Journal of Mid-life Health Journal of Mid-life Health
Home | About us | Editorial board | Search | Ahead of print | Current Issue | Past Issues | Instructions | Online submission | Subscribe | Advertise Users Online: 1680  Print this pageEmail this pageSmall font sizeDefault font sizeIncrease font size 

 Table of Contents 
Year : 2013  |  Volume : 4  |  Issue : 3  |  Page : 140-146  

The role of oxidative stress in menopause

Department of Andrology, Center for Reproductive Medicine, Cleveland Clinic, Cleveland, Ohio, USA

Date of Web Publication26-Sep-2013

Correspondence Address:
Ashok Agarwal
Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195
Login to access the Email id

Source of Support: Support is from the Center for Reproductive Medicine, Glickman Urological and Kidney Institute, Cleveland Clinic, Conflict of Interest: None

DOI: 10.4103/0976-7800.118990

Rights and Permissions

This review will discuss the concept of reproductive aging, which includes the definition of menopause, its symptoms, and predisposing conditions. It will elaborate upon the contributory factors implicated in the pathogenesis of menopause, focusing most prominently on oxidative stress. Specifically, this paper will explain how oxidative stress, in the form of free radicals and antioxidant deficiencies, has been directly linked to the decline of estrogen during reproductive aging. Additionally, this paper will elaborate upon the treatment options aimed at mitigating the menopausal symptoms and hormonal deficiencies that can lead to various disease processes. Treatment options such as hormonal therapy, antioxidant supplementation, and lifestyle modification have been explored for their effectiveness in treating and preventing the symptoms and sequelae of menopause. The majority of information in this review was obtained through PubMed and the National Library of Medicine. While most references in this paper are original research articles, a limited number of references are comprehensive reviews on the topic.

Keywords: Antioxidants, cardiovascular disease, catalase, estrogen, hormonal therapy, hot flashes, malonaldehyde, menopause, osteoporosis, oxidative stress, phytoestrogens, reproductive aging, superoxide dismutase, Vitamin A, Vitamin C, Vitamin E

How to cite this article:
Doshi SB, Agarwal A. The role of oxidative stress in menopause. J Mid-life Health 2013;4:140-6

How to cite this URL:
Doshi SB, Agarwal A. The role of oxidative stress in menopause. J Mid-life Health [serial online] 2013 [cited 2022 Dec 10];4:140-6. Available from:

   Introduction Top

Menopause, a form of reproductive aging, is defined as the permanent cessation of ovarian follicular activity and eventually, the menstrual cycle. [1],[2] Normally, menopause is a natural process of the body; however, it can be the result of other causes such as surgery, chemotherapy, or iatrogenic insult. [1] Additionally, two hormones (progesterone and estrogen) integral to reproductive aging are no longer produced during menopause. [3],[4],[5] Specifically, the decline and eventual cessation of estrogen production has been shown to cause a variety of symptoms during menopause, affecting each woman differently. These include hot flashes, night sweats, breast tenderness, vaginal dryness, irregular menses, mood changes, vaginal atrophy, osteoporosis, heart disease, and sometimes premature ovarian failure. [6] Many therapies have targeted this hormonal decline in estrogen and have also expanded to include lifestyle modifications, such as diet and exercise. [7] Additionally, foods rich in antioxidants have been shown to be of great benefit in women experiencing menopausal symptoms because they help to eliminate oxidative stress within the body. Overall, this paper will discuss in great detail the stress of free radicals and antioxidant deficiencies, both of which play a role in the pathogenesis of menopause. [3]

   Methods Top

The majority of information in this review was obtained through English-only articles from the PubMed and National Library of Medicine databases. Only literature containing up-to-date and relevant information on the topic was selected, starting from 1988 to 2013. Specifically, the following key terms were used to generate the literature search for this review paper: Menopause, oxidative stress, antioxidants, estrogen, free radicals, herbal antioxidants, pharmacotherapy, hormonal therapy, phytoestrogens, osteoporosis, cardiovascular disease, and vasomotor disturbances. While most references in this paper are original research articles, a limited number of references are comprehensive reviews on the topic.

   Hormonal and Chemical Imbalances of Menopause Top

Menopause is a gradual process that occurs over a period of years in females who are typically between 45-55 years of age. It marks the beginning of a woman's age-related fertility decline via a decrease in the number of ovarian follicles produced. [2] This change in reproductive potential is the direct result of a decline in production of hormones by the ovaries, which causes physical manifestations that negatively impact the quality of life of menopausal women. [3] In regards to the hormonal changes that occur, the earliest involves a rise in follicle stimulating hormone (FSH) followed years later by a rise in luteinizing hormone (LH). [4] Studies have attributed this rise in FSH during menopause to a decreased production of inhibin B, a dimeric glycoprotein that suppresses FSH. [8] Specifically, this compound was found to decline during both the follicular and luteal phases of the menstrual cycle, causing a rise in the FSH levels, and is therefore considered an early indicator of reproductive aging. [3] Overall, these hormonal imbalances resulting from the permanent cessation of ovarian function contribute to significant changes in the menstrual bleeding patterns during the perimenopausal period. [6]

In addition to changes in FSH and LH levels, there is a substantial decrease in the amount of estrogen produced during menopause. Acting as a lipophilic hormone, estrogen normally helps to promote female secondary sexual characteristics, such as breast development and female patterned hair growth. It not only plays a pertinent role in the female reproductive system, but also induces a variety of beneficial effects in other areas of the body. [9] Specifically, this hormone increases hepatic production of binding proteins like sex hormone binding globulin, maintains appropriate fluid balance in the body by allowing for salt and water retention, promotes coagulation, and it allows for a favorable lipid profile via increases in high density lipoprotein (HDL) and decreases in low density lipoprotein (LDL). [9],[10]

