Abstract
This study assessed the relationship between regular physical activity and reproductive performance in obese infertile patients who receive assisted reproduction cycles with stable bodyweight. A total of 216 obese infertile women at their first fresh assisted reproduction attempt with stable body mass index (BMI) and available data on their physical activity carried out up to the beginning of the treatment cycle were enrolled in this observational cohort study. Clinical and biological data were recorded and analysed. There were 41 obese patients who did regular physical activity and 175 obese controls who did not. Total pregnancies (16/41, 39.0% versus 28/175, 16.0%, respectively; P = 0.002) and live births (10/41, 24.4% versus 13/175, 7.4%, respectively; P = 0.004) were significantly higher in patients who did physical activity regularly compared with those who did not. After adjusting for confounders, in obese infertile patients who did physical activity regularly, the relative risks for a clinical pregnancy and live birth were 3.22 (95% CI 1.53–6.78; P = 0.002) and 3.71 (95% CI 1.51–9.11; P = 0.004), respectively. In conclusion, regular physical activity carried out before a assisted reproduction cycle is significantly related with improved reproductive performance in obese infertile patients, irrespective of bodyweight loss.
Body weight loss improves not only spontaneous pregnancy rates but also those of assisted reproductive techniques (ARTs). Moreover, almost all studies refer to body weight loss due to lifestyle intervention programs consisting in hypocaloric diet and increased physical activity. Instead, very little is known about the specific effects of physical activity alone on human reproduction. Based on these considerations, we designed the present study to assess the relationship between regular physical activity and reproductive outcome in infertile obese patients who receive ARTs. Two-hundred-sixteen obese infertile women with stable body mass index (BMI) and at their first fresh ART attempt were enrolled, and clinical and biological data were recorded and analyzed. Our results demonstrate that the chances to obtain a pregnancy and a baby are 3-fold higher in obese infertile patients who does physical activity regularly in comparison with those who does not, suggesting that regular physical activity before ART cycles improves the reproductive performance in obese women irrespective to body weight loss.
Keywords
Introduction
Obesity is an increasingly prevalent condition in Western countries and has been defined as a new worldwide epidemy (
Flegal et al., 2012
). Obesity is closely related to a raised risk of chronic diseases, such as cardiovascular disease, type 2 diabetes mellitus, gastrointestinal disease, osteoarticular disease and cancer (Flegal et al., 2013
).The role that obesity plays in human reproduction is well known (
Michalakis et al., 2013
). Obese women experience a longer time to conception and an increased infertility rate (Gesink Law et al., 2007
). Lower pregnancy and live birth rates, as well as higher miscarriage rates, have also demonstrated in obese patients when compared with nonobese controls both in natural and assisted conceptions (Gesink Law et al., 2007
, Koning et al., 2012
). In addition, an increased incidence of pregnancy complications, including a higher risk for fetal malformations, has been shown (Knight et al., 2010
).The exact mechanism by which obesity acts is only partially known. Insulin resistance and adipokines could play a crucial role (
Pasquali et al., 2003
). Conversely, there are more confused and sparse data on the intercorrelations between hyperandrogenism and obesity in humans. Moreover, a high proportion of women with polycystic ovary syndrome (PCOS) are obese and abdominal obesity is significantly related to hirsutism in PCOS (Pasquali et al., 2003
). Studies using oocyte donation as a research model suggest that the final target of obesity could be the ovary and/or the endometrium (Styne-Gross et al., 2005
, Wattanakumtornkul et al., 2003
). However, the precise mechanism by which obesity acts is still unclear.International guidelines and consensus conferences have reached different conclusions regarding whether or not to treat infertility in obese patients (
National Institute for Clinical Excellence, 2004
). Consolidated clinical data (ESHRE Task Force on Ethics and Law, 2010
, Nelson and Fleming, 2007
) suggest that weight loss should always be the primary goal in obese patients before starting an infertility treatment or planning a pregnancy, but various cut-off values of body mass index (BMI) or bodyweight have been suggested. Weight loss can reduce the need for in vitro fertilization (IVF) in anovulatory patients, since a weight loss of at least 5% is useful not only to regularize menstrual cycles but also in terms of pregnancies, with a total pregnancy rate of about 50% after 6 months of treatment (ESHRE Task Force on Ethics and Law, 2010
, Nelson and Fleming, 2007
).Bodyweight loss improves not only spontaneous pregnancy rates but also those of assisted reproduction treatment (
Chavarro et al., 2012
, Domar et al., 2012
, ESHRE Task Force on Ethics and Law, 2010
, Ramezanzadeh et al., 2012
, Twigt et al., 2012
). Moreover, almost all studies refer to bodyweight loss due to lifestyle intervention programmes consisting of a hypocaloric diet and increased physical activity (Chavarro et al., 2012
, Domar et al., 2012
, ESHRE Task Force on Ethics and Law, 2010
, Ramezanzadeh et al., 2012
, Twigt et al., 2012
). Instead, very little is known about the specific effects of physical activity alone on human reproduction.Based on these considerations, the aim of this observational cohort study was to assess the relationship, if any, between regular physical activity and reproductive outcome in infertile obese patients treated with assisted reproduction treatment.
