Human Reproduction, Vol. 14, No. 11, 2704-2708,
November 1999
© 1999 European Society of Human Reproduction and Embryology
Growth hormone response to thyrotrophin releasing hormone in women with polycystic ovarian syndrome
1 Department of Endocrinology, PANAGIA Hospital, Thessaloniki, Departments of 2 Biological Chemistry and 3 Obstetrics and Gynaecology, University of Ioannina and 4 Department of Obstetrics and Gynaecology, University of Thessalia, Larissa, Greece
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Abstract |
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Recent clinical studies have suggested that women with polycystic ovarian syndrome (PCOS) may have disturbances of growth hormone (GH) kinetics and the GH/insulin-like growth factor (IGF)-I system. The knowledge that in various metabolic abnormalities there is a paradoxical sensitivity of pituitary somatotrophs to thyrotrophinreleasing hormone (TRH) administration led to this investigation of the GH secretory response to TRH in women with PCOS. Twenty-four women with PCOS and 18 control women were studied. TRH was given as a single i.v. injection (time 0) and blood samples for GH measurements were obtained at –15, 0, 15, 30, 60 and 90 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (
max). The GH response to TRH (mean ± SEM) was greater in women with PCOS (max 2.47 ± 1.73 versus 0.47 ± 0.06 ng/ml, P < 0.05 and GH AUC 8.05 ± 2.10 versus 2.58 ± 0.18 ng/ml/90 min, P < 0.05). According to GH response to TRH, two PCOS subgroups were identified: (i) normal responders (n = 14) who showed max GH response (0.36 ± 0.06 ng/ml)and GH AUC (1.93 ± 0.64 ng/ml/90 min) similar to that in the controls and (ii) over-responders (n ± 10) who showed a paradoxical increase in GH concentrations in response to TRH (max GH response 5.43 ± 1.27 ng/ml and GH AUC 16.62 ± 3.51 ng/ml per 90 min) that was significantly higher than in normally responding PCOS patients (P < 0.0001) or in controls (P < 0.0001). These data demonstrate an enhanced GH response to TRH administration in a subgroup of women with PCOS.
Key words: growth hormone/insulin/insulin-like growth factor-I/polycystic ovarian syndrome/thyrotrophin releasing hormone
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Introduction |
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Polycystic ovarian syndrome (PCOS) is a common condition in women of reproductive age associated with menstrual irregularity, anovulation, hirsutism, hyperandrogenism and metabolic disorders. Excessive production of androgens, insulin resistance and hyperinsulinaemia are the most striking disturbances. A role for an altered growth hormone (GH)/insulin-like growth factor (IGF)-I axis in women with PCOS has also been postulated (Kazer et al., 1990
; Piaditis et al., 1995). It has been reported that women with PCOS have lower circulating concentrations of GH and reduced pituitary stores of GH than normal women (Acar and Kadanali 1993; Lee et al., 1993; Micic et al., 1996). It has also been shown that women with PCOS have a greater suppression of GH response to growth hormone releasing hormone (GHRH) during treatment with gonadotrophin-releasing hormone agonist (GnRHa), suggesting that a different level of sensitivity in the somatotrophic axis exists in PCOS (Kaltsas et al., 1998). On the other hand, recent studies have suggested that there is a relationship between GH secretion and gonadal function (Adashi et al., 1985; Katz et al., 1993). In particular, women with GH deficiency have delayed menarche and impaired reproductive function (De Boer et al., 1997), while normal reproductive function is achieved after GH treatment (Blumenfeld and Lunenfeld, 1989; Homburg et al., 1990). It is known that the chronic anovulation and infertility associated with PCOS can often be successfully treated with clomiphene citrate, but stimulation of the ovaries with exogenous gonadotrophins is a more acceptable treatment for clomiphene citrate resistant patients. Recently, co-treatment with GnRH agonists has been incorporated into stimulation protocols for women with PCOS. GH has also been used in combination with human gonadotrophins for induction of ovulation in women with PCOS (Shoham et al., 1992). Although the results of such treatment are controversial (Shaker et al., 1992), a recent prospective randomized study has shown no benefit (Homburg et al., 1995). In-vitro data have shown that GH can influence steroidogenesis in human granulosa and luteal cell cultures (Mason et al., 1990; Ovesen et al., 1994), while in-vivo studies have demonstrated a paradoxical sensitivity of pituitary somatotrophs to GnRH or thyrotrophin-releasing hormone (TRH) in various metabolic abnormalities (Irie and Tsushima, 1972; Faglia et al., 1973; Gonzales-Barcena et al., 1973; Takahashi et al., 1975; Panerai et al., 1977; Gil-Ad et al., 1981; Sack et al., 1985). With this in mind and the theory that PCOS may be a syndrome with neuroendocrine abnormalities, GH secretory response to TRH was investigated further in women with PCOS. |
Materials and methods |
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Patients
Twenty-four women with PCOS, aged 20–28 years, were studied. The clinical diagnosis of PCOS was based on the presence of perimenarcheal onset and hirsutism. All women had hyperandrogenaemia (elevated serum free testosterone and
4-androstenedione) and the typical ultrasound appearances of PCOS (
10 cysts 2–8 mm in diameter associated with an increase in ovarian stroma). None of the women had used any hormonal or other medication during the 3 months before the onset of the study.
