Page 1 of 30
Accepted Preprint first posted on 21 July 2014 as Manuscript EJE-14-0252
1 1
European Survey of Diagnosis and Management of the Polycystic Ovary Syndrome: results of
2
the ESE PCOS Special Interest Group’s Questionnaire
3 4
The ESE PCOS Special Interest Group: Conway Gerard1, Dewailly Didier2, Diamanti-
5
Kandarakis Evanthia3, Escobar-Morreale Hector F.4, Franks Steven5, Gambineri Alessandra6,
6
Kelestimur Fahrettin7, Macut Djuro8, Micic Dragan8, Pasquali Renato6*, Pfeifer Marija9, Pignatelli
7
Duarte10 Pugeat Michel11, Yildiz Bulent12
8
* Group coordinator
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Affiliations: (1) Conway Gerard (Department of Endocrinology, University College London Hospitals, London NW1 2BU, UK); (2) Dept. of Endocrine Gynaecology and Reproductive Medicine, hopital Jeanne de Fiandre, Centre Hospitalier de Lille, France; (3) 3rd Dept. of Medicine, Neuroendocrine Clinic, University of Athens-Medical School, Athens, Greece); (4) Department of Endocrinology & Nutrition, Universidad de Alcalá & Hospital Universitario Ramón y Cajal & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid, Spain; (5) Institute of Reproductive and Developmental Biology, Imperial College London, London, UK; (6) Division of Endocrinology, Department of Medical and Surgical Sciences. St. Orsola-Malpighi Hospital, Bologna, Italy; (7) Department of Endocrinology, School of Medicine, Erciyes University, Kayseri, Turkey; (8) Clinic for Endocrinology, Diabetes and Metabolic Diseases, School of Medicine, University of Belgrade, Belgrade, Serbia; (9) Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia; (10) Pignatelli Duarte (Dept of Endocrinology, Hospital S. Joao, Porto, Portugal); (11) Inserm U863 IFR6, Fédération d’Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Université Lyon-1, Lyon, France; (12) Department of Internal Medicine, Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey).
26 27
Word count: Abstract 283; Text: 3593
28
Address for correspondence
29 30 31
Renato Pasquali, M.D. Division of Endocrinology, Dept. of Medical and Surgical Sciences, University Alma Mater Studiorum, St. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. (e-mail: [email protected])
32
Copyright © 2014 European Society of Endocrinology.
Page 2 of 30
2 33
Abstract
34
Background: There is evidence for differences between endocrinologists and other specialists in
35
their approach to diagnosis and management of the polycystic ovary syndrome (PCOS).
36
Objective: A mailed survey consisting of a simple questionnaire aiming to understand current
37
practice for diagnosis and management of the PCOS by specialists across Europe.
38
Methods: The questionnaire consisted of 23 questions grouped to achieve information on (i) the
39
general characteristics of the respondents, (ii) patients with PCOS seen by endocrinologists (iii) the
40
main diagnostic criteria (iv) biochemical parameters used in the differential diagnosis of
41
hyperandrogenism, (v) long-term concerns and, finally (vi) treatment choices. A total of 357
42
questionnaires, representing 13.3% of the members of ESE were available for final analysis; 93% of
43
the respondents were endocrinologists
44
Results: In relation to the diagnostic criteria, respondents were most likely to select menstrual
45
irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates
46
were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that
47
the NIH criteria were followed by the majority of respondents. The most frequent biochemical
48
parameters in the differential diagnosis of hyperandrogenism were total testosterone or free
49
androgen index (FAI). Obesity and type 2 diabetes were regarded as the principal long-term
50
concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%),
51
lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility,
52
such as clomiphene citrate alone or combined with metformin were prescribed by 9% and 23%,
53
respectively, whereas only 6% used other methods for induction of ovulation.
54
Conclusion: The survey the ESE has produced is a good start for evaluating the perspective in the
55
diagnosis and treatment of PCOS by endocrinologists in Europe.
56
Page 3 of 30
3 57
Introduction.
