Scientists Find a Way To Reverse Infertility

Currently, one in every five women of childbearing age in the US are unable to get pregnant after trying for a year. Dr. Corina Rosales and her teams at Houston Methodist Hospital and Weill Cornell Medicine found a way to reverse infertility by reducing the concentration of plasma high-density lipoproteins (HDLs) in a sterile mouse model. This work was published in the Journal of Lipid Research.

Reversing infertility by targeting HDLs

The mechanisms by which HDLs affect fertility still remain unclear, but it is known that ovaries are studded with receptors for HDL, indicating that HDLs must play some role in female fertility. Additionally, abnormalities in HDL metabolism and high concentrations of HDLs have been shown to reduce female fertility. The functionality of HDLs are impacted by modifications made by external proteins and factors, such as bacterial serum opacity factor (SOF). SOF alters the structure of HDLs such that it is easier for the liver to dispose of excess cholesterol that may be preventing conception. Additionally, SOF can reduce plasma HDL concentrations, thereby suggesting its potential in restoring female fertility by targeting HDLs. Rosales et al. wanted to determine if constitutively expressing SOF via an adeno-associated virus (AAV_SOF) would rescue fertility in Scarb1^-/- mice, which are considered infertile due to their deficiency in the HDL receptor.

Assessing the impact of AAV_SOF treatment on lipoprotein concentrations and ovary morphology

The researchers isolated SOF from a bacterial expression system and cloned it into a pAAV-TBG-mcs plasmid to create the AAV_SOF. They used female Scarb1^-/- mice and wild type mice, and either injected them with AAV_SOF or AAV_GFP (control). Then, the mice were placed with male Scarb1^-/- mice and were followed for five months, during which they were maintained in a continuous breeding scheme. For this set of experiments, the mice were either treated with AAV_SOF or probucol, which is an established drug used to lower cholesterol levels. The metrics used to measure fertility included: the number of days to first litter, litter size, percent fertile females and survival based on the percent of litters surviving until weaning. After this data was collected, the mice were sacrificed and their plasma was collected by heart puncture, followed by organ collection. They used enzyme-based assays for free cholesterol (FC), total cholesterol (TC), phospholipids (PL) and triglyceride to determine plasma and tissue lipid concentrations. Additionally, they tested cholesteryl ester (CE) concentrations and protein via the DC protein assay. The key findings from this study were:

• The isolated ovaries of untreated Scarb1^-/- mice had duplicates of major functional components, such as primordial, primary and secondary follicles, as well as fewer follicles undergoing maturation and the total absence of corpora lutea, compared to the ovaries from wildtype mice.
  
• The isolated ovaries of the Scarb1^-/- mice that received AAV_SOF treatment showed normal ovary morphology, most prominently including the presence of the corpus luteum.
  
• In the mice who were observed to have gained fertility, AAV_SOF was able to reduce plasma concentrations of all lipids, HDL-TC, FC and CE.
  
• The time to first litter, litter size and percent fertile mice were similar between mice who received the AAV_SOF treatment and the mice who received the probucol treatment.

Using AAV_SOF to restore fertility in sterile female mice

High concentrations of HDLs can cause physiological damage to ovaries and thereby reduce female fertility. In order to combat this, Rosales et al. designed AAV_SOF, which could constitutively express SOF, a protein known to lower HDL levels. As expected, AAV_SOF was able to lower the concentration of HDLs in the plasma, as well as cholesterol and other lipids, and thereby rescue the fertility of previously sterile mice. Additionally, AAV_SOF was able to return the ovaries to healthy morphology and physiological function. Both AAV_SOF treatment and oral probucol treatment improved fertility to a similar degree as they both demonstrated similar values for time-to-first litter, litter size and percent of fertile mice. However, the oral probucol required daily treatment to restore fertility whereas a single AAV_SOF dose had a lasting impact for more than thirty weeks and restored fertility. 

Rosales et al. found a way to reverse infertility in female mice, by targeting dysfunctional and overpopulated HDLs that were responsible for the unhealthy ovary morphology and function in sterile mice. By bringing HDLs, cholesterol and other lipids to normal levels, the previously sterile mice became fertile and were able to give birth to pups. Infertility impacts millions of people across the world, and nearly two million cycles of in vitro fertilization are performed around the globe every year, costing around $10,000 per cycle. Therefore, AAV_SOF treatment could provide an inexpensive medical solution to infertility.

That being said, it is important to note that this therapy is only a potential solution for individuals with HDL-associated infertility and therefore only targets a subset of the population dealing with infertility. Additionally, there has not been much research into Scarb1 mutations in humans, so further research is needed to understand if and how a therapy like this could be implemented in humans.

Implementation in the clinic

Rosales et al. tested ways to reduce high plasma HDL-FC concentrations in mice, but how do we implement this therapy in humans? Firstly, it is important to conduct lipid panels on women visiting in vitro fertilization clinics, in order to assess if similar patterns of plasma HDL-FC concentrations are seen in humans experiencing infertility compared to mice with infertility. After conducting such tests, it will become clearer if the AAV_SOF would be relevant and reasonable to use in humans. This therapy has the potential to be a life changing treatment for women with HDL-associated infertility, but it will require years of further investigation before possible implementation.

Reference: Rosales C, Yelamanchili D, Gillard BK, Liu J, Gotto AM Jr, Pownall HJ. Serum opacity factor rescues fertility among female Scarb1-/- mice by reducing HDL-free cholesterol bioavailability. J Lipid Res. 2023;64(2):100327. doi: 10.1016/j.jlr.2022.100327

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