|Year : 2016 | Volume
| Issue : 3 | Page : 81-89
Treating an obese infertile patient – Is there an algorithm for success?
Gautam Nandkishore Allahbadia
Rotunda-The Center for Human Reproduction, Bandra, Mumbai, Maharashtra, India
|Date of Web Publication||21-Apr-2017|
Gautam Nandkishore Allahbadia
Rotunda-The Center for Human Reproduction, 36 Turner Road, No. 101, 1st Floor, B-Wing, Bandra (West), Mumbai - 400 050, Maharashtra
Source of Support: None, Conflict of Interest: None
The effect of obesity on female reproduction has been well documented to have a significant effect on ovulation, particularly in patients with a predisposition to this, but it can also increase the time required to conceive and the risk of early miscarriage in patients with normal ovulation patterns. Obesity in infertile women increases the costs of fertility treatments, reduces success rates and increases significantly the risks of many complications of pregnancy and for the newborn. Studies suggest that even a modest loss of 5%–10% of body weight can restore ovarian cyclicity. However, there are gaps in knowledge regarding the benefits and cost-effectiveness of a lifestyle modification program versus bariatric surgery targeting obese infertile women and integrated into the in vitro fertilization (IVF) clinics. Polycystic ovary syndrome is a common cause of ovulatory dysfunction impacting women of reproductive age. Factors such as the individual's body weight influence the severity of the phenotype and risk of metabolic comorbidities. Obesity and insulin resistance are thought to potentiate disruptions in antral follicle development that result in chronic anovulation, and as such, have become important therapeutic targets of dietary interventions aimed at weight loss. Obesity is associated with higher doses of ovulation inducing medications to achieve ovulation or stimulation for IVF. Obese women undergoing IVF also have a reduced chance of clinical pregnancy and live birth as compared to normal weight women. Particularly in late reproductive years, the benefits of postponing pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age. Recent research suggests that mild ovarian stimulation might yield healthier oocytes in obese women.
Keywords: Algorithm, infertility, obesity, successful treatment
|How to cite this article:|
Allahbadia GN. Treating an obese infertile patient – Is there an algorithm for success?. IVF Lite 2016;3:81-9
| Introduction|| |
Women of reproductive age are gaining 5–7 kg/decade while being overweight or obese is now 1.7 times more common than it was 30 years ago. Moreover yet the average age for women to give birth is now almost 30 years old, and fertility itself after the age of 30 continues to progress. In parallel to this, the average age of women having their first infertility consultation has been pushed back by 3.5 years over the past 20 years, and the proportion of women over the age of 35 has multiplied by 3.5. Several epidemiological studies on large cohorts of pregnant women have perfectly revealed the link between weight at the time of conception and the chances of pregnancy. The risk of taking more than 1 year to conceive is increased by 27% if the woman is overweight and 78% if she is obese.
Leaving aside the ovulation problems linked with polycystic ovarian syndrome (PCOS), where weight has a significant impact on anovulation and infertility that ensues, many obese women have no difficulty in becoming pregnant and having children. However, for ovulating women with normal fertility, any increase in body mass index (BMI) by even 1 point above 39 kg/m 2 reduces the rate of spontaneous pregnancies in 1 year to 4%. A BMI >25 kg/m 2 is also linked with an increase in early miscarriages and recurrent miscarriages. Putative mechanisms for obesity-related ovulatory dysfunction, apart from PCOS, have been proposed. Insulin-induced suppression of hepatic sex hormone-binding globulin (SHBG) leads to reduction in gonadotropin secretion due to increased production of estrogen from the conversion of androgens by adipose aromatase., In addition, increased adipose-derived adipokine production can directly inhibit ovarian function., Even with normal menstrual cycles, obese women exhibit low gonadotropin secretion, prolonged folliculogenesis, and diminished luteal progesterone levels.,
Obesity is associated with higher doses of ovulation inducing medications to achieve ovulation or stimulation for in vitro fertilization (IVF). In normogonadotropic anovulatory women, increased BMI and abdominal obesity are associated with a decreased odds ratio (OR) of ovulation in response to clomiphene citrate (CC) (increased BMI; OR 0.92 [0.88–0.96]; increased waist-to-hip ratio: OR 0.60 [0.40–0.89]). When gonadotropins are used for ovulation induction, obesity is correlated with an increased total dose of follicle-stimulating hormone (FSH) administered, fewer mature follicles, and a decreased chance of ovulation., Several large retrospective analyses (1721–8145 women undergoing IVF or intracytoplasmic sperm injection [ICSI]) also confirm that obesity impairs ovarian responsiveness to gonadotropin stimulation (i.e., increased duration, the amount of gonadotropin administered, cycle cancellation; decreased oocytes retrieved).,,,, In this regard, adipose-derived leptin impairs FSH- and/or IGF-I-stimulated granulosa cell steroidogenesis 102.,
| Discussion|| |
Obese women with regular menstrual cycles, however, can still experience decreased fecundity. A Dutch study of 3029 ovulatory women (with at least one patent tube and a partner with a normal semen analysis) found a 4% lower spontaneous pregnancy rate (PR) per kg/m 2 increase in women with a BMI >29 kg/m 2 (hazard ratio: 0.96, 95% confidence interval [CI] 0.91–0.99 vs. a BMI 21–29 kg/m 2). Moreover, in a prospective study of 448 women undergoing donor insemination, presumed to be ovulatory by cervical mucus and basal body temperature assessments, increased abdominal adiposity impaired conception, adjusting for BMI.
