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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3327-3332
Copyright © 2003 by The Endocrine Society

Ovarian Age-Related Responsiveness to Human Chorionic Gonadotropin

Terhi Piltonen, Riitta Koivunen, Aimo Ruokonen and Juha S. Tapanainen

Departments of Obstetrics and Gynecology (T.P., R.K., J.S.T.) and Clinical Chemistry (A.R.), Oulu University Hospital, FIN-90014 Oulu, Finland

Address all correspondence and requests for reprints to: Prof. Juha S. Tapanainen, Department of Obstetrics and Gynecology, Oulu University Hospital, P.O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland. E-mail: juha.tapanainen{at}oulu.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Human fertility starts to decline after the age of 30 yr, but the change in ovarian endocrine function, i.e. estrogen biosynthesis, with advancing age is not well understood. To study age-related changes in androgen secretion and ovarian capacity to synthesize/release androgens in response to human chorionic gonadotropin (hCG) stimulation, 44 healthy women (aged 20–44 yr) were investigated. Just before a single im injection of 5000 IU hCG, blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), and estradiol (E2) assays were collected. Further samples were taken at 24, 48, 72, and 96 h. The responses of 17-OHP, A, and T to hCG, i.e. areas under the curves (AUC; 96 h), correlated negatively with age (17-OHP: r = -0.427; P = 0.004; A: r = -0.266; P = 0.081; T: r = -0.354; P = 0.018). Despite a decreasing capacity of the ovaries to secrete these estrogen precursors, the basal serum levels of E2 remained unchanged. This may be due to the rise in serum FSH levels observed as early as after the age of 25 yr [<=25 yr: FSH, 5.1 ± 0.5 (±SE) U/liter; >25 yr: FSH, 7.7 ± 0.9 U/liter; P = 0.01]. No correlation was found between age and serum inhibin B levels. In conclusion, ovarian androgen secretion capacity starts to decline as early as before the age of 30 yr. Despite that, circulating E2 levels remain normal for years, possibly due to compensatory mechanisms, reflected by the gradual rise in serum FSH levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE MAJORITY OF the 1–2 million follicles present at birth become atretic by undergoing apoptosis, and only about 400 of them will eventually ovulate during reproductive life (1). The period of optimal fertility lasts until the age of about 30 yr and decreases gradually thereafter (2, 3, 4). The follicle pool is decreased significantly by the age of 37–38 yr (5, 6) and at menopause; around the age of 50 yr, the number of follicles is reduced to almost zero. Considering that the transition from regular to irregular menstrual cycles takes 6–7 yr regardless of age at menopause (7, 8, 9) and that subfertility occurs even earlier, there is obviously a significant declining trend in ovarian function at a relatively young age. As a sign of ovarian endocrine aging, serum FSH levels start to rise at 35–40 yr of age (10, 11, 12). Similarly to those of FSH, serum LH concentrations also rise with age, although considerably later (13). Furthermore, an inverse correlation between serum inhibin B levels and age has been observed in some studies (14, 15, 16), but not in all (11).

Although there is an age-related increase in serum gonadotropin levels, changes in ovarian estradiol (E2) secretion are not clear, and data concerning its serum levels are conflicting (17, 18, 19). According to the two-cell-two-gonadotropin theory, LH regulates androgen production in thecal cells, and FSH stimulates estrogen synthesis in granulosa cells (20, 21). As the relative proportion of ovarian follicular cells decreases and that of stromal cells increases with age, there may be changes in the contributions of these two cell compartments with regard to estrogen biosynthesis. We therefore investigated ovarian basal and gonadotropin [human chorionic gonadotropin (hCG)]-stimulated capacity to secrete androgens essential for estrogen biosynthesis in 44 women, aged 20–44 yr.


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

Forty-four female volunteers (aged 20–44 yr; body mass index, 19.0–31.8) participated in the study. All of the women had regular cycles (28–35 d) and normal-appearing ovaries in transvaginal ultrasonography. One subject was taking medication for depression, and one used antihistamines for allergy; their hormone values did not differ from those of the other subjects. Otherwise the subjects took no medication. Six subjects had previously been diagnosed as having mild or moderate endometriosis, which did not affect the ovaries, and they had not received any medical treatment before the hCG test. Informed written consent was obtained from each subject, and the study was approved by the ethics committee of Oulu University Hospital (Oulu, Finland).

hCG test

All subjects underwent hCG stimulation 2–5 d after spontaneous menstrual bleeding. The follicular phase was confirmed by measuring basal serum progesterone (P) levels. Fasting blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), and E2 assays were collected before a single im injection of 5000 IU hCG (Pregnyl, Organon, Oss, Holland) between 0700–0900 h and thereafter at 24, 48, 72, and 96 h.

