Polycystic Ovarian Disease: Treatment Protocols
Polycystic Ovarian Disease: Treatment Protocols
Abstract: We should stress that that before addressing failure for any treatment protocol, the treatment cycle should be properly evaluated and monitored. For failed treatment with Gonadotropin, there is a question to be addressed, do we embark on ovarian drilling (the replacement of the obsolete wedge resection) or do we start In vitro fertilization? Introduction: Pathophysiology: The diagnosis of PCOD does not require the presence of polycystic ovaries. However, it is believed that 80-100% of women with PCOD have polycystic ovaries, which are defined as the presence of 8 or more small (2-8 mm) follicles in each ovary. Polycystic ovaries also can be present in other causes of androgen excess and in approximately 20% of normal women. Conclusions
Stein and Leventhal were the first to recognize an association between the presence of polycystic ovaries and signs of hirsutism, amenorrhea, oligomenorrhea and obesity. Subsequently, it was reported that after successful wedge resection of the ovaries in women diagnosed with Stein-Leventhal syndrome, menstrual cycles became regular and these patients were able to conceive. Consequently, it was thought that a primary ovarian defect was the main culprit, and the disorder came to be known as polycystic ovarian disease (PCOD). Further biochemical, clinical, and endocrinological studies have shown an array of underlying abnormalities, though it may occur in women without ovarian cysts. Since the era of Stein and Leventhal, many treatment protocols have been implemented for the treatment of PCOD. The aim of any treatment is to get a live birth of a singleton from a healthy mother. To achieve such result, treatment by Clomiphene Citrate, Gonadotropin and Gonadotropin analogs (GnRh-a) have been reviewed. Most of the work done are on the favor of Rec-FSH as a treatment without the addition of GnRh-a. It should be stressed on the importance of adding Metphormin for Hyperinsulinemic patients as it improves the treatment results as far as ovulation rate, pregnancy rate, abortion rate and ovarian hyperstimulation are concerned.
In 1935 the pathology of polycystic ovarian disease (PCOD) was described by Stein and Leventhal. It is a clinical syndrome consisting of menstrual irregularities featuring amenorrhea, oligomenorrhea, infertility, masculine type hirsutism and obesity. Since that time many theories have been postulated for the pathology causing the disorder. In the meanwhile and because of the uncertainty of the underlying etiology, many treatment protocols, surgical and medical have been recommended to control that disorder.
It is given 50mg twice daily starting on the second day of the menstrual cycle and given for 5 days. The treatment cycle should be monitored by ultrasonic folliculometry and hormonal assays, so as to know whether ovulation is induced or not. 50-80% of cases will ovulate by CC however pregnancy rate is only 40-50% (Cudmore and Tupper, 1966 ; Johnson et al, 1966). Before addressing failure of treatment, we should know is it failure to get ovulation or failure to get pregnancy. If it is failure to get ovulation we shift to Gonadotropin treatment. If it is failure to get pregnancy (and we did had good ovulation, we address the case as unexplained infertility for which we either do Controlled Ovarian Hyperstimulation (COH) with or without Intrauterine insemination (IUI) and if failed we shift to In Vitro Fertilization (IVF).
The Gonadotropin used is either Human menopausal Gonadotropin (HMG), Urinary Gonadotropin (uFSH), Purified Gonadotropin (p FSH) or recombinant FSH (Rec-FSH). The Rec-FSH is produced by genetic engineering from Chinese Hamster Ova (CHO) and it is pure FSH. The idea of using FSH alone without LH in these patients is that the high levels of LH lead to poor oocyte quality, reduced rate of fertilization and pregnancy and increased rate of early abortion. The use of Rec-FSH will guarantee purity of FSH, lower dosage needed to induce ovulation and shortage of stimulation period required for sound ovulation.
The gonadotropin is used by either step up or step down method. By step up we start with small dosage of 75U and increase it up to 150U. In step down method, we start by high dosage of 150U and gradually decrease the dosage. Both methods have comparable results. Rec-FSH is more superior to uFSH (Coelingh Bennink et al. 1998, Daya and Gunby, 2000), Rec-FSH is the Gonadotropin of choice.
The addition of GnRh analog: In the past many voices said that the addition of GnRh-a to gonadotropin treatment will improve the treatment results. However Fleming (1988), Hamburg (1990) and Hompes (1986), did not find any significant difference as far as pregnancy rate is concerned. Regarding Ovarian hyperstimulation and abortion rate, there was no significant difference. So, At the moment, the addition of GnRh-a is not recommended.
As long as hyperinsulinemia is associated with higher levels of androgen and lower diameters of follicles, the addition of insulin sensitizers is highly recommended.
The hyperimsulinemic women (45%of PCOD) are associated with higher levels of Estrogen, higher number of immature small follicles (nuisance follicles), higher incidence of ovarian hyperstimulation and higher incidence of abortion. From here we got the idea of adding Metformin to the treatment protocol, either in addition to CC or FSH.
