DOI: http://dx.doi.org/10.26510/2394-0859.pbe.2018.03

Research Article

Polycystic ovarian syndrome: a curse to young women's

Noopur Srivastava*, Shashi Pratap Singh, Anurag Shukla, Kanchan Lata Gupta

Department of Pharmacology, Advance Institute of Biotech and Paramedical Sciences, Uttar Pradesh, India

*For correspondence

Noopur Srivastava,

Department of Pharmacology, Advance Institute of Biotech and Paramedical Sciences, Uttar Pradesh, India.

Email: s.noopur@ymail.com

 

 

 

 

 

 

 

Received: 22 January 2018

Revised: 19 February 2018

Accepted: 20 February 2018

ABSTRACT

The endocrine system is the group of glands that secrete hormone directly into the circulatory system moves towards distant target organs and affects them. This system release hormones that help control many important body functions. Dysfunctioning in the endocrine system may develop many disorders like diabetes, thyroid, growth disorders and sexual dysfunction. Poly cystic ovarian syndrome is one of the common endocrine disorder. PCOS is a common condition that causes a range of symptoms including irregular periods, unwanted hair growth, acne and weight problems. Increased circulating levels of testosterone can be considered as the major cause of development of polycystic ovarian syndrome. It is a male hormone, but women's bodies make it too. Higher than normal testosterone level, makes women to experience PCOS. The physicians target on regular menstruation. In order to maintain the regular periods physicians basically administer Estrogen and Progesterone injection. Metformin is used during PCOS to treat insulin resistance developed in those women. Insulin resistance means that their bodies do not respond well to the hormone insulin that controls blood sugar levels. This causes blood sugar level to rise and this may lead to greater production of testosterone. Corticosteroids, vitamins, contraceptives pills are also prescribed for symptomatic treatment of PCOS. Changing of lifestyles may greatly help in management of poly cystic ovarian disorder. Regular exercise and weight management is the key for complete treatment of PCOS. This review contains all the information regarding PCOS.

Keywords: Polycystic ovarian syndrome, Insulin sensitivity, Excess androgen production, Obesity, Hirustism, Acne, Infertility

 

Introduction

The Endocrine System is derived from two words "Endo" meaning "internal" and "Ecrino" meaning "to secrete". The Endocrine system is considered as the bunch or collection of various glands performing different function in a human body which pour their secretions i.e. Hormones directly into the blood. These secretions i.e. hormones reaches their site of action to accomplish their physiological functions.1

The endocrine system performs the same task as the nervous systems. The major difference between these two is that, the endocrine system uses hormones for signaling while nervous system sends impulses to various organs in order of maintain the normal physiology of the human body. This system includes many glands like- adrenal gland, hypothalamus, ovaries, pancreas, pineal gland, pituitary gland, testes, thymusand thyroid. These entire glands carry out their particular functions. Normal secretions of hormones from these glands help in controlling important body functions.1,2

Undetermined changes in the hormonal levels of the human body affect the normal physiology of the body which results in various kinds of Endocrine disorders. Endocrine disorders occur due to 2 reasons:2

  • Excess amount or less amount of secretion i.e. hormonal imbalance.
  • Due to development of lesions or cyst or tumors affecting hormone levels.

Dysfunctioning of the endocrine glands develops many disorders or syndrome like diabetes, thyroid, growth disorders, metabolic syndrome, cushing's syndrome, cancers, polycystic ovarian syndrome and obesity.2

PCOS: Polycystic ovarian syndrome affect the ovaries in females is a one type endocrine disorder. Many cysts can be easily identifies inside the ovaries through ultrasound. The major causes if PCOS are excess androgen production in female body and insulin resistance. Testosterone is considered as the main reason to experiencing PCOS in girls and women's.3

The evidences for the presence of PCOS are: obesity, irregular periods or absence of periods, acne, excess hair growth on body parts like face, thighs, armpits and problems in conceiving.4

