Introduction: What is PCOS and what is Chinese medicine?
Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterised by excess androgen secretion manifested by hirsutism, ovarian dysfunction with or without polycystic ovaries. Stein and Leventhal first described it in 1935. Until the late 1950s and early 1960, there has been a controversy on the origin of increased androgen whether adrenal or ovarian; however, because of the successful treatment by ovarian wedge resection. Besides, the knowledge that ovarian oestrogen synthesis pathway includes the production of an androgen (androstenedione) lead to the belief that PCOS is an ovarian disorder.
There are two important remarks on defining PCOS, first is the disorder’s aetiology is still largely unknown. Thus, the diagnosis is one of exclusion from other causes of excess androgen like adrenal or ovarian androgen-secreting tumors and Cushing syndrome.
PCOS is also associated with insulin resistance; therefore, syndrome like type C insulin resistance syndrome need exclusion, further, disorders that may result in ovulatory dysfunction like hypercalcitonaemia and thyroid disorders need to be excluded. The second point is the disorder is a syndrome (a collection of symptoms and signs) with no single diagnostic test, but rather a heterogeneous disorder characterised by excess androgen, ovulatory dysfunction and polycystic ovaries.
Traditional Chinese medicine (TCM) is a multimodal practice it includes herbal medicine that involves using different plant parts and categorized according to the observed effect on the body. Acupuncture is the part of TCM mostly investigated and the theory is that it stimulates specific points on the body surface serving to remove blockage of vital energy flow lines. TCM also includes burning cones or stick or dried woods on or near the skin surface usually combined with acupuncture, a process known as moxibusation.
In addition, TCM includes cupping, Chinese massage and mind body therapy. In the view of traditional Chinese therapists, the human being is a part of the universe round and is subjected to its forces. In other words, the body is composed of organs and tissues with specific functions but are interconnected and interdependent on each other and to the universe around.
There are few key concepts to TCM; first is the Yi-Yang theory, which assumes there are two opposing yet complementary forces that shape the world and the life. Second is the body’s vital energy or life force is called qi, which circulates in a network of pathways (meridians). Health is a process of maintaining and balancing qi. TCM explains how the body works in the lights of the five elements (fire, water, earth, metal and wood), and depends on eight principles to analyse the symptoms and classify diseases. These principles are cold-heat, interior-exterior, excess-deficiency and Yin-Yang.
Scientific research is limited on TCM because of it complexity and the ambiguity of its concepts; however, researchers showed interest in acupuncture and herbal therapies. The FDA considered acupuncture safe as long as the needles used are sterile and the treatment applied by an experienced practitioner.
Epidemiology of PCOS
Prevalence rates of PCOS are variable in different studies because of many reasons. Zacur in a review study suggested the absence of a global agreed upon definition is one factor responsible for the variability of the prevalence rates. A second factor is estimates of the prevalence of PCOS are greatly affected by the nature of the population, which is being assessed.
Women populations selected on account of the presence of a symptom associated with the syndrome (e.g. hirsutism, acne, and menstrual cycle disturbances) would display a prevalence of PCOS greater than that existing in the general population. A third factor is the prevalence rate varies according to the diagnostic criteria used in different studies.
In general population, the prevalence rate among females in the reproductive period is 4 to 12%; however, among females with menstrual disorders, the rate rises to 37-90%. National differences in prevalence rates of PCOS exist, one study showed a rate of 26% in Britain using the UK-European definition of PCOS.
However, using the much more stringent US criteria which do not utilize ovarian morphology, the prevalence rate for PCOS ranged from 4.5–11.2% from an unselected group of white Europeans and blacks in a population-based study in Alabama. Prevalence rate of 9% reported in Greece and 6.5% in Spain. The highest reported prevalence of PCO has been 52% amongst South Asian immigrants in Britain, of whom 49.1% had menstrual irregularity.
