Amenorrhea is the absence or abnormal cessation of the menses. Primary and secondary amenorrhea describe the occurrence of amenorrhea before and after menarche, respectively. The majority of the causes of primary and secondary amenorrhea are similar. Timing of the evaluation of primary amenorrhea recognizes the trend to earlier age at menarche and is therefore indicated when there has been a failure to menstruate by age 15 in the presence of normal secondary sexual development (two standard deviations above the mean of 13 years), or within 5 years after breast development if that occurs before age 10. Failure to initiate breast development by age 13 (two standard deviations above the mean of 10 years) also requires investigation. In women with regular menstrual cycles, a delay of menses for as little as 1 week may require the exclusion of pregnancy; secondary amenorrhea lasting 3 months and oligomenorrhea involving less than nine cycles a year require investigation. The prevalence of amenorrhea not due to pregnancy, lactation, or menopause is approximately 3–4 %. Although the list of potential causes of amenorrhea is long, the majority of cases are accounted for by four conditions: polycystic ovary syndrome, hypothalamic amenorrhea, hyperprolactinemia, and ovarian failure. Secondary amenorrhea, which is defined as 3 months absence of menstruation, occurs in approximately 3–5 % of adult women [1, 2].

According to the American Society of Reproductive Medicine, Functional Hypothalamic Amenorrhea (FHA) is one of the most common causes of secondary amenorrhea; therefore, it is responsible for 20–35 % of secondary amenorrhea cases and approximately 3 % of cases of primary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea therefore, DeSouza et al. estimated that approximately 50 % of women who exercise regularly experience subtle menstrual disorders and approximately 30 % of women have amenorrhea, for that reason the incidence of FHA is higher in athlete women. The complex of distorted eating, amenorrhea, and osteoporosis was first described in 1997 and is known as female athlete triad. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences of these clinical conditions are complex hormonal changes manifested by profound hypoestrogenism leading to several short and long-term health implications [3].

As it is known, hypoestrogenism can interfere with the cardiovascular system function in many ways, this is the reason why Cardiovascular disease (CVD) is the leading cause of death in women in developed countries and, interestingly, proportionally more women die from CVD than men. Coronary and peripheral vessels contain estrogen receptors that permit estradiol to play a regulatory role in vascular function. Estrogen excites the synthesis of nitric oxide (NO) through both genomic and nongenomic effects, leading to the augmented production of endothelial-derived NO, causing vasodilatation [4]. Estradiol exerts a positive, cardioprotective effect through its influence on the endothelial, myocardial, and vascular function and metabolic parameters [5]. In contrast, hypoestrogenism can lead to endothelial dysfunction, an impaired bioactivity of nitric oxide, perturbation in autonomic function, activation of the rennin–angiotensin system, and lipid profile changes [6]. These physiological and pathological phenomena are reflected in clinical studies. Several investigators have demonstrated a correlation between FHA and endothelial dysfunction. It was clearly shown that the flow-mediated dilation of the brachial artery, which is a precise predictor of coronary endothelial dysfunction, is impaired in women with FHA. It is suggested that the decrease of endothelial NO bioavailability is caused by chronic estrogen deficiency. Moreover, some authors have proved the protective effect of exogenous estrogens in young women against impaired vessels’ dilatation. Rickenlund et al. documented significantly increased brachial artery dilatation after 9 months of treatment with low-dose combined contraceptives (30 μg of ethinyl estradiol and 150 μg of levonorgestrel): from 1.42 ± 0.98 % before treatment to 4.88 ± 2.20 % during treatment [7].

A Women’s Ischemia Syndrome Evaluation (WISE) study found a significant association between premenopausal angiographic coronary artery disease (CAD) and hypothalamic hypogonadism [8]. O’Donnell et al. recently showed that young athletes with chronic hypoestrogenemia displayed an impaired peripheral vascular function that was combined with lower resting blood pressures and heart rate and reduced ischemic responses to occlusion challenge compared to ovulatory women. Impaired cardiovascular function in hypothalamic amenorrhea is believed to be linked mainly to hypoestrogenism, but it is also aggravated by negative energy balance and metabolic disturbances [9]. Patients with FHA are characterized by an impaired lipid profile and are at risk of glucose metabolism abnormalities. Women with exercise-related amenorrhea present higher serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride concentrations than healthy individuals [10]. On the other hand, premenopausal women with hypoestrogenism of hypothalamic origin present an increased frequency of diabetes mellitus. Moreover, Ahmed et al. showed that coronary artery disease (detected in coronarography) has an increased prevalence and extent among women with diabetes and hypothalamic hypoestrogenism in comparison to women with diabetes alone. These observations substantiate the importance of cyclic ovarian function as an indicator of cardiovascular health. However, the influence of hypoestrogenism in young women of hypothalamic origin on cardiovascular health requires further studies. Especially the issue of the long-term consequences of FHA on CVD risk needs to be cleared to possibly minimize the risk of cardiovascular events in this group of women [11].

Despite the large number of studies investigating the effects of menopause on cardiovascular outcomes and endothelial function, currently, little is known about the cardiovascular effects of Premature Ovarian Failure (POF) in young women. Flow mediated vasodilatation (FMD) of the brachial artery is the most common method in the assessment of endothelial function and measures the changes in arterial diameter in response to increased blood flow by stimulating endothelial nitric oxide production. It has been shown previously that endothelial function assessed by FMD is impaired in patients with POF; in particular it has been found that FMD was significantly lower in women with POF. New findings suggested that Circulating Endothelial Progenitor cells (EPC) originate from the bone marrow and play an important role in vascular homeostasis for both repair and regeneration of damaged endothelium. This line of progenitor cells has recently been recommended as a novel biomarker of endothelial function showing a close relationship with FMD. Circulating EPCs may have an important contribution to estrogen-induced cardiac protection but they have not been studied in POF previously. Also decreased EPCs may lead to accelerated vascular remodeling like increased carotid intima media thickness (CIMT) due to chronic impairment of endothelial maintenance [12]. Remarkably, polycystic ovary syndrome (PCOS) patients who have chronic anovulation and hyperandrogenism have been shown to have decreased EPC counts and increased CIMT. In this view, Kalantaridou et al. evaluated endothelial dysfunction in a patient group including 18 patients with POF compared to age-matched premenopausal women investigating the relationship between POF and EPC, endothelial function, carotid intima media thickness (CIMT), and left ventricular diastolic function [13, 14].

This group of research found lower FMD in patients with POF compared to healthy age-matched controls. Furthermore, there was a significant correlation between estradiol and FMD, consistent with previous studies where low levels of estradiol were associated with endothelial dysfunction. The association between EPCs and endothelial function has been evaluated in different previous studies, suggesting that EPCs may play a critical role in maintaining endothelial function in mature blood vessels in addition to mature endothelial cells. In this study, it has been demonstrated for the first time a lower circulating number of EPCs in patients with POF. It has been also found that there is a significant correlation between estradiol level and EPC which may be one of the mechanisms impairing endothelial function. In this view, Kalantaridou and colleagues demonstrated that hormone replacement restored endothelial function within 6 months of treatment among patients with POF.