any antioxidants, hormones, or medication affecting the central nervous system was prohibited during the study with a minimum washout time of 3 months. Subjects were included only if they had normal serum TSH, blood hemoglobin, leukocyte, and thrombocyte levels and their urine drug screen was negative.

One woman in the premenopausal group had previously used HT for 3 months, and 13 women in the postmenopausal group had used HT (average time of use 74 months, range 3–156 months). All had discontinued the use at least 12 months before the study (average washout period 52 months, range 12–147 months). The subjects kept a sleep diary for 3 wk before and 1 wk after the 24-h hormone sampling to ensure a regular sleep-wake schedule (2200–2300 h to 0600–0700 h).

Protocol design

The design was a prospective, randomized, placebo-controlled, double-blind intervention. An indwelling catheter was inserted into a forearm vein (near the crook of the arm) 2.5 h before the commencement of the blood sampling in the evening. The catheter was kept patent with a slow heparinized saline infusion. Beginning at 2100 h, a 2-ml blood sample was remotely drawn every 20 min for the duration of 24 h. At night (2300–0700 h), plastic tubing connected to the catheter ran through a soundproof lock into an adjacent room, allowing repeated blood sampling without disturbing the subject’s sleep. The last sample was drawn at 2100 h in the following evening.

After the baseline sampling, the subjects were randomized for the treatment period of 6 months in six-person blocks. Premenopausal women received cyclic EPT (2 mg estradiol valerate for 16 d and 2 mg estradiol valerate plus 1 mg norethisterone (NETA) for 12 d; Mericomb; Novartis, Basel Switzerland) or placebo, with administration beginning during the first day of their menstrual cycle. Postmenopausal women received continuous EPT (2 mg estradiol valerate plus 0.7 mg NETA; Merigest; Novartis) or placebo. Randomization was performed at the pharmacy of the Turku University Hospital where randomization codes were kept secret until data analyses were completed. Nine premenopausal women were randomized into the EPT and eight into the placebo group. In the postmenopausal group, nine women received EPT and nine women placebo. After 3 months of treatment, the subjects were interviewed to ensure compliance, and a blood sample was drawn to control for 17β-estradiol (E2) and FSH.

At the end of the 6-month treatment period, the sampling protocol was repeated identically to baseline. Premenopausal women were studied in the beginning of their menstrual cycle both at baseline (in the follicular phase) and after treatment (on unopposed estrogen). All subjects followed regular eating hours, and they had similar food composition during both sampling periods. The blood samples were drawn into EDTA tubes and placed in the refrigerator for 20 min. Thereafter, they were centrifuged to separate serum, frozen, and kept at –28 C until the next day and then stored at –70 C until assayed.

Hormone assays

Serum GH, PRL, and total cortisol levels were measured with the AutoDELFIA assays (PerkinElmer Life and Analytical Sciences, Wallac Oy, Turku, Finland). The PRL and GH assays were solid-phase, two-site fluoroimmunometric assays based on the direct sandwich technique (in which two monoclonal antibodies are directed against two separate antigenic determinants on those hormone molecules). The cortisol assays were solid-phase, two-site fluoroimmunometric assays based on the competitive reaction between europium-labeled cortisol and sample cortisol for a limited amount of binding sites on cortisol-specific, biotinylated monoclonal antibodies. The analytical sensitivity (zero standard mean + 2 SD) was 0.03 mU/liter for GH, 0.04 ng/ml for PRL, and 15 nmol/liter for cortisol.

GH peak detection

To ensure reproducible and unambiguous detection of the serum GH peaks, we designed a simple computer algorithm for this task. The results were validated against experienced manual scorer’s visual judgment. Missing observations were first linearly approximated from the available adjacent observations, and the GH levels were then approximated with cubic splines. GH peaks of less than 1.0 mU/liter or below two times the individual signal baseline were excluded. To exclude false observations caused by signal noise, it was also required that within an 8-min window before and after each GH peak, the signal amplitude must change at least 0.03 mU/liter for the postmenopausal and 0.06 mU/liter for the premenopausal group.