Basically two kinds of treatments are advised to the patients of PCOS by the doctor's i.e. non-pharmacological and pharmacological treatment. Non-Pharmacological treatments includes proper diet, regular exercise, excess facial growth manages by the hair removal treatments.5 Pharmacological treatments include medicines like oral contraceptives, metformin, clomiphene, gonadotropins, spironolactone.5

Disease, disorder or syndrome

In the daily language or in common words there is no difference known between these three words. But in the medical terminology there is a huge difference in these words i.e. disease, disorder and syndrome. These three words represent different types of pathological conditions of the body. Let's clarify the vast difference between the words.6

Disease can be consider as the summation of all the pathological consequences by which a patient suffers that deteriorate or alters his normal physiological conditions and health. Further, the disease can be explained with the help of an example like typhoid. Typhoid is caused by a bacteria namely, salmonella typhi which act as a parasite in the human body. The bacteria develop the pathological consequences in the body and causes typhoid fever. No Salmonella typhi, no typhoid fever.6

Disorder - lack of order or out of order. It can be described as a complete state of confusion whether mental or physical that largely affects the normal functioning. This can be explained by understanding any one disorder like Bipolar disorder. In bipolar disorder there are elevated changes in mood. The person suffering from bipolar disorder undergoes extensive alteration in moods. It is a kind of mood disorder i.e. alteration in mood.7

Syndrome is defined as the occurrence of more than one medical symptom together at a time. Example PCOS many symptoms occurs in proximity points presence of PCOS.8

Figure 1: Illustration of the polycystic ovarian syndrome. Polycysts are shown in the ovaries.9

Figure 2: A case study found related to PCOS. An ultrasound report of a female of ovary and uterus showing presence of cyst in the left ovary highlighted in the red box.

Figure 3: The observation of the above report is clearly explained in this report. It shows the presence of cyst in the left ovary of approximately 18 mm×21 mm.

Figure 4: A, B=Obese, C, D=Lean. This Figure 4 confirming the concept of insulin resistance in PCOS women's. Six groups are considering namely (i) Obese and lean Women's with PCOS, (ii) Obese and lean hyper androgenic women, (iii) Obese and lean Control or healthy women's. Graph A and C showing insulin response in obese women's and lean women's respectively. Insulin responses significantly increased in Obese PCOS women's can be concluded from the graph. Graph B and C represents glucose response in Obese and lean women's respectively.12

Figure 5: Showing the abnormal feedback mechanism of Hypothalamic Ovarian axis and the various outcomes comprising PCOS.14

Polycystic ovarian syndrome

PCOS is the most common endocrine disorder in girl's and women's affects around 6% of the total female population during their reproductive life period. It is the most common syndrome affecting the young women's.3,4 The presence of PCOS is identified by the appearance of more the one sign and symptoms at a time. Women with a PCOS have a polycystic appearance of ovary as shown in the ultrasound report and menstrual irregularities.8,9 The treatment of PCOS involves various methods involving pharmacological and non-pharmacological treatments. The major problem that arises during the treatment is the lack of communication between the patient's and doctor (if doctor is male) as the females feel uncomfortable to discuss about their problems because it is related to periods irregularities.10

Causes of polycystic ovarian syndrome

PCOS is the syndrome related to the ovarian dysfunction showing hyperandrogenism and polycystic ovaries. Insulin metabolism is supposed to be the major cause of appearance of PCOS. Increase in the levels of insulin causes more androgen levels and also causes arrest of the follicular development. The weight of the female also increases during PCOS resulting in more severe hyperandrogenism. The major cause of the PCOS is insulin resistance, anovulation, pituitary dysfunction, enhanced ovarian androgen production.4,10

Insulin resistance and anovulation

It is considered to be the major pathway for PCOS. It is a kind of post receptor deficit that means impairment of some events producing resistance to insulin.10 Insulin resistance occurs when the target cells to not respond to the normal levels of insulin. Women with PCOS produce more insulin and hence insulin level increases in the blood, hyperglycemia which directly affects the ovaries and therefore ovaries in turn releases more testosterone i.e. male hormone, hyperandrogenism. Insulin also causes release of insulin-like growth factor 1 (IGF-1). All the three hormones i.e. insulin testosterone and IGF-1 causes arrest the growth of follicles causing accumulation of small follicles which are less than 10 mm in diameter that do not undergo ovulation thereby resulting in anovulation, a major cause of infertility.11

