CHAPTERS CONTRIBUTED

MEDICAL TREATMENT OF PCOD: WHAT IS NEW?

Dr. PANKAJ DESAI MD, FICOG, FICMCH
Chief of Unit in Obgyn (VRS)
Medical College and S.S. G. Hospital
Baroda, INDIA
Email: drpankajdesai@gmail.com

Dr. JAYASHREE SHRIDHAR MD (O. & G.)
Consultant IVF Specialist
KRGs blessed mom clinic
INDORE
Emil: jayashreesridhar67@gmail.com


INTRODUCTION:

Polycystic Ovarian Syndrome or PCOS as it is popularly known is also loosely referred to also as Polycystic Ovarian Disease or PCOD. However for some puritans such a crossover of terminologies may not be acceptable. In that case it will be better to clarify at the inception of this chapter itself that when other somatic manifestations of the condition are also evident it is referred to as PCOS but when confined to the polycystic appearance of the ovaries it is known as PCOD. It should however be stressed that the difference is simply ignored by most clinicians and by and large the approach to the subject with PCOs or PCOD remains the same.

PCOS is the commonest specific cause of anovulation in clinical practice. Though most of these subjects are diagnosed when they seek treatment for anovulatory infertility, this condition can also be picked up in young adolescents who come with features of menstrual irregularities, over-weight and hirsutism. In this chapter the focus is confined to anovulatory subjects seeking infertility treatment only as this is in-line with the theme of this book.

It is estimated that at least 75% subjects of anovulatory infertility have PCOS 1. It is very well known that the basic underlying cause of this condition is hormonal imbalance. In addition to the endocrine disturbance leading to menstrual irregularities, anovulatory infertility and hyperandrogenism, it has been found that many women with PCOS also have insulin resistance leading to hyperinsulinemia 2.

The area of concern for a gynecologist is not merely confined to anovulation but also to the long-term implications of this condition. These include development of Type II Diabetes, cardiovascular complications and a condition known as Syndrome X 3. There are also fears that the estrogen dominance in PCOS can also increase the vulnerability of subjects having this condition to carcinoma endometrium, breast cancers and probably ovarian cancers.

A well-managed patient of PCOS is a very satisfying situation for a gynecologist. It is now well known that PCOS is a multi-system endocrinopathy involving women from menarche to menopause. In essence PCOS is a complex metabolic, endocrine, reproductive disorder that results in production of androgens and is associated with insulin resistance. It is a harbinger of a life-long condition that can lead to serious sequel such as diabetes mellitus, hyperlipidemia, endometrial cancer, central obesity and sleep apnea. It has a prevalence of 5% -10% of female population in developed countries. 3.7-22.5% prevalence rate have been reported in India with almost 1/3rd of adolescents being diagnosed with PCOS 4.

PREDISPOSING FACTORS:

Following conditions are known to predispose the girl child to PCOS:
a) Intrauterine exposure to androgen excess.
b) Fetal growth retarded female fetuses are at a higher risk of PCOS.
c) Fathers with history of premature balding (at a risk of metabolic syndromes) whose daughters are at higher risk of developing PCOS.
Adolescents showing one biochemical marker or one clinical feature mentioned below must be followed up closely:
1) Biochemical- Family history of diabetes mellitus, obesity, dyslipidemia and PCOS
2) Clinical- Irregular Menses, Body Mass Index (BMI)>24.9 kg/m2, Androgen excess (acne, hirsutism), pubertal deviation.

MANAGEMENT:
Management strategies for PCOS should include both pharmacological and non-pharmacological approaches. There should be a holistic approach aimed at improvement of all aspects of PCOS.