Ethnic differences in PCOS prevalence have not been explored enough. However, Dunaif and coworkers reported an increased rate of PCOS among Caribbean Hispanic women. However, Knochenhauer et al, in a sample of 195 black women and 174 white women in the US, found that the prevalence of PCOS among black women was comparable to that of whites (3.4% versus 4.7%). There may also be ethnic variation in overt features of PCOS when the prevalence of biochemical manifestations is similar across the races.
A study carried out comparing women with PCOS from the USA, Japan and Italy reported less obesity in Japanese women, yet comparable rates of androgen excess and insulin resistance. Factors affecting expression of the syndrome are still unclear, dietary and lifestyle factors are blamed. Genetic variations in hormone actions, such as variability in gonadotrophins subunits forms or receptors function (affecting the expression of androgens, gonadotrophins or insulin) are also considered.
Balen et al. summarized the epidemiological key points of PCOS as follows:
- A number of correlations have been made of biochemical changes with clinical features of PCOS. High serum testosterone concentrations correlate with clinical hyperandrogenism and infertility. High LH concentrations are associated with infertility and menstrual cycle disturbances; and insulin resistance correlates with ovarian volume and androgen concentrations.
- The degree of insulin resistance correlates with intermenstrual interval.
- PCOS accounts for 95% of cases of hyperandrogenism, 95% of cases of acne in adult women, 90% of women with oligomenorrhea and 30–50% of women with amenorrhea.
- Polycystic ovaries are seen on ultrasound in between 22% and 33% of Caucasian women, of whom approximately three-quarters have clinical manifestations of the syndrome.
- There are significant racial differences in clinical presentation, most noticeably with respect to hirsutism.
- There are racial differences in the rate of insulin resistance, for example this has led to approximately 50% of women from South Asia who live in the UK having PCOS.
PCOS Diagnostic Criteria
The National Health Institute (NIH) Criteria (1990)
The US NIH sponsored an expert conference on polycystic ovary syndrome in April, 1990, where participant agreed that PCOS features are hyperandrogenism and or hyperandrogenaemia and chronic anovulation. They also agreed that diagnosis is one of exclusion of related disorders as hyperprolactinaemia, congenital adrenal hyperplasia and thyroid disorders. PCOS phenotypes described were:
- hirsutism, hyperandrogenaemia, and oligo-ovulation,
- hyperandrogenaemia and oligo-ovulation,
- hirsutism and oligo-ovulation.
Polycystic ovaries were considered suggestive not diagnostic. One study showed there is no significant racial difference in mean age, BMI, or other body features regarding these three phenotypes. However, the same study showed that fasting insulin levels were highest in patients with hirsutism; hyperandrogenaemia and oligo-ovulation are lowest in females with oligo-ovulation and hirsutism only.
The 2003 Rotterdam Criteria
The Rotterdam expert conference in 2003 concluded that, after exclusion of related disorders, PCOS diagnosis needs at least two of the following three criteria; first is either oligo- or anovulation. The second criteria was either clinical or biochemical proof of hyperandrogenaemia, and third was polycystic ovaries.
Participants added the following phenotypes; 1) females with polycystic ovaries showing clinical and – or biochemical evidence of excess androgen, but no signs of ovulatory dysfunction. In addition to 2) females with polycystic ovaries and ovulatory dysfunction, but have no signs of androgen excess.
The 2006 Androgen Excess Society (AES) criteria
The task force of AES reviewed the available literature and concluded there are three criteria to diagnose PCOS; first is excess androgen evidenced either clinically or biochemically. Second is ovarian dysfunction in the form of oligo or anovulation. In this respect, the task force considered the polycystic appearance of the ovary a sign of ovarian dysfunction. Third, the task force confirmed that diagnosis can only be made after exclusion of other causes oh hyperandrogenaemia or ovulatory disorders.
Finally, the task force added one phenotype of females with polycystic ovaries, hyperandrogenism, but apparently normal ovulation. The task force suggested that phenotypes do not diagnose the disorder unless associated with a morbidity much like diabetes is defined by those glucose levels much like diabetes diagnosed by blood glucose levels not accompanying complications.
