Polycystic Ovarian Syndrome – PCOS

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder affecting between 4% and 8% of reproductive aged women. About 20% of couples seeking fertility treatment do so due to anovulation and 85%-90% of those have PCOS. Usually these patients do not ovulate and pregnancy does not occur. The symptoms and signs of PCOS are very heterogenous and presents with menstrual irregularities like oligomenorrhoea or amenorrhoea, hirsutism, acne, alopecia and a characteristic appearance of the ovaries on ultrasound examination.  Due to abnormal follicular development, the ovaries have multiple small follicles usually measuring <5mm dispersed around the periphery of the ovary in a pattern often referred to as a “string of pearls”.

This ultrasound appearance alone does not mean the patient has polycystic ovarian syndrome. Other clinical findings which comprise the syndrome include:

  • Polycystic appearing ovaries
  • Hyperandrogenism . Increased:
    • testosterone
    • DHEAS – dehydroepiandrostenendione sulfate (adrenal gland)
  • Hirsutism (male pattern hair growth such as facial hair)
  • Hyperinsulinemia (increased insulin secretion) and Insulin Resistance
  • Abnormal uterine bleeding oligo-ovulation (irregular ovulation)
  • Amenorrhea (absence of uterine bleeding)
  • Infertility
  • Obesity. Not clear if this is a cause or an effect. Not all patients with PCOS are overweight.
  • Laboratory findings Elevated LH Reversal of the LH/FSH ratio as LH becomes higher than FSH throughout the menstrual cycle
  • Other hormone elevations:
    • Estrogens
    • 17-OHP – 17 hydroxyprogesterone
  • Skin abnormalities Acanthosis Nigricans (darkened scaly like rash commonly on patients neck)
  • Skin tags – small outgrowths of skin
  • Possible long term effects Increased risk of cardiovascular disease from increased lipids
  • Increased risk of endometrial cancer
  • Increased risk of breast abnormalities
  • Increased risk of developing type II diabetes mellitus
  • Increased risk of heart disease

Infertility:

PCOS is associated with infertility. The most likely cause of infertility is anovulation or lack of ovulation. Ovulation can be induced by gonadotropins or by correction of insulin resistance. Some investigators have reported a lower than normal fertilization rate during IVF in women with PCOS. There may also be a higher miscarriage rate in women with PCOS also, but this has been debated. Women with PCOS are at increased risk of ovarian hyperstimulation when taking gonadotropins. A history of PCOS and/or irregular menses should be reported to physician before taking any fertility medications.

Diagnosis:

Diagnosis can be made by history of irregular menses, physical examination ( obesity, hirsutism, acne, acanthosis niagricans) laboratory investigation ( raised LH) and polycystic ovaries on ultrasound ( necklace appearance of cysts, which arranged at periphery of the ovary).

Treatment of infertility due to PCOS:

Ovulation induction:PCOS is one of the most common causes of infertility in women due to anovulation. The induction of ovulation in women with PCOS is a complex issue, which requires a thorough understanding of the syndrome and a careful and individual assessment of each patient. Different pharmacological agents are used to make the women ovulatory. Some are causing ovulation by increasing production of pituitary gonadotropins, some directly stimulates the ovaries and some reduces the androgen production and make the ovaries sensitive to stimulating agents. Ovualtion inducing agents are

  • Antioestrogens

i. Clomiphene Citrate
ii. Tamoxiphene
iii. Aromatase inhibitor

  • Low dose gonadotropins
  • Pulsatile GnRHa
  • Adjuvant therapies

1. Insulin sensitizers
Metformin
Pioglitazone
Rosiglitazone
Troglitazone
2. Glucocorticoids
3. Bromocriptine
4. Ketaconazole
5. d chiro-inositole

Antioestrogens
Clomiphene Citrate
Climiphene citrate (CC) alone or in combination with weight loss continues to be the first line of treatment for anovulatory infertility associated with polycystic ovary syndrome. Clomiphene is widely available and relatively well accepted in terms of safety, simplicity, side effects and cost. However, although approximately 70-90% of women ovulate during treatment with CC, only about half of those conceive. The reasons for this relatively low pregnancy rate are not clear, but may be related to the high LH levels, the antioestrogenic effects of clomiphene at the level of the endometrium and at the level of the cervical gland secretion and perhaps due to the adverse effects on the oocytes.

Alternative therapies:
Antioestrogens other than clomiphene citrate:

Tamoxiphene:
Tamoxiphene appears to be as effective as CC for induction of ovulation but is not licensed for that purpose. It can be considered as an alternative to CC in women who suffer intolerable side effects such as hot flushes.

Aromatase inhibitors:
Aromatase inhibitors are antioestrogenic agents which exerts their action by inhibiting aromatase enzyme.