Estrogen's release is mediated by FSH produced from the anterior pituitary gland, which in turn stimulates the granulosa cells of the ovary to synthesize estrogen. Specifically, in the ovary, estrogen is produced from the conversion of androgens via the enzyme aromatase [11] [Figure 1]. Moreover, estrogen is synthesized in three forms: Estradiol, estriol, and estrone. [12] Specifically, 17β-estradiol is the most common and potent form of estrogen predominating during the premenopausal and perimenopausal periods; whereas estrone, the much weaker form, is prevalent during the postmenopausal phase. The latter form of estrogen is normally produced from the conversion of androstenedione in adipose tissue and the liver. [13] In addition to being produced in the ovaries and a portion of the ovary known as the corpus luteum, estrogens are synthesized in smaller amounts by other tissues, such as adrenal glands, fat cells, breast tissue, and hepatocytes. [12]
Figure 1: Two cell theory of estrogen production: Luteinizing hormone stimulates the production of androstenedione from cholesterol in the theca cells. This androgen is then transported to the granulosa cells, where it is converted to estrone. Follicle stimulating hormone then promotes the conversion of estrone to 17β-estradiol in the ovaries

Click here to view

Another reproductive hormone that declines significantly during menopause is progesterone. Also lipophilic in nature, progesterone promotes the secretory stage of the endometrium in order to prepare the uterus for implantation and decreases the maternal immune response to allow for the body's acceptance of pregnancy. [5],[14] Moreover, this hormone thickens cervical mucus so it is impenetrable to sperm, inhibits lactation during pregnancy such that its fall after delivery triggers milk production, and decreases the contractility of the uterine smooth muscle. Overall, it is evident that a wide variety of hormonal and chemical changes occur in the female body as a result of menopause.

   Implications of Oxidative Stress in Menopause Top

Oxidative stress plays an integral part of the aging process and results from the overproduction of free radicals such as reactive oxygen species (ROS), which overwhelm the body's antioxidant defense mechanisms. Normally, antioxidants neutralize ROS and thus help to prevent over exposure from oxidative stress. [15],[16] However, as the body ages, antioxidant levels decline, leaving the human body susceptible to a variety of age-related pathologies, such as non-alcoholic liver cirrhosis and atherosclerotic heart disease. [17],[18] This decline combined with a gradual loss of estrogen in the female reproductive system is highly associated with the various sequelae of menopause such as heart disease, vasomotor disturbances, and osteoporosis. [18],[19] The marked reduction in estrogen has been shown to increase levels of oxidative stress in the body, depending on the concentration and chemical structure of this hormone. Specifically, at high concentrations, estrogen tends to have a beneficial antioxidant effect by inhibiting the 8-hydroxylation of guanine DNA bases. However, at low concentrations, this hormone has pro-oxidant like effects, especially when its chemical structure contains a catechol. These effects include breaks in genetic material, formation of DNA adducts, and oxidation of bases. [20] Additionally, serum concentrations of inflammatory cytokines and pro-oxidant biomarkers such as glutathione, 4-hydroxynenal, and malonaldehyde were found to be higher in postmenopausal women than in premenopausal women. [21] The elevation of cytokines and pro-oxidant makers suggests that there is a high degree of oxidative stress in the postmenopausal state. [21],[22]

Cardiovascular effects of menopause

Estrogen has been shown to play a physiologic role in the cardiovascular system by protecting against heart disease. This is facilitated via its atheroprotective effect on plaque stabilization and collateral vessel formation. [23],[24] This hormone also has favorable effects on insulin, glucose, and lipoprotein levels in the serum. [24] However, because the antioxidant effect of estrogen is lost once women reach menopause, the incidence of atherosclerosis increases. [17] This is due to a variety of factors, one of which is a higher level of oxidized LDL in the blood. [21],[24] Also, there is an overexpression of the angiotensin receptor, AT-I, in menopausal women, which contributes to the endothelial dysfunction and increased vasoconstriction seen in atherosclerosis. [25] Additionally, studies have shown that postmenopausal women have low levels (<1 μM) of nitric oxide, a natural vasodilator in the body. Such low levels have been shown to play a role in cardiovascular disease by allowing for more smooth muscle proliferation, inflammation, and atherogenic effects on the vasculature. [26],[27] The higher levels of nitric oxide normally seen in premenopausal women provide cardioprotective effects and inhibit the propagation of smooth muscle typically seen in heart disease. [27] Furthermore, the marked reduction of estrogen during menopause increases free fatty acid levels. This makes postmenopausal women more susceptible to the metabolic syndrome and insulin resistance, both of which are implicated as risk factors for cardiovascular disease. [28] Thus, it is evident that the effects of declining estrogen and other substances during menopause can predispose women to cardiovascular disease.

Vasomotor disturbances

Oxidative stress is also involved in the pathogenesis of menopausal symptoms, such as vasomotor disturbances. These disturbances include hot flashes or night sweats. Hot flashes are defined as a sudden feeling of warmth usually over the face, neck, and chest. During a hot flash, the metabolic rate temporary increases, which often results in sweating, panic, and irritability. [29],[30] Throughout menopause, there are repeated episodes of such vasomotor disturbances, which results in a prolonged increase of the metabolic rate. This increase has been show to contribute to the formation of oxidative stress by placing a hindrance on antioxidants and their function in neutralizing ROS. [29]


Osteoporosis is defined as a reduction in bone mineral density, which occurs when there is an imbalance between the creation of new bone and removal of old bone. A decline in estrogen has been shown to play a major role in this decreased bone mass during the onset of menopause, especially because it has a variety of protective effects on bone marrow and bone cells. [31],[32] This can be seen via estrogen's significant impact on bone-resorbing osteoclasts, which are cells involved in the breakdown of organic bone and removal of mineralized matrix. In particular, this hormone allows for increased bone formation by reducing the production and function of these osteoclasts as well as increasing osteoclast apoptosis. This effect on the osteoclastic cells of the bone is facilitated via estrogen's inhibition of two signaling molecules, RANKL and CSF-1, which are involved in osteoclast differentiation and survival. [31],[32],[33],[34] However, due to the estrogen deficiency during menopause, this beneficial effect on the bone is lost.

