Polycystic ovarian syndrome

Posted On April 26, 2018


PCOD or polycystic ovarian syndrome is an enigmatic entity so far. The syndrome was first described in 1935 when American gynecologists Irving F. Stein, Sr., and Michael L. Leventhal associated the presence of ovarian cysts with anovulation. For many years these factors were used as the diagnostic criteria of the syndrome. A lot of research has been in place over last 78 years but till today the exact cause of the syndrome is not clear. Broadly there is a finding of multiple cystic changes in the periphery of the ovary. This is combined with hyperandrogenism and neuroendocrine manifestations of increased LH levels. It is considered to be a lifestyle disease. It is closely related to the metabolic syndrome associated with insulin resistance at tissue levels, with subsequent hyperinsulinemia. It affects a sizeable percentage of females.
Diagnosis
In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if any 2 out of 3 criteria are met.
• Oligoovulation and/or anovulation
• Excess androgen activity
• Polycystic ovaries (by gynecologic ultrasound)
• Other entities are excluded that would cause these
In 2006 the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of:
• Excess androgen activity
• Oligoovulation/anovulation and/or polycystic ovaries
• Other entities are excluded that would cause excess androgen activity
Ultrasound crieteria: The Rotterdam consensus defined the polycystic ovary as having 12 or more follicles, measuring between 2 and 9 mm , and/or an ovarian volume >10 cm.
Excess androgen activity: Excess androgen activity may be manifested as hirsuitism, acne, or androgen-dependent alopecia. Elevated levels of testosterone(abnormal ovarian androgen production) or Dehydroepiandrosterone(Increased adrenal production of androgen) are biochemical markers of hyperandrogenism.
Etiopathology of PCOS: PCOS is a familial condition. It can have a genetic etiology, with an autosomal dominant mode of inheritance. Girls with low birth weight as well as a family history of diabetes mellitus or premature cardiovascular disease are at high risk for developing PCOS.
Many pathophysiologic hypotheses have been proposed to explain the clinical findings of PCOS.
• The neuroendocrine defect
• The insulin hypothesis
• The ovarian hypothesis, a primary defect of sex steroid synthesis or metabolism results in exaggerated ovarian androgen secretion and anovulation.
• A fourth hypothesis for a primary defect at the level of the ovary comes from the classic polycystic ovary morphology seen
histologically or by pelvic ultrasonography.
• Inflammatory markers are increased in PCOS1.

