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*CLOMIPHENE
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2394-2398
Copyright © 1998 by The Endocrine Society

Original Studies

Decline in Insulin-Like Growth Factor I Levels after Clomiphene Citrate Does Not Correct Hyperandrogenemia in Polycystic Ovary Syndrome

Tarek M. Fiad, Thomas P. Smith, Sean K. Cunningham and T. Joseph McKenna

Department of Investigative Endocrinology, University College, and St. Vincent’s Hospital, Dublin, Ireland

Address all correspondence and requests for reprints to: Prof. T. J. McKenna, Department of Investigative Endocrinology, St. Vincent’s Hospital, Elm Park, Dublin 4, Ireland.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
It is widely accepted that the action of clomiphene citrate (CC) is mediated through its antiestrogenic properties on the hypothalamic-pituitary axis. Although insulin-like growth factor I (IGF-I) enhances the thecal cell response to LH, and estrogen treatment is associated with a reduction in IGF-I levels, CC is known to decrease circulatory IGF-I levels in polycystic ovary syndrome (PCOS) patients. The impact of lowering IGF-I levels on androgen levels in PCOS is unknown. This study was designed to examine the impact of CC treatment on the interrelationships of IGF-I, androgens, and estrogens in normal subjects and patients with PCOS. IGF-I, gonadotropin, androgen, estrogen, and sex hormone-binding globulin levels were measured in 8 PCOS patients and 10 normal subjects before and after treatment with the antiestrogen CC. Studies were performed in the early follicular phase, days 4–6 of the menstrual cycle in normal subjects. In normal subjects, CC treatment led to a significant increase in estradiol (84 ± 10 to 234 ± 62 pmol/L, untreated and CC treated; P < 0.05) and estrone (125 ± 14 to 257 ± 29 pmol/L; P < 0.05) levels with a significant lowering of IGF-I levels (297 ± 25 to 230 ± 17 µg/L; P < 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 ± 11 to 245 ± 58 pmol/L; P < 0.05) and estrone (301 ± 32 to 401 ± 90 pmol/L; P < 0.05) levels and a significant lowering of IGF-I levels (330 ± 43 to 214 ± 27 µg/L; P < 0.05) were observed after CC treatment. However, no significant correlation was observed between changes in IGF-I and changes in estradiol in either group. Compared to pretreatment levels, no significant changes in the following parameters were observed after 5 days of CC treatment in either study group: testosterone, testosterone/sex hormone-binding globulin ratio, and androstenedione.

The relationship among CC treatment, gonadotropin, estrogen, and IGF-I levels is complex. Changes in blood IGF-I levels are not associated with changes in androgen levels, although paracrine and or autocrine effects cannot be excluded.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CLOMIPHENE citrate (CC) is a drug with mixed estrogenic and antiestrogenic properties that has been extensively used as the first line treatment of anovulatory infertility associated with polycystic ovary syndrome (PCOS) and to induce superovulation in in vitro fertilization programs. Despite ample clinical experience, the mechanism of action of CC has only been partially clarified (1). The principal antiestrogenic site of action of CC is reported to be on the hypothalamic-pituitary axis (2, 3, 4); however, it was suggested that other additional actions of CC may contribute to its ovulation induction properties (1). Evidence is emerging that insulin-like growth factors (IGFs), their receptors, and their binding proteins (IGFBPs), acting by autocrine and/or paracrine mechanisms, are important regulators of follicular development and maturation (5, 6). Administration of estrogens to women with regular periods, PCOS patients (7), and postmenopausal women (8) is associated with a decline in IGF-I levels. However, after administration of the antiestrogen CC to PCOS patients, it was found, surprisingly, that IGF-I levels were reduced (9). IGF-I receptors have been detected on human thecal cells (10). Furthermore, in animal and human ovaries, IGF-I has been shown to potentiate the ability of LH to stimulate androgen production by thecal cell (10, 11), which may contribute to the ovarian hyperandrogenemia in PCOS. The IGF-I-lowering effect of CC would be expected to have a beneficial effect on ovarian hyperandrogenemia. This study was designed to elucidate the impact of the CC-related fall of IGF-I levels in PCOS patients on the regulation of ovarian androgen secretion and to extend the studies of the effects of CC treatment to normal subjects.


