INTRODUCTION:

PCOD also known as polycystic ovary disease is an endocrine, heterogeneous disorder generally occurring in reproductive age group women. 26% of cases of PCOD are present globally that affects at least 7% of infertile women¹. This condition is usually diagnosed by increase in androgen (male hormone), irregular ovulation, and appearance of enlarged ovaries with multiple small cysts on ultrasound (PCO-Polycystic Ovaries)². In United States of America, according to the National Institutes of Health Office of Disease Prevention, PCOD affects approximately 5 million women of childbearing age³. Women’s bodies tend to produce androgen even though it is a male sex hormone. Women who are affected with PCOD can produce androgen in higher-than-normal level. This will affect the development and production of eggs during ovulation period⁴.

Unwanted changes are observed in a women body. If not treated, it may lead to serious health issues, such as diabetes, weight gain and heart disease .Many tiny cysts are observed in women ovaries. This is the reason it is called Polycystic Ovary Disease. The cause of PCOD is not yet known but is often considered hereditary. If any of your relatives (mother, aunts, and sisters) are affected with PCOD, risk of developing it may be increased⁵. PCOD are strongly interlinked by the pathogenesis of various individual disorders such as reproductive dysfunction and endocrine, metabolic dysfunction. Psychological impairments CNS depression and other mood disorders are also associated with PCOD⁶.The guidelines warn that affected women are at high risk for insulin resistance, hypertension, type 2 diabetes, glucose intolerance, cardiovascular morbidity and mortality. Psychiatric symptoms such as anxiety and depression are also observed^7;8. PCOD diagnosis includes healthy lifestyle and therapeutic interventions targeting their symptoms. Interventions can include metformin; combined oral contraceptive pills, spironolactone, Due to its efficacy, safety, and ease of administration Clomiphene Citrate (CC) is recommended as first line treatment for induction of ovulation in patients with PCOD Alternatives for CC-resistant patients include gonadotropin therapy and laparoscopic ovarian diathermy^9-13.

PATHOPHYSIOLOGY:

The Pathophysiology of PCOD is complex and remains unclear. PCOD is a chronic disorder. It was described for the first time by Stein and Leventhal in 1935¹¹. PCOD is a reproductive, heterogeneous and metabolic disorder. The Various pathogenic mechanism of PCOD includes Insulin resistance, Gonadotropin Release, and Ovulatory Dysfunction¹⁴.

A. Ovary, Adrenal, and Androgen Excess:

PCOD is characterized by excessive ovarian or adrenal androgen secretion. Over 50% of patients with the polycystic ovary syndrome (PCOS) demonstrate excess levels of adrenal androgens, particularly dehydroepiandrosterone sulphate (DHS). Nonetheless, the mechanism for the adrenal androgen excess remains unclear.

B. Insulin resistance:

Insulin resistance is the key pathogenic factor in PCOD. Insulin resistance and hyperinsulinemia are commonly detected in women with PCOD. Due to excess level of androgen which leads to increase insulin resistance in peripheral tissues, The insulin resistance in PCOD has been characterized in adipocyte by Post binding defect in insulin receptor mediated signal transduction in Skeletal muscle¹⁵. Obesity increases hyperandrogenism, hirsutism, infertility and menstrual irregularity complications both independently and by exacerbating the insulin resistance of PCOD. Obesity is present in 30-60% of patient with PCOD with BMI greater than 30 Kg/m2 and is associated with hyperinsulinemia. Even lean women with PCOD manifest Insulin resistance; increasing body mass index (BMI) exacerbates insulin resistance¹⁶.

C. Neuroendocrine Factors:

Neuroendocrine disorder that affects 5% to 20% of women of reproductive age is the leading cause of infertility. Increased Luteinizing hormone pulse frequency, Luteinizing hormone pulse amplitude, and increased Luteinizing hormone and follicle-stimulating hormone ratios are described in women with PCOD. Increased LH pulse amplitude and pulse frequency observed in PCOS are likely driven by increased pulsatile GnRH secretion. GnRH neurons express estrogen receptor-β, but they do not express AR, progesterone receptor. Steroid-mediated negative feedback is indirect and is mediated through the hypothalamic neuronal network upstream of the GnRH neuron^17,18.

