Sign of oogenesis

The precursors of oocytes are the proliferating primordial germ cells (PGCs). They develop in fetal life and start the meiosis process that had been arrested in the diplotene stage of prophase I. The germinal vesicle (GV) stage lasts for several years in humans. The GV-arrested oocytes are surrounded by a single layer of flattened granulosa cells (GC) and compose the primordial follicles, usually formed during fetal life in primates (Hunt and Hassold, Reference Hunt and Hassold2008). Subsequently, GC proliferation and oocyte growth promote preantral follicle development, under the control of intraovarian factors, either activating or inhibitory. At this stage, GC express follicle-stimulating hormone (FSH) receptors that stimulate follicular growth and oestradiol (E2) production and control GC proliferation.

Preantral follicles are also reactive to the transforming growth factor (TGF) family and the androgens, insulin and insulin-like growth factor-1. A critical component is the formation of theca cell (TC) layers from the ovarian stroma, which provide follicles with luteinizing hormone receptors. Starting from cholesterol, LH coordinates the production of androgen that is converted to E2 in GC. Oestrogens also regulate FSH receptor activation and LH receptor expression in GC (Canipari et al., Reference Canipari, Cellini and Cecconi2012). During this growth phase, the oocyte secretes the zona pellucida (ZP) glycoproteic shell around the ooplasm, responsible for the interaction with sperm cells at the time of fertilization and critical for avoiding polyspermy and abnormal fertilization.

The pulsatile secretion of FSH stimulates the transition to the antral phase, identified by the presence of the antral cavity filled with follicular fluid (FF) and by the differentiation of the cells around the oocyte, the cumulus cells (CC), and mural GC lining the antrum. FSH is produced from a cohort of antral follicles, the follicle with the higher mitotic rate of GC and elevated E2 production becomes the dominant follicle, while the less mature follicles proceed to atresia. The preovulatory follicle containing the GV-arrested oocyte at this point is ready to respond to the LH surge that triggers meiotic maturation and ovulation (Rajkovic and Pangas, Reference Rajkovic and Pangas2017).

The process of meiotic resumption is a delicate and intricate one, which involve the cooperation between hormones and signalling pathways (Canipari et al., Reference Canipari, Cellini and Cecconi2012; Liu et al., Reference Liu, Zhang, Li, Liu, Wang, Zhang, Hao and Deng2019). The LH signal induces the activation of mitosis promoting factor (MPF) and mitogen-activated protein kinase (MAPK) signalling leading to the formation of the first meiotic spindle together with the extrusion of the first polar body (PBI), and the oocyte arrested at metaphase II (MII). At ovulation, the oocyte is released into the fallopian tube. After fertilization, the second meiosis will be completed by the extrusion of the second polar body and male and female pronuclei formation. The release of progesterone is essential to prepare the endometrium for implantation (Edson et al., Reference Edson, Nagaraja and Matzuk2009).

Obesity and inflammation

Adipose tissue is not only involved in energy storage but it is an endocrine organ that secretes numerous bioactive and chemical signals (Berg and Scherer, Reference Berg and Scherer2005). Accumulating evidence suggests that obesity is linked to a chronic low-grade inflammation state (Hotamisligil, Reference Hotamisligil2006). Increased lipid storage in adipose tissue and metabolic organs leads to cellular lipid toxicity, inflammation and oxidative stress (Snider and Wood, Reference Snider and Wood2019), which induces metabolic dysfunctions like type II diabetes and cardiovascular diseases (Wang YC et al., 2011; Finkelstein et al., Reference Finkelstein, Khavjou, Thompson, Trogdon, Pan, Sherry and Dietz2012). Chronic inflammation is associated with persistent and irregular chemokine and cytokine production (Snider and Wood, Reference Snider and Wood2019).