As stated earlier, the menopause induced hormonal deficit has been linked to an increase in inflammatory cytokines within the serum such as tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, and IL-12. These cytokines stimulate osteoclast and osteoblast formation, leading to increased bone turnover and eventually, bone loss. [22] Specifically, TNF-α, produced from macrophages and granulocytes, negatively impacts the bone by contributing to increased osteoclast formation. This occurs via direct stimulation of pro-osteoclastogenic activity of stromal cells. [22] Additionally, the high levels of FSH during menopause stimulate osteoclast differentiation and TNF-α production, both of which play an important role in osteoporotic bone loss. [35] Overall, it is evident from the role of pro-inflammatory cytokines and estrogen in bone remodeling that oxidative stress is a major contributor to bone density loss in osteoporosis.

Effects of oxidative stress on menopause

In healthy, premenopausal women there is usually an appropriate balance between free radical species and antioxidant mechanisms. As such, the level of oxidative stress in these women is not sufficient enough to affect the ovaries until the onset of menopause. In the aforementioned paragraphs, it has been stated that menopause creates a pro-oxidant state in the body due to the decline of the natural antioxidant, estrogen. [9],[15] Consequently, the question often arises if oxidative stress can lead to menopause. The majority of studies have shown that oxidative stress alone in premenopausal women cannot induce menopause, but rather can lead to a variety of pathologies. Specifically, studies have reported that oxygen radicals have an important physiologic role within the ovary. However, the continuous synthesis of these harmful agents over time may lead to an increased cumulative risk of ovarian pathology. This includes premature ovarian failure, which is suggested to be exacerbated under conditions of reduced antioxidant status such as infection and autoimmune disease. [36]

   Treatment Options for Menopause Top

Menopausal hormone therapy

MHT has been extensively researched as a potential treatment for the debilitating symptoms and sequelae of menopause. The aim of hormonal therapy is to enhance antioxidant defense mechanisms and decrease levels of oxidative stress in postmenopausal women. [37] A variety of researchers have found an association between MHT and its beneficial effect on oxidative stress. As such, most studies favor its administration to menopausal women. However, due to the fact estrogen has antioxidant and pro-oxidant characteristics, as well as a multitude of adverse side effects, some studies have not approved its use for the treatment of menopausal symptoms. A few studies even suggest that MHT has no significant effects on oxidative stress levels. [38],[39]

Hormonal therapy has been shown to improve a variety of menopause-induced pathologies in the body, such as atherosclerotic heart disease. Specifically, the estrogen-progestin pill has been shown to reduce the risk of cardiovascular disease by opposing atherosclerosis. This is carried out via estrogen's downregulation of inflammatory markers such as chemokines and cell adhesion molecules. [24] Furthermore, it has been shown to potentially stabilize atherosclerotic plaques by reducing the expression of matrix metalloproteinases and the production of plasminogen activator inhibitor-1. [40] MHT also aids the cardiovascular system by downregulating both angiotensin receptor gene expression and smooth muscle proliferation. The former effect helps to lower blood pressure, while the latter aids in the prevention of atherogenesis. Additionally, the high concentrations of estrogen in MHT promote the dilation of vessels through the production of prostacyclin, inhibition of endothelin synthesis, and blockage of calcium channels. [40],[41]

In addition to its advantageous effect on the cardiovascular system, hormonal therapy has been shown to have a similar effect on vasoactive biomarkers. For example, a study conducted on healthy postmenopausal women demonstrated that MHT given for 1 year significantly reduced levels of catecholamines, mean blood pressure, and LDL cholesterol while increasing levels of nitrite and nitrate. This suggests that MHT has a cardiovascular benefit in those who are menopausal. [38] Interestingly, it also showed that the amount of oxidative stress in the body was not greatly altered by 12 months of MHT usage. This was measured via the oxidative stress biomarker 8-epi PGF , which did not significantly differ from its baseline value. [38] Other studies discussing the effect of hormonal therapy on oxidative stress showed decreases in serum lipid peroxides and upregulation of overall antioxidant status. Overall, it is clear that a definitive relationship exists between MHT and oxidative stress levels; however, the nature of this relationship cannot be confirmed. [42],[43]

There are a considerable number of risks and side effects associated with MHT. These include increased risk of a pulmonary venous embolism, stroke, and cardiovascular events as well as a high incidence of estrogen-dependent breast, ovarian, and endometrial cancers. [39] It has been suggested that there is a certain window during the postmenopausal period in which MHT is most beneficial. Outside this time frame, estrogen intake can have detrimental effects on the body. The timing of MHT is crucial because the longer menopause continues, the greater the estrogen deficiency, which leads to a decreased activity of estrogen receptors. This reduced receptor activity, in turn, leads to severe endothelial dysfunction and eventually decreased vascular responsiveness as well as decreased effectiveness of MHT. [44]

Overall, current research indicates that postmenopausal women should use the lowest possible dose of MHT due to the aforementioned side effects. [45] However, long-term use of MHT may prevent cardiovascular disease if started in women at the onset of menopause. As such, the benefits of this pharmacotherapy seem to outweigh the risks for women under 60-year-old. [46]

Selective estrogen receptor modulators

SERMs are a class of compounds that act on the estrogen receptor, exhibiting agonistic actions of estrogen in some tissues and antagonistic actions in others. Two examples of SERMs are raloxifene and tamoxifen. [47] The former drug has antagonistic action in the uterus and breast, but agonistic action on the bone. Thus, the main use of raloxifene is to prevent and treat osteoporosis. Tamoxifen, however, acts as an agonist of estrogen receptors in the uterus but has antagonistic effects on the breast. Thus, its main use is to treat breast cancer. Similar to estrogen, raloxifene acts as an antioxidant due to the phenolic rings comprising its chemical structure. [47],[48] Specifically, raloxifene's mechanism of action aims at decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, an enzyme that produces free radical species. This is facilitated via the downregulation of rac1 protein, which is required for NAPH oxidase activation. [49]

Additional beneficial effects of this SERM includes an increase in superoxide dismutase levels, a free radical scavenger, an increase in nitric oxide release, and a compound that suppresses smooth muscle proliferation and atherogenesis. Furthermore, raloxifene improves the lipid profile by preventing macrophage lipid oxidation and it also decreases levels of pro-oxidant biomarkers with the blood, such as malonaldehyde. [49],[50] Additionally, raloxifene may play a protective role in the cardiovascular system by improving endothelial function and decreasing blood pressure levels as demonstrated in a study conducted on hypertensive rats. [50] Overall, by targeting the estrogen-mediated pathways, harmful results of oxidative stress can be prevented in postmenopausal women.