Materials and methods
Institutional review board approval was not required since all couples included underwent routine IVF or intracytoplasmic sperm injection (ICSI) in this reproductive medicine centre in Italy, and no additional/experimental intervention was performed. At IVF/ICSI scheduling, all patients signed an informed consent to use their nonsensitive data for scientific purposes.
Study population
This study retrospectively reviewed all IVF/ICSI cycles performed in the study institution between 1 March 2009 and 30 June 2012. Elective inclusion criteria were primary infertility requiring an IVF/ICSI procedure, female obesity and stable BMI. Obesity was defined as BMI >30 kg/m2 and classified as class I (BMI 30–34.9 kg/m2), class II (BMI 35–39.9 kg/m2) or class III (BMI ⩾40 kg/m2). BMI was defined ‘stable’ when the change in patients’ bodyweight was lower than 5% in two measurements performed at IVF/ICSI cycle scheduling and at cycle start (at least 6 months from first measurement).
Exclusion criteria: were unavailable data on live birth and/or BMI; use of cryopreserved embryos; adherence to a specific diet programme; any changes in diet and physical activity; tobacco smoking; drug use; alcohol abuse (more than two alcoholic beverages per day); uterine diseases (such as submucous fibroids, polyps, Müllerian defects); previous pelvic surgery; major medical diseases (previous or current malignancy or premalignancy, diabetes, cardiovascular disease); clinical history of (or suspicion of) endometriosis, antiphospholipid antibody syndrome, recurrent miscarriage; patients with obese partner or with partner’s BMI not recorded; and severe sperm pathology (such as severe teratozoospermia and oligozoospermia, obstructive/non obstructive azoospermia, asthenozoospermia or cryptozoospermia).
Treatment
Ovarian stimulation in obese patients was achieved using individualized protocols of gonadotrophins, recombinant FSH (Gonal-F; Merck Serono, Geneva, Switzerland) or highly purified FSH (Fostimon; IBSA Institut Biochimique, Lugano, Switzerland) FSH, human menopausal gonadotrophin (HMG; Menogon; Ferring, Lausanne, Switzerland) or highly purified HMG (Meropur; Ferring) in short or long gonadotrophin-releasing hormone agonist (GnRHa; Enantone; Takeda Pharmaceutical, Osaka, Japan) down-regulated cycles. The criteria to start gonadotrophin administration were serum oestradiol concentration <50 pg/ml and an absence of follicle(s) with diameter >10 mm. The ovarian response was monitored by use of serum oestradiol assays and serial sonograms.
In the presence of at least three follicles with diameter >17 mm, human chorionic gonadotrophin (HCG; Gonasi; IBSA Institut Biochimique) was injected to complete oocyte maturation. Oocyte retrieval was performed 34–36 h after HCG administration by ultrasound-guided transvaginal aspiration. All patients received progesterone for 15 days as luteal phase support until β-HCG assay. Semen samples were collected by masturbation after 3–5 days of abstinence. The preparation for conventional IVF or ICSI was performed following the World Health Organization (WHO) standard protocol (
World Health Organization, 2010
).In all cases, oocyte retrieval and embryo transfer were performed by the same experienced operator (GBLS). For conventional IVF, oocytes were cultured individually and inseminated in microdrops of fresh medium under mineral oil with 100,000 activated spermatozoa. For ICSI, after the removal of the cumulus and corona cells, nuclear maturation assessment of oocytes was performed using an inverted microscope to ensure the injection of metaphase-II oocytes only.
Oocyte fertilization was assessed at 18–20 h (day 1) from insemination/injection and confirmed by the presence of 2 pronuclei and the alignment of nucleolar precursor bodies. In all cases, embryonic development was assessed on days 2 and 3 (i.e. after 41–43 h and 65–67 h from insemination/injection, respectively). The best-quality embryos were transferred on day 2 or 3 after IVF/ICSI. The number of embryos to transfer was defined according to internal guidelines and in accordance with the patients’ age.
