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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3769-3775
Copyright © 2004 by The Endocrine Society

Ovarian Age-Related Responsiveness to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome

Terhi Piltonen, Riitta Koivunen, Antti Perheentupa, Laure Morin-Papunen, Aimo Ruokonen and Juha S. Tapanainen

Departments of Obstetrics and Gynecology (T.P., R.K., L.M.-P., J.S.T.) and Clinical Chemistry (A.R.), Oulu University Hospital, FIN-90014 Oulu, Finland; and Departments of Obstetrics and Gynecology and Physiology (A.P.), University of Turku, FIN-20521 Turku, Finland

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


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Ovarian steroid secretion capacity starts to decline as early as around the age of 30 yr. Whether an age-related decrease in androgen secretion, as in normal women, also occurs in women with polycystic ovary syndrome (PCOS) and whether the enhanced androgen production in PCOS remains throughout the fertile period of life are not known. The aim of this study was to determine the age-related serum basal and gonadotropin-stimulated androgen levels in women with PCOS and to compare the results with those obtained from our previous study in healthy women with normal ovaries. Human chorionic gonadotropin (hCG) stimulation tests were carried out among 42 women with PCOS (age, 16–44 yr; body mass index, 31.02 ± 1.1 kg/m2). An im injection of 5000 IU hCG was given 2–4 d after spontaneous or progestin-induced menstrual bleeding, and blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone, androstenedione (A), testosterone (T), and estradiol assays were collected at 0, 24, 48, and 96 h. In women with PCOS, basal serum T and A levels were about 50% higher than in healthy women. The responses of A and T to hCG [area under the curve (AUC), 96 h)] were significantly higher in women with PCOS than in normal women [A, 1183.6 ± 60 (±SE) vs. 814.4 ± 39 (P ≤ 0.001); T, 192.9 ± 12 vs. 117.4 ± 6; P ≤ 0.001]. In PCOS women, the hCG-stimulated A levels correlated negatively with age (AUC of A: r = –0.044; P = 0.004), and a similar trend was also observed in AUC T levels (AUC of T: r = –0.125, P = 0.425). Despite the higher androgen secretion capacity in PCOS, the basal and hCG-stimulated serum estradiol levels were similar to those observed in normal women. LH correlated positively with age, but basal FSH and inhibin B levels remained unchanged. In conclusion, in PCOS basal serum levels of androgens and ovarian androgen secretion capacity are markedly increased and remain high throughout the reproductive years, although the decreasing ovarian capacity to release androgens in response to hCG stimulation seen in healthy women also occurs in PCOS.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
HUMAN FERTILITY STARTS to decline markedly around the age of 35 yr (1, 2). This change is also reflected in changes in ovarian endocrine function. In fact, the ovaries lose their maximal steroid production capacity before any clinical signs of ovarian aging, e.g. menstrual irregularity or decreased fertility, are observed. Our previous studies in normal healthy women of fertile age have shown that ovarian steroid secretion and responsiveness to gonadotropin stimulation start to decline as early as around the age of 30 yr (3). Even though the secretion of androgens, which are essential precursors for estrogen biosynthesis, starts to decline relatively early, serum estradiol (E2) levels remain unchanged until late fertile age (3).

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women. Such women suffer from oligo/amenorrhea, infertility, and insulin resistance. The majority of women with PCOS also have elevated serum androgen levels and/or suffer from hyperandrogenic symptoms (4, 5, 6); therefore, it was of interest to study whether these women, in addition to having elevated serum basal androgen levels, have enhanced androgen secretion capacity in response to gonadotropin stimulation. Furthermore, another question was whether these women maintain their higher androgen secretion to a later age than healthy women. Thus, we determined the age-related serum basal and human chorionic gonadotropin (hCG)-stimulated androgen levels in women with PCOS and compared the results with those obtained from our previous study in healthy women with normal ovaries (3).


