Metformin and Reproductive System

**99**

and stress [8].)

**Chapter 6**

**Abstract**

**1. Introduction**

*Elham Pourmatroud*

Metformin in Health Issues and

Metformin is one of oldest drug in reproductive medicine era; but most of times

Metformin is a component of many herbal therapeutic substances, which has been known since 1500 BCE in Egyptian medicine [1]. In Europe, a herbal remedy was used for ameliorating polyuria and polydipsia; from the Middle Ages, its name was *Galega officinalis* (or the French lilac) [2]. However, just in the early 1900s, the

Everybody knows that the incidence and prevalence of diabetes mellitus (DM) is increasing constantly. Diabetes is one of the most common noncommunicable diseases and is considered as one of the top five universal causes of precocious death in both developed and non-developed countries. So the immense numbers of studies about metformin, which is the most prevalent and popular remedy for it, could be predictable. As a result, it is no wonder that there is a scanty paper about other

Metformin has been called "the aspirin of the twenty-first century [4]." This old-fashioned drug was famous only as antidiabetic drug until recent years. So, what makes this drug so hear saying and impressive for life longevity [5], prevention from cancers [6] and useful in patients with chronic kidney disease, congestive heart failure or chronic liver disease [7]. At the present time, evidence suggests that metformin's wide-spectrum advantages are mediated by at least two relevant pathways: first, by inhibition of intracellular metabolic activity of mitochondria and second, the cellular nutrition-sensing system mediated by mTOR [4]. ("The mammalian target of rapamycin" is one kind of the kinase family that mediates metabolism and cell growth as a reaction to growth factors, nutrients,

it is equal to polycystic ovary (PCO) syndrome especially obese patients. If it is still valuable or not, could have another health benefit or new fertility roles, and could be effective as well in male reproductive system will be discussed. According to increased rate of metabolic disorders and cardiovascular problems and cancers, there are several investigations on this old used drug. Those studies had been magnified its role as "the aspirin of current century," which might have a promising

role in longevity of the life. So, the chapter will be interesting.

**Keywords:** metformin, reproductive, health, fertility, metabolic

effective element "guanidine" was extracted [3].

worthful aspects of metformin.

Reproductive System

### **Chapter 6**

## Metformin in Health Issues and Reproductive System

*Elham Pourmatroud*

### **Abstract**

Metformin is one of oldest drug in reproductive medicine era; but most of times it is equal to polycystic ovary (PCO) syndrome especially obese patients. If it is still valuable or not, could have another health benefit or new fertility roles, and could be effective as well in male reproductive system will be discussed. According to increased rate of metabolic disorders and cardiovascular problems and cancers, there are several investigations on this old used drug. Those studies had been magnified its role as "the aspirin of current century," which might have a promising role in longevity of the life. So, the chapter will be interesting.

**Keywords:** metformin, reproductive, health, fertility, metabolic

### **1. Introduction**

Metformin is a component of many herbal therapeutic substances, which has been known since 1500 BCE in Egyptian medicine [1]. In Europe, a herbal remedy was used for ameliorating polyuria and polydipsia; from the Middle Ages, its name was *Galega officinalis* (or the French lilac) [2]. However, just in the early 1900s, the effective element "guanidine" was extracted [3].

Everybody knows that the incidence and prevalence of diabetes mellitus (DM) is increasing constantly. Diabetes is one of the most common noncommunicable diseases and is considered as one of the top five universal causes of precocious death in both developed and non-developed countries. So the immense numbers of studies about metformin, which is the most prevalent and popular remedy for it, could be predictable. As a result, it is no wonder that there is a scanty paper about other worthful aspects of metformin.

Metformin has been called "the aspirin of the twenty-first century [4]." This old-fashioned drug was famous only as antidiabetic drug until recent years. So, what makes this drug so hear saying and impressive for life longevity [5], prevention from cancers [6] and useful in patients with chronic kidney disease, congestive heart failure or chronic liver disease [7]. At the present time, evidence suggests that metformin's wide-spectrum advantages are mediated by at least two relevant pathways: first, by inhibition of intracellular metabolic activity of mitochondria and second, the cellular nutrition-sensing system mediated by mTOR [4]. ("The mammalian target of rapamycin" is one kind of the kinase family that mediates metabolism and cell growth as a reaction to growth factors, nutrients, and stress [8].)

In this chapter we are going to talk about three different fields of metformin action in detail.

### **2. Health issues**

In accordance with aging, there are some significant changes in the body and elevation in prevalence of some specific disease and abnormality [9].


The life span has been regulated by pharmacologic, genetic, and dietary interferences in several sample systems. The most considerable mechanism in aging phenomenon is DNA damage; the endogenous, potent factors are reactive oxygen species (ROS), alkylation, and hydrolysis [10]. Thus, most studies in this subject are focusing on it.

Through the metformin role in aging, it leads to decreased insulin levels, inhibition of mTOR, decreased IGF-1 signaling, endogenous production of reactive oxygen species, inhibition of mitochondrial complex 1, activation of AMP-activated protein kinase (AMPK), and reduction in DNA damage.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein complex that governs transcription of DNA. Metformin inhibits NF-kB, a key point in inflammatory process [11]. Also, by lowering the reactive oxygen species and improving the endothelial function [12], reduction in coronary heart diseases and cerebrovascular accidents after metformin administration could be expected. With those mechanisms, the effectiveness in blood hemostasis is considerable; reduction in systemic production of the tissue type plasminogen activator, Von Willibrand factor, and plasminogen activator inhibitor [13], furthermore modulation the fibrin threads formation in both diabetic and non-diabetic patients [14].

According to one recent meta-analysis, metformin is operative in reducing body weight of simple obesity (in nondiabetic, non-polycystic ovary syndrome (PCOS) patients), by reducing the absorption of glucose in the intestine, decreasing

**101**

dysfunction [34].

**3. Fertility issues**

known enzyme: AMPK.

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

muscle glucose uptake and use [15].

metformin.

production of glucose in the liver, and ameliorating insulin sensitivity via increasing

The role of metformin in the nervous system is proposed excitingly. Alzheimer is a disease with an advanced insulin resistance of the brain cell which leads to formation of the amyloid cells [16]. Undesirable oxidative damages and inactivation of AMPK pathway [17] and making delay in mitochondria programmed cell death could be mediated by metformin [18]. Besides Alzheimer, other neurological diseases like Parkinson and amyotrophic lateral sclerosis have the same mechanism. As a result of conversion in the insulin resistance, depletion in intestinal absorption of carbohydrate and leptin secretion, and enhancing effects of glucagon-like peptide-1 on fat cells, metformin could be applied for weight reduction [19].