Obese women undergoing IVF also have a reduced chance of clinical pregnancy and live birth as compared to normal weight women.,,,,, A systematic review of 27 IVF studies, 23 of which were retrospective, shows that overweight women (BMI, >25 kg/m 2) undergoing IVF have a 10% lower live birth rate (LBR) than women of normal weight (BMI, <25 kg/m 2) (OR 0.90 (95% CI 0.82–1.0). Although a smaller retrospective IVF study did not find a relationship between BMI and pregnancy outcome, a meta-analysis of 33 IVF studies including 47,967 cycles concludes that overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR] 0.90, P< 0.0001) and live birth (RR 0.84, P= 0.0002) compared to women with a BMI <25 kg/m 2. In a recent retrospective study of 4,609 women undergoing first IVF or IVF/ICSI cycles, obesity reduced embryo implantation (controlling for embryo quality and day of embryo transfer [ET]), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0–34.9 kg/m 2), 61% (BMI, 35.0–39.9 kg/m 2), and 68% (BMI, >40.0 kg/m 2) compared to women with a BMI 18.5–24.9 kg/m 2. More specifically, of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had 12% (95% CI 0.79–0.99) and 25% (95% CI 0.63–0.90) reductions in IVF-related LBR, respectively (reference BMI, 18.5–24.9 kg/m 2). In this cohort, there was a 2% (95% CI 0.97–0.99) decrease in LBR for every 1-unit increase in BMI. In another retrospective analysis of 487 couples undergoing assisted reproduction, obesity had the greatest negative impact on pregnancy outcome in young women (<25 years [OR 0.93, 95% CI 0.87–0.98]; reference BMI, 18.5–24.9 kg/m 2).
A very recent retrospective study by Vural et al. recruited 780 women who underwent IVF. Women with PCOS were excluded from the study. Women under and above 35 years were categorized into three groups as normal weight, overweight, and obese. The main outcome measures were ovarian response, oocyte maturity, and clinical PRs. Despite oocyte count and fertilization rate that decreased in both younger and older obese women, this difference was not statistically significant. In age-matched normal weight controls, the clinical PRs were significantly decreased in older obese women. On the other hand, poor ovarian response was observed significantly in young obese women without effect on PRs. These results suggested that obesity in young and old women has different outcomes and different steps of the IVF process may be affected.
PCOS is a common reproductive disorder that can be diagnosed when two of the following three criteria are present menstrual irregularity, hyperandrogenism, and polycystic ovaries. Factors such as the individual's body weight influence the severity of the phenotype and risk of metabolic comorbidities. While anovulatory infertility is a common issue among lean and obese reproductive-aged women with PCOS, obesity is associated with resistance to oral ovulation induction agents, lower PRs and a higher risk of pregnancy complications. Lifestyle modification is recommended as first-line therapy among obese women with PCOS to optimize their outcomes. Caloric restriction as well as bariatric surgery has been shown to promote sporadic ovulation in obese women with PCOS, but improvements have occurred across a wide range of patients and little has been garnered about the factors that distinguish responders from nonresponders.
Obesity alters oocyte morphology, reduces oocyte fertilization in some , but not all ,, studies and impairs embryo quality in women <35 years of age. These human findings support rodent studies, whereby diet-induced obesity induces follicle apoptosis, oxidative stress in cumulus-oocyte complexes, meiotic defects in oocytes with impaired fertilization, abnormal embryogenesis with reduced blastocyst survival, and abnormal fetal growth.,,, The decreased PR of obese IVF women using their own oocytes can be overcome with the use of donor oocytes, suggesting that oocyte quality rather than endometrial receptivity is the primary factor impairing IVF outcomes in obese women using autologous oocytes.,
The objective of a recent study was to assess the relationship between BMI and oocyte number and maturity in participants who underwent minimal stimulation (mini-IVF) or conventional IVF. Participants who underwent their first autologous cycle of either conventional (n = 219) or mini-IVF (n = 220) were divided according to their BMI to analyze IVF outcome parameters. The main outcome measure was the number of oocytes in metaphase II (MII). In conventional IVF, but not in mini-IVF, the number of total oocytes retrieved (14.5 ± 0.8 vs. 8.8 ± 1.3) and MII oocytes (11.2 ± 0.7 vs. 7.1 ± 1.1) were significantly lower in obese than normal BMI women. Multivariable linear regression adjusting for age, day 3 FSH, days of stimulation, and total gonadotropin dose revealed that BMI was an independent predictor of the number of MII oocytes in conventional IVF (P = 0.0004). In addition, only in conventional IVF, BMI was negatively correlated with the total number of 2PN oocytes, as well as the number of cleavage stage embryos. Zhang et al. concluded that female adiposity might impair oocyte number and maturity in conventional IVF but not in mini-IVF. Their data suggest that mild ovarian stimulation might yield healthier oocytes in obese women.
