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Department of Obstetrics and Gynecology, New Jersey Medical School, Newark, New Jersey 07103
Address all correspondence and requests for reprints to: Dr. Harry J. Lieman, Department of Obstetrics, Gynecology, and Women’s Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461.
Abstract
GH and IGF-I secretion decrease with age. The decline in serum GH with age appears to be associated with menopause. Prior studies of GH release before and after oral and transdermal hormonal replacement in the postmenopausal patient have shown no change or an increase in GH secretion. To distinguish the somatotropic axis effects of aging from those of estrogen deficiency, we compared eight prematurely menopausal women, aged 25–40 yr, with eight postmenopausal women, aged 51–70 yr, both before and after estradiol replacement. All women had a body mass index below 28 kg/m2. All were evaluated twice with frequent blood sampling every 10 min for 24 h. Studies were performed in the absence of exogenous hormones and 6–8 wk after transdermal estradiol replacement, targeted to achieve a serum estradiol level of 367 pmol/liter. GH pulsatility was analyzed. Variables tested included mean GH levels, interpulse baseline mean, pulse frequency per 24 h, and pulse amplitude. Transdermal estrogen replacement had a significant effect on mean GH levels and mean basal GH levels in both the premature ovarian failure and the age-appropriate postmenopausal group. No differences were noted in GH pulse frequency, GH pulse amplitude, IGF-I, IGF-binding protein-1, and IGF-binding protein-3 before and after treatment. A pronounced age effect was noted between the two groups. The premature ovarian failure women secreted significantly greater mean GH than the age-appropriate postmenopausal group regardless of treatment, with a significance level of P = 0.026. Interpulse baseline GH means were greater in the premature ovarian failure women than in the age-appropriate postmenopausal group, but the significance of this relationship was obliterated after adjustment for body mass index. Pulse amplitude was significantly increased in the premature ovarian failure women compared with age-appropriate postmenopausal women (P = 0.006). No significant changes were detected in the GH pulse frequency between the premature ovarian failure and postmenopausal groups. We conclude that moderate doses of transdermal estradiol supplementation do not exert a great effect on the somatotropic axis in women. Age and body composition appear to be the predominant influences on GH activity in women.
GH SECRETION varies throughout life. It increases during puberty, peaks in late puberty, and declines in older age. Ho et al. (1) demonstrated these changes by combining data from 24-h GH studies in the literature and expressed secretion relative to the prepubertal years. The decline during aging seems to be related to a decrease in GH production and an increase in clearance rate (2) as well as a loss of sleep-associated GH release (3). The secretion of IGF-I, the principal peripheral tissue mediator of GH, parallels that of GH throughout life. After the initial rise in puberty, there is also a progressive decline with age (4, 5, 6).
Endogenous estradiol has been shown to influence GH secretion in a variety of models. Animal studies have demonstrated that estrogen stimulates GH release via effects on the hypothalamic secretion of somatostatin (SRIF) and GHRH (7). Estrogen has also been shown to inhibit hepatic IGF-I mRNA production in the rat (8). Based on this information, Ho et al. (9) propose that estrogen-mediated increases in GH occur secondary to the fall in circulating IGF-I levels. The observations of Rose et al. (10) and Martha et al., (11) suggest that gonadal steroids are important regulators of GH, as the increase in GH secretion is simultaneous with the growth spurt of adolescents. GH levels are also known to peak in the late follicular phase of the menstrual cycle at the time when estradiol levels are high (12).
Exogenous estrogen exerts disparate effects on the somatotropic axis that appear dependent upon dosage and route. Oral estrogens increase GH release in postmenopausal women, with a concomitant decrease in IGF-I, whereas transdermal estradiol exerts a far lesser effect on GH or IGF-I (13). Bellantoni et al. (14) did not observe any significant differences in GH and IGF-I economy, as assessed by challenge testing, before and after treatment with transdermal estrogens. Friend et al. (15) replaced postmenopausal women with oral or transdermal estradiol at high doses and found significant increases in GH secretion with similar decreases in the IGF-I levels. This study concluded that the effects seen are most likely related to the inhibited negative feedback from reduced IGF-I levels and that the effects of estrogens on the somatotropic axis are identical regardless of route, provided a large enough dose is administered.
