POI Guide 2026
POI_guide_2026
User Manual:
Open the PDF directly: View PDF 
.
Page Count: 12
ESHRE PAGES
ESHRE Guideline: management
of women with premature ovarian
insufficiency†
The ESHRE Guideline Group on POI, L. Webber1,*, M. Davies1,
R. Anderson2, J. Bartlett3, D. Braat4, B. Cartwright5, R. Cifkova6,
S. de Muinck Keizer-Schrama7, E. Hogervorst8, F. Janse9, L. Liao1,
V. Vlaisavljevic10, C. Zillikens11, and N. Vermeulen12
1
University College London Hospital, London, UK
2
University of Edinburgh, Edinburgh, UK
3
The Daisy Network, Rossendale, UK
4
Radboudumc Nijmegen, Nijmegen, The Netherlands
5
ST5 Obstetrics and Gynaecology trainee London KSS, London, UK
6
Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer Hospital, Prague, Czech Republic
7
Erasmus University Medical Center, Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands
8
Applied Cognitive Research (SSEHS),
Loughborough, UK
9
UMC Utrecht, Utrecht, The Netherlands
10
Department of Reproductive Medicine (Slovenia), University Medical Centre,
Canterbury, UK
11
Erasmus MC Rotterdam, Rotterdam, The Netherlands
12
European Society of Human Reproduction and Embryology,
Grimbergen, Belgium
*Correspondence address. E-mail: lisa.webber@uclh.nhs.uk
Submitted on December 14, 2015; resubmitted on December 14, 2015; accepted on January 11, 2016
study question: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available
evidence in the literature?
summary answer: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the
diagnosis and treatment of women with POI.
what is known already: NA.
study design, size, duration: This guideline was produced by a multidisciplinary group of experts in the field using the methodology
of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included
papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative
to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology
(ESHRE) members and professional organizations were asked to review the guideline.
participants/materials, setting, methods: NA.
main results and the role of chance: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46
recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations
were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on
puberty induction resulted in five recommendations.
limitations, reasons for caution: The main limitation of the guideline is that, due to the lack of data, many of the recommenda-
tions are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome.
wider implications of the findings: Despite the limitations, the guideline group is confident that this document will be able to
guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline
group has formulated research recommendations on the gaps in knowledgeidentified in the literaturesearches, in an attempt to stimulate research
on the key issues in POI.
study funding/competing interest(s): The guideline was developed and funded by ESHRE, covering expenses associated
with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not
†
ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.
&The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
Human Reproduction, Vol.31, No.5 pp. 926–937, 2016
Advanced Access publication on March 22, 2016 doi:10.1093/humrep/dew027
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to
disclose.
trial registration number: NA.
Key words: premature ovarian insufficiency / POI / European Society of Human Reproduction and Embryology / guideline / evidence based
Introduction
This European Society of Human Reproduction and Embryology (ESHRE)
guideline on the management of women with premature ovarian insuffi-
ciency (POI) offers best practice advice on the care of women with POI,
both primary and secondary. The patient population comprises women
younger than 40 years (which includes Turner Syndrome patients) and
women older than 40 years, but with disease onset before the age of 40.
Furthermore, this clinical guideline provides recommendations on the
initial assessment and management of women with POI. The initial as-
sessment includes diagnosis, assessment of causation and basic assess-
ment. The management includes hormonal treatment. Since POI has
consequences for health apart from gynaecological issues, these are
also described. Consequences of POI and treatment options are
included in the following domains: fertility and contraception, bone
health, cardiovascular issues, psychosexual function, psychological func-
tion and neurological function.
Other topics discussed are puberty induction, life expectancy and
implications for relatives of women with POI.
This guideline is limited to POI and does not apply to women with low
ovarian reserve.
Materials and Methods
The guideline was developed according to a well-documented methodology,
universal to ESHRE guidelines (Vermeulen et al., 2014).
In short, 31 key questions were formulated by the guideline group and
structured in PICO format (Patient, Intervention, Comparison, Outcome).
For each question, we searched the databases (PUBMED/MEDLINE,
Cochrane library, PsycInfo) from inception to 1 April 2014. The literature
searches were limited to studies written in English. Based on the evidence,
and after constructing evidence tables and quality assessment, draft recom-
mendations were written by the assigned expert guideline group member.
Two additional meetings were organized to discuss the evidence and recom-
mendations and to reach consensus on the final formulation of the recom-
mendations.
For each recommendation, a grade (A–D) was assigned based on the
strength of the supporting evidence (scored from 1++ to 4). In the case of
absence of evidence, the guideline development group (GDG) could decide
on writing good practice points(GPPs), based on clinical expertise (see Table I).
After finalization of the guideline draft, an invitation to review was published
on the ESHRE website. In addition, an invitation to review was sent to members
of the ESHRE special interest group Reproductive Endocrinology (n¼6000)
and to professional organizations on human reproduction, gynaecology, endo-
crinology and menopause (n¼79). Three hundred and ninety-eight com-
ments from 34 reviewers were processed by the methodological expert
(N.V.) and the chair of the GDG (L.W.) either by adapting the content of
the guideline and/or by replying to the reviewer. The review process was sum-
marized in the review report, published on the ESHRE website.
The guideline will be considered for update 4 years after publication, with
an intermediate assessment of the need for updating 2 years after publication.
Key questions and
recommendations
The current document summarizes the key questions and the recom-
mendations for clinical practice. Further background information
and the supporting evidence for each recommendation can be found in
the full version of the guideline available at http://www.eshre.eu/
Guidelines-and-Legal/Guidelines.
What should this condition be called?
Primary ovarian insufficiency was first described in 1942 and has, since then,
been described with different names and definitions (Albright et al., 1942).
The term ‘premature ovarian insufficiency’ should be used to describe
this condition in research and clinical practice
GPP
How should POI be defined?
POI is a clinical syndrome defined by loss of ovarian activity before the age
of 40 years. POI is characterized by menstrual disturbance (amenorrhea
or oligomenorrhea) with raised gonadotrophins and low estradiol.
.............................................................................................................................................................................................
Table I Interpretation of the grades of recommendations for the initial assessment and management of women with POI
(Vermeulen et al., 2014).
Grades of recommendations Supporting evidence
A Meta-analysis, systematic review or multiple RCTs (high quality)
B Meta-analysis, systematic review or multiple RCTs (moderate quality)
Single RCT, large non-randomized trial, case– control or cohort studies (high quality)
C Single RCT, large non-randomized trial, case–control or cohort studies (moderate quality)
D Non-analytical studies, case reports or case series (high or moderate quality)
GPP Expert opinion
The grade of the recommendations is only based on the strength of the supporting evidence. In formulating strong or weak recommendations, the guideline group took the strength of the
supporting evidence into account, but weighted it against the benefits and harms, and the preferences of clinicians and patients.
Guideline for managing premature ovarian insufficiency 927
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
What is the prevalence of POI in the general
population?
The prevalence of POI is 1%. Population characteristics such as ethni-
city may affect the prevalence.
In view of the long-term health consequences of POI, efforts should be
made to reduce the incidence of POI. Modifiable factors may include:
(i) gynaecological surgical practice, (ii) lifestyle—smoking, (iii) modified
treatment regimens for malignant and chronic diseases.
Diagnosis of POI
Summary of diagnostic workup in Table II.
What are the symptoms of POI?
Clinicians should enquire about symptoms of estrogen deficiency in
women presenting with oligomenorrhea or amenorrhea
GPP
POI needs to be excluded in women with amenorrhea/oligomenorrhea
or estrogen-deficiency symptoms below the age of 40 years
GPP
What investigations should be performed
for diagnosis of POI?
The diagnosis POI is based on the presence of menstrual disturbance and
biochemical confirmation.
Although proper diagnostic accuracy in POI is lacking, the GDG
recommends the following diagnostic criteria: (i) oligo/amenorrhea for
at least 4 months, and (ii) an elevated FSH level .25 IU/l on two
occasions .4 weeks apart
GPP
What are the known causes of POI and
how should they be investigated?