In IVF programs, the advantages of mild-stimulation have long been appreciated while there was a call for more patient-friendly approach in ovarian stimulation around 20 years ago. However, the concept is yet to get widespread acceptance in the IVF community. The main impediment has been a lack of robust outcome data that can assure the success of IVF Lite at least as good as those of conventional IVF. The randomized controlled trials that compared sequential CC and low-dose gonadotropins (as mild/minimal stimulation) with conventional long protocol were either small in sample size or heterogeneous in character. Nevertheless, recent meta-analyses and systematic reviews found no difference in PRs or LBRs between sequential CC-gonadotropin protocol (mild protocol) and conventional IVF protocols.,,
More recently, a prospective cohort of 163 good prognosis patients undergoing IVF with sequential CC and low-dose gonadotropin regimen reported a cumulative-LBR of 70% from a fresh and subsequent frozen ET up to 3 cycles.
A large retrospective cohort study of 20,244 cycles from Japan using a protocol comprising of extended CC (up to the trigger day) + gonadotropin and subsequent single vitrified-thaw ET found the treatment outcomes in all age-groups were comparable with those in the Registry of the Society for Assisted Reproduction in the USA.
Akpinar et al. set up a study to determine if BMI has an effect on the outcome ofIVF in patients with PCOS undergoing controlled ovarian hyperstimulation (COH). The study included 337 cycles. Patients were stratified into the three groups as follows: normal weight, overweight, and obese. The primary outcome measures were response to ovarian hyperstimulation, the fertilization rate, the implantation rate (IR), and the clinical and on-going PRs. Total gonadotropin consumption increased, and the number of retrieved oocytes decreased as the BMI increased. The IR and clinical PR were similar in all three groups. In response to the mid-luteal long protocol, the cycle cancellation rate was lower and the number of retrieved oocytes was higher in the overweight and obese groups, than the antagonist (ANT) protocol. The BMI did not affect the outcome of IVF in women with PCOS. Additional research is required to better understand the role of stimulation protocols on the cycle outcome.
The aim of a study by Bjelica et al. was to compare the efficacy of combinations of CC-metformin and letrozole-metformin in obese patients who are resistant to CC alone. The investigation was conducted as a retrospective study involving 60 moderately obese patients with PCOS. Thirty-one of them received the CC-metformin, and 29 letrozole-metformin therapy. Stimulation was carried out for the procedures of intrauterine insemination (IUI). The age of patients, duration of infertility, and BMI in both groups was similar. There was the statistically significant difference in the thickness of the endometrium for the group having the letrozole-metformin therapy (8.9 ± 1.7 mm) compared with the group receiving the CC-metformin treatment (6.3 ± 1.3 mm). The number of follicles was not statistically significantly different. PR in the first cycle of IUI in the CC group was 6.4%, and 17.2% in the letrozole group, which also was not statistically different. After the third IUI cycle, the PR was significantly higher in the letrozole group (20.6%), whereas in the CC group, it was (9.6%). This retrospective study demonstrated the advantages of the use of letrozole over CC in combination with metformin in moderately obese patients with PCOS who are resistant to stimulation with CC alone.
Rothberg et al. evaluated the feasibility of a brief, intensive weight loss intervention (IWL) to improve reproductive outcomes in obese subfertile women. Obese women (BMI, 35–45 kg/m 2) with anovulatory subfertility were randomized to IWL or standard-of-care nutrition counseling (SCN). IWL included 12 weeks of very-low-energy diet (800 kcal/day) +4 weeks of a low-calorie conventional food-based diet (CFD) to promote 15% weight loss. SCN included 16 weeks of CFD to promote ≥5% weight loss. Women were transitioned to weight maintenance diets and referred back to reproductive endocrinology for ovulation induction. Thirty-nine women were screened; 25 (64%) were eligible to participate, and 14 of those eligible (56%) agreed to be randomized, seven in each group. One withdrew from the IWL group and two from the SCN group. Percent weight loss was greater in the IWL group than in the SCN group (13% ±5% vs. 4% ±4%). Three of six women in the IWL group conceived and delivered term pregnancies. No pregnancies occurred in the SCN group. After rigorous screening, 44% of eligible women completed the study. IWL was associated with greater percentage weight loss and improvements in insulin sensitivity.
A study by Vural et al. explored the effects of overweight and obesity on IVF outcomes of poor ovarian responders (PORs). They retrospectively evaluated 188 POR undergoing IVF cycles. Patients were categorized into three groups: Group 1 was normal weight POR (18.5–24.9 kg/m 2, n = 96); Group 2 was overweight POR (25.0–29.9 kg/m 2, n = 52); and Group 3 was obese POR (≥30.0 kg/m 2, n = 40). Main measured outcomes included IVF outcomes. The oocyte maturity, total gonadotropin dose-duration, and cycle cancellation rates were similar. Obese women had significantly decreased luteinizing hormone (LH) levels. LH <4 mIU/mL had a sensitivity (62%) and a specificity (86%) for IVF failure (area under the curve: 0.71). Fertilization rates of obese subjects were significantly lower than normal and overweight subjects (P = 0.04). Obese women's clinicalPRs were significantly lower (15%) than normal weight women (33.3%, P= 0.01). Despite similar counts of recruited mature oocytes, obese POR women had decreased fertilization and clinical PRs. Obesity rather than overweight significantly decreased IVF outcomes in POR.