1) PHYSICAL ACTIVITY
Benefits of 150 min/week of physical activity include decreased incidence of diabetes mellitus in PCOS, spontaneous resumption of menses, reduced hyperandrogenism and reduction of Body Mass Index (BMI)5. Risk modification and symptom relief is clearly achieved with weight loss. All strategies for weight loss including bariatric surgery may be adopted in PCOS. The combination of weight reducing medications and group lifestyle modification is more effective than either alone. Bariatric surgery as a treatment for obesity is highly relevant to PCOS population and has shown to reverse the metabolic, reproductive problems and that of Hirsutism. In a study of morbidly obese PCOS weight loss was paralleled by a decrease in hirsutism, testosterone and DHEAS. Ovulatory cycles were restored 6.

Obesity and PCOS: Adipose tissues are now accepted as endocrine organs. They synthesize a number of biologically active compounds that regulate metabolic homeostasis. One of them, adiponectin secreted by the adipose tissue increases the insulin sensitivity which in turn sets off the cascade of metabolic syndrome. Therefore all steps including surgery that can reduce obesity are logically expected to give good results in controlling and reversing PCOS.

2) PHARMACOLOGICAL
a) Oral Contraceptive Pills (OCP) - They are used as first line treatment for menstrual irregularities associated with PCOS. They have the following advantages:
1) Increase SHBG (decrease testosterone)
2) Decrease LH (decrease testosterone)
3) Inhibition of 5 α-Reductase
4) Lipid Friendly (increase HDL)
5) Decreased incidence of functional cysts
6) Protection against endometrial hyperplasia

An ideal OCP is the one which has minimal androgenic effect, have low dose of estrogens and has third generation of progestins like norgestral, desogestral. OCPs containing cyproterone acetate are useful for hirsute adolescents. Pills with drosperinone are good for obese PCOS beyond 16 years of age and in whom epiphysis fusion has occurred. This is because in subjects in whom epiphyseal fusion has not occurred, estrogens are discouraged 7.

b) Biguanides: Metformin (1500-2000mg/day) acts by blunting of hepatic gluconeogenesis, decreasing intestinal absorption of glucose and by increasing peripheral glucose uptake and utilization. Metformin is an insulin sensitizer that decreases intraovarian androgen production. It also favors orderly follicular growth in response to ovulogens and gonadotropins. Metformin induces regular cycles in 68-95% of patients8. It improves ovulation, controls hirsutism and hyperandrogenism. It is mainly beneficial for metabolic and glycemic abnormalities. Vitamin B12 deficiencies and lactic acidosis are major side effects in prolonged Metformin therapy 9. Hypotension and dizziness are also common which can be dealt with by starting the dose at night and gradually increasing to daytime.

c) Statins: PCOS is characterized by presence of hyperandrogenism, insulin resistance, oxidative stress and systemic inflammation. Statins decrease the theca-interstial cell steroidogenesis. It is to be used with caution in those trying for conception because of teratogenicity. Dose recommended is 10-20mg/day. Life threatening myopathies need to be kept in mind. PCOS is not one disease. It is a group of diseases and by next decade we can find out which phenotype benefits from metformin and which of those from statins 10.

d) Dichiroinositol and Myoinositol (DCI and MI): These agents mediate action of insulin. Both MI and DCI glycols exert beneficial effects at metabolic, hormonal and ovarian levels. The combined administration of MI and DCI in physiological plasma ratio (40:1) should be considered as first line approach in overweight PCOS patients thereby reducing the risk of metabolic syndrome 11.

e) N-Acetyl Cysteine (NAC): It is historically a mucolytic which appear beneficial in HIV infection, smokers, epilepsy, cancer as a powerful antioxidant and antiapoptotic effect. However it’s utility in PCOS shows inconsistent effect. Dosage and duration varied from1.2 to 2 grams/day for 5 days to 5 to 6 weeks 12.

SPECIAL SITUATIONS:
Hirsutism in PCOS:
It occurs in 80% of PCOS subjects, with excess terminal body hair around upper lip, breast nipples, linea Alba and male pattern body hair. Red Flags with hirsutism include
• Rapid Onset
• Rapid Progression
• Late onset outside of early reproductive years
• Virilization
• Testosterone > 150 ng/dl
• LH low
• DHGAS >800
In presence of the above red flags, further investigations for other hirsutism causing conditions should be considered 13.