Age also plays a highly significant role in the GH axis decline. Wilshire et al. (16) evaluated GH secretion in older reproductive aged women vs. younger women and demonstrated significantly lower GH levels in the former despite higher estradiol levels on the day of sampling. Bellantoni et al. (14) studied the effects of transdermal estrogen on GH and IGF-I in postmenopausal women of different ages and found that age in postmenopausal women is associated with decreases in peak and integrated GH responses to GHRH and basal IGF-I levels. A more recent study (17) comparing the effects of oral and transdermal estrogen on the GH axis in older vs. younger postmenopausal women suggests that the GH axis is more active in younger postmenopausal woman.
The present study was performed to better differentiate age-related changes in GH secretion from gonadal steroid-related changes. We evaluated several parameters of somatotropic axis function in age-appropriate menopausal (AAM) patients and compared them to women with idiopathic premature ovarian failure (POF). Both groups of women still retained their ovaries and had normal phenotypes. We observed GH secretory patterns before and after exogenous estradiol administration and examined the differences to assess the impact of aging in the presence and absence of estrogen.
Subjects and Methods
Subjects
All participants gave their informed consent for the following studies, and institutional review board approval was obtained before their initiation. Sixteen women were studied: 8 with POF and 8 with AAM. Women with POF were required to meet criteria that ruled out systemic disease or gonadal ablation as a cause of their premature menopause. All women were 1) at least 90% normal weight for height (18) and had a body mass index (BMI) less than or equal to 28 kg/m2, 2) had normal PRL and TSH levels, 3) had menarche at 10–15 yr, 4) had regular menstrual cycles of 25–35 d in length before the onset of ovarian failure, 5) received no hormonal therapy within 6 months of the current study (see below), 6) had serum FSH below 40 IU/liter and estradiol below 147 pmol/liter before enrollment in the study, 7) had at least 1 yr of amenorrhea before the study or no unscheduled menses while receiving estrogen/progestin replacement (discontinued 6 months before the study), 8) had onset of amenorrhea before the age of 35 yr, 9) were 40 yr or younger at the time of the study, 10) had a 46,XX karyotype on at least 50 cells counted, and 11) had no evidence of autoimmune polyglandular failure, with normal sequential multianalysis-18; normal complete blood count; negative anti-TG, antimicrosomal, antimitochondrial, and antiadrenal antibodies; negative antinuclear antibody (except for participant 6, with a stable antinuclear antibody 1:160 that antedated her menopause, did not change with 5 yr of follow-up, and was not associated with any clinical or biochemical evidence of autoimmune disease); and normal 1-h cortisol response to 250 µg exogenous cortrosyn. Women with AAM met criteria 1–7 and had their menopause at age 50 yr or older.
Sampling technique and protocol
All women were admitted to a metabolic testing unit and underwent two 24-h frequent blood-sampling sessions. Some started their studies at 0800 h and others at 2000 h. During the hospital admission, 2-ml blood samples were withdrawn from an indwelling iv catheter every 10 min. Participants were sampled with and without 8 wk of estradiol supplementation. In half the subjects, estradiol supplementation was provided for at least 8 wk before the first study. In these women, long-term estrogen replacement was not discontinued before the study. Such patients were transferred to transdermal estradiol for 6–8 wk before their first frequent sampling session. Subjects were then weaned off estradiol for the second study, 8 wk later. This order was reversed in the other half of the subjects. Estradiol was administered in the form of transdermal skin patches (Estraderm, Ciba-Geigy, Morris Plains, NJ.) One participant who had a skin reaction to the reservoir patch was switched to a weekly matrix patch (Climara, Berlex, NJ) with maintenance of adequate circulating estradiol. Participants were sampled every 2 wk to document achievement of target estradiol concentrations of at least 367 pmol/liter while receiving replacement. Target estradiol levels were achieved by using combinations of 0.1- and 0.05-mg patches as needed. Another participant developed a skin rash from the transdermal estradiol and was treated with oral estradiol (Estrace, Bristol-Myers Squibb Co., New York, NY; 2 mg/d) to achieve the desired circulating estradiol concentrations. As her results were similar to those of the rest of the women in her group, and her inclusion or exclusion did not affect statistical outcomes, her data were included in the final analysis.
All participants had a regular diet during the hospital admission and were able to move about their hospital rooms freely. The phlebotomists recorded meal times and sleep intervals on the frequent sampling log sheets. Electroencephalogram sleep monitoring was not performed. Therefore, no information regarding sleep stage was obtained.