D. Gonadotropin release and hyperandrogenism:

In PCOD, the increased stimulatory effect of Luteinizing hormone stimulation of the ovarian theca cells is increased; these cells increase the production of androgen mainly androstenedione, testosterone, women with PCOS require higher levels of progesterone to slow the frequency of GnRH pulse secretion, resulting in inadequate follicle stimulating hormone synthesis and persistent Luteinizing hormone stimulation of ovarian androgens. The decreased sensitivity of the GnRH pulse generator may help to explain the genesis of PCOD during puberty.Around 60%-80% women affected PCOD have increase androgen level^19-21.

E. Ovulatory dysfunction:

In PCOD, the disturbance of follicular level in ovaries to increase AMH (Anti-Mullerian Hormone) production by granulose cell. Anovulation with decrease progesterone release and increase estrogen release then increase risk of endometrial carcinoma via endometrial hyperplasia [P1]. Lower FSH level result in disturb the follicular development in ovary lead to amenorrhea and anovulation. Hypersecretion of Luteinizing hormone is significant cause of infertility and miscarriage in women with PCOD²².

Cause and Risk Factor:

The precise factor that causes PCOD is not clear, yet it is believed to be because of abnormal hormonal balance. Women affected with PCOD have been reported with number of abnormalities^23,24. Inherited (Genetic) cause: PCOD often runs in progeny. It can be inherited from the family members (mother, aunt or sister) who may carry the symptoms for the same .This may lead to increase in the risk of PCOD in an individual²⁵.Insulin Resistance: Majority of women with PCOD have Insulin Resistance, for which their bodies recompense by producing more insulin. Insulin hormone secreted by pancreas ,controls the level of glucose(a type of sugar)in the blood .In case of PCOD, the body may not respond to insulin which is known as Insulin Resistance. This leads rise in the glucose levels. To prevent the rise, more insulin production occurs. Excess insulin produces androgen-a male hormone, which further causes PCOD symptoms: acne, weight gain, irregular periods, and problem in ovulating. Other hormones which are raised in PCOD are Luteinizing Hormones (LH) –stimulates ovulation, Prolactin–stimulates breast glands for milk production, and sex hormone binding Globulin .These have abnormal effect on ovaries and decrease high level of testosterone respectively, when raised^26,27.

Family history of PCOD:

According to a cross sectional study assessed at RAKMHSU, UAE, participants with positive family history of PCOD were observed at little higher risk to be diagnosed with PCOD as compared with participents without history²⁸.

Family history of diabetes:

PCOD results in developing IR which can lead to an increased risk of causing Type 2 diabetes. Also women with PCOD have high risk of developing gestational diabetes (diabetes during pregnancy²⁹.

Family history of infertility:

Women with PCOD are more likely to cause infertility. This is because of the increased level of androgen which can reduce or even stop the ovulation frequency.

Obesity:

According to a study conducted in Dehradun, it is concluded that obesity causes hyperandrogenism due to peripheral conversion of estrogen to androgen, causing PCOD.Thus obesity apparently increases the risk of developing PCOD³⁰.

Fast food diet habits:

There is a link between hormonal imbalance and unhealthy food habits. Diet with fats and proteins from a person’s diet may form advanced glycation end products (AGEs) when subjected to sugar in blood stream .These compounds are likely to increase bodily stress and inflammation which is linked to diabetes and cardiovascular issues. PCODs already possess the chances of metabolic syndrome (Diabetes and cardiovascular issues) Along with diet factor, lack of Physical Activity have enormous effect on the development of PCOD.

Stress:

Women with PCODs experiences an increase in the risk of mental health issues associated with anxiety, depression, stress and low self-esteem .The risk of mental health issues is considered to be significantly higher in women with PCOD³¹.

Environmental exposure risk:

Endocrine –disrupting chemicals may cause risk in prenatal and early postnatal development, during the organ system development. These chemicals involve plastic bottles and conainers, lining of metal food cans, detergents, cosmetics, toys³².