Assays

Serum concentrations of T and P were analyzed using an automated chemiluminescence system (T: ACS-180, Ciba-Corning, Medfield, MA; P: Advia Centaur, Bayer Corp., New York, NY). Inhibin B concentrations were analyzed by commercial ELISA using a specific ßB-subunit of inhibin (Serotec Ltd., Oxford, UK). Serum concentrations of FSH and LH were analyzed by fluoroimmunoassays (Wallac, Inc., Turku, Finland), and RIAs were used for 17-OHP, A (Diagnostic Products, Los Angeles, CA), and E2 (Orion Diagnostica, Oulunsalo, Finland) following the instructions of the manufacturers. Areas under the curve (AUCs) for the 17-OHP, A, T, and E2 responses were calculated by the trapezoidal method. The intra- and interassay coefficients of variation were 3.8% and 4.3%, respectively, for FSH, 4.9% and 6.5% for LH, 5.2% and 6.4% for inhibin B, 5.0% and 5.4% for 17-OHP, 5.0% and 8.6% for A, 4.0% and 5.6% for T, 5.7% and 6.4% for E2, and 3.7% and 5.4% for P, and the external quality control of the hormone assays was organized by national (Labquality Ltd., Helsinki, Finland) and international (Murex Biotech Ltd., Dartford, UK) companies.

Statistics

Huynh-Feldt’s correction was used to measure significance within a group and also to determine whether the stimulation patterns differed between the groups. To compare serum hormone levels and ovarian responses to hCG (AUCs) between different age groups at each time point, the independent samples t test was used as a post hoc test for normally distributed variables, and the Mann-Whitney U test was used for variables with skewed distribution. Pearson’s correlation coefficient (r) was calculated to correlate age with FSH, LH, inhibin B, and steroid AUC 96 h data (Figs. 1Go and 2Go). The limit of statistical significance was set at P <= 0.05.



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  		FIG. 1. Pearson’s correlation (r) between age and basal serum concentrations of FSH, LH, and inhibin B.

 


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  		FIG. 2. Pearson’s correlation (r) between age and AUC at 96 h for 17-OHP, A, T, and E2. The values are stated as mean values over 96 h.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal hormone levels

Steroids. None of the subjects had serum P concentrations over 7.1 nmol/liter, confirming that the study was performed during the follicular phase (Table 1Go). Significant decreases in serum 17-OHP and A concentrations were seen as early as after the age of 25 yr (Table 1Go). Similarly, serum T levels showed a decreasing tendency, but the changes were not statistically significant. Serum E2 levels were comparable in all age groups (Table 1Go). When the age division was set at 35 yr, only 17-OHP concentrations differed significantly, which may be the result of great individual variation. Other steroid levels did not differ significantly from those in younger women, which may also be due to great individual variation.


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  		TABLE 1. Serum basal hormone levels in different age groups

 
FSH, LH, and inhibin B. Serum FSH levels were higher in the older age groups when the age division was set at 25, 30, or 35 yr (Table 1Go). This observation was also supported by the positive correlation between FSH levels and age (Fig. 1Go). No correlation to age was observed in serum LH and inhibin B levels (Table 1Go and Fig. 1Go).

Hormone responses to hCG

AUCs. AUCs at 24, 48, and 96 h, reflecting the responses to hCG, are shown in Table 2Go. AUCs of all steroids at 24 h showed a decreasing tendency with age, and the responses of 17-OHP and T to hCG were significantly higher in women 25 and 30 yr or younger compared with older subjects. Similarly, in women 25 and 30 yr of age or younger, the 48 and 96 h AUCs of 17-OHP and T were greater than in older subjects, and a similar trend was observed in the AUCs of A. Furthermore, the AUCs of 17-OHP and T at 96 h correlated negatively with age (Fig. 2Go). The serum E2 response to hCG, the AUC at 96 h, was significantly increased in women more than 30 yr of age compared with those 30 yr or younger.


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  		TABLE 2. AUC at 24, 48, and 96 h, reflecting the steroid responses to hCG stimulation

 
Response patterns. Huyhn-Feldt’s correction showed that the responses of all steroids to hCG in women 30 yr or younger and more than 30 yr were significant, and the response patterns in these two age groups were similar, except for that of E2 (Fig. 3Go). In women 30 yr or younger, the serum E2 concentration reached a maximum 24 h after hCG, whereas in older women, serum E2 concentrations increased gradually up to 96 h.