The aim of a study by Ozekinci et al. was to investigate the influence of BMI on the IVF treatment outcomes in a cohort of women undergoing their first IVF, using an ICSI. This retrospective cohort study included 298 cycles from women younger than 38 years old undergoing IVF-ICSI at a University infertility clinic. The treatment cycles were divided into three groups according to the BMI of the women involved: normal weight (18.5≤ BMI <25 kg/m 2, 164 cycles), overweight (25≤ BMI <30 kg/m 2, 70 cycles), and obese (BMI ≥30 kg/m 2, 64 cycles). The underweight women (BMI <18.5 kg/m 2) were not included in the analysis due to small sample size (n = 22). The patient characteristics and IVF-ICSI treatment outcomes were compared between the BMI groups. The total gonadotropin dose (P < 0.001) and duration of stimulation (P = 0.008) were significantly higher in the obese group than the normal BMI group. There were no significant differences across the BMI categories for the other IVF-ICSI cycle outcomes measured, including the number of retrieved oocytes, mature oocytes, embryos suitable for transfer, proportion of oocytes fertilized, and cycle cancellation rates (P > 0.05 for each). In addition, clinical pregnancy, spontaneous abortion, and the on-going PRs per transfer were found to be comparable between the normal weight, overweight, and obese women (P > 0.05 for each). Obese women might require a significantly higher dose of gonadotropins and longer stimulation durations, without greatly affecting the pregnancy outcomes.
Ovarian responsiveness to ovulation induction agents is essential for a successful clinical outcome in assisted reproductive technology (ART) cycles. Kilic et al. aimed to evaluate the accuracy of multinominal logistic models for the prediction of ovarian reserve and pregnancy in women undergoing ART cycles. 1970 patients who underwent ovarian stimulation for ART programs were evaluated. Patients were designated to ovarian response with BMI and age. When evaluating the factors affecting the egg quantity in poor responder and high responder patient groups according to the BMI, the authors observed that there was a lower probability of extracting less than five eggs in patients with a BMI of over 30 kg/m 2. The BMI was not an influential parameter for the amount of eggs obtained when comparing normo- and high-responder patient groups.
The aim of a recent study by Marci et al. was to assess the role of obesity in women undergoing COH stimulated either with gonadotropin-releasing hormone (GnRH) agonists or with GnRH ANTs. Records of 463 women undergoing IVF treatment were reviewed. The influence of BMI on treatment outcome was examined, after accounting for differences in stimulation protocols. In the agonist group (286 patients), the total amount of gonadotropins used was significantly higher in patients with a BMI ≥25 kg/m2, than those with a normal BMI. The same result was found in the ANT group (177 patients). No significant differences were found in length of stimulation, number of oocytes retrieved or number of embryos transferred. In both the ANT and the agonist group, the number of clinical pregnancies was found to be higher in patients with normal BMI, suggesting that obesity could impair the ovarian response to exogenous gonadotropins. Considering the results obtained and the many theoretical advantages of GnRH ANTs, ovarian stimulation with GnRH ANTs is an efficient treatment for both women with normal and high BMI.
A study by Kumbak et al. evaluated women with a high BMI (>40 kg/m 2) and low BMI (<18 kg/m 2) undergoing assisted reproduction treatment and determined whether the type of GnRH analog used has an impact on cycle parameters and outcome. The study analyzed 65 women with high BMI and 118 with low BMI. In the former group, PCOS was significantly more prevalent in the agonist long protocol (ALP) group (P = 0.01) and gonadotropin consumption was lower, peak estradiol concentrations, and total number of oocytes retrieved were higher in the ALP group compared with the ANT group. IR, PR per ET and early pregnancy loss rate (EPLR) were similar in both stimulation groups, with overall rates of 21.6%, 55.4%, and 44.4%, respectively. In women with low BMI, peak estradiol concentrations, total oocytes retrieved, mature oocytes, and transferred embryos were higher in the ALP group than ANT group. IR, PR/ET and EPLR were similar in both groups, with overall rates of 24.3%, 52.5%, and 16.1%, respectively. In all patients, no difference was found between ALP and ANT protocols concerning treatment outcome. Contrary to the reasonable EPLR observed in women with low BMI, the high rate found in women with high BMI is remarkable.
Oocyte donation is particularly interesting model for studying the extra-ovarian effects of weight, that is, independent of the response to stimulation and the oocyte quality because donated oocytes are transferred to the recipient's uterus after fertilization. Studies on this model suggest that weight has an impact on the endometrium and early embryonic development. In fact, the rate of successful pregnancies among recipients who are overweight or obese is significantly reduced compared to recipients of a normal weight. Obesity also appears to alter endometrial receptivity during IVF since third-party surrogate women with a BMI >35 kg/m 2 have a lower LBR (25%) than those with a BMI <35 kg/m 2 ( 49%, P< 0.05).
A “Mediterranean” style diet is also linked to a 40% increase in the chances of IVF/ICSI treatments being successful. Until now, the only medication approved for the long-term management of obesity has been orlistat., As a lipase inhibitor, orlistat interferes with hydrolysis of dietary fat into absorbable free 254 fatty acids, thereby decreasing fat absorption from the gut by approximately 30%., Orlistat (120 mg orally with meals) also decreases absorption of fat-soluble vitamins, primarily Vitamin D so that supplementation with a multivitamin containing Vitamin D, administered at least 2 h before or after orlistat ingestion, is recommended. Gastrointestinal side effects are common. Contraindications for the use of orlistat include chronic malabsorption syndromes and cholestasis. Metformin has been proposed as a weight loss medication. Metformin is a biguanide that inhibits hepatic glucose production and increases peripheral tissue sensitivity to insulin, resulting in reduced circulating insulin and androgen levels accompanied by decreased body weight and visceral fat., Metformin alone is not associated with weight loss; however, when metformin is combined with a low-calorie diet, weight loss has been demonstrated.
