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Tuesday, 31 March 2015

The Holistic prevention, management and treatment of Polycystic Ovarian Syndrome: Diseases Associated to PCOs(Revised edition with Citations)



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                           Polycystic Ovarian Syndrome


Polycystic Ovarian Syndrome is defined as endocrinologic diseases among reproductive-age women caused by undeveloped follicles clumping on the ovaries that interferes with the function of the normal ovaries associated with a high risk for metabolic disorder(1) as resulting of enlarged ovaries(2), leading to hormone imbalance(excessive androgen and anti-müllerian hormone (AMH) )(1)(3)(4)(5), induced Hirsutism(6)(7), reproductive disorder(10(12)), risks of type 2 diabetes(9)(10)(11), metabolic syndrome(10)(12) and early cardiovasular disease(8)(13), acne(10)(14), endometrial cance(18)(19),weight gain and obesity(15)(16)(17). The syndrome effects over 5% of women population or 1 in 20 women.
Unfortunately, according to studies, women with PCOs after the reproductive age, are associated to  continuously increase risk of type II diabetes, with no increasing altered glucose tolerance(20), CVD and hypertension(21).


                         Diseases associated to PCOs


1. Hyperprolactinemia
Hyperprolactinemia and polycystic ovary syndrome (PCOS) are on the list of the most frequent causes of female infertility(109).
Prolactin, produced by the anterior pituitary gland primarily plays important breast development during pregnancy and milk production after birth. Hyperprolactinaemia in women with polycystic ovary syndrome (PCOS) effects the normal function of the hypothalamus and pituitary gland(110), leading to ovulatory infertility(111), decreasing in menstruation and sometimes lost of menstruation(112) and sexual desire(114). In men, hyperprolactinemia has shown a reduction in seminal volume and total sperm count accompanied with a decrease in libido and lost spontaneous erections. and sexual desire(113). But according to Medical University of Lodz, and Medical Centre of Postgraduate Education, " Hyperprolactinemia does not seem to be more frequent in PCOS women than in healthy subjects and it should not be considered as characteristic feature of PCOS - both are distinct clinical entities...."(108).
Chinese medical herbs-Huiru Yizeng Yihao(NO.1 HRYZ), has shown effectively for treatment of sex hormone disorder of hyperprolactinemia and HMG mice models(149).

2. Vagina bleeding
Women with polycystic ovary syndrome (PCOS) associated to dysfunctional uterine bleeding (DUB) are more common in their extremes of reproductive life(115)(116). According to study, Oral contraceptive pill has a significantly therapeutic effect for treatment in DUB and metrorrhagic forms of PCOS(117)(118). Chinese formulated herbs product (Kuntai) has shown effectively in alleviating menopausal symptoms of irregular bleeding(150).

3. Ovarian cysts
Women with PCOs Have shown to susceptible to dysfunctional follicular development, with small follicles and cysts(119) of which may interfere with normal conception(120)(121)(122), probably due to angiogenic factors and factors of communication of the interactions between luteal vascular and nonvascular tissues(123). Oral contraceptive users have found to have a lower incidence of ovarian cysts(124)(125)(126). Chinese herbs, Penyan Kang (formula for treating pelvic inflammation) showed effectively in treating of ovarian cyst with no abnormality and adverse effect(127)(128).
Warming acupuncture plus moxibustion combined with oral administration of Quyu Decoction in Chinese traditional medicine therapy significantly increased the cured rate for ovarian cysts, according to Shandong Provincial Institute of TCM,(151).

4. Uterine cancer
According to a joint study, PCOS might increase the risk of uterine cancer in a PCOS cohort consisted of 3,566 patients, and the comparison cohort consisted of 14,264 matched control patients without PCOS(129). But according to David Geffen School of Medicine at UCLA, there are insufficient data to evaluate any association between PCOS and vaginal, vulvar and cervical cancer or uterine leiomyosarcoma(130). Therefore, a large-scale, well-designed studies are necessary to confirm the association between PCOS and gynecological cancer risk(129). Herbal Scutellaria barbata D. Don (SB) has been found effectively in anti-tumor proliferation against human uterine leiomyoma(152).

5. Fatty liver diseases(NAFLD)
Women with PCOs, especially to those women are BMI > 25 kg/m², glucose level > 80 mg/dL, E2/T < 80 and ALT > 19 IU/L (134) have shown to associated to nonalcoholic fatty liver disease(131)(132)(133) as a result of abnormal lipid handling by the liver, due to higher triglyceride and cholesterol and lower HDL level(133). Lifestyle interventions and weight loss, accompanied pharmacologic interventions have shown effectively for treatment of NAFL(129). Total alkaloids in herbal Rubus aleaefolius Poir (TARAP)(153), Celastrus orbiculatus Thunb. (COT(154), hawthorn fruit(155) showed effectively in ameliorating high-fat diet-induced NAFLD through antioxidant activities.
 
