Definition, Aetiology

Premature ovarian insufficiency (POI) is characterized by oligo/amenorrhoea with high gonadotropin and low estradiol levels in women before 40 years of age. Follicle-stimulating hormone (FSH) cut-off value is above 40 IU/L [2] or over 25 IU/L [3] on two occasions more than 4 weeks apart. It is not ‘the loss or cessation’ of ovarian activity but a significant decrease. Some significantly decreased level of ovarian activity is present for the whole life and an extremely low number of follicles always remain. Possible initiation of ovarian activity depends of the complete endocrine milieu. Our goal will be to diagnose ovarian insufficiency in the very beginning, with FSH over 15 IU/L in order to initiate therapy on time.

The etiology of POI still remains an enigma for many cases. There are well-known chromosomal abnormalities, enzyme changes, autoimmune diseases, FSH receptor gene polymorphism, inhibin B mutations, rare infection diseases, etc. However, in our study on 1500 POI patients, stress was a triggering factor in 56 per cent cases. Among many stressors divorce or separation from the partner was the most prominent one.

POI and AGING

In 2009, the Nobel Prize in Physiology or Medicine was awarded to Drs Blackburn, Szostak and Greider for the explanation of how chromosomes are protected by telomere and the enzyme telomerase. Telomerase is responsible for the synthesis of chromosomal DNA ends. A significant association was found between shortening of telomerase repeats upon successive cell division, limiting viability and ending with cell death and a reduction of the replicative life span of cultured human cells, consistent with the early genetic evidence that short telomeres induce senescence. Introduction of telomerase into the normal human cells extends life span [4]. Mutations in genes encoding components of the telomerase complex cause hereditary disease characterized by defects in the stem cell renewal and tissue maintenance. Stressors triggering POI can influence telomerase and accelerate the biological clock.

In such an imbalance of homeostasis and loss of adaptive mechanism, resistance and resilience, POI is in the correlation with the inflammatory aging. Oxidative stress refers to an imbalance between oxidation and antioxidation leading to neutrophil infiltrations. Increase in interleukin 6, interleukin 8, interleukin 1 β, interleukin 10, tissue growth factor beta, interferon γ, prostaglandin E2 and decrease of tumour necrosis factor α, interleukin 2 were detected in POI. Antioxidants help organisms to fight against free radicals. They can be divided into two groups:

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  Enzymatic: superoxide dismutase, catalase, glutathione peroxidase, transferase, tiol disulphid oxidoreductase;

  
  
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  Non-enzymatic: transferin, ferritin, lactoferin, haemoglobin, lactoferrin, albumin, glutathione, ascorbic acid, A-tocopherol, ubihinon, beta-carotene, uric acid, bilirubin.

Decreased gama-glutaril transpeptide and diacron reactive oxygen metabolites were found, while C-reactive protein was increased. In POI patients DNA damage continues to accumulate leading to cell death. Autophagic cleansing capacity declines gradually. Dysfunctional protein accumulation in mitochondria increases levels of reactive oxygen species and oxidative stress [5]. Resveratrol restores ovarian function by increasing AMH and decreasing inflammation through upregulation of expression of the peroxisome proliferator-activator receptor and SIRT1 (sirtun) inhibiting interferon γ-induced inflammatory cytokines [6].

Hypoestrogenism, hypoprogesteronism and hypoandrogenism lower DHEA-S in POI and induce detrimental life events leading to increased mortality rates and premature death. Typical symptoms and signs of POI are hot flushes (narrower thermo-ventral zone), mood swings, anxiety, depression, loss of concentration, insomnia, loss of libido, dyspareunia, etc. Late complications of untreated POI are cardiovascular diseases, osteoporosis, cognitive impairment, depression, Alzheimer’s disease, Parkinson’s disease, etc., thus significantly decreasing quality of life and life expectancy.

Cardiovascular Diseases

William Harvey’s discovery that the heart pumps blood and the blood circulates (1628) was fundamental for later understanding that gonadal steroids influence all blood vessels and organ functions, creating optimal quality of life.

Tao XY [7] found 48 per cent higher risk for ischaemic heart disease in POI patients, compared to the risk in women with the last menstruation around the age of 50 years. Ten observational studies (1966–2012) on 190 588 women with 9440 events showed that POI is an independent risk factor for ischaemic heart disease and coronary vascular disease [8]. It has been well documented that untreated women have a higher mortality rate [9, 10, 11] (Table 5.1).

Wu X in Shanghai Women’s Health Study in a group of 1003 POI patients found increased risk of mortality with hazard ratio (HR) of 98 per cent, confidence interval of 1.29 [12].

Women with POI are at increased risk of cardiovascular diseases and should be informed about risk factors which they can modify through behavioural changes (stopping smoking, regulating body weight, limiting alcohol intake, controlling stressors, etc.).

Hypoestrogenism exerts effects on many levels: lipids, insulin resistance, obesity, inflammation, hypertension, vasoconstriction, endothelial dysfunction, autonomic nervous system dysfunction, nitric oxide disturbances, impaired flow-mediated dilatation [13]. Benefits of early initiation of estrogens and progestogens and menopausal hormone therapy (MHT) have been confirmed in many recent trials and in meta-analysis. The dose and type of hormones at initiation of therapy appeared crucial to obtaining coronary heart disease benefits [14].