Chemokines are molecules with chemotactic activity directed at specific leukocytes populations. These compounds are released by stromal cells and endothelial cells, whereas their receptors are located on the leukocytes’ surface, allowing a specific targeting during immune responses (Shimizu et al., Reference Shimizu, Kaji, Murayama, Magata, Shirasuna, Wakamiya, Okuda and Miyamoto2011). Persistent inflammation induces changes in cell metabolism and microbiome modifications that can induce a de novo inflammatory response (Garn et al., Reference Garn, Bahn, Baune, Binder, Bisgaard, Chatila, Chavakis, Culmsee, Dannlowski, Gay, Gern, Haahtela, Kircher, Müller-Ladner, Neurath, Preissner, Reinhardt, Rook, Russell, Schmeck, Stappenbeck, Steinhoff, van Os, Weiss, Zemlin and Renz2016; Kuroda and Sakaue, Reference Kuroda and Sakaue2017). Low-grade chronic inflammation in adipose tissue has a pivotal role in obesity-related complications as insulin resistance, metabolic syndrome and type 2 diabetes (Kuroda and Sakaue, Reference Kuroda and Sakaue2017). In the context of obesity, adipocyte hypertrophy results from the storage of increased circulating triglycerides (Engin, Reference Engin2017).

Macrophages are recognized as a centre of inflammatory response in obesity, producing cytokines and chemokines (Cinti et al., Reference Cinti, Mitchell, Barbatelli, Murano, Ceresi, Faloia, Wang, Fortier, Greenberg and Obin2005). Furthermore, macrophage infiltration into adipose tissue is enhanced by obesity (Xu et al., Reference Xu, Barnes, Yang, Tan, Yang, Chou, Sole, Nichols, Ross, Tartaglia and Chen2003; Ouchi et al., Reference Ouchi, Parker, Lugus and Walsh2011; Kuroda and Sakaue, Reference Kuroda and Sakaue2017). Notably, cytokines and adipokines released into the bloodstream might promote an inflammatory response in other organs, including the ovary (Ouchi et al., Reference Ouchi, Parker, Lugus and Walsh2011; Wang and Huang, Reference Wang and Huang2015; Xie et al., Reference Xie, Anderson, Timme, Kurz, Fernando and Wood2016). Due to the interdependence of inflammation and oxidative stress, it is not surprising that obesity is a state of chronic oxidative stress, producing ROS and overcoming the antioxidant system (Piya et al., Reference Piya, McTernan and Kumar2013; Rimessi et al., Reference Rimessi, Previati, Nigro, Wieckowski and Pinton2016).

Investigators have identified a symbiotic relationship between different anatomical sites, including skin, colon and vagina, with local bacteria changes (Cho and Blaser, Reference Cho and Blaser2012; Belizário et al., Reference Belizário, Belizário and Napolitano2015). In the gut, there is a symbiotic relationship between its microbiome, the intestinal epithelia, immune system and inflammatory responses. Gut dysbiosis can be identified in obese patients, with an increased ratio of two bacteria families: Firmicutes and Bacteroidetes (Ley et al., Reference Ley, Bäckhed, Turnbaugh, Lozupone, Knight and Gordon2005; Turnbaugh et al., Reference Turnbaugh, Ley, Mahowald, Magrini, Mardis and Gordon2006; Riva et al., Reference Riva, Borgo, Lassandro, Verduci, Morace, Borghi and Berry2017).

This change induces a loss of tight junctions among cells with increased epithelial permeability (Saad et al., 2006) and leakage of lipopolysaccharides (LPS), resulting in low-level endotoxemia and induction of systemic inflammation (Figure 1). Increased fatty acid and LPS in the blood circulation, associated with gut microbiome changes and high caloric diet, have been described by several authors (Ley et al., Reference Ley, Bäckhed, Turnbaugh, Lozupone, Knight and Gordon2005; Saad et al., 2006; Turnbaugh et al., Reference Turnbaugh, Ley, Mahowald, Magrini, Mardis and Gordon2006; Cani et al., Reference Cani, Amar, Iglesias, Poggi, Knauf, Bastelica, Neyrinck, Fava, Tuohy, Chabo, Waget, Delmée, Cousin, Sulpice, Chamontin, Ferrières, Tanti, Gibson, Casteilla, Delzenne, Alessi and Burcelin2007; Cox and Blaser, Reference Cox and Blaser2013). Together, these studies have established the now well accepted paradigm that obesity is a chronic condition characterized by low-grade inflammation, oxidative stress and increased gut permeability.