Eighteen healthy, normally menstruating women, aged 21–29 years, were used as controls. They were studied in the early follicular phase, whereas the women with PCOS were studied on day 4 following a spontaneous or a progesterone-induced menstrual bleeding. The study was approved by the Local Ethical Committee and informed consent was obtained from all subjects. Patients were instructed to eat meals containing at least 150 g of carbohydrates per day for 3 days prior to the study. On the day of the study, subjects were instructed to report after an overnight fast and underwent a 75 g oral glucose tolerance test (OGTT). Venous blood samples for glucose and insulin measurement were obtained before and at 30 min intervals for the first 3 h after glucose administration. Two days later, a TRH test was performed in the morning after an overnight fast. Blood samples in relation to a bolus i.v. injection of TRH (time 0) were obtained at –15, 0, 15, 30, 60 and 90 min. GH was measured in these blood samples. The dose of TRH was 200 µg (Relefact; Hoechst AG, Frankfurt (M), Germany). In the blood samples taken at –15 and 0 min, IGF-I, oestradiol, free testosterone, 4-androstenedione, prolactin and free fatty acids (FFA) were also measured. All blood samples were immediately centrifuged at 1000 g for 10 min at 4°C. Supernatant serum was aspirated, aliquotted and stored at –20°C until assayed.
Hormone assays
Insulin was measured by radioimmunoassay using a CIS bioInternational Kit (Gif-sur-Yvete, France). The results are expressed as µIU/ml. GH was measured by immunoradiometric assay (IRMA) using a Sorin Biomedica Kit (Dia Sorin, Salugia, Italy). The results are expressed as ng/ml. Free testosterone was measured by radioimmunoassay using a Coat-A-Count Kit (Diagnostic Products Corporation, Los Angeles, CA, USA). The results are expressed as pg/ml. 4-androstenedione was measured by radioimmunoassay using a Radim Kit (Pomezia, Rome, Italy). The results are expressed as ng/ml. Prolactin was measured by radioimmunoassay using a Medgenix Diagnostics Kit (Fleurus, Belgium). The results are expressed as ng/ml. The lower limits of detection for insulin, GH, free testosterone, 4-androstenedione and prolactin were 3.6 µIU/ml, 0.15 ng/ml, 0.15 pg/ml, 0.1 ng/ml and 0.35 ng/ml respectively, while inter-assay and intra-assay coefficients of variation were 6.9 and 6.4%, 7.5 and 6.1%, 8.1 and 7.2%, 7.6 and 5.1% and 7.1 and 6.4% respectively. Glucose concentrations were determined by the glucose oxidase technique. A colorimetric assay kit (Sigma Chemical Co., St Louis, MO, USA) was used for glucose oxidase measurement. An enzymatic method was used for determination of serum FFA (Wako Chemicals Gmbh, Neuss, Germany). The intra- and inter-assay coefficients of variation for this assay were 2.9 and 3.7% respectively, while the lower limit of detection was 0.1 mmol/l. IGF-I concentrations were measured by RIA following acid-ethanol extraction. Kits were purchased from Nichols Institute, San Juan Capistrano, CA, USA. The inter- and intra-assay coefficients of variation were 5.8% and 4.4% respectively and the results are expressed as ng/ml. The lower limit of detection of IGF-I was 0.06 ng/ml. Serum oestradiol was measured using a competitive immunoassay based on enhanced luminescence. Kits were purchased from Amersham (Amerlite Estradiol-60 assay; Amersham Pharmacia Biotech UK Ltd, Little Chalfont, Bucks, UK). The results are expressed as pg/ml. The lower limit of detection for oestradiol was 50 pg/ml, while inter-assay and intra-assay coefficients of variation were 9.3 and 8.5% respectively.
