University of Birmingham Polycystic ovary syndrome and endometrial hyperplasia Charalampakis, Vasileios; Tahrani, Abd A.; Helmy, Ahmed; Gupta, Janesh K.; Singhal, Rishi DOI: 10.1016/j.ejogrb.2016.10.001 10.1016/j.ejogrb.2016.10.001 License: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) Document Version Peer reviewed version Citation for published version (Harvard): Charalampakis, V, Tahrani, AA, Helmy, A, Gupta, JK & Singhal, R 2016, 'Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility', European Journal of Obstetrics & Gynecology and Reproductive Biology, vol. 207, pp. 220-226. https://doi.org/10.1016/j.ejogrb.2016.10.001, https://doi.org/10.1016/j.ejogrb.2016.10.001 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. • Users may freely distribute the URL that is used to identify this publication. • Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. • User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) • Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 03. Jun. 2020
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University of Birmingham
Polycystic ovary syndrome and endometrialhyperplasiaCharalampakis, Vasileios; Tahrani, Abd A.; Helmy, Ahmed; Gupta, Janesh K.; Singhal, Rishi
Citation for published version (Harvard):Charalampakis, V, Tahrani, AA, Helmy, A, Gupta, JK & Singhal, R 2016, 'Polycystic ovary syndrome andendometrial hyperplasia: an overview of the role of bariatric surgery in female fertility', European Journal ofObstetrics & Gynecology and Reproductive Biology, vol. 207, pp. 220-226.https://doi.org/10.1016/j.ejogrb.2016.10.001, https://doi.org/10.1016/j.ejogrb.2016.10.001
Link to publication on Research at Birmingham portal
General rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or thecopyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposespermitted by law.
•Users may freely distribute the URL that is used to identify this publication.•Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of privatestudy or non-commercial research.•User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?)•Users may not further distribute the material nor use it for the purposes of commercial gain.
Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.
When citing, please reference the published version.
Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has beenuploaded in error or has been deemed to be commercially or otherwise sensitive.
If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access tothe work immediately and investigate.
Title: Polycystic ovary syndrome and endometrial hyperplasia:an overview of the role of bariatric surgery in female fertility
Author: Vasileios Charalampakis Abd A. Tahrani AhmedHelmy Janesh K. Gupta Rishi Singhal
PII: S0301-2115(16)30949-6DOI: http://dx.doi.org/doi:10.1016/j.ejogrb.2016.10.001Reference: EURO 9618
To appear in: EURO
Received date: 24-6-2016Revised date: 27-8-2016Accepted date: 1-10-2016
Please cite this article as: Charalampakis Vasileios, Tahrani Abd A, HelmyAhmed, Gupta Janesh K, Singhal Rishi.Polycystic ovary syndrome andendometrial hyperplasia: an overview of the role of bariatric surgery in femalefertility.European Journal of Obstetrics and Gynecology and Reproductive Biologyhttp://dx.doi.org/10.1016/j.ejogrb.2016.10.001
This is a PDF file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copyediting, typesetting, and review of the resulting proofbefore it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers thatapply to the journal pertain.
Bariatric surgery has been shown to be superior to medical therapy in achieving glycaemic
control targets and diabetes remission in patients with Type 2 diabetes. The remission rate of
Type 2 diabetes varies between studies due to variation in the definition of remission, which is
much stricter in recent studies, the diabetes duration, the beta cell reserve at the time of
surgery and the follow up after surgery. Overall, remission rates decrease over longer follow up
and with longer diabetes duration and mire advanced beta cell failure. In addition diabetes
remission rates are different for the 3 main procedures and reveal the escalating complexity of
their physiology. In general bariatric surgery is a fast and efficient treatment for diabetes. This
was highlighted 20 years ago by Pories et al who reported diabetes and glucose tolerance
impairment resolution rates of 83% and 99% respectively, with follow up of up to 14 years after
GBP [51]. Buchwald’s meta-analysis reported a remission rate that ranged from 48% for AGB, to
84% for GBP and to 98% for BPD [36]. This study did not include SG data. The above results
have been confirmed by more recent studies that also included SG which offered a remission
rate of 66-71% [46,52]. The most recent meta-analysis reported remission rate after GBP to be
66% after applying stricter criteria and with a follow up 2-5years [53].
Similarly, bariatric surgery has significant impact on other obesity-related comorbidities.
Hypertension remission rates are approximately 20-43, 40-70 and 45-68% for AGB, SG and GBP
respectively. Sleep apnoea remission rates are 29-68, 57-87 and 66-80% and dyslipidaemia
remission rates are 27-59, 40-62 and 63-97%, respectively [36,46,52].
