Polycystic Ovary Syndrome Treatment

### **Chapter 5**

## Effects of Acupuncture Treatment on Polycystic Ovary Syndrome (PCOS)

*Gunasekaran Ramanathan*

### **Abstract**

Polycystic ovarian syndrome (PCOS) is an imbalance of endocrine hormones with a group of symptoms that occur in the reproductive age of females. It is diagnosed by androgen excess and ovarian dysfunction. Many pharmacological-based drugs and treatments are available, however, the effectiveness of existing therapies is less. Yet no cure for PCOS, but symptoms can be managed with medications and lifestyle modifications. Hence, an alternative treatment method is needed for a complete cure. Currently, much clinical evidence has revealed that Acupuncture (AP) and Electro-acupuncture treatment (EAT) are effective treatments for regulating reproductive hormone levels, normalizing testosterone, reducing ovarian cysts, enhancing ovulation, and weakening insulin resistance in normal and obese women with PCOS. Further, β-endorphin has a more crucial role in PCO, AP, or EAT, which may alter the formation of β-endorphin. The mechanism of AP and EAT for PCOS has not been widely reviewed so far. A good understanding of the AP and EAT would be helpful in women with PCOS. This chapter aimed to overview the probable mechanisms and experimental evidence-based data of acupuncture treatment on PCOS in animal models and human patients. We hope that the chapter study will contribute to a better understanding of the PCOS and AP treatment.

**Keywords:** acupuncture, electro-acupuncture treatment, PCOS, anovulation, ovarian cysts anovulation, HR variability

### **1. Introduction**

Polycystic ovary syndrome (PCOS) is an endocrine disorder. In the modern lifestyle, the disorder affects many reproductive-age women worldwide. In 2010 data worldwide, 116 million (3.42%) women were affected by PCOS [1]. PCO is majorly associated with the dysfunction of ovaries. Based on studies, many factors are involved. The clinical signs of PCO are hyperandrogenism, ovulatory dysfunction, metabolic dysfunction, and obesity [2, 3] further, it is associated with cardiovascular disease CVD, cancer, diabetes, and endometrial dysfunction [4, 5], but the exact cause, etiology, and pathophysiology are not clearly understood. Yet there is no

perfect treatment for all diagnosed with PCOS [6, 7]. Depending on the patient, the PCO management method and selection of the best therapy option and their priorities vary [8, 9].

The current management, therapy, and pharmacological medications are less effective in PCOS, yet some complicated women with PCOS are left untreated [10]. Currently, the pharmacological therapy for women with PCOS is using an oral estrogen receptor modulator, but it's 40–50% ineffective in many cases. It's linked with side effects such as breast tenderness, headaches, mood swings, arthralgias, myalgias, and fatigue [11, 12]. Further studies showed pituitary Gonadotropin (GnH) hormone is effective in inducing ovulation; however, it causes overstimulation syndrome and the development of multiple follicles [13].

Recent research showed that complementary and alternative medicine (CAM) as alternative therapy might benefit the management of PCOS [14]. The CAM therapeutic input has classes of physical, nutritional, and psychological, or all in combination [15]. Hence, clear-cut PCOS pathogenesis and perfect management are urgently needed. In this book chapter, we update the pathogenesis and current management, particularly the beneficial effects of electro-acupuncture on PCOS.

### **2. What is acupuncture treatment?**

Acupuncture has origins in traditional Chinese medicine (TCM) [16], More than 3000 years, ago acupuncture treatment was used; it's a basic part of CAM [14] acupuncture is a specific type of sensory stimulation in the skin and muscles using thin needles. It may be useful to treat some chronic pain, and some abnormal physical conditions, and as a complementary treatment for many disorders [17].

### **3. How is acupuncture working?**

TCM describes that a person's health results from a tuneful balance of the complementary extremes of Chinese Yin and Yang of the life force known as Qi marked "chi." It believes that disease is the result of an imbalance of these forces. In the human body, the Qi flows through specific pathways, or meridians. These energy flows and pathways are accessible through specific acupuncture points. In the human body 361, acupuncture points have been identified. Inserting selected thin needles into these suitable acupoints with suitable combinations will bring the flow of energy back into balance [18].

Stimulation of many acupuncture points affects multiple sensory neuron activity. These points are called the receptive fields. The physical insertion of a thin needle may affect pain processing in the muscles and central nervous system (CNS), further increasing blood flow to certain organs and parts of the body [19]. However, the exact mechanism of action of acupuncture is not clear.

### **4. What's electro-acupuncture treatment (EAT)?**

In China1950s EAT was developed for its precise use in surgical operations. In the early days, acupuncture was used for analgesia; while using it, the anesthetists had

### *Effects of Acupuncture Treatment on Polycystic Ovary Syndrome (PCOS) DOI: http://dx.doi.org/10.5772/intechopen.113799*

to rotate the needles manually throughout the surgery, which was difficult, so they developed an electro-acupuncture (EA) apparatus. EAT, in which acupuncture is united with electrical stimulation. Initially, EA analgesia was used largely in China, and interest showed in the West. It's useful to reduce the use of analgesic drugs during surgery. However, EA in practice is personal and depends on their experience. Some practitioners said EA is against the spirit of 'natural' acupuncture therapy, but others said EAT is good for patients with chronic nociceptive pain and good for drug addiction.

The analgesic effects of EAT are more effective than those of the manual acupuncture method. An fMRI study of normal adults found that stimulation with EA at a frequency of 3 Hz on acupuncture point LI-4 Hegu produced fMRI signal increases in the precentral gyrus, postcentral gyrus/inferior parietal lobule, and putamen/insula [20], whereas normal acupuncture through specific needle manipulation manually of the same acupuncture point produced decreases in fMRI signals in the putamen/ insula, posterior cingulate, and superior temporal gyrus [21]. EA also increases the tissue content of endorphins [22].

Electro-acupuncture (EA) can be used for seizures, dizziness, aphasia, headache, chorea, stroke, drug addiction, PCO, and many more. Currently, two modes of EA are used commonly: high-intensity high-frequency (50 to 200 Hz) and low-intensity low-frequency (1 to 4 Hz). In this EA therapy, instead of hand stimulation through a needle, electro-stimulation is used to treat the diseases**.** In EAT-specific needles are placed in the scalp (anastomotic linkage of lymphatic drainage) and connected with an electro-acupuncture machine to stimulate the acupuncture points**.** The pulse duration, intensity, and frequency of the electric current must be altered depending on the patient. EAT stabilizes the treatment through its fast rotation; we can stimulate more than two points simultaneously and control the current level depending on the patient. Usually, EAT duration is 10 to 20 minutes per time for 7–10 days depending on the disease.

EAT should be used with caution. Use the needle in the right position, not bend or break. When the intensity of the current used for acupuncture points close to the brain area, medulla, lateral line of the occipital area, or other areas, at all times the right amount of current must be used. Do not increase the current suddenly to a large amount because it may cause an increase in heart rate (HR) and breathing stops. It's contraindicated for cancer, heart diseases, and brain diseases.

### **5. Electroacupuncture treatment for PCOS**

Conventional therapy (first-line) is not yet satisfactory, but the nonpharmacological therapy of normal acupuncture and EA has become popular. Based on multiple clinical trials, both manual acupuncture and EAT have a good effect on treating women with PCO [23–27]. Earlier studies and clinical trials suggested that proper acupuncture treatment improves menstruation and ovulation [28, 29]. It has also been reported that EAT decreases testosterone levels and improves insulin sensitivity in animals and humans with PCOS [23]. Further, it regulates the levels of the anti-Müllerian hormone (AMH) and hypothalamic–pituitary-ovarian (HPO) axis. A recent animal models PCO study explain that acupuncture could improve insulin resistance inhibit the PI3K/AKT/mTOR pathway, or activate the protein kinase (AMPK) pathway [30]. Further, it reduces anxiety and improves

### **Figure 1.**

*Manual or EAT improves PCOS-related symptoms such as pregnancy rate, ovulation rate, sexual hormonal imbalance, metabolic dysfunction, and insulin resistance through different biological mechanisms.*

health-related quality of life [31]. Acupuncture treatment for patients with PCOS decreases the abnormally increased luteinizing hormone (LH) [29, 32] and increased testosterone [33] without side effects; it's less expensive treatment [34]. Collectively, the manual or EAT for PCOs improves the pregnancy rate. Ovulation rate, sexual hormonal imbalance, metabolic dysfunction, and insulin resistance (**Figure 1**).

### **6. Methods of electroacupuncture treatment**

Stimulation through EA is more effective and can be easily quantifiable compared to manual acupuncture, further reducing the bias. Earlier studies showed Zigong (EX-CA 1), Sanyinjiao (SP 6), Zhongji (CV 3), and Guanyuan (BL 26) acupuncture points were chosen for the formula. In addition to that, three arbitrary acupuncture points have been selected based on phases of the menstrual cycle: 1) after menstruation, using acupuncture points for the needle: Taixi (KI 3) and Taichong (LR 3). 2) In the ovulatory period, using acupuncture points: Xuehai (SP 10) and Mingmen (CV 4). 3) Using acupuncture points before the beginning of the next menstruation: Geshu (BL 17) and Xuehai (SP 10).

The broadly used acupuncture point was SP6 (Sanyinjiao) for reproductive problems, nourishing organs, and activating blood; the second ST29 (Guilai) acupoint was used for reducing pain and regulating circulation and menstruation. An EAT, or manual acupuncture needle stimulation, induces and enhances muscle conduction and various chemical signals to stimulate the central release of various factors through sympathetic nerve conduction, which is believed to regulate the woman's reproductive axis (**Figure 2**).

*Effects of Acupuncture Treatment on Polycystic Ovary Syndrome (PCOS) DOI: http://dx.doi.org/10.5772/intechopen.113799*

### **Figure 2.**

*The most of the acupuncture needle points are on the abdominal area for human and animal for PCO, the acupuncture point SP6 (Sanyinjiao)for reproductive problem, nourishing organs, and activating blood. The acupuncture point ST29 (Guilai) was used for reducing pain and regulate menstruation.*

### **7. Needle using**

An earlier study [35] showed that each acupuncture point needled used a filiform needle (length 25–50 mm and diameter 0.25–026 mm) to attain a *Deqi* sensation3 (at the needling acupuncture point, feel a sensation like numbness and swelling, and it radiates along the reliable meridian). Needled used in each acupuncture point will be a filiform needle (length 25–50 mm and diameter 0.25 mm) to achieve a *Deqi* sensation. Then, an auxiliary needle (length: 13 mm and diameter: 0.18 mm) will be inserted to a depth of 2 mm and 2 mm lateral to the first needle without achieving *Deqi*.4. With the help of an EA instrument, fixed or required electrical current will be given at the acupuncture point, with one electrode to the auxiliary and the other electrode to the filiform needle [35].

Duration of treatment: Electrical stimulation for a minimum of 30 min for each session. From the 50th day of menstruation three times per week or withdrawal bleeding until before the next menstruation for three menstrual cycles.

Expected outcome: Primary outcome: the ovulation rate. Secondary outcomes: ovulation time point, endometrial thickness, dominant follicle rate, and follicular size Hormone level: FSH, LH, GnRH, Estradiol (E2) level, and pregnancy rate.

### **8. EAT rectifies the anovulation in PCO**

### **8.1 Experimental evidence**

Experimental evidence PCOS is a complex metabolic and endocrine disorder [36]. In the reproductive age of females, many cases of anovulation occur, which leads to infertility. EA treatment is a safe and effective treatment for anovulation in women 5A suitable EA treatment may effectively reduce the number of ovarian cysts, reduce ovarian volume, and enhance blood flow to the ovaries. Further, it reverses the insulin levels and insulin sensitivity back to normal, which reduces the blood glucose level. Further, it controls the sympathetic activity to normal [37]. Only very few animal model studies are available on the effect of EAT on the sympathetic activity in PCOS. Hence, in our laboratory, we aimed to assess the effect of EAT on anovulation and increased sympathetic nerve activity in EV-induced PCO rate models.