Figure 1. Illustrates how changes in the gut microbiota following oxidative stress and inflammation impair oocyte competency. LPS, lipopolysaccharide; ROS, reactive oxygen species.

Cytokine and chemokine signalling in the ovary

As previously discussed, the process of folliculogenesis starts with the recruitment of primordial follicles, progressing through the proliferation of granulosa and thecal cells, oocyte maturation, steroidogenesis and ovulation (Richards et al., 1988; McLaughlin and McIver, Reference McLaughlin and McIver2009). Each stage involves paracrine and endocrine environmental dialogue between the oocyte and somatic cell layers, mediated mainly by a vast ensemble of hormones and cytokines (Pasquali and Gambineri, Reference Pasquali and Gambineri2006), critical for producing a mature, competent oocyte (Eppig, Reference Eppig1985; Richards and Hedin, Reference Richards and Hedin1988; Buccione et al., Reference Buccione, Schroeder and Eppig1990; Oktay et al., Reference Oktay, Karlikaya, Akman, Ojakian and Oktay2000).

Cytokines are key regulators of ovarian physiology, contributing to creating an appropriate environment for follicle selection and growth (Field et al., Reference Field, Dasgupta, Cummings and Orsi2014). They support resident and infiltrating leukocytes to process a complex spectrum of signals resulting from direct-cell contact with their environment (Połeć et al., Reference Połeć, Ráki, Åbyholm, Tanbo and Fedorcsák2011). Therefore, leukocytes are the most relevant cytokine producers in the ovary, although ovarian somatic cells, including stromal, luteal, granulosa and thecal cells, are also an important source of those compounds (Gilchrist et al., Reference Gilchrist, Rowe, Ritter, Robertson, Norman and Armstrong2000).

Evidence suggests that primordial-to-primary follicle transition is mediated by pre-GC, surrounding oocyte in primordial follicles. Pre-GC action in animal models is mediated by a range of cytokines, such as stem cell factor, fibroblast growth factor (FGF-2) and leukaemia-inhibitor factor (LIF) (Nilsson and Skinner, Reference Nilsson and Skinner2004; Wang and Roy, Reference Wang and Roy2004). During the follicular phase, activated T-lymphocytes, macrophages, monocytes and neutrophils can be found in the theca layer (Wu et al., Reference Wu, Fujii, Sini, Van der Hoek, Jasper, Ryan, Robker, Robertson and Norman2006). Granulocyte–macrophage colony-stimulating factors (GM-CSF) increase preantral follicle progression, and decrease granulosa cell proliferation and oestradiol (E2) and progesterone (P4) synthesis (Wang and Roy, Reference Wang and Roy2004; Zhang et al., Reference Zhang, Fang and Wang2008). Interleukin-8 (IL-8) stimulates follicular progression from preantral to preovulatory stage, inhibits E2 synthesis by GC and increases P4 production by theca and GC (Shimizu et al., Reference Shimizu, Imamura, Magata, Murayama and Miyamoto2013).

These mechanisms regulate cumulus expansion and ovulation as well as participate in the luteinization process following the LH surge (Brännström and Enskog, Reference Brännström and Enskog2002; Jang et al., Reference Jang, Park, Moon, Dam, Cho and Chun2015). As cytokines mediate folliculogenesis, it is reasonable to investigate their potential role as biomarkers and assess their diagnostic and prognostic value in MAR treatments, considering that morphological evaluation is still the main method of assessment for oocyte maturity, despite evidence of a highly subjective intraoperator variation (Rienzi et al., Reference Rienzi, Vajta and Ubaldi2011). As an example, Jasper and collaborators (Reference Jasper, Robertson, Van der Hoek, Bonello, Brännström and Norman2000) identified a specific role for GM-CSF in the development of the corpus luteum.