Additionally, prescription of metformin with antiretroviral agents (especially in HIV treatment) has been showed a reduction in their side effects like the risk of

One meta-analysis has concluded that metformin plays a role in the decline of liver cancer risk in type 2 diabetes patients [21]. The anti-tumorigenic sequel of metformin in pancreatic cancer [22], colorectal cancer [23], prostate cancer [24], and lung cancer [25] and its role in lowering the risk of cancer-related mortality have been proposed. From another aspect, in colorectal cancers' cell, metformin inhibits an essential energy source: adenosine A1 receptor (ADORA1) [26]. As we mentioned before, lowering the insulin levels by metformin ends in reduction in the levels of P13K pathway. (The PI3K/AKT/mTOR pathway is an intracellular signaling pathway with significant regulating function in all of the cellular stages: quiescence, proliferation, cancer, and longevity.) Moreover metformin by forcing effect on AMPK lowers the ATP ratio in cells causing switch-off of cell growth and proliferation in breast cell [27]. In breast cancer, metformin has an inhibitory effect at early stages of cell differentiation [28]; indeed, the antineoplastic effects need higher-dose consumption and more clinical evidences [29]. With those outstanding impressive mechanisms of metformin, a smaller size and slower progression of thyroid cancer [30] and advantageous effect on endometrium cancer

insulin insensitivity, weight obtain, dyslipidemia, and hyperglycemia [20]. In cancerous issue, there are several studies that depict the effectiveness of

including progesterone-resistant cancer cells [31] have been pointed.

effects on aggressive malignancies like melanomas [33].

of metformin in health jeopardies in nondiabetic patients.

Metformin could have an adjuvant task in treating cervical cancer, particularly in types with liver kinase B1 (LKB1) positive (a gen with tumor suppression efficacy) [32]. Eventually, there is an update study about metformin's anti-metastatic

From another aspect, metformin decreases the frequency of preeclampsia, by reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the modification in endothelial

It must be highlighted that all of mentioned witnesses are extra glycemic effects

Metformin as a hydrophilic biguanide is present in many tissues like the hypothalamus, pituitary, and gonads moreover than famous places (liver, pancreas, and adipose tissues). It could be accumulating in specific tissues more than plasma level by particular transportation system, in which one of those places is the reproductive system [35]. Metformin activates the cytoplasmic protein kinase, which is a well-

### *Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

*Metformin*

action in detail.

**2. Health issues**

static hypotension

In this chapter we are going to talk about three different fields of metformin

In accordance with aging, there are some significant changes in the body and

• Endocrine system: type 2 diabetes, thyroid disease, osteoporosis, and ortho-

elevation in prevalence of some specific disease and abnormality [9].

• Cardiovascular: hearth failure, hypertension, and CVD

• Optical: macular degeneration, cataract, and presbyopia

• Auditory: presbycusis and conductive hearing loss

• Skeletal: osteoporosis, kyphosis, and scoliosis

• Renal: chronic kidney disease

• Immune: increased risk of infections

• Neurological: delirium, cognitive impairment, and dementia

• Muscular: impaired mobility, muscular strength, and sarcopenia

• Gastrointestinal: dysphagia, constipation, and malabsorption

• Dermal: dryness and lower elasticity and pressure ulcer

protein kinase (AMPK), and reduction in DNA damage.

The life span has been regulated by pharmacologic, genetic, and dietary interferences in several sample systems. The most considerable mechanism in aging phenomenon is DNA damage; the endogenous, potent factors are reactive oxygen species (ROS), alkylation, and hydrolysis [10]. Thus, most studies in this subject are

Through the metformin role in aging, it leads to decreased insulin levels, inhibition of mTOR, decreased IGF-1 signaling, endogenous production of reactive oxygen species, inhibition of mitochondrial complex 1, activation of AMP-activated

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein complex that governs transcription of DNA. Metformin inhibits NF-kB, a key point in inflammatory process [11]. Also, by lowering the reactive oxygen species and improving the endothelial function [12], reduction in coronary heart diseases and cerebrovascular accidents after metformin administration could be expected. With those mechanisms, the effectiveness in blood hemostasis is considerable; reduction in systemic production of the tissue type plasminogen activator, Von Willibrand factor, and plasminogen activator inhibitor [13], furthermore modulation the fibrin threads formation in both diabetic and non-diabetic patients [14]. According to one recent meta-analysis, metformin is operative in reducing body weight of simple obesity (in nondiabetic, non-polycystic ovary syndrome (PCOS) patients), by reducing the absorption of glucose in the intestine, decreasing

**100**

focusing on it.

production of glucose in the liver, and ameliorating insulin sensitivity via increasing muscle glucose uptake and use [15].

The role of metformin in the nervous system is proposed excitingly. Alzheimer is a disease with an advanced insulin resistance of the brain cell which leads to formation of the amyloid cells [16]. Undesirable oxidative damages and inactivation of AMPK pathway [17] and making delay in mitochondria programmed cell death could be mediated by metformin [18]. Besides Alzheimer, other neurological diseases like Parkinson and amyotrophic lateral sclerosis have the same mechanism.

As a result of conversion in the insulin resistance, depletion in intestinal absorption of carbohydrate and leptin secretion, and enhancing effects of glucagon-like peptide-1 on fat cells, metformin could be applied for weight reduction [19].

Additionally, prescription of metformin with antiretroviral agents (especially in HIV treatment) has been showed a reduction in their side effects like the risk of insulin insensitivity, weight obtain, dyslipidemia, and hyperglycemia [20].

In cancerous issue, there are several studies that depict the effectiveness of metformin.

One meta-analysis has concluded that metformin plays a role in the decline of liver cancer risk in type 2 diabetes patients [21]. The anti-tumorigenic sequel of metformin in pancreatic cancer [22], colorectal cancer [23], prostate cancer [24], and lung cancer [25] and its role in lowering the risk of cancer-related mortality have been proposed. From another aspect, in colorectal cancers' cell, metformin inhibits an essential energy source: adenosine A1 receptor (ADORA1) [26].

As we mentioned before, lowering the insulin levels by metformin ends in reduction in the levels of P13K pathway. (The PI3K/AKT/mTOR pathway is an intracellular signaling pathway with significant regulating function in all of the cellular stages: quiescence, proliferation, cancer, and longevity.) Moreover metformin by forcing effect on AMPK lowers the ATP ratio in cells causing switch-off of cell growth and proliferation in breast cell [27]. In breast cancer, metformin has an inhibitory effect at early stages of cell differentiation [28]; indeed, the antineoplastic effects need higher-dose consumption and more clinical evidences [29]. With those outstanding impressive mechanisms of metformin, a smaller size and slower progression of thyroid cancer [30] and advantageous effect on endometrium cancer including progesterone-resistant cancer cells [31] have been pointed.