EAT: Repeated low-frequency EAT was carried out for 20 minutes for the PCO group for two days up to 8–10 weeks. Just before EAT rats were anesthetized, the needles were inserted into the erector spinae muscle in the somatic segment and bilaterally in the biceps femoris related to the nerve innervations of the ovaries, inserted to a depth of 0.3–0.51 cm. 6 These are connected to the EA machine using the frequencies of 80 Hz (burst frequency) and 2 Hz (frequency low), and until local muscle contraction, the intensity was adjusted to be from 0.8 to 1.31 mA. After the experimental period, animals were anesthetized and the blood samples were collected to measure plasma epinephrine (EPI) and norepinephrine (NE) levels in high-performance liquid chromatography (HPLC).

### **8.2 Histological study of the ovaries**

For the histological study of ovaries, the control and experimental groups were euthanized, ovaries were removed, and the near connective fat tissue was removed. The tissue sections were stained with hematoxylin–eosin (NICE chemicals), and then the slides were used to study the follicles. The slides were viewed under a light microscope, and a well-trained pathologist determined the morphological variation of the normal and abnormal follicles in the follicular population. In this case, a normal ovary has become a polycystic ovary (PCO). We can see on the outer border of the ovary many small fluid-filled sacs present. These sacs are called cysts, which contain immature eggs. The cystic follicle's failure to release eggs leads to anovulation.

Most of the follicles are cystic in appearance, and stromal hyperplasia was seen. Follicles become atretic; otherwise, the ovary and follicles were considered healthy.

We got the following result: After the experimental period of 30, and 60 days, the normal, EV-induced PCO and EA treatment rates were killed. After 30 days, PCO rates showed a progressive decline in the number of primary and secondary follicles, but after 60 days, there were many morphological variations seen in the PCO rat's follicles compared to normal healthy follicles, and follicular cysts appeared, big-size atretic follicles, and stromal hyperplasia were also seen. It confirms that the ovary attains PCOS (**Figure 3B**) similar result was also observed in an earlier study [38]. Repeated EAT after 60 days showed the abnormal follicle morphology back to normal and the number of ovarian cysts considerably reducing (**Figure 3C**). Furthermore, no considerable morphological differences were seen between the healthy rats ovary (Control group **Figure 3A**) and the EAT group rats' ovary (**Figure 3**).

*Effects of Acupuncture Treatment on Polycystic Ovary Syndrome (PCOS) DOI: http://dx.doi.org/10.5772/intechopen.113799*

### **Figure 3.**

*Hematoxylin and eosin-stained ovary section. A. The normal control rats ovaries with healthy follicles and corpus luteum, B. EV-induced rat's ovaries showed cystic appearance, and C. After electroacupuncture treatment in PCOS rats showed reappearance of healthy follicles.*

### **8.3 Epinephrine and norepinephrine levels in rat plasma**

In our study, the EV-treated PCO rats showed a significant increase in the epinephrine (EPI) and norepinephrine (NE), but after 60 days of EAT, the PCO group rates showed a significant decrease in both EPI and NE levels (P < 0.001). When it's compared to the control group with the EAT group, the EPI and NE levels are back to normal (**Table 1**).


### **Table 1.**

*Epinephrine and norepinephrine level in rat plasma (Normal and PCO, EAT).*

### **9. The potential mechanisms of EAT and anovulation**

Chronic anovulation is a main cause of infertility; in both animals and humans, anovulation is the supreme characteristic of PCOS [39]. EAT improves the development and maturation of follicles and oocytes and prevents anovulation [26, 40]. It's by increasing the expression of P450arom, inhibiting the overexpression of, and upregulating the IRS-1/PI3K/GLUT4 pathway. Further, EA improved *in vitro* fertilization [41]. Various animal model studies also reported that EA improves ovulation dysfunction by reducing granulosa atrophy, improving follicular arrest, inhibiting the PI3K/AKT/mTOR pathway, and downregulating LncMEG3 expression [42, 43]. EAT also improves the preovulatory follicle number and development of corporalutea. It's by increasing the hilum blood vessels and blood supply [44].

In women, a range of reproductive hormonal disturbances cause PCO. EAT rectifies the hormonal imbalance of decreased GnRH, estradiol, and increased LH in women with PCO [45]. Acupuncture reduces the abnormal serum sex steroid levels of the adrenal cortex and ovaries. In the PCO animal model study, EAT improved the number of corpora lutea, disturbed estrous cycles, and upregulated the arcuate nucleus kisspeptin protein [46].

### **10. EAT rectifies the autonomic alteration in women with PCOS**

### **10.1 Experimental evidence**

Heart rate (HR) fluctuation is a sign of autonomic imbalance. Based on earlier studies, it's an initial risk for heart problems, and it may lead to CVD. Further, studies showed that a group of PCOS women has a risk of CVD [4]. Therefore, in our laboratory, we aimed to investigate the autonomic alteration of the HR in women with PCOS and the effect of EAT on it. For this study, we used the estradiol valerate (EV)-induced PCO rat model [47]. In this study, the vaginal smear was taken periodically from the control and experimental group rats. The EV-induced PCO model rat group shows a prolonged diestrus stage compared to the control group; we determine its PCO group rat [47].

**Heart rate variability (HRV) analysis**: Our laboratory's heart rate variability (HRV) was assessed in the normal control group and experimental PCO group rats before and after EAT. It's done from the frequency domain and the time domain analysis. In the time domain analysis, the following data were obtained: mean RR interval, SDNN (standard deviation of RR interval), and rMSSD. For frequency domain analysis, there were two major spectral components: high frequency (HF 0.8–2.5 Hz) and low frequency (LF 0.2–0.8 Hz).

**EAT**: For this study, we carried out low-frequency EAT in the conformed PCOS rats; each treatment was given once in two days for 15–20 minutes, given up to 4–5 weeks. The EA needles were inserted in the erector spinae muscle in the somatic segment and bilaterally in the biceps femoris related to the nerve innervations of the ovaries, with a needle depth of 0.3–0.5 cm. Then it connected to an EA electrical stimulator with a burst frequency of 80 Hz and a low frequency of 2 Hz.

**The result obtained:** The EV-induced PCO rate showed a significant reduction (p < 0.05). in the time domain R-R interval, SDNN, and rMSSD compared to the control group, but after 4–5 weeks of EAT, the PCO group rats showed a significant increase in the R-R interval, SDNN, and rMSSD (p < 0.05). It indicates that the repeated low frequency EAT has beneficial effects on PCOS rats; the RR interval and HR significantly returned to normal (**Table 2**).


*In comparison with the control group the PCO group showed a significant decrease (p < 0.05)\*. And comparison with the PCOS group with PCO + EAT showed a significant increase (p < 0.05)\*\*.*

### **Table 2.**

*The control group, PCO, and PCO + EAT groups were compared in time domain indices the values are in mean ± SD.*

The frequency domain analysis of the PCOS rats showed a significant increase in the low-frequency power LF and LF/ HF ratio. But total power TP (p < 0.05) and high-frequency power HF, when compared to control, significantly decreased. However, after 4–5 weeks of EAT, the LF and LF/HF ratios significantly decreased and the HF and TP increased when compared to untreated PCOS (**Table 3)**.

### **10.2 Mechanisms EAT on HR variability in PCO**

In our study, short-term HRV analysis of the EV-induced PCO rat showed a significant decrease in the total power (TP), which is an index of overall HRV. A further significant increase in LF nu showed increased sympathetic activity, and a significantly decreased HF nu indicates decreased parasympathetic activity. Furthermore, the LF/HF ratio also increased, which indicates an imbalance between sympathetic nerve and parasympathetic nerve activity. Earlier studies also showed an increase in LF and LF/HF ratio, which is due to increased sympathetic activity [48]. In another study, EV-induced PCO model rats significantly increased the synthesis of intraovarian nerve growth factor (NGF), which is a strong marker for sympathetic activity [49]. Increased activity of sympathetic nerves is also linked with obesity and CVD [50, 51]. In a comparative study, PCOS was treated with exercise with low-frequency EAT, which has shown significantly decreased high muscle sympathetic activity [52]. In the EV-induced PCOS, model rats showed the EAT decreased the high ovarian NGF and high mRNA expression of NGF [37, 53, 54] and adrenergic receptors [55].

### **10.3 The mechanisms of acupuncture treatment on hyperandrogenism**

Hyperandrogenism is a condition in which overproduction of the male sex hormone (testosterone), even though these hormones are present in women at lower levels. But in some women, excess levels of male sex hormones androsterone, androstenedione, and testosterone causes Cushing syndrome, PCO, and malfunction of the adrenal gland. Erlaier's studies showed that hyperandrogenism is the most important mechanism and clinical feature of PCOS [56]. EAT normalizes the blood testosterone level in women with PCOs [28]. Further, in the rate model PCO, the low-frequency EAT also reduces the serum androgen level through the hypothalamic *Oprk1* and *Oprm1* central opioid receptors [57]. In another study in PCO women, EAT regulates the AMH and P450arom through this mechanism, it reduces the increased androgen level [58]. A similar result was also observed in the rat model PCO study by Sun et al. [59]. Another PCO animal model study also reveals that acupuncture treatment reduces abnormally increased androgen secretion and reduces the number of androgen receptors [60].


**Table 3.**

*The frequency domain analysis comparison between groups \* and \*\* indicates significant.*

### **10.4 Obesity and PCO**

Obesity has increased the amount of body fat and is a complex disease. It's the root of many diseases and health problems like diabetes, high cholesterol, heart disease, high blood pressure, and liver disease. Its comorbidity is associated with cardiometabolic dysfunction like hypertension, type 2 diabetes mellitus (T2D), PCOs, and other metabolic syndromes. Increasing women's body weight and obesity are the main factors in the pathogenesis of PCOS. It is also associated with endometrial carcinoma, hyperinsulinemia, and insulin resistance. PCO is a good example of a metabolic disorder, which also includes insulin resistance and cardiometabolic risk (**Figure 4**).

Earlier studies reported that women being overweight is the reason for PCOs [61–63]. Conversely, weight loss reduces the risk of reproductive failure, metabolic features of PCOs, and hyperandrogenism [64, 65]. It indicates that treating obesity is the first step to preventing infertility and PCO. Currently, pharmaceutical treatments for obesity are available; however, due to security reasons, there are various limits [66, 67]. Acupuncture treatment is an alternative intervention method for obesity [68]. Some studies suggest that EAT is more effective compared to manual acupuncture, but the effective frequency determination is controversial. In some obesity cases, a combination of diet modification, or exercise, and EAT is essential for weight loss [69, 70].

### **10.5 Mechanisms of acupuncture treatment on obesity linked PCO**

Acupuncture therapy is believed to regulate the hypothalamic–pituitary axis and neuroendocrine. It modulates energy metabolism and eating habits, gastrointestinal

**Figure 4.** *Summary of obesity linked with PCOS.*

### *Effects of Acupuncture Treatment on Polycystic Ovary Syndrome (PCOS) DOI: http://dx.doi.org/10.5772/intechopen.113799*

tract (GIT) secretions, GI hormones and classic hormones secretions, and nervous system functions [71]. The hypothalamus arcuate nucleus (ARC) contains two microcircuits, agouti-related peptide (AgRP) and neuropeptide-(NPY), which are important for energy balance and have an antagonistic role'. Its signals to stimulate hunger and food intake, and the POMC (pro-opiomelanocortin) signals reduce food intake and satiety. ARC is involved in the central regulation of body weight, energy expenditure, and selected food intake, stimulation of this area alters food intake [72]. Animal model study reveals that EAT reduces food intake; and weight loss and increases the peptide *α*-MSH and mRNA expression in ARH. Furthermore, EAT significantly reduces the energy intake and body weight in 14-week high-fat diet-fed rats and upregulates the amphetamine-regulated transcript (CART) and cocaine in ARC. It indicates that the valuable effects of EAT act through ARC [73, 74].

