Polycystic Ovarian Syndrome (PCOS) is a complex hormonal disturbance that affects the entire body and has numerous implications for general health. Polycystic ovary syndrome is one of the most common reproductive problems of women & a major cause of infertility. The incidence is about 40 – 60 % in our practice at a baseline scan. In PCOS, classic ovarian morphology includes a thickened cortex, multiple subcapsular follicular cysts, hyperplasia and luteinization of the theca interna,
stromal hyperplasia, and multiple immature follicles suggestive of arrested folliculogenesis (Hughesdon, 1982). Ovary size ranges from normal to substantially enlarged. It results in irregular ovulation or anovulation thus resulting in infertility. It may be associated with obesity, signs & symptoms of androgen excess – hirsutism & acne, or amenorrhea. Later on in life these women have a higher chance of developing diabetes Mellitus, cardiovascular disease, hypertension, hyperlipedemia, endometrial & breast carcinoma.


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The Pathogenesis of PCOS

Exact cause for this disorder is unknown, but appears to have a major genetic component. Many candidate genes have been proposed and it is likely that a number of genes are involved in the
development of this heterogeneous syndrome. The main cause for clinical symptoms & biochemical changes seen in polycystic ovary syndrome is a result of interaction between the genetic component & environmental factors like weight. In this regard, a number of different hypotheses have been proposed for the pathogenesis of PCOS.

These include

  1. Hypothalamic-pituitary abnormalities which result in gonadotropin-releasing hormone
    (GnRH) and luteinizing hormone dysfunction.
  2. A primary enzymatic defect in ovarian or combined ovarian-adrenal steroidogenesis.
  3. A metabolic disorder characterized by insulin resistance with compensatory
    hyperinsulinemia that exerts adverse effects on the hypothalamus, pituitary, ovaries, and,
    possibly, adrenal glands.

There are three different ways to make the diagnosis of PCOS:

  • Symptoms and physical findings - menstrual cycle abnormalities; increased sexual hair growth, acne and obesity
  • Hormonal testing and
  • Ultrasound - It is basically an ultrasound diagnosis & may or may not be associated with clinical signs & biochemical changes. An ultrasound scan shows an enlarged ovary with increased stroma & number of small follicles < 10 mm in size distributed in the periphery
    Probably most individuals will have abnormalities in all three, some only in two, and possibly only in one.

As polycystic ovary syndrome arises from combination of familial & environmental factors that interact to cause characteristic menstrual & metabolic disturbances. Alteration of the environmental component is fundamental to the management & drugs should be used after adequate counseling & action relating to life style alterations. Weight loss, altered diet, exercise & improving psychological attitude is very important for both successful management & long-term health. If polycystic ovaries are discovered incidentally on scan & menstrual cycles are regular with spontaneous ovulation , no treatment is necessary.

PCOD is associated with excess androgens – male hormone and may have insulin resistance with high fasting insulin levels, which may require treatment.

Laboratory Testing

It is probably best performed in the morning, on day 2 or 3 of a spontaneous or induced menstrual cycle. The days around ovulation or mid-cycle should be avoided. Hormonal evaluation in patients on oral contraceptive will often give misleading results with suppression of gonadotropin, ovarian steroid and SHBG levels and therefore should be deferred in these patients.
Hormone Assays

The PCOS patient is evaluated for the following hormones.

  1. Several determinations of total and free testosterone or a free androgen index
  2. Serum LH and FSH. (An increased LH/FSH ratio > 2 is found in 60-70 percent of women
    with PCOS, and is more likely to occur in non-obese women)
  3. Measurement of serum sex hormone-binding globulin
  4. Measurement of serum prolactin, dehydroepiandrosterone sulfate, 17 alpha-hydroxyprogesterone and androstenedione levels
  5. Lipid profile, including serum HDL and LDL cholesterol, and triglycerides
  6. Plasma fasting insulin
  7. TSH

Characteristic biochemical abnormalities of PCOS include elevated serum androgen levels, decreased SHBG levels, disordered gonadotropin release with increased LH relative to FSH secretion, and acyclic (tonic) estrogen levels in the midfollicular range of the normal menstrual cycle associated with chronic anovulation. Hyperinsulinemia secondary to insulin resistance appears to be a unique feature of PCOS and not of hyperandrogenic states in general (Dunaif et al, 1987). Biochemical abnormalities may wax and wane, and attempts to categorize this disorder by biochemical profiles are problematic. At times PCOS can be associated with elevated prolatin levels. Both obesity and physical inactivity are major factors which synergize with the inherent post-receptor defect leading to Insulin Resistance in PCOS. Obesity increases the likelihood of an individual being insulin resistant. Although not all obese people are insulin resistant, obesity is associated with insulin resistance in the majority of women, and most non-obese oligomenorrheic women with PCOS are insulin resistant