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

Eight patients with a clinical diagnosis of PCOS, all of whom had hirsutism, oligomenorrhea (defined as eight or fewer menses per yr), hyperestrogenemia, and a LH/FSH ratio greater than 2, participated. Ultrasound findings in all patients were consistent with polycystic ovaries with increased stroma and multiple cysts (12). Cushing’s disease was excluded using the overnight dexamethasone suppression test (13), and all patients had ACTH-stimulated 17-hydroxyprogesterone levels less than 5.0 nmol/L, thereby excluding congenital adrenal hyperplasia of the most common type, 21-hydroxylase deficiency (14). None of these patients had used any hormonal treatment before the study.

Normal subjects

Ten healthy normal cycling women without clinical or hormonal evidence of endocrine disease served as controls. Ovulation was confirmed by the demonstration of luteal phase progesterone levels. All of these volunteers had normal ovaries on ultrasound examination, and none had used hormonal contraception before entering the study.

Study protocol

The LH secretory characteristics and IGF-I, androgen, sex hormone-binding globulin (SHBG), and estrogen levels were examined before and in response to treatment with the antiestrogen CC in PCOS patients and normal subjects. Each participant was admitted to the Education and Research Center of St. Vincent’s Hospital at 0800 h on the appropriate study day. An indwelling iv catheter was inserted in a forearm vein, and patency was maintained by flushing the catheter with normal saline. Studies were performed in the early follicular phase, on days 4–6 of the menstrual cycle in normal subjects. Normal subjects were evaluated 1) untreated and 2) on the fifth day of CC administration, which was commenced on the first day of a spontaneous menstrual bleed. PCOS patients were studied 1) at a variable stage of the follicular phase when plasma progesterone levels excluded a functioning corpus luteum at that time, and 2) under similar conditions, but on the fifth day of administration of CC (given in a dose of 50 mg daily for 5 days). On each study day, blood samples were obtained for the measurement of IGF-I, testosterone (T), androstenedione, SHBG, estrone, and estradiol. In addition, on each study day, blood sampling for LH determination was performed at 15-min intervals for 6 h, followed by a GnRH test that required blood samples for the measurement of LH and FSH before and 10, 20, 30, 45, and 60 min after GnRH injection (100 µg, iv). The study protocol was approved by the ethics and research committee of St. Vincent’s Hospital, and written informed consent was obtained from each participant before enrollment in the study.

Assays

Plasma levels of T, androstenedione, estrone, estradiol, and 17-hydroxyprogesterone were measured by specific RIAs similar to that previously described for aldosterone (15). These RIAs were performed after extraction into diethyl ether and, in the case of androgens and estrogens, after the isolation of the steroids by chromatography over Celite columns (16). Plasma progesterone was measured by RIA without extraction using antiserum to 11{alpha}-hydroxyprogesterone-11{alpha}-hemisuccinate-human serum albumin (catalogue no. 07-170016, ICN Biomedicals, Costa Mesa, CA), progesterone-11{alpha}-glucuronide-[125I]iodotyramine (catalogue no. IM. 140, Amersham, Aylesbury, UK) and progesterone standards (Sigma Chemical Co., Poole, UK) diluted in charcoal-stripped plasma. Incubation of diluted specimens and standards with antiserum and labeled progesterone was performed at 37 C for 1.5 h in the presence of excess cortisol to displace progesterone from plasma binding proteins. Plasma SHBG was measured by immunometric assay (17) and the T/SHBG ratio (T nanomoles per L; SHBG, nanomoles per L) x 100 (T/SHBG), was used as an indirect index of free T levels (18). IGF-I was measured using a commercial two-site immunoradiometric assay with prior acidic ethanol sample extraction (Diagnostic System Laboratories, Webster, TX).

Serum LH and FSH were measured in duplicate employing a Delfia two-site fluoroimmunoassay assay (Wallac, Turku, Finland). The average intraassay reproducibility of LH, estimated from duplicate measurements of three plasma pools at 5.2, 21.5, and 44.1 U/L, in at least 20 assays, was 5.8% (19). The minimum LH value to detect a pulse was 1.26 U/L.