This biochemical finding correlated well with clinical evidence of women undergoing ovarian hyperstimulation, who presented significantly increased plasma and follicular GM-CSF levels compared with non-stimulated patients (Jasper et al., Reference Jasper, Robertson, Van der Hoek, Bonello, Brännström and Norman2000). Yanagi and co-workers showed a positive correlation between FF granulocyte colony-stimulating factor (G-CSF) concentration and oocyte quality and maturity, and used by others to predict live birth (Yanagi et al., Reference Yanagi, Makinoda, Fujii, Miyazaki, Fujita, Tomizawa, Yoshida, Iura, Takegami and Nojima2002). Similar results have been reported by others investigating macrophage-stimulating factor (M-CSF) (Salmassi et al., Reference Salmassi, Mettler, Jonat, Buck, Koch and Schmutzler2010). Finally, analyzing the cytokine profiles of the FF at the time of oocyte retrieval might offer a useful and non-invasive analytical strategy for assessing the development potential of the oocyte and the embryo (Field et al., Reference Field, Dasgupta, Cummings and Orsi2014).

Obesity ovarian function and oocyte competency

It has been established that high lipid content negatively impacts ovarian function and oocyte competence (Douchi et al., Reference Douchi, Kuwahata, Yamamoto, Oki, Yamasaki and Nagata2002). In this vein, obesity is associated with irregular menses, anovulatory cycles and polycystic ovarian syndrome (Rich-Edwards et al., Reference Rich-Edwards, Goldman, Willett, Hunter, Stampfer, Colditz and Manson1994). It has been reported that women with a high BMI are three times more likely to be infertile compared with women with a normal weight (Rich-Edwards et al., Reference Rich-Edwards, Goldman, Willett, Hunter, Stampfer, Colditz and Manson1994; Douchi et al., Reference Douchi, Kuwahata, Yamamoto, Oki, Yamasaki and Nagata2002; Metwally et al., Reference Metwally, Cutting, Tipton, Skull, Ledger and Li2007).

A linear association between BMI and increased need for gonadotropin stimulation, lower serum oestradiol concentration on the day of HCG administration, lower cumulus–oocyte complexes retrieved, and poorer quality blastocysts describe the average profile of obese women facing MAR treatment (Metwally et al., Reference Metwally, Cutting, Tipton, Skull, Ledger and Li2007; Minge et al., Reference Minge, Bennett, Norman, Norman and Robker2008). Obesity compromises follicle growth and development mostly due to a depletion of the primordial follicle pool, advancement of follicles to antral stage, and an increase in atretic follicles number (Minge et al., Reference Minge, Bennett, Norman, Norman and Robker2008; Wu et al., Reference Wu, Russell, Wong, Chen, Tsai, St John, Norman, Febbraio, Carroll and Robker2015; De Araújo et al., Reference De Araújo, Podratz, Sena, Merlo, Freitas-Lima, Ayub, Pereira, Santos-Silva, Miranda-Alves, Silva and Graceli2018). The adverse effects of maternal obesity on fertilization and preimplantation embryo development are probably multifactorial and initiate in the ovary at the follicular phase of the developing oocyte. However, mechanisms by which obesity interferes with the reproductive system are still debated.

Robker and colleagues found a higher level of triglycerides in FF in obese women. They noted that a high concentration of fatty acids within the bloodstream increases the ovary’s insulin levels at the follicular level and the oocyte surrounding the CC, compromising ovarian function (Robker et al., Reference Robker, Akison, Bennett, Thrupp, Chura, Russell, Lane and Norman2009). Moreover, insulin-like growth factor-1, transforming growth factor-beta, insulin and LH are involved in higher leptin levels in the follicles, which may inhibit ovarian granulosa and thecal cell steroidogenesis. Therefore, data have suggested that the obesity-dependent reduction in the number of primordial follicles and augmentation in the number of antral and atretic follicles leads to a reduction in the ovarian reserve, contributing to subfertility (Valckx et al., Reference Valckx, Arias-Alvarez, De Pauw, Fievez, Vlaeminck, Fransen, Bols and Leroy2014; Wang N et al., 2014).

