Endocannabinoid activation and polycystic ovary syndrome:

A systematic review

 

Suruj Kaushik*, Trilochan Satapathy, Amit Roy, Pushpa Prasad Gupta, Prerna Purabiya

Department of Pharmacology, Columbia Institute of Pharmacy, Tekari, Raipur, Chhattisgarh-493111, India

 

ABSTRACT:

Polycystic Ovarian Syndrome (PCOS) is the major cause of female infertility that affecting 5-10% of women of reproductive age (18-44 years). Many cases, the women do not find that they suffer from this syndrome until they try to get pregnant. The etiology includes the multiple fluid sacs or cysts grow in either or both ovaries where in some cases symptoms persist and others have no symptoms. The syndrome is characterized by chronic absence of ovulation as well as high levels of androgens. The major cause that contributes this syndrome includes mutation of one or more gene that causes hormonal imbalance, life style disturbance as well as environmental factors. Symptoms of PCOS include Infertility, hirsutism, menstrual irregularities, male pattern baldness, excessive hair growth on face, abnormal cholesterol or triglyceride levels etc. Treatment focuses on clinical improvement of patients suffered from the condition. The therapies include insulin sensitizing medications such as metformin that at present has gaining great interest. Use of metformin may reduce the risk of hyperinsulinism, type-2 diabetes, and metabolic syndrome. Other medications include oral contraceptives or anti-androgen medications also proved beneficial in some cases. Clomiphene Citrate was used in many cases alone or in combination for ovulation induction in oligomenorrheic women. In this review, we have tried to explore the beneficial use of non psychoactive Cannabidiol to reduce the stress and pain during the Polycystic Ovarian Syndrome.

 

INTRODUCTION:

Most of the women in their reproductive stage (18 to 44 years of age) suffer hormonal imbalance that leads to major problem like infrequent or prolongation of menstrual period as well as the ovaries develop collections of follicles there by unable to release eggs regularly. This condition referred as polycystic ovary syndrome (PCOS). The condition may be due to excess secretion of male hormone androgen than normal level. According to the data published else where a total 2.2 and 26.7 percent of women in this age group have as polycystic ovary syndrome¹. Most of the PCOS cases are symptom less and not diagnosed. This condition affects the woman’s ovaries, the reproductive organs that produce estrogen and progesterone (androgens) hormones that regulate the menstrual cycle².

 

 

During ovulation, the released eggs by ovaries can be fertilized by a man’s sperm. Two major hormones such as Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) control ovulation³. At first FSH stimulates the ovary to produce a follicle, a sac that contains an egg secondly the LH triggers the ovary to release a mature egg⁴. During PCOS some changes is generally seen in ovaries that include occurrence of cysts (small fluid like sacs grow inside the ovaries), increased levels of male hormones that in turn leads to disrupt the menstrual cycle etc⁵. The exact cause of this syndrome is not fully clear however, recent research revealed that, alteration in the levels of male hormone, Inflammation, Insulin resistance, genetic cause have been linked with this syndrome. The difference between the normal ovary and polycystic ovary is given below for easy differentiation.

 

 

Fig: 1 Diagrammatic representation of Difference between normal and polycystic ovary

 

Complications of PCOS:

Major complications of poly cystic ovary syndrome are as follows.

 

Ø Infertility,

Ø Hirsutism,

Ø Menstrual irregularities,

Ø Hair loss (Male pattern baldness)

Ø Excessive hair growth on face

Ø Virilisation,

Ø Cystic acne

Ø Dark patchy or black skin

Ø Miscarriage or premature birth

Ø Nonalcoholic steatohepatitis caused by fat accumulation in the liver

Ø Abnormal cholesterol or triglyceride levels

Ø Type 2 diabetes or prediabetes

Ø Sleep disorder (apnea)

Ø Depression, anxiety and eating disorders

Ø Abnormal uterine bleeding

Ø Endometrial cancer

Ø Obesity is associated with PCOS

 

Standard Diagnosis procedure of PCOS:

Generally, the physician takes the history including sign and symptoms of a person suffered from poly cystic ovary syndrome. This includes menstrual pattern, absence of breast development, life style parameters such as diet, exercise, obesity, hirsutism and acne etc. Family history of the patient needed to explore infertility, any gynecological disorders, age of puberty etc⁶. Sometimes physical examinations also required that includes general body habitus, obesity, body mass index, blood pressure, presence of acne, male pattern of baldness and evidence of acanthosis nigricans. It has been observed that, Girls with PCOS with elevated hyperandrogenism such as clitoromegaly, deepening of the voice or a masculine body habitus should alert one to the possibility of virilizing adrenal/ovarian tumors or congenital adrenal hyperplasia⁷. Ultrasonography is the instrumental procedure that helps to identify small ovarian follicles. As per the Rotterdam criteria, twelve or more small follicles can be seen in an ovary during ultrasound examination. The numerous follicles contribute to the increased size of the ovaries that is 1.5 to 3 times larger than normal⁸. Laboratory tests include determination of Serum levels of androgens and testosterone level may be elevated. Dehydroepiandrosterone sulfate (DHEA-S) levels above 700-800 mcg/dL are considered as adrenal dysfunction. Other parameters need to be investigated are the ratio of LH to FSH (LH: FSH), determination of lipid profile, oral glucose tolerance test (OGTT) etc⁹.

