Polycystic Ovarian Disease: Treatment Protocols

Abstract:
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. 

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:
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.

Pathophysiology:

• Endocrinologic abnormalities:
• Hyperandrogenic state manifested with high serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate. 
• High levels of luteinizing hormone (LH) leading to increased stimulation of the ovarian theca cells. In turn, these cells increase the production of androgens (e.g., testosterone, androstenedione).
• Lower level of follicle stimulating hormone (FSH), which lead to inability of the ovarian granulosa cells to aromatize the androgens to estrogens, leading to decreased estrogen (Estradiol) levels and consequently anovulation. 
• The more important from diagnostic point of view is the high LH/FSH ratio; higher than 2.
• Hyperinsulinemia: There is high levels of insulin like growth factor 1 (IGF-1) which increase insulin resistance that in turn lead to high insulin levels (hyperinsulinemia). The latter causes dyslipidemia and elevated levels of plasminogen activator inhibitor (PAI-1) in patients with PCOD. Elevated PAI-1 levels constitute a risk factor for intravascular thrombosis. 
• Pathologic appearance:
• Polycystic ovaries are enlarged bilaterally and have a smooth-thickened capsule that is avascular. On cut section, subcapsular follicles in various stages of atresia are seen in the peripheral part of the ovary. The most striking feature of the PCOD ovary is the hyperplasia of the theca stromal cells surrounding arrested follicles. On microscopic examination, luteinized theca cells are seen.
• Clinical Picture:
• Menstrual Abnormalities: In the form of amenorrhea (absent menstruation for more than 12 continuous months), oligomenorrhea (menstrual cycle every 5 weeks or more; but less than 12 months) and irregular menstrual cycles.
• Infertility due to the associated ovulation abnormalities.
• Hyperandrogenism: Hirsutism; Excessive growth of terminal hair in androgen-dependent areas where terminal hair is not normally found: face (above the lip; on the chin; and sideburns), upper back, neck, chest, shoulders, medial thighs, linea alba, and circumareolar region. 
• These patients may also have acne, male pattern balding or alopecia, increased muscle mass, deepening voice, or clitoromegaly due to hyperandrogenism.
• Obesity: Obesity may be present in 45% of women with PCOD, it is android type of obesity with increased waist hip ratio.
• Diabetes mellitus: About 10% of obese women with PCOD have type 2 diabetes mellitus by age 40 years. About 35% of obese women with PCOD have impaired glucose tolerance by age 40 years.
• Ultrasonic findings:
• Increased size of ovaries, more than 9CC, with peripherally oriented cystic structures (more than 8) and each is less than 9mm in diameter with no dominant follicles seen. However; the ultrasonic picture alone is not enough for the diagnosis of PCOD as this picture was seen in normal women with (Polycystic appearing ovaries) (Lotfi 1991).
• Laboratory Findings:
• High LH and increased LH/FSH ratio, very diagnostic.
• Elevated androgen levels of Testosterone and dehydroepiandrosterone and Androstenedione
• Normal serum estradiol and increased serum estrone concentrations leading to Low Estradiol/Estrone ratio.
• Of obese women with PCOD, 35% have impaired glucose tolerance and 10% have diabetes mellitus

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.

Treatment Protocols:

• General:
• Diet control to alleviate hyperinsulinemia and weigh control is very crucial for the treatment.
• They benefit from a low-calorie diet for weight reduction.
• Start with decreasing the intake of carbohydrates and fat in every meal. Keep encouraging them that the loss of weight is not going to be dramatic.
• Encourage moderate physical activity in these patients provided they have no contraindications to vigorous physical activity. 
• Medical Treatment:
• Clomiphene Citrate (CC)
  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). 
• Gonadotropin
  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.
• GnRh analogs
  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.
• Insulin Sensitizers
  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.
• Surgery
  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.

Conclusions

• The diagnosis of PCOD needs ultrasound in addition to laboratory assays.
• The treatment cycle should be carefully monitored by hormonal assays and ultrasonic folliculometry to prove the occurrence or failure of ovulation and in turn failure of the treatment protocol.
• CC is the first line of treatment.
• High Insulin level is a good marker for the poor prognosis of any treatment protocol.
• Metformin should be added to the treatment protocol especially for hyperinsulinemic and obese patients.
• Rec-FSH is the Gonadotropin of choice.
• The addition of GnRh-a is not recommended.
• Ovarian drill by laparoscopy should be carefully used on selective scale.

References:

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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

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