In 2011, over 340,000 bariatric surgical procedures were performed worldwide, with the United States/Canada performing the largest number of operations (over 100,000 cases). Common bariatric surgical procedures are either restrictive (i.e., sleeve gastrectomy [SG], laparoscopic adjustable gastric band [LAGB]) or combined restrictive/malabsorptive [Roux-en-Y gastric bypass, RYGB]). Restrictive procedures create a small gastric pouch with staples or a band that fills rapidly to induce early satiety. The RYGB creates a small stomach pouch and attaches it to a loop of jejunum to shorten the length of the intestinal tract, restricting food intake and causing malabsorption. Besides limiting energy intake and/or absorption, bariatric surgery also can alter food preference, insulin secretion, gut hormones, microbiology, and bile acid release., In 2011, the most commonly performed bariatric procedures worldwide were RYGB (47%), SG (28%), and LAGB (18%). More recently, laparoscopic SG has gained popularity over LAGB. The percentage of excess body weight lost at 2 years or more after bariatric surgery is 63%–49%, with obese individuals showing postoperative decreases in total body weight after 2, 10, 15, and 20 years of 23%, 17%, 16%, and 18%, respectively. Bariatric surgery in women can restore menstrual regularity,, correct ovulation,, shorten folliculogenesis in ovulatory cycles, reduce serum T levels, diminish percent body fat, and improve both sexual function  and the chance of pregnancy,, with weight loss predicting conception. Available evidence, although limited, suggests that IVF after bariatric surgery can be safe provided that special nutritional requirements after surgery are met. Of 5 women (BMI, 23–39 kg/m 2) undergoing IVF following bariatric surgery 1–5 years earlier, 4 women had term deliveries without complications related to previous surgery. One IVF patient remaining obese after previous bariatric surgery, however, experienced empty follicle syndrome at oocyte retrieval, perhaps from reduced intrafollicular human chorionic gonadotropin bioavailability.,
The RYGB leads to weight loss, improved insulin sensitivity and may improve ovarian function. In 31 premenopausal women, 18 eu- and 13 oligo-/amenorrhoic, Kjær et al. followed the changes in follicular phase sex hormones 3, 6, and 12 months after RYGB. The average weight loss during the 1st postoperative year was 39.6 kg. The insulin sensitivity and serum insulin improved markedly, especially within the first 3 postoperative months. SHBG increased progressively and was doubled after 12 months. In contrast, total and free androgens and DHEA declined about 50% during the first 3 postoperative months and remained fairly constant hereafter. One year after surgery, 85% (11/13) of the women with oligo-/amenorrhea gained regular menstrual cycles. The results indicated that some of the endocrine changes related to regulation of ovarian function occur very early after bariatric surgery.
Delaying pregnancy until 1–2 years after bariatric surgery has been recommended to avoid fetal exposure to nutritional deficiencies from rapid maternal weight loss,,, although limited data suggest that pregnancy within the 1st year after bariatric surgery may not necessarily increase the risk for adverse maternal or perinatal outcomes.,, Particularly in late reproductive years, the benefits of postponing pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age.
| Recent Advances|| |
Obese women exhibit decreased fertility, high miscarriage rates, and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. Bradford et al. hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (Chlorocebus aethiops) during weight gain. Ten months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (P = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7–9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells were up-regulated. Using integrated miRNA and gene expression analysis, Bradford et al. demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation, and survival. The observed HFHF diet-induced changes were consistent with the development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.
| Conclusions|| |
Obesity is a major public health concern, and obesity among women of childbearing age can have a negative impact on fertility. The mechanism of action between obesity and infertility is complex and includes hormonal factors, alterations in ovulation, and changes in the menstrual cycle. Maternal obesity has also been linked to spontaneous abortion and poorer maternal and fetal health outcomes. Many interventions exist to help childbearing women achieve a lower BMI. These include lifestyle modifications (diet/physical activity) and surgical and pharmacologic interventions. Obesity influences menstrual cycle and ovulation irregularities increases pregnancy complications and complication rates in ARTs in women. Weight loss through lifestyle changes or bariatric surgery has positive effects on hormonal parameters and fertility. The mechanisms by which excessive fat delays time to pregnancy appear rooted in ovulatory problems and direct effects on oocytes, causing poorer embryo development, as well as in effects on the endometrium. Weight loss in women has been shown to improve conception, but not necessarily LBRs following fertility treatment and further research in this area is needed.
| References|| |
Ramlau-Hansen CH, Thulstrup AM, Nohr EA, Bonde JP, Sørensen TI, Olsen J. Subfecundity in overweight and obese couples. Hum Reprod 2007;22:1634-7.
van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, et al.
Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum Reprod 2008;23:324-8.
Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril 2008;90:714-26.
McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, et al.
Obesity and sex steroid changes across puberty: Evidence for marked hyperandrogenemia in pre-and early pubertal obese girls. J Clin Endocrinol Metab 2007;92:430-6.