Exercise has been shown to modulate levels of oxidative stress within the body through a variety of mechanisms. Studies have reported transient increases in ROS concentrations following acute aerobic and anaerobic exercise. However, this increased oxidative stress may serve as a necessary signal for upregulation of antioxidant defense mechanisms and eventual reduction of free radical species. [50],[51] Specifically, exercise training has been associated with reduced basal oxidant production and free radical leak during oxidative phosphorylation, both of which contribute to the high oxidative stress levels seen during menopause. [51] Moreover, physical activity has been shown to alleviate menopausal symptoms and sequelae, such as sweating, anxiety, depression, hot flashes, osteoporosis, and cardiovascular disease. [52],[53] In particular, one study reported that postmenopausal women had higher levels of oxidative stress associated with increased fat content than women who were premenopausal. Therefore, exercise in this population is helpful to reduce body fat, which is highly beneficial in augmenting the antioxidant capacity of the body. [54],[55] Overall, exercise has been proven to be a valuable, cost-effective option in alleviating menopausal symptoms and improving the redox balance in healthy, postmenopausal women. [7]

   Dietary Treatment of Menopause Top

Consumption of foods rich in antioxidants may be helpful in enhancing the beneficial effects of pharmacotherapy for postmenopausal patients. [56],[57] Specifically, women who cannot tolerate the adverse side effects of MHT or are prone to develop estrogen-dependent breast cancer may find it advantageous to use dietary antioxidants to control the symptoms of menopause. Supplementation with antioxidants will not only improve the quality of life of menopausal women exposed to high amounts of oxidative stress, but also from other lifestyle-related factors such as smoking, stress, excessive alcohol consumption, and unhealthy eating habits. [57] The following antioxidants were found to be beneficial to women in the perimenopausal and postmenopausal phases: Vitamin C, Vitamin E, phytoestrogens, melatonin, Acanthopanax senticosus, klamin, Curcuma longa, grape polyphenols, and lycopene. Only the most relevant antioxidants will be discussed.

Vitamin C and E

Two dietary vitamins, vitamin C (ascorbic acid) and E (α-tocopherol), can be used to thwart the onset of various disorders associated with an age-related decrease in estrogen. Rich in their antioxidant capacity, these vitamins scavenge free radicals and neutralize oxidative stress. [58] One study assessing the effect of these vitamins on postmenopausal women found higher levels of the oxidative stress marker, malonaldehyde, and lower levels of the antioxidant enzymes, catalase and superoxide dismutase, in those who did not incorporate vitamin C and E in their diet. [59] These vitamins were not only helpful in achieving a favorable redox balance in the body, but they also are associated with a reduced risk of cardiovascular disease. This is mediated via their inhibition of cholesterol synthesis and LDL-cholesterol oxidation. [58],[60]

In regards to the symptoms of menopause, both vitamins have been shown to reduce the intensity and number of hot flashes via promotion of adrenal function. This allows for increased hormonal production, specifically estrogen, allowing for a greater antioxidant defense system in postmenopausal women. When considering vitamin C alone, its intake has been associated with a protective effect on bone. This can be seen through its suppressive action on osteoblast and osteoclast activity, which thereby prevents accelerated bone turnover and eventual bone loss. [61],[62]

However, at high doses, vitamin C and E have deleterious effects on the body. Specifically, large quantities of vitamin C (>2,000 mg/day) have been suggested to cause diarrhea, abdominal cramps, bloating, nausea, vomiting, and kidney stones. [61] While high doses of vitamin E (>1,000 mg/day) may increase the risk of bleeding by having an anticoagulant-like effect on the body and may also increase the risk of birth defects. Thus, when using vitamin C and E to quell the adverse effects of menopause, it is important that appropriate dosages be used. [56]

   Conclusion Top

Within the female reproductive system, menopause is a key physiological phenomenon associated with eventual cessation of ovarian function and thus, the menstrual cycle. During this time period, estrogen becomes deficient, which is an established antioxidant in the body. This leads to oxidative stress in various tissues due to the release of ROS, leading to the development of a variety of symptoms and pathologies that characterize menopause. Specifically, oxidative stress has been linked to an increased risk of osteoporosis and cardiovascular disease and a greater frequency of vasomotor symptoms. Therefore, a multitude of therapies have been employed to target this estrogen deficit and unfavorable redox balance, the most promising of which are MHT therapy and SERMs. However, for those who cannot tolerate the adverse side effects of these pharmacological therapies, exercise and antioxidant supplementation can also be used to quell the symptoms of menopause. However, further investigation needs to be done regarding the efficacy and safety of these various treatments when used in clinical practice. Overall, because a wide variety of treatment options are now available to prevent and reverse the negative effects of oxidative stress associated with reproductive aging, the specific treatment selected should be chosen based on the history and clinical presentation of the patient.

   Take Home Message Top

Though the levels of oxidative stress rise inevitably in menopause due to declining levels of estrogen, this article has put forth methods that women can use to curb the deleterious sequelae effects of this condition.

