Management of Women with Clomiphene Citrate Resistant Polycystic Ovary Syndrome Evidences

Article No. 2

Management of Women with Clomiphene Citrate Resistant Polycystic Ovary Syndrome-Evidences

---

DEFINITION

Clomiphene resistance is defined as failure to ovulate after receiving 150 mg of CC daily for 5 days per cycle, for at least three cycles. In women with PCOS, incidence of clomiphene resistance is approximately 15 to 40%.

RISK FACTORS

Insulin resistance, hyperandrogenemia, and obesity represent the major factors involved in CC resistance; and avert the ovaries from responding to raised endogenous FSH levels following CC therapy.

MANAGEMENT

Various treatment modes mainly rely upon ovarian stimulation with FSH, a reduction in insulin concentrations and a decrease in LH and androgen levels. The proposed treatment options for patients with clomiphene citrate resistance are mentioned below:

ADJUVANTS IMPROVING OVARIAN RESPONSE TO CLOMIPHENE

• LIFESTYLE MODIFICATION AND AGGRESSIVE WEIGHT LOSS : Weightloss is recommended for anovulatory obese PCOS women who have a BMI > 29 kg/m2 before starting ovulation induction therapy. In these women, weight loss of upto 10% of body weight often restores ovulatory cycles. Metformin has an additive effect to diet and exercise to improve parameters of hyperandrogenism and insulin resistance. Anti-obesity pharmacological agents have been used in obese women with PCOS. Orlistat which blocks intestinal absorption of fat, has displayed a weight loss-independent effect on androgens and insulin resistance. Morbidly obese women are found to improve markedly after sustained weight loss following bariatric surgery. It should be noted that these treatments should not be considered as first-line therapy for obesity in women with PCOS.
• DEXAMETHASONE : Dexamethasone reduces circulating DHEAS, T, and LH levels and the LH/FSH ratio after 2 weeks of treatment. Recommended protocol involves administration of dexamethasone tablets 2mg /day starting from day 3 to day 12 of the cycle along with clomiphene from day 3 to day 7. It is found that mean number of follicles >18 mm and mean endometrial thickness were slightly higher in the patients who received clomiphene and dexamethasone in cc resistance.
• ORAL CONTRACEPTIVE PILLS : They have shown to reduce serum LH, estradiol and androgen levels. These hormonal changes, especially the reduced androgenic milieu, could act improving the ovarian microenvironment, and thus the ovarian response to CC. Suppression of the hypothalamic pituitary- ovarian axis for 3 months with combined oral contraceptives (COC) (0.03 mg of ethinyl estradiol and 0.15 mg of desogestrel) followed by CC, at dosage of 100 mg/day on days fifth to ninth of the cycle, has shown to improve ovulation and pregnancy rates in CC resistant women in comparison with repeated cycles of CC alone.
• INSULIN SENSITISERS : Insulin sensitizers such as biguanides (metformin) and inositols (myoinositol, D-chiro-inositol) have shown to improve metabolic abnormalities in PCOS patients.
  
  METFORMIN is a biguanide that reduces levels of LH, hyperinsulinemia and decreases ovarian levels of androgen. Metformin being an insulin sensitizer, reduces hepatic gluconeogenesis, improves insulin sensitivity by increasing peripheral glucose uptake and utilization. It lowers circulating total and free androgen levels with a resulting improvement of the clinical sequelae of hyperandrogenism along with its direct action on ovarian theca cells to decrease androgen production. Recommended dosage is 850mg twice daily or 500mg thrice daily. Metformin in combination with CC increased the likelihood of ovulation. Its potential gastrointestinal side effects must be considered before prescribing the drug which has shown to increase in drop out rates in many studies. There is no evidence available that it improves live birth rates whether used alone or in combination with CC.
  
  INOSITOLS Available evidence suggests that restoring inositol levels by oral supplementation ameliorates insulin resistance, hyperandrogenism, menstrual regularization, and oocyte quality in PCOS patients. Myoinositol (MI) and D chiro-inositol (DI) are the most studied inositol isoforms which are classified as insulin sensitizers. Many studies have shown that MI has the most marked effect on metabolic profile whereas DI reduces hyperandrogenism better. Combined administration of MI and DI in physiological plasma ratio of 40:1 may be considered as first line therapy in obese PCOS patients. Recommended doses used in various studies range from 2-4 gram daily for MI and 1-1.2 gram daily for DI either alone or in combination for 3-6 months. According to one study, when myoinositol was used in combination with CC, ovulation rate was 72% and of these 72%, 43% became pregnant.
• N ACETYL CYSTEINE : It is a mucolytic drug which has antioxidant effects via increasing cellular levels of reduced glutathione. Mechanism suggested is to increase insulin sensitivity and reduction in testosterone. The suggested treatment options are NAC treatment 1.2- 1.8g/day for 5 to 6 weeks. The efficacy of metformin–CC combination therapy is higher than that of NAC – CC for inducing ovulation and achieving pregnancy among CC-resistant PCOS patients. One study has shown ovulation rate of 45% and pregnancy rate of 20% in CC+NAC group in comparison to CC+placebo group with 28% ovulation rate and 9.4% conception rate.