Biochemical pregnancies were assessed 12 days after embryo transfer by a positive quantitative serum β-HCG assay higher than 10 IU/l. In case of positive pregnancy test, micronized progesterone support (200 mg t.i.d.; Prometrium; Rottapharm Madaus, Monza, Italy) was continued until 35 days after embryo transfer.
Assessments
All available clinical and biological data were recorded for each subject. In case of more than one cycle, only the data of the first cycle for each patient was recorded. Specifically, this study noted patients’ demographic and anthropometric characteristics objectively assessed during the couple evaluation, instrumental data at ultrasound, ovarian stimulation regimens used, drugs and protocols used for luteal-phase support, characteristics of oocytes retrieved and embryo transfer and embryo morphology.
In the pretreatment work up, each woman underwent transvaginal ultrasound to exclude pelvic diseases, measure ovarian dimensions and perform the antral follicle count and clinical evaluations, consisting of anthropometric measurements, including height, weight, BMI and waist-to-hip ratio (WHR). Specifically, BMI was calculated as the ratio between the weight and the square of the height, and WHR as the ratio between the waist (considered to be the smallest circumference of torso between the 12th rib and the iliac crest) and the circumference of the hip (considered as the maximal extension of the buttocks). All measurements were performed with the patient without clothes and shoes, in a standing position with relaxed abdomen, arms at their sides and joined feet.
Rates of implantation, biochemical, clinical and total pregnancy and miscarriage and live birth were also noted. Implantation rate was defined as the number of gestational sacs divided by the number of embryos transferred; biochemical or clinical pregnancy rates were defined as the number of biochemical (diagnosed by the detection of β-HCG in serum that did not develop into a clinical pregnancy) or clinical (diagnosed by ultrasonographic visualization of one or more gestational sacs) pregnancies per initiated cycle, respectively; total pregnancy rate was defined as the sum of clinical and biochemical pregnancies per initiated cycle; miscarriage rate was defined as the number of miscarriages in the first 12 weeks of gestation per clinical pregnancy; live birth rate was defined as the number of deliveries that resulted in at least one live-born baby per initiated cycle. All definitions reported were in agreement with the International Committee for Monitoring Assisted Reproductive Technology and the WHO Revised Glossary on ART Terminology (
Zegers-Hochschild et al., 2009
).- Zegers-Hochschild F.
- Adamson G.D.
- de Mouzon J.
- Ishihara O.
- Mansour R.
- Nygren K.
- Sullivan E.
- Vanderpoel S.
The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2004159.
Hum. Reprod. 2009; 24: 2683-2687
Self-administered semiquantitative general health questionnaires formulated on the basis of a well-validated international questionnaire (Global Physical Activity Questionnaire; www.who.int/chp/steps/GPAQ%20Instrument%20and%20Analysis%20Guide%20v2.pdf) were commonly used at IVF/ICSI scheduling and treatment start and were analysed. On the basis of the results, physical activity was categorized and graded: (a) no weekly physical activity; (b) light physical activity most of the week; (c) strenuous physical activity (subjective feeling of increased heart rate, breathing and perspiration) for at least 20 min once or twice per week; and (d) strenuous physical activity for at least 20 min three or more times per week. The questionnaire was administered to each subject at the IVF/ICSI scheduling during counselling on the role of lifestyle modification programmes in infertile obese women and was rechecked at treatment start.
Each patient was coded. Demographic and anthropometric data, physical activity and reproductive outcomes were recorded by two researchers, each blinded with regard of data of the other. The final analysis was made by a third researcher who matched the coded charts of each patient.
Patients were then categorized into two groups on the basis of regular physical activity (yes/no). Specifically, those women who reported both light and strenuous physical activity were defined as having regular physical activity.
Statistical analysis
The primary endpoint of the study was the live birth rate. Since no data about the effect of physical activity on reproductive outcomes were available in order to calculate the sample size, this study arbitrarily included all patients with available and clear data on their physical activity in the cohorts.
The normal distribution of continuous variables was evaluated using the Kolmogrov–Smirnov test and continuous data were expressed as the mean ± standard deviation (SD). Continuous data were analysed by Student’s t-test for unpaired data. For categorical variables, the Pearson chi-squared test was performed. Fisher’s exact test was used for the frequency tables when more than 20% of the expected values were less than five.