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

Forty-two women with previously diagnosed PCOS [age, 16–44 yr; body mass index (BMI), 19.2–44.1 kg/m2] participated in the study. All patients had oligomenorrhea (intermenstrual interval, >35 d) or irregular menstruation (menstrual interval, >7 d from one period to another). Other inclusion criteria were hyperandrogenism [hirsutism score, >7 according to Ferriman and Gallwey (7); acne; or serum testosterone, ≥2.7 nmol/liter], and polycystic ovaries were observed on transvaginal ultrasonography (at least eight follicles 3–8 mm diameter in one plane in one ovary). One patient took medication for bronchial asthma, and two patients used antihistamines for allergy. The subjects were otherwise healthy and took no medication, including oral contraceptive pills. Progestin (dydrogesterone) was used in subjects with oligomenorrhea (menstrual interval, >2 months) to induce menstrual bleeding. A break of at least 2 months in the use of oral contraceptive pills was required before the study. The PCOS group was divided into two age groups, setting the division at 30 yr.

The results of studies in PCOS patients were compared with previously published results in 44 healthy regularly cycling women, 20–44 yr old, who were stimulated similarly with hCG in the early follicular phase of the menstrual cycle (3). All control subjects had normal ovaries on transvaginal ultrasonography, and their early follicular phase progesterone (P) levels were 7.1 nmol/liter or less.

Informed written consent was obtained from each subject, and the study was approved by the ethics committee of Oulu University Hospital (Oulu, Finland).

hCG tests

All subjects underwent hCG stimulation 2–4 d after spontaneous or progestin-induced menstrual bleeding. 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, The Netherlands) between 0700–0900 h and thereafter at 24, 48, and 96 h.

Assays

Serum concentrations of T and P were analyzed using an automated chemiluminescence system (Advia Centaur; Bayer Healthcare LCC, Diagnostic Division, Terrytown, NY). Inhibin B concentrations were analyzed by ELISA (Serotec Ltd., Oxford, UK). Serum concentrations of FSH and LH were analyzed by fluoroimmunoassays (Wallac, Ltd., Turku, Finland), and RIAs were used for 17-OHP, A (Diagnostic Products Corp., Los Angeles, CA), and E2 (Orion Diagnostica, Oulunsalo, Finland), following the instructions provided by the manufacturers.

Areas under the curve (AUCs) for the 17-OHP, A, T, and E2 responses were calculated using the trapezoidal method. The 72 h point for control subjects was not included in the analysis, because in the present study the protocol was simplified, and blood samples were not obtained at 72 h.

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. The external quality control of the hormone assays was organized by national (Labquality Ltd., Helsinki, Finland) and international (Bio-Rad Laboratories EQAS, Irvine, CA) 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 test was used for variables with skewed distribution. Pearson’s correlation coefficient (r) was calculated to correlate age and BMI with the hormone levels measured. Multiple linear regression analysis and ANOVA were used to adjust the impact of BMI on the hormonal changes/differences. The limit of statistical significance was set at P ≤ 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Basal steroid levels

Basal hormone levels are shown in Table 1Go. Low basal serum P levels (≤5.6 nmol/liter) in all subjects confirmed that the study was performed during the follicular phase of the menstrual cycle. P levels did not change in the PCOS groups, but they were 20–40% lower in women with PCOS than in the control women, probably as a result of the anovulatory status of the women with PCOS. Basal androgen levels were similar in women with PCOS under and over 30 yr of age (Table 1Go). However, basal A and T levels were about 50% higher in women with PCOS compared with the control women in both age groups, and this was also the case after BMI adjustment (Table 1Go). No difference was observed in basal E2 levels in the PCOS groups or compared with the controls. BMI correlated positively with E2 levels in the women with PCOS, but it did not correlate with androgen levels or age.