O’Gorman and collaborators used the FF lipid profile as a predictor of oocyte quality. They compared the fatty acid composition from FFs to which oocytes were fertilized and developed to embryos with those fluids in which oocytes after fertilization could not cleave, and were arrested at the zygote stage. Nine fatty acids were significantly different between FF from the cleaved and the non-cleaved sample (O’Gorman et al., Reference O’Gorman, Wallace, Cottell, Gibney, McAuliffe, Wingfield and Brennan2013). When the oocyte reaches the end of the growth phase in the follicle, it acquires the ability to resume meiosis (Canipari et al., Reference Canipari, Cellini and Cecconi2012). It is also important that the oocyte achieves cytoplasmic maturation with the right amount of mitochondria supporting the energy requirement at the early stage of embryo development.

Together with nuclear maturation, this condition makes the oocyte competent for fertilization and embryo development, implantation and the resulting in pregnancy to term (Mao et al., Reference Mao, Lou, Lou, Wang and Jin2014). Moreover, meiotic maturation necessitates the resumption of meiosis, spindle formation and correct chromosomes migration, which relies on the GV breakdown, progression from prophase I to metaphase II and extrusion of the first polar body. Errors at this stage of maturation might lead to spindle alteration and abnormalities in chromosome segregation, resulting in embryo aneuploidies, implantation failure and miscarriage (Turner and Robker, Reference Turner and Robker2015). Several animal studies have reported that maternal obesity negatively affects oocyte function leading to defective mitochondria heritage.

For instance, diet-induced maternal obesity mice have revealed a decrease in oocyte quantity and quality, as indicated by disrupted meiotic spindle morphology and oxidative stress, leading to poor oocyte fertilization and embryo aneuploidy (Zhang et al., Reference Zhang, Han, Ma, Hou, Yu, Sun, Xu, Schedl, Moley and Wang2015; Hou et al., Reference Hou, Zhu, Duan, Liu, Wang and Sun2016; Wang H et al., 2018). Therefore, it is essential to improve weight loss through a periconceptional lifestyle, with a low energy diet and exercise in obese women. It has been demonstrated that even a modest weight loss of 10% in obese women might be effective in improving hormonal profiles, menstrual regulatory, ovulation and pregnancy rates following IVF/ICSI cycles (Norman et al., Reference Norman, Noakes, Wu, Davies, Moran and Wang2004; Rondanelli et al., Reference Rondanelli, Perna, Faliva, Monteferrario, Repaci and Allieri2014).

Mitochondrial dysfunction: potential implication of gut microbiome in infertility

As pointed out earlier, obesity is characterized by the accumulation of intracellular lipid, including LPS, triglycerides, cholesterol and free fatty acids in the blood circulation and ovarian cells. Elevated lipid content might modify the functionality of several cellular organelles, including the endoplasmic reticulum (ER) and mitochondria (Borradaile et al., Reference Borradaile, Han, Harp, Gale, Ory and Schaffer2006). Abnormal ER function or oxidative stress might lead to a change in protein secretion pathways (Ozcan and Tabas, Reference Ozcan and Tabas2012). At the same time, calcium released from the ER modifies mitochondrial membrane potential inducing uncoupling of oxidative phosphorylation, producing ROS and reactive lipid peroxides.

All these mechanisms that generate oxidative stress and apoptosis are not only cytotoxic but might cause damage to mitochondrial function (Malhotra and Kaufman, Reference Malhotra and Kaufman2007; Vannuvel et al., Reference Vannuvel, Renard, Raes and Arnould2013). Mitochondria are fundamental for oocyte maturation and embryo development to the blastocyst stage (Igosheva et al., Reference Igosheva, Abramov, Poston, Eckert, Fleming, Duchen and McConnell2010; Van Blerkom, Reference Van Blerkom2011; Babayev and Seli, Reference Babayev and Seli2015). In oocytes, their crucial role involves the process of oxidative phosphorylation and energy production (ATP), vital for the meiotic completion and spindle formation. This represents a compelling concern; therefore, a high level of embryos generated by MAR treatments display several abnormal chromosomes, most of them are due to a high frequency of chromosome mis-segregation in oocytes that generate aneuploid in oocytes and embryos (Wang S et al., 2019; Wang S et al., Reference Wang, Liu, Shang, Liu, Zhai, Yang and Zhang2021).