58
The requirement that all pathological conditions characterized by androgen excess in women
59
should attract increasing interest from endocrinologists is shared by many members of the European
60
Society of Endocrinology (ESE). The polycystic ovary syndrome (PCOS) represents the most
61
common clinical condition characterized by androgen excess, but the diagnosis can be made only
62
after the exclusion of all other potential conditions with a well defined etiology [1-3]. Therefore,
63
androgen excess, clinically indicated by hirsutism and established by the finding of increased blood
64
testosterone level, is usually considered as the main criterion for the definition of PCOS by
65
,endocrinologists. In contrast, menses abnormalities and chronic anovulation together with
66
polycystic ovarian morphology in ultrasound are the criteria favoured by gynaecologists, whose
67
primary interest is usually focused on ovarian dysfunction [4]. Both approaches have been a matter
68
of discussion with some controversies that preclude a clear and decisive consensus on management
69
[1-3]. It should be noted that none of the diagnostic criteria for PCOS (1,3) are the result of a formal
70
consensus process, in fact they were based on expert opinion rather than evidence. This may justify
71
some different perspectives and concerns on the major criteria currently used to define PCOS.
72
However, even in women whose primary reason for presentation is ovarian dysfunction, PCOS is
73
often characterized by the presence of different degrees of insulin resistance and compensatory
74
insulin excess, and many patients are overweight or obese, conditions which play an important role
75
in the pathogenesis of androgen excess [4]. In addition, women with PCOS are characterized by an
76
increased susceptibility to develop glucose intolerance and type 2 diabetes (T2D) [5,6]. These
77
metabolic disorders are particularly common in women with the classic hyperandrogenic-
78
anovulatory phenotype [7,8]. Arguments in favour of the inclusion of metabolic issues while
79
characterizing the PCOS phenotype in each single patient have emerged in recent years, although
80
this is still a matter of intense debate [7,8]. Some different perspectives in the definition, diagnosis
81
and treatment of PCOS between endocrinologists and gynaecologists have been documented [9]. As
Page 4 of 30
4 82
an unfavourable consequence, women might receive a different diagnosis or treatment depending
83
on the specialist to whom they are referred.
84
We therefore planned a survey, on behalf of the European Society of Endocrinology (ESE),
85
consisting of a simple questionnaire aimed at understanding the usual procedure in diagnosis and
86
management of PCOS by specialists, mostly endocrinologists, across Europe. It is of importance to
87
note that the methodology we employed in the current study is very similar to that pursued by the
88
former NIH criteria (1) that was based on a survey of the participants in the NIH-NICHD
89
conference on PCOS.
90
Material and Methods
91
In 2012, the ESE PCOS Special Interest Group prepared a questionnaire to be sent to all
92
ESE-members with the aim of collecting some information on the current practice in the
93
management of PCOS in different European countries as a first step towards preparing a position
94
statement on the management of this condition. The study was approved by the institutional review
95
board of the ESE.
96
The questionnaire consisted of 23 questions, some of which envisaged two or more responses.
97
Respondents were characterized according to age, type of hospital or medical school, clinical
98
speciality, and practice settings. In addition, specific questions were prepared to obtain information
99
on (i) the estimated prevalence of PCOS in the country of residence, (ii) the diagnostic criteria used
100
to define PCOS, (iii) treatment choices, (iv) long-term concerns about PCOS, and (v) collaboration
101
with other specialists. The list of questions was developed on the basis of scientific evidence on
102
which all the members of the group agreed at the first meeting in Paris, January 2012. Conversely,
103
several other questions were defined in order to obtain information from members of the ESE on
104
their most common diagnostic procedures and on their concerns regarding metabolic issues.
Page 5 of 30
5
105
The complete list of questions and of all potential answers is reported in Table 1.In June 2012, the
106
ESE secretariat placed the questionnaire on the ESE website and the completed questionnaires were
107
collected between June 2012 and April 2013. Every member of the ESE received an e-mail
108
invitation sent on two occasions during this period.
109
Only
110
(http://www.bioscientifica.com) organized by Bioscientifica (Bioscientifica LTD, Bristol UK). In
111
order to achieve the goal, a further effort was planned during the 15th European Congress of
112
Endocrinology held in Copenhagen, Denmark, 27 April - 1 May 2013, when the collection of
113
questionnaires was considered completed. At the end, a total of 364 questionnaires (corresponding
114
to 13.5% of ESE members) were available for analysis, for a 4.8% error at the 95% confidence
115
level. No duplicates were found.