Forward stepwise multivariate logistic regression analysis was performed to identify independent influencing factors for the live birth. Cox proportional-hazards model was used to calculate the relative risk (RR) and 95% confidence interval (CI) for the most relevant clinical endpoints (StatsDirect release 2.4.3). All calculations were adjusted for confounders.
The level of statistical significance was set at P < 0.05 for all statistical analyses. The Statistical Package for Social Sciences version 15.0.1 (SPSS, Chicago, IL, USA) was used for all calculations.
Results
A total of 4612 IVF/ICSI cycles were screened and, after checking for inclusion and exclusion criteria, 216 cycles (86, 39.8%, IVF and 130, 60.2%, ICSI cycles) were included in the final analysis.
The proportion of obese patients who did regular physical activity was significantly lower than obese patients who did not (41/216, 19.0% versus 175/216, 81.0%; P < 0.0001). Among patients who regularly exercised, 22/41 (53.7%) reported light physical activity, whereas 19/41 (46.3%) reported strenuous physical activity. In particular, 15/41 (36.6%) and 4/41 (9.8%) patients reported a strenuous physical activity once or twice per week and three times or more per week, respectively. None of the patients were athletes and/or body builders, neither was the physical activity performed in a competitive manner or consisted of a structured exercise-training programme.
All demographic and anthropometric data are reported in Table 1. WHR was significantly lower in patients who exercised regularly in comparison with those who did not (0.82 ± 0.11 versus 0.94 ± 0.09, respectively; P < 0.0001). The proportion of patients with polycystic ovaries (6/41, 14.6% versus 56/175, 32.0%; P = 0.043) was also significantly lower in the group of patients who did regular physical activity. No other differences between groups were detected. Specific treatment characteristics are reported in Table 2 and no differences were detected.
Table 1Demographic and clinical characteristics of infertile obese patients who did and who did not do regular physical activity.
| Regular physical activity (n =41) | No regular physical activity (n =175) | |
|---|---|---|
| Age (years) | 37.1 ± 3.0 | 37.3 ± 3.6 |
| Body mass index (kg/m2) | 33.3 ± 2.7 | 32.7 ± 2.5 |
| Class of obesity | ||
| Class I | 32 (78.0) | 130 (74.3) |
| Class II | 9 (22.0) | 45 (25.7) |
| Class III | 0 (0.0) | 0 (0.0) |
| Waist-to-hip ratio | 0.82 ± 0.11 | 0.94 ± 0.09 |
| Duration of infertility (months) | 30.4 ± 11.2 | 31.3 ± 10.4 |
| Cause of infertility | ||
| Ovulatory | 10 (24.4) | 55 (31.4) |
| Tubal | 11 (26.8) | 53 (30.3) |
| Male | 13 (31.7) | 47 (26.9) |
| Unexplained | 7 (17.1) | 27 (15.4) |
| Other | 3 (7.3) | 9 (5.1) |
| Antral follicle count | 12.5 ± 9.5 | 11.9 ± 10.1 |
| Polycystic ovaries | 6 (14.6) | 56 (32.0) |
| Years of education | 15.3 ± 4.9 | 14.8 ± 4.6 |
| Work status | ||
| Full time | 16 (39.0) | 66 (37.7) |
| Part time | 7 (17.1) | 31 (17.7) |
| Retired | 0 (0.0) | 1 (0.6) |
| Homemaker | 5 (12.2) | 26 (14.9) |
| Unemployed | 13 (31.7) | 51 (29.1) |
| Socioeconomic status (Euros) | ||
| <10,000 | 16 (39.0) | 75 (42.9) |
| 10,000–20,000 | 11 (26.8) | 42 (24.0) |
| 20,000–30,000 | 5 (12.2) | 17 (9.7) |
| >40,000 | 9 (22.0) | 41 (23.4) |
Values are mean ± SD or n (%) and were analysed by Student’s t-test or chi-squared test, respectively.
a P < 0.0001.
b P = 0.043.
Table 2Treatment characteristics of infertile obese patients who did and who did not do regular physical activity.
| Regular physical activity (n =41) | No regular physical activity (n =175) | |
|---|---|---|
| Assisted reproduction treatment | ||
| IVF cycles | 14 (34.1) | 72 (41.1) |
| ICSI cycles | 27 (65.9) | 103 (58.9) |
| Prevention of LH surge | ||
| GnRH-agonist long | 28 (68.3) | 122 (69.7) |
| GnRH-agonist short | 13 (31.7) | 53 (30.3) |
| Type of gonadotrophin used | ||
| rFSH | 29 (70.7) | 115 (65.7) |
| hpFSH | 2 (4.9) | 9 (5.1) |
| hpHMG | 10 (24.4) | 49 (28.0) |
| HMG | 0 (0.0) | 2 (1.1) |
| Protocol | ||
| Step-up | 17 (41.5) | 61 (34.9) |
| Step-down | 22 (53.7) | 105 (60.0) |
| Other | 2 (4.9) | 9 (5.1) |
| Treatment used for triggering ovarian maturation | ||
| hpHCG | 35 (85.4) | 155 (88.6) |
| rHCG | 6 (14.6) | 20 (11.4) |
Values are n (%). There were no statistically significant differences.