ALTERNATIVE THERAPY IN CLOMIPHENE RESISTANCE

• LAPAROSCOPIC ELECTROCAUTERISATION OF OVARIAN STROMA (LEOS) : LOD drains the ovarian follicles containing a high concentration of androgen and inhibin. It is a successful second line treatment avoiding risk of OHSS and multiple pregnancy. If cycles remain anovulatory till 8 weeks post LOD, adjuvant therapy with CC or gonadotrophins is required. Four punctures per ovary using a power setting of 30 W applied for 5s per puncture (i.e. 600 J per ovary) are sufficient to produce an optimal response (67% spontaneous ovulation rate and 67% conception rate). Also, different studies argued for unilateral LOD being equally efficacious as bilateral drilling in inducing ovulation. A Cochrane review found no difference in the rates of miscarriage, ongoing pregnancy or live birth between LOD and gonadotrophins.Poor response has been noted in cases with marked obesity (>35 BMI), marked hyperandrogenism (testosterone >4.5nmol/l), free androgen index >15, more than 3 years of infertility. Higher probability of pregnancy is seen in cases with high LH >10IU. The claim that it might affect the ovarian reserve is no more than a theoretical concern since a recent report concluded that LOD, when applied properly, does not seem to compromise the ovarian reserve in PCOS women.
• GONADOTROPINS : Gonadotrophins have been used as a second line treatment for CC-resistant PCOS women, however it is expensive, requires extensive monitoring and associated with significantly increased risk for ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. It is recommended to give recombinant FSH in low dose and begin with a low dose of gonadotrophin, typically 37.5– 75 IU/day, increasing after 7 days or more if no follicle >10 mm has yet emerged, in small increments, at intervals, until evidence of progressive follicular development is observed. Protocols utilizing clomiphene on cycle days 5-9, and then gonadotropins (injectable FSH) on days 9-12 have been used successfully for ovulation induction in clomiphene resistant cases.

CONCLUSION

With the advent of extensive research on newer molecules to overcome insulin resistance with associated metabolic disturbances, fertility outcomes can be improved. Many studies have demonstrated that lifestyle modification has led to increased insulin sensitivity and resulted in improved ovulation and fertility. Lifestyle modification with weight reduction, dietary changes and exercise, should be the first intervention in treatment of obese PCOS with clomiphene resistance. Therefore, no medical treatment should be considered in such patients with anovulation if lifestyle intervention has not been practiced. Once this goal is achieved , then they can be started on adjuvants either alone or in combination with CC followed by alternatives if first approach fails to cause ovulation.

RECOMMENDED READING

1. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. (2008). Consensus on infertility treatment related to polycystic ovary syndrome. Fertility and Sterility, Vol.89, No.3 ,pp.505-522
2. Vause, TD.; Cheung, AP.; Sierra, S.; Claman, P.; Graham, J.; Guillemin, JA.; Lapensée, L.; Stewart, S.; Wong, BC. & Society of Obstetricians and Gynecologists of Canada. (2010). Ovulation induction in polycystic ovary syndrome. Journal of Obstetrics and Gynaecology Canada, Vol.32, No.5, pp. 495-502.
3. Hum. Reprod. (2006) 21 (7): 1805-1808. doi: 10.1093/humrep/del053 Clomiphene citrate and dexamethazonein treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study AboubakrElnashar1, Emad Abdelmageed,
4. FertilSteril. 1996 Nov;66(5):761-4. An extended 10-day course of clomiphene citrate (CC) in women with CC-resistant ovulatory disorders Fluker MR1, Wang IY, Rowe TC
5. Hum. Reprod. (2006) 21 (7): 1805-1808. doi: 10.1093/humrep/del053 First published online: March 16, 2006 Clomiphene citrate and dexamethazone in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study AboubakrElnashar1 , Emad Abdelma
6. Abu Hashim, H.; El-Shafei, M.; Badawy, A.; Wafa, A. &Zaglol, H. (2011). Does laparoscopic ovarian diathermy change clomiphene-resistant PCOS into clomiphene-sensitive? Archives of Gynecology and Obstetrics, Vol. 284, No. 2, pp.503-507.