Treatment of Pcod:

A. Synthetic Medication^33,34

PCOD is a multifaceted syndrome that affects multiple organ systems. Treatment should be individualized based on the patient’s presentation and desire for pregnancy. Treatments include birth control pills to regularise periods, Devices and medications used to treat manifestations of PCOD, and their ADR, are described in Table.1

Herbal medications:

Role of medicinal plants in polycystic ovarian syndrome reported that the herbal extracts were effective in treating PCOD and improved the levels of sex hormones, insulin resistance, hyperandrogenism, ovulation, and PCOD symptoms.

Ginger (Zingiber officinale):

Zingiber officinale, commonly called ginger, belongs to the family of Zingiberaceae. Rhizomes of ginger have medicinal properties and are extensively used for different purposes. It is mostly used for Pharmacological reported activity antimicrobial, anticancer, antiviral, analgesic antidiabetic, antioxidant, nephron-protective, sedative, hepato-protective, anti-inflammatory, antiemetic^37-43. Different biological activites are due to active constituents of ginger such as 6-gingerol, shogal, 6-gingerol, zingiberene, zingeberone, gingerenone^44,45. Insulin sensitivity and obesity is a major concern of PCOD. Ginger has a significant effect on type 2 diabetes; it increases insulin sensitivity and also reduces body weight by increasing High Density Lipoproteins^46-47. Ginger can be a promising supporting therapy for insulin resistance patients. In few study also found that due to anti-oxidant and anti-inflammatory properties of 6-gingerol it reduces level of sex harmones and improves ovulation in wistar rats induced with PCOD⁴¹. Ginger can be used as adjuvant therapy for treatment of PCOD.

Coconut palm (Cocos nucifera):

Cocos nucifera belongs to the family Arecaceae commonly called nariyal in Hindi and naral in Marathi. The active constituents of C.nucifera possess antimicrobial, antihypertensive, antioxidant^48,49. The flowers of Cocos nucifera help in reducing major symptoms of Letrozole-induced PCOD in female rats. Monitoring found that it increases weight of the ovary i.e. shows estrogenic effect, increased level of High Density Lipoproteins and due to good antioxidant properties helps to cure poly cystic ovaries⁵⁰. The extract of C.nucifera lowers the elevated level of harmones such as FSH and LH to normal and flavonoids such as 3, 5-Dihydroxy-6-methyl-2, 3-dihydro-4Hpyran-4-one responsible for hypoglycaemic effect^51,52. Thus, Cocos nucifera can be used as supporting therapy in PCOD.

Turmeric (Curcumin longa):

Curcumin longa is found in rhizomes of plants and traditionally used as a medicinal plant in India. Curcumin belongs to the family zingiberaceae and is used as an additive in food in daily life⁵³. Curcumin contains some flavonoids, volatile oils, turmerone etc. which possess antioxidant, and anti-inflammatory, anti-hyperlipidemic and hypoglycaemic activities⁵⁴. Curcumin significantly decreases or prevents increase of blood sugar level, decreases elevated levels of harmones and improves lipid profile in letrozole induced wistar rat. It also improves ovulation. So, due to powerful antioxidants, antihyperlipidemic and hypoglycemic activities can be used in management of PCOD⁵⁵.

Liquorice (Glycyrrhiza glabra):

Liquorice belongs to family-leguminosae used against various diseases. The reported pharmacological activities of liquorice are anti-ulcer antiviral, anti-fungal, anticancer, anti-allergenic anti-diabetic, anti-oxidant, anti-thrombic, anti-malarial, anti-bacterial, immune-stimulant, etc. Glycyrrhizic acid is an active constituent of liquorice along with some flavonoids including liquirtin, isoliquertin liquiritigenin and rhamnoliquirilin^56,57. glabrene and glabridin chemical components of liquorice mimic estrogen activity and reduce low density lipoproteins. One study found that liquorice significantly increases the fertilization rate of oocytes and improves development of embryos in PCOD induced mice. If liquorice is given with spironolactone it is very much effective in women suffering from PCOD^58,59.