Metformin could have an adjuvant task in treating cervical cancer, particularly in types with liver kinase B1 (LKB1) positive (a gen with tumor suppression efficacy) [32]. Eventually, there is an update study about metformin's anti-metastatic effects on aggressive malignancies like melanomas [33].

From another aspect, metformin decreases the frequency of preeclampsia, by reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the modification in endothelial dysfunction [34].

It must be highlighted that all of mentioned witnesses are extra glycemic effects of metformin in health jeopardies in nondiabetic patients.

### **3. Fertility issues**

Metformin as a hydrophilic biguanide is present in many tissues like the hypothalamus, pituitary, and gonads moreover than famous places (liver, pancreas, and adipose tissues). It could be accumulating in specific tissues more than plasma level by particular transportation system, in which one of those places is the reproductive system [35]. Metformin activates the cytoplasmic protein kinase, which is a wellknown enzyme: AMPK.

AMPK is a sensitive and important sensor of cellular energy homeostasis.

Hypothalamic neurons secrete gonadotropin-releasing hormone (GnRH) that stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production from the pituitary gland. GnRH function in the brain has an AMPKdependent pathway. Metformin as an AMPK activator decreases the amplitude of FSH and LH secretion.

### **3.1 Male reproductive system**

Spermatogenesis is under noticeable hormonal regulation, especially by pituitary hormones (FSH and LH). LH stimulates the Leydig cells (LCs) to secrete testosterone and dihydrotestosterone, although FSH arouses Sertoli cells (SCs) of seminiferous tubules to maintain the cycle of spermatogenesis and inhibin secretion. Respectively, testosterone and inhibin secretion from the testis cause a negative feedback with inhibitory effects on FSH and LH. This regular system is necessary for normal spermatogenesis [36].

During spermatogenesis, the evolution process of germ cells into mature and motile spermatozoa needs specific nutrient sources which are obtained mainly from sugars (particularly glucose and fructose) and other metabolites such as lactate and citrate. Those metabolites are the most principal fuels for ATP production in germ cells and spermatozoa [37].

Moreover, production of lactate by glycolytic pathway in the SCs [38] and secretion into intratubular fluid is a necessary step for germ cell spermatogenesis. This is another energy-making way, important for motility enhancement. This process is controlled directly by glucose metabolism [39]. After primary spermatozoa production, they will store in the epididymis. Here final maturation occurs by advancement in motility function and fertilization capacity. All of those processes demand high energy and depend on glucose transporter (GLUT) proteins for carrying glucose through sperm's lipidic membrane inside the sperm cell [40]. In effect, regular and correct male fertility through this long journey is closely related to glucose metabolism.

Metformin's effect on human male reproductive function still is obscure. Extensively, current data are extracted from normal animal model studies, particularly rodents and diabetic men.

In healthy male animals, exposure to metformin displays adverse reproductive outcomes like:


In diabetic men, according to hyperglycemic state and excessive ROS production, metformin improves antioxidant environment of the testis and enhances steroidogenesis. This favorable amelioration in the testis leads to increase in concentration of motile sperm and normal morphological sperm [44]. Furthermore, metformin increases endothelial nitric oxide synthase phosphorylation [45] and the contractility in the corpora cavernosa [46], so sexual disorders like retrograde ejaculation or erectile dysfunction could be mended.

**103**

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

increases anaerobic respiration and lactate secretion [48].

subfertile woman, unexpectedly, there is scanty study about it.

abnormal zygotes after in vitro fertilization [49].

**3.2 Female reproductive system**

flow could be increased [56].

androstenedione [61] from theca cells.

The author declares no conflict of interest.

receptivity [57].

**4. Conclusion**

**Conflict of interest**

Recently, evidences of metformin efficacy in nondiabetic men are increasing. As remarked above, lactate synthesis by SCs is a crucial step in testicular metabolic cycle, which produces more desirable energy substrate for springing up germ cells and has a prominent anti-apoptotic effect [47]. Also, some studies showed that metformin plays a role as a suppressor of complex I of the mitochondrial electron transport chain that directly decreases oxidative metabolism and accordingly

Surprisingly, adding metformin in cryopreservation media during sperm freezing practice (for fertility preservation) reduces sperm permanent damage and improves the rate of success in fertilization process and decreases the number of

As it is well-known, metformin has a crucial role in PCOS pathogenesis amelioration and not surprising the large number of studies about its efficacy and widespread utilization. But, when we are looking for its usage in non-PCOS infertile or

Insulin resistance could have significant negative role in various conditions such as stress [50], aging [51], obesity [52], depression [53], and inactive lifestyle [54]. Infertile women often have one of those conditions. Moreover, ovarian dysfunction induces "stress response mechanism" owing to abnormal cortisol secretion and increased level of catecholamines [55]. Besides that, by enhancing in insulin-like growth factor-binding protein-1 and glycodelin level, uterine vascularity and blood

Those beneficial effects had been demonstrated in a study on about 200 patients

(non-PCOS) with repeated IVF failure. In this study in a period of 8–12 weeks, low-dose (500 mg/day) metformin administration before IVF cycle significantly increases the pregnancy rate by improving in oocyte quality and endometrium,

In another bovine study, it was shown that IGF-1 has a dual positive role in follicle regulation which increases FSH effectiveness as an autocrine regulator of granulosa cell growth that could illustrate metformin worth in infertility treatment procedures [58]. Moreover, in vitro experiment studies show that metformin could decrease the progesterone [59] and estradiol [60] secretion from granulosa cells and

As we reviewed in this chapter, metformin did not equal to NIDDM and PCOS, anymore. In all of the mentioned fields, researches are increasing more and more.

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

*Metformin*

FSH and LH secretion.

**3.1 Male reproductive system**

cells and spermatozoa [37].

to glucose metabolism.

outcomes like:

larly rodents and diabetic men.

1.Decrease in testosterone production [41].

3.Reduction in Sertoli cell numbers [42].

4.Decrease in sperm quality parameters [43].

ejaculation or erectile dysfunction could be mended.

2.Reduction in seminiferous tubules diameter and testis size.

necessary for normal spermatogenesis [36].

