PCOS and Endometrial Cancer Risk: The Dilemma of Weight Loss and Weight Cycling

September is Polycystic Ovarian Syndrome (PCOS) Awareness Month. As part of our ongoing series on PCOS, today we are going to talk about endometrial cancer.

PCOS is a hormonal disorder usually characterized by very strong insulin resistance. This insulin resistance causes many problems in the body, including irregular menstrual cycles, strong susceptibility towards weight gain, unwanted hair growth on the face and body (hirsutism), hair loss on the head (alopecia), cystic acne, body tags, a strong tendency towards diabetes, infertility, and many other symptoms.

Among other risks, PCOS is associated with a high risk for endometrial cancer (cancer in the lining of the uterus). Because PCOS tends to cause an irregular menstrual cycle, a woman's uterine lining may not get sloughed off each month. Some women with PCOS have extra long cycles (35 or more days), while others go months or even years without a menstrual cycle. This causes the lining of the uterus (the endometrium) to build up excessively; in time, atypical cells may develop. This is called endometrial hyperplasia, or overgrowth of the uterine lining. This hyperplasia can eventually turn into endometrial cancer.

This is why it is so important that women with PCOS get treatment. They need to have regular periods so that this overgrowth does not occur. There are many options for this, including progesterone treatments; birth control pills; insulin sensitizers like metformin, TZDs, or inositols; and androgen blockers.

However, most doctors' first recommendation is weight loss.

The Weight Loss Dilemma

The majority of women with PCOS have an "overweight" or "obese" BMI. Because of the very significant insulin resistance with PCOS, these women have a strong tendency towards weight gain over time.

Women of size with PCOS face a difficult dilemma in how they approach their weight. Care providers push them to lose weight, often telling them weight loss can "cure" PCOS or get rid of most of their symptoms. Weight loss is considered by many to be the first line of therapy for PCOS.

It's true that some short-term research does seem to suggest benefits from weight loss for women with PCOS, especially in shocking the system into ovulation. But this research is almost always based on fairly short follow-ups because most weight comes back within a few years after a significant weight loss. The very loss that leads to short-term benefits may backfire later into weight gain and worsened insulin resistance.

The critical question is whether women are better off in the long term trying to lose weight, or whether the high potential for weight cycling overcomes the possible benefit of weight loss. In particular, we need to know how weight loss and weight cycling affects the chances of getting endometrial cancer.

Here are two studies that demonstrate this weight loss dilemma. One study (Luo 2017) looked at intentional weight loss in "obese" women and how that affected their risk for endometrial cancer. (The study did not look specifically at women with PCOS but weight and PCOS are so tightly tied together that weight is a pretty fair proxy for presumed PCOS when discussing endometrial cancer.)

In the study, those women who intentionally lost weight lowered their chances for endometrial cancer. The effect was particularly strong in obese women who intentionally lost weight. So if  you can lose weight and keep it off, it looks like there might be some benefit.

However, remember that the majority of women who lose weight gain it back, and often end up at a higher weight than they started. In the Luo study, women who gained weight were at increased risk for endometrial cancer. So you take a calculated risk; if you lose weight and keep it off, you might significantly reduce your risk for endometrial cancer. However, if you regain that weight and end up heavier than you started, you probably have increased your risk for endometrial cancer.

Weight fluctuations up and down the scale may also have its own independent effect. The second study (Welti 2017) found that weight cycling 4-6 times was associated with an increase in risk for endometrial cancer. Many women of size cycle far more times than that; how increased is their risk?

Summary

High BMI women with PCOS face a difficult dilemma when deciding what to do to lessen their risk for endometrial cancer.

Intentional weight loss ─ if they can keep it off ─ might lower their risk for endometrial cancer. On the other hand, if the weight loss attempt leads to weight cycling and/or overall weight gain ─ as it does for so many ─ then that weight loss attempt probably actually increases their risk. 

In other words, high BMI women with PCOS are faced with a game of Russian Roulette when it comes to weight loss and endometrial cancer.  

There are no easy answers here. Each individual woman gets to make her own choices about weight loss as a treatment for PCOS, taking into account her own personal weight history and habits.

Although most doctors don't acknowledge it, it is a perfectly reasonable choice not to pursue weight loss as a treatment for PCOS. That doesn't mean that lifestyle is irrelevant. One can choose to emphasize sensible nutrition and exercise as a treatment for PCOS without measuring the worth of those treatments by weight loss. A Health At Every Size® approach can work for PCOS.