 

Endocannabinoids and polycystic ovary syndrome (PCOS):

Endocannabinoids are the endogenous ligands for Cannabinoid receptors. These are derived from phospholipids such as Anandamide [AEA], 2-arachidonoylglycerol [2-AG]) and have a complex effects on change in body weight and metabolic regulation. The endocannabinoid system consists of 2 G-protein–coupled Cannabinoid receptors i.e. CB1 and CB2. Receptor CB1 occurs in the brain, gastrointestinal organs, skeletal muscles and adipose tissue whereas CB2 is expressed in peripheral immune cells. Endocannabinoids increase food intake and promote weight gain by activating central endocannabinoid receptors. The principal bio-active component of Cannabis i.e. D9-tetrahydrocannabinol (D9-THC) and its related compound D8-THC exert their central psychoactive effects acting via cannabinoid receptor CB1, while their peripheral effects are mostly mediated by the cannabinoid receptor CB2^10-11. The effects of exogenous cannabinoids on human fertility have been extensively studied in marijuana smokers, and it has been clearly demonstrated that, at high doses, they can alter trophoblast development and invasiveness, oviductal transport, prostaglandin production by human gestational tissues and endometrial decidualisation^12-16.

Signal transduction and biological activity:

AEA and 2-AG exert most of their biological effects by binding to the cannabinoid receptors CB1 and CB2. These are seven-transmembrane G-protein-coupled receptors that share 44% homology¹⁷. A new putative cannabinoid receptor, CB3 or GPR55, has been recently identified¹⁸ but its biological significance has not been completely elucidated¹⁹. When specific ligand binding of CB receptors activates several signaling pathways leading to reduced intracellular Camp concentrations, activation of MAP kinases, regulation of ionic current and activation or inhibition of inducible nitric oxide synthase²⁰. The signal transduction pathways activated by endocannabinoids exerted biological response within the CNS as well as in the peripheral tissues. At the CNS level, endocannabinoids modulate pain initiation, psychomotor behaviour, memory, thermogenesis and appetite²¹ where as in the periphery, they act on reproductive system²² as well as on energy balance²³.

 

The endocannabinoid system and the ovary:

Recently, it has been reported that the entire endocannabinoid system is activate the ovarian level and CB1R and CB2R, NAPE-PLD and AEA, have been identified in ovarian tissue²⁴ Immunostaining shows expression of CB1Rand CB2R in the medulla and cortex of the ovary. In the cortex, the receptors are expressed in the granulosa cells of primordial, primary, secondary and tertiary follicles and in the theca cells of secondary and tertiary follicles. Both receptors have also been observed in the corpus luteum and corpus albicans. NAPE-PLD, on the other hand, is expressed in the granulosa and theca cells of secondary and tertiary follicles, in the corpus luteum and in the corpus albicans, suggesting that AEA is mainly produced from the granulosa of growing follicles but not from oocytes²⁴. The changes in reproductive functions induced by cannabis derivatives strongly suggest that they exert potent negative effects on the ovulatory cycle. The primary negative effects are ascribed to a hypothalamic action, although some of these down-regulating influences may be mediated directly at the level of the pituitary and the ovary. At systemic level, cannabinoids are able to modulate the hypothalamic–pituitary–gonadal axis and they have been shown to down-regulate blood LH levels, by indirectly modifying GNRH secretion²⁵. In vitro studies on rats have also demonstrated that D9-THC exerts a direct inhibitory effect on both folliculogenesis²⁶ and ovulation²⁷. In support of these findings, in humans, a direct adverse effect on the ovary has been clearly documented, as cannabis users are at a higher risk of primary infertility due to anovulation²⁸. Some evidence also suggests that the endocannabinoid system could interact with ovary function through the modulation of pathways involved in energy balance and metabolism control. Indeed, obesity is commonly associated with menstrual irregularities, chronic oligo-anovulation and infertility²⁹. and regular ovulation is restored after simple management strategies aimed at weight reduction lead into improved natural conception³⁰. Intriguingly, some authors suggested that there are several possibilities that specific, still undefined dysfunctions of the endocannabinoid system may be implicated in some pathological condition such as polycystic ovary syndrome (PCOS), which affects the ovary^21-32. PCOS is one of the most common causes of infertility due to anovulation in women. It is important to underlie that cardinal feature of PCOS such as insulin resistance, androgen hyper secretion and obesity might be influenced by the endocannabinoid system. In rats, it has been shown that AEA activation of CB1R in pancreatic beta cells can induce insulin hyper secretion and insulin resistance^33-34. These observations suggest that a local effect of endocannabinoid signaling in the pancreas might also play a role in PCOS-associated insulin resistance.