Neuro endocrine hypothesis2: Gradual increase in testosterone levels during pubertal progression may gradually impair progesterone inhibition of daytime GnRH in girls who develop PCOS .This leads to increased GnRh/LH pulses. In ovulatory cycles there is a slowing of GnRh pulse during the luteal phase in response to increased progesterone levels.. In contrast to this, in PCOS patients there is a persistently rapid GnRh pulse frequency even in the luteal phase. This is because of impaired sensitivity
of the GnRH pulse generator to suppression by progesterone. The persistently rapid GnRH pulse frequency favours LH production over FSH.
Under normal circumstances, the theca cells of the ovarian follicles produce androgens  under the control of LH. These androgens
are then aromatized into estrogens, primarily estradiol, by the adjacent granulosa cells. FSH stimulates the granulosa cell growth and aromatase capacity. In PCOS there is increased LH pulsefrequency. This induces theca cells to produce
more androgens. The relative FSH deficiency also interferes with granulosa cell aromatization to estrogens in the ovary and impairs follicle maturation and ovulation. The increased production of androgens by the theca cells further makes the GnRh pulse
regulator more insensitive to progesterone and the cycle of anovulation continues further.
The Insulin Hypothesis:  
In women with PCOS, basal insulin secretion is increased and hepatic insulin clearance is reduced, resulting in hyperinsulinemia.
There is also impaired suppression of hepatic gluconeogenesis. Inhibition of hepatic production of sex hormone binding globulin further increases circulating free testosterone levels. The insulin receptor belongs to a family of tyrosine kinase receptors, including insulinlike growth factor- 1 (IGF- 1) receptor. Elevated serum concentration of insulin could act directly via the IGF-I receptor to increase androgen production. Ovarian theca cells are directly induced to produce more testosterone. It is interesting that in contrast to adipocytes  and muscles, ovarian cells are insulin sensitive and allows insulin to activate it’s homologous receptor, resulting in androgen production. PCOS patients show decreased glucose transport in adipocytes. Further, insulin
resistance in PCOS adipocytes leads to increased circulating Free Fatty Acid levels that, in turn, produce peripheral insulin resistance. There is impaired glucose transport into the muscles, reduced by 35-40%, due to reduction in Insulin-stimulated activation of PI3-kinase. This is independent of obesity. As a result, the glucose in blood remains elevated for a longer time and further stimulates pancreatic beta cells. These cells enhance their secretion of insulin to improve glucose uptake in muscles.
Low-grade inflammation in polycystic ovary syndrome: Recent evidence indicates a condition of low-grade chronic inflammation in PCOS that could be considered one of the potential links between PCOS and long-term metabolic (type 2 diabetes) and cardiovascular complications.3 Many studies have demonstrated that in women with PCOS a positive relationship exists between CRP values and insulin resistance, body weight and fatty mass. CRP is a classic marker for low grade inflammation. Other classic markers that are elevated are IL-18 and TNFα. Adipose tissue secretes several adipocytokines that, together with adipocyte
hypoxia and subsequent necrosis, draw many inflammatory cells, such as monocytes and T cells. A vicious circle is established with a continuous release of inflammatory mediators that are responsible for the development of  insulin resistance, dyslipidemia, endothelial dysfunction, and metabolic and cardiovascular long-term complications. In addition, inflammation also has an impact on the regulation of the synthesis and secretion of androgens in the ovary and in the adrenal, contributing to the
maintenance of the syndrome.
Clinical Evaluation of PCOS
Menstrual Abnormalities
• Patients with PCOS may have oligomenorrhea (i.e., menstrual bleeding that occurs at intervals of 35 days to 6 months, with < 9 menstrual periods per year) or secondary amenorrhea (an absence of menstruation for 6 months).
PCOS may manifest itself as early as the first decade of life by premature pubarche or menarche. Oligoamenorrhea, although
very common soon after menarche, may be an early symptom of PCOS, especially in overweight girls with hirsutism or acne. It
has been suggested that in adolescents, all  3 elements of Rotterdam criteria should be fulfilled in this group for diagnosis of PCOS.
In the reproductive age, Infertile patients may have hypothyroidism or hyperprolactinaemia or diminished ovarian reserve which can cause abnormalities in menstrual pattern and should be differentiated from PCOS.
