Andrea Giannini1, Andrea R. Genazzani1 and Tommaso Simoncini1
(1)
Division of Obstetrics and Gynecology, Department of Experimental and Clinical Medicine, University of Pisa, Via Roma, 67, Pisa, 56126, Italy
Tommaso Simoncini
Email: tommaso.simoncini@med.unipi.it
Management of women with spontaneous premature ovarian insufficiency (POI) should be multidisciplinary [1], with professionals from the various specialties providing the appropriate care to meet the different needs of these women. Specific areas of management include counseling and emotional support, diet and nutrition supplement advice, hormone replacement therapy (HRT), and reproductive health care, including contraception and fertility issues. Ideally, these women should be seen in a dedicated clinic separate from the routine menopause clinic.
The failure in ovarian estrogen production at POI may result in early physical symptoms, which may be weakening, as well as urogenital atrophy, sexual dysfunction, mood changes, bone loss, and metabolic changes that later on prompt the development of cardiovascular disease (CVD) and diabetes. Vasomotor symptoms (VMS) such as hot flushes and cold or night sweats and vaginal dryness are the most common symptoms of onset of the disease; however, frequent climacteric symptoms include sexual dysfunction, mood swings, and anxiety [2]. Hormonal withdrawal also results in increased risk of cardiovascular diseases (CVD), metabolic syndrome, osteopenia, osteoporosis, and urogenital and cognitive disorders if a sufficient estrogen milieu is not re-established [3].
VMS are common hallmarks of early or premature menopause [4]. A hot flush is a sudden episode of vasodilation in the face and neck, which lasts 1–5 min and is accompanied by profuse sweating. Women experiencing hot flushes are reported to have a narrower thermoneutral zone, so that subtle changes of core temperature produce thermoregulatory mechanisms such as vasodilation, sweating, or shivering. Decreasing estrogens and inhibin as well as increasing FSH explain only in part the impaired thermoregulation, which is associated with changes in brain neurotransmitters and peripheral vascular reactivity.
Hot flushes usually occur in the late perimenopause and the first postmenopausal years; however, young patient with POI may indicate VMS, sleep disturbances, and irritability together with menstrual irregularities as some of the first symptoms to occur [5–7].
It is well known that estrogens regulate the dynamic interplay of the bone resorption and formation process. The postmenopausal estrogen decline leads to the unbalance of bone remodeling resulting in excessive resorption because of excess production of the cytokine receptor activator of nuclear factor κB ligand (RANKL) by the osteoblasts, which, upon binding to its receptor RANK on the surface of pre-osteoclasts and mature osteoclasts, stimulates osteoclastogenesis and bone resorption. Osteoprotegerin (OPG), a cytokine secreted by osteoblasts upon estrogen stimulation, is a natural inhibitor of RANKL. Estrogen deficiency is associated with decreased OPG production, further enhancing the RANKL activity [8–10]. Moreover, the age-associated decline in intestinal calcium absorption, vitamin D deficiency and impaired synthesis of active 1,25-dihydroxyvitamin D3 by the kidney contribute to accelerated bone resorption, diminished bone strength and elicited fractures upon minimal skeletal load; thus, the earlier the age at menopause, the higher the risk of osteoporosis later in life [11–13].
For that reason, patients with POI must be educated on osteoporosis prevention and early diagnosis of osteopenia.
Osteoporosis is defined as reduced bone mineral density measured by dual energy X-ray absorptiometry (DXA). While the estimated prevalence of osteoporosis within women aged 40–65 years is low [14], there is a mean vertebral bone loss of 6.4 % and neck of femur loss of 5 % across the menopause transition even with earlier onset for such women with POI [15]. The available data do not support DXA screening for postmenopausal women aged up to 60 years who have no identifiable medical condition or use of medication that is associated with an increased risk of osteoporosis or past history of low trauma fracture [16]. In line with this, the American College of Preventative Practice has recommended that DXA screening be restricted to women between 50 and 65 with one major (such history of menopause prior to age 45 or fragility fracture) or two minor risk factors (such as cigarette smoking or weight under 57 kg) [17]. However, there is growing debate as to which women less than 65 years merit screening such that, presently, no specific recommendations have general acceptance.
Whereas menopause in itself is not associated with weight gain, it often leads to increase of total body fat and redistribution of body fat from periphery to the trunk resulting in the development of visceral adiposity. Abdominal obesity, as well as menopausal estrogen decline, is associated with adverse metabolic modifications such as insulin resistance and predisposition to the development of type 2 diabetes as well as dyslipidemia characterized by high triglycerides, low high-density lipoprotein (HDL) cholesterol, and increased small dense low-density lipoprotein (LDL) particles. Estrogens are able to exert potent vasoactive functions, promoting vascular elasticity and restoration and modifying reactive dilation and local inflammatory [18–20].
