Patterns of hormonal response to the GnRH agonist leuprolide in brothers of women with polycystic ovary syndrome: a pilot study

T. Sir Petermann1,3, A. Cartes1, M. Maliqueo1, D. Vantman1, C. Gutiérrez1, H. Toloza1, B. Echiburú1 and S.E. Recabarren2

1 Laboratory of Endocrinology, Department of Medicine, San Juan de Dios Hospital, School of Medicine, University of Chile and 2 Laboratory of Animal Physiology and Endocrinology, School of Veterinary Medicine, University of Concepción, Chillán, Chile

3 To whom correspondence should be addressed at: Laboratory of Endocrinology, Department of Medicine W. Division, School of Medicine, Las Palmeras 299, Interior Quinta Normal, Casilla 33052, Correo 33, Santiago, Chile. Email: tsir{at}med.uchile.cl


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: The aim of this study was to evaluate the effect of a single dose of leuprolide acetate on gonadotrophin and gonadal steroid secretion in brothers of women with polycystic ovary syndrome (PCOS), in order to assess P450c17{alpha} activity. An oral glucose tolerance test (OGTT) and a lipid profile were also performed. METHODS: Twenty-two unrelated brothers of women with PCOS (PCOSb) and 14 brothers of normal cycling women (Cb), matched for age, underwent a leuprolide acetate test (10 µg/kg s.c.) and an OGTT with measurement of circulating concentrations of gonadotrophins, steroid hormones, glucose, insulin and lipids. RESULTS: Clinical and basal hormonal parameters were similar in both groups. After leuprolide administration, PCOSb exhibited a significant increase of 17{alpha}-hydroxyprogesterone (17-OHP) compared to Cb (P<0.05). However, only 45% of PCOSb showed a supranormal increase of 17-OHP (2 SD above the respective control group mean values, P<0.003) with a normal gonadotrophin response (group 1). The other 55% of the PCOSb exhibited a normal 17-OHP response to the analogue (group 2). However, in group 2, basal steroid concentrations did not show a uniform pattern: six of the PCOSb exhibited high basal androstenedione (2 SD above the respective control group mean values), three were very similar to Cb, and the other three presented lower basal testosterone concentrations (2 SD below the respective control group mean values) than those observed in Cb. CONCLUSIONS: This study shows that different responses to leuprolide in PCOS brothers make evident the heterogeneity of this syndrome in which P450c17{alpha} activity could be involved.

Key words: GnRH agonist/male phenotype/polycystic ovary syndrome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder affecting women of reproductive age, characterized by hyperandrogenism and chronic anovulation in the absence of specific disorders of the pituitary, ovaries or adrenal gland (Hull, 1987Go; Zawadzky and Dunaif, 1992Go; Ehrmann et al., 1995Go; Franks, 1995Go; Knochenhauer et al., 1998Go).

In view of the high prevalence of affected individuals, a genetic cause of the syndrome was suggested many years ago (Cooper et al., 1968Go). This has been investigated in several studies on PCOS phenotypes in different populations (Crosignani and Nicolosi, 2001Go) and in family studies which demonstrated that a high number of female relatives are affected (Lunde et al., 1989Go; Lander and Schork, 1994Go; Franks et al., 1997Go; Legro et al., 1998aGo). Most of these studies have used ovarian morphology (Carey et al., 1993Go; Jahanfar et al., 1995Go) and endocrine abnormalities such as hyperandrogenaemia and anovulation to assign affected status (Legro et al., 1998bGo). However, the reproductive phenotypes in male members of PCOS families have been less documented in the literature. Some of the phenotypes proposed include: abnormalities in hair distribution, such as increased hair growth (Cooper et al., 1968Go), balding (Ferriman and Purdie, 1979Go; Lunde et al., 1989Go; Carey et al., 1993Go; Govind et al., 1999Go) or premature male balding (Carey et al., 1993Go; Govind et al., 1999Go). Other studies have described abnormalities in plasma LH levels (Cohen et al., 1975Go) and, recently, in dehydroepiandrosterone sulphate (DHEAS) concentrations in male members of PCOS families (Legro et al., 2002Go).