• Heavy menstrual bleeding may be present . Differentiation from other causes of abnormal menstruation has to be kept in mind while evaluating the patient
Hyperandrogenism
• Hyperandrogenism clinically manifests as excess terminal body hair in a male distribution pattern. Hair is commonly seen on the upper lip, on the chin, around the nipples, and along the linea alba of the lower abdomen.
• Some patients have acne and/or malepattern hair loss (androgenic alopecia). It should be differntiated from normal
pubertal acne in adolescents.
• In the extreme form of PCOS termed hyperthecosis, there may be, clitoromegaly, increased muscle mass, voice deepening,
etc. This should be differentiated from androgen-producing tumors, exogenous androgen administration, or virilizing
congenital adrenal hyperplasia. Hirsutism and obesity may be present even before menarche in adolescent girls with PCOS.
Infertility: Infertility may be the presenting complaint in PCOS. Other causes of anovulation have to be ruled out in these patients. PCOS women also tend to have miscariage, and may require continuation of treatment with insulin sensitisers even after conception, to prevent miscarriage.
Obesity and metabolic syndrome: Approximately 50% of women with polycystic ovarian syndrome (PCOS) have abdominal obesity,
characterized by a waist circumference greater than 35 inches (> 88 cm). It may also be part of metabolic syndrome which many patients with PCOS suffer from. Women with PCOS have an increased prevalence of coronary artery calcification and thickened carotid intima media, which may be responsible for subclinical atherosclerosis. Approximately 10% of women with PCOS have type 2 diabetes mellitus, and 30-40% of women with PCOS have impaired glucose tolerance by 40 years of age.
Sleep apnea: Many women with PCOS have obstructive sleep apnea syndrome (OSAS), which is an independent risk factor
for cardiovascular disease. Individuals with obstructive sleep apnea experience apnea/hypopnea episodes during sleep.
Acanthosis nigricans: Acanthosis nigricans is a diffuse, velvety thickening and hyperpigmentation of the skin, present at the nape
of the neck, axillae, area beneath the breasts, intertriginous areas, and exposed areas (e.g.,elbows, knuckles). In PCOS, it could be the result of insulin resistance.
Blood pressure: Patients with signs and symptoms of metabolic syndrome may have elevated blood pressure, with a systolic blood pressure of 130 mm Hg or higher and a diastolic blood pressure of 85 mm Hg or higher. Incidence of pregnancy induced hypertension is higher in women with PCOS who conceive.
Investigations
Tests to Clinch Diagnosis of PCOS
• Exclude pregnancy as cause of amenorrhoea.
• Ultrasonography: Not mandatory if diagnosis is made clinically and biochemically. polycystic ovary is diagnosed as one having
12 or more follicles, measuring between 2 and 9 mm, and/or an ovarian volume >10 cm. In adolescents, overdiagnosis is
possible on usg.this is because, ovarian  morphology changes throughout the life cycle, with relatively stable, lowvolume
ovaries in the prepubertal period, increasing to a maximum size and antral follicle count around menarche, and undergoing a progressive decrease in size and antral follicle count throughout reproductive life to a nadir following menopause. Thus ovaries will be large and probably looking polycystic also , at menarche, even though the girl is having normal cycles.
• Serum Testosterone: Mean levels in PCOS are in the range of 60–80 ng/dL and are unlikely to exceed 150 ng/dL. Circulating
bioavailable testosterone levels are usually elevated, while total testosterone may be normal due to low levels of sex hormonebinding
globulin. Oral contraceptives, normalize the levels of circulating androgens in women with PCOS.
Recommended Investigations after
Diagnosis
• Blood glucose levels: to check for glucose intolerance.
• Lipid levels: usually there is high triglycerides, lower HDL and elevated LDL.
Other Tests to Consider
• FSH and LH levels: An increased ratio of luteinizing hormone to follicle-stimulating hormone >2 is found in 60 to 70% of women
with PCOS and is more likely to occur in nonobese than in obese women.
• Prolactin levels: A pituitary cause or medication use will increase levels.
• Thyroid levels: Thyroid abnormalities to be excluded as cause for menstrual abnormalities.
• Oestradiol and FSH levels: High FSH means premature ovarian failure.
• 17- hydroxyl progesterone: To rule out late onset adrenal hyperplasia.
• DHEAS: A marker for adrenal androgen production. Elevated in adrenal tumours.
• Androstenedione: Elevated in ovarian androgen secreting tumours 24 hour urine
cortisol: In case of cushingoid features.
Tests for Metabolic syndrome: Metabolic syndrome is characterized by

