Early and premature menopause in women with diabetes mellitus Type 2

Abstract

Those women who have early menopause have major cardiovascular and metabolic risk. The menopause below 40 years of age has been associated to increase in the risk of early beginning of osteoporosis, cardiovascular disease and diabetes mellitus, disorders characterized by hyperglycemia and glucose intolerance due to deficiency of insulin, decrease of the effectiveness of its action or both. The menopausal hormone therapy is the principal therapeutic tool, with the aim to contribute estrogens to suppress the clinical symptomatology and to make a favorably impact on the estrogen-dependent tissues. The existing data regarding menopausal hormone therapy in women experiencing menopause at the median age should not be extrapolated to women experiencing premature menopause.

Keywords::

• climacteric
• diabetes mellitus
• early menopause
• hormonal therapy
• premature menopause

The International Diabetes Federation defines diabetes mellitus (DM) as a group of heterogeneous disorders characterized by hyperglycemia and intolerance to the glucose due to deficiency of insulin, decrease of the effectiveness of its action or both [1]. DM is a chronic disease without therapeutic measures, has negative impact on quality of life, but triggers serious complications and high economic costs. The OMS estimates that the prevalence of people with DM will be duplicated in the next 25 years, with an increase in the expense of $130–300 million [2]. DM Type 2 (DM2) is associated with aging; it is the most common chronic disease in the postmenopausal period and an important factor that predisposes to cardiovascular disease.

It has been informed that women with DM2 present cessation of menstruation several years before than nondiabetic women; nevertheless, other studies indicate that there are no differences in the age of menopause between diabetic and nondiabetic women [3]. It is accepted that the menopause is earlier in women with DM Type 1 (DM1) due to the premature gonadal failure, expression of the autosomal polyglandular syndrome, which tends to accompany DM1 [4].

Major prevalence of cardiovascular and metabolic diseases as the DM2 has been indicated in the postmenopause. In addition, these women tend to have major presence of sexual and psychological disorders [4]. The progressive and irreversible loss of follicles, typical of the age, would carry the disorder and cessation of the ovarian cycle, which is expressed clinically with irregularities of the cycle, amenorrhea and changes in organ systems with the appearance of local and systemic manifestations that affect negatively the quality of life [5].

There are variations in the natural age of the menopause. The age range of 48–52 years is universally considered for the last menstruation, which is the natural menopause. The North American Menopause Society considers 51 years of age as the mean for the natural menopause [6]. In a study carried out in 6079 Latin American women [7], all of them with age greater than or equal to 55 years were in postmenopause. In other Latin American study [8], with a total of 17,150 healthy women, aged between 40 and 59 years, accompanying patients to health care centers in 47 cities of 15 Latin American countries, the mean age of the entire sample was 49.4 ± 5.5 years.

The menopause that is established beyond 50 years tends to be not related to morbid alterations, contrary to what occurs when it is presented before the age of 45 years. The early menopause is defined as the irreversible cessation of the menstruations between 40 and 45 years, and the premature menopause or premature ovarian failure as the final menstrual retirement before the age of 40 years. These two groups have medical connotations that is totally different in comparison to women who present menopause in the physiological age group [3,4,9].

The loss of the menstrual bleedings for more than 12 months, accompanied by FSH >40 IU/l, before the age of 45 years is a strong criteria to define the presence of early or premature menopause, which could be induced by genetic, family or ethnic factors. The low socioeconomic, educational and nutritional levels, the low or little parity, the smoking habit, the low bodyweight and the reduced body mass index, as well as have never used oral contraceptives are implied [10]. It has been indicated that all these factors when work together or in an isolated way cause direct or indirect deleterious effect about the ovarian function, the hypophyseal gonadotropins or about the steroid precursors, leading to the irreversible deterioration of the ovarian follicle with the establishment of hypoestrogenic state. Still, uncertainties exist on involved mechanisms.

It has been indicated that mutations in the gene-encoding mitochondrial DNA polymerase gamma could be associated with premature menopause and Parkinson disease [11]; the early menopause could be associated with autoimmune diseases as hypothyroidism, DM and Addison disease [4].

The menopause below 40 years of age has been associated with increased risk of early beginning of osteoporosis, cardiovascular disease and Parkinson disease, while it is protective against breast neoplasm [3]. Data of the Framingham study indicated that women who have early menopause have major cardiovascular risk. The early or premature menopause caused by bilateral oophorectomy could be associated with early decline of the cognitive activity [4]. A possible explanation for these effects is the impact that generates the exposition of the tissues to the circulating levels of insufficient estrogens [10].

Monterrosa et al. [7] found that women in the age group of 40–44 years, who were in natural postmenopause, had odds ratio: 2.76 (95% CI: 1.32–5.67) to present DM2, significant that are not in the older age groups.