Other useful laboratory determinations

Glucose and Glucose Tolerance Testing (GTT) may be considered in PCOS patients, especially those with BMI greater than 25 kg/m2 , and those having first degree relatives with diabetes or have elevated serum lipid levels, or those having delivered over a nine-pound infant. The American Diabetic Association (ADA) has designated individuals with fasting glucose levels over 126 mg/dl, as diabetic. The ADA recommends a two-hour screening after a 75 gram glucose load, as definitive testing. Studies indicated that on the initial with a 2-hour GTT, 30-40 percent of PCOS already have IGT or T2DM

A Hemoglobin A1c blood test is a unique marker of how well diabetes is controlled. There is usually no reason to measure this in a PCOS patient unless diabetes or glucose intolerance is confirmed.

A Lipid panel is a useful test for the general evaluation of health risks in all patients, but is of special importance in PCOS. These individuals have a distinct tendency toward abnormalities. When abnormalities are found, treatment can be prescribed which may alter significantly the risk of heart attach and stroke. The panel includes tests that measure the concentration of cholesterol, triglyceride and relative concentration in lipoproteins.

All PCOS patients need not be obese. Both obese and non obese patients have hormonal imbalance, only difference is that mechanism for development of hormonal imbalance is different in the two groups.

Obesity may be both a manifestation of the hyperandrogenic state and a contributor to it. Increased adiposity has been associated with decreased hepatic SHBG synthesis and increased androgen bioavailability. In addition, adipose cell aromatase converts androgens to estrogens, and chronically high levels of estrogen promote adipocyte replication in vitro. This supports the clinical observations of increased menstrual irregularities and of hirsutism in obese women that may be corrected with weight reduction. However, not every obese woman has hyperandrogenism or ovulatory disturbances. Weight reduction is an effective therapeutic modality for PCOS, but it is not possible to predict which obese women will experience improved menstrual function with weight reduction.


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Treatment

There are several treatments for each of the manifestations of PCOS; the choice among the available treatments for hirsutism, menstrual irregularity, infertility and insulin resistance/obesity depends upon the woman's goals. Most if not all of the manifestations or PCOS can be reversed by weight loss in those women who are obese. The issue of fertility should always be discussed with the woman first, because whether she wants to become pregnant is a major determinant of the choice of therapy.

Hirsutism: hirsutism can be treated by removal of hair by shaving, depilatories or electrolysis. Hair growth may be slowed by administration of oral contraceptives and antiandrogens (e.g., spironolactone, cyproterone acetate, flutamide, and finasteride) which decrease androgen secretion and action. The latter treatments may also reduce acne. Antiandrogens act primarily by interfering with target tissue binding of androgens to their intracellular receptor. They may be used alone or in combination with oral contraceptive pills for masculinizing signs that are not responsive to a single agent. Antiandrogens can improve insulin sensitivity slightly in women with PCOS. This group of medications can be used only when not attempting a pregnancy or without some form of adequate birth control.

Menstrual irregularity: Menstrual irregularity is best treated by an oral contraceptive or oral progesterone in the second half of cycle. Oral contraceptive also inhibits ovarian androgen. An oral contraceptive, therefore, is the best overall treatment for women with the PCOS who do not wish to become pregnant. Progesterone may be used to regulate the menstrual cycle and blood levels of LH may be reduced by progestins, they appear to be of little use in reduction of hair growth, or possibly metabolic derangements

Infertility: It is critical to complete a basic evaluation of the couple before initiating therapy in an infertile woman with PCOS. Initial evaluation should include a semen analysis of the male. Drugs used for ovulation induction should result in unifollicular ovulation, minimizing the risk of ovarian hyperstimulation syndrome & multiple pregnancies. The drugs used are clomiphene citrate, letrazole, or gonadotropins, pulsatile administration of gonadotropin-releasing hormone (GnRH). Approximately 80 percent of women with the PCOS ovulate in response to clomiphene citrate. These regimens are complex and expensive and are best carried out by experienced physicians.