More than 10 years ago, Rosenfield and colleagues reported that women with well-defined PCOS have a supranormal plasma 17{alpha}-hydroxyprogesterone (17-OHP) response to stimulation with the GnRH agonist nafarelin, suggesting an abnormal regulation of the androgen-forming enzyme cytochrome P450c17{alpha} (Barnes et al., 1989Go; Rosenfield et al., 1990Go). Later, this pattern of ovarian steroidogenic response was described in hyperandrogenic adolescents and post-pubertal girls with premature pubarche during childhood, after a challenge with the GnRH agonist leuprolide acetate (Ibañez et al., 1993Go; 1994Go). Currently, leuprolide acetate in a dose of 10 µg/kg is used as an effective method in testing the pituitary–gonadal axis in men and women (Ghai and Rosenfield, 1994Go; Rosenfield et al., 1996Go).

Although increased ovarian cytochrome P450c17{alpha} activity is now a well-recognized feature of this syndrome, cytochrome P450c17{alpha} activity has not been evaluated in the male members of PCOS families. Therefore, the aim of the present study was to evaluate the effect of a single dose of the GnRH agonist leuprolide acetate on gonadotrophin and gonadal steroid secretion in brothers of women with PCOS (PCOSb), in order to assess P450c17{alpha} activity. Because metabolic abnormalities are frequent in this syndrome, an oral glucose tolerance test (OGTT) and a lipid profile were also performed in PCOSb.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Subjects
Twenty-two unrelated brothers of 22 women with PCOS (PCOSb) were recruited from patients attending the Unit of Endocrinology and Reproductive Medicine, University of Chile between 2002 and 2003. If the PCOS women had more than one brother, we selected that brother who was aged 20–30 years independently of body mass index (BMI).

Diagnosis of PCOS was made in the probands according to the diagnostic criteria for PCOS of the NIH consensus (Zawadzky and Dunaif, 1992Go) and the Rotterdam ESHRE/ASRM Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group (2003). Inclusion criteria were: chronic oligomenorrhoea or amenorrhoea, hirsutism, serum testosterone concentration >0.6 ng/ml, and/or free androgen index (FAI) >5.0, androstenedione ({Delta}4A) concentration >3.0 ng/ml and characteristic ovarian morphology on ultrasound based on the criteria described by Adams et al. (1986)Go. Patients with and without clinical signs of hyperinsulinaemia (waist:hip ratio >0.85), and with different grades of hyperinsulinaemia evaluated by an OGTT, were included.

All women were anovulatory as indicated by progesterone measurements and ultrasound examinations. Hyperprolactinaemia, androgen-secreting neoplasm, Cushing's syndrome and attenuated 21-hydroxylase deficiency, as well as thyroid disease, were excluded by appropriate tests.

By design, 14 brothers of normal cycling women acted as the control group (Cb). The Cb were selected according to age and BMI of the PCOSb and had a normal medical history and physical examination. The sisters of these volunteers had a history of regular 28–32 day menstrual cycles, absence of hirsutism and other manifestations of hyperandrogenism and normal ultrasound and hormonal status. These women were recruited from hospital staff and university students in the same city area as the PCOS patients, with the same socio-economic status.

In general, most brothers who were invited agreed to participate in the study, except for three brothers who were unable to participate due to their working schedule. All subjects had given their written consent to their participation in the study which was approved by the local ethics committee.

Study protocol
All males underwent a leuprolide acetate test and an OGTT. The OGTT was performed ≥3 days before the leuprolide acetate test. A clinical history was obtained and a physical examination was conducted. Height, weight and blood pressure were measured. BMI was used as a measure of overall adiposity and was defined as weight (kg)/height2 (m2). Premature male pattern baldness (PMPB) was assessed by the Hamilton scale and defined as significant frontoparietal hair loss (type IV of Hamilton, 1951Go). Waist circumference was measured to the nearest 0.5 cm at the point of narrowing (as viewed from behind) between the umbilicus and xiphoid process. Testicular volume was assessed by the Prader orchiometer.