116
Statistical analysis
135
questionnaires
(5%)
were
obtained
using
the
web-based
survey
117
Descriptive statistics and Student’s t test or Fisher’s exact test were used to analyze the data,
118
as needed. A level of p
Accepted Preprint first posted on 21 July 2014 as Manuscript EJE-14-0252
1 1
European Survey of Diagnosis and Management of the Polycystic Ovary Syndrome: results of
2
the ESE PCOS Special Interest Group’s Questionnaire
3 4
The ESE PCOS Special Interest Group: Conway Gerard1, Dewailly Didier2, Diamanti-
5
Kandarakis Evanthia3, Escobar-Morreale Hector F.4, Franks Steven5, Gambineri Alessandra6,
6
Kelestimur Fahrettin7, Macut Djuro8, Micic Dragan8, Pasquali Renato6*, Pfeifer Marija9, Pignatelli
7
Duarte10 Pugeat Michel11, Yildiz Bulent12
8
* Group coordinator
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Affiliations: (1) Conway Gerard (Department of Endocrinology, University College London Hospitals, London NW1 2BU, UK); (2) Dept. of Endocrine Gynaecology and Reproductive Medicine, hopital Jeanne de Fiandre, Centre Hospitalier de Lille, France; (3) 3rd Dept. of Medicine, Neuroendocrine Clinic, University of Athens-Medical School, Athens, Greece); (4) Department of Endocrinology & Nutrition, Universidad de Alcalá & Hospital Universitario Ramón y Cajal & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid, Spain; (5) Institute of Reproductive and Developmental Biology, Imperial College London, London, UK; (6) Division of Endocrinology, Department of Medical and Surgical Sciences. St. Orsola-Malpighi Hospital, Bologna, Italy; (7) Department of Endocrinology, School of Medicine, Erciyes University, Kayseri, Turkey; (8) Clinic for Endocrinology, Diabetes and Metabolic Diseases, School of Medicine, University of Belgrade, Belgrade, Serbia; (9) Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia; (10) Pignatelli Duarte (Dept of Endocrinology, Hospital S. Joao, Porto, Portugal); (11) Inserm U863 IFR6, Fédération d’Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Université Lyon-1, Lyon, France; (12) Department of Internal Medicine, Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey).
26 27
Word count: Abstract 283; Text: 3593
28
Address for correspondence
29 30 31
Renato Pasquali, M.D. Division of Endocrinology, Dept. of Medical and Surgical Sciences, University Alma Mater Studiorum, St. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. (e-mail: [email protected])
32
Copyright © 2014 European Society of Endocrinology.
Page 2 of 30
2 33
Abstract
34
Background: There is evidence for differences between endocrinologists and other specialists in
35
their approach to diagnosis and management of the polycystic ovary syndrome (PCOS).
36
Objective: A mailed survey consisting of a simple questionnaire aiming to understand current
37
practice for diagnosis and management of the PCOS by specialists across Europe.
38
Methods: The questionnaire consisted of 23 questions grouped to achieve information on (i) the
39
general characteristics of the respondents, (ii) patients with PCOS seen by endocrinologists (iii) the
40
main diagnostic criteria (iv) biochemical parameters used in the differential diagnosis of
41
hyperandrogenism, (v) long-term concerns and, finally (vi) treatment choices. A total of 357
42
questionnaires, representing 13.3% of the members of ESE were available for final analysis; 93% of
43
the respondents were endocrinologists
44
Results: In relation to the diagnostic criteria, respondents were most likely to select menstrual
45
irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates
46
were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that
47
the NIH criteria were followed by the majority of respondents. The most frequent biochemical
48
parameters in the differential diagnosis of hyperandrogenism were total testosterone or free
49
androgen index (FAI). Obesity and type 2 diabetes were regarded as the principal long-term
50
concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%),
51
lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility,
52
such as clomiphene citrate alone or combined with metformin were prescribed by 9% and 23%,
53
respectively, whereas only 6% used other methods for induction of ovulation.
54
Conclusion: The survey the ESE has produced is a good start for evaluating the perspective in the
55
diagnosis and treatment of PCOS by endocrinologists in Europe.
56
Page 3 of 30
3 57
Introduction.