abdominal obesity (waist circumference >35 in),
dyslipidemia (triglyceride level >150 mg/dL,
high-density lipoprotein cholesterol [HDL-C]
level < 50 mg/dL), elevated blood pressure,
a proinflammatory state characterized by
an elevated C-reactive protein level, and a
prothrombotic state characterized by elevated  plasminogen activator inhibitor-1 (PAI-1) and fibrinogen levels.

Insulin levels need not be tested to determine hyperinsulinemia.

Management of PCOS
Lifestyle modifications: In obese women with PCOS, even if medications are given, life style modifications by way of exercise and a diet plan is essential to minimise lipid irregularities and decreasing insulin resistance and the levels of testosterone, insulin, and luteinizing hormone in the body.
Insulin sensitizers: When administered to  insulin-resistant patients, these drugs act to increase target tissue responsiveness to
insulin and thereby reduce the stimulus for compensatory hyperinsulinemia.

Metformin: Metformin is a second-generation biguanide. The drug activates glucose transporters to facilitate passage of glucose into
hepatic and muscle cells, thereby decreasing peripheral insulin resistance and lowering serum glucose levels4. In general, clinical
studies have shown that metformin treatment (500 mg three times per day or 850 mg twice daily with meals) increases the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response to clomiphene citrate (CC) in women with PCOS.
Metformin does not stimulate insulin release and, when administered alone, does not cause hypoglycemia. Side effects of
metformin include gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhoea) that are dose-dependent and generally tend to
resolve after several weeks of treatment; a gradual increase in dose also helps to improve tolerance. Lactic acidosis is a rare but serious potential adverse effect of metformin therapy. Therefore, metformin should not be prescribed to patients with renal, hepatic, or major cardiovascular disease or hypoxia because such patients are predisposed to elevated lactate levels. Precautionary temporal withdrawal of metformin is advised for patients scheduled for surgery or for radiologic procedures involving the use of intravascular iodinated contrast.
Other Drugs used in the Management of PCOS
Raloxifene
Raloxifene is a SERM approved for the treatment of osteoporosis in postmenopausal women , with antiestrogenic effects at the level
of the hypothalamus and/or pituitary similar to CC. Raloxifene may have a favorable impact on markers of endometrial receptivity compared with CC, and it has been shown to increase FSH levels in premenopausal women. Ernesto de Paula Guedes Neto et al5 have, in a study, proved that 100 mg of Raloxifene for five days is as efficacious as clomiphene in inducing ovulation, with a more favourable effect on the endometrium.

Pioglitazone
Hyperinsulinemia caused by insulin resistance in PCOD causes hyperandrogenemia. Metformin is traditionally used to improve this
resistance and lower the blood glucose levels. However, many patients cannot tolerate the side effects of Metformin and some are resistnant to it. Pioglitazone is another insulin sensitizing agent which can be used to improve ovulation in PCOS. Its action is different from Metformin. It acts after insulin binding by insulin receptors to improve the action of insulin, reduces its resistance to hormones, and inhibits glucose production in the liver3. pioglitazone may be effective in cases of dexamethasone- or
metformin-resistant PCOS in the dose of 30 mg per day.

Atrovastatin and Simvastatin7,8
The cholesterol lowering Statins, Atorvastatin in the dose of 20 mg or Simvastatin 20 mg per day has been found to be effective in reducing inflammation, biochemical hyperandrogenemia, and metabolic parameters in patients with PCOS after a 12-week period. Homocysteine levels have also been found to be lower with the use of Statins in PCOS patients.

Insositol
The inositol phosphoglycans (IPGs) are putative mediators in a nonclassic insulin signaling cascade for glucose uptake and use. Insulinresistant women with PCOS display decreased insulin stimulated release of d-chiro-inositol (DCI)-containing IPGs (DCI-IPGs) during an oral glucose tolerance test (OGTT), which was related to impaired coupling between insulin action and the release of the DCIIPG. Oral nutritional supplementation with inositol, part of the vitamin B complex (B8) and an intracellular second messenger, was  demonstrated to enhance insulin sensitivity  and improve the clinical and hormonal characteristics of patients with PCOS.9 Treatment of PCOS patients with myoinositol in one study provided a decreasing of circulating insulin and serum total testosterone as well as an improvement in metabolic factors10. 2g myoinositol twice daily can improve oligomenorrhea, and ovulation in PCOS patients. Continued treatment may also result in significant weight loss (and leptin reduction) and an associated change in HDL cholesterol11.