Furthermore, specially obesity-linked areas are the Satiety center" in the ventromedial hypothalamus (VMH) and "the feeding center" in the lateral hypothalamus (LH) [75]. Stimulation of these LH centers through EA reduces the excitation of LH, and inhibits hyperorexia-obesity and regulates the catecholamine, ATPase, 5-hydroxytryptamine (5HT) levels in LH [76, 77]. In 1999, Su et al. reported that stimulation of the satiety center, tends to prevent obesity. Through EAT stimulation of the VMH center the levels of dopamine (DA), tyrosine (Tyr), and tryptophan (Typ) ratio were elevated, increasing the excitability of VMH [78].

Research studies believe that normal acupuncture or EAT stimulation increases the spontaneous discharges of nerve cells of the paraventricular nucleus (PVN)

### **Figure 5.**

*Neuroendocrine regulation under the effectiveness of acupuncture treatment in the animal model studies. The arcuate nucleus of the hypothalamus (ARH), Ventrosomedial hypothalamus (DMH) lateral hypothalamic area (LHA), paraventricular nucleus (PVN), perifornical nucleus (PeF) Ref [82].*

important area for feeding and drinking and decreases the activity of the perifornical nucleus (PeF) The PeF nucleus is important for wakefulness and sleep [79, 80]. Stimulation of the most important acupuncture point in the Stomach 36 (ST36, EA *zusanli*) upregulates the proopiomelanocortin (POMC) in neurons of the Nucleus *Tractus solitarius* (NTS) and hypoglossal nucleus (HN) preventing food intake and leading to weight loss (**Figure 5**) [81].

### **10.6 Mechanisms of acupuncture treatment on insulin resistance with PCO**

Most PCO women are insulin-resistant, particularly obese females [83]. When cells do not respond to insulin, they cannot easily uptake glucose from the blood. It leads to hyperglycemia and excess insulin in the blood (hyperinsulinemia), both of which induce reproductive failure and PCO [84]. Many clinical studies have proved that EAT has beneficial effects on insulin resistance in PCOS patients, and EAT inhibited the insulin resistance of PCO females via activation of the IRS-1/PI3K/GLUT4 pathway [25, 26]. In 2020, Peng Y et al. [7]. reported that in a PCO rat model study, EAT activates the AMPK pathway to suppress SREBP-1 expression, ultimately, inactivating insulin resistance, oxidative stress, and mitochondrial dysfunction (**Figure 6**).

### **Figure 6.**

*The effects of EAT on the insulin pathway. EAT upregulates the insulin receptor substrates-1/PI3K/GLUT4 pathway and increases the GLUT4 expression or triggers the adenosine monophosphate-activated protein kinase (AMPK) pathway or stops the PI3K/AKT/mTOR pathway. It also decreases the levels of tumor necrosis factor-α and interleukin-6 both are involved in insulin resistance Ye et al. [85].*

The present book chapter summarizes various clinical studies of women with PCOs and PCO animal model studies. Further, it explains the mechanisms of acupuncture and EAT on PCOS-related key symptoms of hyperandrogenism, insulin resistance, ovulatory dysfunction, obesity, and negative emotion. Further, the main acupoints were used for treating women with PCOS, and animals were also described in this chapter.

*Effects of Acupuncture Treatment on Polycystic Ovary Syndrome (PCOS) DOI: http://dx.doi.org/10.5772/intechopen.113799*

### **Author details**

Gunasekaran Ramanathan1,2

1 Department of Physiology, Swamy Vivekanandha Medical College Hospital and Research Institute, Thiruchangode, TN, India

2 The Tamilnadu Dr. MGR Medical University, Chennai, India

\*Address all correspondence to: gunasekaranrr@gmail.com

© 2023 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.

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### **Chapter 6**

## Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome

*Isam Al Jashi, Claudia Mehedintu, Miruna Tanase, Mihaela Plotogea, Bogdan Morosan, Edu Antoine and Cristina Gladys Al Jashi*

### **Abstract**

Polycystic ovary syndrome (PCOS), affecting 5–10% of women, is characterized by irregular ovulation and excess androgen hormones. The multifactorial causes include hormonal imbalances, insulin resistance, genetics, and obesity. Diagnosis involves identifying criteria like oligo/anovulation, hyperandrogenism, and micropolycystic ovarian appearance. Traditional treatments include progesterone-based medication and oral contraceptives. However, fertility-focused treatments such as clomiphene, metformin, purified FSH, or LH are administered for those seeking to restore fertility. This article explores "ProFecund Ino," a myo-inositol-based treatment for PCOS. It touts benefits such as improved hormonal balance, regulated menstrual cycles, stimulated ovulation, enhanced insulin sensitivity, and positive effects on the nervous system. The study involving 200 women with PCOS showed a 38% pregnancy rate with ProFecund Ino and additional pregnancies resulted from ovarian stimulation and IVF procedures. The conclusion underscores the efficacy of myo-inositol-based treatments in conjunction with assisted reproductive techniques, significantly increasing pregnancy chances for women with PCOS.

**Keywords:** polycystic ovary syndrome (PCOS), myo-inositol, ProFecund Ino, fertility treatment, women's health

### **1. Introduction**

Also known as Stein-Leventhal syndrome or chronic hyperandrogenic anovulation, polycystic ovary syndrome (PCOS) is an endocrinological condition characterized by the absence of ovulation and the presence of excessive amounts of androgenic hormones in the female body.

Clinically, PCOS is manifested by amenorrhea (lack of menstrual cycles) or irregular menstrual cycles, accompanied by obesity and manifestations caused by excess androgen hormones (acne, hirsutism, etc.).

### **2. Epidemiology**

PCOS affects 5–10% of the total female population worldwide and up to 26.7% of the female population of childbearing age (15–44 years) [1].

It is estimated that 70% of women with PCOS are still undiagnosed [2].

PCOS symptoms most frequently occur in girls with recent menses and in women in the premenstrual period (with worsening symptoms, especially pelvic pain).

### **3. Causes and risk factors**

The exact cause is not fully elucidated. However, certain favorable factors can be described:


### **4. Signs and symptoms**


### **5. Diagnosis**

According to the Rotterdam Consensus of 2003 still in force, the diagnosis of polycystic ovary syndrome (PCOS) is made in the presence of at least two of the following three criteria:


*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*

3.Ovaries with a micropolycystic appearance—the micropolycystic appearance of the ovaries is detected by transvaginal ultrasound in 75% of PCOS patients, consisting of at least one ovary with a volume > 10 cm3 or presenting at least 12 follicles with a diameter between 2 and 9 mm.

### **6. Treatment**

Classic treatment includes progesterone-based medication (Medroxyprogesterone) and oral contraceptives.

In the case of women who want to regain their fertility (with the hope of obtaining a future pregnancy), antiestrogens (clomiphene), metformin, and purified FSH or LH are administered.

### **7. ProFecund Ino**

### **7.1 Active ingredients per daily dose**


### **7.2 Mode of presentation**

Box with 30 sachets of 3 g of product.

### **7.3 Administration method**

Two sachets per day.

The recommended courses for obtaining a stable result over time are three months.

### **7.4 Benefits**


### **8. Myo-inositol**

### **8.1 Definition**

Myo-inositol is a pseudovitamin consisting of nine molecules with a similar structure (isomers), found especially in cereals and citrus fruits.

Usually, the term inositol is used for the stereoisomer myo-inositol. With a similar structure to glucose, inositol is involved in cell signal transmission.

### **8.2 Indications**

### *8.2.1 Adjuvant in PCOS*

One of the causes of polycystic ovary syndrome is insulin resistance. Myo-inositol contributes to increasing insulin sensitivity and improving the activity of insulin receptors.

Also, it contributes to changing the FSH/LH ratio, lowering the testosterone level, and restoring the normal menstrual cycle.

### *8.2.2 Pregnancy*

In pregnant women carrying fetuses with neural tube defects, low levels of inositol have been observed compared to women with normal pregnancies. Inositol can prevent a wide range of neural tube defects resistant to folic acid supplementation.

### **8.3 Interactions and adverse effects**

This shows a high safety profile for most adults. Among the possible side effects that may occur when taking it are nausea and dizziness, fatigue, or headache.

It is considered safe to be given in hospital to premature babies with ARDS (acute respiratory distress syndrome).

In the case of bipolar affective disorders, it is recommended to avoid the administration of inositol, as it may trigger the worsening of symptoms.

No interactions with other drugs are known to date.

### **9. Vitex agnus-castus**

### **9.1 Characteristics**


*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*


### **9.2 Mechanism of action**

Vitex agnus-castus is not a hormone. Vitex acts on the hypothalamus and pituitary gland where it improves specific hormone secretion or the transmission of the necessary chemical signals to the ovaries for the release of estrogens and progesterone.

Vitex agnus-castus →↑ ↓ → *LH FSH* and prepares the body for ovulation.

### **9.3 Vitex and progesterone**

Vitex potentiates the hormones involved in ovulation, also participating in the rebalancing of the hormonal balance:


Vitex is highly effective in maintaining adequate progesterone levels during the luteal (postovulatory) phase, levels necessary for pregnancy.

### **9.4 Interactions and other side effects**

• No known drug-extract interactions have been reported for Vitex in humans

Careful use is recommended when prescribed among:


### **10. Quatrefolic**

Whereas folic acid requires three intermediate steps to reach the level of active folate, L-Methylfolate (Quatrefolic) is a metabolized folic acid, which leads to its immediate and complete absorption as biologically active folate.

### **10.1 Benefits: Increased solubility in water**


### **10.2 Benefits: Increased bioavailability**

• The bioavailability of QuatrefolicTM is visibly increased compared to MetafolinTM and folic acid

### **10.3 Safety of use**


### **10.4 Medical uses of quatrefolic**


*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*


### **11. Vitamin B2 (riboflavin)**

It is a water-soluble vitamin with an important role in the proper functioning of the entire human body. Water-soluble vitamins, such as vitamin B2, are transported through the bloodstream, and the amount that is no longer needed is eliminated from the body through urine.

Another important aspect is that people must consume vitamin B2 every day, because the body can only store small amounts, and the reserves of this nutrient are consumed quickly.

### **11.1 Mechanism of action**

It acts as an antioxidant, which controls the presence of harmful free radicals inside our body. Riboflavin is necessary for the production of an antioxidant called glutathione, which acts as a "destroyer" of free radicals and, at the same time, detoxifies the liver.

There are many diseases that can be prevented with the help of an adequate dose of riboflavin. This vitamin is also useful in the treatment of genital conditions:

Helps overall metabolism to convert macronutrients: carbohydrates, lipids, and proteins into energy. It also participates in improving the immune system, helps the body to balance acidity, and is important for hair, nails, and eyes.

### **11.2 Vitamin B2: deficiency**


### **11.3 Studies**

Numerous clinical studies have shown that riboflavin functions as an antioxidant nutrient, effectively mitigating lipid peroxidation and reducing oxidative reperfusion injury. Additionally, a lack of riboflavin may elevate the susceptibility to specific forms of cancer.

Riboflavin may also have neuroprotective effects in certain neurological conditions (e.g., Parkinson's disease, migraine, and multiple sclerosis) through its role.

Less well known is the fact that vitamin B2 provides growth stimulants for children and helps support healthy vision along with vitamin A.

### **12. Gonal**

### **12.1 Description**

Gonal-F (follitropin alpha) is a human follicle-stimulating hormone (FSH) gonadotropin, which is a glycoprotein hormone produced using recombinant DNA technology.

Follitropin alfa possesses a dimeric structure composed of two glycoproteins, the α- and β-subunits, which are non-covalently linked and not identical. The α-subunit comprises 92 amino acids, while the β-subunit has 111 amino acids. Both their primary and tertiary structures closely resemble those of human follicle-stimulating hormone.

The biological activity of follitropin alfa *in vivo* has been standardized against the initial International Standard for Recombinant Human Follicle-Stimulating Hormone, established in 1995 by the Expert Committee on Biological Standards of the World Health Organization.

It is important to note that Gonal-F does not contain any luteinizing hormone (LH) activity.

Gonal-F is a sterile, freeze-dried powder designed for subcutaneous injection following reconstitution. Each Gonal-F multidose vial is supplied with 600 IU (equivalent to 44 micrograms) or 1200 IU (equivalent to 87 micrograms) of follitropin alfa, which delivers 450 IU (about 33 micrograms) or 1050 IU (around 77 micrograms) of follitropin alfa, respectively. These vials also contain 30 milligrams of sucrose, 1.11 milligrams of dibasic sodium phosphate dihydrate, and 0.45 milligrams of monobasic sodium phosphate monohydrate.