   References Top

1.Mishra GD, Kuh D. Health symptoms during mid-life in relation to menopausal transition: British prospective cohort study. BMJ 2011;344:e402.  Back to cited text no. 1
2.te Velde ER, Scheffer GJ, Dorland M, Broekmans FJ, Fauser BC. Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol 1998;145:67-73.  Back to cited text no. 2
3.Li Q, Geng X, Zheng W, Tang J, Xu B, Shi Q. Current understanding of ovarian aging. Sci China Life Sci 2012;55:659-69.  Back to cited text no. 3
4.Djahanbakhch O, Ezzati M, Zosmer A. Reproductive ageing in women. J Pathol 2007;211:219-31.  Back to cited text no. 4
5.Fitzgerald C, Zimon AE, Jones EE. Aging and reproductive potential in women. Yale J Biol Med 1988;71:367-81.  Back to cited text no. 5
6.Hoffman B, Schorge J, Halvorson L, Bradshaw K, Cunningham F. William's Gynecology, 2 nd ed. New York City: The McGraw Hill Companies; 2012. p. 1-1399.  Back to cited text no. 6
7.Gudmundsdottir SL, Flanders WD, Augestad LB. Physical activity and cardiovascular risk factors at menopause: The Nord-trøndelag health study. Climacteric 2013.  Back to cited text no. 7
8.Welt CK, McNicholl DJ, Taylor AE, Hall JE. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endrocrinol Metab 1999;84:105-11.  Back to cited text no. 8
9.Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: Altered profiles of steroid and pituitary hormones, SHBG, and bone mineral density. Maturitas 1995;21:103-13.  Back to cited text no. 9
10.Velarde MC. Pleiotropic actions of estrogen: A mitochondrial matter. Physiol Genomics 2013;45:106-9.  Back to cited text no. 10
11.Merlotti D, Gennari L, Stolakis K, Nuti R. Aromatase activity and bone loss in men. J Osteoporos 2011;2011:230671.  Back to cited text no. 11
12.Sluijmer AV, Heineman MJ, Koudstaal J, Theunissen PH, de Jong FH, Evers JL. Relationship between ovarian production of estrone, estradiol, testosterone, and androstenedione and the ovarian degree of stromal hyperplasia in postmenopausal women. Menopause 1998;5:207-10.  Back to cited text no. 12
13.Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Biol Med (Maywood) 2004;229:1127-35.  Back to cited text no. 13
14.Dodd JM, Crowther CA. The role of progesterone in the prevention of preterm birth. Int J Womens Health 2009;1:73-84.  Back to cited text no. 14
15.Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The role of oxidative stress of female reproduction: A review. Reprod Biol Endrocrinol 2012;10:1-32.  Back to cited text no. 15
16.Ruder EH, Hartman TJ, Bumberg J, Goldberg MB. Oxidative stress and antioxidants: Exposure and impact on female infertility Hum Reprod Update 2008;14:345-57.  Back to cited text no. 16
17.Witteman JC, Grobbee DE, Kok FJ, Hofman A, Valkenburg HA. Increased risk of atherosclerosis in women after the menopause. BMJ 1989;298:642-4.  Back to cited text no. 17
18.Becker BN, Himmelfarb J, Henrich WL, Hakim RM. Reassessing the cardiac risk profile in chronic hemodialysis patients: A hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Nephrol 1997;8:475-86.  Back to cited text no. 18
19.Bittner V. Menopause, age, and cardiovascular risk: A complex relationship. J Am Coll Cardiol 2009;54:2374-75.  Back to cited text no. 19
20.Wang Z, Chandrasena ER, Yuan Y, Peng KW, van Breemen RB, Thatcher GR, Bolton JL. Redox cycling of catechol estrogens generating apurinic/apyrimidinic sites and 8-oxo-deoxyguanosine via reactive oxygen species differentiates equine and human estrogens. Chem Res Toxicol 2010;23:1365-73.  Back to cited text no. 20
21.Signorelli SS, Neri S, Sciacchitano S, Pino LD, Costa MP, Marchese G, et al. Behaviour of some indicators of oxidative stress in postmenopausal and fertile women. Maturitas 2006;53:77-82.  Back to cited text no. 21
22.McLean RR. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep 2009;7:134-9.  Back to cited text no. 22
23.McCrohon JA, Nakhla S, Jessup W, Stanley KK, Celermajer DS. Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: A sex-specific effect. Circulation 1999;100:2319-25.  Back to cited text no. 23
24.Tchernof A, Calles-Escandon J, Sites CK, Poehlman ET. Menopause, central body fatness, and insulin resistance: Effects of hormone-replacement therapy. Coron Artery Dis 1998;9:503-11.  Back to cited text no. 24
25.Arnal JF, Scarabin PY, Tremollieres F, Laurell H, Gourdy P. Estrogens in vascular biology and disease: Where do we stand today? Curr Opin Lipidol 2007;18:554-60.  Back to cited text no. 25
26.Cohen RA. The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Dis 1995;38:105-28.  Back to cited text no. 26
27.Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-42.  Back to cited text no. 27
28.O'Sullivan AJ, Martin A, Brown MA. Efficient fat storage in premenopausal women and in early pregnancy: A role for estrogen. J Clin Endocrinol Metab 2001;86:4951-6.  Back to cited text no. 28
29.Kronenberg, F. Hot flashes: Epidemiology and physiology. Ann N Y Acad Sci 2006;592:52-86.  Back to cited text no. 29
30.Freedman RR. Biochemical, vascular, and metabolic mechanisms in menopausal hot flashes. Fertil Steril 1998;70:332-7.  Back to cited text no. 30
31.Farr JN, Khosla S, Miyabara Y, Miller VM, Kearns AE. Effects of estrogen with micronized progesterone on cortical and trabecular bone mass and microstructure in recently postmenopausal women. J Clin Endocrinol Metab 2013;98:E249-57.  Back to cited text no. 31
32.Gallet M, Saïdi S, Haÿ E, Photsavang J, Marty C, Sailland J, et al. Repression of osteoblast maturation by ERRα accounts for bone loss induced by estrogen deficiency. PLoS One 2013;8:e54837.  Back to cited text no. 32