For the OGTT, subjects were admitted to the Clinical Research Centre in the morning (08:30–09:00) after 3 days of a diet containing 300 g of carbohydrate per day and an overnight fast of 10 h. A 75 g OGTT was done and subjects were classified according to World Health Organization criteria. Serum glucose and insulin were measured before the glucose load and 30, 60, 90 and 120 min after. Lipid profile was also measured before the glucose load.

For the leuprolide acetate test, subjects were admitted again to the Clinical Research Centre in the morning (08:30–09:00). Baseline blood samples were obtained in the fasting state. Leuprolide acetate (10 µg/kg, Lupron; Abbott Laboratories, USA) was administered s.c., and blood samples were drawn 12 and 24 h later, according to the maximal responses for gonadotrophins and sex steroids described by Rosenfield et al. (1996)Go in adult males. LH and FSH were measured at baseline, and at 12 and 24 h after leuprolide administration. Testosterone, {Delta}4A, 17-OHP and DHEAS were determined at baseline and 24 h after the leuprolide challenge.

Data analysis
Maximal values after leuprolide testing were defined as the peak value for gonadotrophins at 12 h and for steroids at 24 h. The response to leuprolide was considered supranormal if the peak plasma 17-OHP concentration was >6.44 ng/ml. This value represents 2 SD above the mean values in normal men, who exhibited a peak serum 17-OHP concentration of 4.36±1.04 ng/ml (mean±SD) after leuprolide administration.

The measurements derived from the OGTT included the following: (i) serum fasting glucose and serum fasting insulin; homeostasis model assessment for insulin resistance (HOMAIR) according to Matthews et al. (1985)Go and whole-body insulin sensitivity index (ISI composite) according to Matsuda and De Fronzo (1999)Go; (ii) serum 2 h glucose and 2 h insulin; (iii) area under the curve of glucose (glucose AUC) and insulin (insulin AUC); (iv) serum lipid profile, total cholesterol (TC), triglycerides (TG) and HDL cholesterol (HDLc).

Assays
Serum LH and FSH were determined by electrochemiluminiscence (Roche, Switzerland). The intra- and inter-assay coefficients of variation were respectively 1.1 and 2.1% for LH, 1.67 and 3.7% for FSH.

Serum glucose was determined by the glucose oxidase method (Photometric Instrument 4010; Roche). The coefficient of variation (CV) of this method was <2.0%. Serum insulin and testosterone were assayed by radioimmunoassay (Diagnostic System Laboratories, USA), {Delta}4A, 17-OHP and DHEAS were assayed by radioimmunoassay (Diagnostic Products Corp., USA). Sex hormone-binding globulin (SHBG) was determined by radioimmunometric assay (DPC, USA). The intra- and inter-assay CV were 5.0 and 8.0% for insulin; 7.0 and 11.0% for testosterone; 3.7 and 4.9% for androstenedione; 3.5 and 5.0% for 17{alpha}-hydroxyprogesterone; 4.4 and 6.3% for DHEAS and 3.8 and 7.9% for SHBG. The lipid profile was determined by standard colorimetric assays (Photometric Instrument 4010; Roche). The CV of this method was <3.0%.

Statistical analysis
Results are reported as means and ranges. Within a group, results were tested for normality with the Wilk–Shapiro test and using Student's t-test or Mann–Whitney test. Comparisons between PCOSb (group 1, group 2) and Cb were performed using analysis of variance. In order to abolish the false positives in multiple comparisons, we used a Bonferroni test. The significance level was set at 5% for comparison between two groups and 0.3% for multiple comparisons.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Table I shows the clinical characteristics of Cb and PCOSb. By design, age and BMI were not different between groups. Waist circumference and birthweight were also similar between groups. PMPB and testicular volume were not different between Cb and PCOSb.


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Table I. Clinical characteristics of control brothers (Cb) and polycystic ovarian syndrome brothers (PCOSb)

 
Table II shows the hormone levels before and after leuprolide administration of Cb and PCOSb. Basal levels of gonadotrophins and sex steroids were not significantly different between Cb and PCOSb. However, after leuprolide administration, PCOSb showed a maximal 17-OHP response, which was significantly higher (P<0.05) than that observed in Cb.