GnRH = gonadotrophin-releasing hormone; HCG = human chorionic gonadotrophin; HMG = human menopausal gonadotrophin; hp = highly purified; r = recombinant.
The reproductive outcomes in both groups are summarized in Table 3. No significant differences between groups were detected in stimulation length, gonadotrophin dose or cancellation rate. Peak oestradiol concentration on day of ovulation triggering, and the numbers of dominant follicles on day of ovulation trigger, retrieved oocytes, metaphase-II oocytes, embryos transferred and high-quality embryos were also not significantly different between groups. Similarly, no significant differences were observed in the rates of fertilization, biochemical pregnancy, miscarriage, multiple pregnancy and ovarian hyperstimulation syndrome (Table 3). On the other hand, implantation rate was significantly (P < 0.001) higher in women who did physical activity regularly than in those who did not. In the same group, the total (P = 0.002) and clinical (P = 0.001) pregnancy rates, as well as the live birth rate (P = 0.004), were significantly higher than in the control group (Table 3).
Table 3Reproductive outcomes of infertile obese patients who did and who did not do regular physical activity.
| Regular physical activity (n =41) | No regular physical activity (n =175) | P-value | |
|---|---|---|---|
| Stimulation length (days) | 15.2 ± 3.7 | 14.8 ± 4.0 | NS |
| Gonadotrophin dose (IU) | 2610.4 ± 225.3 | 2650.2 ± 255.2 | NS |
| Cancellation rate | 4/41 (9.8) | 20/175 (11.4) | |
| Poor response | 3/41 (7.3) | 8/175 (4.6) | NS |
| High risk for OHSS | 1/41 (2.4) | 12/175 (6.9) | |
| Dominant follicles on day of ovulation triggering | 9.3 ± 2.6 | 10.0 ± 3.2 | NS |
| Peak oestradiol concentration on day of ovulation triggering (pg/ml) | 728.8 ± 376.8 | 837.1 ± 410.3 | NS |
| Retrieved oocytes | 6.9 ± 4.1 | 7.4 ± 3.8 | NS |
| MII oocytes | 4.8 ± 3.7 | 5.1 ± 3.9 | NS |
| Fertilization rate | 156/198 (78.8) | 538/720 (74.7) | NS |
| Embryos transferred | 2.2 ± 1.1 | 1.9 ± 1.4 | NS |
| High-quality embryos | 54/148 (36.5) | 115/306 (37.6) | NS |
| Implantations | 22/97 (22.7) | 23/332 (6.9) | <0.001 |
| Total pregnancies | 16/41 (39.0) | 28/175 (16.0) | 0.002 |
| Biochemical pregnancies | 4/41 (9.8) | 12/175 (6.9) | NS |
| Clinical pregnancies | 12/41 (29.3) | 16/175 (9.1) | 0.001 |
| Miscarriages | 2/12 (16.7) | 3/16 (18.8) | NS |
| Live births | 10/41 (24.4) | 13/175 (7.4) | 0.004 |
| Multiple pregnancies | 1/12 (8.3) | 2/16 (12.5) | NS |
| OHSS | 5/41 (12.2) | 23/175 (13.1) | NS |
Values are mean ± SD or n (%).
OHSS = ovarian hyperstimulation syndrome.
a Grade I, II and IIIa embryos (
Nicoli et al., 2010
).Using logistic regression analysis, live birth rate was significantly influenced by polycystic ovaries (P = 0.022), WHR (P = 0.007) and physical activity intensity (P = 0.014), whereas no effect of age, BMI, type of infertility or IVF procedure was detected on the primary endpoint.
For infertile obese women who regularly exercised, the adjusted relative risks for clinical pregnancy (3.22, 95% CI 1.53–6.78; P = 0.002) and live birth (3.71, 95% CI 1.51–9.11; P = 0.004) after an IVF/ICSI cycle were significantly higher than in those who did not regularly exercise.
