Towards a novel treatment targeting obesity in women with polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a common condition that affects 1 in every 12 women. It is associated with a hormone imbalance that causes irregular periods and difficulty in getting pregnant as well as skin problems, including extra hair and spots. However, a major concern that particularly bothers women with PCOS is their difficulty in maintaining a healthy weight and the increased risk of diabetes. Women with PCOS are more likely to be obese and insulin resistant and develop diabetes during pregnancy or in later life. As well as having a major impact on the health and wellbeing of women this has implications for health service resources. Obesity makes all the features of PCOS much worse and weight loss improves PCOS. However, women with PCOS find losing weight difficult. European and American professional societies of reproductive medicine have come together to call for new research into obesity and PCOS.

Using our previous research, which was featured in the New Scientist magazine, and combining it with other published research we have developed a new and exciting idea for a treatment that will specifically target obesity in PCOS to improve the symptoms and long-term health and wellbeing of these women. When it comes to obesity there is a mismatch of energy intake and energy expenditure. Diets are designed to lower energy intake and exercise is designed to raise energy expenditure, and currently weight loss strategies involve a combination of both. When it comes to energy expenditure 60-65% of energy is used just keeping the body alive and functioning. Around 20-25% is used during exercise and 10-15% is burned off after eating, which is why we feel hot after a big meal. This process is called postprandial thermogenesis and it is the result of nerve signals from the brain to tissues, such as fat, that increase heat generation to burn off calories. Women with PCOS have 25% less postprandial thermogenesis than women of the same weight without PCOS. This suggests a reduced energy expenditure in women with PCOS and explains why they are more likely to gain weight and find losing weight more difficult.

When we eat the brain senses the intake of food and then signals to the other tissues to switch on heat generation and burn off calories. One hormone that is involved in telling the brain about food intake is insulin. Insulin increases when we eat in order to move the sugar from the blood into the tissues. Women with PCOS tend to be insulin resistant which means they need more insulin to move the sugar out of the blood stream. We think their brain is less sensitive to insulin and so the signals to burn off the calories are reduced. That means if we can increase insulin in the brain we can improve postprandial thermogenesis. When insulin is sprayed up the nose, nerves at the top of the nose transport it into the brain. This works in sheep models, which have the features of PCOS. They have less signals to the fat to tell it to burn calories after eating and less compounds in the fat that burn calories. Intranasal insulin was able to improve this and increase thermogenesis without affecting the glucose and insulin in the blood.

This research brings together scientists and clinicians, from four different universities, who are experts in PCOS and tissue analysis. It is designed to test if a nasal insulin spray with food will switch on the signals to the fat and the genes and compounds in the fat that burn off calories in women. We will be able to determine whether intranasal insulin can as well as increase energy expenditure after eating in obese women with PCOS as well as finding out if it has any benefit in obese women who don't have PCOS.

If these experiments show the same things happen in women with PCOS this would help develop new treatments that can help facilitate weight loss in obese women with PCOS. This would improve the symptoms associated with PCOS as well their current and long-term health.

Obesity worsens the symptoms and consequences of PCOS, but women with PCOS find losing weight difficult. This is not because of increased energy intake but rather a consequence of weight-independent reduction in postprandial energy expenditure (PPEE). There is an unmet need for treatment that improves postprandial thermogenesis (PPT) in PCOS to facilitate weight loss. The ASRM-ESHRE consensus on women's health highlights the need for strategies to tackle obesity in PCOS.
The solution may be intranasal insulin (INI) with food, which increases central insulin signalling without systemic effects. This drives sympathetic activation of subcutaneous adipose tissue (SAT) to augment thermogenesis. This solution has been developed and successfully tested in an ovine model of PCOS with an identical PPT deficit. However, we do not know if the reduction in PPT in women with PCOS has the same mechanistic underpinnings. As INI is well-tolerated, we will use it as a tool to examine whether it increases sympathetic drive to SAT, alters SAT function towards increased thermogenesis and increases PPEE in women with PCOS, and determine if these effects are PCOS-specific.
We will study obese women with and without PCOS. The effect of INI on PPEE will be assessed by indirect calorimetry after being fed a standard meal on two occasions with either intranasal placebo or INI in random order. SAT microdialysis will be used to assess the sympathetic thermogenic drive. Biopsies will be used to examine the effect of PCOS and INI on SAT gene expression and mitochondrial function. The primary outcome is the effect of INI on PPEE in obese women with PCOS. Secondary outcomes will determine if this is PCOS-specific and give additional mechanistic information of the effect of PCOS and INI on SAT function.
Proof of concept will facilitate industrial partnership and support the development of a clinical efficacy trial of INI as a novel repurposed solution for weight management in women with PCOS.