PREVENTION OF POLYCYSTIC OVARIAN SYNDROME: SKY HIGH …

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Das et al. World Journal of Pharmacy and Pharmaceutical Sciences
PREVENTION OF POLYCYSTIC OVARIAN SYNDROME: SKY HIGH
OBJECT THROUGH NATURAL PRODUCTS
2 , Soumalya Sarkar
3 , Souvik Mukherjee
4 and Souranava
Howrah, West Bengal, India.
2 Department of Pharmacy, Bengal College of Pharmaceutical Sciences and Research,
Durgapur, West Bengal, India.
3 Drug Discovery Research Center, Translational Health Science and Technology Institute,
Faridabad, Haryana, India.
4 UGC-SAP Research Lab, Department of Pharmacy, Guru Ghasidas Vishwavidyalaya
(A Central University), Bilaspur C.G. India.
5 Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University),
Bilaspur C.G. India.
Polycystic ovarian syndrome (PCOS) is a diverse hormonal disorder
that affects about one in 15 women worldwide. It is a most important
disorder considered as elevated levels of male androgens, acne and
hirsutism. It can even cause insulin resistance, anovulation and
infertility on prolong incidence of cysts. However PCOS is a
remediable disorder, it can be treated by use of natural remedies or
allopathic medication. The natural remedies include treatment with
phytoestrogen and non-estrogenic herbs such as Liquorice, Ginseng,
Black cohosh, Dong qui, Hops and Kelp etc. These are effective and
safe better than allopathic medicine. In this review, an attempt has
been made to study the potential of natural products for treatment of
Polycystic Ovarian Syndrome.
KEYWORDS: PCOS, Hormone, Liquorice, Ginseng, Black cohosh, Dong qui, Hops and
Kelp.
SJIF Impact Factor 7.421
Volume 8, Issue 8, 515-546 Review Article ISSN 2278 – 4357
*Corresponding Author
Saptarshi Das
Assistant Professor,
Department of
Pharmaceutical Analysis,
Bharat Technology,
DOI: 10.20959/wjpps20198-14396
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1. INTRODUCTION
Herbs can be described usually in trade as a plant, plant phase or extract there of used for
flavor, or medicinal purposes. Traditional drugs are naturally going on provisions with
minimal or no industrial dispensation that have been used to cure various illnesses.
Traditional plant derived drug treatments are receiving broad interest in world health. Plant
based drug has attached promotive, preventive, healing and rehabilitative role. Herbal remedy
has grasped a rotating point. It is struggling to be diagnosed as a science-a particular
discipline with its very own identity. [1]
It has grown to be necessary to exhibit that herbal
remedy can match other fields of medicinal drug in the integrity of its scientific work and its
realistic use. Benefit of natural therapy compared to traditional remedy is that natural therapy
is protected with lesser facet effects and presence of more than one energetic compounds in
medicinal herbs altogether offers a potentiating effect. [2]
The ovary is the vital part of the
female reproductive organ which harvests the ovum. The word ovary is native to the Latin
term ovarium meaning egg or nut. Ovaries produce and secretes hormones which play a very
vital role in menstruation cycle, fertility throughout menopause. The female gonads - ovaries
are white colored, situated along the lateral wall of the uterus known as ovarian fossa. The
ovaries consist of three parts which are the capsule, outer cortex and inner medulla. [3]
At the
age of puberty, the ovaries begin to secrete hormones in elevated levels resulting in the
development of the secondary female characteristics and onset of menstrual cycle. [4]
Therefore, the ability to produce ovum and reproduce is attained with the onset of female
puberty. The principal function of the ovary is gamete production called oogenesis which is
aided by its other functions of hormone secretion and ovarian aging. In normal circumstances
the ovum is released from the follicle into the fallopian tube. Unfortunately if the ovum is not
released, it may conduct to development of an ovarian cyst. Cluster of cell aggregates
forming a pouch with a distinct membrane and division unlike surrounding tissue is called as
cyst. Small cysts are common in healthy women. [5]
In certain cases, it has been found that
some women have more follicles than usual, which inhibits normal follicular growth and
regular cycles. This is known as polycystic ovary syndrome (PCOS). Polycystic ovarian
syndrome is a serious hormonal disorder. The word poly is derived from Greek, means
many. [6]
Polycystic ovary syndrome (PCOS) is a multivariate disease of the female
reproductive system, owing to a huge difficulty for clinicians and researchers all around the
world. [7]
The PCOS morphology includes luteinized inner theca, non-maturating and atretic
follicles, tiny follicular cyst, stromal abnormal hyperplasia, thickening of ovarian cortex and
ovarian abnormal hyperplasia. These clinical indications infer obstruction in oogenesis. [8]
The
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etiology of PCOS hasn’t been completely resolved nevertheless it is correlated with
hyperandrogenemia, hyperinsulinemia/insulin resistance, aberration in luteinizing hormone to
follicle stimulating hormone ratio, metabolic and inflammatory amiss, advance glycation end
products, unfold protein response and stress in endoplasmic reticulum. [9-13]
Each female with
PCOS need to be treated as per their own requirements, symptoms or other clinical
manifestations. Treatment strategies are made to increase the quality of life and safeguard
continuing vitality and health. [14]
The pharmacological strategies to ameliorate PCOS often
include drugs such as metformin, orlistat, pioglitazone, vitamin D and hormonal
contraceptives in combination with other therapeutic remedies. [15-19]
A recent case control
study also found that the expression serum levels of microRNA-320 were lower in PCOS
patients as compared to the control and hence it could be a noninvasive diagnostic biomarker
for PCOS. [20]
In this review it will be summarized possible herbal remedies for polycystic
ovarian syndrome treatment. These are prevent ovarian cysts as well as cure them. Herbal
products may take higher time to treat PCOS but daily usage may cure the disorder from its