Multivitamins
Jorge et al,12 in a prospective study concluded that consuming multivitamin supplements at least three times per week was associated with a reduced risk of ovulatory infertility. This association appeared to be mediated in part by folic acid.
Vitamin D3  Selimoglu et al have, using a single dose of 300,000 units of 25-hydroxyvitamin vitamin D3 orally, in PCOS women in a study, concluded that PCOS women are mostly deficient in vitamin D3 and supplementing them with vitamin D3, can have a beneficial effect in improving insulin resistance in obese women with PCOS13 .

N-Acetyle Cysteine
N- acetyle cysteine as an adjunct to clomiphene citrate or Metformin could improve insulin sensitivity in PCOS subjects14,15,16. 1.8 gm/day in normal weight women (600 mg three times a day) and 3 gm/day in extremely obese women for 5 to 6 weeks are the dosages recommended.

Arginine
Nitric oxide (NO) has a positive role in oocyte maturation and ovulation. L-Arginine is a positive NO enhancer. In one study,
Eight patients with PCOS displaying oligoamenorrhea from at least 1 year underwent a combined treatment with N-acetylcysteine
(NAC) (1200 mg/day) plus L-arginine (ARG) (1600 mg/day) for 6 months. It concluded that prolonged treatment with NAC+ARG might restore gonadal function in PCOS.17 This effect seemed associated to an improvement in insulin sensitivity.

Alpha Lipoic Acid
Controlled-release alpha lipoic acid (CRLA) 600 mg twice daily for 16 weeks in one study was found to improve insulin sensitivity18.
Triglyceride values also decreased.

Ovulation Induction in Infertile Patients When lifestyle modification and/or use of insulin-sensitizing agents fail to restore ovulation in women with PCOS desiring pregnancy, ovulation induction is necessary.

Clomiphene citrate is superior to metformin alone for inducing ovulation.
Laparoscopic Ovarian Drilling: Laparoscopic ovarian drilling is used to create multiple perforations (approximately ten holes
per ovary) in the ovarian surface and stroma.19 It is thought to destroy ovarian androgenproducing tissue and reduce the peripheral
conversion of androgens to oestrogens . A fall in the serum levels of androgens and luteinising hormone (LH) and an increase in folliclestimulating hormone (FSH) levels have been demonstrated after ovarian drilling.

PCOS in the Adolescent
If hyperandrogenism is the presenting complaint, OC pills containing cyproterone acetate for 6 months are found to be effective
in decreasing signs of hyperandrogenemia Testing in adolescents presenting with PCOSlike symptoms is given in Table 1. In patients  with associated obesity diet and exercise are mandatory. Metabolic syndrome is also becoming increasingly common adolescents.

The reduction of bodyweight in this young age group may require the collaboration of the pediatrician, dietitian, and sychotherapist.
Adolescents with isolated cycle irregularity may be placed on a cyclical progestin regimen to induce withdrawal bleeding. Metformin, by decreasing insulin resistance, alleviates many of the hormonal disturbances and restores menses in a considerable proportion of patients. It may be used alone or in combination with oral contraceptives. In patients who cannot tolerate Metformin, alternative therapy like myo-inositol can be considered. Independently of medical treatment, restoration and maintenance of bodyweight within normal range is of paramount importance.
Conclusion
PCOD is an enigmatic disease. Life-style modifications form an important aspect of treatment. Symptomatic treatment for
presenting complaints like infertility, hirsuitism, and irregular menstruation will be necessary. Metformin is useful in lowering insulin levels, but all patients may not tolerate it. Adjuvant treatment with many agents have been found useful, but the number of studies with these agents are not very large.

 


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