Assays
GH was measured in serum using a commercially available sensitive fluoroimmunometric assay (DELFIA, Wallac, Inc., Gaithersburg, MD). The mean intraassay coefficient of variation (CV) was 4.0%, and the mean interassay CV was 5.6%. GH was analyzed in 10-min interval samples from each subject and in pooled sera from each admission. The minimal detection limit for this GH assay was approximately 0.01 µg/liter. The test cross-reactivities with PRL, TSH, and FSH were less than 0.001%, and that with LH was less than 0.1%. Estradiol was measured using a direct RIA (Pantex, Santa Monica, CA). Intra- and interassay CVs for this assay were 2.8% and 9.7%, respectively. The limit of sensitivity for the estradiol assay was 37 pmol/liter, and cross-reactivity with estrone was estimated to be less than 0.001% by the manufacturer.
Pooled samples were also analyzed for IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3. IGF-I levels were determined using an extraction assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra- and interassay CVs were 2.7% and 6.8%, respectively. Serum concentrations of IGFBP-1 were determined by an immunoradiometric assay (Diagostics Systems Laboratories, Inc., Webster, TX). The intraassay CV was 3.6%, and the interassay CV was 4.6%. Serum levels of IGFBP-3 were analyzed by RIA (Nichols Institute Diagnostics). The intra- and interassay CVs were 5.6% and 5.8%, respectively.
Statistics
The frequent sampling GH data were analyzed to statistically compare somatotropic axis activities of the AAM women and the younger women with POF and within each group before and after treatment with estrogen.
GH pulse patterns were analyzed objectively with the pulse detection program PULSEFIT (19). The program is based on a dynamic model that reiteratively fits a differential equation to frequent sampling data by assuming that pulsatile hormone levels follow a pattern of rapid increase after an injection event, followed by exponential decay. The mean, baseline, frequency of pulses, and the amplitude of GH secretion were determined with the PULSEFIT program.
All data points within each variable studied from both groups of women were checked for normal distribution with the Shapiro-Wilke test. If identified as an abnormal distribution, log transformations were used to normalize the data. A multiple ANOVA was used to assess the relationships of the studied variables between the two groups of women and within each group before and after treatment. Statistical significance was declared for differences found to have P < 0.05. The comparison of BMI between the groups was performed by t test. Normalization of data, Shapiro-Wilke test, multiple ANOVA, and t tests were performed with JMP, version 3.1 statistical software (SAS Institute, Inc., Cary, NC). The graphs were created using EXCEL 97(Microsoft Corp., Redmond, WA).
Results
General characteristics of the study population
Women with POF had a mean age of 35 ± 1.66 yr (mean ± SE), and women with AAM had a mean age of 59 ± 2.55 yr. All were at least 1 yr postmenopausal. The mean BMI of the POF group was 22.3 ± 0.92, and the mean BMI of the AAM group was 25.6 ± 0.97 (P = 0.03). Mean circulating estradiol levels before replacement therapy (POF vs. AAM, 59 vs. 72 pmol/liter) were not significantly different between groups (POF range, 37–118 pmol/liter; AAM range, 43–118 pmol/liter). Estrogen replacement caused a significant increase in each group. Comparison of both groups after estrogen treatment revealed no statistical difference in the means for the younger women (389 pmol/liter; range, 220–654 pmol/liter) compared with the older women (538 pmol/liter; range, 202–1035 pmol/liter).
Age-related characteristics of GH secretion
Mean GH secretion in the POF women was greater (mean, 0.7
µg/liter; range, 0.3–2.5 µg/liter) than mean GH secretion in the
AAM subjects regardless of estradiol levels (mean, 0.3 µg/liter;
range, 0.04 -1.0 µg/liter). The significance persisted even after
adjustment for BMI (P = 0.026; Figs. 1
and 2).
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).
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).
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GH response to estradiol
Estradiol therapy had no effect on any parameters of GH secretion once the BMI differences were taken into account. In all women studied mean GH levels before estradiol replacement were not significantly different after therapy (preestradiol, 0.4 µg/liter; range, 0.04–1.3; postestradiol, 0.6 µg/liter; range, 0.09–2.5; P = 0.65). Interpulse mean GH levels were similarly not significantly different before and after therapy (preestradiol therapy, 0.04 µg/liter; range, 0.01–0.1 µg/liter; posttherapy, 0.06 µg/liter; range, 0.01–0.4 µg/liter; P = 0.4).
Although age group differences were noted with regard to pulse
frequency, estrogen did not cause any significant change
(P = 0.74). Pretreatment frequency was 9.95 pulses/24
h, with a range of 4–18 pulses/24 h. This compares to 10.22 pulses/24
h, posttreatment levels and a range of 6–16 pulses/24 h. Hormone
replacement also had no significant effect on GH mean amplitude
(P = 0.34). Before treatment, amplitude levels were 1.3
µg/liter (range, 0.1–6.5). Postestrogen treatment amplitude levels
were 1.8 µg/liter (range, 0.3–8.8). Table 1 summarizes these results.