Although maternal age is considered one of the main factors responsible for human embryo aneuploidy, it needs to be considered that this question also involves young women. During meiosis maturation, a necessary process occurs, i.e. crossover (CO) recombination, which is imperative to assure genetic variety in the future generation. Faulty or atypical CO arrangements due to several elements, including the kinetochore, spindle formation, checkpoints, energy affluence, oxidative stress, BMI and age might play a crucial role in the correct process of chromosome segregation. Therefore, abnormal CO configuration might lead to mis-segregation, which is the primary cause of embryo aneuploidy, implantation failure and miscarriage (Hunter, Reference Hunter2015; Wang S et al., 2019; Wang S et al., Reference Wang, Liu, Shang, Liu, Zhai, Yang and Zhang2021).

Those findings are reinforced by animal studies demonstrating that oocytes collected from diet-induced obese mice have weakened quality and decreased embryo development (Minge et al., Reference Minge, Bennett, Norman, Norman and Robker2008; Pohlmeier et al., Reference Pohlmeier, Xie, Kurz, Lu and Wood2014). Table 1 illustrates the major effects that obesity might have on oocyte maturation. Recent studies have suggested the important role of the gut microbiome in influencing female subfertility and infertility. Several authors have illustrated the association of PCOS with decreased diversity of the gut microbiome (Lindheim et al., Reference Lindheim, Bashir, Münzker, Trummer, Zachhuber, Leber, Horvath, Pieber, Gorkiewicz, Stadlbauer and Obermayer-Pietsch2017; Liu et al., Reference Liu, Zhang, Shi, Zhang, Li, Wang, Ling, Fu, Dong, Shen, Reeves, Greenberg, Zhao, Peng and Ding2017; Insenser et al., Reference Insenser, Murri, Del Campo, Martínez-García, Fernández-Durán and Escobar-Morreale2018). Furthermore, Elgaart and colleagues reported in Drosophila melanogaster that the loss of gut microbes repressed oogenesis (Elgart et al., Reference Elgart, Stern, Salton, Gnainsky, Heifetz and Soen2016). Figure 1 shows the mechanism by which changes in the gut microbiome might affect infertility.

Table 1. Obesity negatively impacts both meiotic and cytoplasmic maturation of the oocyte

Although future investigations need to evaluate these preliminary results further, it however seems that inflammation and oxidative stress processes might impair ovary function and oocyte competency, through which the change in gut permeability increased the leakage of LPS. The increased concentration of LPS in the blood circulation once reaching the FF might arrest the meiotic resumption, damage the spindle structure and mitochondrial membrane potential, compromising oocyte competency (Magata and Shimizu, Reference Magata and Shimizu2017). However, studies showing a causative effect of gut microbiome changes on obesity-dependent changes in the ovary are still required.

Therefore, it might be common that obese women might experience abnormalities in folliculogenesis and ovulation, which can be overcome by controlled ovarian stimulation (Pohlmeier et al., Reference Pohlmeier, Xie, Kurz, Lu and Wood2014). Oocyte quality and embryo development, implantation and pregnancy outcomes are deeply influenced by endocrine and metabolic environment (Pasquali and Gambineri, Reference Pasquali and Gambineri2006). Evidence has suggested that obese women are three times more likely to be infertile compared with women with a normal weight (Rich-Edwards et al., Reference Rich-Edwards, Goldman, Willett, Hunter, Stampfer, Colditz and Manson1994). Finally, multiple studies have reported that obese women undergoing MAR treatments have decreased pregnancy and implantation rates and show higher miscarriage rates compares with their lean counterparts (Rich-Edwards et al., Reference Rich-Edwards, Goldman, Willett, Hunter, Stampfer, Colditz and Manson1994; Douchi et al., Reference Douchi, Kuwahata, Yamamoto, Oki, Yamasaki and Nagata2002; Kumbak et al., Reference Kumbak, Oral and Bukulmez2012; Kawwass et al., Reference Kawwass, Kulkarni, Hipp, Crawford, Kissin and Jamieson2016).