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  		TABLE 1. Serum basal hormone levels in different age groups

 
AUCs and stimulation patterns

The ovarian capacity to synthesize and secrete androgens in response to hCG stimulation was increased in women with PCOS. AUCs of A and T were 40–80% higher in women with PCOS compared with control women in both age groups (P = 0.001 to P < 0.001; Fig. 1Go and Table 2Go), and the AUC of 17-OHP was 25% higher in older women with PCOS than in control women over 30 yr of age, but this difference did not reach statistical significance (Table 2Go). In the PCOS groups, the AUC of A was lower in older women compared with those less than 30 yr of age, and it correlated negatively with age (P = 0.016; r = –0.436; P = 0.004; Table 2Go and Fig. 2Go). A similar, but nonsignificant, decreasing trend was seen in AUC T (r = –0.125; P = 0.425; Fig. 2Go). The AUC of E2 remained unchanged in women with PCOS, and the responses were comparable to those in control women (Fig. 2Go and Table 2Go). BMI did not correlate with AUC of A, but it did correlate positively with AUC of T (Fig. 3Go). After BMI-adjusted analyses using multiple linear regression analysis and ANOVA, the differences between PCOS and control groups as well as the age-related decrease in AUC A in PCOS subjects remained significant.



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  		FIG. 1. Basal and hCG-stimulated (AUC, 96 h) A and T levels in women with PCOS and in control women (3 ) 30 yr or younger and older than 30 yr of age.

 

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  		TABLE 2. AUC at 96 h reflecting the steroid responses to hCG stimulation

 


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  		FIG. 2. Pearson’s correlation (r) between age and AUC at 96 h for A, T, and E2, and age vs. basal FSH in PCOS (•; n = 42) and control women ({circ}; n = 44) (3 ). The AUC values shown are the mean values over 96 h.

 


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  		FIG. 3. Pearson’s correlation (r) between BMI and AUC of A and T in PCOS (•; n = 42) and control women ({circ}; n = 44) (3 ). The AUC values shown are the mean values over 96 h.

 
The stimulation patterns of all steroids were similar in women with PCOS under and over 30 yr of age (Table 2Go and Fig. 4Go). When we compared the stimulation patterns in women with PCOS with those in the controls (3), the maximum concentrations of A and T were reached earlier in women with PCOS.



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  		FIG. 4. Responses of serum 17-OHP, A, T, and E2 to a single dose of hCG (5000 IU) in women with PCOS, aged 16–30 yr (•; n = 19) and 31–44 yr ({circ}; n = 23). Statistical significance between the groups at each time point: *, P ≤ 0.05.

 
FSH, LH, and inhibin B

Basal serum levels of FSH did not change over time in women with PCOS (Table 1Go and Fig. 2Go), whereas in our previous study of healthy women, FSH concentrations started to increase as early as at the age of 30 yr (3). In contrast, basal serum levels of LH correlated positively with age in PCOS women (r = 0.310; P = 0.046). The LH/FSH ratio did not differ between the PCOS groups, but it was significantly increased compared with that in control women (Table 1Go). Inhibin B levels remained unchanged over time in women with PCOS and were about 20% higher than those in control women (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present results demonstrate that the ovarian capacity to synthesize and release androgens is pronounced in women with PCOS, and it remains high throughout the reproductive years, whereas the production of E2 is constant and comparable to that observed in healthy women.

Because LH regulates androgen synthesis in thecal cells, and dysfunction of these cells is common in women with PCOS (8, 9, 10), we studied ovarian thecal cell/stromal function using hCG tests. Both basal and hCG-stimulated serum levels of A and T were increased about 50% in women with PCOS compared with those in healthy women. Interestingly, the age-related decrease in the T secretion capacity seen in normal healthy women after the age of 30 yr (3) was not significant in PCOS, although there was a significant age-related decrease in the AUC of A. The nonsignificant age-related decrease in the AUC of T may be explained by the large individual variation, and it is possible that the decrease would have become significant with a larger number of subjects. Based on power analysis, 172 patients would have been needed to demonstrate this. However, the results confirm earlier findings that women with PCOS have an increased androgen response to hCG/LH and/or GnRH agonist stimulation (9, 11, 12, 13, 14). Furthermore, the present results extend these observations by demonstrating that despite the decrease in A production, the enhanced activity of thecal cells and/or ovarian stroma in women with PCOS remains until very late fertile age. In line with the present results, basal T levels in women with PCOS have been shown to remain unchanged up to the age of 42 yr (15), although in another study, both A and T levels decreased from 17–29 to 30–42 yr (16). It is possible that some of the hormonal differences observed between PCOS and control subjects could be explained by the higher BMI in the PCOS group. However, after BMI adjustment all differences, i.e. basal serum A and T as well as the AUC of A and the AUC of T, remained significant.