### **12.2 Indications**

Gonal-F is indicated for:


### **12.3 Mechanism of action**

Gonal-F encourages the growth of ovarian follicles in women who do not suffer from primary ovarian failure. To trigger the final maturation of the follicle and induce ovulation when a natural LH surge is absent, human chorionic gonadotropin (hCG) is

*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*

administered after Gonal-F, but only when patient monitoring reveals that adequate follicular development has occurred.

In men with hypogonadotropic hypogonadism, Gonal-F is effective in stimulating spermatogenesis.

### **13. Cetrotide**

### **13.1 Description**

Cetrotide is a medication employed to prevent premature ovulation, which refers to the premature release of eggs from the ovaries. This medication is typically given to women who are undergoing ovarian stimulation treatment, a fertility procedure aimed at stimulating the ovaries to produce a greater number of eggs.

Cetrotide's active ingredient is cetrorelix.

### **13.2 Mechanism of action**

The active ingredient in Cetrotide, cetrorelix, functions by inhibiting the actions of luteinizing hormone-releasing hormone (LHRH) within the body. LHRH regulates the production and release of another hormone known as luteinizing hormone (LH), which is responsible for initiating the process of ovulation. In the context of fertility treatment, ovarian stimulation is utilized to encourage the ovaries to generate a greater number of eggs. By blocking the effects of LHRH, Cetrotide effectively suppresses the production of LH, thereby preventing premature ovulation. This is important because premature ovulation can result in the release of immature and unsuitable eggs for use in assisted reproductive techniques like *in vitro* fertilization (IVF).

### **14. Study objective**

This study aims to increase the chances of obtaining a pregnancy in women diagnosed with polycystic ovary syndrome.

### **15. Materials and method**

This prospective, interventional study had a duration of 24 months, was conducted between January 2021 and February 2023, and was carried out in four national medical centers in Bucharest:


To this purpose, a group of 200 women (aged between 22 and 36 years old) were included.

### **16. Inclusion criteria**


### **17. Results and discussions**

The number of pregnancies installed versus women included in the study: out of the total number of 200 patients who have finalized the study:

38% (76) got pregnant by the end of it;

76% of the remaining patients (94) continued IVF protocol and managed to obtain a pregnancy;

15% will continue with another IVF procedure.

Our study was based on a batch of 200 patients with the environment of origin as shown below (**Figure 1** and **Table 1**):

Our batch of patients was divided between smokers and non-smokers as shown below (**Figure 2** and **Table 2**):

**Figure 1.**

*Patients distribution by living environment.*


**Table 1.**

*Patients distribution by living environment.*

*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*

The batch presented a small percentage of obese patients (**Figure 3** and **Table 3**):

Out of the 200 women participating in the study, 6% presented comorbidities during their pregnancies. Ten of them presented thrombophilia and two of them gestational diabetes, as shown in **Figure 4** and **Table 4**.

After undergoing between three and six months of ProFecund Ino treatment, 70% of the patients presented follicular quality improvement (**Figure 5** and **Table 5**).

### **Figure 2.**

*Smokers vs. nonsmokers distribution.*


### **Table 2.**

*Smokers vs. nonsmokers distribution.*

**Figure 3.** *Normal weight vs. obesity distribution.*


### **Table 3.**

*Normal weight vs. obesity distribution.*

### **Figure 4.**

*Comorbidities.*


### **Table 4.** *Comorbidities.*

In total, 38% out of all included patients (76) obtained pregnancy after only following the proposed treatment with ProFecund Ino. All of the 76 patients were at most 32 years old at the time of pregnancy diagnostic (**Table 6**).

The remaining 124 patients continued the ProFecund Ino treatment and started ovarian stimulation with medium dose Gonal F (Follitropin Alpha) and Cetrotide, followed by an IVF procedure. This led to another 94 pregnancies, which represents 76% of the remaining batch. Thirty of the patients (24%) did not obtain a pregnancy and will continue the ProFecund Ino treatment and will undergo a new procedure (**Table 7**).

### **18. Conclusions**

Patients with polycystic ovary syndrome who underwent the myo-inositol (ProFecund Ino – women, ProFecund B – men with relatively good sperm quality) treatment (both partners for at least four months) managed to obtain a pregnancy in 38% of the cases (**Figures 6** and **7**).

*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*

### **Figure 5.**

*Follicular quality.*


**Table 7.** *IVF + Profecund Ino.*

IVF treatment succeeded in 47% of the total cases after undergoing ProFecund Ino treatment, proceeding with a medium dose of Follitropin Alpha – (Gonal 200 IU) for 7 to 8 days, followed by inhibition with Cetrotide (Cetrorelix) starting on the sixth day of the stimulation process. On the aspiration day, the follicle presented a better quality.

Patients who presented thrombophilia (5%) received antithrombotic treatment with an antiplatelet agent (Aspirin, 75 mg daily) and anticoagulant agent (Clexane,

**Figure 6.** *ProFecund Ino ONLY.*

**Figure 7.** *IVF + ProFecund Ino.*

**Figure 8.** *Overall results.*

*Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.114150*


**Table 8.** *Overall results.*

4000UI daily) associated with progesterone. All 10 patients managed to get pregnant and had a full-term delivery.

Patients with gestational diabetes did not necessitate insulin, glucose levels were managed with strict diet.

All patients who carried their pregnancies to term showed an improvement in their polycystic ovary syndrome.

As shown in **Figure 8** and **Table 8**, the main purpose of the study was achieved by obtaining a pregnancy in 85% of the participants and by being able to fulfill their wish of completing their family.

### **Author details**

Isam Al Jashi1,2, Claudia Mehedintu3 , Miruna Tanase2 , Mihaela Plotogea4 \*, Bogdan Morosan5 , Edu Antoine4 and Cristina Gladys Al Jashi6

1 Faculty of Medicine, "Titu Maiorescu" University, Bucharest, Romania

2 Department of Obstetrics and Gynecology, "Unirea Medical Centre" (Regina Maria), Bucharest, Romania

3 Department of Obstetrics and Gynecology, "Filantropia" Clinical Hospital, Bucharest, Romania

4 Department of Obstetrics and Gynecology, "Nicolae Malaxa" Clinical Hospital, Bucharest, Romania

5 Hyllan Pharma, Bucharest, Romania

6 Department of Obstetrics and Gynecology, "Sf. Pantelimon" Emergency Clinical Hospital, Bucharest, Romania

\*Address all correspondence to: nicole\_plotogea@yahoo.co.uk

© 2024 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.

### **References**

[1] Unfer V et al. Myo-inositol effects in women with PCOS: A meta-analysis of randomized controlled trials. Endocrine Connections. 2017;**6**(8):647-658. Available from: https://www.ncbi.nlm. nih.gov/pmc/articles/PMC5655679/

[2] Zheng X et al. Inositol supplement improves clinical pregnancy rate in infertile women undergoing ovulation induction for ICSI or IVF-ET. Medicine (Baltimore). 2017;**96**(49):e8842. Available from: https://www.ncbi.nlm. nih.gov/pubmed/29245250

[3] Laganà AS et al. Myo-inositol supplementation reduces the amount of gonadotropins and length of ovarian stimulation in women undergoing IVF: A systematic review and metaanalysis of randomized controlled trials. Archives of Gynecology and Obstetrics. 2018;**298**(4):675-684. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/30078122

[4] Palatnik A et al. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. Journal of Clinical Psychopharmacology. 2001;**21**(3):335- 339. Available from: https://www.ncbi. nlm.nih.gov/pubmed/11386498

[5] Scientific Opinion on the Substantiation of Health Claims related to Riboflavin (vitamin B2). Available from: https://www.efsa.europa.eu/en/ efsajournal/pub/1814

### **Chapter 7**

## Inositols in the Treatment of Polycystic Ovary Syndrome in Reproductive Age

*Neda Smiljan Severinski, Ulla Marton and Anđelka Radojčić Badovinac*

### **Abstract**

Polycystic ovary is part of an endocrine syndrome in which different pathophysiological mechanisms lead to a similar reproductive outcome: anovulation, irregularity of the menstrual cycle, and infertility. Hormonal and metabolic disorders are associated with reproductive adverse outcomes, which represent a vicious circle with dysfunctional ovaries. Hyperandrogenemia, disorder of carbohydrate metabolism, and sex hormone synthesis led to reproductive abnormalities. One of the most crucial questions still remains, whether the polycystic ovary is the cause or the consequence of all known disorders. Inositols are in the treatment of PCOS capable of restoring ovulation with the impact on the carbohydrate metabolism, by increasing the sensitivity of cells to insulin, which releases the sex hormones-binding protein and improves hyperandrogenemia. Nine stereoisomers of inositol are known, myo-inositol and chiro-inositol are the most studied in the reproductive age. By normalizing the level of androgens in the blood, the growth of and the balance of sex hormones is established. A variety of metabolic pathways of these molecules are recognized in different tissues, such as fat, muscle, or ovarian tissue. Still, it is not clear which isomer has better reproductive or metabolic effects, and there are controversies about their effectiveness in the treatment of reproductive disorders.

**Keywords:** D-chiro inositol, inositol, myoinositol, polycystic ovary, pregnancy

### **1. Introduction**

Polycystic ovarian syndrome (PCOS) is defined as a heterogeneous disorder involving a variety of serious clinical manifestations, hormonal disorders, unbalanced metabolic functions, and psychological disorders in women of reproductive age with the main impact on infertility [1]. Rotterdam criteria covered all aspects of this well-acknowledged syndrome with a wide variety of clinical presentations. The four phenotypes of PCOS syndrome are defined, and there is one fundamental criterion—hyperandrogenemia with or without hyperandrogenism in three phenotypes [2]. Evidence suggests the role of different external and internal factors as disorders in the metabolism of carbohydrates with hyperinsulinemia and insulin

resistance (IR). Metabolic disorders have an impact on hormonal production, causing serious hormonal dysfunction and disorder that interferes with the dysfunction of ovaries. Polycystic ovary is characterized by a significantly larger content of primordial follicles, therefore enhanced number of granulosis cells that synthesize up to 75 times more anti-Müllerian hormones in granulosa cells of normal ovaries [3]. In women of reproductive age, anovulation, and irregular, extended menstrual cycles are the main causes of infertility. Anovulation is treated primarily by ovulation induction with clomiphene citrate or aromatase inhibitors. Failure of ovarian response in PCO patients on clomiphene induction has introduced gonadotropins as an optional medicamentous treatment to achieve ovulation. The use of gonadotropins includes significant risks of hyperstimulation, thrombo-embolic incidents, or ovarian torsions with possible ovarian necrosis. Niche for the introduction of new promising molecules for therapeutic indications as a useful, effective, and safe tool for restoring spontaneous ovulation has put inositols in focus. Inositols became very interesting and promising molecules due to their biochemical pathways, which are safe in their action and have an effective role in the metabolism of carbohydrates, just like insulin. Inositols are messenger molecules with an impact on enhanced insulin effect in the cells, and specific foods contain them in significant quantities. A positive effect of inositols on ovarian function, ovulation, carbohydrate metabolism, infertility treatment, the incidence of gestational diabetes, and eutrophic newborns after infertility treatment was observed. Inositols improve development of follicules and oocytes, oocyte maturation, fertilization, implantation, and post-implantation development, bringing positive outcomes in IVF procedures in patients with PCOS by reducing the occurrence of gestational diabetes. Reproductive abnormalities are more common in women with higher BMI and continue to rise with higher BMI. Obese women are more likely to have anovulatory cycles and menstrual irregularities. Obesity complicated by metabolic abnormalities can further worsen the outcome of treatment in PCOS patients. Inositols as "messenger" molecules that have a role in insulin signaling with increase effects of insulin intracellularly through phosphoglycan mediators. Naturally, inositols are synthesized mostly in the kidney, with the highest concentration in the brain, where they play a substantial role in neurotransmitters and some steroid hormones binding to their receptors. There are nine isomers of inositol, and differences in the action of these molecules in different tissues, such as fat, muscle, or ovarian tissue, have also been noted. It is not entirely clear which isomer has better reproductive or metabolic effects, and there are controversies and discussions about their effectiveness in the treatment of reproductive disorders, which we will present in this chapter.