The interassay coefficients of variation (CVs) were 11.2%, 7.5%, and 7.7%, respectively, at plasma T concentrations of 0.7, 1.8, and 5.9 nmol/L; 9.1%, 6.8%, and 6.6% at plasma androstenedione concentrations of 2.0, 5.4, and 12.0 nmol/L; 24.3%, 19.2%, and 19.5% at estradiol concentrations of 115, 840, and 2300 pmol/L; 22.4%, 18.2%, and 16.4% at plasma estrone concentrations of 138, 785, and 1657 pmol/L; 17.3%, 12.9%, and 14.8% at plasma progesterone levels of 4.6, 27.5, and 109 nmol/L; 5.9%, 5.6%, and 5.3% at plasma SHBG concentrations of 30, 74, and 146 nmol/L; 7.6%, 5.2%, and 6.4% at plasma IGF-I concentrations of 61, 195, and 384 µg/L; 5.4%, 6.6%, and 8.1% at plasma FSH concentrations of 5.6, 18.4, and 42.4 U/L; and 7.9%, 7.6%, and 7.0% at plasma LH concentrations of 5.2, 21.5, and 44.1U/L.

LH pulse detection

LH pulse characteristics were analyzed employing a cluster analysis program (20). LH values were analyzed in duplicate and a cluster size of 2 x 1 (2 points for a nadir and 1 point for a peak), with a t statistic of 1 for both the up-stroke and the down-stroke was used to provide an optimal sensitivity and specificity over 90% (21). Missing LH values were calculated as a mean of the levels immediately proceeding and following the missing value. LH pulse frequency was defined as the number of LH peaks detected over 6 h. A LH peak was defined as a point flanked on both sides by a significant decreases in the LH concentration, and the LH height was the maximum LH value attained within a peak. The LH pulse amplitude was defined as the LH increment from the preceding nadir to the following peak. For each subject, the means of the LH pulse frequency, height, and amplitude over 6 h were used in the final analysis of the data. The integrated LH level is the mean of the LH values over 6 h. The gonadotrope sensitivity to GnRH was defined as the maximum LH increment after GnRH administration in excess of the basal value obtained immediately before GnRH injection.

Statistical analysis

Differences between control and patient groups were analyzed by nonparametric Mann-Whitney U unpaired t test, and differences in values before and after treatment in the same group were analyzed by the Wilcoxon signed Rank paired t test (StatView II software program for the Apple Macintosh computer, Abacus Concepts, Berkeley, CA). Differences were considered significant at P < 0.05. Values are given as the mean and SE unless stated otherwise.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical features in control subjects and PCOS patients

PCOS patients had a significantly higher body mass index than control subjects (weight/height2, 29.6 ± 2.3 and 22.4 ± 0.3; P < 0.05) and fewer menses per yr (5.6 ± 1.3 and 11.8 ± 0.1; P < 0.05). Using the hirsutism score system devised by Ferriman and Gallwey (22), PCOS patients were significantly more hirsute than control subjects (9.8 ± 1.9 and 1.3 ± 0.3; P < 0.05). The two groups were of similar age (23.0 ± 1.1 and 21.9 ± 0.9, yr).

Gonadotropin, IGF-I, androgen, and estrogen profiles in control subjects and PCOS patients in response to CC treatment (Table 1Go and Fig. 1Go)

Compared to values in normal subjects, PCOS patients demonstrated significantly elevated mean T/SHBG ratios (13.3 ± 1.0 and 2.9 ± 0.4; P < 0.05) and levels of androstenedione (10.4 ± 0.8 and 6.7 ± 1.1 nmol/L; P < 0.05) and estrone (301 ± 32 and 125 ± 14 pmol/L; P < 0.05), and a decreased mean SHBG level (20 ± 3.0 and 54 ± 6.0 nmol/L; P < 0.05). Normal subjects and PCOS patients had similar levels of IGF-I and similar levels of estradiol. Normal subjects and PCOS patients had similar LH pulse frequencies, FSH concentrations, and FSH responses to GnRH. Treatment of normal subjects with the antiestrogen CC led to a significant rise in FSH, whereas in PCOS patients, treatment with CC was associated with a significant increase in the LH pulse frequency, but no change in the other gonadotropin characteristics were observed. Compared to CC-treated normal subjects, CC-treated PCOS patients had a significantly higher LH pulse amplitude. Values for LH pulse height, integrated LH levels, and the maximum LH response to GnRH were not different between CC-treated control subjects and PCOS patients .