Pasquali R, Casimirri F, Platè L, Capelli M. Characterization of obese women with reduced sex hormone-binding globulin concentrations. Horm Metab Res 1990;22:303-6.
Agarwal SK, Vogel K, Weitsman SR, Magoffin DA. Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary. J Clin Endocrinol Metab 1999;84:1072-6.
Greisen S, Ledet T, Møller N, Jørgensen JO, Christiansen JS, Petersen K, et al.
Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells. Acta Obstet Gynecol Scand 2000;79:931-5.
Santoro N, Lasley B, McConnell D, Allsworth J, Crawford S, Gold EB, et al.
Body size and ethnicity are associated with menstrual cycle alterations in women in the early menopausal transition: The Study of Women's Health across the Nation (SWAN) Daily Hormone Study. J Clin Endocrinol Metab 2004;89:2622-31.
Grenman S, Rönnemaa T, Irjala K, Kaihola HL, Grönroos M. Sex steroid, gonadotropin, cortisol, and prolactin levels in healthy, massively obese women: Correlation with abdominal fat cell size and effect of weight reduction. J Clin Endocrinol Metab 1986;63:1257-61.
Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril 2002;77:91-7.
Mulders AG, Laven JS, Eijkemans MJ, Hughes EG, Fauser BC. Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A meta-analysis. Hum Reprod Update 2003;9:429-49.
Souter I, Baltagi LM, Kuleta D, Meeker JD, Petrozza JC. Women, weight, and fertility: The effect of body mass index on the outcome of superovulation/intrauterine insemination cycles. Fertil Steril 2011;95:1042-7.
Fedorcsák P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, et al.
Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod 2004;19:2523-8.
Shah DK, Missmer SA, Berry KF, Racowsky C, Ginsburg ES. Effect of obesity on oocyte and embryo quality in women undergoing in vitro
fertilization. Obstet Gynecol 2011;118:63-70.
Moragianni VA, Jones SM, Ryley DA. The effect of body mass index on the outcomes of first assisted reproductive technology cycles. Fertil Steril 2012;98:102-8.
Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: Retrospective study. BMJ 2000;321:1320-1.
Pinborg A, Gaarslev C, Hougaard CO, Nyboe Andersen A, Andersen PK, Boivin J, et al.
Influence of female bodyweight on IVF outcome: A longitudinal multicentre cohort study of 487 infertile couples. Reprod Biomed Online 2011;23:490-9.
Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to pregnancy. Hum Reprod 2007;22:414-20.
Zaadstra BM, Seidell JC, Van Noord PA, te Velde ER, Habbema JD, Vrieswijk B, et al.
Fat and female fecundity: Prospective study of effect of body fat distribution on conception rates. BMJ 1993;306:484-7.
Thum MY, El-Sheikhah A, Faris R, Parikh J, Wren M, Ogunyemi T, et al.
The influence of body mass index to in-vitro
fertilisation treatment outcome, risk of miscarriage and pregnancy outcome. J Obstet Gynaecol 2007;27:699-702.
Marci R, Lisi F, Soave I, Lo Monte G, Patella A, Caserta D, et al.
Ovarian stimulation in women with high and normal body mass index: GnRH agonist versus GnRH antagonist. Gynecol Endocrinol 2012;28:792-5.
Koning AM, Mutsaerts MA, Kuchenbecker WK, Broekmans FJ, Land JA, Mol BW, et al.
Complications and outcome of assisted reproduction technologies in overweight and obese women. Hum Reprod 2012;27:457-67.
Dokras A, Baredziak L, Blaine J, Syrop C, VanVoorhis BJ, Sparks A. Obstetric outcomes after in vitro
fertilization in obese and morbidly obese women. Obstet Gynecol 2006;108:61-9.
Rittenberg V, Seshadri S, Sunkara SK, Sobaleva S, Oteng-Ntim E, El-Toukhy T. Effect of body mass index on IVF treatment outcome: An updated systematic review and meta-analysis. Reprod Biomed Online 2011;23:421-39.
Petersen GL, Schmidt L, Pinborg A, Kamper-Jørgensen M. The influence of female and male body mass index on live births after assisted reproductive technology treatment: A nationwide register-based cohort study. Fertil Steril 2013;99:1654-62.
Vural F, Vural B, Çakiroglu Y.In vitro
fertilization outcomes in obese women under and above 35 years of age. Clin Exp Obstet Gynecol 2016;43:233-7.
Jarrett BY, Lujan ME. Impact of hypocaloric dietary intervention on ovulation in obese women with PCOS. Reproduction 2016. pii: REP-16-0385.
Depalo R, Garruti G, Totaro I, Panzarino M, Vacca MP, Giorgino F, et al.
Oocyte morphological abnormalities in overweight women undergoing in vitro
fertilization cycles. Gynecol Endocrinol 2011;27:880-4.
Zhang D, Zhu Y, Gao H, Zhou B, Zhang R, Wang T, et al.
Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro
fertilisation: A cohort study of 2628 Chinese women. Gynecol Endocrinol 2010;26:325-32.
Orvieto R, Meltcer S, Nahum R, Rabinson J, Anteby EY, Ashkenazi J. The influence of body mass index on in vitro
fertilization outcome. Int J Gynaecol Obstet 2009;104:53-5.