Statistics

The differences in body mass index (BMI) and age between EPT and placebo groups were tested with two-sample t test. Analysis of covariance (ANCOVA) was used in comparisons of the mean serum GH, PRL, and cortisol levels and number of the peaks in GH levels between the groups. BMI was used as a covariate in baseline comparisons. BMI and baseline levels were used as covariates when analyzing the mean levels after the 6-month treatment period. Baseline comparisons between postmenopausal and premenopausal women were done with combined EPT and placebo groups. In addition, after the treatment, mean 24-h hormone levels of postmenopausal women in the EPT group were compared with the corresponding baseline levels of all premenopausal women to study whether postmenopausal women on EPT would reach the premenopausal hormone state. In the analyses, nighttime refers to the time period from 2300–0700 h and daytime to the time period from 0720–2100 h. The difference between daytime and nighttime mean concentrations was tested with paired t test. Hormone values below the analytical sensitivity were given a number half of the value of the analytical sensitivity. P values < 0.05 were considered statistically significant. All the statistical analyses were performed with SAS System for Windows, release 9.1 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Altogether, 34 women completed the treatment period and the second 24-h sampling. At the 3-month check up, one premenopausal (EPT) woman dropped out for personal reasons. For six postmenopausal women, the second 24-h sampling was performed before 6 months of treatment. One woman from the postmenopausal EPT group attended the second sampling after 3 months, two women after 4 months, and one woman after 5 months, mainly due to side effects. One postmenopausal woman from the placebo group developed a venous thrombosis of the eye, shortening the treatment period to 5 months, and another attended the second sampling after 4 months of treatment. Furthermore, one subject from the postmenopausal EPT group was deleted from the PRL analysis as an outlier due to exceptionally high levels.

The postmenopausal EPT and placebo groups did not differ in terms of age, FSH, or E2 levels at baseline (Table 1Go). BMI was greater in the EPT group than in the placebo group at baseline and after treatment. EPT lowered FSH and increased E2. The premenopausal EPT and placebo groups were similar in age, BMI, FSH, or E2 levels (Table 1Go) at baseline and after treatment.


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  		TABLE 1. Baseline characteristics for the study groups at baseline and after 6 months treatment, expressed as mean (SD)

 
GH

At baseline, postmenopausal women had lower mean 24-h GH, nighttime GH, and maximum GH than premenopausal women (Table 2Go). The mean daytime levels, the minimum values (Table 2Go), or the number of peaks (Table 4Go) did not differ. After EPT, postmenopausal mean 24-h GH levels did not differ from premenopausal baseline levels (P = 0.885; Tables 2Go and 3Go).


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  		TABLE 2. Concentrations of GH, PRL, and cortisol, expressed as mean (SD), for postmenopausal and premenopausal women at baseline.

 

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  		TABLE 4. The number of peaks and the outside peak values (mU/liter) of GH concentration, expressed as mean (SD), for the study groups at baseline and after 6 months treatment

 

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  		TABLE 3. Concentrations of GH, PRL, and cortisol, expressed as mean (SD), in postmenopausal and premenopausal women at baseline and after 6 months of treatment in the EPT group and in placebo group

 
In postmenopausal women at baseline, there was no difference between the EPT and placebo groups in any of the studied GH levels (Tables 3Go and 4Go). After treatment, mean 24-h GH, daytime GH, the maximum GH value (Table 3Go), and the number of peaks during 24 h and during daytime (Table 4Go) were higher in the postmenopausal EPT group compared with the placebo group. The mean nighttime GH, the minimum GH value (Table 3Go), or the number of peaks during nighttime (Table 4Go) did not differ. The mean nighttime GH did not differ from daytime GH in either group at baseline (EPT P = 0.705; placebo P = 0.052) or after treatment (EPT P = 0.582; placebo P = 0.712).

In premenopausal women, the studied levels of GH did not differ between the EPT and placebo groups at baseline or after treatment (Tables 3Go and 4Go). The mean nighttime concentrations were higher compared with daytime in both groups at baseline (EPT P = 0.013; placebo P = 0.031), but after treatment, the difference in placebo group disappeared (EPT P = 0.002; placebo P = 0.300).

PRL

At baseline, postmenopausal women had lower mean 24-h PRL, mean nighttime PRL and maximum PRL than premenopausal women. The mean daytime levels or the minimum values did not differ (Table 2Go). After EPT, postmenopausal mean 24-h PRL levels did not differ from premenopausal baseline levels (P = 0.777, Tables 2Go and 3Go).