AMPK is a sensitive and important sensor of cellular energy homeostasis. Hypothalamic neurons secrete gonadotropin-releasing hormone (GnRH) that stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production from the pituitary gland. GnRH function in the brain has an AMPKdependent pathway. Metformin as an AMPK activator decreases the amplitude of

Spermatogenesis is under noticeable hormonal regulation, especially by pituitary hormones (FSH and LH). LH stimulates the Leydig cells (LCs) to secrete testosterone and dihydrotestosterone, although FSH arouses Sertoli cells (SCs) of seminiferous tubules to maintain the cycle of spermatogenesis and inhibin secretion. Respectively, testosterone and inhibin secretion from the testis cause a negative feedback with inhibitory effects on FSH and LH. This regular system is

During spermatogenesis, the evolution process of germ cells into mature and motile spermatozoa needs specific nutrient sources which are obtained mainly from sugars (particularly glucose and fructose) and other metabolites such as lactate and citrate. Those metabolites are the most principal fuels for ATP production in germ

Moreover, production of lactate by glycolytic pathway in the SCs [38] and secretion into intratubular fluid is a necessary step for germ cell spermatogenesis. This is another energy-making way, important for motility enhancement. This process is controlled directly by glucose metabolism [39]. After primary spermatozoa production, they will store in the epididymis. Here final maturation occurs by advancement in motility function and fertilization capacity. All of those processes demand high energy and depend on glucose transporter (GLUT) proteins for carrying glucose through sperm's lipidic membrane inside the sperm cell [40]. In effect, regular and correct male fertility through this long journey is closely related

Metformin's effect on human male reproductive function still is obscure. Extensively, current data are extracted from normal animal model studies, particu-

In healthy male animals, exposure to metformin displays adverse reproductive

In diabetic men, according to hyperglycemic state and excessive ROS production, metformin improves antioxidant environment of the testis and enhances steroidogenesis. This favorable amelioration in the testis leads to increase in concentration of motile sperm and normal morphological sperm [44]. Furthermore, metformin increases endothelial nitric oxide synthase phosphorylation [45] and the contractility in the corpora cavernosa [46], so sexual disorders like retrograde

**102**

Recently, evidences of metformin efficacy in nondiabetic men are increasing. As remarked above, lactate synthesis by SCs is a crucial step in testicular metabolic cycle, which produces more desirable energy substrate for springing up germ cells and has a prominent anti-apoptotic effect [47]. Also, some studies showed that metformin plays a role as a suppressor of complex I of the mitochondrial electron transport chain that directly decreases oxidative metabolism and accordingly increases anaerobic respiration and lactate secretion [48].

Surprisingly, adding metformin in cryopreservation media during sperm freezing practice (for fertility preservation) reduces sperm permanent damage and improves the rate of success in fertilization process and decreases the number of abnormal zygotes after in vitro fertilization [49].

### **3.2 Female reproductive system**

As it is well-known, metformin has a crucial role in PCOS pathogenesis amelioration and not surprising the large number of studies about its efficacy and widespread utilization. But, when we are looking for its usage in non-PCOS infertile or subfertile woman, unexpectedly, there is scanty study about it.

Insulin resistance could have significant negative role in various conditions such as stress [50], aging [51], obesity [52], depression [53], and inactive lifestyle [54]. Infertile women often have one of those conditions. Moreover, ovarian dysfunction induces "stress response mechanism" owing to abnormal cortisol secretion and increased level of catecholamines [55]. Besides that, by enhancing in insulin-like growth factor-binding protein-1 and glycodelin level, uterine vascularity and blood flow could be increased [56].

Those beneficial effects had been demonstrated in a study on about 200 patients (non-PCOS) with repeated IVF failure. In this study in a period of 8–12 weeks, low-dose (500 mg/day) metformin administration before IVF cycle significantly increases the pregnancy rate by improving in oocyte quality and endometrium, receptivity [57].

In another bovine study, it was shown that IGF-1 has a dual positive role in follicle regulation which increases FSH effectiveness as an autocrine regulator of granulosa cell growth that could illustrate metformin worth in infertility treatment procedures [58]. Moreover, in vitro experiment studies show that metformin could decrease the progesterone [59] and estradiol [60] secretion from granulosa cells and androstenedione [61] from theca cells.

### **4. Conclusion**

As we reviewed in this chapter, metformin did not equal to NIDDM and PCOS, anymore. In all of the mentioned fields, researches are increasing more and more.

### **Conflict of interest**

The author declares no conflict of interest.

*Metformin*

### **Author details**

Elham Pourmatroud Payam IVF Center, Tehran, Iran

\*Address all correspondence to: e.pourmatroud@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**105**

10.7326/M16-1901

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

> [8] Hall MN. mTOR-what does it do? Transplantation Proceedings. 2008;**40**(10 Suppl):S5-S8. DOI: 10.1016/j.transproceed.2008.10.009

Metformin as a tool to target aging. Cell Metabolism. 2016;**23**(6):1060-1065. DOI: 10.1016/j.cmet.2016.05.011

[10] Hoeijmakers JHJ. DNA damage, aging, and cancer. The New England Journal of Medicine. 2009;**361**:1475- 1485. DOI: 10.1056/NEJMra0804615

[11] Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N,

[12] De Jager J, Kooy A, Lehert P, Bets D, Wulffele MG, Teerlink T, et al. Effects of short-term treatment with metformin on markers of

2005;**257**(1):100-109. DOI: 10.1111/j.1365-2796.2004.01420.x

[14] Charles MA, Morange P, Eschwege E, Andre P, Vague P,

Juhan-Vague I. Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: The BIGPRO1 study. Biguanides and the prevention of the risk of obesity. Diabetes Care.

[13] Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes & Metabolism. 2003;**29**(4 Pt 2):6S44-6S52. DOI: 10.1016/S1262-3636(03)72787-6

endothelial function and inflammatory activity in type 2 diabetes mellitus: A randomized, placebo-controlled trial. Journal of Internal Medicine.

et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;**26**(3):611-617. DOI: 10.1161/ 01.ATV.0000201938.78044.75

[9] Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA.

[1] Witters LA. The blooming of the French lilac. The Journal of Clinical Investigation. 2001;**108**(8):1105-1107.

[2] Thomas I, Gregg B. Metformin; a review of its history and future: From lilac to longevity. Pediatric Diabetes. 2017;**18**(1):10-16. DOI: 10.1111/

[3] Watanabe C. Studies in the metabolic changes induced by the administration of guanidine bases. The Journal of Biological Chemistry.

[4] Romero R, Erez O, Hüttemann M, Maymon E, et al. Metformin, the aspirin of the 21st century: Its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. American Journal of Obstetrics and Gynecology. 2017;**217**(3):282-302. DOI: 10.1016/j.