Pituitary dysfunction

Luteinizing hormone (LH) is secreted from Anterior Pituitary gland in response to GnRH pulse from the Hypothalamus. Gonadotropin releasing hormone is secreted from the Hypothalamus and stimulates the Pituitary gland to release LH. The LH level is maintained by the negative feedback mechanism from the ovary or due to the increased insulin levels. Alteration in the LH levels cause due to the increase in the frequency an amplitude of GnRH pulse from Hypothalamus known as Pituitary dysfunction. Excessive secretion of the LH in blood is the main cause for PCOS.11 Altered GnRH pulse also because deficient release of follicular stimulating hormone (FSH) that is the major cause the arrest of the primary follicles and inhibits their development into fully mature follicles and hence ovulation is ceased.13

Enhanced ovarian androgen production

Excessive LH affects the theca cells of the ovaries that results in the overproduction of the androgens. As the result extreme levels of androgen arrest the follicular development hence inhibits ovulation causing Anovulation or oligo-ovulation and irregular menstrual cycles and infertility.11,15 Increased androgen level also alters the lipid profile and results in hyperlipidaemia. An effect of androgen on the skin causes hirustism, acne and acanthosis nigricans.14

Symptoms

The Symptoms of the PCOS can be broadly classified into four categories. Firstly, menstrual disorders - Irregular menstrual cycle i.e. oligomenorrhea occurring due to anovulation. Secondly, metabolic syndrome - weight gain i.e. obesity also appears in females suffering from PCOS and symptoms related to Insulin resistance i.e. Hyperinsulinemia and Diabetes. Thirdly, Excess androgen production - causing excessive hair growth on the face, chest, back, stomach, upper arms, inner thighs. The hair growth is numbered on the scale of 0 to 8. No hair growth signifies 0 point, Excessive hair growth given 4 point and complete hirustism that is hair growth in all areas in scored 8. Acne starts developing on the face and the skin becomes oily. Hirustism and acne is the result of increase in 5-alpha reductase activity in sebaceous gland and hair follicles. Patches of dark and thick skin appear on the neck, arms breasts i.e. Acanthosis Nigerians. The hair gets thin and alopecia or baldness occurs. Fourth, Ultrasound - Oversized ovaries appears with the polycysts on the ultrasound.16

Figure 6: Representing the changes in the morphology of the women's body during PCOS. Growth of the upper lips hairs, development of dark patches on the chin, enlargement and hair growth on the breast, deposition of belly fat, growth of pubic hairs, thickening of the thighs and development of dark patches on other portions of the body.16

Table 1: This table representing the various signs and symptoms for the diagnosis of the presence of PCOS. 23

Category Specific abnormality Recommended diagnosis
Androgen excess Hyperandrogenism Excessive hairs [hirustism], acne, alopecia, increased testosterone levels
Menstrual history Oligo-ovulation or anovulation Irregular periods Period less than once a month, amenorrhea
Ovarian appearance Ovary size and morphology on ultrasound Presence of cyst about 18 mm x 21 mm. At least one ovary with ;less the 12 follicle of 2-9 mm and ovarian volume less than 10 ml

Complications or morbidities that may arise due to polycystic ovarian syndrome

The causes of PCOS also results in other serious complications. Metabolic, endocrine Psychiatric and CVS complications are easily observable in females suffering from PCOS. Metabolic complications involve obesity due to alteration in BMI. Endocrine complications causes due to increase androgen production by ovaries.14 These complication includes precipitation of diabetes and appearance of hyperlipidaemic profile causing increase in LDL, Triglycerides and Cholesterol that further results in Cardiovascular problems like Atherosclerosis and arterial stiffness causing accumulation of angina pectoris and ischemic conditions.10,17 Psychiatric morbidities involves depression, anxiety, mood swings and bipolar disorders. A study showed on an average each women that is suffering from PCOS experiences the Psychiatric problems.10