root. [21]
(a) Ovary (b) Ovarian Cyst (c) Polycystic Ovary
Fig.1: structure of (a) ovary (b) ovarian cyst (c) polycystic ovary [22]
2. Symptoms of Pcos: Irregular ovulation is a general symptom of PCOS. Several cysts
produce androgens. PCOS indicates the appearance of ‘hyper-androgenism’ symptoms such
as weight gain, facial and body hair, abdominal and subcutaneous fat, enlargement of the
clitoris, hair loss, deep voice, oily skin, acne etc. Insulin resistance is an important symptom
of PCOS. It results in hyper-insulinemia. Elevated insulin level is blamable for the alteration
of fat around the abdomen or central adiposity. Other than above symptoms hypertension,
cardiovascular issues, dyslipidemia, etc. are important symptoms of PCOS. [23-25]
The PCOS
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suffering patients often possess sugar cravings, fatigue, frequent urination, delayed healing,
blurred vision, mood swing, tingling sensation, anxiety and depression. Other symptom of
this disease is Sleep disorder in which breathing repeatedly stops and starts. PCOS can put a
female at the risk for uterine cancer, as the prevailing elevated level of estradiol and the lack
of progesterone due to ovarian malfunction enhance the chance of endometrial
hyperplasia. [26]
Mucus lacking endocervix, and smooth vagina is an important characteristic
of PCOS. Due to the endocrine system imbalance in PCOS, skin develops light brown or
black patches, a condition known as ‘acanthosis nigricans’. However, PCOS symptoms can
be deliberated as a spectrum. Hirsutism is mild or lacking in PCOS suffering patients but
hirsutism more affect patients with origin of Middle Eastern and Mediterranean. [27]
3. PATHOGENESIS OF PCOS
(a) Elevated level of androgens: Increased level of androgen hormone is considered as the
main cause of PCOS. Under normal state, the ovaries and adrenal glands are both contributed
about the production of testosterone. [28]
Half of testosterone is generally produced from direct
testosterone secretion, whereas another half is produced by peripheral conversion of
circulating androstenedione. Androgen production is not produced direct negative feedback
in females, recent research works are also described that elevated level of androgen is also
produced the negative feedback with female sex hormone. [29]
Both the ovaries and adrenal
glands are secreted androgens in response to their tropic hormones LH and ACTH
respectively. Ovarian theca cells synthesize C19 androgens are synthesized by the influenced
of luteinizing hormone, and androgen. Then it is converted to estradiol by aromatase enzyme
in granulosa cells. Increased androgen secretion is a principal characteristic of polycystic
ovarian syndrome. [30-32]
present during pregnant state in affected women. [33]
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Fig. 2: Elevated level of androgen production during PCOS [34]
(b) Ovulatory dysfunction: During ovarian follicular development, primordial follicles are
recruited into a group of growing follicles, from which one antral follicle is selected to
ovulate. These actions require coordinated three interaction viz reproductive, metabolic and
intraovarian interactions. In PCOS, ovarian hyperandrogenism, hyperinsulinemia from
insulin resistance and altered intra-ovarian paracrine signaling can disrupt follicle growth. [35]
The consequent follicular arrest in PCOS is accompanied by menstrual irregularity, an
ovulatory subfertility and the accumulation of small antral follicles within the periphery of
the ovary, giving it a polycystic morphology. [36]
(c) Insulin resistance: a common feature of PCOS that arises in part from adipose tissue
dysfunction, results in compensatory hyperinsulinemia, which maintains normal glucose
levels but adversely effects ovarian androgen production. [37-38]
Abnormal folliculogenesis and
the development of PCOS; these abnormalities may arise from environmental insults as well
as genetic predisposition Hyperinsulinemia also amplifies luteinizing hormone (LH)-
stimulated and insulin-like growth factor 1 (IGF-1)-stimulated androgen production, elevates
serum free testosterone levels through decreased hepatic sex hormone-binding globulin
production, and enhances serum IGF-1 bioactivity through suppressed IGF-binding protein
production. [39]
follicle-stimulating hormone (FSH)-induced granulosa cell differentiation, which arrests
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granulosa cell proliferation and subsequent follicle growth. Finally, overproduction of anti-
Mullerian hormone (AMH) by the granulosa cells of ovarian follicles in PCOS. [40]
(d) Obesity and adipose tissue dysfunction: In PCOS Adiposity-dependent insulin
resistance is inextricably linked with PCOS. The molecular mechanisms underlying insulin
resistance of PCOS remain elusive; however, primary defects in insulin-mediated glucose
transport, GLUT4 production and insulin or adrenergic regulated lipolysis in adipocytes,
despite normal insulin binding. These defects in insulin action seem to represent perturbed
intracellular insulin signaling or action by paracrine, autocrine and endocrine factors, with
abnormal insulin receptor auto phosphorylation or altered phosphorylation of insulin-receptor
substrate, glycogen synthase kinase 3 or serine/threonine-protein kinase AKT identified in
fibroblasts, adipocytes and myocytes of some women with PCOS. [41]
In addition, insulin
resistance in PCOS might partially represent dysfunctional adipogenesis from an impaired
capacity of regional adipose tissue stores to properly expand with increased dietary caloric
intake. Adipose tissue secretes approximately 100 factors that regulate metabolic function,
appetite, neural activity, digestion and inflammation; this tissue is also heavily infiltrated by
macrophages, and crosstalk occurs between adipocytes, macrophages and pluripotent cells
that induces complex paracrine interactions. [42]
(e) Gonadotropin abnormalities: LH hypersecretion rises serum immunoactive and
bioactive LH levels in about 70% of women with PCOS, and increased LH pulse amplitude
and frequency induces a twofold to threefold elevation in circulating LH versus FSH levels.