Chromosomal analysis should be performed in all women with
non-iatrogenic POI (Bachelot et al., 2009;Rocha et al., 2011;Jiao et al.,
2012;Kalantari et al., 2013)
C
Gonadectomy should be recommended for all women with detectable
Y chromosomal material (Rocha et al., 2011)
C
Fragile-X premutation testing is indicated in POI women (Genetics
Committee of the Society of Obstetricians and Gynaecologists of
Canada et al., 2008;Bachelot et al., 2009)
B
The implications of the fragile-X premutation should be discussed
before the test is performed
GPP
Autosomal genetic testing is not at present indicated in women with POI,
unless there is evidence suggesting a specific mutation (e.g. BPES:
blepharophimosis–ptosis –epicanthus inversus syndrome)
GPP
Screening for 21OH-Ab (or alternatively adrenocortical antibodies
(ACA)) should be considered in women with POI of unknown cause
or if an immune disorder is suspected
C
Refer POI patients with a positive 21OH-Ab/ACA test to an
endocrinologist for testing of adrenal function and to rule out Addison’s
disease (Chen et al., 1996;Bakalov et al., 2002;Dal Pra et al., 2003;
Husebye and Lovas, 2009)
Screening for thyroid (TPO-Ab) antibodies should be performed in
women with POI of unknown cause or if an immune disorder is
suspected
C
In patients with a positive TPO-Ab test, thyroid stimulating hormone
(TSH) should be measured every year (Kim et al., 1997;Hollowell et al.,
2002;Goswami et al., 2006)
There is insufficient evidence to recommend routinely screening POI
women for diabetes (Kim et al., 1997)
D
There is no indication for infectionscreening in women with POI (Kokcu,
2010)
D
The possibility of POI being a consequence of a medical or surgical
intervention should be discussed with women as part of the consenting
process for that treatment
GPP
Although no causal relation has been proved for cigarette smoking and
POI, there is a relation to early menopause. Therefore, women who are
prone to POI should be advised to stop smoking
GPP
In a significant number of women with POI, the cause is not identified and
these women are described as having unexplained or idiopathic POI.
How often should tests for autoantibodies
be repeated?
If 21OH-Ab/ACA and TPO-Ab are negative in women with POI, there is
no indication for re-testing later in life, unless signs or symptoms of these
endocrine diseases develop (Betterle et al., 1997)
C
.............................................................................................................................
.............................................................................................................................................................................................
Table II Summary of diagnostic workup for POI.
Test Implications
Positive test Negative test
Genetic/chromosomal
Karyotyping (for diagnosis of Turner syndrome) Refer to endocrinologist, cardiologist and geneticist A second analysis of the karyotype in epithelial cells
(in case of high clinical suspicion)
Test for Y-chromosomal material Discuss gonadectomy with the patient
Fra-X Refer to geneticist
Autosomal genetic testing
a
Antibodies
b
ACA/21OH antibodies Refer to endocrinologist Re-test in case of clinical signs or symptoms
TPO-Ab Test TSH every year
Fra-X, fragile X; TPO-Ab, thyroid antibodies; ACA, adrenocortical antibodies.
a
Not at present indicated in women with POI, unless there is evidence suggesting a specific mutation (e.g. BPES).
b
POI of unknown cause or if an immune disorder is suspected.
928 The ESHRE Guideline Group on POI
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
What are the implications for relatives
of women with POI?
Relatives of women with the fragile-X premutation should be offered
genetic counselling and testing (Genetics Committee of the Society of
Obstetricians and Gynaecologists of Canada et al., 2008;Finucane et al.,
2012)
B
Relatives of women with non-iatrogenic POI who are concerned about
their risk for developing POI should be informed that: (i) currently there
is no proved predictive test to identify women that will develop POI,
unless a mutation known to be relatedto POI was detected, (ii) thereare
no established POI preventing measures, (iii) fertility preservation
appears as a promising option, although studies are lacking and (iv) their
potential risk of earlier menopause should be taken into account when
planning a family
GPP
Sequelae of POI
What are the consequences of POI
for life expectancy?
Untreated POI is associated with reduced life expectancy, largely due to
cardiovascular disease (Ossewaarde et al., 2005;Amagai et al., 2006;
Rocca et al., 2006;Hong et al., 2007;Wu et al., 2014)
C
Women with POI should be advised on how to reduce cardiovascular
risk factors by not smoking, taking regular exercise and maintaining a
healthy weight
GPP
What are the consequences of POI for fertility?
Women with POI should be informed that there is a small chance of
spontaneous pregnancy
GPP
Women with POI should be advised to use contraception if they wish to
avoid pregnancy
GPP
What fertility interventions are effective?
Inform women with POI that there are no interventions that have been
reliably shown to increase ovarian activity and natural conception rates
(van Kasteren and Schoemaker, 1999)
A
Oocyte donation is an established option for fertility in women with POI
(Sauer et al., 1994;Templeton et al., 1996;Sung et al., 1997;Oyesanya
et al., 2009)
C
Inform women considering oocyte donation from sisters that this carries
a higher risk of cycle cancellation (Sung et al., 1997)
C
In women with established POI, the opportunity for fertility preservation
is missed
GPP
What are the obstetric risks associated
with POI?
Women should be reassured that spontaneous pregnancies after
idiopathic POI or most forms of chemotherapy do not show any higher
obstetric or neonatal risk than in the general population (Signorello et al.,
2012;Scottish Intercollegiate Guidelines Network (SIGN), 2013)
B
Oocyte donation pregnancies are high risk and should be managed in an
appropriate obstetric unit. Women and their partners should be
encouraged to disclose the origin of their pregnancy with their obstetric
team (Pados et al., 1994;Abdalla et al., 1998;Soderstrom-Anttila et al.,
1998;Nelson and Lawlor, 2011;Stoop et al., 2012)
C
Antenatal aneuploidy screening should be based on the age of the oocyte
donor (Bowman and Saunders, 1994;Donnenfeld et al., 2002)
C
Pregnancies in women who have received radiation to the uterus are at high
risk of obstetric complications and should be managed in an appropriate
obstetric unit (Bath et al., 1999;Larsen et al., 2004;Wo and Viswanathan,
2009;Signorello et al., 2010;Scottish Intercollegiate Guidelines Network
(SIGN), 2013)
C
Pregnancies in women with Turner Syndrome are at very high risk of
obstetric and non-obstetric complications and should be managed in an
appropriate obstetric unit with cardiologist involvement (Bryman et al.,
2011;Hadnott et al., 2011;Karnis, 2012;Hagman et al., 2013)
D
A cardiologist should be involved in care of pregnant women who have
received anthracyclines and/or cardiac irradiation (Mulrooney et al., 2009;
Scottish Intercollegiate Guidelines Network (SIGN), 2013)
D
How should fitness for pregnancy be assessed
in women with POI?
Women presenting for oocyte donation who are suspected of having
POI should be fully investigated prior to oocyte donation, including
thyroid and adrenal function as well as karyotype (Abdalla et al., 1998)
C
Women previously exposed to anthracyclines, high-dose
cyclophosphamide or mediastinal irradiation should have an
echocardiogram prior to pregnancy, and referral to a cardiologist if
indicated (Felker et al., 2000;Gorton et al., 2000;Bar et al., 2003;van
Dalen et al., 2006;Altena et al., 2012)
D
Women with Turner Syndrome should be assessed by a cardiologist
with a specialist interest in adult congenital heart disease and should have
a general medical and endocrine examination
GPP
Women with POI should have their blood pressure, renal function and
thyroid function assessed prior to pregnancy (Haddow et al., 1999)
C
Pregnancy in some women can be of such high risk that clinicians may
consider oocyte donation to be life threatening and therefore
inappropriate
GPP
What are the consequences of POI for bone
health?
POI is associated with reduced bone mineral density (BMD) (Ratcliffe
et al., 1992;Hadjidakis et al., 1999;Park et al., 1999;Conway et al., 1996;
Castaneda et al., 1997;Bakalov et al., 2003;Han et al., 2008;Michala
et al., 2008;Bachelot et al., 2009;Popat et al., 2009;Freriks et al., 2011)
B
Reduced BMD is very likely to indicate that POI is associated with an
increased risk of fracture later in life, although this has not been
adequately demonstrated
GPP
What are the treatment options for bone
protection and improvement?
Women should maintain a healthy lifestyle, involving weight-bearing
exercise, avoidance of smoking, and maintenance of normal body weight
to optimize bone health
GPP
A balanced diet will contain the recommended intake of calcium and
vitamin D. Dietary supplementation may be required in women with
inadequate vitamin D status and/or calcium intake, and may be of value
in women with low BMD (Bours et al., 2011;Challoumas et al., 2013)
C
Estrogen replacement is recommended to maintain bone health and
prevent osteoporosis; it is plausible that it will reduce the risk of fracture
(Prior et al., 1997;Lindsay et al., 1980;Kanis et al., 2013)
C
The combined oral contraceptive pill may be appropriate for some
women but effects on BMD are less favourable (Crofton et al., 2010)
C
Other pharmacological treatments, including bisphosphonates, should
only be considered with advice from an osteoporosis specialist.
Particular caution applies to women desiring pregnancy (Stevenson
et al., 2005;Shapiro et al., 2011)
C
Guideline for managing premature ovarian insufficiency 929
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
How should bone health be monitored
in women with POI?