Discussion
As far as is known, the current report is the first clinical study aimed to investigate the relationship between regular physical activity and reproductive outcomes in infertile obese patients who underwent IVF/ICSI cycles. The current data demonstrate a strong and direct association between regular physical activity and reproductive outcomes in obese women with stable BMI who have received assisted reproduction treatment, suggesting a potential beneficial effect of physical exercise on fertility that is independent from weight loss. Specifically, obese women under regular physical activity had higher total pregnancy and live birth rates. Moreover, the likelihood of becoming pregnant and of having a baby from assisted reproduction treatment was at least 3-times higher in those who regularly exercised in comparison with those who did not. However, it should be emphasized that this study recorded the physical activity carried out up to the beginning of the IVF/ICSI cycle, whereas data on the effects of physical activity during the treatment were not explored.
The most relevant determinants of regular physical activity on reproductive outcome seemed to be mainly related to its effect on the implantation rate. Regarding this, implantation could be affected by two factors: the first is the ovarian/oocyte/embryo target, and the second is the endometrial target. This study’s findings seem to exclude an effect of physical activity on the ovarian response to gonadotrophins such as on the oocyte and embryo quality, as demonstrated by the lack of any difference between groups in preovulatory follicles, metaphase-II oocytes and top-quality embryos. This point is more difficult to explore since the data available in literature are controversial. In particular, insulin sensitizers can act at the ovarian level, reducing the response to the gonadotrophin stimulation (
Falbo et al., 2010
, Palomba et al., 2008
, - Palomba S.
- Giallauria F.
- Falbo A.
- Russo T.
- Oppedisano R.
- Tolino A.
- Colao A.
- Vigorito C.
- Zullo F.
- Orio F.
Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study.
Hum. Reprod. 2008; 23: 642-650
Palomba et al., 2010a
, Palomba et al., 2011a
, - Palomba S.
- Falbo A.
- Carrillo L.
- Villani M.T.
- Orio F.
- Russo T.
- Di Cello A.
- Cappiello F.
- Capasso S.
- Tolino A.
- Colao A.
- Mastrantonio P.
- La Sala G.B.
- Zullo F.
- Cittadini E.
METformin in High Responder Italian Group
Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial.
Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial.
Fertil. Steril. 2011; 96: 1384-1390
Palomba et al., 2011b
). However, physical activity, through insulin sensitization, can restore ovarian function (Yusuf and Anand, 2011
) and sensitize the ovary to clomiphene citrate during simple ovulation induction (Palomba et al., 2010a
). However, in these last studies (Palomba et al., 2010b
, - Palomba S.
- Falbo A.
- Giallauria F.
- Russo T.
- Rocca M.
- Tolino A.
- Zullo F.
- Orio F.
Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial.
Hum. Reprod. 2010; 25: 2783-2791
Yusuf and Anand, 2011
), only patients with PCOS were included and the effect of physical activity was biased by the loss of bodyweight.On the basis of this consideration, this study is inclined to propose a mechanism related to a direct action on the endometrium, mediated by a local insulin-sensitizing effect induced by physical activity. Unfortunately, due to the retrospective design of the study, this work was unable to evaluate differences in any metabolic or hormonal parameters that could support the hypothesis, despite indirect data seeming to strongly suggest it. Lower WHR was indeed observed in obese women who had regular physical activity in comparison with those who did not. WHR was found to be an index of insulin resistance, being a better indicator of abdominal fatness and cardiovascular disease than BMI or bodyweight (
Falbo et al., 2009
). In addition, characteristics related to insulin resistance, such as polycystic ovaries (Honnma et al., 2010
, Mioni et al., 2004
, Wang et al., 2010
), were less frequently present in women undergoing regular physical activity.Regarding this, reported data (
Kim et al., 2009
, Mioni et al., 2012
) propose the expression of endometrial proteins involved in the endometrial mechanism of the insulin-resistant state. More recent studies demonstrate that the reduction of insulin resistance at the endometrial level, induced by insulin-sensitizing agents, was related to changes in the expression of glucose transporter endometrial protein (- Mioni R.
- Mozzanega B.
- Granzotto M.
- Pierobon A.
- Zuliani L.
- Maffei P.
- Blandamura S.
- Grassi S.
- Sicolo N.
- Vettor R.
Insulin receptor and glucose transporters mRNA expression throughout the menstrual cycle in human endometrium: a physiological and cyclical condition of tissue insulin resistance.
