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Long-Term Complications of Anovulation
Introduction
Anovulation, especially if untreated, is associated with several short-, middle long-, and long-term health sequelae. WHO 1 and WHO 3 anovulatory states are characterized by hyopogonadism, and therefore, they cause hypo-estrogenism. Long-lasting underexposure to estrogens may lead, in these circumstances, to osteoporosis (i.e., decreased bone mineral density [BMD]), mood and cognitive disturbances, and sexual dysfunction as well as accelerated cardiovascular aging and subsequent cardiovascular disease and, if left untreated, a reduced life span. Similarly, since WHO 2 anovulation and especially PCOS are associated with obesity, insulin resistance, and metabolic syndrome, these women also have an increased risk of develop type 2 diabetes, hypertension, and probably cardiovascular disease.
WHO 1 Hypogonadotropic Hypogonadism (HH)
Functional hypothalamic amenorrhea is related to profound impairment of reproductive functions, including anovulation and infertility. Women’s health, in this disorder, is disturbed in several aspects, including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of HH. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. HH patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects (1).
Patients with HH are threatened by a low peak bone mass (PBM) not only due to hypo-estrogenism. Other important factors include improper diet (low calcium and vitamin D3 intake), undernutrition, and excessive exercise. Moreover, HH individuals had a decreased fat tissue mass and an imbalanced relationship between body weight, fat tissue mass, and lean body mass. More attention should be paid to exercise among women. For most of the young women, exercise causes a positive effect, improving health and physical fitness. However, excessive exercise (exercise-related hypothalamic amenorrhea) does not improve BMD but leads to osteopenia. Abnormally low BMD and osteoporosis in exercising women relate to premature bone loss and micro-architectural deterioration (1).
Several investigators have demonstrated a correlation between HH and endothelial dysfunction. The Women’s Ischemia Syndrome Evaluation (WISE) study found a significant association between premenopausal angiographic coronary artery disease and hypothalamic hypogonadism. Impaired cardiovascular function in hypothalamic amenorrhea is believed to be linked mainly to hypo-estrogenism, but it is also aggravated by negative energy balance and metabolic disturbances. Patients with HH are characterized by an impaired lipid profile and are at risk of glucose metabolism abnormalities. However, the influence of hypo-estrogenism in young women with HH on cardiovascular health requires further studies. Especially the issue of the long-term consequences of HH on CVD risk needs to be cleared to possibly minimize the risk of cardiovascular events in this group of women (1).
Women with HH endorsed more dysfunctional attitudes, had greater difficulty in coping with daily stresses, and tended to endorse greater interpersonal dependence than eumenorrheic women. WHO 1 patients present a particular susceptibility to common life events, restrictive disordered eating, depressive traits, and psychosomatic disorders. Psychological problems are aggravated by the fact that HH is associated with anxiety, depressive symptoms, and high rates of mood disorders. The mediating effects of anxiety and depression may explain the occurrence of sexual dysfunction, which is potentially associated with WHO 1 anovulation. Finally, the hormonal background of sexual dysfunction in FHA may be related to profound hypo-estrogenism and hypoandrogenemia (1).
WHO 2 Normogonadotropic Normo-Estrogenic Anovulation (PCOS)
Women with PCOS are more likely to have upper body fat distribution compared with weight-matched controls. Greater abdominal or visceral adiposity is associated with greater insulin resistance, which could exacerbate the reproductive and metabolic abnormalities in PCOS (2). It is known that obesity is associated with PCOS, but its causal role in this condition has yet to be determined. Very few studies report the association of BMI with menstrual irregularity. Few randomized controlled studies have been performed on lifestyle interventions, but these suggest substantial reproductive and metabolic benefits (3,4).
Insulin resistance is a prevalent finding in women with PCOS. It is most prevalent and severe in those with the classic phenotype, involving hyperandrogenism and chronic anovulation. Women with PCOS assessed by the Rotterdam criteria yet with regular cycles are metabolically less abnormal. The cellular and molecular mechanisms of insulin resistance in PCOS differ from those in other common insulin-resistant states, such as obesity and type 2 diabetes. In vivo insulin action is profoundly decreased in skeletal muscle secondary to signaling defects, but hepatic insulin resistance is present only in obese women with PCOS. There is a synergistic negative effect of having both PCOS and obesity on insulin action. Pancreatic beta-cell dysfunction is also present in PCOS but may be more related to type 2 diabetes risk factors as this dysfunction is most severe in women with a first-degree relative who has type 2 diabetes. Extensive evidence indicates that hyperinsulinemia contributes directly to reproductive dysfunction in PCOS. Women with the classic hyperandrogenic PCOS phenotype have significantly increased rates of the metabolic syndrome compared with reproductively normal women of similar age and weight (2).
Insulin resistance is a prominent feature of PCOS. There is now compelling evidence from epidemio-logic data that PCOS is associated with increased risk of impaired glucose tolerance, gestational diabetes, and type 2 diabetes. Screening making use of an oral glucose tolerance test is indicated in obese women with PCOS and/or those with increased visceral adiposity as measured by waist circumference. Risk of impaired glucose metabolism or diabetes is highest in women who have both oligo-ovulation or anovulation and hyperandrogenism, and the risk is further amplified by obesity. Management of women at risk for type 2 diabetes should include diet and lifestyle improvement as the first-line treatment. Metformin treatment is indicated in those with impaired glucose metabolism who do not respond adequately to calorie restriction and lifestyle changes. In those with frank diabetes, metformin is safe and effective whereas there is concern about the use of thiazolidinediones and glucagonlike peptide-1 analogues in women of reproductive age (2).
PCOS at any age is characterized by greater odds for elevated CVD risk markers. Elevated markers occur without obesity and are magnified with obesity. Dyslipidemia, impaired glucose tolerance as well as type 2 diabetes (classic risk indicators of atherosclerosis and CVD) are more prevalent in women with PCOS even when weight matched with normal control women. Dyslipidemia reflected by altered levels of triglycerides, HDL, LDL, and non-HDL is prevalent in women with PCOS and is more severe in hyperandrogenic women. Non-HDL cholesterol and waist measurement appear to be the best clinical indicators of elevated CVD risk. All markers reflect a greater magnitude of risk when women are diagnosed into the hyperandrogenic phenotypes compared to the non-hyperandrogenic phenotype (2).
Although most of the surrogate markers do predict a higher CVD risk in women with PCOS, there is only very limited data available on the real hard clinical end points, that is, stroke and coronary heart disease and myocardial infarction. In fact, there are only two long-term follow-up studies indicating women with polycystic ovary syndrome do not have markedly higher than average mortality from circulatory disease even though the condition is strongly associated with diabetes, lipid abnormalities, and other cardiovascular risk factors (5,6).
There are some data to support that women with PCOS have a two- to threefold increased risk for endometrial cancer. Most endometrial cancers are well differentiated and have a good prognosis. Limited data exist that do support the conclusion that women with PCOS are not at increased risk for ovarian cancer. Similarly, there are no data to support the fact that women with PCOS are at greater risk to develop breast cancer (2).
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