The fact that diabetes comes at an early age of the menopause could have clinical implications. A North American population study indicated that women who present natural menopause before 40 years of age had an increase of 50% in the mortality compared with women whose nonsurgical menopause was at 50 years of age [12]. A cohort study of Snowdon et al. [13] reported an increase of 95% in the mortality, associated with any cause, when the menopause appears before 40 years of age; and an increase of 35% in women aged between 40 and 49 years compared with women whose nonsurgical menopause occurred at the age of 50 years or more. It could be explained by several interrelated causes such as environmental, genetics or hormonal. The role of these endocrine disruptors in sexual behavior, menopause and some gonadal diseases (cessation of the ovarian cycle) has been examined due to their modulation of estrogen receptor activity. Some endocrine disruptors may also modify DNA methylation in the regulatory region of specific genes [14].

Besides the increase of the cardiovascular risk, the early menopause tends to be associated with early presence of menopausal symptoms due to the estrogen deficiency to minor age. The menopausal hormone therapy (MHT) is the principal therapeutic tool, with the aim to contribute estrogens to suppress the clinical symptomatology and to make a favorable impact on the estrogen-dependent tissues [3,6,7,9]. In the pronouncement of the North American Menopause Society of 2010 [6] about MHT in premature menopause indicated that ‘There are inadequate data regarding MHT in these populations. Most observational reports suggest an increased risk of CHD with early menopause in the absence of MHT and a protective effect of MHT when is administered. The existing data regarding MHT in women experiencing menopause at the median age should not be extrapolated to women experiencing premature menopause. The risks attributable to MHT use by these young women receiving may be smaller and the benefits potentially greater, than those in older women who commence MHT at or beyond the median age of menopause, although no comparative data exist’. It was countersigned in the Position Statement of 2012 [3].

No agency has approved MHT for the prevention of DM2. Nevertheless, in the WHI study, [15], it was demonstrated that the MHT decreased in 21% the risk of beginning of the DM2, [hazard ratio (HR): 0.79; 95% CI: 0.67–0.93], that is 15 fewer cases per 10,000 women per year of therapy. The protective effect of MHT on diabetes risk was less apparent among women with smaller waist circumferences, suggesting that abdominally obese women may benefit more from MHT use or that baseline metabolic status may influence response to MHT. With the same data, it is possible to indicate that to prevent one new case of DM2 over 5 years would require treating 133 women with MHT. Similar results were observed in the Heart and Estrogen/Progestin Replacement Study trial [HR: 0.65; 95% CI: 0.48–0.89] [16] and the WHI-ET trial [17], where there was a 12% reduction [HR: 0.88; 95% CI: 0.77–1.01] in incident DM2 or 14 fewer cases per 10,000 women per year. It also has been documented in the NHS [4]. Even there are no clear mechanisms to explain these findings although hormonal effects on the resistance to the insulin have been involved. Monterrosa et al. [7] did not observe the decrease of the risk of diabetes with MHT.

In this regard, an Endocrine Society Scientific Statement determined that in the Postmenopausal Estrogen and Progestin Intervention trial, fasting glucose levels were reduced in women assigned to MHT; however, 2-h postchallenge glucose levels, which may be associated with CHD risk, were elevated. The effects of the MHT on the secretion of insulin, clearance and tolerance to the glucose are unsubstantial. The endogenous estrogens, in contrast with MHT, are associated with major risk of diabetes, an effect that could be due to inverse association between endogenous estrogen and sensibility to insulin [4]. It is not considered suitable to recommend the MHT for the prevention of DM2 in early or not even natural postmenopause [3,5,6,9].

Mascarenhas-Melo et al. [18] suggest that postmenopausal diabetic women have worse cardiometabolic profile with more atherogenic lipid sketch and proinflammatory and proangiogenic profile than other women. The contents of HDL-c subpopulations and mediators of inflammation and angiogenesis as TNF-α, hsCRP, uric acid and VEGF named as the ‘non-classical’ markers are which better explain this situation. And measures orientate to multitherapeutic intervention, directed to obesity, atherogenic lipid particles and inflammatory mediators, are necessary to prevent some cardiovascular complications of diabetes in this group of women.

Women who present DM2 and receive MHT could require lower doses of medication to control DM2 [4]. To administer transdermal, estrogens could have advantages on the oral route due to its better impact on triglycerides and thrombotic factors that tend to be modified in the DM2 and to be related with an increase in the cardiovascular risk. There are no available clinical trials in this regard.

In the absence of contraindications, it is recommended to women in early or premature menopause the use of MHT until the median age of natural menopause with periodic reassessment. Longer duration of treatment can be considered if needed [3,9]. Prospective randomized trials are needed to determine the ideal rate for MHT in these groups of women.

To conclude, it is important to indicate that DM2 could advance the age of menopause, condition that implies major risk for different morbidities, specifically vascular and metabolic. The MHT might have beneficial effects in the diabetic women, but individualized clinical recommendations and monitoring must be borne in mind when its use is recommended. Therefore, postmenopausal women with DM2, specially early and premature, must receive sanitary integral attention that includes not only the effective managing of the DM2 but also to consider the use of the MHT, but contraindication can be considerate.

Financial & competing interests disclosure

The authors alone are responsible for the content and writing of this paper. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.