Low dose gonadotropins:
For anovulatory patients who do not respond to other ovulation inducing agents,  gonadotropin is the supreme drug for induction of ovulation.

Pulsatile GnRHa:
Gonadotropin releasing hormone (GnRH) agonists are synthetic peptide analogues of hypothalamic GnRH. The repeated administration causes pituitary desensitization and induces a reversible state of medical hypophysectomy. The idea of using GnRH agonists in ovulation induction in PCOS stems from the assumption that the endogenous secretion of relatively large amounts of LH may well be the cause of the higher incidence of development of the ovarian hyperstimulation syndrome. Moreover, the high tonic secretion of LH may be deleterious to the quality of the ovum is reduced by GnRHa. Therefore, the use of GnRHa in order to suppress endogenous gonadotropin secretion in PCOS patients and to mimic hypogonadotrophic hypogonadism seemed to be a logical approach for ovulation induction.

Combined treatment with GnRHa and gonadotropins:
The use of combined treatment for women with PCOS is indicated in cases who have been found to have persistently raised follicular phase LH levels, proven premature LH surges on hMG treatment alone, an inadequate luteal phase , or those who have had two or more early pregnancy losses on clomiphene or hMG. It has been suggested that increased luteinizing hormone (LH) secretion in PCOS may interfere with fertility.

 GnRH antagonist
Though GnRHa suppress LH concentration, higher number of follicles during stimulation is an adverse effect. GnRH antagonists have some advantages over agonists. Since the antagonist suppress LH immediately, it can be administered in the late follicular phase when the LH peak is expected thereby reduce premature LH surge in PCOS patients.

Monitoring
Ultrasound assessment of the ovary can be performed at baseline before the initiation of each cycle. Serial ovarian ultrasound is an excellent method of determining follicle growth and development in response to gonadotropin stimulation. In particular, documentation of all follicles greater than 10 mm may be helpful to predict the risk of multiple pregnancies. Adherence to the chronic low-dose regimen of FSH administration in women with PCOS should markedly reduce the likelihood of excessive ovarian stimulation and OHSS. However, before ovulation induction with gonadotropins, it is mandatory to counsel the patient about the risks associated with higher-order multiple pregnancies after polyovulation.

Efficacy
Overall, low-dose regimens result in a monofollicular ovulation rate of approximately 70%, a pregnancy rate of 20%, and a multiple live birth rate of 5.7%. Correspondingly, there is a low incidence of multiple pregnancies (<6%) and OHSS (<1%) .

Adjuvant therapy
i). Insulin sensitizers
At least five different modalities have been used to lower insulin levels in PCOS. These include weight loss, diazoxide, metformin, thiazolidinedeones (pioglitazone, rosiglitazone, troglitazone is no longer available for use) and D-chiro inositol. Among all drugs metformin is the most comprehensively evaluated drug. Both metformin and the thiazolidinediones effect reductions in insulin levels but they do so by fundamentally different mechanism. None of the insulin sensitizing drugs have Food and Drug administration (FDA) approval for use in PCOS.

Metformin
Metformin is a biguanide antihyperglycemic that is approved for the management of type 2 diabetes mellitus. The mechanism by which metformin enhance insulin sensitivity are not fully characterized. At a molecular level, metformin may increase the activity of the enzyme adenosine monophosphate-activated protein kinase Metformin appears to suppress hepatic glucose output, decreased intestinal absorption of glucose, increased insulin mediated glucose utilization in peripheral tissues and has an antilypolytic affect on fatty acid concentration reducing gluconeogenesis . It does not produce hypoglycemia in either normal subjects or patients with type 2 diabetes. It is rapidly absorbed from the small intestine and without metabolism largely excreted in the urine. It is available in a generic form as 500 mg, 850mg and 1000 mg tablets. The target dose of metformin is in the range of 1500 mg to 2550mg . Metformin is given with meals to reduce the gastrointestinal side-effects. The most common side-effects of metformin are diarrhea, nausea, vomiting, flatulence, indigestion and abdominal discomfort. The gastrointestinal side-effects may be caused by high intestinal metfromin concentration that cause builds up of lactic acid in the bowel. A rare problem caused by metformin is lactic acidosis, which is fatal in as many as 30%-50% of cases . Chances of lactic acidosis is increased when patients have renal insufficiency.

So it should not be prescribed if serum creatinine level is greater than 1mg/dL. Liver disease, congestive heart failure and previous history of lactic acidosis are other contraindications of metformin therapy. Metfromin should be temporarily suspended for all major surgical procedures that involve restriction of fluid intake. Among metformin users in 10% of cases lactic acidosis occurred after the intravenous administration of iodinated contrast agents. So most authorities recommend that metformin should be discontinued 48 hours before any radiologic procedure that involves intravenous administration of iodinated contrast material. Though some authorities believe that it is safe to give contrast media to person taking metformin as long as renal function is known to be normal.