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Table II. Basal and maximal hormonal response to leuprolide acetate in control brothers (Cb) and polycystic ovarian syndrome brothers (PCOSb)

 
Nevertheless, after leuprolide administration, only 45% of the PCOSb (PCOSb-1, n=10) showed a supranormal increase of 17-OHP (P<0.003, 2 SD above the respective control group mean values) with testosterone and {Delta}4A being comparable to those observed in Cb. LH and FSH secretion and LH:FSH ratio were also similar to those observed in Cb. In the PCOSb-1 group, baseline hormonal concentrations were not different from those observed in the control group (Figure 1).



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Figure 1. Basal and post-stimulated gonadotrophin and steroid hormone concentrations in control brothers (Cb) and PCOS brothers (PCOSb) according to the response to leuprolide acetate administration (PCOSb-1 = group 1; PCOSb-2 = group 2).

 
The other 55% of the PCOSb (PCOSb-2, n=12) exhibited a normal 17-OHP response to the analogue. In this group, post-stimulated testosterone and {Delta}4A were not significantly different from those observed in Cb. Moreover, LH and FSH secretion and LH:FSH ratio were also similar to those observed in Cb. However, in this group, basal steroid concentrations did not show a uniform pattern. Six of the PCOSb-2 exhibited basal {Delta}4A concentrations >4.95 ng/ml (mean + 2SD). This value represents 2 SD above the mean values in normal men, who exhibited a baseline serum {Delta}4A concentration of 3.05±0.95 (mean±SD). Three subjects were very similar to Cb, and the other three presented testosterone concentrations <2.81 ng/ml (mean–2SD). This value represents 2 SD below the mean values in normal men, who exhibited a baseline serum testosterone concentration of 6.37±1.78 ng/ml (mean±SD). In these PCOSb, post-stimulated testosterone was also significantly lower [Cb: 8.85 ng/ml (4.86–16.01); PCOSb: 4.44 ng/ml (3.98–4.68); P=0.002] and FSH tended to be significantly higher [Cb: 6.66 IU/l (2.78–15.05); PCOSb: 11.4 IU/l (6.5–16.0); P=0.052) than those observed in the Cb.

The clinical and metabolic characteristics of Cb and the different groups of PCOSb are presented in Table III. In general, clinical and metabolic parameters were similar between Cb and PCOSb, taken as one whole group. In a comparison between the two groups of PCOSb, the subjects of group 2 presented lower HDLc and higher 2 h glucose and AUC glucose than the subjects of group 1 (P<0.003).


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Table III. Clinical, endocrine and metabolic characteristics of control brothers (Cb) and polycystic ovarian syndrome brothers (PCOSb) according to the response to leuprolide acetate

 
The clinical, endocrine and metabolic characteristics of probands of the different groups of PCOSb are presented in Table IV. In general, clinical characteristics were not different between groups. In relation to endocrine and metabolic parameters, probands of PCOSb of group 1 were less insulin resistant than those of group 2 (P<0.05), reflected by fasting insulin levels and HOMAIR.


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Table IV. Clinical, endocrine and metabolic characteristics of probands according to their brothers' response to leuprolide acetate

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In the present study, we found that most brothers of PCOS women showed an abnormal hormonal profile. Of these brothers, approximately half exhibited hormonal changes after leuprolide testing, resembling those described in the PCOS syndrome and suggesting an increased cytochrome P450c17{alpha} activity. In the remaining brothers, other abnormalities in sex steroid concentrations were observed.

No historical or physical findings distinguished the men with supranormal responses to leuprolide from those with normal responses (group 1), similar to that described by Ehrmann et al. (1992)Go for PCOS women. In this group, baseline hormonal concentrations were not different from those observed in the control group. This observation, and the fact that exaggerated 17-OHP responses to leuprolide stimulation were not mediated by a hyperresponsiveness of LH, suggest an increased testicular androgen sensitivity to LH stimulation in these men, similar to that previously described by Ibañez et al. (1996)Go for the ovarian response in hyperandrogenic women. It has been proposed that insulin excess could play a role in this dysfunction (Nestler and Jakubowicz, 1997Go). However, the clinical and metabolic characteristics of these subjects were not compatible with insulin resistance and/or hyperinsulinaemia which could increase cytochrome P450c17{alpha} activity. Something similar was observed in the probands of this group of PCOSb (group 1), who were less insulin resistant than those of group 2. These observations favour the concept that the defect underlying the abnormal response to leuprolide testing present in these PCOS brothers is probably intrinsic, indicating a familial aggregation of a genetic steroidogenic dysfunction.