Statistical analysis
The GH release in response to TRH administration and insulin levels after OGTT were estimated by computing the area under the curve (AUC), using the trapezoidal rule. The mean of the values at –15 and 0 min was used as baseline value. The GH peak concentration in response to TRH was defined as the highest concentration reached in each individual and the response was expressed as the difference from the baseline value (max). Women with PCOS who had max GH responses higher than the mean +2 SD of the max GH responses observed in normal controls were defined as over-responders. Where data were normally distributed, unpaired t-test was used for the comparison of the results. Correlations between variables were assessed by linear regression analysis. Statistical significance was considered for P < 0.05. For some parameters, data were not normally distributed and in this case, non-parametric tests such as Mann–Whitney U-test and Wilcoxon rank sum test were also applied.
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Results |
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Women with PCOS had age, body mass index (BMI) and basal oestradiol, FFA, glucose and GH levels similar to the controls but significantly higher basal
4-androstenedione, free testosterone, insulin and IGF-I concentrations (Table I). The PCOS group also had a significantly greater max GH response (mean ± SEM) to TRH compared with the control group (2.47 ± 0.73 versus 0.47 ± 0.06 ng/ml, P < 0.05) and greater GH AUC (8.05 ± 2.10 versus 2.58 ± 0.18 ng/ml/90 min, P < 0.05) (Figure 1).
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According to GH response to TRH, two PCOS subgroups were identified (Figure 2
): (i) normal responders (n = 14), who showed max GH response (0.36 ± 0.06 ng/ml) and GH AUC (1.93 ± 0.64 ng/ml/90 min) similar to that in the controls (0.47 ± 0.06 ng/ml and 2.58 ± 0.18 ng/ml/90 min respectively) and (ii) over-responders (n = 10), who showed a paradoxical increase in GH concentrations in response to TRH (max GH response 5.43 ± 1.27 ng/ml) that was significantly higher than in normal responding PCOS patients (P < 0.0001) or in controls (P < 0.0001). The over-responders also had higher GH AUC (16.62 ± 3.51 ng/ml/90 min) than the normal responders (1.93 ± 0.64 ng/ml/90 min, P < 0.0001) and the controls (2.58 ± 0.18 ng/ml/90 min, P < 0.0001) and higher basal GH levels than the normal responders (3.47 ± 0.90 versus 0.49 ± 0.09 ng/ml, P < 0.001) and the controls (3.47 ± 0.90 versus 1.81 ± 0.20 ng/ml, P < 0.05). Free testosterone concentrations were lower in the over-responders than the normal responders (3.90 ± 0.50 versus 5.64 ± 0.56 pg/ml, P < 0.05), while they had also lower basal insulin levels (14.19 ± 2.34 versus 26.92 ± 3.27 µIU/ml, P < 0.01) and lower insulin AUC (438.09 ± 68.05 versus 684.14 ± 79.71 µIU/ml/180 min, P < 0.05) (Table II).