Obese women: miscarriage and endometrial receptivity

Several authors have investigated the relationship between obesity and impaired endometrium receptivity in humans. Boots and Stephenson (Reference Boots and Stephenson2011), in a systematic review and meta-analysis, investigated this aspect in natural conception. Data were analyzed and compared in three groups: normal-weight, overweight and obese patients. The authors found a higher miscarriage rate of 13.6% in 3800 obese versus 10.7% in 17,146 normal-weight patients, concluding that high BMI is linked with a higher miscarriage rate in women who conceive naturally (Boots and Stephenson, Reference Boots and Stephenson2011). However, many studies have used the oocyte-donation model to clinically investigate this concern with generally contradictory results (Bellver et al., Reference Bellver, Rossal, Bosch, Zúñiga, Corona, Meléndez, Gómez, Simón, Remohí and Pellicer2003, Reference Bellver, Melo, Bosch, Serra, Remohí and Pellicer2007, Reference Bellver, Pellicer, García-Velasco, Ballesteros, Remohí and Meseguer2013; Wattanakumtornkul et al., Reference Wattanakumtornkul, Damario, Stevens Hall, Thornhill and Tummon2003; Styne-Gross et al., Reference Styne-Gross, Elkind-Hirsch and Scott2005; DeUgarte et al., Reference DeUgarte, DeUgarte and Sahakian2010).

A 2003 study investigated ∼700 oocyte-donation cycles and found no differences in implantation or pregnancy rates in obese recipients. However, results revealed a significant difference in abortion rates between the obese (38.1%), the normal (13.3%) and overweight (15.5%) groups, even if the sample included only 50 patients in the obese group (Bellver et al., Reference Bellver, Rossal, Bosch, Zúñiga, Corona, Meléndez, Gómez, Simón, Remohí and Pellicer2003). In a subsequent analysis, the authors investigated more than 2600 patients who were undergoing a first egg-donation cycle, including 122 obese recipients. They reported a trend towards lower pregnancy rate when BMI increased (38.3% versus 45.5%) (Bellver et al., Reference Bellver, Melo, Bosch, Serra, Remohí and Pellicer2007). In 2013, in a subsequent analysis including more than 9000 first egg-donation cycles with oocytes donated by normoweight donors, the same group reported a significant reduction in implantation, pregnancy and clinical pregnancy according to the increased BMI (Bellver et al., Reference Bellver, Pellicer, García-Velasco, Ballesteros, Remohí and Meseguer2013).

A study by Desolle and collaborators observed a statistically significant decrease in pregnancy rates when obese recipients received frozen embryos from donated oocytes (Dessolle et al., Reference Dessolle, Daraï, Cornet, Rouzier, Coutant, Mandelbaum and Antoine2009). Although this study was relatively small, with 450 cycles and only 33 obese patients, the authors speculated that obesity could be considered an independent risk factor for pregnancy failure. Another systematic review and meta-analysis including almost 48,000 cycles noted that obese women resulted in significantly lower clinical pregnancy and live birth rates than patients with normal BMI (Rittenberg et al., Reference Rittenberg, Seshadri, Sunkara, Sobaleva, Oteng-Ntim and El-Toukhy2011). A recent study also investigated the effect of BMI and increase risk of miscarriage following the transfer of euploid blastocysts in almost 3500 cycles of in vitro fertilization with preimplantation genetic testing for aneuploidy (PGT-A).

The authors found that miscarriage rates were significantly higher in obese women compared with women with normal weight. Live birth rates were also reduced in obese patients, indicating that endometrial receptivity, rather than aneuploidy, is responsible for these results (Cozzolino et al., Reference Cozzolino, García-Velasco, Meseguer, Pellicer and Bellver2021). Therefore, according to these reports, there is agreement between BMI and adverse pregnancy outcome and excess weight induces an extra ovarian detrimental effect that decreased uterine receptivity and live birth rates (Wang JX et al., 2002; Bellver et al., Reference Bellver, Melo, Bosch, Serra, Remohí and Pellicer2007; DeUgarte et al., Reference DeUgarte, DeUgarte and Sahakian2010; Sobaleva and El-Toukhy, Reference Sobaleva and El-Toukhy2011; Aydogan Mathyk et al., 2021). However, some other studies have presented divergent results (Styne-Gross et al., Reference Styne-Gross, Elkind-Hirsch and Scott2005; Levens and Skarulis, Reference Levens and Skarulis2008; McClamrock, Reference McClamrock2008; Norman et al., Reference Norman, Chura and Robker2008). A meta-analysis published by Metwally and co-workers reported no evidence for increased risk of miscarriage in obese patients undergoing IVF cycles (Metwally et al., Reference Metwally, Ong, Ledger and Li2008).