Cinnamon (Cinnamomum zeylanicum):

Cinnamon belongs to the family Lauraceae. It is used in different types of foodstuffs, for fragnance and for clinical purposes. The active constituents of cinnamon are cinnamaldehyde, essential oils, polyphenols and procynidins which possess anti-oxidant, anti-inflammatory, anti-microbial and hypoglycaemic activities⁶⁰. It is found that polyphenols and procynidins of cinnamon extract increase insulin sensitivity, decrease low density lipoproteins in women’s with PCOD. It potentiates the activity of insulin. It shows that cinnamon can be supporting therapy in PCOD. Supplementation of cinnamon significantly regulates the menstrual cycle and is very much effective in poly cystic ovary disorder^61,62.

Peppermint (Mentha piperita):

Mentha piperita, commonly called Peppermint having a wide variety of therapeutic uses belongs to the family Lamiaceae. Peppermint is composed of essential oil such as acetaldehyde, amyl alcohol, limone, citronellol, menthol and some flavonoids and phenolic acids^63,64. In animal model study peppermint oil reduces weight and testosterone level in PCOD condition. Infertility is a major problem associated with PCOD which leads to anovulation. Peppermint intake can improve ovulation⁶⁵. The combination of peppermint with flaxseed extract in PCOD induced animals effectively improved endocrine hormone secretions and restored ovarian morphology⁶⁶. Antioxidant property Peppermint supplementation caused improvement of ovarian cysts, necrosis of hyperplasia of luminal epithelial cell and stromal mesenchymal cells⁶⁷.

Pomegranate (Punica granatum L):

Pomegranates have numerous health benefits and have been widely used to cure different diseases since ancient times. It contains flavonoids, hydrolysable tannins such as ellagitannin and ellagic acid, minerals and vitamins. It possesses strong antioxidant, anti-inflammatory, hepatoprotective, antimicrobial, antiviral, antidiarrheal and anti-diabetic activity⁶⁸. Obesity is a major risk factor of PCOD. The leaf extract of pomegranate significantly reduces body weight and triglycerides level⁶⁹. A few studies found that pomegranate extract reduces the level of hormones estrogen, free testosterone in female wistar rats induced with PCOD⁷⁰. Supplementation of Ethanolic extract of pomegranate leaves helps to decrease glucose level which is a major concern of PCOD⁷¹. We can use pomegranate in routine as complementary therapy to get cure from poly cystic ovarian disorder.

Aloe vera (Aloe Barbados aloe):

Aloe vera is the most widely used plant for its medicinal activities. Phytosterols present in aloe vera successfully restored steroidogenesis. The major phytoconstituents are anthraquinones, chromones, poly-saccharides, and enzymes which have antioxidant, anti-inflammatory and hypoglycemic activity⁷².A woman with PCOD commonly suffered with insulin resistance aloe vera effectively increases insulin sensitivity⁷³. A female rat induced with PCOD using aromatase inhibitor letrozole. Then the rat was treated orally with formulation of aloe vera gel of dose 1ml daily for 45 days. It was found that rats rehabilitate estrus cycle and steroidogenesis. It reduces triglycerides and increases high density lipoprotein levels⁷⁴.

Bamboo (Bambusa bambos):

Bambus bambos belong to the family poaceae commonly called Indian thorny bamboo. It is widely used in ayurvedic medicines for laxative, diuretic and anti-inflammatory properties. It shows reduction in blood glucose level and decreases low density lipoproteins and triglycerides levels in rats. Strong antioxidant activity of bamboo seeds helps in treatment of PCOD by restoring estrus cyclicity. It was reported that when rats fed on bamboo seeds they become sexually active into such an extent that each female rat gives birth to as many as 800 offsprings during the season of bamboo flowering^75,76.