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In the PCOS group, a positive correlation was found between basal GH and
max GH (r = 0.549, P < 0.01), basal GH and GH AUC (r = 0.736, P < 0.0001), max GH and GH AUC (r = 0.858, P < 0.0001), while a negative correlation was seen between GH AUC and insulin AUC (r = –0.405, P < 0.05). In the over-responders, a positive correlation was found between GH AUC and max GH (r = 0.745, P < 0.05) and in the normal responders a negative correlation between max GH and basal insulin (r = –0.540, P < 0.05). |
Discussion |
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In the present study, GH response after TRH administration was evaluated in 24 women with PCOS and a paradoxical increase in GH in 10 of them (41.6%) was found. An explanation of this over-response is difficult. Paradoxical GH responses after TRH administration have also been reported in acromegaly (Faglia et al., 1973
), anorexia nervosa (Irie and Tsushima, 1972), depression (Takahashi et al., 1975), severe liver disease (Panerai et al., 1977), renal failure (Gonzalez-Barcena et al., 1973) and other disorders (Gil-Ad et al., 1981; Sack et al., 1985). However, as the precise mechanism is unclear, an explanation of the findings can only be speculative. A deviation of the central nervous system (CNS) hypothalamic somatotrophic axis as a result of disruption of the normal neuroendocrine regulatory mechanisms and/or an alteration of the cellular receptors of the somatotroph cells in adenomatous tissue has been postulated in acromegaly (Ishibashi and Yamaji, 1978; Hanew et al., 1980). Such disrupted neurotransmitting abnormalities may exist in PCOS and lead to an abnormal neuroendocrine secretory control of the somatotrophs, so that TRH may stimulate these oversensitive somatotroph cells resulting in GH release. The possibility that TRH acts at the hypothalamic level cannot be excluded, based on the known wide distribution of TRH in hypothalamic and brain structures (Evain-Brion et al., 1983). In favour of this hypothesis, and indicative of a possible secretory disturbance, are the higher basal GH concentrations in over-responders compared with normal responders and normal controls and the positive correlation that was observed between basal GH concentrations and the GH response to TRH administration in this study. It is also known that women with PCOS often have increased hypothalamic opioid activity (Givens et al., 1980; Worstman et al., 1984) ascribed to dysfunction of a variety of hypothalamic neurotransmitters, which may also modify the action of TRH. Another possible explanation for the increased GH response to TRH may be a direct stimulating effect of TRH on GH secretion from the pituitary or an aberrant reduction in somatostatin secretion by activating cholinergic neurotransmission or both.
A modulatory influence of FT and insulin levels on the secretory balance of hypothalamic neurons regulating GH secretion cannot be excluded. In a previous study (Anapliotou et al., 1989), a paradoxical increase of GH secretion was observed after TRH stimulation in 48.4% of the studied PCOS patients, but the correlations between obesity or insulin and max GH were not investigated. It is of interest that in women with PCOS obesity and hyperinsulinaemia negatively influence GH secretion and that these two parameters may have an additive deleterious action on GH secretions (Villa et al., 1999). It is known that insulin suppresses basal and GHRH stimulated GH secretion from rat anterior pituitary cells in culture (Yamashita and Melmed, 1986) and that testosterone stimulates somatostatin release (Devesa et al., 1992). Another possibility is that hyperandrogenaemia and hyperinsulinaemia reduced the acute stores of releasable pituitary GH pool in the normal responders group, which had significantly higher insulin and free testosterone concentrations than the over-responders. In favour of this assumption is also the negative correlation between max GH and basal insulin concentrations that was found in the normal responders. On the other hand, it is rather unlikely that GH secretion was influenced by BMI, IGF-I or oestradiol concentrations, because their values were similar between the two PCOS subgroups. Moreover, dopaminergic deficiency (Quigley et al., 1981), which has been postulated to exist in PCOS, could not account for the oversecretion of GH in the over-responders, since it would be also be expected to have an effect on basal prolactin concentrations, which were not different in both subgroups of PCOS patients. Furthermore, earlier reports have demonstrated that free fatty acids are able to block GH response to a number of stimuli (Imaki et al., 1985). Because the two PCOS subgroups had similar free fatty acid concentrations, this mechanism must be excluded.
As PCOS is a heterogeneous disorder, it may be impossible to isolate a single factor that alone could explain the paradoxical action of TRH on GH secretion. Rather, several independent abnormalities, acting in concert, could contribute to this paradoxical GH effect.
In conclusion, the present study demonstrates enhanced GH response to TRH administration in a subgroup of women with PCOS. The results of this study could have clinical implications since they demonstrate a new pharmacological stimulus which, it is speculated, could be used as a test of GH secreting capacity to single out those women who may benefit from additive GH, following the establishment of a correlation between the response of GH secretion and gonadotrophin requirements (Menashe et al., 1993)
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To whom correspondence should be addressed
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Submitted on February 17, 1999; accepted on July 27, 1999.
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