A large study using the Latin American Registry of ART investigated the effect of obesity on pregnancy outcomes in more than 107,000 patients undergoing autologous IVF/ICSI treatments. It noted that BMI was not associated with the percentage of pregnancy, live birth and miscarriage (MacKenna et al., Reference Mackenna, Schwarze, Crosby and Zegers-Hochschild2017). Similar findings were described in a systematic review published by Jungheim and co-workers, indicating that obesity has no adverse effect on IVF outcomes in patients undergoing oocyte-donation programmes (Jungheim et al., Reference Jungheim, Schoeller, Marquard, Louden, Schaffer and Moley2010).

A multicentre randomized study, published by Einarsson and colleagues in 2017, demonstrated that an intensive weight reduction programme prior to IVF treatment resulted in a substantial weight loss, but it did not increase live birth rates in moderately obese women scheduled for MAR treatments, compared with women undergoing IVF without weight loss (Einarsson et al., Reference Einarsson, Bergh, Friberg, Pinborg, Klajnbard, Karlström, Kluge, Larsson, Loft, Mikkelsen-Englund, Stenlöf, Wistrand and Thurin-Kjellberg2017). However, the frequency of live births after spontaneous pregnancy was higher in the weight reduction group. The same authors in a subsequent follow-up trial published in 2019 showed that, for women with a BMI ≥ 30 and < 35 kg/m² and scheduled for IVF, the weight reduction did not increase their chance of a live birth. It needs to be mentioned that all data reported in this trial were self-reported by the participants, which could affect the results (Kluge et al., Reference Kluge, Bergh, Einarsson, Pinborg, Mikkelsen Englund and Thurin-Kjellberg2019).

Another recent randomized, double-blinded study performed across 19 IVF units in China analyzed 877 infertile women scheduled for IVF who had a BMI ≥ 25 kg/m². The main aim of this paper was to investigate whether pharmacologic weight-loss intervention before MAR cycles could obtain an increase in live birth rate among overweight or obese women. Results showed that the live birth rate was not significantly different between the two groups (25.5% in the weight-loss group versus 25.6% in the groups without weight reduction), concluding that treating obese women with Orlistat, prior to IVF treatment induces a weight reduction, however, it did not increase the live birth rate among overweight patients (Wang Z et al., Reference Wang, Zhao, Ma, Sun, Hao, Yang, Ren, Jin, Lu, Wu, Ling, Hao, Zhang, Liu, Yang, Zhu, Li, Bao, Wang, Liu, Chen, Tan and Shi2021).

Furthermore, some authors have recently investigated gene expression profiles to identify whether the luteal phase endometrial transcriptome is altered in obese women during the window of implantation. Preliminary results, which need to be confirmed, have shown that during the window of implantation, obese women display endometrial dysregulation and a different gene expression compared with normal-weight control women (Bellver et al., Reference Bellver, Martínez-Conejero, Labarta, Alamà, Melo, Remohí, Pellicer and Horcajadas2011; Metwally et al., Reference Metwally, Preece, Thomas, Ledger and Li2014).

Finally, the transcriptomic profile of endometrial genes in infertile obese women has been reported and results demonstrated that obesity is associated with significant endometrial transcriptomic differences compared with normal-weight patients. This variation in obese women might partially explain decreased implantation rates and a rise in the number of miscarriages observed in obese women undergoing MAR treatments (Comstock et al., Reference Comstock, Diaz-Gimeno, Cabanillas, Bellver, Sebastian-Leon, Shah, Schutt, Valdes, Ruiz-Alonso, Valbuena, Simon and Lathi2017).