Metformin (Glucophage) reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). It is a major drug used in obese patients with type 2 diabetes. It is given by mouth 500 mg three times daily after meals.
Documented hypersensitivity; renal impairment (serum creatinine greater than or equal to 1.5 mg/dL in males and 1.4 mg/dL in females or a CrCl of less than 60 mL/min); any condition resulting in low CrCl, such as cardiovascular collapse from acute myocardial infarction, septicemia, and metabolic acidosis with or without coma; including diabetic ketoacidosis; metformin should be temporarily withheld at the time of or prior to a radiologic procedure involving intravenous administration of iodinated contrast material and restarted 48 hours subsequent to the procedure after renal function has been reevaluated and found to be normal.
It was found that in a study done by (Nestler et al., 1998) when Metformin was given to obese anovulatory women, high rate of ovulation occurred compared to placebo. The same happened if the metformin was added to CC, leading to reduction of nuisance follicles, reduced estradiol on day of Human chorionic gonadotropin injection , reduced rate of ovarian hyperstimulation and reduced rate of abortion.
So far, most of work done on that area did not find significant increase of fetal abnormalities, on the contrary the abortion rate was decreased.
Wedge resection of the ovaries is mentioned to be condemned; it is the operation that is associated with destruction of already diseased ovaries, and might transfer the patient from ovulatory problem to ovulatory and tubal problem, that is because of the postoperative adhesions.
Laparoscopic ovarian drill is the substitute for wedge resection. The postoperative adhesion is lower that in wedge resection.
The question is, If there is good ovulation but no pregnancy, will the patient benefit from Ovarian drill or shall we consider it as unexplained infertility and move to COH with or without IUI or IVF.
If there was resistance to get ovulation by either CC or FSH, A trial of drill would not do any harm. The drill should be followed by Ovarian stimulation, because the effect of the drill would not last long.
We should stress that that before addressing failure for any treatment protocol, the treatment cycle should be properly evaluated and monitored. For failed treatment with Gonadotropin, there is a question to be addressed, do we embark on ovarian drilling (the replacement of the obsolete wedge resection) or do we start In vitro fertilization?
The diagnosis of PCOD does not require the presence of polycystic ovaries. However, it is believed that 80-100% of women with PCOD have polycystic ovaries, which are defined as the presence of 8 or more small (2-8 mm) follicles in each ovary. Polycystic ovaries also can be present in other causes of androgen excess and in approximately 20% of normal women.
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Originally presented: Lotfi, G (2002): Polycystic ovary syndrome: Treatment protocol. Obstetrics and gynecology annual meeting, Suez Canal university, Ismaila. Egypt. April 25-26, 2002
Adams J, Polson DW, Franks S: Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed) 1986 Aug 9; 293(6543): 355-9.
Conway GS, Agrawal R, Betteridge DJ: Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992 Aug; 37(2): 119-25.
Coulam CB, Annegers JF, Kranz JS: Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 1983 Apr; 61(4): 403-7.
Cumming DC, Yang JC, Rebar RW: Treatment of hirsutism with spironolactone. JAMA 1982 Mar 5; 247(9): 1295-8.
Donesky BW, Adashi EY: Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil Steril 1995 Mar; 63(3): 439-63.
Ehrmann DA, Barnes RB, Rosenfield RL: Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999 Jan; 22(1): 141-6.
Johnson JE Jr, Cohen MR, Goldfarb AF et al, The efficacy of clomiphene citrare for induction of ovulation. A controlled study. Int J Fertil 1966. 11, 265-270
Kiddy DS, Hamilton-Fairley D, Bush A: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992 Jan; 36(1): 105-11.
Lotfi,G: Polycystic ovary: Normal variation. Post Graduate Doctor. 1991. 16.
Nestler JE, Jakubowicz DJ, Evans WS: Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998 Jun 25; 338(26): 1876-80.
Polson DW, Adams J, Wadsworth J: Polycystic ovaries--a common finding in normal women. Lancet 1988 Apr 16; 1(8590): 870-2.
Rittmaster RS: Hirsutism. Lancet 1997 Jan 18; 349(9046): 191-5.
Stein I, Leventhal M.: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935; 29: 181.
Stein IF: Duration of infertility following ovarian wedge resection. West J Surg 1964; 72: 237.
Stumvoll M, Nurjhan N, Perriello G: Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995 Aug 31; 333(9): 550-4.
Velazquez EM, Mendoza S, Hamer T: Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994 May; 43(5): 647-54.
Zawadzki JK,, Dunaif A: Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In Dunaif A, Givens JR, Haseltine FP, et al, ed. Current issues in Endocrinolgy and Metabolism. Oxford: Blackwell Scientific Publications; 1992: 377.