[5] Onkan B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend *C. elegans* healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010;**5**(1):e8758. DOI: 10.1371/journal.

[6] Wu L, Zhu J, Prokop LJ, Murad MH. Pharmacologic therapy of diabetes and overall cancer risk and mortality: A meta-analysis of 265 studies. Scientific Reports. 2015;**5**:10147. DOI: 10.1038/

[7] Crowley MJ, Diamantidis CJ,

McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Annals of Internal Medicine. 2017;**166**(3):191-200. DOI:

DOI: 10.1172/JCI14178

pedi.12473

**References**

1918;**33**:253-265

ajog.2017.06.003

pone.0008758

srep10147

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

### **References**

*Metformin*

**104**

**Author details**

Elham Pourmatroud

Payam IVF Center, Tehran, Iran

provided the original work is properly cited.

\*Address all correspondence to: e.pourmatroud@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Witters LA. The blooming of the French lilac. The Journal of Clinical Investigation. 2001;**108**(8):1105-1107. DOI: 10.1172/JCI14178

[2] Thomas I, Gregg B. Metformin; a review of its history and future: From lilac to longevity. Pediatric Diabetes. 2017;**18**(1):10-16. DOI: 10.1111/ pedi.12473

[3] Watanabe C. Studies in the metabolic changes induced by the administration of guanidine bases. The Journal of Biological Chemistry. 1918;**33**:253-265

[4] Romero R, Erez O, Hüttemann M, Maymon E, et al. Metformin, the aspirin of the 21st century: Its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. American Journal of Obstetrics and Gynecology. 2017;**217**(3):282-302. DOI: 10.1016/j. ajog.2017.06.003

[5] Onkan B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend *C. elegans* healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010;**5**(1):e8758. DOI: 10.1371/journal. pone.0008758

[6] Wu L, Zhu J, Prokop LJ, Murad MH. Pharmacologic therapy of diabetes and overall cancer risk and mortality: A meta-analysis of 265 studies. Scientific Reports. 2015;**5**:10147. DOI: 10.1038/ srep10147

[7] Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Annals of Internal Medicine. 2017;**166**(3):191-200. DOI: 10.7326/M16-1901

[8] Hall MN. mTOR-what does it do? Transplantation Proceedings. 2008;**40**(10 Suppl):S5-S8. DOI: 10.1016/j.transproceed.2008.10.009

[9] Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metabolism. 2016;**23**(6):1060-1065. DOI: 10.1016/j.cmet.2016.05.011

[10] Hoeijmakers JHJ. DNA damage, aging, and cancer. The New England Journal of Medicine. 2009;**361**:1475- 1485. DOI: 10.1056/NEJMra0804615

[11] Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;**26**(3):611-617. DOI: 10.1161/ 01.ATV.0000201938.78044.75

[12] De Jager J, Kooy A, Lehert P, Bets D, Wulffele MG, Teerlink T, et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: A randomized, placebo-controlled trial. Journal of Internal Medicine. 2005;**257**(1):100-109. DOI: 10.1111/j.1365-2796.2004.01420.x

[13] Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes & Metabolism. 2003;**29**(4 Pt 2):6S44-6S52. DOI: 10.1016/S1262-3636(03)72787-6

[14] Charles MA, Morange P, Eschwege E, Andre P, Vague P, Juhan-Vague I. Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: The BIGPRO1 study. Biguanides and the prevention of the risk of obesity. Diabetes Care.

1998;**21**(11):1967-1972. DOI: 10.2337/ diacare.21.11.1967

[15] Ning HH, Le J, Wang Q, et al. The effects of metformin on simple obesity: A meta-analysis. Endocrine. 2018;**62**(3):528-534. DOI: 10.1007/ s12020-018-1717-y

[16] Culmsee C, Monnig J, Kemp BE, Mattson MP. AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. Journal of Molecular Neuroscience. 2001;**17**(1):45-58. DOI: 10.1385/JMN:17:1:45

[17] Santomauro Junior AC, Ugolini MR, Santomauro AT, Souto RP. Metformin and AMPK: An old drug and a new enzyme in the context of metabolic syndrome. Arquivos Brasileiros de Endocrinologia e Metabologia. 2008;**52**(1):120-125. DOI: 10.1590/ S0004-27302008000100017

[18] Kroemer G, Reed JC. Mitochondrial control of cell death. Nature Medicine. 2000;**6**(5):513-519. DOI: 10.1038/74994

[19] Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;**50**(7):856-861. DOI: 10.1053/ meta.2001.24192

[20] Sheth SH, Larson RJ. The efficacy and safety of insulinsensitizing drugs in HIV-associated lipodystrophy syndrome: A metaanalysis of randomized trials. BMC Infectious Diseases. 2010;**10**:183. DOI: 10.1186/1471-2334-10-183

[21] Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: A systematic review and

meta-analysis. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(7):2347-2353. DOI: 10.1210/ jc.2012-1267

[22] Cerullo M, Gani F, Chen SY, Canner J, Pawlik TM. Metformin use is associated with improved survival in patients undergoing resection for pancreatic cancer. Journal of Gastrointestinal Surgery. 2016;**20**(9):1572-1580. DOI: 10.1007/ s11605-016-3173-4

[23] Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: A meta-analysis. Diabetes Care. 2011;**34**(10):2323-2328. DOI: 10.2337/ dc11-0512

[24] Yu H, Yin L, Jiang X, Sun X, Wu J, Tian H, et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: A meta-analysis of epidemiological observational studies. PLoS One. 2014;**9**(12):e116327. DOI: 10.1371/journal.pone.0116327

[25] Sakoda LC, Ferrara A, Achacoso NS, Peng T, Ehrlich SF, Quesenberry CP, et al. Metformin use and lung cancer risk in patients with diabetes. Cancer Prevention Research (Philadelphia, Pa.). 2015;**8**(2):174-179. DOI: 10.1158/1940- 6207.CAPR-14-0291

[26] Lan B, Zhang J, Zhang P, Zhang W, Yang S, Lu D, et al. Metformin suppresses CRC growth by inducing apoptosis via ADORA1. Frontiers in Biosciences (Landmark Ed). 2017;**22**:248-257. DOI: 10.2741/4484

[27] Camacho L, Dasgupta A, Jiralerspong S. Metformin in breast cancer—An evolving mystery. Breast Cancer Research. 2015;**17**:88. DOI: 10.1186/s13058-015-0598-8