Estrogen reduces cholesterol levels, decreases low-density lipoproteins (LDL) cholesterol levels and upregulates apolipoprotein B₁₀₀ receptor. Small dense LDL particles, prone to oxidative damage, clear through scavenger mechanisms and become embedded in the subendothelial space. Estradiol increases high-density lipoprotein, particularly HDL₂ subfraction. It inhibits hepatic lipase activity and increases the hepatic synthesis of apolipoprotein A1, the main protein component of HD_l and HDL₂. Oral estrogens increase triglycerides, while androgenic progestogens reduce or reverse them. Transdermal estradiol reduces triglycerides, reducing the risk of coronary heart disease (CHD). Matrix metalloproteinase normalizes vascular remodelling by estradiol therapy. Oral and transdermal estrogens and progestogens reduce activity of angioconverting enzyme (ACE) reducing cardiovascular disease. Progestogen drospirenone has antimineralocorticoid effects and influences the renin–angiotensin–aldosterone system by blocking the effects of aldosterone [15].

Estradiol therapy has antioxidative effects, by increasing levels of endothelial nitric oxide synthase and production of nitric oxide regulating blood pressure, platelet function, vascular smooth muscle proliferation and the expression of adhesion molecules. It reduces the release of endothelin 1, a potent vasoconstrictor exerting anti-inflammatory effects on blood vessels. Calcium channels are inhibited and BKCa channels stimulated by estradiol therapy inducing vasodilatation and improving arterial function, heart rate variability, baroreceptor sensitivity. It modulates arrhythmia vulnerability. Slopes are steeper and QT dynamics are impaired in POI. Canpolat and colleagues showed that therapy with 17 β estradiol could exert an antiarrhythmic effects by inhibition of Ca 2⁺ channels [16]. In Table 5.2 most prominent effects of estradiol therapy are presented. Vascular effects show beneficial changes in vasodilation and vasoconstriction mechanisms, vascular remodelling and inflammatory cytokines. Data obtained with ambulatory blood pressure monitoring and with transdermal estradiol and drospirenone are concordant with definitively positive effects on blood pressure compared to control group.

MHT is strongly recommended and has to be initiated early, at the onset of symptoms in an adequate dose. Therapy should be continued until the average age of the natural menopause at least. According to International Menopause Society (IMS) statements, there is no time limiting for menopause hormone therapy. It has to be individually tailored, with appropriate dosages and routes of administration.

Metabolic Changes

Estradiol regulates many of the key enzymes involved in mitochondrial bioenergetics including glucose transporters, required for the regulation of glucose uptake in cells and tissues. GLUT4 is regulated by insulin receptor Akt/Tor signalling network. Disturbances in insulin metabolism in the endometrium decrease endometrium receptivity and fertility rate and trigger obesity, insulin resistance and diabetes mellitus later in life [17]. Adipocyte hypertrophy, adipose tissue inflammation, fat liver, changes of glucose uptake from the circulation, without changes in ‘de novo’ free fatty acid synthesis create redistribution of body fat to centripetal, metabolic type. Kulaksizoglu and colleagues found increased serum glucose, insulin homeostatis model of assessment insulin resistance (HOMA) in POI patients with hypoestrogenism [17].

Tissue resistance to insulin increases the risk of developing coronary heart disease and type 2 diabetes mellitus. Estrogen has beneficial effects on the metabolism of glycose and insulin improving insulin sensitivity. Oral estrogens have greater effects compared with transdermal estrogen. These effects can be impaired by addition of androgenic progestogens (norgestrel, medroxyprogesterone acetate), while non-androgenic progestogens do not have this unwanted effect.

Hypoestrogenism leads to weight increase of 5 kg, and redistribution of fatty tissue to more central type, leading to metabolic syndrome. MHT reverses this change of body fat distribution by increasing levels of endothelial nitric oxide synthase and production of nitric oxide.

Decreased dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEA-S) in POI patients result in increased ratio of cortisol to DHEA creating ‘cortisol potentiated diseases’: obesity, insulin resistance, diabetes mellitus type 2, osteoporosis, neurodegeneration.

Hyperinsulinism increases LH directly in the pituitary. Treating insulin resistance with metformin alters energy metabolism in cells. It lowers glucose levels by inhibiting hepatic gluconeogenesis and opposing the actions of glucagon. The primary site of metformin action is at the mitochondria. The inhibition of mitochondrial complex I of the electron transport chain induces a drop in energy charge, resulting in adenosine triphosphate (ATP) decrease. Adenosine monophosphate (AMP) increases binding of P-site adenylate cyclase enzyme and inhibition of activity leading to defective cAMP protein kinase A (CAMPK) signalling on glucagon receptors. AMPK is an energy sensor and a master coordinator of an integrated signalling network that comprises metabolic growth pathways acting in synchrony to restore cellular energy balance. It switches on the catabolic pathway that generates ATP and switches off anabolic pathways. Stimulation of 5’-AMP activated protein kinase confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin increases glucose uptake in skeletal muscles. It blocks insulin receptor /R/3 K/Akt/mTOR signalling in the hyperplastic endometrial tissue inducing GLUT4 expression and inhibits AR expression [18].

Metformin suppress food intake by increasing levels of glucagon-like peptide1, interaction with ghrelin and leptin on the T-cell memory by altering fatty acid metabolism [19]. Insulin resistance with increasing LH in the menopause plays a role in adrenal tumorigenesis showing us that early detection and treatment of insulin resistance can be protective for many diseases [20].