### **2. Metabolic consequences and effect of insulin and inositol**

Mechanisms of insulin action and signal transmission to cells of various tissues that use glucose as an energy source are well known. Insulin forms a complex with the insulin receptor that activates phosphatidyl inositol-3 kinase, which is an enzyme that increases the concentration of *phosphoinositides* (PIPs) in cells that integrate molecules into the cell membrane. Four cellular processes are activated in this way: glucose uptake, glycogenesis, antigluconeogenesis, and antilipolysis [4]. Phosphatidyl inositol-3 kinase also activates another messenger of insulin, phosphatidyl inositol*,* which also stimulates all metabolic activities of insulin and therefore acts synergistically with insulin and enhances its action.

*Inositols in the Treatment of Polycystic Ovary Syndrome in Reproductive Age DOI: http://dx.doi.org/10.5772/intechopen.113150*

Inositols generally enhance the effects of insulin and regulate intracellular functions: *phosphoinositides* (PIPs)—integrate molecules into the cell membrane *inositol polyphosphates* (InsPs)—are cytoplasmic "second" messengers and *inositol phosphoglycans* (IPGs) regulate mitochondrial metabolism [5]. Inositols are very stable polar molecules that belong to the family of nine *hexahydroxycyclohexane stereoisomers*. They were initially isolated from muscles and later from numerous cells and tissues of mammals. In addition to insulin signal transmission, they are very active in cellular processes such as calcium transport, association of cytoskeletal proteins, lipid metabolism, modulation of the serotoninergic pathway, cell growth and differentiation, and oocyte maturation. Inositol isomers have been proven to have an important role in various medical conditions such as neurodegenerative diseases (scyllo inositol), diabetes (D-chiro inositol, DCI), malignant diseases, metabolic syndrome, or PCO syndrome (myo-inositol, MI).

Myo-inositol is the most widespread molecule among inositols in nature and mammalian cells (99%); the rest is D-chiro inositol (1%). Myo-inositol is converted into DCI by epimerization (the metabolic pathway is stimulated by the tissue-specific NAD/NADH epimerase that is dependent on insulin), which significantly changes the concentration ratio of these molecules in tissues such as the liver, adipose tissue, or muscle, respectively, to the brain. Myo-inositol is found in cells in free form or bound in cell membranes (in the composition of *phosphoinositide*), i.e., it is a protector of hyperosmotic stress in cells. As a second messenger, it regulates the activity of a number of hormones, such as follicle-stimulating hormone (FSH), thyroidstimulating hormone (TSH), and insulin. In mammals, a tissue-specific epimerase converts MI to DCI in an insulin-dependent manner, and different ratios of these epimers have been confirmed in different tissues. D-chiro inositol is an important molecule in the insulin signaling pathway and, together with galactosamine, significantly affects molecular mechanisms (activation of molecules that alleviate the consequences of glucose metabolism disorders). However, paradoxically in women with IR and pre-eclampsia the concentration of DCI is elevated and it is suspected that DCI contributes to IR [6, 7].

### **3. Ovary, insulin resistance, and hyperandrogenemia**

Ovarian function disorders in PCOS represent a growing heterogeneous, multifaceted complex entity, combined with a metabolic disorder caused by deterioration in the metabolism of carbohydrates and insulin resistance (IR). Insulin resistance is defined as a subnormal biological response to normal insulin levels, decreased sensitivity, or response to metabolic action of insulin. Clinically, insulin resistance can be described as the insufficient cell response of a known quantity of endogenous or exogenous insulin to increase glucose uptake and reduced sensitivity or answer to the metabolic effect of insulin. The significant association of PCO syndrome and IR is seemingly, obvious highly, complex and problematic. The frequency of association between IR and PCO according to the literature, depends on the studied population and different criteria used in the published studies. Although IR is significantly associated with PCO syndrome, it is not established as diagnostic criteria for PCO syndrome. Similarly, there are no general recommendations for screening for IR in patients with PCO syndrome. Obesity is frequently associated with PCO syndrome and plays a key role in hyperinsulinemia and IR. There are debates about interactions and relations of obesity, IR, and PCO syndrome. Accumulation of adipocytes

in adipose tissue plays an important role in the endocrine function of the ovary. The enhanced production of leptin in adipocytes inhibits the expression of aromatase mRNA in granulosa cells, causing interruption of androgen conversion to estrogen. Production of adiponectin in adipocytes has insulin-sensitizing, anti-diabetic, and anti-inflammatory effects. It is unclear whether obesity is the cause of IR or worsens already-existing IR in PCO syndrome. Published data indicate that obesity is an additional circumstance that aggravates IR in patients with already previously existing IR [8, 9]. Systemic hyperinsulinism can be endogenous (obesity, gestational diabetes, diabetes type 2, extreme IR caused by mutation of the insulin receptor gene, autoantibodies on insulin receptor, insulinoma) or exogenous (diabetes mellitus type 1). HOMA-IR is a frequent parameter used in estimating IR in large epidemiological population studies and is calculated as a ratio of fasting insulin and glucose values. HOMA-IR can be increased in code-slender or obese patients with PCO syndrome in comparison to patients without PCO syndrome. According to the published results [9], cut-off value of HOMA-IR is 3.15 for patients with PCO syndrome, while in the general population, the defined cut-off value of HOMA-IR is 2.5. The assessment of insulin resistance is one of the major questions for clinicians, remaining how to distinguish wide variability in insulin-sensitive female patients in relation to insulin insensitivity and what criteria are acceptable in different ethnic groups. The fact is that not all women with IR have PCO syndrome, and the same IR is not present in all women with PCO syndrome. Insulin levels depend on several factors, such as metabolism and clearance of insulin, enzymatic degradation of the insulin - receptor complex, obesity, age, and androgen level. It should be taken into concern during the evaluation of the patient. To conclude, there might be some additional factor that leads to hyperandrogenism, which is an obligatory diagnostic criterion included in PCO syndrome and associated with hyperinsulinemia or some additional trigger. Hyperandrogenism has an important impact on the mechanism of PCOS, including IR, inflammation, and oxidative stress. Hyperandrogenism aggravates IR through different routes, by inhibiting insulin degradation in the liver and reduction of insulin sensitivity. Still, we need to define the necessary criterion for the diagnosis of HA as an additional trigger for the development of PCO syndrome with hyperinsulinemia.

Insulin resistance and compensatory hyperinsulinism, contribute to increased production of androgens. Insulin has a modality as gonadotropin in the ovary triggering ovarian steroidogenesis, stimulating androgen synthesis in the adrenal glands, and modulates pulsatility of LH by increasing LH binding sites and androgen-producing response to LH. Hyperandrogenemia is responsible for reproductive disorders like ovulatory dysfunction, anovulation, oligomenorrhea, infertility, acne, and alopecia, which are clinical signs of PCO syndrome. Hyperandogenemia is associated with obesity and increased visceral fat, which are not rare in patients with PCO syndrome. An increase in fat tissue promotes IR, HA, and hyperinsulinemia, and again, we are in the same circle of alternating disorders [1]. The genomic, transcriptomic, and proteomic profile of visceral fatty tissue in women with PCO syndrome is different from that of healthy women, more similar to a man's fatty tissue, and hence suggests the metabolic effect of HA on typical obesity in PCO syndrome [10]. Beyond the multifactorial pathophysiology of PCOS, one of the hypotheses suggests a pathogenetic role of high levels of androgens that are the main cause of abdominal and visceral fatty tissue accumulation. Both stimulate IR and compensatory hyperinsulinism. Hyperinsulinism is responsible for androgen synthesis in the ovary and adrenal glands and promotes leptin-mediated inflammation in women with PCO syndrome, so the vicious circle closes [1]. Heterogeneity of PCO syndrome most likely arises from

### *Inositols in the Treatment of Polycystic Ovary Syndrome in Reproductive Age DOI: http://dx.doi.org/10.5772/intechopen.113150*

obesity, abdominal fat, and IR. Central hepatic insulin resistance can be present in slender patients with PCO syndrome, while the peripheral IR is tied to adipose tissue and muscles and is characteristic of female patients who are obese.

Since some inositols (MI, DCI) are mediators of insulin, they can potentially change the metabolism of various tissues. Inositols are credited with acting as a second messenger, in response to external or endocrine signals, reducing IR, improving ovarian function by reducing androgen levels, and alleviating metabolic, menstrual, and cutaneous hyperandrogenic features of PCOS. Noticeably, inositols are involved in the action of several endocrine systems (insulin, thyroid hormone, gonadotropins) and lipids with hormone-like activity signals (as prostaglandins). Myo-inositol and DCI are the two most abundant members of nine stereoisomeric inositols. The specificities of the inositols metabolism in the ovary and differences compared to other tissues are known. D-chiro inositol is synthesized *in vivo* by epimerization from MI, and the degree of epimerization defines insulin-dependent epimerase. The ratio of MI and DCI concentration in ovarian tissues is 70:1, while the ratio in women with PCOS is pathologically decreased. Type 2 diabetes mellitus, with its pathophysiological pathways, can dramatically impair DCI levels, resulting in low intracellular levels of DCI due to reduced activity of epimerase (hyperinsulinemia reduces activity of epimerase). In PCO syndrome, ovaries are in a state in which tissue-selective resistance to metabolic effects of insulin seems to be contradictory and associated with ovarian sensitivity to insulin unlikely liver, fat, and muscle tissue. In PCO syndrome with pronounced hyperinsulinemia, in the ovary, there is an accelerated conversion of MI to DCI (increased ratio, excessive synthesis of DCI) due to accelerated epimerization. As a consequence, deficiency of MI in the ovary causes specific reproductive disturbances [11]. This phenomenon, called the D-chiro inositol paradox, is a rebound effect on hyperinsulinemia. The mechanism involves tissuespecific metabolic pathways that decrease the synthesis of DCI in the liver, muscles, and fat tissue as a response to hyperinsulinemia; under the same circumstances, DCI synthesis increases within the ovaries while synthesis of MI is lacking. Therefore, DCI is effective in treating and reducing IR but not in reducing ovarian disorders in PCO patients [12].

### **4. Treatment of reproductive disorders with inositols**

Reproductive abnormalities in PCO syndrome may appear with different clinical presentations. Disorders of ovulation, oligomenorrhea, amenorrhea, and menstrual cycle irregularities are the most common infertility causes in patients with PCO syndrome [13]. The different clinical PCOS phenotypes require proper assessment of the biochemical and medical features to adopt the best pharmacological treatment and therapeutic strategy in patients with PCO syndrome. The aim of the pharmacological treatment may be hyperandrogenemia, oligo-ovulation, or IR. The therapeutic management and selection of the best therapy should be done upon the clinical features of the target patient and her priorities—regulation of menstrual disturbance, ovulation abnormalities, oligo-ovulation, hyperandrogenism or IR, or altogether. Before drug administration, diet and healthy lifestyle advice must be given to all patients with PCOS regardless of their weight.

Physical activity and exercise (150 min of moderate or 75 min of intense exercise per week) play a key role in weight reduction and the prevention of obesity. That approach has been proven to be the best way to improve insulin sensitivity. Weight

reduction with calorie intake restriction and the introduction of physical activity would be the first step in treatment for obese women diagnosed with PCO syndrome. With weight loss, the free testosterone level decreases, as does the incidence of metabolic syndrome. Changes in lifestyle and diet lead to lower insulin and free androgen levels, inducing the restoration of body composition, hyperandrogenism, and IR. There is very much to discover, for a better understanding of pathogenesis, how the reduction of fat tissues modifies all metabolic pathways and improvements in the metabolism of glucose or lipids, reproductive outcome, mood, quality of life, and therapy satisfaction [14]. Weight reduction leads to better self-esteem.