6. Hypertension
The prevalence of hypertension was 19.2% in the women with PCOS, which was much higher than healthy women, in a study of Han Chinese population(136). Young women with PCOS and higher BMI may  be at an increased risk of hypertension, according to the from survey 4 in 2006 (n = 8,612, age of 28-33 years(135) but this result has been challenged by the study at Serviço de Endocrinologia do Hospital das Clínicas da Universidade de São Paulo(137). Certain medical herbs and spices, such as Molle (Schinus molle), Maca (Lepidium meyenii Walp), Caigua (Cyclanthera pedata) and ginger (Zingiber officinale) were found to have highest anti-hypertension through their phenolic profiles, antioxidant activities(156).

7. Insulin resistance(IR)
Epidemiologically(138)(139)(140)(141), strong evidences linking insulin resistance in women with PCOs
may be resulted of pathogenesis involved several associated hormonal pathways(139), including autoimmune thyroid disease(142)(143) or phenotypes(141). Life style interferences, including  modest reduction in dietary carbohydrate may be beneficial  on body composition, fat distribution, and glucose metabolism, according to University of Alabama at Birmingham(144). Traditional Chinese herbal formula containing Puerariae radix, Lycium barbarum, Crataegus pinnatifida, and Polygonati rhizoma (PLCP), alleviated IR in comparison to metformin, through its actions of phytochemicals puerarin, 3'-methoxypuerarin, daidzin, daidzein, and ononin(157).

8. Cushing's syndrome 
PCO and PCOS are common in women with Cushing's syndrome(146). The mimic symptoms such as obesity and insulin resistance, menstrual abnormalities and hyperandrogenism in women with polycystic ovary syndrome (PCOS) and Cushing's syndrome (CS) have caused confusing in diagnosis(147). According to Charles Drew University of Medicine and Science, testosterone levels of <1.39 nmol/L may be useful to discriminate between mild CS and PCOS(148) and hirsutism and menstrual abnormalities were found more common in initial PCOS diagnosis than in CS(145).
(146).

9. Obesity
In US, 80% of women with PCOs are found be either over weight of obese, according to statistic(158). Obesity also exhibited complication of some features of PCOS including hyperandrogenism, hirsutism, infertility and pregnancy (159) and exacerbated many aspects of the phenotype, especially cardiovascular risk factors such as glucose intolerance and dyslipidemia(159). According to Karolinska Institutet, lifestyle interventions to induce weight loss and adjuvant pharmacologic treatments may be the most successful strategy to improve symptoms of PCOS(160). Pi transportation, dampness resolving and phlegm expelling herbs (PTDRPEH) in traditional Chinese effectively reduce body weight and TNF-alpha in the adipose tissue, inhibit fat diet-induced obesity and insulin resistance (IR), through attenuating leptin resistance, and elevating serum levels of leptin and adiponectin(161).

10. Amenorrhea
Polycystic ovary syndrome was found to be the most common cause of secondary amenorrhea in Korean women(163) and women in US.(164) with secondary of severe hyperthyroidism. Herbal extracts including Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia in TCM has shown more efective in treating polycystic ovary syndrome (PCOS) associated oligo/amenorrhoea and hyperandrogenism than pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate (and Cimicifuga racemosa)(162).

11. Miscarriages
Epidemiologically, linking miscarriage and recurrent miscarriage to PCOs are inclusive(165)(166)(167), but some researchers still insisted that raising levels luteinising hormone (LH), one of the complications in women with PCOs may be associated with increased rates of miscarriage(168)(169)(170). According to Net doctor, Women with raised LH have a 4 fold increased risk of  miscarriage(170).
 
12. Metabolic syndrome
Metabolic syndrome, a collection of symptoms that can lead to diabetes(174)(175) and heart disease(175)(176)(177) has found to be associated to women with PCOs, probably due to genetic mutation of certain genes(171)(172), increased accumulation of adipose tissue and insulin resistance(173). Herbal Coccinia indica and American ginseng, Gymnema sylvestre, Aloe vera, vanadium, Momordica charantia, and nopal and supplement Chromium may be the alternative options for glucose control in patients with diabetes(178), and TCM  herbs and herbal formula Ligusticum chuanxiong Hort., Dalbergia odorifera T. Chen and Corydalis yanhusuo WT Wang may also be effective for the treatment of CVD(179).