Cardiovascular complications arise due to altered lipid profile. These include heart problems, hypertension, high blood pressure etc. The patients shown high level of C-reactive protein and lipoprotein A revealing high risk of cardiovascular diseases.18 These are the biomarkers of CVD disease. Biomarkers are those substances whose presence in the serum indicated the risk of particular disease. 19

PCOS if left undiagnosed or untreated can concomitant to endometrial cancer. The major cause of the carcinoma is increased estrogen exposure to the ovaries causing endometrial hyperplasia.17 Alteration in Endocrine and Gynecologic systems prevails to infertility. If the woman's with PCOS plans for pregnancy should consult the doctor. The complete term should be under the expert guidance. Any inaccuracy in the treatment can cause miscarriage or any kind of complication or may develop abnormalities in the fetus.20

Diagnosis

The diagnostic criteria for PCOS are given by different societies that are summarized in the table given above. These criteria are specified by National Institute of Health/ National Institute of child Health and Human Disease (NIH/NICH), European Society for human Reproduction and Embryology/ American Society for Reproductive Medicine (ESHRE/ASRM) and Androgen Excess and PCOS Society.21-23

Treatment

As PCOS is a syndrome that is more than one symptom appears so the treatment of PCOS also involves more than one medication in order to suppress all the symptoms of the PCOS and overall treatment of the syndrome. The main focus of the therapy is to treat all the manifestations of the problem. The overall course of the medication conquers all the symptoms, refurbishment of the fertility and prevention of the further complications may occur due to PCOS.25

The treatment guideline are proposed by "The American Task Force" and The PCOS Australian Alliance Guidelines". The overall therapy advised by the doctors for the treatment of PCOS is majorly divided into two sections i.e. Non-pharmacological treatment and Pharmacological treatment.25

Non-pharmacological treatment

Non pharmacological treatment means treatment without medicines. It involves lifestyle modification which is a key point for the treatment of the problem. As it is shown earlier obese women's has more insulin response than lean women's.12 Obese women's are more prone to the consequences occur due to the Polycystic Ovarian Syndrome. Basically physician advises regular exercise and a healthy diet to the women's suffering from PCOS. These two helps to maintain the body weight and also to restore the fertility. Excess hairs on the body i.e. Hirustism can be controlled with the use of cosmetic treatments like cosmetic hair removal or laser hair removal, electrolysis, bleaching, depilatory agents, waxing.12

Doctors in general advice the females to practice aerobic exercise for maximum oxygen consumption. These exercise includes walking, running, jogging, cycling and yoga.26 In a study it has been confirmed that aerobic exercise not only decreases the body weight but also improves the condition of insulin sensitivity and thereby also a significant increase in follicle development is seen in MRI. Aerobic exercise are also very necessary in controlling the BP.27 The females should practice a moderate amount of aerobic exercise that helps to reduce type II diabetes and also reduces the high risk of cardiovascular collapse.28-30

Pharmacological treatment

These pharmacological agents are used to suppress the symptoms like Hyperinsulinemia, Biochemical androgen excess, Anovulation and polycystic morphology on ultrasound. Firstly as the patients arrive the physician in absence of menses the first action that a doctor takes is the administration of the Estrogen (10 mg) And Progestron (50 mg) injection.25,30

Metformin

Metformin is used for the treatment of Diabetes and also helps to reduce the Androgen excess. It reduces hepatic glucose production. It is used against insulin resistance as it improves the peripheral insulin sensitivity hence helps in reducing blood glucose levels and provide good response to ovulation induction.25 Metformin acting on the cells increases the cAMP concentration and regulates the AMPK mediated transcription of genes which results in cessation of hepatic gluconeogenesis thereby resolving the insulin sensitivity and ultimately reducing glucose levels and hence androgen production by the theca cells. A study shows that the drug also reduces the BMI in obese females and hence useful for weight loss along with regular exercise.31,32