Hyperinsulinemia and IR are key goals of treatment in patients with PCO syndrome and include the administration of insulin-sensitizing drugs (e.g. metformin). There is still no definite cure or medication for this heterogeneous endocrine disorder with various clinical appearances. The routine approach after advising on lifestyle modification and weight loss is symptomatic therapy with different agents including oral antidiabetics, progesterone, contraceptives, or antiandrogens. The efficiency and efficacy of some other drugs as thiazolidinediones, berberine, or inositols have not been enough investigated and the effects of these drugs are still unclear in infertility treatment.

Classic gynecological treatment in reproductive-age patients with PCO syndrome implies regulation of the menstrual cycle with the administration of combined oral hormonal contraception or progestins. Induction of ovulation is required in PCOS patients with anovulatory cycles if there is a desire for motherhood. The first-line treatment for ovulation induction is clomiphene citrate and letrozole, especially if it is a fertility problem tied only to anovulation without co-existing male factor or tubal obstruction. In the cases of combined male–female infertility, couples are treated with assisted reproductive technologies (*in vitro* fertilization) and stimulation of ovaries with gonadotropins. The use of gonadotropins carries significant risks of ovarian hyperstimulation, and that's why they have indicated targeted protocols for ovarian stimulation. From the point of patient safety, treatment with an antagonist for ovarian stimulation and the "freez all" approach are the best options if there is ovarian hyperstimulation. Ovarian stimulation in agonistic protocol in combination with metformin can reduce the risk of hyperstimulation [15]. Some patients are resistant to ovulation inductors due to persistent hyperandrogenemia, hyperestrogenemia, and IR. This abnormality is further worsened in overweight PCOS patients, especially with visceral and abdominal fatty tissues, since SHBG level is reduced due to hyperinsulinemia, and androgen levels are increasing. Since hyperinsulinemia stimulates androgen synthesis in patients with PCO syndrome, the attention of researchers is focused on inositol phosphoglycans as post-receptor mediators or secondary messengers of insulin signals [16].

Administration of MI in patients with PCO syndrome after 12 weeks has a positive effect on the hormonal status of the patients. It has proven a significant reduction in the concentration of LH, PRL, androgens, and of LH/FSH ratio and ratio glucose/insulin. Increased sensitivity to insulin had been observed by reduction of HOMA-IR. In PCO patients treated with *in vitro* fertilization procedure and inositols it has been observed shorter duration of ovarian stimulation and minor total dose of applied gonadotropins. Severe ovarian hyperstimulation syndrome is significantly more often present in patients with PCO syndrome and associated with increased number of antral follicles. The positive effect of MI was observed in improved response to ovarian stimulation. The group of PCOS patients treated with

### *Inositols in the Treatment of Polycystic Ovary Syndrome in Reproductive Age DOI: http://dx.doi.org/10.5772/intechopen.113150*

MI had significantly more large follicles (> 16 mm) on hCG day administration, compared to control group, which had significantly more small follicles (< 12 mm). The application of MI contributes not only to the safety of infertility treatment but also to the better quality of the follicles. The final reproductive outcome, the proportion of conceived pregnancies and births, decreased incidence of gestational diabetes, and giving birth to eutrophic children are also significantly better in MI users [17, 18]. In patients with PCO syndrome, a higher concentration of DCI in the urine (higher elimination) and at the same time a reduced concentration in the plasma was observed compared to healthy eumenorrhoic women, while no such differences were observed for MI. According to the previously published data, MI supplementation improves many ovarian functions, oocyte quality, ovulation, higher chance of conception with better reproductive outcomes, as well as minor total gonadotropin dose during ovarian stimulation. Both stereoisomers MI and DCI additionally improve the regulation of glucose metabolism, lipid metabolism, and clinical signs of hyperandrogenemia [19–21]. Thus, significant dysregulation of inositol metabolism was demonstrated in patients with PCO syndrome, which indicates a connection with hyperinsulinemia and IR.

Already initial studies have proven the significant effectiveness of DCI in reducing lipid biomarkers, increasing insulin sensitivity, reducing androgen levels, and increasing the frequency of ovulation. These effects are mainly related to the positive systemic effect of DCI on the metabolic syndrome, but not to the effect on the ovary [22, 23], while MI has proven direct positive effects on ovarian function at the cellular level. Administration of higher doses of DCI (2.4 g/day), seems to have a negative effect on ovarian function, more significantly in PCO patients who do not have diagnosed IR. The release of a larger amount of DCI-phosphoglycan with hyperinsulinemia stimulates the biosynthesis of testosterone in ovarian theca cells, which increases hyperandrogenemia and leads ovarian follicles to growth arrest, atresia, or even to anovulation [24, 25].

Newer published studies indicate on positive effects of combined preparations which contain both stereoisomers MI and DCI on ovarian function in patients with PCO syndrome treated with *in vitro* fertilization procedures. The analysis of seven factors of oocyte quality has proved the positive impact of the combined administration of MI and DCI on oocyte quality, with preparations that contained a higher concentration of DCI in relation to MI. The known physiological ratio of MI and DCI in the plasma is 40:1 (in the ovary 100:1), but it seems that the effect on cell quality is still more dependent on the concentration of DCI than on the physiological ratio. The effect of these changes on developing embryos after ICSI fertilization remains unclear, as well as the effect on conception [26]. Studies on the preventive effect of inositol on the occurrence of gestational diabetes in the population of patients with PCO syndrome have also been published [27, 28]. The effect of MI and DCI was evaluated in the population of pregnant women diagnosed with gestational diabetes in mono-formulations or in combination. It was found that there is a significant beneficial effect on metabolic factors and reduction of IR in pregnant women diagnosed with gestational diabetes, and according to the results of the study, it has been shown that DCI has a more significant effect than MI [29, 30]. The choice of medical treatment including inositols depends on undelaying endocrinological and metabolic disorders and treatment goals. The applications of inositols showed clinical benefits in almost all outcomes compared to metformin independently and in combination with other forms of treatment for reproductive disorders.

### **5. Conclusions**

Inositols are very interesting and promising molecules with consideration on their role in carbohydrate metabolism and consideration on their impact on cells with increasing effects of insulin intracellulary. They act as "messenger" molecules, increasing the sensitivity of insulin in targeted cells. Inositols have a positive impact on follicle maturation, they can improve the mechanism of dominant follicle selection by a reduction in free androgen levels by increasing aromatase activity and induction of SHBG production. According to literature data, it has been proved that inositol had favorable effect on several results of outcomes in patients with PCO syndrome. Present scientific results proved that inositols have a beneficial impact on ovarian function establishing ovulation, a positive effect on carbohydrate metabolism, on occurrences of gestational diabetes, and giving birth to eutrophic newborns. The positive effects of both stereoisomers MI and DCI as well as their combinations, on metabolic parameters, IR, regulation of glucose metabolism, and reproductive disorders have been scientifically proven. According to the data published so far, DCI has its greatest effectiveness in states with pronounced IR. Myo-inositol, on the other hand, has proven positive direct effects on ovarian function at the cellular level. Replacement of a single isomer, or their combination, is based on different actions and biological roles. The choice of treatment depends on which underlying disorder we want to treat. The clinical application of these substitutes has proven the beneficial effects of these molecules independently and in combination with other forms of treatment for reproductive disorders.

### **Acknowledgements**

The publication is supported by H2020 MESOC–measuring the social dimension of culture; under Grant Agreement no. 870935. Uniri-biomed-18-161project: Extracellular vesicles in human follicular fluid: content and role in oocyte maturation and embryo quality.

### **Conflict of interest**

The authors declare no conflict of interest.

*Inositols in the Treatment of Polycystic Ovary Syndrome in Reproductive Age DOI: http://dx.doi.org/10.5772/intechopen.113150*

### **Author details**

Neda Smiljan Severinski1 \*, Ulla Marton2 and Anđelka Radojčić Badovinac3,4

1 Faculty of Medicine Rijeka, Department of Gynecology and Obstetrics, Clinical Hospital Center Rijeka, University of Rijeka, Croatia

2 Faculty of Medicine Rijeka, University of Rijeka, Poliklinika "dr. Marton", Zagreb, Croatia

3 Department of Biotechnology, University of Rijeka, Rijeka, Croatia

4 Faculty of Medicine Rijeka, Department of Medical Biology and Genetics, University of Rijeka, Rijeka, Croatia

\*Address all correspondence to: nedass@uniri.hr

© 2023 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.

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### **Chapter 8**

## Exercise Interventions for the Management of Polycystic Ovary Syndrome (PCOS): An Update of the Literature

*Lisa Vizza*

### **Abstract**

Polycystic Ovary Syndrome (PCOS) affects 6–10% women of reproductive age, and the diagnosis requires two of the three criteria: (1) menstrual irregularity; (2) polycystic ovaries on ultrasound; (3) elevated hormones (such as testosterone). Approximately 50–70% women have underlying insulin resistance and/or have a body mass index (BMI) greater than 28.0 kg/m<sup>2</sup> , and if not managed, it can worsen the symptoms of PCOS. The first line of treatment for PCOS includes lifestyle management such as diet and/or exercise. Previous studies evaluated interventions such as aerobic, aerobic plus resistance and high intensity aerobic. These interventions formed part of the initial guidelines for the management of PCOS, although the guidelines did not include recommendations of resistance training in isolation. More recently, new studies have emerged which assessed resistance training interventions in isolation in PCOS, where these findings led to an update in the guidelines in PCOS to recommend resistance training as part of the management. The chapter will look to provide an update of the exercise literature in PCOS, as well as provide recommendations for future research.

**Keywords:** Polycystic Ovary Syndrome, lifestyle interventions, women's health, resistance exercise, aerobic exercise

### **1. Introduction**

Polycystic Ovary Syndrome (PCOS) is a common endocrine condition, and affects approximately 6–10% of women during the reproductive years [1]. The diagnosis of PCOS requires two of the following three items as per the Rotterdam criteria: 1: menstrual irregularities (i.e., oligomenorrhea, amenorrhea); 2: polycystic ovaries on ultrasound; 3: androgen excess (i.e., elevated testosterone levels) [2].

The pathophysiology of PCOS is complex. Possible mechanisms include genetics, environmental and transgenerational factors, and can affect metabolic, reproductive and psychological outcomes [3, 4]. Insulin resistance may also be involved in the pathophysiology of PCOS [5, 6], where elevated levels may worsen features of PCOS (e.g., androgens, menstrual irregularity, and reproductive outcomes such as follicular arrest). A high proportion may also have underlying insulin resistance (50–70%) [7] and can be present in both overweight and non-overweight women with PCOS [5]. Interestingly, recent studies have also proposed a possible related intrinsic insulin resistance that are noted in PCOS versus their control counterparts [5].

Women with PCOS may also demonstrate an elevated body mass index (BMI) (>50% with BMI >25.0 kg/m<sup>2</sup> ) [8] infertility (70–80%) [9], and may also be at risk of future chronic diseases (e.g., cancer, cardiovascular disease, and diabetes) [10]. Anxiety and depression are also noted in this cohort (26–52%) [11], which can negatively affect quality of life [12, 13].

The first line treatment for the management of PCOS includes lifestyle modifications such as diet and/or exercise. Previous guidelines recommend 150 minutes of exercise per week, of which 90 minutes should be at a moderate to high intensity [14]. These guidelines were formed in accordance to previous literature which assessed aerobic, resistance and/or aerobic with a dietary component, and high intensity exercise. The initial guidelines did not include recommendations for resistance training as part of the management of PCOS. No studies were available at the time which evaluated this modality in isolation. The benefits of this intervention, such as improved insulin sensitivity and body composition which has been reported in previous diabetes studies [15, 16], could also be beneficial for the management of PCOS.

This limitation led to future studies to evaluate this intervention in isolation, which included both a feasibility study in women with PCOS [17], as well as other studies which incorporated various prescriptions, and these findings will be explored further in this chapter. The reported benefits led to a revision in the guidelines, to recommend resistance training as part of the management for PCOS [18].

The next sections will look to review the different types of intervention studies in PCOS, as well as provide directions for future research.