[28] Hadad SM, Hardie DG, Appleyard V, Thompson AM. Effects

**107**

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

> in Obstetrics & Gynecology. 2018 Dec;**52**(6):706-714. DOI: 10.1002/uog

[35] Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M. Cellular and molecular mechanisms of metformin: An overview. Clinical Science (London, England). 2012;**122**(6):253-270. DOI:

[36] Cheng CY, Mruk DD. A local autocrine axis in the testes that regulates spermatogenesis. Nature Reviews. Endocrinology. 2010;**6**:380-395. DOI:

[37] Grootegoed JA, Oonk RB, Jansen R, et al. Metabolism of radiolabelled energy-yielding substrates by rat Sertoli cells. Journal of Reproduction and Fertility. 1986;**77**:109-118. DOI: 10.1530/

[38] Coonrod S, Vitale A, Duan C, et al. Testis-specific lactate dehydrogenase (LDH-C4; Ldh3) in murine oocytes and pre-implantation embryos. Journal of Andrology. 2006;**27**:502-509. DOI:

[39] Mita M, Hall PF. Metabolism of round spermatids from rats: Lactate as the preferred substrate. Biology of Reproduction. 1982;**26**:445-455. DOI:

Schurmann A. The glucose transporter families SGLT and GLUT: Molecular basis of normal and aberrant function. JPEN Journal of Parenteral and Enteral Nutrition. 2004;**28**:364-371. DOI: 10.1177/0148607104028005364

[41] Tartarin P, Moison D, Guibert E, Dupont J, Habert R, et al. Metformin exposure affects human and mouse fetal testicular cells. Human Reproduction. 2012;**27**(11):3304-3314. DOI: 10.1093/

[42] Riera MF, Regueira M, Galardo MN, et al. Signal transduction pathways

10.1042/CS20110386

10.1038/nrendo.2010.71

jrf.0.0770109

10.2164/jandrol.05185

10.1095/biolreprod26.3.445

[40] Scheepers A, Joost HG,

humrep/des264

of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clinical & Translational Oncology. 2014;**16**(8):746-752. DOI:

[29] Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Research. 2011;**71**(9):3196-3201. DOI: 10.1158/0008-5472.CAN-10-3471

[30] Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocrine-Related Cancer. 2012;**19**(3):447-456. DOI: 10.1530/

[31] Zhuo Z, Wang A, Yu H. Metformin targeting autophagy overcomes

progesterone resistance in endometrial carcinoma. Archives of Gynecology and Obstetrics. 2016;**294**(5):1055-1061. DOI:

10.1007/s00404-016-4148-0

[32] Xiao X, He Q, Lu C, Werle KD, Zhao RX, Chen J, et al. Metformin impairs the growth of liver kinase B1-intact cervical cancer cells.

[33] Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F, et al. Metformin blocks melanoma invasion and metastasis development in AMPK/ p53-dependent manner. Molecular Cancer Therapeutics. 2013;**12**(8):1605-

1615. DOI: 10.1158/1535-7163.

[34] Kalafat E, Sukur YE, Abdi A, Thilaganathan B, Khalil A. Metformin

for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: Systematic review and meta-analysis of randomized trials. Ultrasound

mct-12-1226-t

Gynecologic Oncology. 2012;**127**(1):249- 255. DOI: 10.1016/j.ygyno.2012.06.032

ERC-12-0046

10.1007/s12094-013-1144-8

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clinical & Translational Oncology. 2014;**16**(8):746-752. DOI: 10.1007/s12094-013-1144-8

*Metformin*

diacare.21.11.1967

s12020-018-1717-y

10.1385/JMN:17:1:45

meta.2001.24192

[20] Sheth SH, Larson RJ. The efficacy and safety of insulinsensitizing drugs in HIV-associated lipodystrophy syndrome: A metaanalysis of randomized trials. BMC Infectious Diseases. 2010;**10**:183. DOI:

10.1186/1471-2334-10-183

[21] Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: A systematic review and

1998;**21**(11):1967-1972. DOI: 10.2337/

meta-analysis. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(7):2347-2353. DOI: 10.1210/

[22] Cerullo M, Gani F, Chen SY, Canner J, Pawlik TM. Metformin use

[23] Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes:

A meta-analysis. Diabetes Care. 2011;**34**(10):2323-2328. DOI: 10.2337/

[24] Yu H, Yin L, Jiang X, Sun X, Wu J, Tian H, et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: A meta-analysis of epidemiological observational studies. PLoS One. 2014;**9**(12):e116327. DOI: 10.1371/journal.pone.0116327

[25] Sakoda LC, Ferrara A, Achacoso NS, Peng T, Ehrlich SF, Quesenberry CP, et al. Metformin use and lung cancer risk in patients with diabetes. Cancer Prevention Research (Philadelphia, Pa.). 2015;**8**(2):174-179. DOI: 10.1158/1940-

[26] Lan B, Zhang J, Zhang P, Zhang W,

Yang S, Lu D, et al. Metformin suppresses CRC growth by inducing apoptosis via ADORA1. Frontiers in Biosciences (Landmark Ed). 2017;**22**:248-257. DOI: 10.2741/4484

[27] Camacho L, Dasgupta A, Jiralerspong S. Metformin in breast cancer—An evolving mystery. Breast Cancer Research. 2015;**17**:88. DOI:

10.1186/s13058-015-0598-8

[28] Hadad SM, Hardie DG,

Appleyard V, Thompson AM. Effects

6207.CAPR-14-0291

is associated with improved survival in patients undergoing resection for pancreatic cancer. Journal of Gastrointestinal Surgery. 2016;**20**(9):1572-1580. DOI: 10.1007/

s11605-016-3173-4

dc11-0512

jc.2012-1267

[15] Ning HH, Le J, Wang Q, et al. The effects of metformin on simple obesity: A meta-analysis. Endocrine. 2018;**62**(3):528-534. DOI: 10.1007/

[16] Culmsee C, Monnig J, Kemp BE, Mattson MP. AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. Journal of Molecular Neuroscience. 2001;**17**(1):45-58. DOI:

[17] Santomauro Junior AC, Ugolini MR, Santomauro AT, Souto RP. Metformin and AMPK: An old drug and a new enzyme in the context of metabolic syndrome. Arquivos Brasileiros de Endocrinologia e Metabologia. 2008;**52**(1):120-125. DOI: 10.1590/ S0004-27302008000100017

[18] Kroemer G, Reed JC. Mitochondrial control of cell death. Nature Medicine. 2000;**6**(5):513-519. DOI: 10.1038/74994

[19] Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;**50**(7):856-861. DOI: 10.1053/