13. Infertility
Infertility is condition of inability of a couple to conceive after 12 months of unprotected sexual intercourse or can not carry the pregnancy to full term. It effects over 7 millions couple alone in the U. S. and many times more in the world, because of unawareness of treatments, only 10% seeks help from professional specialist(181). In fact, approximately 21% - 30% of infertility of a couple is caused by male inability to fertilize(182) with men aged 40 years and older. (According to statistics from US Centers for Disease Control and Prevention
* Number of women ages 15-44 with impaired fecundity (impaired ability to get pregnant or carry a baby to term): 6.7 million
* Percent of women ages 15-44 with impaired fecundity: 10.9%
* Number of married women ages 15-44 that are infertile (unable to get pregnant after at least 12 consecutive months of unprotected sex with husband): 1.5 million
* Percent of married women ages 15-44 that are infertile: 6.0%
* Number of women ages 15-44 who have ever used infertility services: 7.4 million)(180).
The infertility rate of women with polycystic ovaries is very high, due to lack of ovulation and others unknown etiology. Medication used for treatment of PCOs infertility include clomiphene citrate(183)(184)(189), metformin(183)(186), letrozole(184)(85)(186)(189), tamoxifen(185)(189), anastrozole(187)(188)....... Traditional Chinese medicine (TCM) recipes formulated by Shen-replenishing herbs or acupuncture to reinforce Gan-Shen, regulate Chong-Ren Channels are found effectively in treating infertile and sub fertile PCOs women(191) when they are used alone or in conjunction with Western medicine(190).

14. Irregular menstruation
Menstrual irregularity and/or elevated androgen levels are found to be associated to women with PCOs(192)(193) due to hormone imbalance. According to a self questionnaire survey, irregular menstrual not only already presents in adolescence in women with PCOS and but also induced infertility in later life(194). Medication used for treatment of PCOs irregular menses include oral contraceptive pill(195) and metformin(195)(196). Herbal extracts such as Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia, may be used for treatment in regulation of ovulation, improved metabolic hormone profile(196).

15. Diabetes 
The prevalence of insulin resistance in women with polycystic ovary syndrome (PCOS), is found to be associated to the critical risk for Type 2 diabetes(198)(199)(200). Insulin-sensitizing medication, such as pioglitazone(202), metformin and thiazolidinediones(203). may be a promising and unique therapeutic option for chronic treatment of PCOS(201). Traditional Chinese acupuncture(204) and herbal formula danzhi xiaoyao pill have shown effectively in reduced PCOs complicated insulin resistance(IR)(205)

16. Acromegaly
Acromegaly is defined as over production of growth hormones caused by a benign(some may behave more aggressive(209) tumor of the pituitary gland(208) and in rare case, it may be caused by tumors of the pancreas, lungs, and adrenal glands, leading to excess GnRH(210), resulting in male pattern hair growth(207). According to University of Athens, polycystic ovary syndrome (PCOS) and PCOS phenotype (PCOSP) are relatively common in women with acromegaly and may account for some of the symptoms related to gonadal dysfunction due to hormone IGF-1 or in combination with  growth hormone GH and/or insulin resistance(206).