It is important to consider bone health at diagnosis in POI, and during
ongoing care
GPP
Measurement of BMDat initial diagnosis of POI should be considered for
all women, but especially when there are additional risk factors (Kanis
et al., 2013)
C
If BMD is normal and adequate systemic estrogen replacement is
commenced, the value of repeated DEXA scan is low
GPP
If a diagnosis of osteoporosis is made and estrogen replacement or other
therapy initiated, BMD measurement should be repeated within 5 years.
A decrease in BMD should prompt review of estrogen replacement
therapy and of other potential factors. Review by a specialist in
osteoporosis may be appropriate
GPP
What are the consequences of POI
for the cardiovascular system?
Women with POI are at increased risk of cardiovascular disease and
should be advised of risk factors that they can modify through
behavioural change (e.g. stopping smoking, taking regular weight-bearing
exercise, healthy weight) (van der Schouw et al., 1996;Cooper and
Sandler, 1998;Hu et al., 1999;Jacobsen et al., 1999,2003,2004;de Kleijn
et al., 2002;Mondul et al., 2005;Atsma et al., 2006;Lokkegaard et al.,
2006;Hong et al., 2007;Baba et al., 2010;Gallagher et al., 2011;Perk
et al., 2012).
B
All women diagnosed with Turner Syndrome should be evaluated by a
cardiologist with expertise in congenital heart disease (Gravholt et al.,
1998;Bondy, 2008;Sharma et al., 2009)
C
Is estrogen replacement cardio-protective?
Despite lack of longitudinal outcome data, hormone replacement
therapy(HRT)withearlyinitiationisstronglyrecommendedinwomen
with POI to control future risk of cardiovascular disease; it should be
continued at least until the average age of natural menopause
(Kalantaridou et al., 2004;Lokkegaard et al., 2006;Ostberg et al., 2007;
Langrish et al., 2009)
C
Should cardiovascular risk factors
be monitored?
Cardiovascular risk should be assessed in women diagnosed with POI.
At least blood pressure, weight and smoking status should be monitored
annually with other risk factors being assessed if indicated
GPP
In women with Turner Syndrome, cardiovascular risk factors should be
assessed at diagnosis and annually monitored (at least blood pressure,
smoking, weight, lipid profile, fasting plasma glucose, HbA1c) (Freriks
et al., 2011)
C
What are the consequences of POI on
psychological wellbeing and quality of life?
A diagnosis of POI has a significant negative impact on psychological
wellbeing and quality of life (Liao et al., 2000;Schmidt et al., 2011;Mann
et al., 2012a,b)
D
What are the management options for
reduced quality of life associated with POI?
Psychological and lifestyle interventions should be accessible to women
with POI (Boivin, 2003;Duijts et al., 2012;Mann et al., 2012a,b)
B
What are the consequences of POI
for sexuality?
Routinely inquire about sexual wellbeing and sexual function in women
with POI
GPP
What are the management options
for the effects of POI on sexuality?
Adequate estrogen replacement is regarded as a starting point for
normalizing sexual function. Local estrogen may be required to treat
dyspareunia (Sarrel, 1987;Rubinow et al., 1998;Pacello et al., 2013)
C
Women with POI should receive adequate counselling about the possibility
of using testosterone supplementation so that they can make an informed
choice, in the knowledge that long-term efficacy and safety are unknown
(Alexander et al., 2004;Kingsberg et al., 2008)
B
What treatments are available for
genito-urinary symptoms in POI?
Local estrogens are effective in treatment of genito-urinary symptoms
(Suckling et al., 2006)
A
Clinicians should be aware that despite seemingly adequate systemic HRT,
women with POI may experience genito-urinary symptoms. Local
estrogens may be given in addition to systemic HRT (Pacello et al., 2014)
D
Lubricants are useful for treatment of vaginal discomfort and dyspareunia
for women not using HRT (Le Donne et al., 2011;Grimaldi et al., 2012)
C
What are the consequences of POI
on neurological function?
The possible detrimental effect on cognition should be discussed
when planning hysterectomy and/or oophorectomy under the age of 50
years, especially for prophylactic reasons (Rocca et al., 2007;Rocca et al.,
2008;Vearncombe and Pachana, 2009;Phung et al., 2010;Bove et al.,
2014)
D
What are the management options for
the effect of POI on neurological function?
Estrogen replacement to reduce the possible risk of cognitive
impairment should be considered in women with POI at least until the
average age of natural menopause (Sherwin, 1988;Phillips and Sherwin,
1992;Sherwin, 1994;File et al., 2002;Kritz-Silverstein and
Barrett-Connor, 2002;Hogervorst and Bandelow, 2010;Bove et al.,
2014)
C
Women with POI should be advised to take lifestyle measures (e.g.
exercise, cessation of smoking, maintaining a healthy weight) to reduce
possible risks for cognitive impairment
GPP
Treatment
Indications for HRT
HRT is indicated for the treatment of symptoms of low estrogen in
women with POI (Piccioni et al., 2004;Madalinska et al., 2006;Absolom
et al., 2008)
C
Women should be advised that HRT may have a role in primary
prevention of diseases of the cardiovascular system and for bone
protection (Lindsay et al., 1980;Prior et al., 1997;Kalantaridou et al.,
2004;Lokkegaard et al., 2006;Ostberg et al., 2007;Langrish et al., 2009;
Kanis et al., 2013)
C
930 The ESHRE Guideline Group on POI
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
What are the risks of HRT?
Women with POI should be informed that HRT has not been found to
increase the risk of breast cancer before the age of natural menopause
(Benetti-Pinto et al., 2008;Soares et al., 2010;Wu et al., 2014)
D
Progestogen should be given in combination with estrogen therapy to protect
the endometrium in women with an intact uterus (Furness et al., 2012)
B
What are the options for HRT?
17-bestradiol is preferred to ethinylestradiol or conjugated equine estrogens
for estrogen replacement (Langrish et al., 2009;Crofton et al., 2010)
C
Women should be informed that whilst there may be advantages to
micronized natural progesterone, the strongest evidence of endometrial
protection is for oral cyclical combined treatment
GPP
Patient preference for route and method of administration of each
component of HRT must be considered when prescribing, as should
contraceptive needs
GPP
Monitoring HRT
Once established on therapy, women with POI using HRT should have a
clinical review annually, paying particular attention to compliance
GPP
No routine monitoring tests are required but may be prompted by
specific symptoms or concerns
GPP
Treatment with androgens
Womenshould be informed that androgen treatment is onlysupported by
limited data, and that long-term health effects are not clear yet (Shifren
et al., 2000;Braunstein et al., 2005;Buster et al., 2005;Simon et al., 2005;
Davis et al., 2006,2008;Tamimi et al., 2006;Panay et al., 2010)
C
If androgen therapy is commenced, treatment effect should be evaluated
after 3–6 months and should possibly be limited to 24 months
GPP
HRT in POI women with special issues
Women with Turner Syndrome
Girls and women with POI due to Turner Syndrome should be offered HRT
throughout the normal reproductive lifespan (Downey et al., 1991;Swillen
et al., 1993;Gravholt et al., 1998;Romans et al., 1998;Ross et al., 1998;
Elsheikh et al., 2000;Khastgir et al., 2003;Mortensen et al., 2009;Crofton
et al., 2010;Kodama et al., 2012)
C
Women with POI and a BRCA gene mutation or after breast cancer
HRT is generally contra-indicated in breast cancer survivors (Antoine et al.,
2007)
B
HRT is a treatment option for women carrying BRCA1/2 mutations but
without personal history of breast cancer after prophylactic bilateral
salpingo-oophorectomy (Armstrong et al., 2004;Rebbeck et al., 2005;
Madalinska et al., 2006)
C
Women with POI and endometriosis
For women with endometriosis who required oophorectomy, combined
estrogen/progestogen therapy can be effective for the treatment of
vasomotor symptoms and may reduce the risk of disease reactivation
(Dunselman et al., 2014)
C
Women with POI and migraine
Migraine should not be seen as a contraindication to HRT use by women
with POI
GPP
Consideration should be given to changing dose, route of administration
or regimen if migraine worsens during HRT
GPP
Transdermal delivery may be the lowest-risk route of administration of
estrogen for migraine sufferers with aura (Nappi et al., 2001)
D
Women with POI and hypertension
Hypertension should not be considered a contraindication to HRT use
by women with POI
GPP
In hypertensive women with POI, transdermal estradiol is the preferred
method of delivery (White, 2007;Langrish et al., 2009)
C
Women with POIand a history of prior venousthromboembolism (VTE)
Women with POI and a history of prior VTE or thrombophilic disorder
should be referred to a haematologist prior to commencing HRT
GPP
Transdermal estradiol is the preferred route of delivery for women with
POI at increased risk of VTE (Canonico et al., 2008)
B
Women with POI and obesity
Transdermal estradiol is the preferred method of delivery for women
with POI requiring HRT who are obese or overweight (Canonico et al.,
2006)
C
Women with POI and fibroids
Fibroids are not a contraindication to HRT use by women with POI
(Ang et al., 2001;Ciarmela et al., 2014)
B
What complementary treatments
are available in POI?