58–60 Increased LH pulse frequency in PCOS, from increased hypothalamic gonadotropin
releasing-hormone (GnRH) pulsatile release, occurs owing to reduced steroid hormone
negative feedback on LH secretion because of androgen excess. [43]
However, PCOS exhibit
reduced hypothalamic feedback inhibition from androgen excess is not for all adolescent girls
with PCOS that may be because the availability of this defect requires a genetic component
or depends on the duration of androgen excess. [44]
(f) Epigenetic changes: In fetal life are implicated in the developmental origins of PCOS.
(g) Premature adrenarche: Some populations of girls with PCOS. Moreover 30% of per
pubertal daughters of Chilean mothers with PCOS developed exaggerated adrenarche
accompanied by higher serum. Obesity further influences the adolescent PCOS phenotype by
unmasking or amplifying symptoms of hyperinsulinemia and hyperandrogenism in
susceptible individuals.
Weight gain worsens metabolic and reproductive abnormalities of PCOS, as evidenced by
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increased total and abdominal obesity as well as insulin resistance, menstrual irregularity and
hyperandrogenism in women with the most severe PCOS. Endocrine disrupting chemical that
is detectable in most individuals. [45]
Rodent studies show that BPA enhances ovarian
androgen production in vitro and induces insulin resistance in vivo. BPA accumulates to an
increased level in women with PCOS owing to the decreased hepatic clearance that arises
from androgen excess which has raised worry that BPA accumulation in susceptible women
might exaggerate the severity of the PCOS phenotype. [46]
(i)Long-term morbidity Subfertility Anovulation: It is the predominant cause of
subfertility in PCOS. In addition, a subgroup of women with PCOS also exhibit impaired
oocyte developmental competence, or the ability of the oocyte to complete meiosis and
undergo fertilization, embryogenesis and development to birth. Obstetrical morbidity Women
with PCOS exhibit gestational androgen excess and hyperinsulinemia, both of which may
adversely affect pregnancy outcome. [47]
Fig. 3: Summery of pathogenesis of PCOS.
3. CURRENT SYNTHETIC DRUG FOR PCOS: The possible drug targets and disease
genes are usually identified from the biological background of PCOS. Previous researchers
were demonstrated differential pathways instead of differential expressed genes, for
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analyzing the pathogenesis of PCOS and the way of drug response. [48-50]
21 PCOS potential
drug targets were verified by various literatures to be associated with the pathogenesis and
treatment of PCOS, which could reflect the status of disease and drug response and 42 drugs
targeting to 13 PCOS potential drug targets were confirmed to be investigated experimentally
or clinically for treating PCOS . One is insulin sensitization agent such as Pioglitazone,
Rosiglitazone; the other is correcting the lipid metabolism disorders agent such as
Repaginate, Telmisartan. [51]
4. HERBAL REMEDIES FOR PCOS
1. Liquorice: Liquorice is also known as yasti consists of dried, unpeeled, roots and stolons
of Glycyrrhiza glabra, belonging to the family Leguminosae. Traditionally liquorice has
medicinal imprtance as an expectorant and demulcent, anti-ulcer, anti-spasmodic, anti-
bacterial, anti-fungal, anti- inflammatory and foam stabilizing agent. [52]
Fig. 5: Liquorice.
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Glycyrrhizic acid is the major biological active compounds in liquorice. Liquiritigenin,
isoliquiritigenin, isoliquiritin, liquiritin, glabidin, and glabrene are some of the
phytoestrogens present in liquorice. Somjen et al., described that, glabridin, and glabrene
flavonoid which are obtained from liquorice root both established estrogen-like activities that
the effects on vascular tissues in both in vitro and in vivo [53]
Fig. 6: Structure of Glabridin and Glabrene.
Liquiritigenin a selective estrogen receptor compound might be one of the biologically active
compound responsible for weight loss. It has been stated that the combined treatment with
Liquorice and spironolactone in hirsute women is effective in PCOS, in order to reduce the
volume depletion induced by spironolactone and possibly boost its anti-androgenic activity. It
helps in proper production of hormones as well as their release through endocrine system.
This herb balances estrogen levels, maintains healthy levels of insulin and promotes liver
health. In addition, it boosts the immune system and reduces inflammation and stress there by
relieving. The effect of Liquorice was explored on the pathway of androgen metabolism in
the luteal phase of the cycle in nine healthy women of 22–26 years old, They were
administered 3.5 g of a commercial preparation of licorice (containing 7.6% W/W of
glycyrrhizic acid) daily for two cycles. They were not on any other treatment. Plasma renin
activity, gonadal androgens and serum adrenal, aldosterone and cortisol were measured by
radioimmunoassay (RIA). Total serum testosterone decreased gradually within two months. It
returned to pretreatment levels after discontinuation. Licorice can reduce serum testosterone
probably due to the block of 17hydroxysteroid dehydrogenase and 17–20 lyase. Licorice
could be considered an adjuvant therapy of hirsutism and polycystic ovary syndrome. [54-59]
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(2) Spearmint Tea: It consists of dried leaves and flowering tops of the plant known as
Mentha spicate, belonging to the family Labiatae. It is used as a carminative and flavoring
agent.
In PCOS condition, obesity, insulin resistance and hyperglycemia all correlate with a high
level of oxidative stress, inducing a hyper and ogenemic environment in the ovary. [60]
Although locally produced androgens serve as substrate for estrogen production in
folliculogenesis, an excessive level of androgens overrides follicular development, resulting
in follicular atresia, disturbed follicular development and anovulation. Elevated visceral
adiposity and hyperinsulinemia are observed in PCOS women, resulting in increased
androgen production of the ovaries and adrenal gland. Reducing body weight of an ovulatory
obese women decreases insulin resistance, testosterone concentration and restores ovulation.