33.Blair HC, Zaidi M. Osteoclastic differentiation and function regulated by old and new pathways. Rev Endocr Metab Disord 2006;7:23-32.  Back to cited text no. 33
34.Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 2005;106:852-9.  Back to cited text no. 34
35.Cervellati C, Bonaccorsi G, Cremonini E, Bergamini CM, Patella A, Castaldini C, et al. Bone mass density selectively correlates with serum markers of oxidative damage in post-menopausal women. Clin Chem Lab Med 2012;51:333-8.  Back to cited text no. 35
36.Behrman HR, Kodaman PH, Preston SL, Gao S. Oxidative stress and the ovary. J Soc Gynecol Investig 2001;8 (1 Suppl Proceedings):S40-2.  Back to cited text no. 36
37.Mueck AO, Seeger H. Estrogens acting as cardiovascular agents: Direct vascular actions. Curr Med Chem Cardiovasc Hemtaol Agents 2004;2:35-42.  Back to cited text no. 37
38.Bednarek-Tupikowska G, Tworowska U, Jedrychowska I, Radomska B, Tupikowski K, Bidzinska-Speichert B, et al. Effects of oestradiol and oestroprogestin on erythrocyte antioxidative enzyme system in postmenopausal women. Clin Endocrinol (Oxf) 2006;64:463-8.  Back to cited text no. 38
39.Clarkson TB, Meléndez GC, Appt SE. Timing hypothesis for postmenopausal hormone therapy: Its origin, current status, and future. Menopause 2013;3:342-53.  Back to cited text no. 39
40.Gyglewski RJ. Prostacyclin and nitric oxide. Acta Haemtatol Pol 1994;25 (2 Suppl 2):75-81.  Back to cited text no. 40
41.Maffei S, Mercuri A, Prontera C, Zucchelli GC, Vassalle C. Vasoactive biomarkers and oxidative stress in healthy recently postmenopausal women treated with hormone replacement therapy. Climacteric 2006;9:452-8.  Back to cited text no. 41
42.Bednarek-Tupikowska G, Tupikowski K, Bidzinska B, Bohdanowicz-Pawalak A, Antonowicz-Juchniewica J, Kosowska B, et al. Serum lipid peroxides and total antioxidant status in postmenopausal women on hormone replacement therapy. Gynecol Endrocrinol 2004;19:57-63.  Back to cited text no. 42
43.Jacobsen AF, Sandset PM. Venous thromboembolism associated with pregnancy and hormonal therapy. Best Pract Res Clin Haematol 2012;25:319-32.  Back to cited text no. 43
44.MacLennan AH, MacLennan A, Wenzel S, Chambers HM, Eckert K. Continuous low-dose oestrogen and progestogen hormone replacement therapy: A randomised trial. Med J Aust 1993;159:102-6.  Back to cited text no. 44
45.Rozenberg S, Vandromme J, and Antoine C. Postmenopausal hormone therapy: Risks and benefits. Nat Rev Endocrinol 2013;9:216-27.  Back to cited text no. 45
46.Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: A 30 year history. Dyn Med 2009;8:1.  Back to cited text no. 46
47.Dutertre M, Smith CL. Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther 2001;295:431-7.  Back to cited text no. 47
48.Jordan CV. Antiestrogenic action of raloxifene and tamoxifene: Today and tomorrow. J Natl Cancer Inst 1998;90:967-71.  Back to cited text no. 48
49.Wassmann S, Laufs U, Stamenkovic D, Linz W, Stash JP, Ahlbory K, et al. Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 2002;105:2083-91.  Back to cited text no. 49
50.Wassmann S, Wassmann K, Nickenig G. Modulation of oxidant and antioxidant enzyme expression function in vascular cells. Hypertension 2004;44:381-6.  Back to cited text no. 50
51.Leeuwenburgh C, Heinecke JW. Oxidative stress and antioxidants in exercise. Curr Med Chem 2001;8:829-38.  Back to cited text no. 51
52.Villaverde GC, Torres LG, Ábalos GM, Argente del Castillo MJ, Guisado IM, Guisado BR et al. Influence of exercise on mood in postmenopausal women. J Clin Nurs 2012;21:923-8.  Back to cited text no. 52
53.Davis SR, Castelo-Branco C, Chedraui P, Lumsden MA, Nappi RE, Shah D, et al. Understanding weight gain at menopause. Climacteric 2012;15:419-29.  Back to cited text no. 53
54.Attipoe S, Park JY, Fenty N, Phares D, Brown M. Oxidative stress levels are reduced in postmenopausal women with exercise training regardless of hormone replacement therapy status. J Women Aging 2008;54:11-9.  Back to cited text no. 54
55.Bloomer RJ. Effective exercise on oxidative stress biomarkers. Adv Clin Chem 2008;46:1-50.  Back to cited text no. 55
56.Kushi LH, Folsom AR, Prinease RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 1996;334:1156-62.  Back to cited text no. 56
57.Miguel J, Ramirez-Bosca A, Ramirez-Bosca JV, Alperi JD. Menopause: A review on the role of oxygen stress and favorable effects of dietary antioxidants. Arch Gerontol Geriatr 2006;42:289-306.  Back to cited text no. 57
58.Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: Results from the women's antioxidant cardiovascular study. Arch Intern Med 2007;167:1610-8.  Back to cited text no. 58
59.Mlakar SJ, Osredkar J, Prezelj J, Marc J. Antioxidant enzymes GSR, SOD1, SOD2, and CAT gene variants and bone mineral density values in postmenopausal women: A genetic association analysis. Menopause 2012;19:368-76.  Back to cited text no. 59
60.Abdollahzad H, Eghtesadi S, Nourmohammadi I, Khadem-Ansari M, Nejad-Gashti H, Esmaillzadeh A. Effect of vitamin C supplementation on oxidative stress and lipid profiles in hemodialysis patients. Int J Vitam Nutr Res 2009;79:281-7.  Back to cited text no. 60
61.McSorely PT, Young IS, Bell PM, Fee JP, McCance DR. Vitamin C improves endothelial function in healthy estrogen-deficient postmenopausal women. Climacteric 2003;6:238-47.  Back to cited text no. 61
62.Morton DJ, Barrett-Connor EL, Schneider DL. Vitamin C supplement use and bone mineral density in postmenopausal women. J Bone Miner Res 2001;16:135-40.  Back to cited text no. 62