**106**

[29] Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Research. 2011;**71**(9):3196-3201. DOI: 10.1158/0008-5472.CAN-10-3471

[30] Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocrine-Related Cancer. 2012;**19**(3):447-456. DOI: 10.1530/ ERC-12-0046

[31] Zhuo Z, Wang A, Yu H. Metformin targeting autophagy overcomes progesterone resistance in endometrial carcinoma. Archives of Gynecology and Obstetrics. 2016;**294**(5):1055-1061. DOI: 10.1007/s00404-016-4148-0

[32] Xiao X, He Q, Lu C, Werle KD, Zhao RX, Chen J, et al. Metformin impairs the growth of liver kinase B1-intact cervical cancer cells. Gynecologic Oncology. 2012;**127**(1):249- 255. DOI: 10.1016/j.ygyno.2012.06.032

[33] Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F, et al. Metformin blocks melanoma invasion and metastasis development in AMPK/ p53-dependent manner. Molecular Cancer Therapeutics. 2013;**12**(8):1605- 1615. DOI: 10.1158/1535-7163. mct-12-1226-t

[34] Kalafat E, Sukur YE, Abdi A, Thilaganathan B, Khalil A. Metformin for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: Systematic review and meta-analysis of randomized trials. Ultrasound

in Obstetrics & Gynecology. 2018 Dec;**52**(6):706-714. DOI: 10.1002/uog

[35] Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M. Cellular and molecular mechanisms of metformin: An overview. Clinical Science (London, England). 2012;**122**(6):253-270. DOI: 10.1042/CS20110386

[36] Cheng CY, Mruk DD. A local autocrine axis in the testes that regulates spermatogenesis. Nature Reviews. Endocrinology. 2010;**6**:380-395. DOI: 10.1038/nrendo.2010.71

[37] Grootegoed JA, Oonk RB, Jansen R, et al. Metabolism of radiolabelled energy-yielding substrates by rat Sertoli cells. Journal of Reproduction and Fertility. 1986;**77**:109-118. DOI: 10.1530/ jrf.0.0770109

[38] Coonrod S, Vitale A, Duan C, et al. Testis-specific lactate dehydrogenase (LDH-C4; Ldh3) in murine oocytes and pre-implantation embryos. Journal of Andrology. 2006;**27**:502-509. DOI: 10.2164/jandrol.05185

[39] Mita M, Hall PF. Metabolism of round spermatids from rats: Lactate as the preferred substrate. Biology of Reproduction. 1982;**26**:445-455. DOI: 10.1095/biolreprod26.3.445

[40] Scheepers A, Joost HG, Schurmann A. The glucose transporter families SGLT and GLUT: Molecular basis of normal and aberrant function. JPEN Journal of Parenteral and Enteral Nutrition. 2004;**28**:364-371. DOI: 10.1177/0148607104028005364

[41] Tartarin P, Moison D, Guibert E, Dupont J, Habert R, et al. Metformin exposure affects human and mouse fetal testicular cells. Human Reproduction. 2012;**27**(11):3304-3314. DOI: 10.1093/ humrep/des264

[42] Riera MF, Regueira M, Galardo MN, et al. Signal transduction pathways

in FSH regulation of rat Sertoli cell proliferation. American Journal of Physiology. Endocrinology and Metabolism. 2012;**302**:E914-E923

[43] Adaramoye O, Akanni O, Adesanoye O, Labo-Popoola O, Olaremi O. Evaluation of toxic effects of metformin hydrochloride and glibenclamide on some organs of male rats. Nigerian Journal of Physiological Sciences. 2012;**27**(2):137-144. DOI: 10.3389/fendo.2018.00675

[44] Rabbani SI, Devi K, Khanam S. Role of pioglitazone with metformin or glimepiride on oxidative stress-induced nuclear damage and reproductive toxicity in diabetic rats. Malaysian Journal of Medical Sciences. 2010;**17**(1):3-11

[45] Labazi H, Wynne BM, Tostes R, Webb RC. Metformin treatment improves erectile function in an angiotensin II model of erectile dysfunction. The Journal of Sexual Medicine. 2013;**10**(9):2154-2164. DOI: 10.1111/jsm.12245

[46] Phé V, Rouprêt M. Erectile dysfunction and diabetes: A review of the current evidence-based medicine and a synthesis of the main available therapies. Diabetes & Metabolism. 2012;**38**(1):1-13. DOI: 10.1016/j. diabet.2011.09.003

[47] Owen M, Doran E, Halestrap A. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal. 2000;**348**(3):607-614. DOI: 10.1042/ bj3480607

[48] Dias TR, Martins AD, Reis VP, Socorro S, Silva BM, et al. Glucose transport and metabolism in Sertoli cell: Relevance for male fertility. Current Chemical Biology. 2013;**7**(3):282-293

[49] Bertoldo MJ, Guibert E, Tartarin P, Guillory V, Froment P. Effect of

metformin on the fertilizing ability of mouse spermatozoa. Cryobiology. 2014;**68**(2):262-268. DOI: 10.1016/j. cryobiol.2014.02.006

[50] Vanltallie TB. Stress: A risk factor for serious illness. Metabolism. 2002;**51**:40-45. DOI: 10.1053/ meta.2002.33191

[51] Paolisso G, Tagliamonte MR, Rizzo MR, Giugliano D. Advancing age and insulin resistance: New facts about an ancient history. European Journal of Clinical Investigation. 1999;**29**:758-769. DOI: 10.1046/j.1365-2362.1999.00522.x

[52] Bjorntorp P, Rosmond R. The metabolic syndrome—A neuroendocrine disorder? The British Journal of Nutrition. 2000;**83**:S49-S57. DOI: 10.1017/s0007114500000957

[53] Wolkowitz OM, Epel ES, Reus VI. Stress hormone-related psychopathology: Pathophysiological and treatment implications. The World Journal of Biological Psychiatry. 2001;**2**:115-143. DOI: 10.3109/15622970109026799

[54] Rosenthal M, Haskell WL, Solomon R, Widstrom A, Reaven GM. Demonstration of a relationship between levels of physical training and insulin-stimulated glucose utilisation in normal humans. Diabetes. 1983;**32**:408- 411. DOI: 10.2337/diab.32.5.408

[55] Jinno M, Watanabe A, Takahashi S, Urakami C. A novel method to detect dysfunction of stress-responsemechanism in women with ovarian dysfunction: Implications of circadian rhythm in salivary cortisol for diagnosis and treatment. Fertility and Sterility. 2007;**88**(Suppl 1):S171. DOI: 10.1016/j. fertnstert.2007.07.594

[56] Jakubowicz DJ, Seppala M, Jakubowicz S, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like

**109**

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism.