According to our results, spearmint oil decreases body weight in the PCOS condition, and
since it has anti-androgenic potential, its administration leads to decrease of androgen
production. Studies show that spearmint leaves decrease cholesterol and, in type II diabetes,
decrease oxidative stress. Additionally, phenolic compounds of spearmint leaf extract
significantly enhance the antioxidant defense system and reduce body weight and levels of
glucose and cholesterol in diabetic male rats. Furthermore, administration of spearmint
decreased the number of atretic follicles and ovarian cysts in PCOS-induced rats, a
circumstance which is also associated with the antioxidant and anti-androgenic effects of
spearmint oil. Moreover, the attenuated level of corpus lutea in PCOS-induced rats increased
in PCOS rats that received spearmint oil, which reflects the higher rate of ovulation in these
groups. Therefore, spearmint oil by reduction of weight and testosterone and having
antioxidant potential can restore follicular maturation and induce ovulation, which,
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respectively, was observed in the lower number of atretic follicles and higher number of
Graafian follicles and corpus lutea in the PCOS-induced rats that received spearmint oil. The
study was carried out in Turkey in a two centre as 30 day randomized controlled trial. Forty
two volunteers were randomized to take spearmint tea twice a day for a 1 month period and
compared with a placebo herbal tea. At 0, 15 and 30 days of the study serum androgen
hormone levels and gonadotropin were checked; the degree of hirsutism was clinically rated.
41 out of 42 patients completed the study. Free and total testosterone levels and degree of
hirsutism were reduced over the 30 day period in the spearmint tea group. LH and FSH were
increased. It was demonstrated and confirmed that spearmint has anti-androgen properties. [61-
63]
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(3) Ginseng saponin: It strengthens the HPA axis and hence restores hormonal balance. It
also boosts immune system and manages stress. It maintaines healthy glucose levels in
women, which is crucial to fight PCOS. Female Sprague-Dawley rats (190-210 g) were
induced polycystic ovary with injection of Estradiol Valerate (EV) intramascular and
separated into three groups: EV control (n=10), EV plus Ginseng Total Saponins (n=10), and
oil control (n=10). Parameter observed in this study include Ovarian morphology and Nerve
Growth Factor (NGF) protein expression. Increased expression of Nerve Growth Factor was
noted in the ovaries and the brain of rats with Poly Cystic Ovary. Ginseng Total Saponins
administration diminished NGF expression in the ovaries. [60]
(4) Flaxseed: In this study the effect of flaxseed supplementation (30 g/day) on hormonal
levels in a 31-year old woman with PCOS was observed. During a four month period, the
patient administered orally 83% of the flaxseed dose. Height, weight measurement and
fasting blood samples monitoring at baseline and 4-month follow-up directed significant
decrease in Body Mass Index (BMI), total serum testosterone, insulin and free serum
testosterone levels. The patient also reported a decrease in hirsutism at the completion of the
study period. The clinically significant decrease in androgen levels with a concomitant
reduction in hirsutism reported in this case study. [62]
(5) Aloe-vera: A. barbadensis Mill. Is one of the oldest known medicinal plants gifted by
nature and is often called miracle plant or natural healer. It belongs to liliaceae family which
includes about 250 species; however only two species, viz. A. barbadensis Mill. and A.
arborescens Mill. Are considered as the most important ones. The innermost part of A. Vera
leaf is a clear, soft moist and slippery tissue which contains vital ingredients, viz.
polysaccharides, vitamins, minerals, amino acid, saponins, anthraquinones etc. Most of the
health benefits associated with this plant have been attributed to polysaccharides contained in
the mucilageous gel of leaves. In the present study, the efficacy of Aloe vera gel formulation
in a PCOS rat model was checked. [63]
Five month old Charles Foster female rats were orally
fed with letrozole, a non-steroidal aromatase inhibitor, to induce PCOS. The rats were then
treated orally with the Aloe vera gel formulation (1 ml dose daily for 45 days). This restored
their estrus cyclicity, glucose sensitivity, and steroidogenic activity. Co-treatment of the
inductive agent (letrozole) with the Aloe vera gel prevented the development of the PCO
phenotype [64]
. Aloe vera gel formulation exerts a protective effect in against the PCOS
phenotype by restoring the ovarian steroid status, and altering key steroidogenic activity. This
can be attributed to phyto-components present in the extract. [63]
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(6) Cinnamon: Cinnamon, which is a spice used to flavor foods, has been possess anti-PCOS
and anti-diabetic properties. In a high-fructose diet induce insulin resistance rat model,
cinnamon extract not only increase systemic insulin sensitivity and dyslipidemia by
improving insulin signaling, but also effectively elevate circulating levels of adipokines
partially mediated via regulation of the expression of multiple genes involved in insulin
sensitivity and lipogenesis. [69]
Several in vitro and in vivo studies have shown cinnamon can
reduce insulin resistance by increasing activation of the IRS/PI-3 kinase insulin signaling
pathway. The extracts from cinnamon stimulate auto phosphorylation of the insulin receptor
and inhibit protein tyrosine phosphatase I. Through these two mechanisms cinnamon extract
make adipocytes to increase the glucose uptake and glycogen synthesis. Oral cinnamon
extract reduced fasting glucose, triglycerides, low-density lipoprotein (LDL), and total
cholesterol in patients with type 2 diabetes mellitus as well as improved insulin sensitivity in
women with PCOS. Based on these findings, we put forward our hypothesis that cinnamon
has an overall impact on PCOS treatment. Previous studies proved dehydroepiandrosterone
(DHEA) induced PCOS model represents similar characteristic seen in human patients, such
as hyperandrogenism, abnormal maturation of ovarian follicles and anovulation. In this
experiment, we tried to gain a deeper understanding of the effect and mechanism of
cinnamon on PCOS using a DHEA induced PCOS like mice model. Cinnamon extract has
been shown to reduce insulin resistance in in vitro and in vivo studies by increasing
phosphatidylinositol 3-kinase activity in the insulin signaling pathway and thus potentiating
insulin action. Fifteen women with polycystic ovary syndrome (PCOS) were randomized to
daily oral cinnamon and placebo for 8 weeks. Comparisons of post-treatment to baseline
insulin sensitivity indices using fasting and 2-hour oral glucose tolerance tests showed
significant reductions in insulin resistance in the cinnamon group but not in the placebo
group. [70]
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Fig. 9: Mechanism of Cinnamaldehyde in PCOS treatment.