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  		FIG. 3. Responses of serum 17-OHP, A, T, and E2 to a single dose of hCG (5000 IU) in women aged 20–30 yr (•; n = 20) and in women aged 31–44 yr ({circ}; n = 24). Statistical significance between the groups at each time point: *, P <= 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study shows that as early as 25–30 yr of age considerable changes in ovarian endocrine function take place. The ovarian capacity to secrete estrogen precursors in response to hCG, reflected by AUC data, was clearly decreased in women older than 30 yr. Similarly, the negative correlations between age and AUCs demonstrated the decreasing androgen secretion capacity with age. Despite the decreases in serum androgen concentrations, E2 levels remained unchanged in women aged 20–44 yr.

Most studies that have involved age-related hormonal changes in the ovary have been focused mainly on gonadotropin, inhibin A and B, and E2 levels. The decline in E2 precursors during aging has been reported in some studies (22, 23, 24), although in most of them the subjects have been older than in the present study. In our study the basal serum levels of A decreased most clearly, which is in agreement with the results of a previous study (25). The contribution of the adrenal glands with regard to 17-OHP, A, and T production is about 30% (26), and a marked decline in circulating adrenal steroids takes place early in reproductive life (25, 27). Hence, the role of the ovaries in this phenomenon cannot be determined on the basis of basal serum hormone concentrations. However, as the responses of 17-OHP, A, and T to hCG mainly reflect ovarian activity (26), and they were decreased at the age 25–30 yr, it is most likely that ovarian hormonal capacity declines relatively early.

Data concerning alterations of serum follicular E2 levels during reproductive life are controversial. Levels of E2 have been shown to decrease (17, 27, 28), remain unchanged (19, 29, 30), or increase (15, 18, 31). Our results indicate that basal serum levels of E2 do not change in women aged 20–44 yr, and it is possible that gradually rising FSH levels compensate for the declining ovarian capacity to synthesize steroids, thus preserving normal E2 levels in older women. Furthermore, the maximal E2 concentrations after hCG were reached more slowly in women more than 30 yr of age. This is probably due to lower numbers of granulosa cells and smaller rapidly releasable stores of E2 precursors.

Several investigators have shown that early follicular phase gonadotropin levels increase with age (11, 15, 17, 18). Most studies show that FSH levels increase beyond the age of 40 yr and that the first detectable rise in LH levels occurs even later (19, 28, 30, 32). In support of the results of previous studies that show elevated levels of LH only in postmenopausal women, we found no correlation between age and LH in women aged 20–44 yr. On the other hand, FSH levels were already elevated after the age of 25 yr, and there was also a positive correlation between age and FSH concentrations. These observations are supported by the results of another study in which FSH levels were found to be increased as early as at the age of 29–30 yr (13). The mechanisms leading to elevated FSH levels are not well understood. The results of some studies suggest that decreased synthesis of inhibin B causes the rise in FSH levels (15). The results of the present study do not support this concept, because there was no correlation between age and serum inhibin B levels. However, there was a decreasing trend in inhibin B levels after the age of 35 yr, which is in line with the results of previous studies (15, 16, 19, 33, 34) and can be explained by the crucially diminished ovarian follicle pool and granulosa cell number. Despite that, we conclude that FSH is a better marker of the decline in follicle number than inhibin B. As basal E2 secretion remained unchanged in women over 35 yr of age compared with that in younger women, it is possible that the hypothalamic-pituitary axis loses its sensitivity to feedback inhibition by E2, causing a rise in serum FSH levels (35), and/or as mentioned above, FSH secretion increases in a compensatory fashion with regard to decreasing ovarian steroid secretion capacity (36). An increase in bioavailable T as a substrate for E2 biosynthesis could also maintain normal E2 levels. This is unlikely, however, because serum free T (37) and SHBG levels remain relatively stable (38) until the menopause transition when a significant decrease in serum SHBG concentration is observed (39).

It is concluded that ovarian endocrine function starts to decline as early as before the age of 30 yr even though follicle number is still high, and the presumed critical level of 25,000 follicles is reached much later (5). Despite a relatively large follicle pool in young women, the ovarian capacity to secrete androgens is decreased earlier than expected, and compensatory mechanisms are needed to maintain optimal estrogen biosynthesis. This is reflected by the gradual rise in FSH levels, which is already seen in women 30 yr or older, and seems to be one of the first signs of reproductive aging.


   Acknowledgments
 
We thank Mr. Risto Bloigu for statistical advice, and Ms. Mirja Ahvensalmi and Ms. Anja Heikkinen for skilful technical assistance.


   Footnotes
 
This work was supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, the Research Foundation of Orion Corp., and Oulu University Hospital.

Abbreviations: A, Androstenedione; AUC, area under the curve; E2, estradiol; hCG, human chorionic gonadotropin; 17-OHP, 17-hydroxyprogesterone; P, progesterone; T, testosterone.

Received October 4, 2002.

Accepted March 16, 2003.


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 Introduction
 Subjects and Methods
 Results
 Discussion
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