The steroid response patterns to hCG were comparable in women with PCOS under and over 30 yr. The maximum androgen concentrations after hCG administration were reached earlier in women with PCOS than in normal women. This early/male-type responsiveness to hCG and/or GnRH agonist has been reported previously (9, 17, 18, 19), and it has been associated with dysregulation of P450c17{alpha}, which may play an important role in the pathogenesis of ovarian hyperandrogenism (20). The different response patterns to hCG in women with PCOS and control women may also be explained by the fact that women with PCOS have greater numbers of small antral follicles (21) and increased ovarian stroma, which also contributes to androgen production. The contribution of the adrenals, liver, and peripheral tissues to the total androgen pool is significant and enhanced in PCOS (22, 23, 24). However, although the basal levels of adrenal androgens are increased by 50–100% in PCOS (25), the adrenals do not seem to be under the control of LH/hCG (26), and therefore, their role in enhanced androgen responses to hCG is unlikely to be significant.

Interestingly, serum levels of E2 in women with PCOS were comparable to those in control women, even though the synthesis of androgens, which are the precursors of E2, was markedly increased. There are several explanations for this observation. Because the aromatase enzyme is the rate-limiting step in estrogen synthesis, factors regulating its activity obviously play a central role. In healthy women, serum FSH levels start to increase as early as at the age of 30 yr, probably as a result of diminished ovarian steroid production capacity (3), whereas in women with PCOS, serum FSH levels remained unchanged between 16 and 44 yr of age. Although FSH-secreting cells may not be very sensitive to changes in serum androgen levels, it is possible that the enhanced androgen secretion in women with PCOS is sufficient to preserve steady FSH secretion and aromatase activity. Furthermore, local conversion of androgens to E2 in the brain (27) may be associated with the unchanged FSH secretion in women with PCOS. In addition, the increased LH levels may reflect greater sensitivity of the pituitary to diminishing androgen production capacity in PCOS. The serum concentrations of anti-Mullerian hormone have been shown to correlate to the number of antral follicles (28), and its levels have been reported to be 2- to 3-fold higher in women with PCOS than in healthy women (29). Furthermore, because anti-Mullerian hormone decreases both aromatase activity and FSH sensitivity of growing follicles (28, 30), it may contribute to the unchanged E2 and FSH concentrations in PCOS. Small follicles also secrete inhibin B, which suppresses FSH release (31, 32), and they could therefore represent one of the factors leading to different serum FSH levels in women with PCOS vs. control women. However, no significant changes in inhibin B levels with age or differences between women with PCOS and control subjects were observed, although a slight decreasing tendency was seen in control women over the age of 35 yr (3).

In conclusion, in PCOS, basal serum levels of androgens and ovarian androgen secretion capacity are markedly increased and remain high throughout the reproductive years. However, similar to healthy women, a decreasing ovarian capacity to release androgens in response to hCG stimulation can also be observed in PCOS. The persistently increased androgen production in PCOS was associated with normal serum E2 levels, emphasizing the key role of the aromatase enzyme as a rate-limiting step in estrogen biosynthesis. However, other regulatory mechanisms to preserve steady E2 levels may also be involved. Whether the pronounced androgen secretion capacity in women with PCOS persists in postmenopausal years remains to be studied.


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


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

Abbreviations: A, Androstenedione; AUC, area under the curve; BMI, body mass index; E2, estradiol; hCG, human chorionic gonadotropin; 17-OHP, 17-hydroxyprogesterone; P, progesterone; PCOS, polycystic ovary syndrome; T, testosterone.

Received October 24, 2003.

Accepted April 21, 2004.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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