(7) Chaste berry: Otherwise, it is also known as vitex. It is the most singled out herb for
restoring normal menstrual cycle in women with PCOS. It regularizes menstrual cycle by
balancing hormonal feedback loop and promoting ovulation. It also regulates the pituitary
gland that has a normalizing effect on the menstrual cycle. It initiates release of LH for
preparing ovulation. It also helps in the release of FSH that stimulates the ovulation. In this
study, 93 women who had tried to conceive for 6-36 months were given a supplement
containing chaste tree, L-arginine, vitamins and minerals. Their progesterone level, menstrual
cycle length, pregnancy rate and side effects were documented. After 3 months, the
supplementation group demonstrated increased mid-luteal progesterone and normalized
menstrual cycles compared to no significant changes in the placebo group. 14 out of the 53
women who received the supplement became pregnant as compared to 4 of the 40 women
who received placebo. 3 other women in the supplement group conceived after 6 months. The
recommended dose is 1-4 ml of 1:2 dried plant tincture of 500-1000 mg of dried berries
daily. [71]
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(8) White peony: The particular herb reduces chances of uterine stagnation by promoting
circulation to female reproductive organ. It discards chances of ovarian cysts. It also relieves
from pain during menstruation, especially when taken along with licorice root. It also lowers
testerone level. In the present study, we investigated the in vivo effects of unkei-to (Japanese
herbal medicine) and its compounds on the Steroidogenesis and cytokine secretion in human
granulosa cells. Unkei-to stimulate the oozes of 17-betaestradiol and progesterone from
highly luteinized granulosa cells obtained from in vitro fertilization patients. Effect observed
due to its various ingredients herb like Paeoniae radix, Paeonia lactiflora, Cinnamomi cortex
and Cinnamomum cassia. The various beneficial actions of unkei-to on the ovary may result
from a combination of different ingredient herbs with different stimulatory effects on both
steroidogenesis and the ovulatory process within the ovary, as well as stimulatory effect on
the hypothalamus-pituitary axis. [62]
(9) Milk thistle: In this study, the effect of silymarin which is known to have insulin
sensitivity effects on the levels of glucose, insulin, testosterone, leutinizing hormone (LH)
and progesterone was tested. Ovulation rate and Homeostasis Model Assessment of insulin
Resistance (HOMA) ratio were determined. A 3-months of treatment were conducted in 60
PCOS patients in three well-matched groups. The first one (n=20), received silymarin
(750mg/day). The second group received metformin (1500mg/day) while the third group
treated by combination of metformin (1500mg/day) and silymarin (750mg/day). All these
groups had taken the drugs in divided doses. The results showed significant increment in
progesterone levels after completion of treatment. In conclusion the addition of silymarin to
metformin in treatment of PCOS patients has improving effect on disturbed hormones and
ovulation rate. [63]
(10) Kasip Fatimah: In this study, effect of a Malaysian herb Kasip Fatimah had been
checked on 9 week old PCOS rats. PCOS was induced in female rats before puberty by
treating continuously with dihydrotestosterone. The PCOS rats were randomly subdivided
into two groups; PCOS herb treated and PCOS control. PCOS herb treated rats received a
daily oral dose of (50mg/kg body weight), dissolved in 1 ml of deionised water, for 4-5
weeks. PCOS controls received 1 ml of deionised water on the same schedule. Result showed
reducing body weight gain in ovariectomized rats. Herb treatment increases uterine weight,
indicating estrogenic effects and improves insulin sensitivity and lipid profile in PCOS rats
without affecting body composition. [64]
(11) Chamomile: Thirty virgin adult cycling Wistar rats, weighting 200 - 220 g were divided
into two groups and housed every six mice into cage under standard conditions (21 ± 2°C,
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12-hour light/ 12-hour dark cycles) for at least one week before and throughout the study.
Estrous cyclicity of 30 virgin adult cycling rats was monitored by vaginal smears obtained
between 0800 and 1200 hours. After about 4 days, each rat received an i.m. injection of
Estradiol Valerate), 2 mg in 0.2 ml of corn oil, to induce PCO. Corn oil was injected to the
rats in the control group. All the rats in the experimental group were evaluated for follicular
cysts 60 days after the injection. Rats with PCOS were treated by multiple doses (25, 50, 75
mg/kg) of intraperitoneal injections of Chamomile alcoholic-extract for ten days. The
histological and hormonal results showed that Chamomile can decrease the signs of PCOS in
the ovarian tissue and help LH secretion in rats. [65]
(12) Astragalus: In this study, 32 women with PCOS were administered with combined
application of astragalus polysaccharides and diane-35 for 3 months. Sex hormones, insulin
sensitivity and blood lipid were evaluated before and after the therapy. After the treatment,
fasting serum insulin levels, LH/FSH ratio was found be reduced and insulin sensitivity index
increased significantly. Astragalus polysaccharides plus diane-35 can be effective in
improving insulin resistance, high androgen hormone status and lipid metabolism in patients
with PCOS and it may be alternative for PCOS. [66]
(13) Curcuma longa (Turmeric): Curcumin is a water-insoluble, low molecular weight,
polyphenolic curcuminoid derivative found in rhizomes of Indian spice, Curcuma longa of
the family Zingiberaceae (turmeric). Turmeric is extensively used as a food additive and
coloring agent in Asian cuisine and also in Indian herbal medicine. Curcumin has been
reported to possess a wide variety of biological effects like anti-inflammatory, antioxidant
hypoglycemic antihyperlipidemic activities and estrogenic effects. A study was conducted in
30 female Albino Wistar rats, using Letrozole-aromatase inhibitor, to induce Polycystic
Ovarian Syndrome. Its effect was comparable to that of Clomiphene citrate, most widely used
treatment for ovulation induction in PCOS condition. Serum levels of Progesterone and
Estradiol were decreased in PCOS induced group. Curcumin restored the hormone and lipid
profile, antioxidant and glycemic status as well as ovarian morphology in Letrozole induced
PCOS animals. Decreased progesterone levels are also indicative of anovulation and
curcumin successfully restore the ovulation. The study suggests that the effects may be
attributed to its multiple pharmacological activities like estrogenic, antihyperlipidemic,
antioxidant and hypoglycemic effects which could be useful in managing PCOS condition
and prevent ovarian cell dysfunction, ovulation and thereby improving fertility. The studies
show that the effect of curcumin is similar to that of Clomiphene citrate. [67]
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(14) Trigonella foenum-graecum (Fenugreek): Another recent study investigated the
efficacy of a novel, fenugreek (Trigonella foenum-graecum of the family Fabaceae) seed
extract in PCOS. Fenugreek is enriched in furostanolic saponins (Furocyst), the trial was
conducted in female subjects suffering from PCOS over a period of 90 consecutive days.