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  		Table 1. Gonadotropin levels (mean ± SE) in control (n = 10) and PCOS (n = 8) subjects in response to CC

 


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  		Figure 1. IGF-I, androgen, and estrogen levels on the control day and on day 5 of CC treatment (mean ± SE) in 10 control subjects and 8 PCOS patients. {square}, Untreated; , CC treated; {dagger}, PCOS significantly different from untreated controls, P < 0.05; *, significantly different from untreated state, P < 0.05; #, CC-treated PCOS significantly different from CC-treated normal subjects, P < 0.05.

 
In normal subjects, treatment with the antiestrogen CC led to a significant rise in estradiol (84 ± 10 to 234 ± 62 pmol/L; P < 0.05) and estrone (125 ± 14 to 257 ± 29 pmol/L; P < 0.05) levels, with a significant lowering of IGF-I levels (297 ± 25 to 230 ± 17 µg/L; P < 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 ± 11 to 245 ± 58 pmol/L; P < 0.05) and estrone (301 ± 32 to 401 ± 90 pmol/L; P < 0.05) levels and a significant lowering of IGF-I levels (330 ± 43 to 214 ± 27 µg/L; P < 0.05) were observed after CC treatment. When regression analysis was applied to changes in IGF-I and estradiol levels in PCOS (r = 0.1) and normal subjects (r = 0.48), a statistically significant relationship was not observed (P > 0.05). No significant changes in T, T/SHBG, androstenedione, or SHBG were observed after 5 days of CC treatment in either study group. Compared to CC-treated normal subjects, T/SHBG ratio and androstenedione remained higher whereas SHBG levels remained lower in CC-treated PCOS patients. IGF-I levels were similar in normal subjects and PCOS patients after CC treatment.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study examined the impact of lowering IGF-I levels in PCOS patients on the regulation of ovarian androgen production and extended the observation to normal subjects. CC led to increased estrone and estradiol levels with lowering of IGF-I levels, whereas androgen levels were unchanged in the two study groups. In addition to synergizing with LH to stimulate androgen production in thecal cells (10, 11), IGF-I has been shown to stimulate granulosa cell estrogen production (23). Furthermore, IGF-I receptors have been detected in thecal cells (10). These observations suggest that lowering IGF-I levels could potentially lower androgen and estrogen levels; however, this was not observed in this study. If a decline in IGF-I levels lowers the androgen concentration, an elevation of LH levels could have negated this effect of IGF-I; however, although an increase in LH pulse frequency was observed, other LH pulse secretory characteristics were similar before and after CC treatment. Mason et al. reported that IGF-I is produced by the theca of normal and polycystic ovaries (24). Therefore, changes in circulating IGF-I levels may not parallel intraovarian levels, and dissociation of systemic and thecal cell IGF-I levels could explain the absence of a beneficial effect of lower serum IGF-I levels on hyperandrogenemia. It is also known that IGFBPs are important regulators of ovarian function; they can sequester IGFs or act directly on cells (25, 26). A previous study showed that ovulation induction with CC increases serum IGFBP-I levels (27). If levels of other potential regulators of IGF-I activity were unchanged, this observed rise in serum IGFBP-I will potentially sequester more IGF-I with a further fall in free IGF-I levels. Levels of IGFBPs were not measured in this study; therefore, the possibility that CC may have an effect on IGFBPs levels cannot be dismissed. Although potential effects of CC on IGFBPs may offer another explanation for the absence of a beneficial effect of lower IGF-I levels on hyperandrogenemia, it has been reported recently that there is a close correlation between free and total IGF-I levels (28). Alternatively, as insulin and IGF-I receptors were detected in human ovarian tissue, our observations are consistent with the idea that spillover action of insulin through IGF-I receptors with subsequent enhancement of androgen production may provide a possible mechanism for hyperandrogenemia in PCOS (29, 30), as insulin is a potent augmenter of LH-induced thecal androgen production (11).