Equally important is the positive effect of bariatric surgery on health related quality of life. An
increasing number of studies indicate that quality of life, measured by both generic and
obesity-specific instruments, markedly improves after a bariatric intervention, although it might
not reach this of non-obese population [54].
Although the above comorbidities are almost consistently reported in every bariatric
publication other significant obesity-related conditions, such as PCOS, EH and infertility, have
attracted less attention.
The impact of bariatric surgery in patients with PCOS and/or EH
PCOS: Life style interventions remain the first-line treatment in women with PCOS, but bariatric
surgery is increasingly recognized as a possible treatment for women with PCOS and was
recently recommended by RCOG as a possible treatment option in women who fail to achieve
significant weight loss with lifestyle interventions and a BMI above 40 kg/m2 (or 35 kg/m2 in the
presence of other obesity comorbidities).
Meta-analysis of randomized and non-randomized trials and case-series found only 13 studies.
The studies included 2130 female patients, with 10 out of 13 of the studies including <100
participants. The mean ages and BMI in the studies included in the meta-analysis ranged 16-44
years (weighted mean 30.8 years) and 44-52 kg/m2 (weighted mean 46.3 kg/m2) respectively,
with a weighted mean of 14 months follow up duration. Overall bariatric surgery resulted in
reductions in PCOS (OR 0.27, 95% CI 0.14-0.52; p<0.001), hirsutism (OR 0.12, 95% CI 0.04-0.36;
p<0.001), menstrual irregularities (OR 0.07, 95% CI 0.03-0.21; p <0.001) and infertility (OR 0.35,
95%CI 0.19-0.65; p<0.001) [13]. While, the meta-analysis concluded that bariatric surgery
effectively attenuated PCOS and its clinical symptomatology, including subfertility, in severely
obese women the lack of RCTs and the heterogeneity of PCOS definitions amongst studies are
major limitations. In another study of 20 women with obesity and PCOS who received GBP and were
followed up for about 4 years, menstruation was corrected in 82%, and hirsutism resolved in 29%
[55]. Of the 10 patients who did not conceive before surgery, 6 patients had become pregnant
within 3 years of surgery [55].
The impact of bariatric surgery in women with PCOS seems to be mediated by improvements in
insulin resistance and androgen levels after surgery [13]. However, improvements in menstrual
cycling and hirsutism did not correlate with the weight loss after surgery, suggesting a role for
weight-independent mechanisms in the impact of bariatric surgery in women with PCOS [56].
The changes in weight loss after GBP are similar in women with and without PCOS.
However, weight-loss via pharmacotherapy and/or life style intervention is also beneficial in
women with PCOS. In a study of 59 obese adolescent females with PCOS aged 12–18 years, who
underwent 1 year of lifestyle intervention (nutrition education, exercise training, and
behavioural therapy), in the 26 girls who lost weight (−3.9kg/m2), testosterone concentrations
decreased significantly by a mean of 0.3nmol/litre and SHBG concentrations increased
significantly by a mean of +8ng/ml compared to the subjects with increasing weight.
Furthermore, the prevalence of amenorrhea and oligoamenorrhea was reduced by 42% and
19%, respectively [57]. A recent meta-analysis suggested that orlistat-induced weight loss in
overweight and obese women with PCOS can reduce testosterone, insulin resistance markers
and improve lipid profile. But due to the small sample size the meta-analysis was inconclusive
on whether orlistat is advantageous over the established second line treatment with metformin
[58].
It is not possible to be certain whether bariatric surgery is superior to lifestyle interventions or
weight loss pharmacotherapy in women with obesity and PCOS due to the lack of randomized
controlled trials. However, bariatric surgery has been proven to be superior to other methods
of weight loss in patients with BMI ≥35 kg/m2 in regards to the durability of the surgical weight
loss, the impact on cardiovascular disease factors, the impact on glucose metabolism and
quality of life.
EH: EH can occur in 7-10% of patients with morbid obesity [30,59-62]. This represents a 23-fold
increase of the risk of EH in morbidly obese females [28]. It has been shown that bariatric
surgery has a positive effect on endometrial histological changes and can ameliorate the risk of
endometrial pathology [30,59,62]. In a meta-analysis of 3 studies involving 890,110
participants, bariatric surgery lowered the risk of endometrial cancer compared with controls
(RR= 0.40, 95% CI 0.20 - 0.79) [63]. Surgically induced weight loss represents a potentially
attractive option for EC prevention and treatments [61], but RCTs are needed. Unfortunately
there are no well-designed studies to report the impact of medical weight management on EH
and even more to compare surgical versus medical treatment. It has been suggested though
that metformin can act as a preventive measure of progression of EH as it is a potent inhibitor
of endometrial cell proliferation by reducing the metabolic syndrome and lowering insulin and
testosterone levels in postmenopausal overweight women [64].