### **2. Exercise interventions in PCOS**

### **2.1 Aerobic interventions-moderate and/or high intensity intermittent, and lifestyle interventions**

Aerobic exercise is defined as an activity that uses large muscle groups, is maintained for a continuous time, and is rhythmic in nature [19]. Previous studies in PCOS assessed interventions such as cycle ergometry or treadmill for three to five sessions a week of 30–60 minutes at 60–70% of VO2max and/or HRmax [20–29], selfselected or self-monitored (i.e. walking, cycle ergometry, treadmill) [30, 31], tailored intervention at an exercise dose of 14 kcal/kg/week) [32], walking and/or jogging [33–36], and interventions that were either moderate and/or high intensity exercise [37–49]. In addition, lifestyle and/or home-based interventions were also assessed in women with PCOS [50–61].

The interventions ranged from 4 to 52 weeks, and were compared to groups that received no training, diet, education, medication, lifestyle plus medication, or electroacupuncture. Sample size across studies ranged between 8 to 183 participants. Limited studies are available that incorporated a long-term follow-up component (>1 year). Outcomes ranged from anthropometric, cardiorespiratory, hematological, menstrual cyclicity, and hemodynamic. Further, recent studies also included other measurements such as quality of life (i.e., anxiety and depression using either the

Hospital Anxiety and Depression Scale (HADS), Polycystic Ovary Syndrome Questionnaire (PCOSQ), Short Form-36 (SF-36)) gene expression, enzymes, protein abundance, and a detailed list of all of these outcomes are reported in **Table 1**.

Adherence rates ranged between 60% and 100% across interventions that used cycling or ramp protocols, self-selected or self-monitored exercise (i.e., walking or a goal of 150 minutes of exercise a week), or a combination of moderate and/or high intensity aerobic exercise [24, 26, 27, 29, 32, 37, 40–42, 48, 50, 51, 73]. Further, adherence was also reported in other ways across studies which included weekly increase (e.g., 21.1%) [60], mean participation per week [58], and levels (e.g. high,











**Moderate and/or high intensity Author, Study design N enrolled (E) and completed (C) Duration (weeks) Intervention Outcomes Significant findings associated with exercise only** speed) and 330s sprint followed by 30s slow running. b. Control 3rd week = 6 sets ratio *Cardiorespiratory* VO2max *Anthropometric* BW, BMI, BF%, WHR, VAT, VAI Samadi et al., 2023 [69], RCT E = 30 C = 30 <sup>12</sup> a. HITT- 3 wk. 30 min (44 min, 8 rounds 20s all out and 10s rest (80–85% HRmax) and Metformin (1500 mg) b. Metformin (1500 mg) *Hemotological* HOMA-IR, SHBG, T, LH, DHEA-S, FSH, FAI *Cardiorespiratory* VO2max *Anthropometric* FM, BMI, WHR, HC *Menstrual cyclicity/ reproductive* Ovarian morphology, menstrual cyclicity BMI, FM FSH, T, SHBG, HOMA-IR Lifestyle interventions Author, Study design N enrolled (E) & analyzed (A) Duration (weeks) Intervention Outcomes Significant findings associated with exercise only Guzick et al., 1994, [70] RCT E = 12 C = 12 12 a. Behavior weight control b. Control Guidance provided to improve physical activity levels *Hemotological* T, SHBG, fasting insulin, glucose, LH *Anthropometric* BW BW, SHBG, trend fasting insulin Hoeger et al., 2004, [54] RCT E = 38 C = 23 48 a. Metformin (1700 mg) b. Lifestyle and placebo c. Lifestyle and Metformin d. Placebo Lifestyle: nutrition (500– 1000 deficit), behavior, exercise (150 min per wk) *Hemotological* SHBG, insulin, glucose, T, FAI, AUCGLU, AUCINS, fasting insulin *Anthropometric* BW, BMI, WHR, WC *Other measurements* Weekly urine samples (pregnanediol) BW, T, FAI, trend fasting glucose Pasquali et al. 2011 [71], NRCT E = 100 C = 65 24 Diet (hypocaloric 1200– 1200 kcal day) followed by mildly restricted intake (500 kcal day deficit), walking 30 min 5 wk *Hemotological* T, SHBG, FAI, A, DHEA-S, 17-OHP, LH, FSH, LH/FSH, E2, LDL, HDL, tg, fasting glucose, fasting insulin, HOMA-IR, QUICKI, C, ISIcomposite WC, A, 17-OHP, LH, C, HDL, tg, fasting glucose, fasting insulin, HOMA-IR, QUICKI, ISIcomposite




*Abbreviations: T, testosterone; SHBG, sex hormone binding globulin; E2, estradiol; LH, luteinizing hormone; FSH, follicle stimulating hormone; P, progesterone; DHEA-S, dehydroepiandrosterone; A, Androstenedione; 17-OHP, 17-Hydroxyprogesterone; FAI, free androgen index; PRL, prolactin; TSH, thyroid stimulating hormone; PDG, pregnanediol-3-glucoronide; C, cholesterol; TC, total cholesterol; Tg, triglycerides; LDL, low density lipoprotein; HDL, high density lipoprotein; VLDL, very low density lipoprotein; Hb, hemoglobin; HOMA-IR, homeostatic model assessment insulin resistance; QUICKI, quantitative insulin-sensitivity check index; GIR, glucose infusion rate; AUCGLU/INS, Area under curve glucose/insulin; IGF-1, insulin growth factor; T4, thyroxine; CRP, C-reactive protein; WBC, white blood cells; NMR, nuclear magnetic resonance spectroscopy; BMI, body mass index; BF%, body fat percentage; FM, fat mass; FFM, fat free mass; AbFm, abdominal fat mass; SCFAT, subcutaneous fat; WC, waist circumference; WHR, waist to hip ratio; HC, hip circumference; SO2S, sum of 2 skinfolds; REE, resting energy expenditure; SBP, systolic blood pressure; DBP, diastolic blood pressure; LTPA, leisure time physical activity; HbA1c, glycated hemoglobin; HR, heart rate; HRR, heart rate reserve; VO2max, maximal oxygen consumption; VO2AT, maximal oxygen consumption at anaerobic threshold; VE/VCO2slope, minute ventilation-carbon dioxide production; AER+RX, aerobic plus resistance; RCT, randomized control trial; RM, repetition maximum; NRCT, non randomized control trial; BDDE-SR, body dysmorphic disorder examination; BW, body weight; FFA, free fatty acid; BMD, bone mineral density; PCOSQ, Polycystic Ovary Syndrome Questionnaire; E1, estrone; E1-s, E1 sulphate; 5-DIOL, 5-androstene-3; ADT-G, androsterone glucuronide; 3G, androstane-3; 17G, 17-diol-17 glucuronide; MADRS-S, Montgomery Åsberg Depression Rating Scale; BSA-S, Brief Scale for Anxiety; SF-36, Short form-36; AFC, Antral follicle count; NS, not significant; NEFA, non esterified free fatty acids; RBC, red blood cell; HTC, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PTL, platelets total level; TBW, total body water; BMR, basal metabolic rate; HRV, heart rate variability; CAT, continuous aerobic training; IAT, intermittent aerobic training; FSRI, Female sexual function index; FRS, figure rating scale; HITT, high intensity interval training; GGT, gamma-glutamyl transferase; ALT, alanine aminotransferase; A/P, Atherogenic index of plasma; TS/C, testosterone to cortisol ratio; VAT, visceral adipose tissue; VAI, visceral adiposity index; CES-D, Center for Epidemiologic Studies Depression Scale; STAI, State-Trait Anxiety Inventory; PSS, perceived stress scale; ACE, adverse childhood experience; TSST,Trier Social stress test; DASS-21, depression anxiety and stress score; IFG, impaired fasting glucose; RER, respiratory exchange ratio; PLT, platelets total level; GDR, glucose disposal rate; IL-6, interleukin-6; MIF, Covinton-Macrophage inhibitory factor; PAI-I, plasminogen activator inhibitor; CD68, cluster of differentiation marker 68; MCP-1, monocyte chemotactic protein-1; IPAQ, international physical activity questionnaire; MSNA, muscle sympathetic nerve activity; AMH, anti-Mullarian hormone; MDA, malondialdehyde; HADS, hospital anxiety and depression scale; TNFα, tumor necrosis factor; PLIN, Perilipin.*

### **Table 1.**

*Summary exercise studies (aerobic, moderate and/or high intensity, lifestyle interventions).*

moderate and low) [27], or there were a few studies that did not report this [20, 21, 23, 25, 28, 33–36, 38, 39, 43–45, 47, 52, 54–57, 59, 61, 71].

Adverse event reporting was also not always reported across interventions [20– 23, 25, 26, 32, 35, 36, 39, 49, 52, 73], and similarly, this was also the same for dropout rates [20, 21, 23–26, 29, 35, 39, 55, 73]. Of the studies that reported dropout rates, this ranged between 10% and 70% across interventions [5, 27, 30, 32, 34, 41–43, 47, 49– 52, 54, 56, 59, 61], where higher dropout rates were reported for interventions that used metformin (>40% [54, 56]), walking (where the volume increased fortnightly-57% [34]), moderate to high intensity exercise (30–60%) [41, 42, 49], and 30 min weekly nutrition/exercise counseling (where one group also received cognitive behavioral therapy (54%)) [51]. Across studies, co interventions was not always reported. While limited studies are available that reported for differences in dropout rates between ethnic groups, interestingly, two studies reported a higher percentage/number in ethnic groups that dropped out from interventions such as lifestyle and metformin (76% versus 62%) [56], and a ramp plus 12-week exercise protocol (25%) [32].

Characteristics of participants recruited in these studies ranged between 20 to 35 years of age, and BMI > 25.0 kg/m2 . Most studies excluded participants with a history of the following which included but was not limited to, cardiovascular, metabolic, or glucose intolerance. Across studies, the main baseline characteristics that were reported included body composition, hematological, cardiovascular, but not all studies reported menstrual cycle status as a baseline characteristic in PCOS. Further items that were not reported (although it is possible some studies could have reported these separately as supplementary materials) included family history, PCOS phenotype, previous pregnancies, or other co morbid conditions such as metabolic syndrome. Further, limited studies have not included other baseline characteristics for example pain perception, where higher prevalence of pain perception has been reported in PCOS in a study using the SF-36, and may be associated with infertility, obesity, inflammation or insulin resistance) [74], as well as sleep disorders (this was reported in one study which included numbers of obstructive sleep apnea) which may be prevalent in this cohort [37, 75].

To our knowledge, only few studies recruited PCOS women with a BMI < 25.0 kg/ m<sup>2</sup> [25, 39], and also, for studies that did not report this, it is unclear as to whether participants in various ethnic groups were recruited. For example, differences in PCOS symptoms (e.g., hyperandrogenism and metabolic symptoms) were noted between Hispanics versus non-Hispanics [76]. Of the two studies that reported higher dropout rates in this group, it would be important to determine as to whether additional strategies are required to improve compliance rates in this group. Further, not all studies reported other ethnicity outcomes such as English language proficiency and Ancestry. Furthermore, it is probable that participants with limited English proficiency requiring translation were also not included in these studies. A previous review reported that approximately 21% of studies excluded participants with low English proficiency from research [77]. Exclusion of these participants from research would not provide a true representation of the study population, particularly in countries such as Australia where the population is culturally diverse.

Overall, the benefits of aerobic interventions that used either moderate and/or a combination of moderate and high intensity in women with PCOS with a BMI > 28.0 kg/m2 ranged from improved body composition (e.g., reduced waist circumference, waist to hip ratio and body weight), hematological (e.g., improved lipids, hormones, insulin sensitivity), cardiorespiratory and hemodynamic (e.g. aerobic fitness, blood pressure), menstrual cyclicity, and other outcomes (e.g., mRNA, protein abundance). Further, for recent studies, quality of life was also improved

following an aerobic intervention, which included improved anxiety and depression scores (using HADS), PCOSQ (domains such as emotions, body hair, weight, and infertility problems), and quality of life (SF-36 on domains such as role physical, physical functioning, general health, and social role).

While further studies are warranted to investigate the benefits of aerobic exercise interventions in lean women with PCOS (BMI <28.0 kg/m<sup>2</sup> ), possible benefits may include a change in left/right follicles and menstrual cyclicity following moderate to high intensity exercise (60–85%) [39], as well as changes in BMI, weight and VO2max following low-high impact exercises at 50–75% HRmax [25].