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IGF-I, IGFBP-1, and IGFBP-3 levels were measured in 22 of the 32 frequent sampling studies. Neither age nor estradiol therapy had any significant effect on these GH parameters. Mean IGF-I levels in the POF group was 190 ng/ml and ranged from 101–293 ng/ml. In contrast, the AAM group had a mean IGF-I level of 139 ng/ml and a range of 45–216 ng/ml (P = 0.23). Estradiol treatment caused no significant changes in the IGF-I level (preestradiol mean IGF-I, 166.5 ng/ml; range, 72–293; postestradiol mean, 162.5 ng/ml; range, 45–270; P = 0.69).
POF women had lower IGFBP-1 levels than the AAM women, but statistically the difference was insignificant (POF, 2.1 ng/ml; range, 0.47–24.94; AAM, 5.0 ng/ml; range, 0.6–44.5; P = 0.06). Estrogen did not cause any changes in this binding protein (preestradiol, 3.0 ng/ml; range, 0.35–39.7; postestradiol, 4.1; range, 0.3–44.5; P = 0.45).
IGFBP-3 had results similar to those of the other binding protein studied. No group differences were identified (POF, 3.8 µg/ml; range, 2.9- 4.6; AAM, 3.5 µg/ml; range, 1.8–4.9; P = 0.53) and hormone therapy also had no significant effect (before estrogen, 3.8 µg/ml; range, 1.9–4.9; posttreatment, 3.5 µg/ml; range, 1.8–4.5; P = 0.35).
Discussion
GH secretion and its modulation by aging and reproductive hormones is a complex issue. This subject has been of particular interest to many investigators in recent years as GH replacement or stimulants of GH secretion may prove to be beneficial in reversing some of the deleterious effects of aging. Specific areas evaluated include the effects of aging and gonadal steroids on the somatotropic axis. These variables are inherently difficult to separate from each other in men and women in particular. As women reach menopause, their ovaries are no longer able to secrete gonadal steroids as they had been able in the reproductive years. Numerous studies have suggested that gonadal steroids play an important role in GH secretion (5, 10, 12). Women deficient in these steroids, such as postmenopausal women, have diminished GH secretion. Estrogen replacement studies (5, 15) measuring the effects on the GH axis before and after hormone replacement confirm this theory and suggest that hormone replacement can restore GH secretion. Simultaneous with this noticeable effect of the changing steroid milieu in the menopausal women and decreased GH secretion, the aging process itself has profound effects on the somatotropic axis as is evident in earlier studies (1, 14, 16). GH secretion diminishes with age. This is the first study to our knowledge to evaluation of the GH axis that uses women with premature ovarian failure as a model for women with age appropriate menopause. This model allows a clear-cut separation of the process of aging from that of ovarian failure. We are able to support the hypothesis that increased age has a far greater effect on diminished GH secretion than does the lack of estrogen.
Although the women in our two study groups have significant differences in their ages, both groups are good examples of healthy women in a hypogonadal state. Prereplacement estradiol levels were not significantly different in each group. Estradiol treatment was given to obtain midfollicular cycle levels as in previous studies (15), and these replacement levels were not significantly different in the younger women compared with the older women.
Previous studies evaluating the effects of exogenous hormone replacement on the somatotropic axis have had mixed results. Our data agree with those of Bellantoni (14, 17) that transdermal estradiol in modest doses does not increase GH secretion in women with AAM. This is in apparent disagreement with findings reported by Friend et al. (15). In that study replacement estradiol concentrations were greater than 600 pmol/liter, and GH secretion increased dramatically. It is likely that large enough amounts of estradiol can override the effect of route of administration (i.e. transdermal). Bellantoni et al. (14) and Weisberger et al. (13) were not able to detect differences in GH after estradiol treatment, and perhaps it is related to lower postreplacement serum estradiol levels (130 pmol/liter).
The GH profile can be separated into interpulse baseline means and amplitude means. Prior studies demonstrating a positive effect of estradiol on GH have shown that overall mean GH secretion increases largely because of increased amplitude secretion. Both animal and human studies have suggested that steroids can cause this change. Interestingly, the younger women had significantly higher mean GH, GH mean amplitude, and increased interpulse interval compared with the respective GH variables measured in AAM women regardless of treatment. Our findings support the idea that age and not estradiol has the greater effect on these parameters of GH secretion.