2001;**86**:1126-1133. DOI: 10.1210/

[57] Fogle RH, Minkhorst OR, Reagan M, Denis AL, Toner TP, Hasty LA. Metformin may improve embryo quality and pregnancy rates in ovulatory (non-PCOS) patients undergoing *in vitro* fertilization (IVF). Fertility and Sterility. 2009;**92**(3):S167.

DOI: 10.14310/horm.2002.1266

biolreprod54.2.331

2006;**75**:342-351

[58] Armstrong DT, Xia P, de Gannes G, Tekpetey FR, Khamsi F. Differential effects of insulin-like growth factor-I and follicle-stimulating hormone on proliferation and differentiation of bovine cumulus cells and granulosa cells. Biology of Reproduction. 1996;**54**(2):331-338. DOI: 10.1095/

[59] Tosca L, Solnais P, Ferre P, et al. Metformin-induced stimulation of adenosine 5′ monophosphate-activated

progesterone secretion in rat granulosa

[60] Tosca L, Chabrolle C, Uzbekova S, et al. Effects of metformin on bovine granulosa cells steroidogenesis: Possible involvement of adenosine 5′ monophosphate-activated protein kinase (AMPK). Biology of Reproduction. 2007;**76**:368-378

[61] Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertility and Sterility. 2001;**76**:517-524

protein kinase (PRKA) impairs

cells. Biology of Reproduction.

jcem.86.3.7295

*Metformin in Health Issues and Reproductive System DOI: http://dx.doi.org/10.5772/intechopen.90465*

*Metformin*

in FSH regulation of rat Sertoli cell proliferation. American Journal of Physiology. Endocrinology and Metabolism. 2012;**302**:E914-E923

metformin on the fertilizing ability of mouse spermatozoa. Cryobiology. 2014;**68**(2):262-268. DOI: 10.1016/j.

[50] Vanltallie TB. Stress: A risk factor for serious illness. Metabolism.

[51] Paolisso G, Tagliamonte MR, Rizzo MR, Giugliano D. Advancing age and insulin resistance: New facts about an ancient history. European Journal of Clinical Investigation. 1999;**29**:758-769. DOI: 10.1046/j.1365-2362.1999.00522.x

[52] Bjorntorp P, Rosmond R. The metabolic syndrome—A neuroendocrine

disorder? The British Journal of Nutrition. 2000;**83**:S49-S57. DOI: 10.1017/s0007114500000957

Stress hormone-related

and treatment implications. The World Journal of Biological Psychiatry. 2001;**2**:115-143. DOI: 10.3109/15622970109026799

[54] Rosenthal M, Haskell WL,

411. DOI: 10.2337/diab.32.5.408

fertnstert.2007.07.594

[56] Jakubowicz DJ, Seppala M, Jakubowicz S, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like

[53] Wolkowitz OM, Epel ES, Reus VI.

psychopathology: Pathophysiological

Solomon R, Widstrom A, Reaven GM. Demonstration of a relationship between levels of physical training and insulin-stimulated glucose utilisation in normal humans. Diabetes. 1983;**32**:408-

[55] Jinno M, Watanabe A, Takahashi S, Urakami C. A novel method to detect dysfunction of stress-responsemechanism in women with ovarian dysfunction: Implications of circadian rhythm in salivary cortisol for diagnosis and treatment. Fertility and Sterility. 2007;**88**(Suppl 1):S171. DOI: 10.1016/j.

2002;**51**:40-45. DOI: 10.1053/

cryobiol.2014.02.006

meta.2002.33191

[43] Adaramoye O, Akanni O, Adesanoye O, Labo-Popoola O, Olaremi O. Evaluation of toxic effects of metformin hydrochloride and glibenclamide on some organs of male rats. Nigerian Journal of Physiological Sciences. 2012;**27**(2):137-144. DOI:

10.3389/fendo.2018.00675

10.1111/jsm.12245

diabet.2011.09.003

bj3480607

[44] Rabbani SI, Devi K, Khanam S. Role of pioglitazone with metformin or glimepiride on oxidative stress-induced nuclear damage and reproductive toxicity in diabetic rats. Malaysian Journal of Medical Sciences. 2010;**17**(1):3-11

[45] Labazi H, Wynne BM, Tostes R, Webb RC. Metformin treatment improves erectile function in an angiotensin II model of erectile dysfunction. The Journal of Sexual Medicine. 2013;**10**(9):2154-2164. DOI:

[46] Phé V, Rouprêt M. Erectile

dysfunction and diabetes: A review of the current evidence-based medicine and a synthesis of the main available therapies. Diabetes & Metabolism. 2012;**38**(1):1-13. DOI: 10.1016/j.

[47] Owen M, Doran E, Halestrap A. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal. 2000;**348**(3):607-614. DOI: 10.1042/

[48] Dias TR, Martins AD, Reis VP, Socorro S, Silva BM, et al. Glucose transport and metabolism in Sertoli cell: Relevance for male fertility. Current Chemical Biology. 2013;**7**(3):282-293

[49] Bertoldo MJ, Guibert E, Tartarin P, Guillory V, Froment P. Effect of

**108**

growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism. 2001;**86**:1126-1133. DOI: 10.1210/ jcem.86.3.7295

[57] Fogle RH, Minkhorst OR, Reagan M, Denis AL, Toner TP, Hasty LA. Metformin may improve embryo quality and pregnancy rates in ovulatory (non-PCOS) patients undergoing *in vitro* fertilization (IVF). Fertility and Sterility. 2009;**92**(3):S167. DOI: 10.14310/horm.2002.1266

[58] Armstrong DT, Xia P, de Gannes G, Tekpetey FR, Khamsi F. Differential effects of insulin-like growth factor-I and follicle-stimulating hormone on proliferation and differentiation of bovine cumulus cells and granulosa cells. Biology of Reproduction. 1996;**54**(2):331-338. DOI: 10.1095/ biolreprod54.2.331

[59] Tosca L, Solnais P, Ferre P, et al. Metformin-induced stimulation of adenosine 5′ monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells. Biology of Reproduction. 2006;**75**:342-351

[60] Tosca L, Chabrolle C, Uzbekova S, et al. Effects of metformin on bovine granulosa cells steroidogenesis: Possible involvement of adenosine 5′ monophosphate-activated protein kinase (AMPK). Biology of Reproduction. 2007;**76**:368-378

[61] Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertility and Sterility. 2001;**76**:517-524

**111**

Section 3

Metformin and Cancer

Section 3