Gynecol. Endocrinol. 2012; 28: 1014-1018
Zhai et al., 2012
), with clinical confirmation of a reduced risk of miscarriage and implantation failure in IVF cycles (Palomba et al., 2013
). Finally, a recent experimental study demonstrated the influence of insulin resistance on the endovascular trophoblast invasion in spontaneous pregnancies (- Palomba S.
- Falbo A.
- La Sala G.B.
Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials.
Br. J. Obstet. Gynecol. 2013; 120: 267-276
Palomba et al., 2012
).Through logistic regression analysis, no influence of age, BMI, different causes of infertility and/or assisted reproduction treatment employed was detected, suggesting that the reproductive benefits of the regular physical activity can be generalized to almost all infertile patients and are not exclusive to well-defined subgroups.
The main strength of this study is the careful selection of only subjects who underwent a first fresh IVF/ICSI cycle, with known physical activity habits and stable BMI for at least 6 months. Only patients with available data on live birth, the primary endpoint, were also included. In addition, patients undergoing a diet programme and who had changes in diet and/or physical activity habit were excluded. Several confounding factors, such as uterine pathological conditions, endometriosis, diabetes mellitus, male obesity and severe sperm pathology, were also considered as exclusion criteria at study entry. In fact, regular physical activity could act per se on some specific conditions, improving the reproductive outcomes.
The current study also has limitations. First, the careful patient selection avoided potential confounders but made the study population not totally representative of the general population. Second, the sample size was suboptimal, giving a quite limited study power (i.e. 51%) to detect a difference in live birth rate, introducing a type II error. Thus, further well-powered prospective studies are needed to confirm these findings. On the basis of the results here obtained and according to the post-study power analysis, 76 patients per arm would be needed to obtain a study power of 80% having live birth rate as the primary end point. On the basis of this, a randomized controlled study is to date in progress in this study institution (NCT01892111, http://www.clinicaltrials.gov) aimed at prospectively evaluating the effects of physical exercise on the effectiveness of IVF/ICSI programmes in infertile obese patients who failed to lose weight with a lifestyle intervention programme.
Third, this study had a retrospective design that included a certain bias. In fact, although almost all data were prospectively recorded at first visit and during the IVF/ICSI programmes, the bias cannot be excluded, especially for the definition and the assessment of regular physical activity. However, in light of the findings obtained, this bias could also be considered a strength, suggesting a stronger effect of physical activity in obese patients if assessed longitudinally. In fact, the retrospective data better guarantee the truthfulness of the results, since counselling and subsequent prospective evaluation could bias the responses of the self-administered questionnaires, with a trend to more frequently reporting regular physical activity. In addition, current findings are limited by the lack of a specific evaluation of the dietary habits, with the only exception being the exclusion of women who adhered to a diet programme and/or who had any changes in diet. In a recent study (
Twigt et al., 2012
), the beneficial effect of a short-term high-protein weight-loss diet was observed in overweight/obese infertile women undergoing IVF cycles. In particular, a reduction in central obesity resulted in an increased likelihood of pregnancy and reduced time to pregnancy (Moran et al., 2011
).Fourth, the current study lacks data regarding body fat composition. Thus, it is possible to postulate that some of the obese patients had a high (and pathological) BMI for increase in muscle mass (and not for an excess of fat). However, none of the patients studied were athletes and/or body builders, neither was the physical activity performed in a competitive manner or consisted in structured exercise training programme.
In conclusion, this observational cohort study demonstrates that regular physical activity carried out before the start of fresh IVF/ICSI cycles is significantly and directly related to improved reproductive performance of obese infertile patients irrespective to bodyweight loss. Further prospective controlled studies are needed to confirm these results and to define the best type of physical activity to suggest.
Acknowledgements
The authors would like to thank Dr Jacqueline Costa of the Azienda Ospedaliera ASMN, IRCCS of Reggio Emilia for language revision and assistance.