Laparoscopic Ovarian Drilling (LOD):
Clomiphene citrate is the first drug of choice in ovulation induction. Tamoxiphene and aromatase inhibitor are other alternatives for induction. When they proved ineffective gonadotropins are the next drug of choice. Gonadotropins are effective ovulation inducing drug but they are expensive, causes hyperstimulation, needs meticulous monitoring and sometimes need much drug to cause ovulation. In those cases where patients need much drug to produce egg or tend to be hyperstimulated surgical treatment could be the next step. First described surgical procedure for PCOS is ovarian wedge resection. Stein and Leventhal described resection of half to three quarters of both of the enlarged ovaries of seven patients. Due to parovarian adhesions, ovarian failure and other complications this procedure fell into disrepute. Alternative surgery is laparoscopic ovarian drilling where ovaries are punctured by electrodiathermy through laparoscope. This procedure is indicated in women with altered FSH:LH ratios, poor response to ovulation inducing agents and during ruling out other factors causing infertility.

                               Laparoscopic ovarian drilling

Indications for Laparoscopic Ovarian Surgery
The main indication for performing laparoscopic ovarian surgery (LOS) is CC resistance in women with anovulatory PCOS. The surgery also may be recommended for patients who persistently hypersecrete LH, either during natural cycles or in response to CC, because it may reduce LH secretion. In addition, LOS may be useful in anovulatory women with PCOS who need laparoscopic assessment of their pelvis or who live too far away from the hospital for the intensive monitoring required during gonadotropin therapy.

Procedure and dose:
Commonly employed methods for LOS include monopolar electrocautery (diathermy) and laser. There does not appear to be a difference in outcomes between the two modalities. Ovarian surgery may also be performed transvaginally by hydrolaparoscopy  but no large RCTs are yet available.
There are many variables in the potential for response after LOS, including the anthropometric characteristics of the patients and ovarian morphology. It has been proposed that the degree of thermal stromal damage should be determined by the size of the ovary.


It is done under general anaesthesia and using current at 50-80 watts depending upon the ovarian size and number of cysts. Five to ten punctures are made 1 cm apart in each ovary. By using unipolar coagulating current ovarian tissue is coagulated to a depth of 4 mm. There is no agreement on the optimum dose of diathermy to apply. Though it is recommended to keep the dose and number of punctured site low, it is not yet certain that which amount of diathermy is most efficacious and which is most commonly associated with postoperative adhesions.

Mechanism of action:

Various theories are proposed in favour of mechanism of action of LOD.
i) Drilling of follicles release androgen rich follicular fluid and also decreases the androgen producing stroma. So as to decrease circulating androgens.
ii) There is transient reduction in inhibin and precipitious fall in LH, which results in increased secretion of FSH and it’s expression.
ii) Crowding of cortex decreases, which allows progress of normal follicles to the surface resulting in resumption of normal ovulation.


Advantages of LOD:
Due to damage of ovarian tissue ovarian androgen and LH synthesis reduced. So ovaries become less responsive and less ovulation inducing drugs or gonadotropins are needed. Miscarriage which occurs due to persistently high LH reduced as a result of reduced LH. In ART cycles hyperstimulation rate is also reduced. Moreover, oocyte quality improves due to low LH. Duration of effect of the procedure lasts for 1-18 months. So after 6 ovulatory cycles COH+IUI is to be considered for another 4-6 cycles. If pregnancy has not occurred assisted reproductive technique can be considered. As effect of procedure does not persist for long it may be wiser to start active fertility treatment after LOD rather than awaiting.

Efficacy
In approximately 50% of LOD-treated women, adjuvant therapy will be required. In these women, the addition of CC can be considered after 12 weeks if no ovulation is detected . The addition of FSH should be considered after 6 months.

Safety
Immediate complications of the surgery are rare. Premature ovarian failure is a concern with ovarian drilling, especially when a large number of punctures are used. However, long-term follow-up of women with PCOS treated by LOD has been reassuring in this respect.

 

Ovulation induction and intrauterine insemination (IUI).
The principle of the management of anovulatory infertility in women with PCOS is to induce regular unifollicular ovulation with a view to minimizing the risk of ovarian hyperstimulation syndrome and multiple pregnancies. ART could be considered in women with PCOS who have failed to conceive in spite of repeated ovulatory cycles IUI is generally considered to be an intermediate step of low to moderate complexity before the application of more sophisticated ART like IVF. More>>

Invitro fertilization (IVF):
IVF is not the primary treatment of infertility in women with PCOS. When all steps of treatment fail then IVF remains the option of treatment. When several ovulatory cycles have failed to achieve pregnancy either spontaneously or through IUI then IVF is indicated. Sometimes another cause of infertility like tubal or male factor defect may co-exist in addition to anovulation, IVF is indicated for them.