Estrogen lack promotes the activation of the renin-angiotensin system, the upregulation of the potent vasoconstrictor endothelin, and the impairment of nitric oxide-mediated vasodilation. Oxidative stress, which is augmented by endothelin and angiotensin-II, may further contribute to the arteriosclerotic process. Therefore, soon after menopause, women show increases in blood pressure, as well as evidence of subclinical vascular disease, demonstrating increased carotid and femoral artery intima-media thickness, coronary artery calcium score, arterial stiffness, and impaired flow-mediated dilation. Clinical events of ischemic heart disease usually manifest 10 years later in women compared to men; they tend, however, to have a more severe prognosis in women [21–23]. The risk of stroke doubles during the first decade after menopause and ultimately exceeds that of men in older ages. Early menopause and primary ovarian insufficiency are consistently associated with increased risk of coronary heart disease, stroke, and mortality if estrogen milieu is not restored [24–28].
The anatomy and function of the female lower genital tract are related to estrogen milieu. Upon menopausal estrogen drop, tissues lining the vagina, the vulva, the bladder, and the urethra undergo atrophy, causing a cluster of symptoms including sense of vaginal dryness, painful intercourse, vulvar pruritus, burning and discomfort, as well as recurrent urogenital infections. Usually, VMS decline throughout the postmenopausal life or after hormonal replacement; on the contrary, urogenital symptoms persist and may have a serious impact on sexual health and quality of life especially in young women with POI [29, 30].
In patients with POI, there is a specific decrease in DHEA and DHEAS levels, and the resulting increased cortisol/DHEA ratio has been hypothesized to be at the basis of the pathophysiology of the so-called “cortisol-potentiated” diseases, such as diabetes, obesity, osteoporosis, and neurodegenerative disorders. Steroids unbalance or withdrawal does not necessarily imply any causal relationship, but patients with POI may reveal general lack of energy and reduced general and sexual well-being and they are less satisfied with their sexual lives. In addition, women with POI have been reported to have more anxiety, depression, somatization, sensitivity, hostility, and psychological distress than women with normal ovarian function [31–33].
Neuroendocrinological studies indicate that estrogens are involved mainly in the maintenance of the homeostasis of the prefrontal cortex, the hippocampus, and the striatum, which are areas controlling learning, elaborations of information, decision, evaluation processes, and language skills. In these regions of CNS, estrogens act both through genomic and non-genomic mechanisms increasing cellular proteins, promoting thus neuronal growth and survival, neural transmission, and function, as well as synaptogenesis [34]. Estrogens, furthermore, limit the inflammatory response in the CNS, helping thus to avoid repeated inflammatory insults which may result in dystrophy and predisposition to degenerative disorders [2]. Most studies indicate that cognitive function is affected by menopause and its hormonal lack, and more precisely, aspects related to verbal memory and fluency. The effect size appears to be small; however, it is often bothersome in the clinical setting for the affected women [35]. Although menopause appears to be associated with changes in cognition, it cannot be assumed that estrogen therapy will prevent cognitive decline. There is general consensus that oral estrogen therapy should not be prescribed to prevent or treat cognitive decline [36, 37]; however, some short-term clinical trials suggest that cognitive and memory functions correlate with sex steroid hormone levels and that estrogen maintained at physiologic levels improves cognitive functions [38]. In summary, some cohort studies reported an increased risk for neurologic impairment following early bilateral oophorectomy, with a suggestion of increased risk when surgical menopause occurs a younger age and reduced risk when estrogen replacement was given. By contrast, two other studies reported limited or memory and cognitive differences among women with early bilateral oophorectomy versus hysterectomy or natural menopause [39, 40].
Recommendations regarding duration of hormonal therapies in patients affected by POI need to be individualized and depend on the endpoints of treatment in different moments of women’s life. For women with premature POI, or early menopause (before age 45), hormonal compounds can be continued at least until the average age of the natural menopause at which the time needed for ongoing HRT should be reconsidered. There are no conventional limits regarding the duration of HRT; it can be used for as long as the woman feels that the benefits balance the risks for her and decisions must be made on an individual and on an ongoing basis. When HRT is initiated for VMS, clinicians should attempt to improve symptom control using the lowest hormonal therapeutic dose through periodic reassessments and dose reduction. The medical choice to continue HRT must be individualized based on patient’s needs, symptom severity, her individualized risk for breast cancer and vascular events, and with due regard to patient’s preference and wishes. In this view and with the aim to prevent long-term complications, patients must be educated to take non-hormonal treatments, do physical activity, and adopt a healthy diet and lifestyle throughout years.
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