Comparative study between the effect of letrozole versus letrozole with Metformin in treatment of anovulation in overweight women.

INTRODUCTION

Ovulation disorders are responsible for around 30% of all infertility cases, and they're often accompanied by irregular menstruation (oligomenorrhoea) or period absence (amenorrhea). Several of the therapies are easy and efficient, so couples might only need to see a doctor once or twice. This makes it simpler for a couple to retain a private love connection than it would be in the stressful, technological setting of an aided pregnancy. Nevertheless, ovulation stimulation does not work for all types of anovulation. Medical or surgical stimulation can be used to treat anovulation, but the cause of the anovulation affects whether or not ovulation induction is feasible. ¹.

In women, ideal body weight is linked to the onset and preservation of reproductive functions; underweight (BMI > 18.5 kg/m2), overweight (BMI 25–29 kg/m2), and obesity (BMI ≤ 30 kg/m2) are all linked to a higher risk of anovulatory infertility ².

Overweight and obesity are linked to irregular menstrual periods, lower spontaneous and aided fertility, and a higher rate of abortion ³. Excess weight and a central body fat distribution are linked to a higher risk of normogonadotrophic anovulation ⁴. Although the mechanism by which weight hinders fertility is uncertain, such

patients have reduced levels of sex hormone-binding globulin (SHBG), as well as higher androgen, insulin production, and insulin resistance ⁵.

Metformin is a biguanide anti hyperglycemic drug that has been proven to alleviate hyperandrogenism, hyperinsulinemia, and monthly cyclicity for both obese and non-obese PCOS women, most probably due to its beneficial impacts on insulin elimination and abdominal obesity ⁶.

New evidence indicates that insulin receptor phosphorylation and insulin receptor substrates could be one of metformin's methods of action ⁷.

 Metformin also seems to have cardio-protective impacts on serum lipids and plasminogen activator inhibitor (PAI)-1, suggesting that it could reduce the chance of developing T2D ⁸. Letrozole is a powerful aromatase inhibitor with good ovulation potential; it blocks estrogen synthesis by a direct effect on hypothalamic-pituitary-ovarian function, which may lead to a rise in rates of pregnancy. ⁹.

A more physiologic hormonal activation of the endometrium, decreased multi-pregnancy rates via single-follicle recruitment, a better adverse effect profile with fewer vasomotor and mood signs, and quick elimination are all possible advantages of aromatase inhibitors ¹⁰.

The study's goal is to compare the effects of letrozole versus letrozole combined with metformin as an ovulation-inducing agent in anovulatory overweight women.

PATIENTS AND METHODS

After ethical committee approval and written consents from the patients, this prospective study was performed on total 100 Anovulatory overweight women attending infertility outpatient Clinic in Al-Hussein University Hospitals and Dar Ismail Hospital for Obstetrics and gynecology, Alexandria, Egypt, from 1st March to 31st December 2019.

Study population:  Anovulatory overweight women attending infertility outpatient Clinic in Al-Hussein University Hospitals and Dar Ismail Hospital for Obstetrics and gynecology, Alexandria, Egypt with the following inclusion criteria:

Inclusion criteria: Anovulatory infertile women for more than one year associated with overweight, BMI ranging from 25 to 29 kg /m², Aged from 21- 35 years old, Standard parameters of the husband’s semen, Normal value of prolactin hormone.

Exclusion criteria: Hypersensitivity to letrozole or metformin, Obese women with BMI ≥29 kg/m² or women with BMI

Study Procedures: All participants were submitted to the following:

A series of blind envelopes numbered 1 to 100 were used to divide the patients into two groups at random. Every patient has been allowed to take an envelope and has been classified into one of two groups:

• Group A: Letrozole group (envelopes number 1-50)

• Group B: Metformin- Letrozole group (envelopes number 51-100).

History: including

The age (female partner and male partner), parity, gravidity, pregnancy results and complications, period length, and the start and intensity of dysmenorrhea, sexual dysfunction, and frequency of coital, The length of infertility, as well as the outcomes of any prior assessments and therapies, Previous surgery, its rationale, and results, as well as a history of or exposure to sexually transmitted diseases, Past abnormal pap smears and treatment, present drugs and allergies, occupation, and tobacco, alcohol, and other drug usage, Birth defects in the family, mental retardation, early menopause or reproductive failure, thyroid disease symptoms, pain in the pelvic or abdomen, galactorrhea, hirsutism, or dyspareunia.

Examination: including Weight and BMI (BMI =Weight (Kg) / Height in metrer2), Thyroid enlargement, nodules, or pain, breast secretions and their characteristics, androgen excess symptoms, vulva, vaginal, cervix, uterus, adnexa, pelvic or abdominal pain, organ enlargement or masses, vaginal or cervical abnormalities, secretions, or discharges, tenderness, mass, or nodularity in the adnexa or cul-de-sac.

Investigation:

BMI is computed by dividing a person's weight in kilograms by the square of their height in meters.

Image:

Transvaginal ultrasound (1^st or 2^nd day of menses, at day 12, after taken HCG by 48 hours, when missed period).

Hysterosalpingograghy (before starting induction).

Laboratory:

Semen analysis for her husband (before starting induction).

Hormonal profile FSH, LH, prolactin and TSH at time of 1^st or 2^nd day of menses.

E2 at day 12 (mature follicles).

Study details and follow up:

The table was randomly divided into two therapy groups: group A, letrozole (50 women), and group B, metformin–Letrozole (50 women).