Treatment strategies for hirsutism include:
A) Reduce Androgens by
• Weight loss
• Hormonal Contraception
• Anti-Androgens
B) Mechanical treatment
• Shaving,
• Laser,
• Electrolysis
C) Pharmacological
• Spironolactone: It acts by binding to androgen receptors and blocking 5-α reductase enzyme activity. It is given in a dose of 25mg, 50mg, 100mg 200mg divided daily. It is to be used with contraception due to its possible teratogenic effects. It is used for 12-18 months with 60-80% reduction in hirsutism. Its side effects include light-headedness, lethargy and menstrual irregularities 14.
• Flutamide: It acts by blocking androgen binding to the tissues. Dosage recommended is 250 mg three times a day. It is a synthetic non-steroidal anti androgen used to treat prostatic cancer. In rare cases, liver dysfunction has been reported 14.
• Finasteride: It is a type II 5α reductase inhibitor. It is administered in a dose of 5 mg once a day. Simultaneous use of combined OCPs is warranted due to its possible teratogenic risk 15.
• Topical Eflornithina: It stops hair growth but hair reappears 12 weeks after stopping treatment 15.

PCOS and infertility:
Clomiphene Citrate (CC) 16:
PCOS falls in WHO category II ovulatory disorder for which clomiphene is the drug of choice. This orally acting non-steroidal compound is the first line agent for ovulation induction in women with PCOS. It acts by reducing the negative feedback of estrogen on secretion of GNRH from hypothalamus and gonadotrophin from pituitary. It leads to a rise in concentration of FSH in the early follicular phase which improves the recruitment of a dominant follicle leading to ovulation. Once a woman is ovulatory to a dose of CC, the same may be continued for 6 months till pregnancy is achieved. If a woman does not respond to 150 mgs. per day of CC, she is labelled as clomiphene resistant. Though ovulation rate using CC is above 80%, pregnancy rate is only up to 36 % and live birth rate is 29 %. This discrepancy between ovulation and pregnancy rate is due to the anti-estrogenic effect of CC on the endometrial receptivity.

Its side effects include GI effects, mastalgia, headache and hair loss are known. Visual blurring or persistent after images are known in 1 to 2 % of the patients. These side effects are completely reversible once CC is stopped. The incidence of twin pregnancy is approximately 7 to 9 % and that of triplet 0.5 %.Though mild OHSS is known, the severe forms are rare.

Metformin 9:
The use of Metformin in obese PCOS has been extensively studied. It increases the uptake and oxidation of glucose by adipose tissues as well as lipogenesis. Diarrhea, nausea, vomiting are seen at the initiation of the therapy. This can be avoided by taking Metformin with meals and increasing the dose gradually. Apart from infertility, indications for use of Metformin in PCOS are
1) 8 or fewer menstrual cycles per year
2) Hirsutism or elevated androgens.
3) Acanthosis nigricans
4) History of gestational diabetes
5) Fasting insulin above 10 miu per ml or pp insulin over 50 miu/ml
When compared with placebo or no treatment, clinical pregnancy with Metformin is higher.
However when used as mono therapy, clinical pregnancy rates with Metformin are lower than that of CC. Addition of Metformin to CC does improve clinical pregnancy and live birth rates. However in CC naive women, addition of Metformin is not of any value.

Tamoxifen 17:
The dose for ovulation induction is 10 to 20 mg per day, starting from the 2nd day of the cycle. Tamoxifen does not thin the endometrium like CC. This can be used in CC naive women as second line therapy, and also in women who experience side effects with CC.