Plasma glucose levels (fasting glucose), serum triglyceride and HDL levels, total leukocyte
count and hemoglobin levels were also monitored at the beginning and end of 90 days
treatment. 94% of patients responded positively to the treatment and significant improvement
in menstrual cycle was also observed following Furocyst treatment resulted in significant
reduction in both ovary volume and ovarian cyst. Also significant increases in LH and FSH
were observed following Furocyst treatment. 12% of study population got pregnant.
Approximately 46% of study population showed reduction in cyst size, while 36% of subjects
showed complete dissolution of cyst. No significant adverse effects were observed. [68]
(15) Cocus nucifera (Coconut): Soumya et al., reported the effect of Cocus nucifera
(Arecaceae) flowers in reducing the major multiple symptoms of letrozole-induced PCOD in
female rats. Antioxidant status (superoxide dismutase (SOD) and glutathione reductase
(GSH)) of the uterus homogenate, lipid profile (total cholesterol (TC), high density
lipoprotein (HDL), low density lipoprotein (LDL), and triglycerideslevels moreover
increased uterine weight, indicating estrogenic effects of the labsinia extract. Treatment with
labisia extract increased insulin sensitivity in PCOS rats without influencing body weight. [69]
(16) Thuja occidentalis (White Cedar): Thuja occidentalis (Cupressaceae) has been used in
folk medicine for the treatment of rheumatism, amenorrhea, cystitis, and uterine carcinomas,
and as an abortifacient and contraceptive. Thujone found in the essential oil was reported to
be responsible for the curative properties of T.occidentalis. A recent study investigated the
activity potential of the essential oil and its major compound thujone obtained from the leaves
of T. occidentalis using an in vivo letrozole-induced PCOS model. The phytochemical
analysis identified the main constituents of the oil is terpene ketones, α and β-thujone,
fenchone, and sabinene, as well as the diterpenes beyerene and rimuene. The levels of serum
gonadotropins, steroids, blood lipid, leptin, and glucose and the values of antioxidant
parameters were monitored in the study. The estradiol and progesterone levels significantly
increased, while the LH and testosterone levels decreased in the T. occidentalis- and α-
thujone-administered groups when compared to the control group. The potential activity of T.
occidentalis in the treatment of PCOS may be related to its hormone-regulating effect. The
study also reported that administration of T. occidentalis essential oil and its active
component, α-thujone, did not cause osteoporosis development the rats was measured by
532
real-time quantitative PCR and immunohistochemistry. The positive effect of the extract in
alleviates the PCOS related hyperandrogenism has been linked to the ovarian expression of
FSHR and AQP-9. The phytochemicals of flavonoid glycosides might be responsible for the
observed effects. [70]
(17) Atractylodes macrocephala (Atractylode): Atractylodes macrocephala Koidz
(Compositae) is a tonic herb widely prescribed in most Asian countries, and it has been
clinically used as the dominant herb in most of the Chinese medicinal formula of treating
PCOS. The effect of Atractylodes macrocephala polar extracts in alleviating
hyperandrogenism in PCOS rats was studied. Hyperandrogenic rat model of PCOS induced
by testosterone propionate is used for the study The plasma levels of total testosterone, sex
hormone binding globulin, androstenedione, luteinizing hormone (LH), follicle stimulating
hormone (FSH), antimullerian hormone were measured by enzyme linked polar extracts. The
extract lowers plasma testosterone and androstenedione levels in PCOS. It also significantly
reduced LH and increased FSH levels. No adverse effects were found on liver function. [71]
(18) Corylus avellana (Hazel nut): Corylus avellana L., Betulaceae, is growing wild in
Europa, Western Asia and Northern Africa as large shrubs or small trees about 3.5–4.5 m
high. One of the most important features of C.avellana is to have the highest ratio of
unsaturated/saturated fattyacids. Demirel et al., reported the activity of the hazelnut oil in the
treatment of polycystic ovarian syndrome in rats. Serum follicle-stimulating hormone,
luteinizing hormone, estradiol, progesterone, testosterone, serum lipid parameters, leptin and
glucose levels were evaluated. The phytosterol content of the oil was determined by HPLC.
According to the phytochemical analysis, the main component of the oil was detected as α-
tocopherol, tocopherol, squalene, β-sitosterol, campesterol and stigmasterol. Serum
gonadotropin levels were determined using radioimmunoassay. After the hazel nut oil
administration treatment group and the reference group exhibited regular estrous cycles. It
has a favorable effect in controlling follicular cysts. High FSH and LH levels levels were
found to be normal. The ethanolic extract of C. avellana seed displayed remarkable
antioxidant activity in total antioxidant and radical scavenging tests. C. avellana seed
regulating the gonadotropins, steroids and serum lipid parameters and possess antioxidant
activity. The author suggested that phytosterols determined, probably promoted the treatment
of PCOS by their antioxidant effect. The improvement in the blood glucose and serum insulin
levels could be associated with the improvement in the serum FSH and LH hormones. [72]
(19) Tribulus terrestris (Puncture vine): Tribulus terrestris, (Zygophyllaceae) commonly
known as Puncture vine or Devil’s eyelashes plays an important role in traditional medicine.