Infertility: Increased BMI is associated with hyperleptinaemia, insulin resistance and
hyperandrogenism all of which contribute to chronic anovulation and subfertility [65].
Abnormal LH pulsatility might also lead to abnormal oocyte recruitment, poor oocyte quality
and altered endometrial development which could affect the function of the corpus luteum
[66]. In addition to its impact on ovulation, obesity affects endometrial development, uterine
receptivity, implantation, and miscarriage [67]. Furthermore, obesity is associated with
increased risk for the mother (miscarriage, gestational diabetes, hypertension, pre-eclampsia,
dysfunctional labour and caesarean section) and for the neonate (congenital malformations,
macrosomia, and admission to a neonatal care unit). The risk of stillbirth is also strongly related
to maternal BMI.
According to a meta-analysis of 13 case-series including 2130 PCOS patients, bariatric surgery
lowers the risk of infertility (OR 0.35, 95%CI 0.19-0.65; p<0.001) [13]. In a different a meta-
analysis of 8 studies (589 women, age 31-45 years, baseline BMI 40.9-50 kg/m2), the weighted
mean incidence for successful pregnancy after bariatric intervention was 0.580 (95% CI 0.539-
0.621, p < 0.001) which is not very far for the expected incidence for the “healthy population”,
in which 1 in 4 couples is expected to be affected by infertility [66].
Obesity is associated with significant adverse outcomes to the mother and newborn. As a
result the British Fertility Society policy and practice guidelines recommend deferring any
treatment until a woman’s BMI is <35 kg/m2, and recommending that BMI <30 kg/m2 is
preferable [67].
For the neonate there is strong evidence that after surgically induced weight loss the risk for
excessive fetal growth is reduced while prematurity and small-for-gestational-age infants is
more frequently expected [65,68]. Interestingly a sub-group analysis showed no increased
prematurity risk after gastric band suggesting a potential correlation of prematurity and
micronutrients malabsorption following other bariatric interventions [68].
Assisted reproduction: Ovarian stimulation is less likely to be successful with clomifene in
obese patients and higher doses of gonadotrophins were required [65]. Despite that more
recent studies have shown that oocyte numbers retrieved and pregnancy rates were not worse
in comparison to normal BMI counterparts [65]. Similarly in intrauterine insemination when
medication dosages were adjusted to overcome the weight-effect, the success of the treatment
cycle was comparable to that of normal-weight women [65]. On the other hand for IVF
methods obese patients had a 65% lower odds of having a live birth (LB) following their first IVF
cycle comparing to patients with a BMI<30kg/m2 [69]. Data from the Society for Assisted
Reproduction Technology (SART) show that the odds of failing to achieve live birth was 18-48%
higher for overweight and obese women (depending on the BMI) and significantly increased
adjusted odds for fetal loss and stillbirth [70]. Thus, overweight and obese women undergoing
ART appear to be disadvantaged with respect to the dosage and duration required for ovarian
stimulation, embryo implantation, pregnancy and LB rates as well as in the frequency of
miscarriage and recurrent early pregnancy loss. Specific data on IVF after bariatric surgery are
limited and quite preliminary but it seems that the bariatric intervention reduces treatment
costs without affecting oocyte or embryo quality [71].
Conclusion
Bariatric surgery results in significant and sustained weight loss and improvements in obesity-
related comorbidities. Non-randomised studies suggest that bariatric surgery could play an
important role in the management of patients with PCOS and/or endometrial hyperplasia but
randomized controlled trials are needed.
Bariatric surgery is an expanding field that is offering sustainable results both for weight loss
and remission of co-morbidities. As new indications for bariatric surgery emerge and more
diseases are more closely linked to the epidemic of obesity, the wider acceptance of weight-loss
surgery as an addition to the treatment options will assist the optimization of the multi-
modality management of conditions such as PCOS and EH which affect a large number of young
population of reproductive age.
Conflict of interest
All authors have no conflict of interest to declare
Acknowledgments
A.A.T. is a clinician scientist supported by the National Institute for Health Research (NIHR) in
the UK. The views expressed in this publication are those of the author(s) and not necessarily
those of the National Health Service, the NIHR, or the Department of Health.
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