Aromatase Inhibitors (AI) 18:
Though the mode of action of AI is similar to CC, letrozole (AI) causes mono follicular development and does not thin the endometrium as much as CC. The clinical pregnancy and live birth rates are comparable. The third generation AI, Anastrozole has a lower ovulation rate than letrozole and lower pregnancy rate. Dosage and Duration: Initial dosage of letrozole is 2.5 mgs to 5 mgs per day for 5 days. The short half-life of letrozole allows it to be completely cleared from the circulation by the time of implantation of embryos thus avoiding the risk of teratogenicity. Pending evidence of lack of teratogenicity, studies to determine the optimum dosage of letrozole, its use as first line of therapy in PCOS is not envisaged.

Low dose Gonadotropins (recombinant FSH, FSH) 19:
These are used as third-line therapy in PCOS women who are CC naive. FSH at the dose of 50 to 75 IU per day for 7 to 10 days and increasing the dose incrementally by 37.5 IU every week till a follicle of 12 mm is developed. This is the low dose step up protocol. Ovulation is triggered when the follicle reaches 18 mm size. The step down protocol involves use of 150 IU of FSH till the dominant follicle develops and the dose of FSH decrease until the triggering of ovulation with HCG. Evidence based recommendations are that gonadotropins should be second-line treatment in women with PCOS who are CC resistant, are anovulatory with no other infertility factor. As far as PCOS and gonadotropin dosage goes, "more is less; less is more". As far as protocols for IVF goes, there's moderate quality evidence that the use of Gnrh antagonist protocol compared with the long agonist, is associated with a substantial reduction of OHSS without reducing the likelihood of live birth.
Gonadotropins when compared to laparoscopic ovarian drilling show that with ovarian drilling 20:
A) One time cost for drilling is higher than that of gonadotropins.
B) Surgical expertise required is higher in lap drilling
C) Intensive monitoring required for gonadotropin therapy.
D) Incidence of multiple pregnancy higher with gonadotropin therapy
E) Potential risk of OHSS for gonadotropin therapy.
F) Laparoscopic surgery in these obese PCOS women is wrought with intra and postoperative risks.
G) Risk of over enthusiastic drilling leading to poor ovarian reserve.
However, results of methodical controlled trials comparing gonadotropins and laparoscopic ovarian drilling are awaited.

Bariatric surgery 21:
Obesity is commonly known to adversely impact fertility. Weight loss improves not only the pregnancy rate but also addresses the maternal and neonatal complications associated with obesity. It also increases the effectiveness of ovulation induction. Women with BMI more than or equal to 35kg/m2 or have tried weight loss methods for 1 year without success, may consider bariatric surgery. It should be kept in mind that bariatric methods can result in malabsorbtive state, poor food tolerance and psychological issues. If at all bariatric surgery is prescribed, issues to be considered-
a) Structured weight management program, involving diet, physical activity and interventions to improve psychological, musculoskeletal and cardiological health, should continue post-operatively.
b) A team of specialist interdisciplinary specialists should manage the pre and post-operative nutritional deficiencies of the patient.
c) Pregnancy should be avoided during periods of rapid weight loss.
d) Patient should be counselled to avoid pregnancy 12-18 months after surgery.
e) Contraception should be discussed prior to surgery.
f) Lifelong multivitamin and iron therapy for substitution to be borne out.

Depression in PCOS:
It is routinely recommend screening for depression and anxiety with appropriate psychological instruments. In patients with PCOS evaluated with depression and /or anxiety, psychological counselling. By an appropriate professional is suggested based on the severity of the disease 22.

CONCLUSION:
PCOS is highly enigmatic but ill understood disease. Though the diagnosis stars at your face, management is need and age oriented. Crux of the management is lifestyle changes, diet, exercises. OCPs, Insulin sensitizers and progestrones for bleeding (whenever lesser than 8 cycles a year). Statins, anti-diabetics and anti-hypertensives are used when needed. Omega-3 Fatty acids and micronutrients (inositol and micro inositol) or N-Acetylcysteine are alternative medicines.

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