 

Management of PCOS by life style modification:

Several interventions those help to reduce body weight or insulin resistance can be considered as beneficial for all the aims to help for treating the PCOS. These include, diet regulation, exercise, yoga, avoid alcohol and tobacco etc. In case of PCOS is associated with overweight or obesity, and then successful weight reduction is the most effective method of restoring normal ovulation and menstruation. Low carbohydrate containing diet will be proved to be beneficial in this regards. Sustained and regular exercise can also be helpful reducing the excess body weight.

 

Management of PCOS by Therapeutic agents:

The First-line therapeutic agent for PCOS in the stage of adolescents is hormonal suppression of ovary (androgens) with daily combination dose of estrogen/ progestin as contraceptive pills or patches. This therapy in turn increases the level of SHBG and reduces free androgens available for production of clinical hyperandrogenism, manifested as acne as well as hirsutism^35-36. Primary and secondary therapeutics such as anti-androgens in the treatment of PCOS include spironolactone and cyproterone acetate that expected to interfere with steroidogenesis. It has been observed from previous studies that, when sprionolactone alone is used without additional hormonal therapy able to causes irregular menstrual bleeding³⁵. Another drug Finasteride belongs to 5-α reductase inhibitor that reduces the conversion of testosterone to dihydrotestosterone (active metabolite). Research based statistics indicated that, this drug candidate may prove to be beneficial in the treatment of hyperandrogenism and subsequent hirsutism, but till yet not approved for its use in the treatment of PCOS^35-36. Ovarian wedge resection (OWR) therapy was on practice up to 1960s for the treatment of anovulatory infertility. After introduction of Clomiphene citrate (an ovulation inducer) and laparoscopic surgery with cauterization facilities of the ovaries the Ovarian wedge resection (OWR) therapy was almost withdrawn. The antidiabetic medication metformin now-a-days gaining much interest in the treatment of polycystic ovary syndrome because of its insulin sensitizing property. It reduces the major risk such as hyperinsulinism and T2DM as well as other metabolic syndromes there by proved helpful for induction of ovulation with regulation of menstrual cycle. Metformin also useful to regulate menstrual cycling and reduce clinical hyperandrogenic effects in young adolescents. The addition of oral contraceptives or anti-androgen medications also proved beneficial in some cases. Clomiphene Citrate (Clome/Fertomid)) was used in experiments for ovulation induction in oligomenorrheic women. The treatment with Clomiphene citrate in anovulatory PCOS conditions in women is associated with an ovulation rate of 60-85% and a pregnancy rate of 30-40%³⁷. The addition of metformin with Clomiphene citrate in resistant women significantly improves ovulation rates.

 

Benefits of using Cannabidiols (CBD) in Poly cystic Ovary Syndrome:

The naturally occurring or phytocannabinoids generally found in cannabis and some other plants whereas synthetic Cannabinoids are manufactured artificially.  The important cannabinoid is the phytocannabinoid tetrahydro cannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant hemp and cannabis that lacks the intoxicating and addictive effects associated with other cannabis compounds such as Tetrahydrocannabinol (THC). Hemp is a species of cannabis that contains less than 0.3% THC. CBD is the medicinal component in cannabis commonly used to ease symptoms such as intense pain. Studies have shown that CBD present in the hemp plant is capable of healing many diseases including Polycystic Ovary Syndrome. A study was conducted by Hollinrake³⁸ in the year 2005 revealed that; women suffered from PCOS are likely to develop anxiety, depression and stress. The patients using Cannabidiol will not only feel calmer but also reap heavily from its antianxiety and anti-stress effect. It helps patients to cope with the painful situations and disturbing conditions because of the fact that Cannabidiols also to help the body system run smoothly by restoring hormonal balance. This in turn helps to manage menstrual irregularity and subsequently increasing in the likelihood of conceives. Cannabidiols also proved helpful to reduce the body fats there by effective in controlling weight gain, which is best considered as one of the risk factors for development of PCOS.

FUTURE PERSPECTIVE:

Despite of many decades of research and experiments conducted, not much work has been done that covers the whole PCOS spectrum. Though the disorder is multifactorial and the data available about polycystic syndrome is insufficient to establish the exact cause and no appropriate therapy is till date established for medicinal cure. One of the most challenging sides of PCOS is its complexity of characteristics. Hence much research is required in future at the genetic level and Pathophysiology of PCOS to determine its cause, prevention, risk factors that can result its successful cure and treatment.

 

CONFLICT OF INTEREST:

Authors declare no conflict of interest.

 

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Received on 23.02.2019           Modified on 28.04.2019

Accepted on 22.06.2019         © RJPT All right reserved