Women with POI should be advised of risk factors that they can modify
through behavioural change (e.g. stopping smoking, taking regular
weight-bearing exercise, healthy weight)
GPP
Women should be informed that for most alternative and
complementary treatments evidence on efficacy is limited and data on
safety are lacking (Rada et al., 2010)
B
Puberty induction
(See also Table III)
How should puberty be induced?
Puberty should be induced or progressed with 17-bestradiol,
starting with a low dose at the age of 12 years with a gradual
increase over 2–3 years (Reiter et al., 2001;van Pareren et al.,
2003;Stephure and Canadian Growth Hormone Advisory
Committee, 2005)
C
In cases of late diagnosis and for those girls in whom growth is not a
concern, a modified regimen of estradiol can be considered (Davenport,
2008)
D
Evidence for the optimum mode of administration (oral or
transdermal) is inconclusive. Transdermal estradiol results in more
physiological estrogen levels and is therefore preferred (Illig et al., 1990;
Cisternino et al., 1991;Ankarberg-Lindgren et al., 2001;Piippo et al.,
2004;Mauras et al., 2007;Nabhan et al., 2009;Torres-Santiago et al.,
2013)
B
The oral contraceptive pill is contra-indicated for puberty induction (Bondy
and Turner Syndrome Study Group, 2007;Davenport, 2010)
D
Begin cyclical progestogens after at least 2 years of estrogen or when
breakthrough bleeding occurs (Bondy and Turner Syndrome Study Group,
2007;Furness et al., 2012)
C
Guideline for managing premature ovarian insufficiency 931
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
Discussion
The ESHRE guideline on the management of women with POI comprises
95 recommendations and four statements on the diagnosis, sequelae and
treatment of POI. The recommendations have been formulated by a
multidisciplinary group of experts based on the best available evidence,
and they have been reviewed by relevant stakeholders. Based on the as-
sessment of the current literature on POI during the development of the
guideline it is clear that evidence is limited. Of the 95 recommendations,
33 (34.7%) were based on expert opinion, and graded as a GPP. Only 15
of the 31 key questions were regarding treatment and management
options, while the other questions dealt with diagnosis, monitoring
and sequelae of POI. From the 61 recommendations on interventions
(not including monitoring), 12 (19.7%) could be based on good quality
evidence (level A or B), 35 (57.4%) were based on moderate quality evi-
dence (C or D) and 14 (22.9%) were formulated as GPP.
The lack of sufficient high-quality evidence on the interventions avail-
able for women was the most significant limitation for the current guide-
line, and has led to a number of topics for future research: (i) the accuracy
of biochemical markers (e.g. FSH, anti-Mullerian hormone) in the diagno-
sis of POI, (ii) long-term health outcomes of POI, examining contributory
factors such as smoking, and the effect of long-term HRT, (iii) fertility
treatment and associated obstetric risks in women with POI, (iv) lifetime
risk of fracture in women with POI, and the impact of interventions,
(v) cardiovascular risk factors in women with POI, (vi) impact of POI on
wellbeing and quality of life, including interventions, (vii) comparisons of
the efficacy, patient’s satisfaction and side effects of the different options
for HRT and (viii) the optimal approach for oncological POI patients.
One of the options explored for the collection of long-term data is a
POI registry, as suggested by Panay and Fenton (2012).
Despite the limitations of guidelines in general, and the limitations in
the evidence supporting the current guideline, the guideline group is con-
fident that this document will help best practice in the management of
women with POI. Efforts will be undertaken to ensure adequate dissem-
ination and implementation of the guideline.
Acknowledgements
The GDG would like to thank invited experts Frank Broekmans, Gerard
Conway, Alberto Falorni, Angela Maas and Anette Tonnes Pedersen for
providing helpful comments as experts on specific areas of this multidis-
ciplinary guideline. The GDG also acknowledges the help of many clini-
cians and patient organizations who refereed the content of the
Guideline.
Authors’ roles
L.W. chaired the GDG and hence fulfilled a leading role in collecting the
evidence, writing the manuscript and dealing with reviewer comments.
N.V., as methodological expert, performed all the literature searches
for the guideline, provided methodological support and was overall co-
ordinator of the guideline production. M.D. was co-chair of the GDG
until December 2014. J.B. represented the patient perspective in the
guideline group. All other authors, listed in alphabetical order, as guide-
line group members, contributed equally to the manuscript, by drafting
key questions, synthesizing evidence, writing the different parts of the
guideline and discussing recommendations until consensus within the
group was reached.
Funding
The study has no external funding; all costs are covered by ESHRE.
Conflict of interest
Dr Davies reports non-financial support from Novo Nordisk, outside the
submitted work; the other authors had nothing to disclose.
References
Abdalla HI, Billett A, Kan AK, Baig S, Wren M, Korea L, Studd JW. Obstetric
outcome in 232 ovum donation pregnancies. Br J Obstet Gynaecol 1998;
105:332– 337.
Absolom K, Eiser C, Turner L, Ledger W, Ross R, Davies H, Coleman R,
Hancock B, Snowden J, Greenfield D et al. Ovarian failure following
cancer treatment: current management and quality of life. Hum Reprod
2008;23:2506–2512.
Albright F, Smith P, Fraser R. A syndrome characterized by primary ovarian
insufficiency and decreased stature. Am J Med Sci 1942;204:625–648.
.............................................................................................................................................................................................
Table III Estrogen substitution therapy in adolescence (adapted from (Bondy and Turner Syndrome Study Group, 2007)).
Age Age-specific suggestions Preparation/dose/comments
12– 13 years If no spontaneous development and FSH elevated, start
low-dose estrogens
17b-estradiol (E2)
Transdermal: 6.25 mg/day
a
E2 via patch
Oral micronized E2: 5 mg/kg/day or 0.25 mg/day
12.5–15 years Gradually increase E2 dose at 6 –12 months interval over
2–3 years
b
to adult dose
Transdermal E2:12.5, 25, 37.5, 50, 75, 100 mg/day (Adult dose: 100– 200 mg/day)
Oral E2: 5, 7.5, 10, 15 mg/kg/day (Adult dose: 2– 4 mg/day)
14– 16 years Begin cyclic progestogen after 2 years of estrogen or
when breakthrough bleeding occurs
Oral micronized progesterone 100– 200 mg/day or dydrogesterone 5–10 mg/day
during 12– 14 days of the month
c
a
The lowest dose commercially available E2 transdermal patches deliver 25 or 50 mg/day; it is not established whether various means of dose fractionation (e.g. administering 1/8, 1/6, 1/4
patch overnight or daily or administering whole patches for 7 –10 days per month) are equivalent.
b
With concomitant GH therapy in Turner Syndrome, to achieve an optimal adult height the increase in E2 dose might be relatively slow; while in cases of late diagnosis and for those girls in
whom growth is not a consideration, E2 may be started at somewhat higher doses and escalated more rapidly.
c
For prolonged treatment progesterone, dydrogesterone or medroxyprogesterone are preferred to other progestogens because of their less negative effect on lipid metabolism and less
androgenic effects (Lobo, 1987).
932 The ESHRE Guideline Group on POI
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
Alexander JL, Kotz K, Dennerstein L, Kutner SJ, Wallen K, Notelovitz M. The
effects of postmenopausal hormone therapies on female sexual
functioning: a review of double-blind, randomized controlled trials.
Menopause 2004;11:749–765.
Altena R, Gietema JA, van Veldhuisen DJ, Reyners AK. Pregnancy unbosoms
the heart of breast cancer survivors. Ann Oncol 2012;23:2206– 2208.
Amagai Y, Ishikawa S, Gotoh T, Kayaba K, Nakamura Y, Kajii E. Age at
menopause and mortality in Japan: the Jichi Medical School Cohort
Study. J Epidemiol 2006;16:161–166.
Ang WC, Farrell E, Vollenhoven B. Effect of hormone replacement therapies
and selective estrogen receptor modulators in postmenopausal women
with uterine leiomyomas: a literature review. Climacteric 2001;4:284–292.
Ankarberg-Lindgren C, Elfving M, Wikland KA, Norjavaara E. Nocturnal
application of transdermal estradiol patches produces levels of estradiol
that mimic those seen at the onset of spontaneous puberty in girls. J Clin
Endocrinol Metab 2001;86:3039–3044.