At baseline, the postmenopausal EPT and placebo groups did not differ in mean 24-h PRL, nighttime PRL, daytime PRL, or the maximum PRL, but after treatment, these levels were higher in the EPT group compared with placebo (Table 3Go). The minimum PRL value was higher in the EPT group at baseline, and the difference remained after treatment but disappeared after controlling for baseline. The mean nighttime PRL concentrations were higher than mean daytime levels at baseline (EPT and placebo P < 0.001) and after treatment (EPT and placebo P < 0.001) in both groups.

The premenopausal EPT and placebo groups did not differ in any of the studied PRL levels at baseline. After the treatment, nighttime PRL and the maximum PRL value were higher in the EPT group (Table 3Go). Nighttime PRL concentrations remained higher compared with daytime in both groups (baseline: EPT P = 0.001, placebo P < 0.001; after treatment: EPT and placebo P < 0.001).

Cortisol

At baseline, there were no differences between postmenopausal and premenopausal women in any of the studied cortisol levels (Table 2Go). Also, no difference was found when comparing postmenopausal women after EPT to premenopausal women at baseline (P = 0.597; Tables 2Go and 3Go).

In postmenopausal women, there was no difference in cortisol levels between the EPT and placebo groups at baseline or after treatment (Table 3Go). However, after EPT, the mean daytime concentration was higher than the nighttime concentration (baseline: EPT and placebo P = 0.430; after treatment: EPT P = 0.010, placebo P = 0.114).

At baseline, the premenopausal EPT and placebo groups did not differ in any of the studied cortisol levels. After treatment, the only difference was that the mean nighttime cortisol was higher in the EPT group compared with the placebo group. (Table 3Go) There was no difference between the nighttime and daytime mean concentrations at baseline or after treatment (baseline: EPT P = 0.329, placebo P = 0.351; after treatment: EPT P = 0.537, placebo P = 0.112).

Profiles of the 24-h concentrations of the GH, PRL, and cortisol in post- and premenopausal women at baseline and after 6 months EPT are shown in Fig. 1Go.


Figure 1
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  		FIG. 1. Profiles of 24-h concentrations of the studied hormones in post- and premenopausal women at baseline and after 6 months EPT. GH profiles are from a representative postmenopausal or premenopausal woman, respectively. For PRL and cortisol profiles, mean concentrations are demonstrated for combined placebo and EPT groups at baseline and for the EPT group after 6 months treatment. Serum hormone levels were determined at 20-min intervals for 24 h. The gray area indicates nighttime when subjects were allowed to sleep.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study provided additional evidence that menopause is associated with decreased 24-h levels of GH and PRL, which are reversible with EPT. In contrast, menopause, postmenopausal EPT, or age had no effect on cortisol concentrations. These EPT effects were specific for postmenopausal women because only minor effects were observed in middle-aged premenopausal women (only nighttime increase of PRL and cortisol). Furthermore, the physiological pattern of higher levels at night than during the day was seen in postmenopausal PRL and premenopausal GH and PRL concentrations. EPT did not alter this pattern.

Most previous studies on the effects of EPT on GH have been rather short-term, included various types of estrogen and progestin, and produced conflicting results. Weissberger et al. (13) (2 months of oral ethinyl estradiol combined with NETA, cyclic) and Fonseca et al. (14) (3 months of oral conjugated equine estrogen combined with chlormadinone, cyclic) found increased GH levels in postmenopausal women after treatment. This is in line with our results of oral estradiol valerate with continuous NETA. In contrast, in a study using oral estradiol valerate combined with medroxyprogesterone acetate, no effect on GH levels was found (15). Results on unopposed oral ET after menopause have been more congruent. Both short-term (6 wk) and long-term (over 3 yr) oral ET has increased mean 24-h and nocturnal GH (16, 17). In our study, EPT increased GH during the day, which might be less physiological. Postmenopausal GH concentrations had no obvious circadian pattern, whereas in premenopausal women, the physiological pattern of higher GH levels at night was present (2).

Our study confirmed the earlier finding of lower PRL levels after menopause (7) as well as higher PRL concentrations at night than during the day (2, 18). Studies on the effects of HT on serum PRL are scarce. In a study by Chang et al. (18), HT (unopposed ethinyl estradiol or combination with medroxyprogesterone acetate) stimulated a rise in PRL in postmenopausal women without affecting the circadian rhythmicity. Also in our study, EPT increased both the nighttime and the daytime PRL levels in postmenopausal women. The circadian rhythm remained unchanged because the mean PRL concentrations remained higher during the night than during the day. Vekemans et al. (19) studied menstruating women and showed that a very high dose of ethinyl estradiol increased PRL more during daytime than during the night. We used conventional dosage of cyclic EPT and observed increased premenopausal PRL only during the night. However, also in premenopausal women, the circadian rhythm was preserved.