Current Western medical treatment
Medical treatment of PCOS is mainly directed to lifestyle change and weight reduction, induction of ovulation and medications to reduce the effects of hyperandrogenaemia. Lifestyle change is a triad of low calorie diet, encouraging physical activity and losing weight.
As expressed by the ACOG Committee on Practice Bulletins, this can reduce many PCOS symptoms and can have positive effects on insulin resistance and impaired glucose tolerance. Weight loss can improve pregnancy rate and helps setting off a cascade of changes to get rid of some undesirable features of PCOS like acne. To date, there is no specific diet or activity plan claimed to be more effective than other in helping PCOS patients.
Medications used to reduce the effect of high androgen levels like hirsutism, acne and irregular periods include oral contraceptives, which are the first line in patients who are not looking for pregnancy. Although they can be beneficial; however, oral contraceptives long use is associated with low risk to certain cancers and may not be suitable to use in overweight patient because they tend to increase weight. There is no best oral contraceptive medication for PCOS.
Insulin sensitizing agents are medications that make the body utilize available insulin and thus help the body cells to utilize glucose. Short-term use of insulin sensitizers helps to regulate both menstruation and ovulation, reduce hirsutism and acne. In addition, better use of insulin reduces the risk to diabetes and cardiovascular disease known to be of higher rates in PCOS patients.
Antiandrogens are medications that either reduce androgen production or minimize their effect on the body. Thus, they help reducing hirsutism, baldness and acne. However, they are teratogenic i.e. cause birth defects so taken with contraceptives and are not suitable for patient who desire to get pregnant.
Clomiphene citrate is the commonest drug used to induce ovulation and treat infertility in PCOS patients. Krysiak et al. reported that patients receiving clomiphene are six times likely to get pregnant than those who do not. However, the drug is known to induce multiple ovulations so patients are likely to get pregnant in twins, triplets, etc.; which make the pregnancy of higher risk.
Metformin is another drug used to induce ovulation when clomiphene fails. Its mechanism of action is not fully explained but it is known to decrease glucose production by the liver and increases glucose utilization by the cells. It also causes decrease in both total and free testosterone and luteinizing hormone to follicle stimulating hormone ratio. In patients not responding to clomiphene, a combination of metformin and clomiphene can be administered. Although it showed success in clinical trials with lesser rates of multiple pregnancies, yet it is still a common occurrence.
If pregnancy does not occur after 6 ovulation cycles with clomiphene citrate, treatment with gonadotrophins is then advised. It is administered either in a low dose step up protocol (75 µI FSH per day) or very low dose step up protocol (37.5 µI FSH per day) monitored by the follicle diameter and serum estradiol level. When the follicle diameter reaches 18-20 mm, ovulation is induced with 10000 µI of human chorionic gonadotrophins. Pretreatment with GnRH (gonadotrophins-releasing hormone) showed no advantage. This treatment is also associated with multiple pregnancies and a higher rate of miscarriages.
Acupuncture for the treatment of PCOS
Evidence suggests that PCOS patients display hypothalamic-pituitary-adrenal axis (HPA axis) abnormalities and anovulation is a result of disturbed feedback from the ovarian hormones to hypothalamus and pituitary (HPG axis disturbances). Hypothalamus-pituitary-gonadal axis (HPG) disturbances results in gonadotrophins releasing hormone (GnRH) pulsatility disturbance with subsequent increase in LH to FSH release. One PCOS pathogenesis theory suggests the disease results from insufficient central β-endorphin inhibition of GnRH; a second theory suggests PCOS is accompanied by elevated sympathetic tone in the ovaries leading to hormonal hyper-responsiveness.
Acupuncture as a word comes from the two Latin words acus, which means needle and punctura, which means to puncture. It is a therapeutic and or a preventive medical procedure involving insertion of one or more solid metallic needles into specific predetermined points on the body surface. It aims at stimulating these points with or without further manual manipulation.