Contraceptive pills

These pills are used for ovulation induction and hirustism treatment in PCOS. The pills improve the LH negative feedback mechanism and increase production of sex hormone binding globulin resulting in reduces androgen production by ovaries. They also decrease the adrenal androgen production. It contains Estrogen and progestin components. Estrogen component decreases LH and hence reduces androgen excess and also helps to resolve acne and hirsutism problem. Progestin component prevents uterus endometrium from the effects of estrogen and helps in regular menses and also secures the uterus from cancer.25,31

Clomiphene citrate

Clomiphene citrate is used for infertility treatment. Clomiphene citrate causes ovulation induction by increasing FSH levels by antagonizing Estrogen receptors at the hypothalamus-pituitary axis. These are selective estrogen receptor modulator are said to be first line treatment ion PCOS. These are referred as anti-estrogenic.13,25 They boost up the GnRH pulse frequency and initiate the FSH release from pituitary gland resulting in follicular development.33

Spironolactone and finasteride

Spironolactone is used for the treatment of hirustism and acne. It possess the antimineralocorticoid activity. It is the Aldosterone antagonist drug. Basically used as diuretic. It is indicated to be used in hypertension. It is used for treatment of androgen excess in PCOS. In PCOS it competes with androgen for binding to the androgen receptor in hair follicles. Spironolactone is said to inhibit the %-alpha reductase activity in hair follicles and sebaceous glands. Hence results in reduced hair growth and less acne.34

Finasteride is also used for the same purpose as the spironolactone. It inhibits the peripheral conversion of testosterone into dihydro-testosterone and affects its binding to the androgen receptors thereby reducing hirustism and acne. It is the potent inhibitor of 5-alpha reductase enzyme. It inhibits both the forms of the enzyme i.e. type I and type II. Finasteride treatment reduces the hirustism score.35

Aromatase inhibitors

Earlier, Aromatase inhibitors were developed for the treatment of Breast cancer in postmenopausal women's.36 These are the potent inhibitor of the enzyme aromatase. The enzyme aromatase is responsible for the conversion of Androstenedione into Estrone and Testosterone and Estradiol. By interfering with the conversion of Testosterone into Estradiol, aromatase inhibitors i.e. Anastrozole and Letrozole decreases the estrogenic activity and causes decline in the estrogen exposure to ovaries and reduces the chances of endometrial cancer and also induces ovulation. As they a decrease the serum estrogen levels and hence also affects the tumor mass and delays the growth of tumor cells.37 These drugs are used as the replacement of Clomiphene citrate as clomiphene results in accumulation of many side effects line increases in urinary frequency, breast soreness, skin rashes etc.38

Figure 7: The figure depicts the mechanism of action of drug finasteride and aromatase inhibitors acting on the biosynthesis pathway of estrogen and hence reducing the serum estrogen level.39

Figure 8: The figure shows the causes and symptoms of the PCOS and the drugs those targets these causes and symptoms and plays role in the management of the polycystic ovarian syndrome.42

Thiazolidinediones (TZD)

Thiazolidinediones are used in the management of PCOS.10 These are the anti-diabetic drugs and helps in the reduction of serum glucose level. These drugs affect the peroxisome proliferate activated receptor. TZD produces activation of PPAR-gamma isoform of PPAR's. In earlier days of the treatment of PCOS, Pioglitazone was preferred but nowadays it is replaced by rosiglitazone due to their side effects. The peroxisome proliferator activated receptors regulates the transcription of insulin responsive genes that are highly involved in the control of glucose production and also helps in the reduction of serum glucose levels. Rosiglitazone also enhances the sensitivity of the tissues toward the insulin and thereby improves the insulin sensitivity. 40

Isotretinonin

In polycystic ovarian syndrome, the drug isotretinonin is administered for the treatment of severe acne. It may be considered as the anti-acne drug. It usually reduces the sebum secretion from sebaceous glands and also causes shrinkage of these glands. Isotretinonin are prescribed for the relief from comedonal acne. But now-a-days this medication is usually avoided because of its adverse drug reaction. Isotretinonin is responsible for increase in insulin sensitivity also headaches decreased appetite and mood swings are observed in females treating with isotretinonin.41