Metwally M, Cutting R, Tipton A, Skull J, Ledger WL, Li TC. Effect of increased body mass index on oocyte and embryo quality in IVF patients. Reprod Biomed Online 2007;15:532-8.
Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, et al.
High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology 2010;151:5438-45.
Minge CE, Bennett BD, Norman RJ, Robker RL. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality. Endocrinology 2008;149:2646-56.
Luzzo KM, Wang Q, Purcell SH, Chi M, Jimenez PT, Grindler N, et al.
High fat diet induced developmental defects in the mouse: Oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One 2012;7:e49217.
Jungheim ES, Schoeller EL, Marquard KL, Louden ED, Schaffer JE, Moley KH. Diet-induced obesity model: Abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology 2010;151:4039-46.
Luke B, Brown MB, Stern JE, Missmer SA, Fujimoto VY, Leach R; SART Writing Group. Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates. Hum Reprod 2011;26:245-52.
Jungheim ES, Schon SB, Schulte MB, DeUgarte DA, Fowler SA, Tuuli MG. IVF outcomes in obese donor oocyte recipients: A systematic review and meta-analysis. Hum Reprod 2013;28:2720-7.
Zhang JJ, Feret M, Chang L, Yang M, Merhi Z. Obesity adversely impacts the number and maturity of oocytes in conventional IVF not in minimal stimulation IVF. Gynecol Endocrinol 2015;31:409-13.
Ferraretti AP, Gianaroli L, Magli MC, Devroey P. Mild ovarian stimulation with clomiphene citrate launch is a realistic option for in vitro
fertilization. Fertil Steril 2015;104:333-8.
Kato K, Takehara Y, Segawa T, Kawachiya S, Okuno T, Kobayashi T, et al.
Minimal ovarian stimulation combined with elective single embryo transfer policy: Age-specific results of a large, single-centre, Japanese cohort. Reprod Biol Endocrinol 2012;10:35.
Akpinar F, Demir B, Dilbaz S, Kaplanoglu I, Dilbaz B. Obesity is not associated with the poor pregnancy outcome following intracytoplasmic sperm injection in women with polycystic ovary syndrome. J Turk Ger Gynecol Assoc 2014;15:144-8.
Bjelica A, Trninic-Pjevic A, Mladenovic-Segedi L, Cetkovic N, Petrovic D. Comparison of the efficiency of clomiphene citrate and letrozole in combination with metformin in moderately obese clomiphene citrate-resistant polycystic ovarian syndrome patients. Srp Arh Celok Lek 2016;144:146-50.
Rothberg A, Lanham M, Randolph J, Fowler C, Miller N, Smith Y. Feasibility of a brief, intensive weight loss intervention to improve reproductive outcomes in obese, subfertile women: A pilot study. Fertil Steril 2016;106:1212-20.
Vural F, Vural B, Çakiroglu Y. The role of overweight and obesity in in vitro
fertilization outcomes of poor ovarian responders. Biomed Res Int 2015;2015:781543.
Ozekinci M, Seven A, Olgan S, Sakinci M, Keskin U, Akar ME, et al.
Does obesity have detrimental effects on IVF treatment outcomes? BMC Womens Health 2015;15:61.
Kilic S, Yilmaz N, Zülfikaroglu E, Sarikaya E, Kose K, Topcu O, et al.
Obesity alters retrieved oocyte count and clinical pregnancy rates in high and poor responder women after in vitro
fertilization. Arch Gynecol Obstet 2010;282:89-96.
Kumbak B, Akbas H, Sahin L, Karlikaya G, Karagozoglu H, Kahraman S. Ovarian stimulation in women with high and low body mass index: GnRH agonist versus GnRH antagonist. Reprod Biomed Online 2010;20:314-9.
Bellver J, Melo MA, Bosch E, Serra V, Remohí J, Pellicer A. Obesity and poor reproductive outcome: The potential role of the endometrium. Fertil Steril 2007;88:446-51.
DeUgarte DA, DeUgarte CM, Sahakian V. Surrogate obesity negatively impacts pregnancy rates in third-party reproduction. Fertil Steril 2010;93:1008-10.
Vujkovic M, de Vries JH, Lindemans J, Macklon NS, van der Spek PJ, Steegers EA, et al.
The preconception Mediterranean dietary pattern in couples undergoing in vitro
fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy. Fertil Steril 2010;94:2096-101.
Colman E, Golden J, Roberts M, Egan A, Weaver J, Rosebraugh C. The FDA's assessment of two drugs for chronic weight management. N Engl J Med 2012;367:1577-9.
Hussain SS, Bloom SR. The pharmacological treatment and management of obesity. Postgrad Med 2011;123:34-44.
Keating GM, Jarvis B. Orlistat: In the prevention and treatment of type 2 diabetes mellitus. Drugs 2001;61:2107-19.
Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, et al.
Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85:2767-74.
Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dé chaud H, Pugeat M. Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab 1995;80:2057-62.
Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg 2013;23:427-36.
Devlieger R, Jans R, Lannoo M, Van der Schueren B, Mattyhs C. Transforming Reproductive Medicine Worldwide. Boston: Craftsman Printing, Inc.; 2013. p. 59-65.
Dixon JB, le Roux CW, Rubino F, Zimmet P. Bariatric surgery for type 2 diabetes. Lancet 2012;379:2300-11.