533
This particular herb enhances the timing of menstrual cycle and blocks menstrual
irregulation. In addition, it acts as a tonic for the reproductive system of women and
nourishes the ovaries. This herb reduces ovarian cysts as well as stimulates ovulation. In an
investigation done in rats with polycystic ovaries induced with estradiol valerate, found that
Tribulus terrestris extract is effective in improvement of ovulation in rats. The extract
treatment normalized estrous cyclicity and steroidal hormonal levels and regularized ovarian
follicular growth. Many herbalists find tribulus is an effective, overall female fertility tonic
and ovarian stimulant, making it an excellent choice for women with polycystic ovary. [73]
(20) Gymnema sylvestre (Gymnema): Gymnema sylvestre (Asclepiadaceae) is an herb which
is used in traditionally in Ayurvedic system of medicine. It has various pharmacological
effects like anti-diabetic, hypoglycemic, and lipid lowering effects. The active constituent of
gymnema is saponins, especially gymnemic acids. It is particularly known for its amazing
potential of blocking sugar. It delays sugar absorption by blocking the paths that sugar
traverses through during digestion process. It is regenerated the pancreatic cells to enhance
insulin production in the absence of which normal ovulation is badly affected. In addition,
gymnemic acid is reduced the lipid level and helped in weight loss. Gymnema has potential
hypoglycemic activity in experimental models of diabetes. It regulates the blood glucose
level. Conventional therapy focusing on metformin therapy for PCOS. Therefore gymnema
can be used for the underlying factor of insulin resistance. Gymnema is well indicated for
PCOS, due to its insulin modulating activity and the added benefits of reducing the elevated
triglycerides associated with PCOS. [74]
534
Fig. 10: Mechanism of Gymnemic acid in the prevention of PCOS.
(21) Punica granatum (Pomegranate): Pomegranate (Punica granatum of the family
Punicaceae) is one of the known fruit and has numerous medicinal propertiesThe fruit
contains vitamins such as B2, C, B1, folic acid, pantothenic acid, sugars, and organic acids.
The seed is reported to contain saturated and unsaturated fatty acids. The effect of
pomegranate extract in the management of PCOS was performed in adult rats using control
and PCOS group. The concentration of serum estrogen, free testosterone and andrestandoin
hormone levels in experimental group was monitored. The study suggests the beneficial
effect of pomegranate extract on hormonal imbalances of polycysticovarian syndrome. The
phytosterols and phenolic compounds found in the extract have positive effect in improving
the complications of PCOS. The study recommends that the consumption of the extract
reduces complications associated with PCOS. [75]
535
(22) Cimicifuga racemosa (Black cohash): Cimicifuga racemosa (Ranunculaceae) is a well-
known medicinal plant for its estrogenic effects. This herb comprises of hormonally active
compound that suppress LH secretion, which causes PCOS in women.
Fig. 11: Black cohash.
A randomized controlled study was conducted in 50 women with PCOS. Ovulation induction,
hormonal profile concentration and outcome of pregnancy rate were studied. The Cimicifuga
racemosa extract treatment significantly reduces the LH level and LH/FSH ratio. The reduced
LH level decreases the excessive androgen level associated with PCOS, ultimately resulted in
better ovulation and implantation rates. Reduced LH increases the sensitivity of ovarian
tissue to circulate FSH, which improves the follicular growth, ovulation and implantation.
The study revealed that phytoestrogens present in cimicifuga racemosa extract increases the
endometrial thicknesses, which improve the implantation rate and pregnancy outcome. [76]
(23) Mimosa pudica (shy plant): Mimosa pudica Linn belongs to family Mimosaceae is
used in folk medicine and traditional systems of medicine in various disorders of female
reproductive system.
536
The effect of Mimosa pudica extract was evaluated by Letrozole induced PCOS rat model.
The biomarkers of ovarian function, plasma testosterone, estrogen and progesterone were
analyzed to determine the fluctuations in sex steroid levels in PCOS induced rats. When
compared with control, the PCOS induced rats showed characteristic ovary with high
incidence of ovarian cysts with a diminished granulosa layer, significant number of atretic
follicles and absence of corpora lutea. Mimosa pudica significantly reduced histopathological
changes in ovary and endocrinological and biochemical changes induced by
hyperandrogenism. Thus Mimosa pudica was found to have a good potential to be a very
good alternative therapy in the treatment of PCOS. [77]
(24) Symplocos racemosa (Lodh Tree): Symplocos racemosa Roxb. From the family
Symplocaceae, is a widely used Ayurvedic remedy mainly for gynecological disorders.
Fig. 13: Symplocos racemosa.