Recent advancements in the treatment of polycystic ovarian syndrome

Above discussed treatment given to the women's suffering from PCOS experiences the large number of adverse effects. Individually each drug develops a side effect like Clomiphene citrate results in increase urinary efficiency.38 Metformin causes nausea, lethargy and metallic taste while oral contraceptives contribute in the accumulation of coronary and cerebral thrombosis, rise in BP or may cause genital carcinomas.43 In order to reduce these side effects scientist are searching for newer treatments with lower side effects. Some of them will be discussed in this section.44

Acupuncture

Acupuncture is a traditional Chinese technique used for the treatment of various complications using needles. Earlier only Chinese doctors uses this technique for treatment but nowadays it is acceptable by the whole words due to its lesser side effects and high degree of relief from the problem. In recent years acupuncture is highly used for the treatment of PCOS. This technique uses the needle for the stimulation of specific points of the body.45 The needles are inserted on the set points of the body. Each complication has its own stimulatory points. In general two methods are for the stimulation of the needle i.e. manual and electrical. In manual techniques the inserted needles are stimulated manually while in electrical stimulation the needles are stimulated by applying electrical signals about 2 Hz are applied for 30 minutes up to 16 days for the treatment of PCOS.46 The needles are inserted in the legs muscles and abdomen muscles this increases the menstrual frequency and also induces the ovulation.47

Naturopathy

In PCOS management, different drugs are used to treat different complications but each one their own side effects. As much as they reduce the symptoms of this syndrome they give rises to different problems in return. For this reasons physicians are now avoiding chemical medications for the treatment of Acne and Hirustism and advice patients for practicing natural treatments or naturopathy for relief. Honey, good natural antibacterial agents with zero side effects is advised for soothing of acne. Tea Tree oil having excellent antibacterial, antifungal properties heals the damaged skin. Green tea effective for improving metabolism thereby helps in weight loss. Aloe Vera and turmeric paste are also applied for the treatment of acne naturally.48

Laparoscopic ovarian drilling

Laparoscopic ovarian drilling (LOD), indicated for ovulation induction in females with polycystic ovarian syndrome. LOD is considered as the surgical treatment also known as 'Ovarian Diathermy'. In usual practice LOD in those females who are resistant to Clomiphene citrate treatment. In LOD, four to ten punctures are made in stoma of ovaries using laser beam. LOD not only induces ovulation but also causes menstruation regular.49

Health supplements

In combination to these agents physicians also prescribe health supplements like antioxidants, Multivitamins, Melatonin, N-acetylcysteine, Myo-inositol, Alfacalcidol and chromium. Melatonin improves ovarian function and oocytes quality and size and hence helps in ovulation induction. N-acetylcysteine helps in improving insulin sensitivity, Myo-inositol treats acne, hirustism and insulin sensitivity. Alfacalcidol, Chromium and L-methylfolate improve insulin sensitivity and prevent cardiovascular risk due to PCOS.50

Conclusion

The endocrine disorder, Polycystic Ovarian Syndrome is the major disorder affecting the fertility in large women's population. The major symptom of PCOS through it can be diagnosed prior to the ultrasound is the absence of menstruation i.e. amenorrhea. Presently, it is the major health problem affecting young women. The major cure for the treatment of PCOS is regular exercise and proper diet plus weight management advised by every doctor. It is long term treatment. The treatment continues for about 2 years or more in some cases. It is characterized by insulin resistance and treated by administration of metformin. For treating irregular periods, oral contraceptives are given. Insulin resistance also causes increased androgen production causing polycystic ovaries and lower levels of estrogen and progesterone and hence results in absence of ovulation and finally irregular menstruation. Many pharmacological agents are used for the treatment of polycystic ovarian syndrome. But the success of all the treatment is based on the weight management as obesity is the major cause of many disorders. So, weight control can speed up the treatment and relieves the patients from PCOS sooner.

Funding: No funding sources

Conflict of interest: None declared

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