Stener-Victorin et al. explained the physiological basis of acupuncture. They suggested that needle insertion into the skin and deeper tissues produces a specific pattern of peripheral nerves’ afferent activity. Besides, low frequency electro-acupuncture stimulates muscle receptors (ergoreceptors) normally activated during muscle exercise, which are responsible for the release of endogenous opioids and oxytocin. These substances are in turn responsible for the functional changes taking place in different body organs.
Of the endogenous opioids, β-endorphin has a vital role in pain relieving effects of acupuncture; it is also released to the blood from the hypothalamus via the anterior pituitary. Corticotrophin-releasing factor produced by the hypothalamus regulates β-endorphin release, the adrenocorticotrophic hormone and the melanocyte stimulating hormone.
Several studies showed acupuncture significantly increases β-endorphin levels for periods up to 24hours. Further, low β-endorphin levels are associated with stress evidenced by high levels of sympathetic markers (corticotrophin-releasing factor and endothelin-1).
Based on this discussion, β-endorphin increased levels secondary to acupuncture affects the HPA axis through promoting the release of ACTH through stimulation of its precursor pro-opiomelanocortin synthesis. A second suggested mechanism is acupuncture reduces stress and anxiety thus, decreases the HPA axis activity with subsequent increase in reproductive functions.
β-endorphin influences gonadotrophins secretion and the menstrual cycle through their effect on GnRH. Evidence that β-endorphin suppresses GnRH release comes from studies on patients with hyperprolactinaemia, animal studies and research that displayed β-endorphin initiates LH mid-cycle heave in normal menstruating females in addition to the high level of β-endorphin in the pre-ovulatory follicle.
Through this effect, animal studies showed that acupuncture therapy normalized GnRH secretion producing an effect similar to treatment with human chorionic gonadotrophins. Thus, although HPA and HPG systems work independently, yet; acupuncture affects both systems through its effect on β-endorphin.
Stener-Victorin et al. suggested oxytocin can alter ovarian hormone endocrine factors through its effect on the nerve growth factors expressed on the ovarian endocrine cells. Stener-Victorin et al. later suggested that oxytocinergic system is activated by the mild non painful stimulation of acupuncture, in addition to its anxiolytic and stress reduction roles. They suggested acupuncture stimulation of the muscle afferents decreases aspartate and glutamate content of the spinal cord dorsal horns; however, the mechanism is topographical and depends on the somatic segments stimulated that are related to the ovary.
Stener-Victorin et al. summarized the actions of acupuncture in PCOS patients and suggested needle insertion in to the skin and muscle stimulates ergoreceptors and cause afferent activity. If acupuncture needles are placed in the same somatic segment of the ovary, they stimulate the oxytocin axis resulting in decreased release and secretion of the ovarian androgens. In parallel, the activity of higher control systems is modulated by the release of opioids, in particular β-endorphin that induces functional changes in different organ systems. In females with PCOS, they suggested an increased sympathetic nerve activity and an increased β-endorphin production or release.
Low-frequency electro-acupuncture influences the central β-endorphin, providing decreased sympathetic tone and decreased LH and release of β-endorphin into the bloodstream. Low-frequency electro-acupuncture may further decrease hypothalamic-pituitary-adrenal (HPA) axis activity by inhibiting release of corticotrophin-releasing factor (CRF), causing decreased adrenocorticotrophic hormone (ACTH) release from the pituitary gland and decreased cortisol and or dehydroepiandrostenedione (sulfate) release from the adrenal cortex and a decrease in sympathetic adrenal axis activity. The adrenal medulla will then decrease nor adrenaline and adrenaline secretion.
Stener-Victorin et al. explained how this applies to treatment strategies of PCOS; they suggested acupuncture alters PCOS symptoms through influencing the endogenous regulatory systems. These include the sympathetic nervous system, the endocrine and neuro-endocrine systems and the changes are mostly through the influence of the endogenous opioids system.