58
The requirement that all pathological conditions characterized by androgen excess in women
59
should attract increasing interest from endocrinologists is shared by many members of the European
60
Society of Endocrinology (ESE). The polycystic ovary syndrome (PCOS) represents the most
61
common clinical condition characterized by androgen excess, but the diagnosis can be made only
62
after the exclusion of all other potential conditions with a well defined etiology [1-3]. Therefore,
63
androgen excess, clinically indicated by hirsutism and established by the finding of increased blood
64
testosterone level, is usually considered as the main criterion for the definition of PCOS by
65
,endocrinologists. In contrast, menses abnormalities and chronic anovulation together with
66
polycystic ovarian morphology in ultrasound are the criteria favoured by gynaecologists, whose
67
primary interest is usually focused on ovarian dysfunction [4]. Both approaches have been a matter
68
of discussion with some controversies that preclude a clear and decisive consensus on management
69
[1-3]. It should be noted that none of the diagnostic criteria for PCOS (1,3) are the result of a formal
70
consensus process, in fact they were based on expert opinion rather than evidence. This may justify
71
some different perspectives and concerns on the major criteria currently used to define PCOS.
72
However, even in women whose primary reason for presentation is ovarian dysfunction, PCOS is
73
often characterized by the presence of different degrees of insulin resistance and compensatory
74
insulin excess, and many patients are overweight or obese, conditions which play an important role
75
in the pathogenesis of androgen excess [4]. In addition, women with PCOS are characterized by an
76
increased susceptibility to develop glucose intolerance and type 2 diabetes (T2D) [5,6]. These
77
metabolic disorders are particularly common in women with the classic hyperandrogenic-
78
anovulatory phenotype [7,8]. Arguments in favour of the inclusion of metabolic issues while
79
characterizing the PCOS phenotype in each single patient have emerged in recent years, although
80
this is still a matter of intense debate [7,8]. Some different perspectives in the definition, diagnosis
81
and treatment of PCOS between endocrinologists and gynaecologists have been documented [9]. As
Page 4 of 30
4 82
an unfavourable consequence, women might receive a different diagnosis or treatment depending
83
on the specialist to whom they are referred.
84
We therefore planned a survey, on behalf of the European Society of Endocrinology (ESE),
85
consisting of a simple questionnaire aimed at understanding the usual procedure in diagnosis and
86
management of PCOS by specialists, mostly endocrinologists, across Europe. It is of importance to
87
note that the methodology we employed in the current study is very similar to that pursued by the
88
former NIH criteria (1) that was based on a survey of the participants in the NIH-NICHD
89
conference on PCOS.
90
Material and Methods
91
In 2012, the ESE PCOS Special Interest Group prepared a questionnaire to be sent to all
92
ESE-members with the aim of collecting some information on the current practice in the
93
management of PCOS in different European countries as a first step towards preparing a position
94
statement on the management of this condition. The study was approved by the institutional review
95
board of the ESE.
96
The questionnaire consisted of 23 questions, some of which envisaged two or more responses.
97
Respondents were characterized according to age, type of hospital or medical school, clinical
98
speciality, and practice settings. In addition, specific questions were prepared to obtain information
99
on (i) the estimated prevalence of PCOS in the country of residence, (ii) the diagnostic criteria used
100
to define PCOS, (iii) treatment choices, (iv) long-term concerns about PCOS, and (v) collaboration
101
with other specialists. The list of questions was developed on the basis of scientific evidence on
102
which all the members of the group agreed at the first meeting in Paris, January 2012. Conversely,
103
several other questions were defined in order to obtain information from members of the ESE on
104
their most common diagnostic procedures and on their concerns regarding metabolic issues.
Page 5 of 30
5
105
The complete list of questions and of all potential answers is reported in Table 1.In June 2012, the
106
ESE secretariat placed the questionnaire on the ESE website and the completed questionnaires were
107
collected between June 2012 and April 2013. Every member of the ESE received an e-mail
108
invitation sent on two occasions during this period.
109
Only
110
(http://www.bioscientifica.com) organized by Bioscientifica (Bioscientifica LTD, Bristol UK). In
111
order to achieve the goal, a further effort was planned during the 15th European Congress of
112
Endocrinology held in Copenhagen, Denmark, 27 April - 1 May 2013, when the collection of
113
questionnaires was considered completed. At the end, a total of 364 questionnaires (corresponding
114
to 13.5% of ESE members) were available for analysis, for a 4.8% error at the 95% confidence
115
level. No duplicates were found.
116
Statistical analysis
135
questionnaires
(5%)
were
obtained
using
the
web-based
survey
117
Descriptive statistics and Student’s t test or Fisher’s exact test were used to analyze the data,
118
as needed. A level of p