Antoine C, Liebens F, Carly B, Pastijn A, Neusy S, Rozenberg S. Safety of
hormone therapy after breast cancer: a qualitative systematic review.
Hum Reprod 2007;22:616– 622.
Armstrong K, Schwartz JS, Randall T, Rubin SC, Weber B. Hormone
replacement therapy and life expectancy after prophylactic oophorectomy
in women with BRCA1/2 mutations: a decision analysis. J Clin Oncol 2004;
22:1045–1054.
Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal
status and early menopause as independent risk factors for
cardiovascular disease: a meta-analysis. Menopause 2006;13:265– 279.
Baba Y, Ishikawa S, Amagi Y, Kayaba K, Gotoh T, Kajii E. Premature
menopause is associated with increased risk of cerebral infarction in
Japanese women. Menopause 2010;17:506–510.
Bachelot A, Rouxel A, Massin N, Dulon J, Courtillot C, Matuchansky C,
Badachi Y, Fortin A, Paniel B, Lecuru F et al. Phenotyping and genetic
studies of 357 consecutive patients presenting with premature ovarian
failure. Eur J Endocrinol 2009;161:179–187.
Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect
asymptomatic auto-immune adrenal insufficiency in young women with
spontaneous premature ovarian failure. Hum Reprod 2002;17:2096–2100.
Bakalov VK, Axelrod L, Baron J, Hanton L, Nelson LM, Reynolds JC, Hill S,
Troendle J, Bondy CA. Selective reduction in cortical bone mineral
density in turner syndrome independent of ovarian hormone deficiency.
J Clin Endocrinol Metab 2003;88:5717 –5722.
Bar J, Davidi O, Goshen Y, Hod M, Yaniv I, Hirsch R. Pregnancy outcome in
women treated with doxorubicin for childhood cancer. Am J Obstet Gynecol
2003;189:853– 857.
Bath LE, Critchley HO, Chambers SE, Anderson RA, Kelnar CJ, Wallace WH.
Ovarian and uterine characteristics after total body irradiation in childhood
and adolescence: response to sex steroid replacement. Br J Obstet Gynaecol
1999;106:1265–1272.
Benetti-Pinto CL, Soares PM, Magna LA, Petta CA, Dos Santos CC. Breast
density in women with premature ovarian failure using hormone
therapy. Gynecol Endocrinol 2008;24:40–43.
Betterle C, Volpato M, Rees Smith B, Furmaniak J, Chen S, Greggio NA,
Sanzari M, Tedesco F, Pedini B, Boscaro M et al. I. Adrenal cortex and
steroid 21-hydroxylase autoantibodies in adult patients with organ-
specific autoimmune diseases: markers of low progression to clinical
Addison’s disease. J Clin Endocrinol Metab 1997;82:932 –938.
Boivin J. A review of psychosocialinterventions in infertility. Soc Sci Med 2003;
57:2325– 2341.
Bondy CA. Congenital cardiovascular disease in Turner syndrome. Congenit
Heart Dis 2008;3:2–15.
Bondy CA, Turner Syndrome Study Group. Care of girls and women with
Turner syndrome: a guideline of the Turner Syndrome Study Group.
J Clin Endocrinol Metab 2007;92:10 –25.
Bours SP, van Geel TA, Geusens PP, Janssen MJ, Janzing HM, Hoffland GA,
Willems PC, van den Bergh JP. Contributors to secondary osteoporosis
and metabolic bone diseases in patients presenting with a clinical
fracture. J Clin Endocrinol Metab 2011;96:1360– 1367.
Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, De
Jager PL. Age at surgical menopause influences cognitive decline and
Alzheimer pathology in older women. Neurology 2014;82:222–229.
Bowman MC, Saunders DM. Rates of aneuploidy in oocytes of older women:
are equivocal findings of concern for postmenopausal embryo recipients?
Hum Reprod 1994;9:1200– 1201.
Braunstein GD, Sundwall DA, Katz M, Shifren JL, Buster JE, Simon JA,
Bachman G, Aguirre OA, Lucas JD, Rodenberg C et al. Safety and
efficacy of a testosterone patch for the treatment of hypoactive sexual
desire disorder in surgically menopausal women: a randomized,
placebo-controlled trial. Arch Intern Med 2005;165:1582–1589.
Bryman I, Sylven L, Berntorp K, Innala E, Bergstrom I, Hanson C, Oxholm M,
Landin-Wilhelmsen K. Pregnancy rate and outcome in Swedish women
with Turner syndrome. Fertil Steril 2011;95:2507–2510.
Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A,
Rodenberg CA, Wekselman K, Casson P. Testosterone patch for low
sexual desire in surgically menopausal women: a randomized trial. Obstet
Gynecol 2005;105:944– 952.
Canonico M, Oger E, Conard J, Meyer G, Levesque H, Trillot N,
Barrellier MT, Wahl D, Emmerich J, Scarabin PY et al. Obesity and risk
of venous thromboembolism among postmenopausal women: differential
impact of hormone therapy by route of estrogen administration. The
ESTHER Study. JThrombHaemost2006;4:1259–1265.
Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement
therapy and risk of venous thromboembolism in postmenopausal women:
systematic review and meta-analysis. Br Med J 2008;336:1227 –1231.
Castaneda S, Carmona L, Carvajal I, Arranz R, Diaz A, Garcia-Vadillo A.
Reduction of bone mass in women after bone marrow transplantation.
Calcif Tissue Int 1997;60:343–347.
Challoumas D, Cobbold C, Dimitrakakis G. Effects of calcium intake on the
cardiovascular system in postmenopausal women. Atherosclerosis 2013;
231:1–7.
Chen S, Sawicka J, Betterle C, Powell M, Prentice L, Volpato M, Rees Smith B,
Furmaniak J. Autoantibodies to steroidogenic enzymes in autoimmune
polyglandular syndrome, Addison’s disease, and premature ovarian
failure. J Clin Endocrinol Metab 1996;81:1871 –1876.
Ciarmela P, Ciavattini A, Giannubilo SR, Lamanna P, Fiorini R, Tranquilli AL,
Christman GM, Castellucci M. Management of leiomyomas in
perimenopausal women. Maturitas 2014;78:168– 173.
Cisternino M, Nahoul K, Bozzola M, Grignani G, Perani G, Sampaolo P,
Roger M, Severi F. Transdermal estradiol substitution therapy for the
induction of puberty in female hypogonadism. J Endocrinol Invest 1991;
14:481– 488.
Conway GS, Kaltsas G, Patel A, Davies MC, Jacobs HS. Characterization of
idiopathic premature ovarian failure. Fertil Steril 1996;65:337–341.
Cooper GS, Sandler DP. Age at natural menopause and mortality. Ann
Epidemiol 1998;8:229– 235.
Crofton PM, Evans N, Bath LE, Warner P, Whitehead TJ, Critchley HO,
Kelnar CJ, Wallace WH. Physiological versus standard sex steroid
replacement in young women with premature ovarian failure: effects on
bone mass acquisition and turnover. Clin Endocrinol 2010;73:707–714.
Dal Pra C, Chen S, Furmaniak J, Smith BR, Pedini B, Moscon A, Zanchetta R,
Betterle C. Autoantibodies to steroidogenic enzymes in patients with
premature ovarian failure with and without Addison’s disease. Eur J
Endocrinol 2003;148:565– 570.
Davenport ML. Moving toward an understanding of hormone replacement
therapy in adolescent girls: looking through the lens of Turner
syndrome. Ann N Y Acad Sci 2008;1135:126 –137.
Guideline for managing premature ovarian insufficiency 933
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
Davenport ML. Approach to the patient with Turner syndrome. J Clin
Endocrinol Metab 2010;95:1487–1495.
Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot C, Rees M,
Moufarege A, Rodenberg C, Buch A, Purdie DW. Efficacy and safety of a
testosterone patch for the treatment of hypoactive sexual desire disorder
in surgically menopausal women: a randomized, placebo-controlled trial.
Menopause 2006;13:387–396.
Davis SR, Moreau M, Kroll R, Bouchard C, Panay N, Gass M, Braunstein GD,
Hirschberg AL, Rodenberg C, Pack S et al. Testosterone for low libido in
postmenopausal women not taking estrogen. N Engl J Med 2008;
359:2005– 2017.
de Kleijn MJ, van der Schouw YT, Verbeek AL, Peeters PH, Banga JD, van der
Graaf Y. Endogenous estrogen exposure and cardiovascular mortality risk
in postmenopausal women. Am J Epidemiol 2002;155:339–345.
Donnenfeld AE, Icke KV, Pargas C, Dowman C. Biochemical screening for
aneuploidy in ovum donor pregnancies. Am J Obstet Gynecol 2002;
187:1222– 1225.