Patients in group A received 2.5 mg of letrozole oral tablets (Femara; Novartis Pharma Services, Switzerland) every day for 5 days starting on the third day of the menstrual cycle, while all patients in group B got metformin HCl (Cidophage; Chemical Industries Development, Cairo, Egypt), 500 mg thrice every day for 6–8 weeks, accompanied by 2.5 mg of letrozole oral tablets (Femara; Novartis Pharma Services, Switzerland) every day starting on the third day of the menstrual cycle for 5 days. Metformin has only been discontinued when a pregnancy has been confirmed.

Transvaginal ultrasound (TVS) was used to monitor all patients on the 1st or 2nd day of menses to exclude any ovarian cysts and on day 12 of the period to determine the mean follicular diameter and thickness of the endometrium. To exclude ovarian hyperstimulation syndrome, RIA measured serum E2 (in picograms/millilitre) at the moment of HCG administration, employing direct double antibody kits (Pantex, Santa Monica, CA).

When one follicle measuring at least 18 mm has been identified, the HCG (a total of 5,000 IU IM, Choriomon; IBSA, Lugano, Switzerland) has been given. Patients have been instructed to have intercourse 24–36 hrs following receiving HCG injections, and a transvaginal ultrasound has been done after 48 hours of triggering to make sure rupture of follicles and ovulation occur. In the absence of menstruation, serum HCG has been measured two weeks later to diagnose pregnancy. In the instance of a woman who had ovulated and had a delayed menstrual cycle, β-HCG has been measured, and pregnancy has been confirmed via transvaginal sonography. Metformin has been stopped when a woman becomes pregnant, and the fetal heart rate has been observed.

Sample Size: According to sample size justification (Steven Thompson equation), the sample size was estimated utilizing the PASS program, and the study included 100 anovulatory overweight women.

Outcome measures:

The primary outcome: the number of follicles that were developing and mature, serum E2 when the follicle became mature before giving triggers to exclude ovarian hyperstimulation syndrome, and triple line endometrial thickness, ovulation rate, and number of ruptured follicles, side effects of the drugs taken.

Secondary outcome: pregnancy (verification of pregnancy was accomplished via a urine test utilizing a pregnancy test kit and transvaginal ultrasound. These women were followed up on and managed as antenatal once the pregnancy was confirmed).

Ethical Considerations: The patient data was anonymous. Patient confidentiality was protected as data presentation was not by the patient’s name but by diagnosis. All participants were asked to give their informed consent. It was in Arabic language and confirmed by date and time. Confidentiality was preserved by assigning a number to the patients’ initials and only the investigator knew it.

Conflict of interest: the candidate declared that there's no conflict of interest and the cost of the study was paid by the candidate.

Statistical analysis: Analysis is to be performed using SPSS for Windows v20.0. Data should be given in the form of a range, mean, and standard deviation (for numeric parametric variables); a range, median, and inter-quartile range (for numeric non-parametric variables); or numbers and percentages (for categorical variables). The difference between two independent groups should be analyzed utilising an independent student's t-test, the mean difference, and its 95 % CI (for numeric parametric variables); or a chi-squared test, the risk ratio, and its 95% CI (for categorical variables). Binary logistic regression analysis is to be performed for estimating the association between good/poor response and the measured variables ROC curves are to be constructed for estimating the validity of measured variables as predictors of good or poor response validity is to be presented in terms of sensitivity, specificity, PPV, and NPV values and their corresponding 95% Cis significance level is set at 0.05.

RESULTS

This study includes 100 patients with anovulation divided into two groups with following study.

t: Student t-test, p: p value for comparing between the studied groups and *: Statistically significant at p ≤ 0.05

Table 1: Comparison of the two study groups based on age and BMI.

Table (1) shows that there were insignificant changes between two groups as regard age, BMI (p-value 0.576, 0.433) respectively.

Table 2: Comparison of the two study groups based on different parameters. 

Table (2) shows that there were insignificant changes between two groups as regard parity and clinical presentation p-value 0.295, 1.000 respectively.

Table 3: Comparison of the two study groups based on infertility duration

Table (3) shows insignificant difference between two groups according to period of infertility.

Table 4: Comparison of the two study groups based on FSH and LH (IU/mL)

Table (4) shows that there were insignificant changes between two groups as regard to FSH, LH p-value 0.592, 0.121 respectively.

Table 5: Comparison of the two study groups based on the number of patients with growing follicles

Table (5) shows insignificant changes between two groups according to number of patients has growing follicles.

Table 6: Comparison of the two study groups based on the number of growing follicles (follicles ≥ 18).

Table (6) shows there were insignificant changes between the two groups in terms of the number of growing follicles (follicles ≥ 18) at day 12 (P-value 0.263)

Table 7: Comparison of the two study groups based on serum E2 (pg/mL)

Table (7) shows there were insignificant changes between the two groups in terms of serum E2 (p- value 0.235).

Table 8: Comparison of the two study groups based on endometrial thickness at the time of HCG need

Table (8) shows that there was a significant rise in group B (8.77) compared to group A (8.23) (p-value 0.012).

Table 9: Comparison of the two study groups based on the number of ruptured growing follicles

Table (9) shows in comparison between two groups as regard number of ruptured follicles after 48 hours of injection of HCG there were insignificant changes between two groups ( p-value 0.834).

Table 10: Comparison between two groups according to pregnancy rate /cycle

Table (10) shows in comparison between two groups as regard pregnancy rate/cycle there were insignificant changes between two groups (p-value 0.539).

Table 11: Comparison between two groups according to side impacts of the drugs utilized in induction.

Table (11) shows in the comparison between the two groups as regards the side impacts of the drugs utilized on induction. There was a significant increase in group B side effects (nausea, vomiting, and difficult breathing) and an insignificant difference in others.