  [Figure 1]

This article has been cited by
1 Treatment with Soluble Activin Type IIB Receptor Ameliorates Ovariectomy-Induced Bone Loss and Fat Gain in Mice
Tero Puolakkainen, Petri Rummukainen, Vappu Pihala-Nieminen, Olli Ritvos, Eriika Savontaus, Riku Kiviranta
Calcified Tissue International. 2022;
[Pubmed] | [DOI]
2 Female infertility caused by organophosphates: an insight into the latest biochemical and histomorphological findings
Mohammad Samare-Najaf, Ali Samareh, Bahia Namavar Jahromi, Navid Jamali, Sina Vakili, Majid Mohsenizadeh, Cain C. T. Clark, Ali Abbasi, Nastaran Khajehyar
Toxin Reviews. 2022; : 1
[Pubmed] | [DOI]
3 The Relationship between F2-Isoprostanes Plasma Levels and Depression Symptoms in Healthy Older Adults
Karen Savage, Lee Gogarty, Ana Lea, Saurenne Deleuil, Karen Nolidin, Kevin Croft, Con Stough
Antioxidants. 2022; 11(5): 822
[Pubmed] | [DOI]
4 Sirtuin 3 Plays a Critical Role in the Antidepressant- and Anxiolytic-like Effects of Kaempferol
Hao-Yuan Li, Jing Wang, Ling-Feng Liang, Shi-Yu Shen, Wei Li, Xiao-Rong Chen, Bing Li, Yu-Qiu Zhang, Jin Yu
Antioxidants. 2022; 11(10): 1886
[Pubmed] | [DOI]
5 Sex Differences in Acute Coronary Syndromes: A Global Perspective
F Aaysha Cader, Shrilla Banerjee, Martha Gulati
Journal of Cardiovascular Development and Disease. 2022; 9(8): 239
[Pubmed] | [DOI]
6 Novel Evidence-Based Combination of Plant Extracts with Multitarget Mechanisms of Action for the Elimination of Hot Flashes during Menopause
Maria Tsoumani, Panagiota Efstathia Nikolaou, Aikaterini Argyropoulou, Ioulia Tseti, Sofia Mitakou, Ioanna Andreadou
Molecules. 2022; 27(4): 1221
[Pubmed] | [DOI]
7 Antioxidant Efficacy of a Standardized Red Orange (Citrus sinensis (L.) Osbeck) Extract in Elderly Subjects: A Randomized, Double Blind, Controlled Study
Vincenzo Nobile, Marta Pisati, Enza Cestone, Violetta Insolia, Vincenzo Zaccaria, Giuseppe Antonio Malfa
Nutrients. 2022; 14(20): 4235
[Pubmed] | [DOI]
Jinal Kapadia, Neeta V. Bhavsar, Nirupa R. Zadafiya, Atul Parashar
[Pubmed] | [DOI]
9 Changes in Bone Metabolism and Antioxidant Defense Systems in Menopause-Induced Rats Fed Bran Extract from Dark Purple Rice (Oryza sativa L. Cv. Superjami)
Soo Im Chung, Su Noh Ryu, Mi Young Kang
Nutrients. 2021; 13(9): 2926
[Pubmed] | [DOI]
10 Systemic Oxidative Stress, Aging and the Risk of Cardiovascular Events in the General Female Population
Martin F. Bourgonje, Arno R. Bourgonje, Amaal E. Abdulle, Lyanne M. Kieneker, Sacha la Bastide-van Gemert, Ron T. Gansevoort, Stephan J. L. Bakker, Douwe J. Mulder, Andreas Pasch, Jumana Saleh, Sanne J. Gordijn, Harry van Goor
Frontiers in Cardiovascular Medicine. 2021; 8
[Pubmed] | [DOI]
11 Effects of Polyphenol Supplementations on Improving Depression, Anxiety, and Quality of Life in Patients With Depression
Kelly Lin, Yanni Li, Eugene Du Toit, Lauren Wendt, Jing Sun
Frontiers in Psychiatry. 2021; 12
[Pubmed] | [DOI]
12 Dietary Antioxidant Vitamins and Minerals and Breast Cancer Risk: Prospective Results from the SUN Cohort
Cesar I. Fernandez-Lazaro, Miguel Ángel Martínez-González, Inmaculada Aguilera-Buenosvinos, Alfredo Gea, Miguel Ruiz-Canela, Andrea Romanos-Nanclares, Estefanía Toledo
Antioxidants. 2021; 10(3): 340
[Pubmed] | [DOI]
13 Cimicifuga racemosa Extract Ze 450 Re-Balances Energy Metabolism and Promotes Longevity
Malena Rabenau, Benjamin Dillberger, Madeline Günther, Sylvia Krippner, Veronika Butterweck, Georg Boonen, Jürgen Drewe, Gunter P. Eckert, Carsten Culmsee
Antioxidants. 2021; 10(9): 1432
[Pubmed] | [DOI]
14 Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice
Esra Gozde Kosebent, Saffet Ozturk
Scientific Reports. 2021; 11(1)
[Pubmed] | [DOI]
15 Effects of Ovariectomy and Exercise Training on Mineral Status in a High-Fat Diet-Induced Obesity Rat Model
Vlasta Masanova, Zora Krivosikova, Monika Ursinyova, Iveta Uhnakova, Anton Kebis, Patricia Kramarova, Ladislava Wsolova, Martin Gajdos
Biological Trace Element Research. 2021;
[Pubmed] | [DOI]
16 Ginkgo biloba Extract (GbE) Restores Serotonin and Leptin Receptor Levels and Plays an Antioxidative Role in the Hippocampus of Ovariectomized Rats
Meira Maria Forcelini Machado, Renata Mancini Banin, Fernanda Malanconi Thomaz, Iracema Senna de Andrade, Valter Tadeu Boldarine, Jéssica de Souza Figueiredo, Bruna Kelly Sousa Hirata, Lila Missae Oyama, João Henrique Ghilardi Lago, Eliane Beraldi Ribeiro, Mônica Marques Telles
Molecular Neurobiology. 2021; 58(6): 2692
[Pubmed] | [DOI]
17 Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress
Du Xiang, Yang Liu, Shujun Zhou, Encheng Zhou, Yanfeng Wang, Stefania D’Adamo