It is also known as Lodhra and is used in Indian System of Medicine as single drug or in
multicomponent preparations. The anti-androgenic properties S. racemosa in the treatment of
PCOS was investigated in letrozole induced rat model. Syplocus racemosa treatment
excibited significant recovery of testosterone, estrogen, progesterone levels and ovarian
tissues. Moreover it showed anti-androgenic effect and prevents ovarian cell dysfunction in
PCOS and improved the fertility. [79]
(25) Withania sominifera and Tribulus Terrestnis ; WS and TT are hot in the first and third
degree respectively suggesting that the drugs possess such a degree of hotness which suits
induction of response in amenorrhea and infertility. On treatment, the histopathological
changes reached up to the normal level, which clearly indicates that the test combination
stimulates the ovarian function as cortex shows primary and secondary follicles with
aggregation of granulosa cells. The result clearly demonstrated that the test combination due
537
to their hot temperament dissolves the cyst. Therefore, it can be concluded that the test
combination normalizes the ovarian functions by alteration of temperament of ovaries. TT
has already been reported for its effect in formation of corpus luteum when administered to
immature rats for 21 days. Moreover TT has also been studied in a very low dose (5 mg/kg
and 10 mg/kg) in alternative treatment of ovarian cysts induced by estradiol valerate in
rat, which further justified the efficacy of the test drugs.Amenorrhea is the prevalent feature
of the disease. The test combination has been described to possess emmenaogogue properties
useful in improving the amenorrhea. Test drugs also have lenitive and resolvent properties,
with these inherited properties may liquefy the viscous matter and resolve the matter forming
cysts, thus correcting and normalizing the ovarian functions. Therefore, the mechanism
proposed by the Unani physicians appears to be comprehensive and very much in
commensuration of the modern approaches of treatment. On account of the results and
discussion it can be concluded that the hydroalcoholic extract of combination WS and TT
exhibited significant recovery of FSH, LH, estradiole, and testosterone levels in serum. The
hydroalcoholic extract demonstrated significant antiandrogenic effects by reducing increased
testosterone level and preventing ovarian dysfunction in rats. This property of the test drugs
may be due to the presence of phytoestrogens in hydroalcoholic extract of the test
combination. Further studies are required to explain the exact mechanism of action of the test
drug combinations. [80]
5. DISCUSSION: We conducted this review to present confirmations on the etiology of
PCOS and introduce plants that have been recently investigated for their effects on this
disease in studies with human subjects and animal models. Most studies investigated the
serum levels of sex hormones, hyperandrogenism, insulin resistance, ovarian weight and
histopathology, ovulation, and the symptoms of PCOS before and after the treatment. By
inducing polycystic ovary syndrome and then, treatment with different extracts the blood
testosterone and LH levels were reduced and the blood progesterone and FSH levels
increased. Also, histopathological changes indicated that there were many types of
follicles in different stages of growth in the treatment groups, including primary follicles,
antral, peri- antral, graafian, corpus luteum, and large oocytes. Most of these studies
reported that the studied herbal extracts were effective in treating PCOS and improved
the levels of sex hormones, insulin resistance, hyperandrogenism, ovulation, and PCOS
symptoms. In these studies, testosterone propionate, estradiol valerate, and letrozole
were used to induce PCOS. In estradiol valerate-induced PCOS, widely used in studies,
538
LH and testosterone increase and FSH decreases. Besides that, letrozole, an aromatase
inhibitor, has been used to induce PCOS. Aromatase is a small member of the
cytochrome p450 family that converts androstenedione to estrogen and testosterone to
estradiol. Hormone changes in such models are associated with increased levels of
testosterone and LH, and decreased levels of estrogen, progesterone, and FSH that are in
agreement with PCOS-induced changes in different species. In women with PCOS,
secretion rate and metabolism of androgens and estrogens are impaired and androgens
levels increase. As a result, insulin resistance causes increase in LH/FSH, and such
hormone changes at theca cell surface and granulosa cause increase in the synthesis of
androgens and decrease in the synthesis of estradiol. Finally, the maturation of follicles is
stopped and therefore ovulation is impaired. Currently, because there is no definite and
ideal treatment for hormonal disorders and associated clinical manifestations, and also
chemical drugs have several side effects, thereby alternative treatment, especially
phytotherapy, can be considered instead of commercially available drugs. Because
medicinal plants contain active compounds as well as has no major adverse effects,
therefore, they have attracted much attention within recent years. For example licorice,
raspberry, and soybean are some of these plants and contains large amounts of certain
phytoestrogens such as biochanin A, daidzein, genistein, and formononetin. The anti-
androgenic property of this plant causes decrease in androgens levels in patients with
PCOS. A study demonstrated that raspberry fruit extract caused decrease in testosterone
through inhibiting NF-kB pathway, and improved ovarian tissue symptoms including the
number of developing follicles, granulosa layer thickness, and the number of corpus
luteum through antioxidant and anti-inflammatory properties. Jelodar et al. reported
that the consumption of V. agnus- castus fruit extract could cause increase in aromatase
activity, and decrease in testosterone through aromatizing testosterone. Isoflavones-rich
diet can be the biochemical basis of preventive effects against cancer. Other studies
indicated that genistein could inhibit 3b-HSD and 17b-HSD in the testicular microsomes
of both human and mouse. It has been reported that isoflavonoids due to having phenolic
ring preferably inhibit the activities of 3b- HSD and 17b-HSD. In addition to inhibiting
steroid-synthesizing enzymes, genistein can be involved in LH receptor’s binding to G-
protein, and affect adenylatecyclase activity if LH receptor does not bind to the G-protein
and block steroidogenesis-stimulated production of LH. Oxidative stress is considered a
pathological characteristic of PCOS, and in women with PCOS, total antioxidant status
declines. Evidence indicates that the levels of ROS in ovarian tissue increase in PCOS,
539
causing imbalance between oxidant and antioxidant systems. Soybean isoflavonoids
exert antioxidant effect because of containing aromatic ring and genistein. P. dactylifera
pollen contains antioxidant compounds such as different vitamins and minerals, e.g.
zinc and selenium, that cause regulation of the body’s antioxidant balance in people
with PCOS . Many of the studied plants including Soybean, Raspberry, A. vera, L. pumila,
C. nucifera, G. max, and G. glabra have anti-androgenic property and certain plants such
as: P dactylifera, G. max, C. sinensis, M. piperita and T. vulgaris have antioxidant
property that are effective in treating PCOS through improving the serum levels of sex
hormones and decreasing oxidative stress. In the light of the evidence, different types of
phytoestrogens and antioxidant compounds found in medicinal plants can improve
PCOS symptoms and therefore be effectively used to treat this syndrome.
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