How science is advancing

How Science is advancing!!

N-acetylaysteine (NAC)

• Mucolytic

• Recently reported to have insulin senitizing properties

• Accordingly we used it with C.C to avoid the anti-oestrogenic effect on cervical mucous

Observation

• Improved ovarian response with development of more than one follicle

Idea

• NAC can be a novel combination to CC

Clinical Trial

• The best candidates to this idea are CC resistant cases

Keeping in mind

• NAC has been used safely since long time (Borgstrom et al 1986).

Objective

• to evaluate the effect of NAC adjuvant therapy in women with PCOS resistant to CC.

Design

• prospective RCT,

• placebo-controlled,

• double blind • Allocation was done using opaque

sealed envelopes

Patients and Methods

• Patients: 150 cases diagnosed as CC-resistant PCOS were

recruited.

• Inclusion criteria

1-Normal semen parameters 2-Clomiphene citrate resistant PCOS3-Normal HSG . 4- No treatment was taken during last 3 ms prior to recruitment.

Intervention

• Participants assigned randomly to receive either

• NAC 600 mg/twice daily (group I) with CC 50 mg/ twice daily or placebo (group II) with CC 50 mg/ twice daily for 5 days starting at day 3 of the cycle.

• Allocation was done using opaque sealed envelopes

Monitoring of the cycle

2. Transvaginal determination of the mean follicular diameter.

3. Measurement of serum E2 levels at time of HCG adminstration.

3. Monitoring intervals were determined by patient response.

Then

• Human chorionic gonadotropin was administered when at least one follicle measured 18 mm

• Timed intercourse was advised 24-36 hours after hCG injection

Success was monitored by

• A serum progesterone level was checked 6-8 days after the administration of hCG.

• A serum hCG level was determined 14 days after hCG injection if menses had not yet occurred.

• Pregnancy was defined as a rise in the serum hCG level on serial determinations at least 2 days apart.

Outcomes

• Primary:

Ovulation rate

• Secondary:

pregnancy rate

Tolerability

Results

• 150 women with PCO resistant to CC were randomized to

• CC +NAC: n = 75 (GroupI)• CC + placebo: n = 75 (GroupII)

Demographics

NS28.5±5.7 30.5 ± 2.6 BMI

NS99.2±12.3 101.3 ±12.4 B WT (Kg)

NS4.4±2.6 5.0 ±2.9 Duration (Ys)

NS28.4±5.7 28.9 ±4.7 Age (Ys)

P valueGroup IIGroup IVariable

Hormonal profile

NS85.9±14.1 81.9±12 Fasting Glucose (mg/dL)

NS17.2±4.4 18.8 ±4.7 Fasting insulin (U/mL)

NS2.1 2.2 LH/FSH ratio

P valueGroup IIGroup IVariable

Clinical outcomes of both groups

Variable Group I

(n=75)

Group II

(n=75)

P

E2 360.3±367.9 120±10.0 P = .0007

Ovulation rate 49.3% 0.1% P < 0.0001

End. Thickness (mm) 5.9±0.7 5.3±1.9 NS

Pregnancy 16/75 0/75 P =0.000065

Multiple Pregnancy 5/75 0/75

Pregnancy rates in patients who received NAC according to their insulin

18.50%19.00%19.50%20.00%20.50%21.00%21.50%22.00%22.50%23.00%

Pregnancy rate

Insulin >20 u/mL

Insulin < 20 u/mL

How To Explain

• Antiapoptotic Odetti et al., 03.

• Antioxidant De Mattia et al., 98.

• Insulin sensitizing effect Fulghesu et al 02.

Potential biological activities of NAC

• Reduces testosterone levels and free androgen index values. Fulghesu et al 02.

• A safe mucolytic drug.

Side effects

• NAC is generally safe & well tolerated

• The most common side effects were :1-Nausea & vomiting.2-Diarrhea.

• It is contraindicated in active peptic ulcer disease.

Conclusions

• NAC is a a novel adjuvant treatment for PCOS patients.

• It is a simple, well tolerated

and inexpensive agent.

• Accepted for publication in Fertil & Steril 2005 Feb

STEP II

A feasible approach to friendly IVF

PILOT STUDY

• The objective of this study was to examine the use of NAC with clomiphene citrate for ovarian stimulation in assisted conception as a model for “Friendly IVF”

Intervention

• Patients were offered NAC, 1,200 mg/day from day 3-7 of the menstrual cycle with CC (100 mg /day) starting on day 3-7. HCG (10,000 IU) was given when leading follicle(s) were ≥18mm followed by ICSI

RESULTS

• Twenty women were enrolled in this pilot study with a mean age of 27.3 ± 1.9 and mean BMI of 28.1 ± 0.8.

• The mean number of follicles >18 mm on the day of HCG injection was 4.8 ± 1.6. The mean number of oocytes retrieved was 3.6±1.2 .

• Four women got pregnant (20%) [all were single ton pregnancy). The implantation rate was 14.3%. No miscarriages were reported till now.

cost of medications

• the number of NAC sachets used was 6 per day for 5 days making a total of 30 costing 27 E.P plus an average of two fillings of clomid = 18 EP,

• thus the total cost of medications in NAC-CC / ICSI cycle = 45 E.P (7$) which is considerably less than the average cost of medications in the long protocol of ICSI cycle (about 2000EP) (~450$).

CONCLUSION II

• a simple NAC-CC protocol is compatible with the concept of `friendly IVF', yielding a reasonable pregnancy rate per cycle started. The results of this study should be substantiated in a larger cohort of patients.

Thank you