Care providers need to recognize that their constant pressure on patients to lose weight may actually backfire and create more risk rather than less. They need to recognize the right of the patient to choose whether or not to pursue weight loss, that it is possible to emphasize healthy lifestyle without tying that to weight loss, and to acknowledge the need for multiple tools beyond weight loss to address the unique needs of their PCOS patients.



References

Cancer Epidemiol Biomarkers Prev. 2017 May;26(5):779-786. doi: 10.1158/1055-9965.EPI-16-0611. Epub 2017 Jan 9. Weight Fluctuation and Cancer Risk in Postmenopausal Women: The Women's Health Initiative. Welti LM, Beavers DP, Caan BJ, Sangi-Haghpeykar H, Vitolins MZ, Beavers KM. PMID: 28069684

BACKGROUND: Weight cycling, defined by an intentional weight loss and subsequent regain, commonly occurs in overweight and obese women and is associated with some negative health outcomes. We examined the role of various weight-change patterns during early to mid-adulthood and associated risk of highly prevalent, obesity-related cancers (breast, endometrial, and colorectal) in postmenopausal women. METHODS: A total of 80,943 postmenopausal women (age, 63.4 ± 7.4 years) in the Women's Health Initiative Observational Study were categorized by self-reported weight change (weight stable; weight gain; lost weight; weight cycled [1-3, 4-6, 7-10, >10 times]) during early to mid-adulthood (18-50 years). Three site-specific associations were investigated using Cox proportional hazard models [age, race/ethnicity, income, education, smoking, alcohol, physical activity, hormone therapy, diet, and body mass index (BMI)]. RESULTS: A total of 7,464 (breast = 5,564; endometrial = 788; and colorectal = 1,290) incident cancer cases were identified between September 1994 and August 2014. Compared with weight stability, weight gain was significantly associated with risk of breast cancer [hazard ratio (HR), 1.11; 1.03-1.20] after adjustment for BMI. Similarly, weight cycling was significantly associated with risk of endometrial cancer (HR = 1.23; 1.01-1.49). Weight cycling "4 to 6 times" was most consistently associated with cancer risk, showing a 38% increased risk for endometrial cancer [95% confidence interval (CI), 1.08-1.76] compared with weight stable women.  CONCLUSIONS: Weight gain and weight cycling were positively associated with risk of breast and endometrial cancer, respectively. IMPACT: These data suggest weight cycling and weight gain increase risk of prevalent cancers in postmenopausal women. Adopting ideal body-weight maintenance practices before and after weight loss should be encouraged to reduce risk of incident breast and endometrial cancers. 

J Clin Oncol. 2017 Apr 10;35(11):1189-1193. doi: 10.1200/JCO.2016.70.5822. Epub 2017 Feb 6. Intentional Weight Loss and Endometrial Cancer Risk. Luo J, Chlebowski RT, Hendryx M, Rohan T, Wactawski-Wende J, Thomson CA, Felix AS, Chen C, Barrington W, Coday M, Stefanick M, LeBlanc E, Margolis KL. PMID: 28165909

PURPOSE: Although obesity is an established endometrial cancer risk factor, information about the influence of weight loss on endometrial cancer risk in postmenopausal women is limited. Therefore, we evaluated associations among weight change by intentionality with endometrial cancer in the Women's Health Initiative (WHI) observational study. PATIENTS AND METHODS: Postmenopausal women (N = 36,794) ages 50 to 79 years at WHI enrollment had their body weights measured and body mass indices calculated at baseline and at year 3. Weight change during that period was categorized as follows: stable (change within ± 5%), loss (change ≥ 5%), and gain (change ≥ 5%). Weight loss intentionality was assessed via self-report at year 3; change was characterized as intentional or unintentional. During the subsequent 11.4 years (mean) of follow-up, 566 incident endometrial cancer occurrences were confirmed by medical record review. Multivariable Cox proportional hazards regression models were used to evaluate relationships (hazard ratios [HRs] and 95% CIs) between weight change and endometrial cancer incidence. RESULTS: In multivariable analyses, compared with women who had stable weight (± 5%), women with weight loss had a significantly lower endometrial cancer risk (HR, 0.71; 95% CI, 0.54 to 0.95). The association was strongest among obese women with intentional weight loss (HR, 0.44; 95% CI, 0.25 to 0.78). Weight gain (≥ 10 pounds) was associated with a higher endometrial cancer risk than was stable weight, especially among women who had never used hormones. CONCLUSION: Intentional weight loss in postmenopausal women is associated with a lower endometrial cancer risk, especially among women with obesity. These findings should motivate programs for weight loss in obese postmenopausal women.