A detailed list of outcomes for each of these studies and their findings are provided in **Table 1**.

### **2.2 Resistance interventions (with or without aerobic intervention)**

Resistance training is a form of exercise that challenges the muscles with unaccustomed loads using free weights and/or machine weights. Resistance training has also been reviewed in studies in PCOS, either in isolation and/or combined with other modalities (e.g., aerobic, dietary component), and the studies incorporated exercises using free weights, machines, aqua aerobics, or Thera bands.

For studies that assessed aerobic and resistance, either in isolation or in combination, the exercise prescription was described across most interventions. For the aerobic intervention, this included 30 minutes on the treadmill/bike at 70–85% HRmax [78], 25–45 minutes at 60–80% HRmax [79], high intensity interval training (e.g. 430 s or 44 minutes at 90–100% maximum speed) [80–82], step routine (5–20 minutes) [83], goal oriented (200–300 minutes total per week) [84], or individually tailored [85]. For the resistance training, the prescription ranged from two to three sessions per week, with some studies prescribing a whole body intervention [81–83], while a number of studies did not describe the intervention in detail [78, 80, 84, 85]. The intensity of the resistance training interventions was determined by either repetitions (8–16 repetitions [78], % 1 Repetition Maximum (RM)) [79–82], Borg scale [83], or was not reported [78, 84–86].

Of the studies that assessed resistance training intervention only, two studies did not describe the intervention in detail [87, 88]. The prescription also varied across studies. For example, a study integrated macrocycles (e.g. four macrocycles (3 weeks of increased intensity, fourth week at a reduced intensity, and progressively increasing the intensity while reducing repetitions between sets (e.g. week 1–60%, 65%, 70%, 65%, week 2–65%, 70%, 75%, and 70%)) [89, 90], while another study used mesocycles (first 3 weeks performed for three sessions a week with the intensity increasing at 5% per week, and for the fourth week, sessions were performed for two sessions a week while the intensity reduced by 5% [47]. For another study, the intervention consisted of two supervised sessions per week of a whole-body routine with each exercise performed for three sets of 8–12 repetitions, and the weight was increased once the participant was able to perform three sets of the exercise at 8–12 repetitions, and it also included two supervised sessions at home using calisthenica [17].

The interventions ranged between 8 to 24 weeks, and most studies included comparator groups such as dietary restriction, no treatment (control), medication (e.g., metformin, calcium, clomiphene). Sample size across studies ranged between 8 to 143 participants. To the best of our knowledge, limited studies are available that included a long-term follow-up, and similar to the aerobic training studies, co interventions

were not always reported. Outcomes ranged from anthropometric, cardiorespiratory, hematological, menstrual cyclicity, and hemodynamic. Further, these studies collected other measurements such as endothelial vasodilation, step count, quality of life (i.e., anxiety and depression), heart rate recovery and telomere content. The listed outcomes are provided in **Table 2**.

For the resistance training interventions, adherence rates were not always reported across all studies. Of those that reported this, this ranged between 70% to 90% for







*Abbreviations: T, testosterone; SHBG, sex hormone binding globulin; E2, estradiol; LH, lutenizing hormone; FSH, follicle stimulating hormone; P, progesterone; DHEA-S, dehydroepiandrosterone; A, Androstenedione; 17-OHP, 17- Hydroxyprogesterone; FAI, free androgen index; TSH, thyroid stimulating hormone; PDG, pregnanediol-3-glucoronide; C, cholesterol; TC, total cholesterol; Tg, triglycerides; LDL, low density lipoprotein; HDL, high density lipoprotein; HOMA-IR, homeostatic model assessment insulin resistance; QUICKI, quantitative insulin-sensitivity check index; IGF-1, insulin growth factor; T4, thyroxine; CRP, C-reactive protein; WBC, white blood cells; BMI, body mass index; BF%, body fat percentage; FM, fat mass; FFM, fat free mass; AbFm, abdominal fat mass; WC, waist circumference; WHR, waist to hip ratio; HC, hip circumference; SO2S, sum of 2 skinfolds; REE, resting energy expenditure; SBP, systolic blood pressure; DBP, diastolic blood pressure; IPAQ, International physical activity questionnaire; HbA1c- glycated hemoglobin; HR, heart rate; HRR, heart rate reserve; VO2max, maximal oxygen consumption; VO2AT, maximal oxygen consumption at anaerobic threshold; VE/VCO2slope, minute ventilation-carbon dioxide production; AER+RX, aerobic plus resistance; RCT, randomized control trial; RM, repetition maximum; NRCT, non randomized control trial; BW, body weight; FFA, free fatty acid; BMD, bone mineral density; PCOSQ, Polycystic Ovary Syndrome Questionnaire; E1, estrone; E1-s, E1 sulphate; 5-DIOL, 5-androstene-3; ADT-G, androsterone glucuronide; 3G, androstane-3; 17G, 17-diol-17 glucuronide; BSA-S, Brief Scale for Anxiety; SF-36, Short form-36; NS, not significant; NEFA, non, esterified free fatty acids; RBC, red blood cell; HTC, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PTL, platelets total level; TBW, total body water; BMR, basal metabolic rate; HRV, heart rate variability; CAT, continuous aerobic training; IAT, intermittent aerobic training; FSRI, Female sexual function index; FRS, figure rating scale; HITT, high intensity interval training; GGT, gamma-glutamyl transferase; ALT, alanine aminotransferase; A/P, Atherogenic index of plasma; TS/C, testosterone to cortisol ratio; VAT, visceral adipose tissue; VAI, visceral adiposity index; CES-D, Center for Epidemiologic Studies Depression Scale; STAI, State–Trait Anxiety Inventory; PSS, perceived stress scale; ACE, adverse childhood experience; TSST,Trier Social stress test; DASS-21, depression anxiety and stress score; IFG, impaired fasting glucose; RER, respiratory exchange ratio; PLT, platelets total level; GDR, glucose disposal rate; IL-6, interleukin-6.*

### **Table 2.**

*Summary exercise studies (aerobic and resistance, and resistance training in isolation).*

supervised training [17, 80], 40–45% for home-based calisthenics training [17], or 60% overall for both supervised and home-based calisthenics training [17]. In addition, similar to the aerobic training studies, dropout rates were also not always reported across these studies. Of the studies that reported this, this ranged between 10%–50%, where a higher drop out rate was reported in studies that included a dietary restriction [79, 85].

Characteristics (e.g., age and BMI) were also similar as per the aerobic studies only (Section 2.1), and in addition, most studies also had similar exclusion criteria as per the aerobic training studies. Further, similar to the aerobic training studies, limited studies included PCOS participants with a BMI < 25.0 kg/m<sup>2</sup> [83], nor did they report on ethnicity outcomes [17, 78–82, 84–86]. Furthermore, other baseline characteristics that were also not included in the aerobic training studies (e.g., family history, co morbidities, pain perception, sleep apnea, previous pregnancy etc.) were also not reported in these studies. Although it may be possible that some studies have reported these as supplementary materials, or this information may not be available due to the exclusion criteria across studies.

The benefits of resistance training interventions in PCOS ranged from improved body composition (e.g., reduced waist circumference, hip circumference, BMI, body weight, and improved lean muscle mass), improved insulin sensitivity and menstrual cyclicity, and quality of life (such as anxiety, depression). In addition, for studies that included normal weight PCOS, possible benefits following a resistance training intervention may include changes in body composition (e.g., waist circumference, hip circumference), shorter menstrual cycle intervals, and hematological changes (e.g., cholesterol).

A detailed list of outcomes for each of these studies and their findings are provided in **Table 2**.

### **2.3 Conclusion and future directions for research**

A large number of exercise interventions have been evaluated in PCOS, and benefits are noted across aerobic, moderate and high intensity, lifestyle and resistance training interventions. Variability was noted across studies in terms of reporting baseline characteristics of PCOS, description of interventions, as well as reporting of co-interventions. Overall, while the benefits of exercise were noted across interventions, higher dropout rates are often noted in women with PCOS, which may affect overall study findings. Although this was not reported across all studies, future studies should also continue to report on both drop out and/or compliance rates across all interventions.

These findings will allow future research to determine as to which interventions would require further strategies for women with PCOS in order to improve overall adherence and compliance. Possible strategies could include the measurement of exercise self-efficacy at baseline to determine predictors of long-term adherence, as well as include a long-term follow-up component to better understand if additional barriers are noted for women with PCOS to adopt the lifestyle behavior change. Further, focus groups and/or interviews with study participants could also be incorporated, and their feedback could be integrated into the intervention to address for any other barriers. Furthermore, studies may also consider and test other methods of delivering the exercise interventions to improve compliance such as Telehealth, home based visits and/or online/zoom.

These strategies could also be incorporated for participants in the cultural and linguistically diverse community (CALD) and will allow researchers to better understand reasons for non-compliance and/or higher drop out which was reported in a few studies. This could also be coupled with further reporting of other baseline characteristics in PCOS to determine if there are any other contributing factors that may result in non-compliance, for example, physical and/or psychological, or whether participants may be using other co-interventions outside of the study that may be more

effective as opposed to the intervention. Further, studies should also look to report other ethnicity measures (e.g., Ancestry, as well as those with limited English language proficiency), to better understand ethnic groups that may be at at risk of poorer outcomes and require ongoing management.

While the majority of studies included PCOS women with a BMI >25.0 kg/m<sup>2</sup> , most studies excluded participants with a history of conditions such as cardiovascular disease, metabolic syndrome, glucose intolerance etc. As women with PCOS are at an elevated risk for the development of these conditions, future studies should look to include these participants with a number of co-morbidities, in order to determine for differences between controls for both baseline characteristics, as well as overall response to exercise. In addition, further studies should also look to report on other outcomes such as previous pregnancies and/or whether they were diagnosed with previous gestational diabetes in pregnancy, in order to understand as to whether it may lead to changes in the metabolic profile and/or symptomology of PCOS versus non pregnant participants, or whether it may lead to differences in the response rate to exercise.

Also, limited studies included PCOS women with a BMI <25.0 kg/m<sup>2</sup> , and further studies are warranted to better understand both the baseline characteristics in this group (physical and psychological) and the benefits of exercise. Studies may also look to incorporate focus groups to better understand the lived experience in this group, and these findings could enable both the researchers and clinicians to incorporate recommendations to improve overall management and tailor interventions appropriately.

### **Conflict of interest**

The author declares no conflict of interest.

### **Notes/thanks/other declarations**

A big thankyou to my family (Raffaele, Rosa, Angela, Laura, Maurizio and Neil), niece and nephews (Chloe, Ollie, Patrick) for their ongoing support to allow me to continue contributing to important research. Also, to close friends (Claudia, Jodie, Maureen, Brunelle, Nancy, Mereani, Michelle, Lana, Kathy, Joanna, Sarah, Chantay) and supervisors at my current role (Christina and Sharon), I am forever thankful for your support, mentorship, feedback, and encouragement for me to work on this chapter and to contribute to this important work.

### **Author details**

Lisa Vizza University of Sydney, Sydney, Australia

\*Address all correspondence to: lisavizza@sydney.edu.au; lisavizza@hotmail.com

© 2023 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.

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### *Edited by Zhengchao Wang*

This book includes three sections, covering the symptoms, causes, and treatment of polycystic ovary syndrome. This book provides a comprehensive overview of the latest PCOS research to benefit the population of women with PCOS. We sincerely thank each chapter's authors for their contributions to our present PCOS book. We hope that this book is meaningful to the clinicians who care for women with PCOS and to the researchers who investigate the complexities of this disorder.

> *Zouhair O. Amarin, Obstetrics and Gynecology Series Editor*

Published in London, UK © 2024 IntechOpen © Md Saiful Islam Khan / iStock

Polycystic Ovary Syndrome - Symptoms, Causes and Treatment

IntechOpen Series

Obstetrics and Gynecology, Volume 3

Polycystic Ovary Syndrome

Symptoms, Causes and Treatment

*Edited by Zhengchao Wang*