Effect of letrozoole therapy in unsuccessful iui in adenomyosis uterus- a pilot study

Study title: EFFECT OF LETROZOLE THERAPY IN UNSUCCESSFUL INTRAUTERINE INSEMINATION IN ADENOMYOSIS UTERUS

Rationale: Infertility due to adenomyosis is nearly 7.5%-22% in reproductive age group females.1 One of the treatment modalities of infertility due to adenomyosis is IUI with ovulation induction. Adenomyosis is a hyperestrogenic condition. Repeated uterine over stretching can lead inflammation and increased local production of estrogen. Hyperestrogenic condition lead to increased uterine contractions damaging the endomyometrial junctional zone. Increased aromatase activity in adenomyosis has lead to use of aromatase inhibitor for symptomatic improvement but there is a dearth of studies that show letrozole as a pretreatment.

Letrozole has not been conventionally used for adenomyosis. Letrozole is an anti aromatase and thus acts peripherally by stopping the estrogen production and might be helpful in reducing the uterine wall thickness and size and will restore endomyometrial junctional zone.

Hence, using letrozole in infertile adenomyotic patients as pretreatment before IUI may improve the success of IUI in these patients significantly.

Aim: To study the effect of letrozole in unsuccessful IUI with adenomyosis.

Primary objective: To study the effect of letrozole therapy for 3 months in cases of unsuccessful IUI with adenomyosis

Secondary objective

1. To compare USG changes in study subjects before and after 3 months of letrozole therapy

2. To compare dysmenorrhea using visual analogue score and menstrual blood flow using pictoral blood assessment chart at 6 and 12 weeks of letrozole therapy

3. To observe side effects of letrozole therapy if any like nausea, vomiting and ovarian cyst, if any other will observe

Study setting: Departments of Obstetrics and Gynecology and Department of Radio diagnosis, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi

Study Design: Interventional Pilot study

Time Frame: April 2024 to August 2025

Participants:

Inclusion criteria- Infertile females aged 20-38 years with adenomyosis and with previous 2 unsuccessful attempts at IUI.

Exclusion criteria-

1. Uterus size>12 weeks

2. Co existent fibroid uterus, adnexal mass, endometriosis, pelvic endometrioma and pelvic inflammatory disease

3. Male infertility

4. Patient with chronic medical disorders- Diabetes Mellitus, Hypertension, Thyroid, tuberculosis and liver disorders

Sample size: Even on extensive research we could not find any article which is related to our primary objective and no study has been done regarding the same world wide. Therefore, we could not calculate the sample size and propose to conduct a pilot interventional trial taking a sample size of 20 for this study.

Statistical analysis:

The success rate of IUI in infertile adenomyotic patients will be reported as %. Before and after medication changes will be compared by Mc Nemar test. p-value of <0.05 will be considered significant. SPSS version 20.0 will be used for statistical analysis.

Methodology:

Ethical clearance will be obtained from the institutional ethics committee of UCMS and this study will be registered in Clinical Trial Registry of India prior to conducting the study.

20 cases of USG diagnosed adenomyosis females who have previous 2 cycles of failed IUI, (proven diagnosis by Ultrasound confirmed- MUSA consensus criteria) and fulfilling the inclusion and exclusion criteria and giving written informed consent will be recruited for the study after ruling out male factor infertility in partner. Details of MUSA criteria are given in Annexure- 2. A detailed history taking and examination including gynecological examination will be done to assess the size of uterus, mobility, tenderness and any adnexal pathology.

At Baseline-

A) VAS score- Visual analogue scale (pain on a scale of 0-10)

B) Pictorial blood assessment chart (PBAC) score will be noted for quantification of menstrual blood loss by the patient.

C) Transvaginal ultrasound (TVS) will be done in postmenstrual phase (Day 8 to Day 12 and if amenorrhea present then any date) for Uterine volume, presence of adenoma, measurement of anterior and posterior wall thickness, myometrial Cysts- number and size, hypoechoic islands- number and size and fan shadowing.

Patient is to be given letrozole 2.5 mg OD for 3 months following which we will compare the uterine ultrasound changes.

Follow up:

Patient will be followed up at 6 weeks and 12 weeks and we will look for compliance of letrozole therapy, VAS, PBAC and side effects and at 12 weeks repeat scan will be done for ultrasound changes in adenomyotic lesions.

Couples diagnosed with female infertility due to adenomyosis having normal ovulation, bilateral tubal patency and normal semen analysis in the male partner will be considered in the study.

The couple will undergo IUI for maximum of 2 cycles as per institutional protocol after 3 months of letrozole therapy, IUI will be performed in all patients after controlled ovarian stimulation with Injection Gonadotrophins as per standard protocol.

Semen preparation will be done as per as standard protocol.

Successful IUI will be defined as positive urine pregnancy test or confirmation on ultrasound or biochemical confirmation.

Outcome measures:

Primary outcome:

Success rate of IUI in patients with uterine adenomyosis after 3 months of letrozole therapy.

Secondary outcome:

1. Compare the changes in the USG parameters of uterus of adenomyotic patients after 3 months of letrozole therapy.

2. Comparison of Mean VAS score at 6 and 12 weeks of letrozole treatment.

3. Change in mean PBAC score for heavy menstrual bleeding from baseline at 6 and 12 weeks of letrozole treatment.

4. To observe any side effects of letrozole therapy including nausea, vomiting, ovarian cyst and any other will be observed.