In contrast to our finding of a borderline increased interpulse interval in POF women relative to AAM women, others have generally not reported changes in the frequency of release of GH pulses related to aging (5, 10, 11). Endogenous or exogenous gonadal steroids have also not generally been associated with changes in GH pulse frequency (12, 13, 15). Our data support the idea that exogenous steroids do not change the frequency of GH pulsatile release.
Evidence suggests that the hypothalamic peptides, GHRH, and SRIF control release of GH. Pulsatile frequency is related to GHRH release and the amplitude peak and baseline levels modulated by SRIF. As GH pulse amplitudes were mostly affected by age and not by estrogen in our study, this observation is most consistent with the idea that aging increases SRIF tone and causes a decrease in GHRH release.
The GH axis is further regulated by IGF-I. Friend et al. (15) noted significant decreases in IGF-I levels after transdermal estradiol supplementation in the postmenopausal patient. Those findings were consistent with previous studies (13) and consistent with the theory of IGF-I feedback and modulation of GH secretion; decreasing IGF-I levels allows for increased secretion of GH. Even though our findings showed increased mean GH levels in the younger women, we did not detect any changes of IGF-I levels in either group before and after hormone replacement. Our findings for IGF-I are similar to Bellantoni et al. (14). The theory that IGF-I secretion parallels GH secretion throughout life (4, 5) is confirmed by our data. The younger women had a tendency to have higher IGF-I levels than the AAM women, although this was not of statistical significance. Not only do these findings suggest that factors other than IGF-I fluctuation play a role in GH modulation, but the results strongly suggest that the age factor is a more significant element than gonadal steroids in the observed IGF-I levels. It is also possible that the slightly lower estradiol levels compared with the study by Friend et al. are a cause of the distinction in IGF-I levels.
Unfortunately, just as it is difficult to separate age changes from gonadal steroid alterations in the climacteric, modifications in body composition with age have effects on the somatotropic axis and make it difficult to distinguish the exact factors we want to study. The lack of body composition data on the women we studied limits our ability to make inferences about the role of relative adiposity vs. aging per se on the GH axis dynamics in our experimental model. Obesity has been proven to have an inverse relationship with GH secretion. Veldhuis et al. (20) observed a significant drop in mean GH levels in obese men compared with nonobese controls. Other studies (2) suggested a dual effect of obesity; the decrease GH secretion in obese individuals is related to diminished GH production as well as increased clearance of GH. Ho et al. (5) determined that even a relative adiposity is negatively correlated to GH secretion. Age-related relative adiposity may cause significant differences in GH regulation when comparing younger to older subjects. In an attempt to avoid obesity-related diminished GH secretion, our study had included only participants with a BMI of 28 or less. Even with these strict criteria, the younger women with ovarian failure still had a significantly lower BMI compared with the AAM women. Adjusting for BMI in our data led to a loss of statistical significance for several of the apparently age- associated variables in GH secretion. In particular, the interpulse mean GH was strikingly and significantly greater in the POF women compared with the AAM women before correction for BMI. Once corrected, this relationship disappeared, underscoring the sensitivity of the GH axis to body composition even within a normal range of BMI. The theory stated earlier that aging increases SRIF tone and diminishes GHRH release, thereby decreasing mean GH levels, is also seen in obesity. Veldhuis et al. (20) confirmed this similar hypothesis in their study on morbidly obese men.
In summary, transdermal estrogen replacement to a midfollicular level did not increase the 24-h GH mean or interpulse baseline mean in women with ovarian failure regardless of their age. On the other hand, younger women with POF had higher levels of mean GH, increased interpulse interval, and increased mean GH amplitude compared with the older women. IGF-I and the IGFBPs were unchanged in either group before and after estrogen therapy. We conclude that younger hypogonadal women have greater GH secretion than the older AAM patients. Transdermal estrogen replacement did not play a detectable role in restoring some of the GH activity, but age and body composition appeared to have the predominant effect on the somatotropic axis.
Footnotes
This work was supported by NIH Grant AG-12222 (to N.S.). This work was presented at the 10th International Congress of Endocrinology, San Francisco, California, June 12–15, 1996.
1 Present address: Department of Obstetrics, Gynecology, and Women’s
Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue,
Bronx, New York 10461. 
Abbreviations: AAM, Age-appropriate menopausal; BMI, body mass index; CV, coefficient of variation; IGFBP, IGF-binding protein; POF, premature ovarian failure; SRIF, somatostatin.
Received August 2, 2000.
Accepted April 25, 2001.
References
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