Downey J, Elkin EJ, Ehrhardt AA, Meyer-Bahlburg HF, Bell JJ, Morishima A.
Cognitive ability and everyday functioning in women with Turner
syndrome. J Learn Disabil 1991;24:32– 39.
Duijts SF, van Beurden M, Oldenburg HS, Hunter MS, Kieffer JM, Stuiver MM,
Gerritsma MA, Menke-Pluymers MB, Plaisier PW, Rijna H et al. Efficacy of
cognitive behavioral therapy and physical exercise in alleviating treatment-
induced menopausal symptoms in patients with breast cancer: results
of a randomized, controlled, multicenter trial. J Clin Oncol 2012;30:
4124– 4133.
Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De
Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A et al. ESHRE guideline:
management of women with endometriosis. Hum Reprod 2014;
29:400– 412.
Elsheikh M, Bird R, Casadei B, Conway GS, Wass JA. The effect of hormone
replacement therapy on cardiovascular hemodynamics in women with
Turner’s syndrome. J Clin Endocrinol Metab 2000;85:614– 618.
Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE,
Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term
survival in patients with initially unexplained cardiomyopathy. N Engl J
Med 2000;342:1077–1084.
File SE, Heard JE, Rymer J. Trough oestradiol levels associated with cognitive
impairment in post-menopausal women after 10 years of oestradiol
implants. Psychopharmacology (Berl) 2002;161:107 –112.
Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL,
McConkie-Rosell A. Genetic counseling and testing for FMR1 gene
mutations: practice guidelines of the national society of genetic
counselors. J Genet Couns 2012;21:752– 760.
Freriks K, Timmermans J, Beerendonk CC, Verhaak CM, Netea-Maier RT,
Otten BJ, Braat DD, Smeets DF, Kunst DH, Hermus AR et al.
Standardized multidisciplinary evaluation yields significant previously
undiagnosed morbidity in adult women with Turner syndrome. J Clin
Endocrinol Metab 2011;96:E1517–E1526.
Furness S, Roberts H, Marjoribanks J, Lethaby A. Hormone therapy in
postmenopausal women and risk of endometrial hyperplasia. Cochrane
Database Syst Rev 2012;8:CD000402.
Gallagher LG, Davis LB, Ray RM, Psaty BM, Gao DL, Checkoway H,
Thomas DB. Reproductive history and mortality from cardiovascular
disease among women textile workers in Shanghai, China. Int J Epidemiol
2011;40:1510–1518.
Genetics Committee of the Society of Obstetricians and Gynaecologists of
Canada, Prenatal Diagnosis Committee of the Canadian College of
Medical Geneticists, Chitayat D, Wyatt PR, Wilson RD, Johnson JA,
Audibert F, Allen V, Gagnon A, Langlois S et al. Fragile X testing in
obstetrics and gynaecology in Canada. J Obstet Gynaecol Can 2008;
30:837– 846.
Gorton H, Wilson R, Robinson A, Lyons G. Survivors of childhood cancers:
implications for obstetric anaesthesia. Br J Anaesth 2000;85:911 –913.
Goswami R, Marwaha RK, Goswami D, Gupta N, Ray D, Tomar N, Singh S.
Prevalence of thyroid autoimmunity in sporadic idiopathic hypoparathyroidism
in comparison to type 1 diabetes and premature ovarian failure. J Clin Endocrinol
Metab 2006;91:4256 –4259.
Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome.
J Clin Epidemiol 1998;51:147–158.
Grimaldi EF, Restaino S, Inglese S, Foltran L, Sorz A, Di Lorenzo G,
Guaschino S. Role of high molecular weight hyaluronic acid in
postmenopausal vaginal discomfort. Minerva Ginecol 2012;64:321 –329.
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J,
O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE et al. Maternal thyroid
deficiency during pregnancy and subsequent neuropsychological
development of the child. N Engl J Med 1999;341:549 –555.
Hadjidakis D, Kokkinakis E, Sfakianakis M, Raptis SA. The type and time of
menopause as decisive factors for bone mass changes. Eur J Clin Invest
1999;29:877–885.
Hadnott TN, Gould HN, Gharib AM, Bondy CA. Outcomes of spontaneous
and assisted pregnancies in Turner syndrome: the U.S. National Institutes
of Health experience. Fertil Steril 2011;95:2251 –2256.
Hagman A, Loft A, Wennerholm UB, Pinborg A, Bergh C, Aittomaki K,
Nygren KG, Bente Romundstad L, Hazekamp J, Soderstrom-Anttila V.
Obstetric and neonatal outcome after oocyte donation in 106 women
with Turner syndrome: a Nordic cohort study. Hum Reprod 2013;
28:1598– 1609.
Han TS, Goswami D, Trikudanathan S, Creighton SM, Conway GS.
Comparison of bone mineral density and body proportions between
women with complete androgen insensitivity syndrome and women
with gonadal dysgenesis. Eur J Endocrinol 2008;159:179–185.
Hogervorst E, Bandelow S. Sex steroids to maintain cognitive function in
women after the menopause: a meta-analyses of treatment trials.
Maturitas 2010;66:56–71.
Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW,
Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in
the United States population (1988 to 1994): National Health and
Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab
2002;87:489–499.
Hong JS, Yi SW, Kang HC, Jee SH, Kang HG, Bayasgalan G, Ohrr H. Age at
menopause and cause-specific mortality in South Korean women:
Kangwha Cohort Study. Maturitas 2007;56:411 – 419.
Hu FB, Grodstein F, Hennekens CH, Colditz GA, Johnson M, Manson JE,
Rosner B, Stampfer MJ. Age at natural menopause and risk of
cardiovascular disease. Arch Intern Med 1999;159:1061– 1066.
Husebye ES, Lovas K. Immunology of Addison’s disease and premature
ovarian failure. Endocrinol Metab Clin North Am 2009;38:389 –405. ix.
Illig R, DeCampo C, Lang-Muritano MR, Prader A, Torresani T, Werder EA,
Willi U, Schenkel L. A physiological mode of puberty induction in
hypogonadal girls by low dose transdermal 17 beta-oestradiol. Eur J
Pediatr 1990;150:86–91.
Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total
mortality and mortality from ischemic heart disease: the Adventist
Health Study. J Clin Epidemiol 1999;52:303 –307.
Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and all-cause
mortality: a 37-year follow-up of 19,731 Norwegian women. Am J
Epidemiol 2003;157:923– 929.
Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and stroke
mortality: cohort study with 3561 stroke deaths during 37-year
follow-up. Stroke 2004;35:1548– 1551.
Jiao X, Qin C, Li J, Qin Y, Gao X, Zhang B, Zhen X, Feng Y, Simpson JL,
Chen ZJ. Cytogenetic analysis of 531 Chinese women with premature
ovarian failure. Hum Reprod 2012;27:2201– 2207.
934 The ESHRE Guideline Group on POI
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
Kalantari H, Madani T, Zari Moradi S, Mansouri Z, Almadani N, Gourabi H,
Mohseni Meybodi A. Cytogenetic analysis of 179 Iranian women with
premature ovarian failure. Gynecol Endocrinol 2013;29:588 –591.
Kalantaridou SN, Naka KK, Papanikolaou E, Kazakos N, Kravariti M,
Calis KA, Paraskevaidis EA, Sideris DA, Tsatsoulis A, Chrousos GP et al.
Impaired endothelial function in young women with premature ovarian
failure: normalization with hormone therapy. J Clin Endocrinol Metab
2004;89:3907–3913.
Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY.
Scientific Advisory Board of the European Society for C, Economic
Aspects of O, Osteoarthritis, the Committee of Scientific Advisors of
the International Osteoporosis F. European guidance for the diagnosis
and management of osteoporosis in postmenopausal women.
Osteoporos Int 2013;24:23– 57.
Karnis MF. Catastrophic consequences of assisted reproduction: the case of
Turner syndrome. Semin Reprod Med 2012;30:116–122.
Khastgir G, Studd JW, Fox SW, Jones J, Alaghband-Zadeh J, Chow JW.
A longitudinal study of the effect of subcutaneous estrogen replacement
on bone in young women with Turner’s syndrome. J Bone Miner Res
2003;18:925–932.
Kim TJ, Anasti JN, Flack MR, Kimzey LM, Defensor RA, Nelson LM. Routine
endocrine screening for patients with karyotypically normal spontaneous
premature ovarian failure. Obstet Gynecol 1997;89:777 –779.
Kingsberg SA, Simon JA, Goldstein I. The current outlook for testosterone in
the management of hypoactive sexual desire disorder in postmenopausal
women. J Sex Med 2008;5(Suppl 4):182– 193; quiz 193.
Kodama M, Komura H, Kodama T, Nishio Y, Kimura T. Estrogen therapy
initiated at an early age increases bone mineral density in Turner
syndrome patients. Endocr J 2012;59:153– 159.
