Induced fertility

A PROCEDURE to produce fertile eggs from the ovaries of patients suffering from a common infertility disorder called primary ovarian insufficiency, or POI, has been developed. The disorder is associated with lack of ovulation and often leads to menopause before the age of 40.

Reasons for POI are not well understood. It causes premature exhaustion of the pool of primordial follicles which are small capsule-like structures in the ovaries that mature and release fertile eggs in every menstrual cycle. In the US, POI accounts for one per cent of all infertility-related problems.

The researchers drew inspiration from the procedure used in the treatment of Polycystic Ovary Syndrome (PCOS), the most common disorder associated with lack of ovulation, affecting about 10 per cent of women of reproductive age in the US. Treatment of PCOS involves surgical removal of the entire or part of ovary, followed by cutting them into smaller parts—or fragmentation—to allow better freezing and grafting of follicles into the patient. The team wanted to study the enzymatic mechanism of the treatment.

The researchers first tested whether fragmentation could instigate growth of immature follicles in mice. For this, they used ovaries from young mice that have primordial or small follicles. These were fragmented in vitro and transplanted into another mouse. They found an increase in the size of the grafted tissue and follicles only when the ovaries had been fragmented into two to four sections. On being activated by the appropriate dose of a hormone called human chorionic gonadotropin (hCG), large and mature follicles were seen to have several fertile, mature oocytes or eggs.

Experiments were carried out to determine what types of proteins were present in ovarian tissues of young mice and it was found that various enzymes of Hippo signalling pathway, were present. Hippo signalling pathway maintains optimal organ sizes in most organs. Signalling pathways involve several proteins in a cascade-like reaction that control cellular processes triggered in response to external or internal stimuli such as presence of a hormone. “We found that Hippo signalling system is active in the ovary,” says Aaron Hsueh from the department of obstetrics and gynecology, Stanford University School Of Medicine, California, US, and one of the authors of the study.

The team then tried to track proteins which had seen a change in level when the ovaries were fragmented. To track such proteins, the researchers focused on actin, a protein that regulates changes in cell shape. Changes in cell shapeÔÇêchange the ratio of “chains” or filamentous form of actin (F actin) and “links” or globular actin (G actin). An increase in the ratio of F actin to G actin was previously known to disrupt Hippo signalling pathway and this was also seen in fragmented ovaries of young mice. Once Hippo signalling is repressed, there is an increased presence of growth-promoting proteins and cell-death inhibitors, which lead to an increase in size of follicles, resulting in follicular maturation. It was also found that treating fragmented ovarian tissues with drugs that activate Akt pathway (an enzyme pathway) increased growth of cells and inhibited their death.

The team tested the procedure on POI patients. The ovaries underwent the same process of fragmentation and treatment with drugs that activate Akt pathway before being transplanted into patients. The patients were also treated with the follicle-stimulating hormone and hCG to induce follicular maturation, after which mature ooctyes were retrieved. They were used for in vitro fertilization and embryo transfer and the authors have reported successful pregnancy in one patient with POI who underwent the procedure. Experts, however, have also raised doubts about the efficacy of this method in dealing with of infertility. “It remains to be determined when this approach will be helpful clinically. Moreover, there are many causes of infertility in women and it is doubtful that this approach will benefit most of them,” said John Eppig, professor at Jackson Laboratories, Maine, US.

The study was published online in Proceedings of National Academy of Sciences on September 30.

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