Exploring the biomarkers that predict successful outcomes in assisted reproduction
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting millions of women of reproductive age worldwide. It is one of the leading causes of infertility due to ovulation disorders 1 . On the other hand, tubal factor infertility, caused by blockage or damage to the fallopian tubes, also presents a significant challenge for many couples hoping to conceive.
Did you know? IVF has become a solution for such couples, but its effectiveness varies. Scientists are actively searching for biological markers that could help predict the success of the procedure.
Some of the most promising candidates are regulatory-transport proteins found in serum and follicular fluid. These proteins create the microenvironment necessary for oocyte maturation, fertilization, and embryo development. Understanding their role opens new avenues for personalized medicine and increases the chances of a long-awaited pregnancy.
To understand how proteins influence IVF success, let's explore the amazing world of the follicle—the structure in the ovary where the egg matures.
These specialized molecules perform two key functions:
Their concentration and balance in blood and follicular fluid serve as indicators of a woman's overall endocrine and metabolic health.
Follicular fluid (FF) is not just a medium. It's an extremely complex cocktail of substances secreted by ovarian cells and diffused from the blood.
It provides the egg with nutrition, oxygen, and protection, creating ideal conditions for its growth and maturation. The composition of FF directly affects oocyte quality and, consequently, subsequent embryo development .
The problem lies in oocyte quality. This syndrome is characterized by:
This inflammation and metabolic disorders dramatically alter the composition of follicular fluid, making it less favorable for egg development. Despite often retrieving many oocytes from PCOS patients, their quality is often poor, leading to low fertilization rates, implantation rates, and high miscarriage risk 2 .
The fallopian tubes are damaged or blocked, making natural conception impossible. However, ovarian reserve and oocyte quality may initially be normal.
Studying the protein profile in these patients helps determine whether their follicular microenvironment is optimal and whether it can compensate for other potential problems.
Research shows that in PCOS, the composition of follicular fluid and serum differs significantly from normal. These changes affect a wide range of proteins.
PCOS exhibits a state of chronic low-grade inflammation. Follicular fluid shows elevated levels of pro-inflammatory cytokines such as TNF-α (Tumor Necrosis Factor alpha) and IL-6 (Interleukin-6) . These molecules disrupt normal oocyte maturation processes and may interfere with embryo implantation.
| Molecule | Function | Level in PCOS | Impact on IVF |
|---|---|---|---|
| TNF-α | Pro-inflammatory cytokine | ↑ Increased | Reduces oocyte quality, disrupts implantation |
| IL-6 | Pro-inflammatory cytokine | ↑ Increased | Associated with insulin resistance, worsens follicular environment |
| Leptin | Hormone regulating energy metabolism | ↑ Increased | May negatively affect embryo development |
| AMH (Anti-Müllerian hormone) | Ovarian reserve marker | ↑ Increased | High levels associated with impaired oocyte maturation |
| Inhibin B | Regulation of FSH secretion | ↓ Decreased or ≈ | May indicate granulosa cell dysfunction |
| CRH (Corticotropin-releasing hormone) | Stress hormone | ↓ Decreased | Disrupts local hormonal balance |
Modern research, such as lipidomic and proteomic analysis, has revealed profound disturbances in lipid metabolism in the follicular fluid of PCOS patients. Abnormal accumulation of triacylglycerides (TAG), diacylglycerides (DAG) and some phospholipids is observed, while levels of lysophosphatidylcholines (LPC) and sphingomyelins (SM) are reduced . These lipids are critically important for building cell membranes and signaling. Their imbalance can disrupt the egg's energy metabolism and its ability to fertilize.
In PCOS, the synthesis and transport of sex hormones is impaired. Excess androgens negatively affect follicular development. Transport proteins, such as SHBG (Sex Hormone-Binding Globulin), play a key role in the availability of these hormones to tissues. Low serum SHBG levels—a common sign of PCOS—lead to an increased proportion of free, biologically active androgens, exacerbating the problem.
One of the most advanced and promising approaches to understanding PCOS is integrative analysis combining lipidomics and proteomics.
Researchers collect follicular fluid and granulosa cells from PCOS patients and control women during follicle puncture in IVF procedures.
Samples are cleaned and prepared for analysis on a mass spectrometer—an instrument that accurately identifies molecular composition and quantity.
The mass spectrometer identifies and measures hundreds of different lipids in follicular fluid.
The same method is used to determine the quantity and type of proteins in granulosa cells.
| Lipid Class | Example | Change in PCOS | Correlation with IVF Parameters |
|---|---|---|---|
| Triacylglycerol (TAG) | TAG(54:4) | ↑ Increased | Negative with embryo quality |
| Diacylglycerol (DAG) | DAG(18:1/18:2) | ↑ Increased | Positive with number of oocytes retrieved |
| Lysophosphatidylcholine (LPC) | LPC(18:2) | ↓ Decreased | Positive with number of mature oocytes (MII) |
| Sphingomyelin (SM) | SM(d14:0/23:1) | ↓ Decreased | Positive with number of mature oocytes (MII) |
| Biomolecule | PCOS | Tubal Factor Infertility | Potential Impact on IVF Outcome |
|---|---|---|---|
| SHBG | ↓ Decreased | ≈ Normal | Worsening oocyte quality in PCOS |
| AMH | ↑ Increased | ≈ Normal (age-dependent) | Disruption of dominant follicle selection |
| TNF-α | ↑ Increased | ≈ Normal (if no other inflammation) | Creating a pro-inflammatory follicular environment |
| Leptin | ↑ Increased (with obesity) | ≈ Normal (with normal BMI) | Disruption of oocyte energy metabolism |
| Inhibins | Altered | ≈ Normal | Imbalance in pituitary-ovarian axis regulation |
Modern research would be impossible without high-tech reagents and equipment.
| Tool/Reagent | Function | Application in Our Context |
|---|---|---|
| High-resolution mass spectrometer | Accurate determination of molecular mass and structure of substances | Analysis of lipid and protein composition of follicular fluid |
| Enzyme-linked immunosorbent assay (ELISA) | Quantitative determination of specific proteins/cytokines | Measuring levels of TNF-α, IL-6, leptin in FF samples |
| Monoclonal antibodies | Highly specific binding to target protein | Detection and purification of specific transport proteins (SHBG) |
| Bioinformatic databases and software | Integration, visualization and statistical analysis of big data | Finding relationships between lipid/protein levels and IVF outcome |
| DICHLORODIETHYLLEAD | 13231-90-8 | C4H10Cl2Pb |
| Vasicine hydriodide | 4966-84-1 | C11H13IN2O |
| Clostebol capronate | 32361-10-7 | C26H39ClO3 |
| L-alpha-Normethadol | 51733-60-9 | C20H27NO |
| Potassium linoleate | 3414-89-9 | C18H31KO2 |
Studying regulatory-transport proteins in serum and follicular fluid is not just an academic interest. It is a bridge to personalized reproductive medicine.
Understanding that the unique "protein-lipid fingerprint" of a PCOS patient significantly differs from that in tubal or other forms of infertility allows us to look at the problem in a new way. In the future, analysis of this profile may become routine practice before starting an IVF cycle. This will allow:
Better forecasting of individual chances of success
Detection of issues like chronic inflammation or specific metabolic disorders
Dietary adjustments or anti-inflammatory therapy to improve follicular environment
Thus, these proteins are not only markers but also potential therapeutic targets. Deep study of the molecular basis of PCOS and tubal infertility gradually brings us closer to the day when the diagnosis of "infertility" will sound less daunting, and treatment will become more effective and targeted, giving thousands of couples worldwide the chance to become parents.