The mean 24-h level of cortisol usually increases with aging (9). In the present study, age or menopausal status did not affect the cortisol levels. Replacing the low endogenous estrogen levels after menopause has produced conflicting outcomes on cortisol. Pluchino et al. (20) and Bernardi et al. (21) studied various types of estrogen combined with different progestins and found decreased cortisol levels in all except in the combination of oral estradiol with NETA. Our results with the same EPT compounds are in line with this. In contrary, Fonseca et al. (22) and Gudmundsson et al. (23) used unopposed conjugated equine estrogen and observed increased cortisol concentrations. In our study, cortisol increased only at nighttime and only in premenopausal women. Like Gudmundsson et al. (23), we used continuous blood sampling for 24 h, whereas the other previous studies determined cortisol levels only from a single morning blood sample. The divergent results of oral HT in postmenopausal women are most probably due to the type of the HT.

Both the administration route of estrogen and its combination with different progestins have importance for the endocrine responses (13, 24). In contrast to transdermal administration, oral estrogens pass first through liver at high concentration and increase the production of binding proteins, such as SHBG (24) and cortisol-binding globulin (25). This may result in no change in active hormone levels despite alterations in total concentrations. Moreover, estrogen induces inhibition of hepatic IGF-I synthesis that results in increased GH secretion through reduced negative feedback (13). Combining oral estrogen with androgenic testosterone-derived progestins such as NETA counteracts the estrogen actions on SHBG and IGF-I synthesis in the liver (24). However, because both unopposed estrogen and its combination with NETA increase GH, also other factors than inhibition of IGF-I synthesis may play a role. The lack of effect on total cortisol during NETA might originate from its probable action on cortisol-binding globulin. EPT containing NETA is commonly prescribed, and therefore, understanding its endocrinological effects is important.

A major limitation of this study was the laborious methodology and study design, which typically results in a relatively small number of subjects. By chance, randomization did not result in similar BMI in the postmenopausal groups. This was controlled by statistical corrections. To avoid iatrogenic disturbance on cortisol concentrations, the iv catheter was inserted 2.5 h before the collection of blood samples was started. In some subjects, side effects shortened the treatment period below the planned 6 months. However, the intervention was never shorter than 3 months. In addition, side effects of HT could have unblinded randomization in some subjects.

Replacing decreased female sex hormone levels after menopause with HT toward fertile levels does not mean that their actions are the same as those of the endogenously secreted sex hormones during premenopause. Restoring the premenopausal hormone milieu, including GH, PRL, and cortisol concentrations, may not solely be beneficial. Increasing GH may predispose to insulin resistance, edema, and arthralgia (1). Higher circulating PRL may increase the risk for breast cancer (26). Chronic elevation of cortisol has been implicated in the pathogenesis of several psychiatric and somatic disorders including depression, obesity, diabetes, and cardiovascular disease (11, 12).

Conclusions

We conclude that menopause decreases the GH and PRL levels and that EPT returns their levels toward those of the middle-aged premenopausal women. In contrast, the 24-h cortisol production is independent of menopause, EPT, or age. As expected, in middle-aged premenopausal women, EPT has fewer effects, which are limited to nighttime increases of PRL and cortisol. GH and PRL are both sleep-promoting hormones (2). Whether their decrease at menopause would explain climacteric sleep complaints and whether their normalization during EPT would mediate the estrogen-induced sleep improvement (27) would be of interest.


   Acknowledgments
 
We thank Novartis Ltd., Basel, Switzerland for supplying estrogen-progestin and placebo.


   Footnotes
 
The study was financially supported by European Commission Grant (QLK6-CT-2000-00499), the Jalmari and Rauha Ahokas Foundation, and the Orion Research Foundation. O.P. was supported by Tampere Tuberculosis Foundation.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 4, 2008

Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass index; E2, 17β-estradiol; EPT, estrogen-progestin treatment; ET, estrogen treatment; HT, hormone therapy; NETA, norethisterone acetate; PRL, prolactin.

Received December 4, 2007.

Accepted February 27, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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