Obesity and insulin resistance: Any treatment that reduces insulin resistance and therefore diminishes insulin secretion in both obese and lean women with the PCOS can have a variety of beneficial effects. Although the mechanism is unclear, many obese women with PCOS resume more regular menstrual cycles after relatively small amounts of weight loss. Almost always, individuals with PCOS gain weight very easily and lose it only with great effort.

Individuals vary in the way their body utilizes calories. Some use calories less effectively, or store fat more easily. A key to the way the body uses energy is insulin. Insulin is a hormone released by the pancreas in response to the breakdown of food into sugars, proteins and fats by the digestive system. Insulin promotes the storage of fat to ensure a constant source of fuel, calories, ensuring the body's most efficient operation. PCOS increasingly has been linked to abnormalities of insulin and glucose metabolism. In the past, this may have been an adaptive advantage allowing survival against cold, or famine. Now, in part a response to today's sedentary lifestyle, obesity has become a genetically related disease which may be treated, but only with great personal conviction and effort. Certainly, weight loss can only be achieved when caloric expenditure exceeds caloric intake, but genetic, metabolic and environmental alterations make this a much more complex equation. With weight loss there is often an improvement in endocrine parameters and sometimes return of menses.

Metformin and troglitazone (Rezulin) are medications used in the treatment of Type 2 diabetes. Metformin is useful only if there is excessive obesity & fasting insulin levels are high with an abnormal glucose tolerance.Both increase insulin sensitivity and, in women with PCOS, may also reduce ovarian androgen production and restore normal menstrual cycles. Studies of metformin in PCOS have been conflicting. Two studies of troglitazone have demonstrated more consistent results. Enthusiasm for the use of troglitazone has been tempered, however, by reports of severe idiosyncratic liver injury. Metformin therapy is of use and continued only if one loses weight after initiation of therapy.

Ovarian Surgery

A laparoscopic ovarian surgery for polycystic ovaries gives an advantage of tubal testing before initiating gonadotropin therapy, results in unifollicular ovulation with correction of endocrinopathy & there is an apparent low rate of miscarriage. Ovarian diathermy may also help in reducing the dose of gonadotropins used & also decreases the risk of ovarian hyperstimulation syndrome & multiple pregnancies. The beneficial effect of laparoscopic diathermy is for 6 –12 months.

The chance of achieving pregnancy is lower compared to the normal population, as the quality of the egg may not be good due to tonic high levels of LH. Most women will conceive either spontaneously or following treatment. But these women may have an increased risk of early pregnancy loss gestational diabetes & pregnancy-induced hypertension when compared with general population. Slim and high LH concentrations have most favorable prognosis

With laparoscopic ovarian surgery there is concern of about the possibility of premature ovarian failure due to ovarian destruction resulting in reduction of ovarian tissue.

Indications for IVF/ICSI in PCOS

  • Other reasons for infertility
  • Failed to conceive despite six ovulatory cycles


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Problems

  • Risk of OHSS and multilple pregnancies
  • Higher rate of miscarriage
  • Hyperinsulinaemia & obesity associated with pregnancy complications – pre-eclampsia, gestational diabetes, UTI, fetal malpresentations, dystosia, PPH, thromboembolism, increased perinatal morbidity & mortality

Determinants of success of Rx

  • Obesity
  • Degree of hyperinsulinaemia
  • Concentration of circulatory LH

    Excess of either makes OI and conception difficult and associated with high rate of miscarriage

Key to Success of Tx - depends on ability to reduce body weight

  • Diet modification
  • Exercise
  • Stress Mx

Weight loss associated with

  • Reduction in insulin concentration
  • Increased insulin sensitivity
  • Increased concentration of SHBG & reciprocal decrease in free testosterone
  • Improvement in reproductive function – menstrual function and fertility

Possible Late Sequelae

  • Diabetes Mellitus – 11 %
  • Cardiovascular disease
  • Hyperinsulinaemia
  • Low low-density lipoprotein
  • Hypertension
  • Endometrial Carcinoma
  • Desire long term monitoring

Is there a permanent cure for PCOD?

Unfortunately PCOD is an inherited condition & there is no available cure. Presently the treatment is symptomatic & is aimed at dealing with hirsuitism, menstrual irregularity or ovulatory disorders.

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