Kokcu A. Premature ovarian failure from current perspective. Gynecol
Endocrinol 2010;26:555– 562.
Kritz-Silverstein D, Barrett-Connor E. Hysterectomy, oophorectomy, and
cognitive function in older women. J Am Geriatr Soc 2002;50:55– 61.
Langrish JP, Mills NL, Bath LE, Warner P, Webb DJ, Kelnar CJ, Critchley HO,
Newby DE, Wallace WH. Cardiovascular effects of physiological and
standard sex steroid replacement regimens in premature ovarian failure.
Hypertension 2009;53:805–811.
Larsen EC, Schmiegelow K, Rechnitzer C, Loft A, Muller J, Andersen AN.
Radiotherapy at a young age reduces uterine volume of childhood
cancer survivors. Acta Obstet Gynecol Scand 2004;83:96 –102.
Le Donne M, Caruso C, Mancuso A, Costa G, Iemmo R, Pizzimenti G,
Cavallari V. The effect of vaginally administered genistein in comparison
with hyaluronic acid on atrophic epithelium in postmenopause. Arch
Gynecol Obstet 2011;283:1319–1323.
Liao KL, Wood N, Conway GS. Premature menopause and psychological
well-being. J Psychosom Obstet Gynaecol 2000;21:167–174.
Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in
oophorectomised women. Lancet 1980;2:1151– 1154.
Lobo RA. Absorption and metabolic effects of different types of estrogens
and progestogens. Obstet Gynecol Clin North Am 1987;14:143–167.
Lokkegaard E, Jovanovic Z, Heitmann BL, Keiding N, Ottesen B,
Pedersen AT. The association between early menopause and risk of
ischaemic heart disease: influence of Hormone Therapy. Maturitas 2006;
53:226– 233.
Madalinska JB, van Beurden M, Bleiker EM, Valdimarsdottir HB, Hollenstein J,
Massuger LF, Gaarenstroom KN, Mourits MJ, Verheijen RH, van Dorst EB
et al. The impact of hormone replacement therapy on menopausal
symptoms in younger high-risk women after prophylactic
salpingo-oophorectomy. J Clin Oncol 2006;24:3576–3582.
Mann E, Singer D, Pitkin J, Panay N, Hunter MS. Psychosocial adjustment in
women with premature menopause: a cross-sectional survey. Climacteric
2012a;15:481– 489.
Mann E, Smith MJ, Hellier J, Balabanovic JA, Hamed H, Grunfeld EA,
Hunter MS. Cognitive behavioural treatment for women who have
menopausal symptoms after breast cancer treatment (MENOS 1): a
randomised controlled trial. Lancet Oncol 2012b;13:309– 318.
Mauras N, Shulman D, Hsiang HY, Balagopal P, Welch S. Metabolic effects of
oral versus transdermal estrogen in growth hormone-treated girls with
turner syndrome. J Clin Endocrinol Metab 2007;92:4154– 4160.
Michala L, Goswami D, Creighton SM, Conway GS. Swyer syndrome:
presentation and outcomes. BJOG 2008;115:737– 741.
Mondul AM, Rodriguez C, Jacobs EJ, Calle EE. Age at natural menopause and
cause-specific mortality. Am J Epidemiol 2005;162:1089 –1097.
Mortensen KH, Hansen KW, Erlandsen M, Christiansen JS, Gravholt CH.
Ambulatory arterial stiffness index in Turner syndrome: the impact of
sex hormone replacement therapy. Horm Res 2009;72:184–189.
Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M,
Donaldson SS, Green DM, Sklar CA, Robison LL et al. Cardiac outcomes in
a cohort of adult survivors of childhood and adolescent cancer:
retrospective analysis of the Childhood Cancer Survivor Study cohort.
Br Med J 2009;339:b4606.
Nabhan ZM, Dimeglio LA, Qi R, Perkins SM, Eugster EA. Conjugated
oral versus transdermal estrogen replacement in girls with Turner
syndrome: a pilot comparative study. J Clin Endocrinol Metab 2009;94:
2009–2014.
Nappi RE, Cagnacci A, Granella F, Piccinini F, Polatti F, Facchinetti F. Course of
primary headaches during hormone replacement therapy. Maturitas 2001;
38:157– 163.
Nelson SM, Lawlor DA. Predicting live birth, preterm delivery, and low birth
weight in infants born from in vitro fertilisation: a prospective study of
144,018 treatment cycles. PLoS Med 2011;8:e1000386.
Ossewaarde ME, Bots ML, Verbeek AL, Peeters PH, van der Graaf Y,
Grobbee DE, van der Schouw YT. Age at menopause, cause-specific
mortality and total life expectancy. Epidemiology (Cambridge, Mass) 2005;
16:556– 562.
Ostberg JE, Storry C, Donald AE, Attar MJ, Halcox JP, Conway GS. A dose –
response study of hormone replacement in young hypogonadal women:
effects on intima media thickness and metabolism. Clin Endocrinol 2007;
66:557– 564.
Oyesanya OA, Olufowobi O, Ross W, Sharif K, Afnan M. Prognosis of
oocyte donation cycles: a prospective comparison of the in vitro
fertilization-embryo transfer cycles of recipients who used shared
oocytes versus those who used altruistic donors. Fertil Steril 2009;
92:930– 936.
Pacello PC, Yela DA, Rabelo S, Giraldo PC, Benetti-Pinto CL. Dyspareunia
and lubrication in premature ovarian failure using hormonal therapy and
vaginal health. Climacteric 2014;17:342– 347.
Pados G, Camus M, Van Steirteghem A, Bonduelle M, Devroey P. The
evolution and outcome of pregnancies from oocyte donation. Hum
Reprod 1994;9:538–542.
Panay N, Fenton A. Premature ovarian insufficiency: working towards an
international database. Climacteric 2012;15:295–296.
Panay N, Al-Azzawi F, Bouchard C, Davis SR, Eden J, Lodhi I, Rees M,
Rodenberg CA, Rymer J, Schwenkhagen A et al. Testosterone treatment
of HSDD in naturally menopausal women: the ADORE study.
Climacteric 2010;13:121–131.
Park KH, Lee SJ, Kim JY, Kim JY, Bai SW, Kim JW. A concomitant decrease in
cortical and trabecular bone mass in isolated hypogonadotropic
hypogonadism and gonadal dysgenesis. Yonsei Med J 1999;40:444–449.
Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM,
Albus C, Benlian P, Boysen G, Cifkova R et al. European guidelines on
cardiovascular disease prevention in clinical practice (version 2012): the
fifth joint task force of the European society of cardiology and other
societies on cardiovascular disease prevention in clinical practice
Guideline for managing premature ovarian insufficiency 935
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
(constituted by representatives of nine societies and by invited experts). Int
J Behav Med 2012;19:403 –488.
Phillips SM, Sherwin BB. Effects of estrogen on memory function in
surgically menopausal women. Psychoneuroendocrinology 1992;17:
485–495.
Phung TK, Waltoft BL, Laursen TM, Settnes A, Kessing LV, Mortensen PB,
Waldemar G. Hysterectomy, oophorectomy and risk of dementia: a
nationwide historical cohort study. Dement Geriatr Cogn Disord 2010;
30:43– 50.
Piccioni P, Scirpa P, D’Emilio I, Sora F, Scarciglia M, Laurenti L, De Matteis S,
Sica S, Leone G, Chiusolo P. Hormonal replacement therapy after stem cell
transplantation. Maturitas 2004;49:327–333.
Piippo S, Lenko H, Kainulainen P, Sipila I. Use of percutaneous estrogen gel for
induction of puberty in girls with Turner syndrome. J Clin Endocrinol Metab
2004;89:3241–3247.
Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N,
Troendle JF, Nelson LM. Bone mineral density in estrogen-deficient
young women. J Clin Endocrinol Metab 2009;94:2277– 2283.
Prior JC, Vigna YM, Wark JD, Eyre DR, Lentle BC, Li DK, Ebeling PR, Atley L.
Premenopausal ovariectomy-related bone loss: a randomized, double-blind,
one-year trial of conjugated estrogen or medroxyprogesterone acetate.
J Bone Miner Res 1997;12:1851–1863.
Rada G, Capurro D, Pantoja T, Corbala
´n J, Moreno G, Letelier Luz M, Vera C.
Non-hormonal interventions for hot flushes in women with a history of
breast cancer. Cochrane Database Syst Rev 2010:CD004923.
Ratcliffe MA, Lanham SA, Reid DM, Dawson AA. Bone mineral density
(BMD) in patients with lymphoma: the effects of chemotherapy,
intermittent corticosteroids and premature menopause. Hematol Oncol
1992;10:181–187.
Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, Isaacs C,
Olopade OI, Neuhausen SL, van’t Veer L et al. Effect of short-term
hormone replacement therapy on breast cancer risk reduction after
bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation
carriers: the PROSE Study Group. J Clin Oncol 2005;23:7804– 7810.
Reiter EO, Blethen SL, Baptista J, Price L. Early initiation of growth hormone
treatment allows age-appropriate estrogen use in Turner’s syndrome. J Clin
Endocrinol Metab 2001;86:1936–1941.
Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd.
Survival patterns after oophorectomy in premenopausal women: a
population-based cohort study. Lancet Oncol 2006;7:821– 828.
Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de
Andrade M, Melton LJ 3rd. Increased risk of cognitive impairment or
dementia in women who underwent oophorectomy before menopause.
Neurology 2007;69:1074–1083.
Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de
Andrade M, Melton LJ 3rd. Increased risk of parkinsonism in women
who underwent oophorectomy before menopause. Neurology 2008;
70:200– 209.
Rocha VB, Guerra-Junior G, Marques-de-Faria AP, de Mello MP,
Maciel-Guerra AT. Complete gonadal dysgenesis in clinical practice: the
46,XY karyotype accounts for more than one third of cases. Fertil Steril
2011;96:1431–1434.
Romans SM, Stefanatos G, Roeltgen DP, Kushner H, Ross JL. Transition to
young adulthood in Ullrich –Turner syndrome: neurodevelopmental
changes. Am J Med Genet 1998;79:140–147.
Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB Jr. Effects of estrogen
on nonverbal processing speed and motor function in girls with Turner’s
syndrome. J Clin Endocrinol Metab 1998;83:3198– 3204.
Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions:
implications for affective regulation. Biol Psychiatry 1998;44:839– 850.
Sarrel PM. Sexuality in the middle years. Obstet Gynecol Clin North Am 1987;
14:49– 62.
Sauer MV, Paulson RJ, Ary BA, Lobo RA. Three hundred cycles of oocyte
donation at the University of Southern California: assessing the effect of
age and infertility diagnosis on pregnancy and implantation rates. J Assist
Reprod Genet 1994;11:92–96.
Schmidt PJ, Luff JA, Haq NA, Vanderhoof VH, Koziol DE, Calis KA,
Rubinow DR, Nelson LM. Depression in women with spontaneous 46,
XX primary ovarian insufficiency. J Clin Endocrinol Metab 2011;
96:E278–E287.
Scottish Intercollegiate Guidelines Network (SIGN). Long Term Follow up of
Survivors of Childhood Cancer. Edinburgh: SIGN, 2013. (SIGN publication
no 132) 2013; Available from URL: http://www.sign.ac.uk.
Shapiro CL, Halabi S, Hars V, Archer L, Weckstein D, Kirshner J, Sikov W,
Winer E, Burstein HJ, Hudis C et al. Zoledronic acid preserves bone
mineral density in premenopausal women who develop ovarian failure
due to adjuvant chemotherapy: final results from CALGB trial 79809.
Eur J Cancer 2011;47:683–689.
Sharma J, Friedman D, Dave-Sharma S, Harbison M. Aortic distensibility and
dilation in Turner’s syndrome. Cardiol Young 2009;19:568– 572.
Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive
functioning in surgically menopausal women. Psychoneuroendocrinology
1988;13:345–357.
Sherwin BB. Estrogenic effects on memory in women. Ann N Y Acad Sci 1994;
743:213– 230; discussion 230 –211.
Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP,
Burki RE, Ginsburg ES, Rosen RC, Leiblum SR et al. Transdermal
testosterone treatment in women with impaired sexual function after
oophorectomy. N Engl J Med 2000;343:682–688.
Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE,
Mertens AC, Whitton JA, Robison LL, Boice JD Jr. Stillbirth and neonatal
death in relation to radiation exposure before conception: a
retrospective cohort study. Lancet 2010;376:624–630.
Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE,
Mertens AC, Whitton JA, Robison LL, Boice JD Jr. Congenital anomalies
in the children of cancer survivors: a report from the childhood cancer
survivor study. J Clin Oncol 2012;30:239– 245.
Simon J, Braunstein G, Nachtigall L, Utian W, Katz M, Miller S, Waldbaum A,
Bouchard C, Derzko C, Buch A et al. Testosterone patch increases sexual
activity and desire in surgically menopausal women with hypoactive sexual
desire disorder. J Clin Endocrinol Metab 2005;90:5226– 5233.
Soares PM, Cabello C, Magna LA, Tinois E, Benetti-Pinto CL. Breast density in
women with premature ovarian failure or postmenopausal women using
hormone therapy: analytical cross-sectional study. Sao Paulo Med J 2010;
128:211– 214.
Soderstrom-Anttila V, Tiitinen A, Foudila T, Hovatta O. Obstetric and
perinatal outcome after oocyte donation: comparison with in-vitro
fertilization pregnancies. Hum Reprod 1998;13:483–490.
Stephure DK, Canadian Growth Hormone Advisory Committee. Impact of
growth hormone supplementation on adult height in turner syndrome:
results of the Canadian randomized controlled trial. J Clin Endocrinol
Metab 2005;90:3360– 3366.
Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J. A systematic
review and economic evaluation of alendronate, etidronate, risedronate,
raloxifene and teriparatide for the prevention and treatment of
postmenopausal osteoporosis. Health Technol Assess 2005;9:1–160.
Stoop D, Baumgarten M, Haentjens P, Polyzos NP, De Vos M, Verheyen G,
Camus M, Devroey P. Obstetric outcome in donor oocyte pregnancies: a
matched-pair analysis. Reprod Biol Endocrinol 2012;10:42.
Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in
postmenopausal women. Cochrane Database Syst Rev 2006;CD001500.
Sung L, Bustillo M, Mukherjee T, Booth G, Karstaedt A, Copperman AB.
Sisters of women with premature ovarian failure may not be ideal ovum
donors. Fertil Steril 1997;67:912– 916.
936 The ESHRE Guideline Group on POI
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
Swillen A, Fryns JP, Kleczkowska A, Massa G, Vanderschueren-Lodeweyckx M,
Van den Berghe H. Intelligence, behaviour and psychosocial development in
Turner syndrome. A cross-sectional study of 50 pre-adolescent and
adolescent girls (4–20 years). Genet Couns 1993;4:7–18.
Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA. Combined
estrogen and testosterone use and risk of breast cancer in
postmenopausal women. Arch Intern Med 2006;166:1483–1489.
Templeton A, Morris JK, Parslow W. Factors that affect outcome of in-vitro
fertilisation treatment. Lancet 1996;348:1402–1406.
Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R,
Hossain J, Santen RJ, Ross JL, Mauras N. Metabolic effects of oral versus
transdermal 17beta-estradiol (E(2)): a randomized clinical trial in girls
with Turner syndrome. J Clin Endocrinol Metab 2013;98:2716– 2724.
van Dalen EC, van der Pal HJ, van den Bos C, Kok WE, Caron HN,
Kremer LC. Clinical heart failure during pregnancy and delivery in a
cohort of female childhood cancer survivors treated with anthracyclines.
Eur J Cancer 2006;42:2549–2553.
van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans JC, Banga JD.
Age at menopause as a risk factor for cardiovascular mortality. Lancet
1996;347:714– 718.
van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic
review on therapeutic interventions to restore ovarian function and
achieve pregnancy. Hum Reprod Update 1999;5:483–492.
van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M,
Otten BJ, Hoorweg-Nijman JJ, Vulsma T, Stokvis-Brantsma WH,
Rouwe CW et al. Final height in girls with turner syndrome after
long-term growth hormone treatment in three dosages and low dose
estrogens. J Clin Endocrinol Metab 2003;88:1119–1125.
Vearncombe KJ, Pachana NA. Is cognitive functioning detrimentally affected
after early, induced menopause? Menopause 2009;16:188–198.
Vermeulen N, D’Angelo A, de Sutter P, Nelen WLDM. Manual for ESHRE
Guideline Development 2014, www.eshre.eu.
White WB. Drospirenone with 17beta-estradiol in the postmenopausal
woman with hypertension. Climacteric 2007;10(Suppl 1):25– 31.
Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and
neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys
2009;73:1304–1312.
Wu X, Cai H, Kallianpur A, Li H, Yang G, Gao J, Xiang YB, Ji BT, Yu T,
Zheng W et al. Impact of Premature Ovarian Failure on Mortality and
Morbidity among Chinese Women. PloS one 2014;9:e89597.
Guideline for managing premature ovarian insufficiency 937
Downloaded from https://academic.oup.com/humrep/article-abstract/31/5/926/1749616
by guest
on 04 April 2018