Fenugreek (Trigonella foenum-graecum):

Fenugreek plant is widely distributed throughout the world and which belongs to the family Fabacecae. is an incredible Ayurvedic herb, Few studies have shown that Fenugreek improves levels of testosterone and estrogen. the plant has anti-inflammatory, antioxidant, carminative, successfully used in lowering blood glucose and hypolipidemic properties⁷⁷. Fenugreek seeds with metformin in PCOS women improved the menstrual cycle and sonographic results⁷⁸. Painful cramps that occur during menstruation due to higher levels of proinflammatory cytokines. On-steroidal anti-inflammatory drugs (NSAIDs) are primary medication treatment in PCOD⁷⁹ but associated with certain adverse side effects. Fenugreek has been used traditionally for pain during menstruation studies^80-82.

CONCLUSION:

Polycystic ovarian disorder is one of the most common reproductive disorders in female. Medications are used to regulate the menstrual cycles, stimulate ovulation and, hyperandrogenism, insulin resistance and obesity associated PCOD. Different drugs are used in the management of PCOD with different symptoms, but effective treatment to manage PCOD is still a challenging. Ayurvedic system has described a large number of such herbal medicines to provide a better understanding of their active principles and mode of action The reviewed some medicinal plants have multipotential beneficial effects in polycystic ovarian disorder. Hence, more pre-clinical and clinical studies are required to explore the effectiveness of herbal medicines in PCOD. Hence this review is an initiation to provide a wide option of herbal sources for the curing the better treatment and management of polycystic ovarian disorder.

ACKNOWLEDGMENT:

The authors would like to acknowledge Dr. Ashwini R. Madgulkar, Principal, AISSMS College of Pharmacy, Pune, for her encouragement and guidance.

CONFLICTS OF INTEREST:

No conflict of interest was declared by the authors. The authors alone are responsible for the content and writing of the paper.

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Received on 24.03.2022 Modified on 20.05.2022

Asian J. Res. Pharm. Sci. 2022; 12(3):219-226.

DOI: 10.52711/2231-5659.2022.00039

Medication	Description	Manifestation Treated
Metformin	Insulin –sensitizing agent	First line Therapy-Insulin resistance Second line Therapy (added to hormonal contraceptives)- Menstrual irregularities Third line Therapy-(added to hormonal contraceptives and Spironolactone)- Hirsutism
Spironolactone	Antiandrogenic antimineralocorticoid	Second line Therapy (added to after 6 months of oral contraceptives therapy if not improved)- Hirsutism Second line Therapy- Acne
Clomiphene	FDA approved for female infertility caused by PCOD. Ovulation induction agent, Selective estrogen receptor modulator	First line therapy- Infertility
Eflornithine (Vaniqa)	Inhibit Hair Growth	Second line Therapy- Mild Hirsutism
Letrozole (Femara)	Nonsteroidal competitive inhibitor of aromatase; inhibits conversion of adrenal androgens	First line Therapy- Infertility
Levonorgestrel- releasing intrauterine system (Mirena)	Intrauterine device	Endometrial hyperplasia Abnormal uterine bleeding (FDA approved)
Finasteride (Proscar)	5- alpha-reductase inhibitor	Hirsutism
Flutamide	Nonsteroidal antiandrogen used mostly for prostate cancer	Hirsutism
Hormonal Contraceptives	Based on mostly anecdotal evidence	First line Therapy- Menstrual irregularities, hirsutism, acne

	Manifestation Treated	Pregnancy or Ovulation induction desired?
	Manifestation Treated	Yes	No
*Anovulation or menstrual irregularities:*	First Line	Comiphene or Letrozole (Femara)	Hormonal contraception
*Anovulation or menstrual irregularities:*	Second Line	Metformin	Metformin
*Insulin Resistance*:	First Line	Metformin	Metformin
*Obesity:*	First Line	Lifestyle Modification	Lifestyle modification
*Hirsutism:*	First Line	Electrolysis and light based therapies (effective for mild cases)	Hormonal contraception, antiandrogen therapy
	Second Line		light based therapies, Monotherapy, electrolysis,
	Third Line		Metformin
*Acene*	First Line	Topical Creams (e.g., antibiotic, benzoyl peroxide)	Hormonal contraception, topical creams, including benzoyl peroxide, tretinoin (Retin –A), adapalene (Differin), antibiotic cream
*Acene*	Second Line		Spironalactone