They also suggested that acupuncture influences ovulation through its regulatory effects on both LH and FSH via its effect on HPG axis without inducing ovarian hyper stimulation syndrome with multiple ovulations and multiple pregnancies.
Han suggested acupuncture can be a manual procedure or as a low frequency electro-acupuncture in 2 Hz or 100 Hz frequency. Each frequency causes the release of different peptides, thus; for a maximal therapeutic effect, Han suggested the use of the two frequencies.
Acupuncture for the treatment of PCOS: Level of evidence
Roberts and Moore reviewed 64 systematic reviews on effectiveness of acupuncture treatment in many conditions. They mapped out the evidence against recommendations of the World Health Organization (WHO), Acupuncture Association of Chartered Physiotherapists (AACP) and the British Medical Acupuncture Society (BMAS).
In their conclusion PCOS was not included among the conditions where acupuncture therapy gave enough recognized evidence. Thus, despite its safety and progress in basic research, there is still a lack of knowledge on how acupuncture works and a low degree of certainty of its results in PCOS treatment. This is probably because of the limitation of acupuncture research for PCOS treatment.
Limitation in acupuncture studies
White et al. recognized some of the limitations in acupuncture studies and suggested variable treatment schedules and inapt control intercessions may result in false negative or false positive results. Further, the great number of variables like point selection and form of stimulation, besides; the unclear form of treatment and research outcome.
In many studies there is no clear research question to challenge, this is important as it is the main factor that decides the control procedure and finally there is lack of studies that specifically answer the measured efficacy results. Randomization and blinding in clinical trials are means to reduce bias and the number of randomized controlled double blind studies for PCOS treatment is limited, if any.
Birch added other limitations to conducting and documenting analytical studies on acupuncture are because of the acupuncture Chinese philosophy. Traditional Chinese medicine looks at acupuncture as a treatment to the whole patient and does not concentrate on isolated patient symptoms.
Therefore, it is difficult to conduct research on this modality according to Western standards that is the double-blind, placebo-controlled trial. One other limitation is the small sample sizes of different studies which increases the liability to statistical errors. At the same time the meta-analysis studies are limited because of the number of variables including different research designs.
Birch identified four other important limitations; first is what the real strategy of acupuncture is? In some literature it is looked upon as an independent single strategy while in others it is an integrated part of a holistic medical strategy. Second, researchers usually do not pay enough attention to the interaction between the patient and the staff, thus; there is an overlook to non-specific effect of acupuncture practice. Third, the training requirements for acupuncture vary considerably, which makes generalization of results a difficult task. Finally, Birch disproved that Sham acupuncture (minimally invasive acupuncture procedure) is enough to consider a control for placebo effects.
Conclusion
Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterised by excess androgen secretion manifested by hirsutism, ovarian dysfunction with or without polycystic ovaries, therefore; diagnosis is by exclusion. The current conventional medical treatment approach for patients with ovulatory disorders, whether or not they are trying to become pregnant, is prescription medications and often lifestyle changes (for PCOS, weight extremes, anorexia, excessive exercise). However, there are four main problems with prescription drugs; cost, possibility of multiple pregnancies, side effects, and effectiveness.
On the other hand, acupuncture also has a very low rate of serious adverse events, does not increase the risk of getting pregnant with twins or triplets. It can be a suitable alternative for some patients who are intolerant, ineligible, or contraindicated for conventional hormonal therapy. There are many research articles that explain its effect on female hormones through actions on HPA axis and HPG axis among other mechanisms.
However, there is still a lack of evidence-based research to determine whether and how acupuncture could have a role in the treatment of patients with PCOS. Acupuncture may represent an important alternative therapy for females with ovulatory problems, particularly PCOS, yet; until prospective, randomized, placebo-controlled acupuncture trials are undertaken, most clinicians will continue to prescribe pharmaceutical options and lifestyle changes to women with ovulatory dysfunction and think of acupuncture as a possible alternative to use when needed.
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