Reproductive Health as a Sentinel of Chronic Disease in Women

“The vitality and performance of women's reproductive axis – as revealed in patterns of menstruation, fertility and pregnancy – yield important information about subclinical disease trajectories.”

“With the exception of the stomach, there is no organ that holds such numerous ramifications of sympathy with other organs as the womb.” – JM Good, 1825 [1].

At the turn of the 19th Century, as John Mason Good assembled his four volume opus on medicine, the chief threats to women's health were infection and childbirth, and many women did not survive to menopause. Two centuries later, women in the developed world succumb to cardiovascular disease or cancer, conditions that rarely strike women of reproductive age. In our modern day fight against these diseases of maturity, we have focused on risk factors and interventions for postmenopausal women. As a result, we have forgotten the wisdom expressed by Good at the dawn of the Victorian era: women's reproductive health is intimately linked with their overall physical and mental health. The vitality and performance of women's reproductive axis – as revealed in patterns of menstruation, fertility and pregnancy – yield important information about subclinical disease trajectories.

Many of the factors that contribute to coronary heart disease, stroke and cancers – inflammation, vasculopathy, angiogenesis, thrombosis, insulin resistance and endocrine profiles – also underlie aberrant menstrual patterns, female infertility, pregnancy complications and pregnancy outcomes such as preterm delivery or fetal growth restriction. As we begin to investigate the value of reproductive characteristics as predictors of future disease, the early literature provides some clues.

Age at menarche is an established risk factor that is already included in prediction models for breast cancer [101]; earlier age at menarche, especially when coupled with late age at first birth, increases the risk of breast cancer [2]. Other features of the menstrual cycle, such as length or regularity, may affect breast cancer risk; although findings are inconsistent, they tend toward higher cancer risk among women with regular cycles [3,4]. It is less appreciated that menstrual cycle length and pattern may predict cardiovascular risk. Women with consistently irregular cycles are at a 20–50% higher risk of coronary heart disease than women with regular cycles, and may be more likely to suffer stroke [5–7]. Menstrual irregularity may represent a hypoestrogenic or a hyerandrogenic endocrine profile; more research is needed to determine how well and why cycle characteristics predict chronic disease risk.

Long and irregular menstrual cycles are a hallmark of polycystic ovary syndrome (PCOS), an underdiagnosed condition that affects 5–10% of women of reproductive age. Women with PCOS are prone to impaired glucose tolerance, Type 2 diabetes, hyperlipidemia and hypertension [8–10]. Even non-obese women with PCOS have a threefold increased risk for Type 2 diabetes [11,12]. Women with PCOS are at elevated risk of cerebrovascular disease [8,9]. However, despite the metabolic recipe for ischemia, women with PCOS may or may not suffer increased risk of coronary heart disease [8–10,13,14]. This enigma requires further research with well-characterized PCOS cases and controls.

The endocrine profile of PCOS – heightened androgens, estrogens, insulin and lower sex hormone-binding globulin – suggests that women with PCOS may be vulnerable to endocrine-related cancers [15]. Indeed, a few studies have reported small increased risks of breast, ovarian, endometrial and even colon cancer associated with PCOS; however, the studies remain few, and are not entirely consistent [16,17]. Given the high prevalence of PCOS, this is an important area for further research.

Infertility affects over 10% of couples. A little less than a third of infertility is attributable to male factors, a little more than a third to female factors and a good proportion eludes diagnosis. Ovulatory disorder, fallopian tube blockage and endometriosis are the chief causes of female infertility. To add insult to injury, infertility predicts an approximate 20% higher rate of cancers in women [18], with the strongest links of anovulation with endometrial cancer, and endometriosis with ovarian and, perhaps, breast cancer [18–21]. The roles of inflammation and insulin resistance in infertility [19–21] suggest elevated risks of diabetes and heart disease in this population, although this has yet to be studied outside of PCOS. New research on the roles of immune function, oxidative stress and vasculopathy in ovulation, conception and implantation may reveal ways in which infertility and latent chronic disease processes overlap.

Spontaneous abortion, or miscarriage, occurs in 10–15% of clinically recognized pregnancies. Most spontaneous abortions are due to unviable chromosomal anomalies resulting from increasing maternal age or bad luck. However, new research is probing the degree to which maternal disorders of inflammation, thrombosis or immune function also explain early pregnancy failures [22,23]; to the extent that these etiologies are also linked to chronic disease risk, some miscarriages – particularly chromosomally normal abortions – may be predictive of a woman's future health. A history of single or recurrent spontaneous abortions is unrelated to future risk of breast cancer [24]. To date, there are no studies of spontaneous abortion as a predictor of future cardiovascular disease.

“A smoothly functioning reproductive axis, marked by regular menstruation and uncomplicated pregnancy, may portend reduced risk of cardiovascular disease.”