It has been suggested that circulating IGF-I levels may have a minor impact on ovarian function, as IGF-I-deficient subjects, such as Laron dwarfs, exhibit normal follicular development (31). Therefore, it is not surprising that the fall in IGF-I levels after CC treatment did not prevent a rise in estrogen levels. Treatment of PCOS patients with octreotide decreases IGF-I and increases IGFBP-3 (32). Octreotide treatment of PCOS patients is associated with a reduced incidence of ovarian hyperstimulation, superovulation, and miscarriage rates, whereas the ovulation induction rate is unaffected (33). These reports and the observation that CC treatment lowers IGF-I levels while facilitating folliculogenesis suggest that low circulating IGF-I levels have no adverse effects on folliculogenesis. Although follicular fluid IGF-I and IGF-II are lower in PCOS than in normal women (34), circulating IGF-I levels are similar in normally ovulating women and PCOS patients (35), further supporting the idea of dissociation between circulating and follicular IGF levels.

Theoretically, administration of an antiestrogen would be associated with an increase in IGF-I levels. The observed fall in IGF-I may have occurred as a consequence of a dominant effect of increasing endogenous estrogen levels or a direct effect of the estrogen-like properties of CC. These potentially competing influences associated with the antiestrogen effect of CC treatment may explain the lack of association of estrogen and IGF-I levels in this study. Furthermore, it has been suggested that estrogen is the primary regulator of GH release from the hypothalamic-pituitary axis in women (36). The dynamics of GH after CC treatment were not examined in this study, and the possibility exists that the antiestrogenic action of CC on the hypothalamic-pituitary axis is associated with a fall in GH secretory capacity, thereby reducing IGF-I levels.

If the hypothesis that hyperestrogenemia is the underlying cause of LH hypersecretion is correct (37, 38), then treating PCOS patients with CC should either correct the hormonal abnormalities in PCOS or render the hormonal profile in CC-treated PCOS similar to that seen in CC-treated control subjects, because although it is recognized that CC has partial antagonist/partial agonist properties, its dominant effect on the hypothalamic-pituitary axis is related to its antiestrogenic properties (2, 3, 4), and therefore, the use of CC can allow for the testing of the effect of hyperestrogenemia on the hypothalamic-pituitary axis in PCOS. However, treatment with CC neither corrected the LH abnormalities in PCOS or rendered the LH pulse characteristics in CC-treated PCOS similar to those observed in CC-treated control subjects. When treatment with CC induces ovulation, a beneficial effect is observed subsequently (3, 39). This favorable effect of ovulation on the dynamics of gonadotropin secretion is most likely a consequence of exposure to luteal phase progesterone; this concept is supported by the observation that treatment of anovulatory PCOS women with the progestogen medroxyprogesterone acetate is associated with lowering of LH and androgen levels (40).

Although higher FSH levels after CC exposure were observed in normal subjects in our study, previously reported increases in LH and FSH levels and LH pulse amplitude in PCOS patients were not observed (3, 41, 42, 43). The varying duration of treatment (3–5 days) and dosage of CC (50–150 mg) may have contributed to the difference reported from various studies. CC (150 mg daily) for 3 days is also associated with a significant decrease in the gonadotrope sensitivity to GnRH (3). Although there was a tendency for the LH and FSH responses to GnRH to decrease after treatment with CC in our study, statistical significance was not achieved. The increased estradiol levels after CC treatment of PCOS patients was not associated with a significant increase in FSH levels. These findings are consistent with the observations made by Fukushima and Maeyama (44), using the antiestrogen tamoxifen and suggest that the rise in estradiol could have come about by a CC-mediated change in the intraovarian IGF/IGFBP balance, a heightening of granulosa cell sensitivity to FSH, changes in FSH bioactivity, or a direct intraovarian action, although a rise in FSH levels earlier during the course of CC treatment cannot be ruled out.

Failure of IGF-I levels to rise when the antiestrogen CC was used may be due to a dominant effect of rising estrogens or a direct effect of CC. Although the possibility that a delayed fall in androgen levels after CC-induced lowering of IGF-I levels cannot be ruled out, the lack of an immediate effect of falling IGF-I levels on androgen levels suggests that circulating IGF-I levels have little influence on androgen production, although the possibility of autocrine- or paracrine-mediated effects cannot be ignored.

Received March 4, 1997.

Revised February 4, 1998.

Accepted March 26, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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