References
- Body mass index and short-term weight change in relation to treatment outcomes in women undergoing assisted reproduction.Fertil. Steril. 2012; 98: 109-116
- Lifestyle behaviors in women undergoing in vitro fertilization: a prospective study.Fertil. Steril. 2012; 97: 697-701
- Lifestyle-related factors and access to medically assisted reproduction.Hum. Reprod. 2010; 25: 578-583
- Does metformin affect ovarian morphology in patients with polycystic ovary syndrome? A retrospective cross-sectional preliminary analysis.J. Ovarian Res. 2009; 2: 5
- Serum and follicular anti-Mullerian hormone levels in women with polycystic ovary syndrome (PCOS) under metformin.J. Ovarian Res. 2010; 3: 16
- Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010.JAMA. 2012; 307: 491-497
- Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.JAMA. 2013; 309: 71-82
- Obesity and time to pregnancy.Hum. Reprod. 2007; 22: 414-420
- Remarkable features of ovarian morphology and reproductive hormones in insulin-resistant Zucker fatty (fa/fa) rats.Reprod. Biol. Endocrinol. 2010; 8: 73
- Transcriptional profiling with a pathway-oriented analysis identifies dysregulated molecular phenotypes in the endometrium of patients with polycystic ovary syndrome.J. Clin. Endocrinol. Metab. 2009; 94: 1416-1426
- Extreme obesity in pregnancy in the United Kingdom.Obstet. Gynecol. 2010; 115: 989-997
- Complications and outcome of assisted reproduction technologies in overweight and obese women.Hum. Reprod. 2012; 27: 457-467
- The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review.Metabolism. 2013; 62: 457-478
- Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients.J. Clin. Endocrinol. Metab. 2004; 89: 4089-4096
- Insulin receptor and glucose transporters mRNA expression throughout the menstrual cycle in human endometrium: a physiological and cyclical condition of tissue insulin resistance.Gynecol. Endocrinol. 2012; 28: 1014-1018
- Diet and IVF pilot study: short-term weight loss improves pregnancy rates in overweight/obese women undertaking IVF.Aust. N. Z. J. Obstet. Gynaecol. 2011; 51: 455-459
- Fertility Assessment and Treatment for People with Fertility Problems. A Clinical Guideline.RCOG Press, London2004
- The preconceptual contraception paradigm: obesity and infertility.Hum. Reprod. 2007; 22: 912-915
- Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures.Reprod. Biol. Endocrinol. 2010; 8: 77
- Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study.Hum. Reprod. 2008; 23: 642-650
- Systemic and local effects of metformin administration in patients with polycystic ovary syndrome (PCOS): relationship to the ovulatory response.Hum. Reprod. 2010; 25: 1005-1013
- Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial.Hum. Reprod. 2010; 25: 2783-2791
- Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial.Fertil. Steril. 2011; 96: 1384-1390
- Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve? A randomized controlled trial.Fertil. Steril. 2011; 96: 1128-1133
- Decidual endovascular trophoblast invasion in women with polycystic ovary syndrome: an experimental case-control study.J. Clin. Endocrinol. Metab. 2012; 97: 2441-2449
- Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials.Br. J. Obstet. Gynecol. 2013; 120: 267-276
- Obesity and reproductive disorders in women.Hum. Reprod. Update. 2003; 9: 359-372
- Impact of body mass index versus physical activity and calorie intake on assisted reproduction outcomes.Eur. J. Obstet. Gynecol. Reprod. Biol. 2012; 163: 52-56
- Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation.Fertil. Steril. 2005; 83: 1629-1634
- The preconception diet is associated with the chance of ongoing pregnancy in women undergoing IVF/ICSI treatment.Hum. Reprod. 2012; 27: 2526-2531
- Different phenotypes of polycystic ovary syndrome by Rotterdam criteria are differently steroidogenic but similarly insulin resistant.Fertil. Steril. 2010; 93: 1362-1365
- Body mass index and uterine receptivity in the oocyte donation model.Fertil. Steril. 2003; 80: 336-340
World Health Organization, 2010. WHO Laboratory Manual for the Examination and Processing of Human Semen. fifth ed., Department of Reproductive Health and Research. pp. 1–287.
- Body-mass index, abdominal adiposity, and cardiovascular risk.Lancet. 2011; 378 (author reply 228): 226-227
- The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2004159.Hum. Reprod. 2009; 24: 2683-2687
- Effects of metformin on the expression of GLUT4 in endometrium of obese women with polycystic ovary syndrome.Biol. Reprod. 2012; 87: 29
Article info
Publication history
Published online: March 24, 2014
Accepted:
March 11,
2014
Received in revised form:
March 10,
2014
Received:
October 29,
2013
Declaration: The authors report no financial or commercial conflicts of interest.Footnotes
Stefano Palomba is professor of obstetrics and gynaecology and a scientific responsible of the department of obstetrics, gynaecology and pediatrics, Arcispedale S Maria Nuova of Reggio Emilia, Istituto di Ricovero e Cura a Carattere Scientifico, University of Modena and Reggio Emilia, Italy.
Identification
Copyright
© 2014 Reproductive Healthcare Ltd. Published by Elsevier Inc. All rights reserved.