Pregnancy complications may be the first warning that a woman is at an elevated risk for future cardiovascular disease [25]. Approximately half of women with gestational diabetes eventually develop Type 2 diabetes [26]. Women with a history of gestational diabetes have a 70% higher risk of cardiovascular disease, attributable largely to their risk of Type 2 diabetes [27]. Several interventions to prevent Type 2 diabetes have been initiated among women with gestational diabetes. Although a handful of studies have indicated links between Type 2 diabetes and breast cancer [28,29], only a few studies have investigated whether gestational diabetes increases risk of cancer. Thus far, reports include increased [28,30], decreased [31] and null associations of gestational diabetes with breast cancer risk [32]. Although gestational diabetes affects only 3% of pregnancies, a larger group of women with glucose intolerance just shy of the gestational diabetes threshold may benefit from glucose screening after pregnancy.

Pre-eclampsia is a hypertensive disorder of pregnancy that affects 5% of pregnancies [33]. A meta-analysis of over 3 million women estimated that pre-eclamptics had roughly double the risks of heart disease, stroke and venous thromboembolism [34]. However, cardiovascular disease may be elevated only among women whose pre-eclamptic pregnancy was their last – suggesting that only pre-eclampsia severe enough to discourage another pregnancy or pre-eclampsia somehow associated with secondary infertility predicts higher cardiovascular risk. Indeed, women with severe pre-eclampsia are less likely to bear another child than women without pre-eclampsia [35–37]. Thus, the pre-eclampsia story may be more complex than it first appeared. Pre-eclampsia has been associated with insulin resistance, endothelial dysfunction and antiangiogenic factors in maternal circulation [33]; these and other cardiovascular risk factors may predate pre-eclamptic pregnancies [38]. Pre-eclampsia appears to be unrelated to future cancer risk [33].

Offspring birthweight predicts maternal lifespan [39]. Mothers of large infants tend to live longer lives, primarily owing to a lower risk of cardiovascular and respiratory disease. For a standard deviation higher birthweight (∼500 g), maternal cardiovascular mortality drops by 25% [39]. Low birthweight (<2500 g) infants comprise approximately 8% of births; their mothers have double the risk of cardiovascular mortality of mothers of normal birth-weight infants (3500 g) [40–42], perhaps owing to insulin resistance, hypertension and inflammation [43]. Although total mortality is lower in mothers of larger infants, offspring birthweight may be positively associated with risk of breast cancer [39,41,44]. Intriguingly, any increased breast cancer risk associated with bearing large infants may be explained by their large, healthy placentas [45,46], which suggests that endocrine, angiogenic and thrombotic processes explain the links between offspring size and breast cancer risk.

Preterm delivery currently affects over 12% of pregnancies in the USA [47]. Mothers who deliver preterm infants have at least double the risk of cardiovascular disease [43,48–51]. The explanation for this may depend on the etiology of the preterm birth, and whether it was spontaneous or medically indicated. Spontaneous preterm birth is associated with uteroplacental inflammation, ischemia and hemorrhage [47]. Women with a history of spontaneous preterm delivery have higher inflammatory levels, larger waist circumference and dyslipidemia years after delivery [43]. For medically indicated preterm births, the main indications are pre-eclampsia and fetal growth restriction [47]. The combination of preterm delivery and pre-eclampsia is particularly predictive of women's future risk of cardiovascular disease [48]. Although studies are not unanimous [32,45,52], several have reported that preterm delivery, especially in a first pregnancy, is associated with an increased risk of future breast cancer [48,53–56] and, perhaps, ovarian cancer [57].

“The extent to which reproductive factors are independent predictors of cardiovascular and cancer risk remains to be tested.”

In summary, the reproductive health of women provides glimpses into subclinical processes and their future risk of chronic disease. A smoothly functioning reproductive axis, marked by regular menstruation and uncomplicated pregnancy, may portend reduced risk of cardiovascular disease. However, reproductive features associated with inefficient reproduction – later age at menarche, irregular cycles, pre-eclampsia and restricted fetal growth – may indicate lower breast cancer risk. We need further work to elucidate the endocrine, metabolic, vascular, immune and inflammatory factors shared by reproductive disorders and chronic disease. Many of the reproductive disorders overlap in definition or etiology, as in the predominance of preterm infants among the low birthweight, or the insulin resistance common to menstrual irregularity, PCOS, subfertility and gestational diabetes. The extent to which reproductive factors are independent predictors of cardiovascular and cancer risk remains to be tested. Perhaps some combination of reproductive factors will prove useful additions to breast cancer and cardiovascular disease prediction algorithms for women. Eventually, information about reproductive health might be used as a form of ‘personalized medicine’ to tailor health advice to women, from early in their lives, in order to change disease trajectories before they emerge as chronic disease at menopause.