17. Etc.

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References
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(177) Cardiometabolic aspects of the polycystic ovary syndrome by Randeva HS1, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H.(PubMed)
(178) Systematic review of herbs and dietary supplements for glycemic control in diabetes by Yeh GY1, Eisenberg DM, Kaptchuk TJ, Phillips RS.(PubMed)
(179) A systems biology approach to understanding the mechanisms of action of chinese herbs for treatment of cardiovascular disease by Li B1, Xu X, Wang X, Yu H, Li X, Tao W, Wang Y, Yang L.(PubMed)
(180) Infertility(CDC)
(181)  Why Do So Few Couples Seek Infertility Treatment? By Jacky Boivin, PhD. Fall 2007
(182) Fertility and the Aging Male by Isiah D Harris, MD,1 Carolyn Fronczak,2 Lauren Roth, MD,1 and Randall B Meacham, MD(PubMed)
(183) Status of clomiphene citrate and metformin for infertility in PCOS by Misso ML1, Teede HJ, Hart R, Wong J, Rombauts L, Melder AM, Norman RJ, Costello MF.(PubMed)
(184) Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial by Badawy A1, Abdel Aal I, Abulatta M.(PubMed)
(185) Comparison of letrozole versus tamoxifen effects in clomiphen citrate resistant women with polycystic ovarian syndrome by El-Gharib MN1, Mahfouz AE1, Farahat MA1(PubMed)
(186) Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial by Badawy A1, Abdel Aal I, Abulatta M.(PubMed)
(187) Anastrozole or letrozole for ovulation induction in clomiphene-resistant women with polycystic ovarian syndrome: a prospective randomized trial by Badawy A1, Mosbah A, Shady M.(PubMed)
(188) Aromatase inhibitors for ovulation and pregnancy in polycystic ovary syndrome by Eckmann KR1, Kockler DR.(PubMed)
(189) Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation by Seyedoshohadaei F1, Zandvakily F1, Shahgeibi S1.(PubMed)
(190) Progress of integrative Chinese and Western medicine in treating polycystic ovarian syndrome caused infertility by Song JJ1, Yan ME, Wu XK, Hou LH.(PubMed)
(191) Chinese herbal medicine for subfertile women with polycystic ovarian syndrome by Zhang J1, Li T, Zhou L, Tang L, Xu L, Wu T, Lim DC.(PubMed)
(192) Comprehensive clinical management of polycystic ovary syndrome by Setji TL1, Brown AJ.(PubMed)
(193) Polycystic ovary syndrome by Kahn JA1, Gordon CM.(PubMed)
(194) Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study by West S1, Lashen H2, Bloigu A3, Franks S4, Puukka K5, Ruokonen A5, Järvelin MR6, Tapanainen JS7, Morin-Papunen L8.(PubMed)
(195) Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome by Al-Zubeidi H, Klein KO.(PubMed)
(196) The effects of treatment with drospirenone/ethinyl oestradiol alone or in combination with metformin on elastic properties of aorta in women with polycystic ovary syndrome by Kaya MG1, Calapkorur B, Karaca Z, Yildirim S, Celik A, Akpek M, Unluhizarci K, Kelestimur F.(PubMed)
(197) Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings by Arentz S, Abbott JA, Smith CA, Bensoussan A.(PubMed)
(198) Polycystic ovary syndrome and insulin: our understanding in the past, present and future by Mayer SB1, Evans WS, Nestler JE.(PubMed)
(199) PCOS in adolescence and type 2 diabetes by Carreau AM1, Baillargeon JP.(PubMed)
(200) New paradigms in PCOS: impaired glucose tolerance and cardiovascular risk. Clinical approach. Ravn P1.(PubMed)
(201) Prevention of diabetes and cardiovascular disease in women with PCOS: treatment with insulin sensitizers by Sharma ST1, Nestler JE.(PubMed)
(202) Effects of the insulin sensitizer pioglitazone on menstrual irregularity, insulin resistance and hyperandrogenism in young women with polycystic ovary syndrome. by Stabile G1, Borrielli I2, Artenisio AC1, Bruno LM1, Benvenga S1, Giunta L1, La Marca A3, Volpe A3, Pizzo A4.(PubMed)
(203) Insulin sensitizers in polycystic ovary syndrome by Pasquali R1, Gambineri A.(PubMed)
(204) [A meta-analysis on acupuncture treatment of polycystic ovary syndrome]. [Article in Chinese] by Ren LN, Guo LH, Ma WZ, Zhang R.(PubMed)
(205) [Effect of danzhi xiaoyao pill on ovulation induction of polycystic ovarian syndrome patients of pathogenic fire derived from stagnation of gan-qi]. [Article in Chinese] by Liu Y1, Mao LH.(PubMed)
(206) Polycystic ovaries and the polycystic ovary syndrome phenotype in women with active acromegaly by Kaltsas GA1, Androulakis II, Tziveriotis K, Papadogias D, Tsikini A, Makras P, Dimitriou K, Stathopoulou A, Piaditis G.(PubMed)
(207() Acromegaly presenting as hirsuitism: Uncommon sinister aetiology of a common clinical sign by Jain R1, Dutta D, Shivaprasad K, Maisnam I, Ghosh S, Mukhopadhyay S, Chowdhury S.(PubMed)
(208) Acromegaly(UCLA health)
(209) Aggressive tumors and difficult choices in acromegaly by Carrasco CA1, Gadelha M, Manavela M, Bruno OD.(PubMed)
(210) Acromegaly(NIH)
(211) Effects of an oral contraceptive containing estradiol valerate and dienogest on circulating androgen levels and acne in young patients with PCOS: an observational preliminary study by Di Carlo C1, Gargano V, Sparice S, Tommaselli GA, Bifulco G, Nappi C.(PubMed)