Oxidative Medicine and Cellular Longevity. 2021; 2021: 1
[Pubmed] | [DOI]
18 The Influence of Menopause and Inflammation on Redox Status and Bone Mineral Density in Patients with Rheumatoid Arthritis
Aleksandra Stojanovic, Mirjana Veselinovic, Nevena Draginic, Marina Rankovic, Marijana Andjic, Jovana Bradic, Sergey Bolevich, Aleksandra Antovic, Vladimir Jakovljevic, Danina Muntean
Oxidative Medicine and Cellular Longevity. 2021; 2021: 1
[Pubmed] | [DOI]
19 Oxidative Stress Risk Is Increased with a Sedentary Lifestyle during Aging in Mexican Women
Martha A. Sánchez-Rodríguez, Mariano Zacarías-Flores, Elsa Correa-Muñoz, Alicia Arronte-Rosales, Víctor Manuel Mendoza-Núñez, Lillian Barros
Oxidative Medicine and Cellular Longevity. 2021; 2021: 1
[Pubmed] | [DOI]
20 Alternatives to hormone therapy for management of climacteric syndrome
G. B. Dikke
Meditsinskiy sovet = Medical Council. 2021; (3): 136
[Pubmed] | [DOI]
21 An Upcoming Approach to Alzheimer's Disease: Ethnopharmacological Potential of Plant Bioactive Molecules
Natália Martins, Sandrina A. Heleno, Isabel C.F.R. Ferreira
Current Medicinal Chemistry. 2020; 27(26): 4344
[Pubmed] | [DOI]
22 The Effects of Evening-Primrose Oil on Menopausal Symptoms: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Karen Christelle, Maryam Mohd Zulkfili, Norhayati Mohd Noor, Nani Draman
Current Women s Health Reviews. 2020; 16(4): 265
[Pubmed] | [DOI]
23 Systemic Oxidative Stress Is Increased in Postmenopausal Women and Independently Associates with Homocysteine Levels
Arno R. Bourgonje, Amaal Eman Abdulle, Areej M. Al-Rawas, Muna Al-Maqbali, Mohsin Al-Saleh, Marvin B. Enriquez, Sultan Al-Siyabi, Khamis Al-Hashmi, Intisar Al-Lawati, Marian L. C. Bulthuis, Douwe J. Mulder, Sanne J. Gordijn, Harry van Goor, Jumana Saleh
International Journal of Molecular Sciences. 2020; 21(1): 314
[Pubmed] | [DOI]
24 Protective effects of tamoxifen and raloxifene on apoptosis and oxidative stress in the kidney and liver of ovariectomized rats
Journal of Cellular Neuroscience and Oxidative Stress. 2020; 12(3): 963
[Pubmed] | [DOI]
25 Effect of Aerobic Training and Crocin Consumption on Bax Gene Expression in the Hippocampal Tissue of Ovariectomized Rats
Parivash Assadpur Shadegan, Ali Khajehlandi, Amin Mohammadi
Gene, Cell and Tissue. 2020; 7(3)
[Pubmed] | [DOI]
26 Tualang honey supplementation as cognitive enhancer in patients with schizophrenia
Rosliza Yahaya, Mohd Nizam Zahary, Zahiruddin Othman, Rusli Ismail, Nik Ahmad Shaiffudin Nik Him, Aniza Abd Aziz, Rahima Dahlan, Azizul Fadzli Jusoh
Heliyon. 2020; 6(5): e03948
[Pubmed] | [DOI]
27 Correlation of serum uric acid and hepatic enzymes in premenopausal and postmenopausal women
International Journal of pharma and Bio Sciences. 2018; 9(2)
[Pubmed] | [DOI]
28 Osteoporosis, vitamin C intake, and physical activity in Korean adults aged 50 years and over
Min Hee Kim,Hae-Jeung Lee
Journal of Physical Therapy Science. 2016; 28(3): 725
[Pubmed] | [DOI]
29 The association between follicle stimulating hormone and glutathione peroxidase activity is dependent on abdominal obesity in postmenopausal women
Aleksandra Klisic,Jelena Kotur-Stevuljevic,Nebojsa Kavaric,Milica Martinovic,Marija Matic
Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2016;
[Pubmed] | [DOI]
30 Prospective study of dietary Non Enzymatic Antioxidant Capacity on the risk of hip fracture in the elderly
Essi Hantikainen,Alessandra Grotta,Weimin Ye,Hans-Olov Adami,Pamela J. Surkan,Mauro Serafini,Karl Michaëlsson,Rino Bellocco,Ylva Trolle Lagerros
Bone. 2016;
[Pubmed] | [DOI]
31 Raloxifene and Tamoxifen Reduce PARP Activity, Cytokine and Oxidative Stress Levels in the Brain and Blood of Ovariectomized Rats
Betül Yazgan,Yener Yazgan,Ishak Suat Övey,Mustafa Naziroglu
Journal of Molecular Neuroscience. 2016;
[Pubmed] | [DOI]
32 Mulberry water extract regulates the osteoblast/osteoclast balance in an ovariectomic rat model
Hsing-Yu Jao,Jeng-Dong Hsu,Yi-Ru Lee,Chien-Sheng Lo,Huei-Jane Lee
Food Funct.. 2016;
[Pubmed] | [DOI]
33 Potential Benefits of Berberine in the Management of Perimenopausal Syndrome
Cristiana Caliceti,Paola Rizzo,Arrigo Francesco Giuseppe Cicero
Oxidative Medicine and Cellular Longevity. 2015; 2015: 1
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Hormonal and Che...
    Implications of ...
    Treatment Option...
    Dietary Treatmen...
   Take Home Message
    Article Figures

 Article Access Statistics
    PDF Downloaded1973    
    Comments [Add]    
    Cited by others 33    

Recommend this journal