Vetter ML, Cardillo S, Rickels MR, Iqbal N. Narrative review: Effect of bariatric surgery on type 2 diabetes mellitus. Ann Intern Med 2009;150:94-103.
Nguyen NT, Nguyen B, Gebhart A, Hohmann S. Changes in the makeup of bariatric surgery: A national increase in use of laparoscopic sleeve gastrectomy. J Am Coll Surg 2013;216:252-7.
Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, et al.
Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56-65.
Zitsman JL, Digiorgi MF, Marr JR, Witt MA, Bessler M. Comparative outcomes of laparoscopic adjustable gastric banding in adolescents and adults. Surg Obes Relat Dis 2011;7:720-6.
Teitelman M, Grotegut CA, Williams NN, Lewis JD. The impact of bariatric surgery on menstrual patterns. Obes Surg 2006;16:1457-63.
Tan O, Carr BR. The impact of bariatric surgery on obesity-related infertility and in vitro
fertilization outcomes. Semin Reprod Med 2012;30:517-28.
Maggard MA, Yermilov I, Li Z, Maglione M, Newberry S, Suttorp M, et al.
Pregnancy and fertility following bariatric surgery: A systematic review. JAMA 2008;300:2286-96.
Legro RS, Dodson WC, Gnatuk CL, Estes SJ, Kunselman AR, Meadows JW, et al.
Effects of gastric bypass surgery on female reproductive function. J Clin Endocrinol Metab 2012;97:4540-8.
Marceau P, Kaufman D, Biron S, Hould FS, Lebel S, Marceau S, et al.
Outcome of pregnancies after biliopancreatic diversion. Obes Surg 2004;14:318-24.
Musella M, Milone M, Bellini M, Sosa Fernandez LM, Leongito M, Milone F. Effect of bariatric surgery on obesity-related infertility. Surg Obes Relat Dis 2012;8:445-9.
Doblado MA, Lewkowksi BM, Odem RR, Jungheim ES.In vitro
fertilization after bariatric surgery. Fertil Steril 2010;94:2812-4.
Hirshfeld-Cytron J, Kim HH. Empty follicle syndrome in the setting of dramatic weight loss after bariatric surgery: Case report and review of available literature. Fertil Steril 2008;90:1199.e21-3.
Dumesic DA, Lesnick TG, Abbott DH. Increased adiposity enhances intrafollicular estradiol levels in normoandrogenic ovulatory women receiving gonadotropin-releasing hormone analog/recombinant human follicle-stimulating hormone therapy for in vitro
fertilization. J Clin Endocrinol Metab 2007;92:1438-41.
Kjær MM, Madsbad S, Hougaard DM, Cohen AS, Nilas L. The impact of gastric bypass surgery on sex hormones and menstrual cycles in premenopausal women. Gynecol Endocrinol 2017;33:160-3.
Apovian CM, Baker C, Ludwig DS, Hoppin AG, Hsu G, Lenders C, et al.
Best practice guidelines in pediatric/adolescent weight loss surgery. Obes Res 2005;13:274-82.
Beard JH, Bell RL, Duffy AJ. Reproductive considerations and pregnancy after bariatric surgery: Current evidence and recommendations. Obes Surg 2008;18:1023-7.
Guelinckx I, Devlieger R, Vansant G. Reproductive outcome after bariatric surgery: A critical review. Hum Reprod Update 2009;15:189-201.
Sheiner E, Edri A, Balaban E, Levi I, Aricha-Tamir B. Pregnancy outcome of patients who conceive during or after the first year following bariatric surgery. Am J Obstet Gynecol 2011;204:50.e1-6.
Dixon JB, Dixon ME, O'Brien PE. Birth outcomes in obese women after laparoscopic adjustable gastric banding. Obstet Gynecol 2005;106 (5 Pt 1):965-72.
Patel JA, Patel NA, Thomas RL, Nelms JK, Colella JJ. Pregnancy outcomes after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis 2008;4:39-45.
Bradford AP, Jones K, Kechris K, Chosich J, Montague M, Warren WC, et al.
Joint MiRNA/mRNA expression profiling reveals changes consistent with development of dysfunctional corpus luteum after weight gain. PLoS One 2015;10:e0135163.
| Authors|| |
Gautam Nandkishore Allahbadia, MD is the Editor-in-Chief of the Journal of Obstetrics and Gynecology of India as well as the IVF Lite (Journal of Minimal Stimulation IVF). He is the Medical Director of Aster IVF and Women Clinic, Dubai, UAE as well as Rotunda - The Center for Human Reproduction, the world-renowned Infertility clinic at Bandra, Mumbai, India. He is a noted world authority on Ultrasound-guided Embryo Transfers and one of the pioneers in Third Party Reproduction in Southeast Asia. Dr. Allahbadia was responsible for India' s fi rst trans-ethnic Surrogate pregnancy involving a Chinese couple' s baby delivered by an unrelated Indian surrogate mother. He cherishes over 150 peer-reviewed publications, 134 book chapters and 22 textbooks, the latest being a comprehensive text, entitled “Minimal Stimulation IVF,” and is on the Editorial Board of several International Journals. Dr. Allahbadia has recently been elected as the Vice-President of the World Association of Reproductive Medicine (WARM), headquartered in Rome, and “Mumbai' s Top Doc” for 2012 by a peer nomination process. You can read more about his work at www.gautamallahbadia.com.