The group of PCOSb with a normal 17-OHP response to the analogue (group 2) was heterogeneous. Six of them exhibited high basal {Delta}4A concentrations, which is also a common biochemical feature in PCOS. This abnormality was previously described by Cohen et al. (1975)Go and was attributed to increased adrenal secretion. According to our results, it can be assumed that the high {Delta}4A concentrations are of adrenal origin, as previously suggested by Cohen et al. (1975)Go, due to the fact that {Delta}4A levels did not increase after the leuprolide challenge.

Three other PCOS brothers of group 2 were characterized by low baseline testosterone concentrations and high baseline FSH concentrations which were accentuated after leuprolide administration. This hormonal pattern, suggestive of a male gonadal dysfunction, has not been previously described in brothers of PCOS women.

Nevertheless, in concordance with this observation we have recently established that some infant boys born to PCOS mothers exhibit low stimulated concentrations of testosterone after leuprolide administration compared with infant boys born after a normal term pregnancy (T.Sir-Petermann et al., 2004Go, unpublished results), suggesting that this phenotype may begin early in life in men. Therefore, it is feasible to speculate that this hormonal pattern of male gonadal dysfunction could reflect the effect of intrauterine factors such as prenatal androgen excess (Sir-Petermann et al., 2002Go) and low birthweight (Francois et al., 1997Go; Cicognani et al., 2002Go) or a combination of intrauterine factors that could affect the testicular physiology during fetal life.

In this pilot study, spermatogenesis was not assessed because this was not our aim. Therefore, at the moment, we cannot establish if this hormonal status could be a marker of subsequent subfertility.

It is interesting to point out that, at the time of the present investigation, none of the PCOS brothers desired fertility. Therefore, further studies are needed to evaluate the long-term effect of these abnormal hormonal profiles on the reproductive function in male members of PCOS families.

Regarding different phenotypes previously proposed in brothers of women with PCOS, in the present study there was no increase in the prevalence of premature balding in the brothers of PCOS women. This observation is similar to that described in a recent publication (Legro et al., 2002Go). We also did not find significant differences in LH and DHEAS concentrations between Cb and PCOSb, as previously described (Cohen et al., 1975Go; Legro et al., 2002Go). Our results are in agreement with a recent publication aimed at evaluating glucose tolerance status, gonadotrophins and androgens in first-degree relatives of patients with PCOS. In this study, no differences in LH and DHEAS concentrations between Cb and PCOSb were observed (Yildiz et al., 2003Go).

Different responses to the GnRH analogue make evident the heterogeneity of this syndrome, suggesting that PCOS is probably not the result of a single genetic defect. However, at the date of the present study, it was not possible to draw conclusions about the type of inheritance of the reproductive component of this condition. Additional studies are needed with more subjects to detect specific biochemical phenotype in male relatives of women with PCOS. Moreover, in order to establish whether an increased 17-OHP level after leuprolide challenge is an inherited component of PCOS, siblings, parents and probands need to be tested.

In summary, these data show that most brothers of PCOS women exhibit hormonal changes that closely resemble those described in this syndrome, thus opening the dilemma of whether this complex endocrine disorder is restricted to women. Further studies are needed to evaluate the long-term impact of these reproductive phenotypes in male members of PCOS families.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The authors express their gratitude to Dr Robert Rosenfield for his editorial comments. This work was supported by a grant from SOCHEM 2002/08, FONDECYT 1000973 and by the Alexander von Humboldt Foundation.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on May 7, 2004; resubmitted on July 26, 2004; accepted on August 18, 2004.





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