Effectiveness of Intrauterine Growth Hormone Administration as an add-on Therapy to Conventional Hormone Therapy Compared to Placebo in Patients With Thin Endometrium Undergoing Frozen Thawed Embryo Transfer

Effectiveness of Intrauterine Growth Hormone Infusion as an add-on Therapy to Conventional Hormone Therapy Compared to Placebo in Patients With Thin Endometrium Undergoing Frozen Thawed Embryo Transfer: A Double-blinded Parallel Exploratory Randomized Controlled Clinical Trial

The purpose of this clinical trial is to see if intrauterine growth hormone infusions can help subjects reach a suitable endometrial thickness in patients who are resistant to routine hormonal therapy for embryo transfer in the In Vitro Fertilization (IVF) cycle.

The primary aim of this study is to assess the effectiveness of injecting Growth hormone directly into the uterus to enhance endometrial thickness. Additionally, we aim to compare the likelihood of pregnancy between patients receiving the Growth hormone infusion and those receiving a placebo.

Study Overview

• Status: Completed
• Conditions: Infertility; Thin Endometrium; Infertility Female
• Intervention / Treatment: Drug: Growh hormone; Other: Placebo

Detailed Description

Infertility impacts approximately 10-15% of couples globally, with over 1 million couples affected in Iran alone, adversely affecting their quality of life. However, Assisted Reproductive Technology (ART), notably In Vitro Fertilization (IVF), has markedly enhanced fertility outcomes for couples facing infertility.

The primary reason for IVF failure is often attributed to difficulties with embryo implantation. A crucial determinant in preparing the uterus for successful implantation is achieving an adequate endometrial thickness. A thin endometrium, typically defined as less than 7 mm in thickness, is associated with a significantly reduced likelihood of successful pregnancy following implantation. As a result, patients with thin endometrium are often deemed unsuitable candidates for implantation.

Despite exploring various pharmacological options, certain patients remain unable to achieve the minimum required endometrial thickness for successful implantation. Prior investigations have examined the impact of subcutaneous growth hormone injections on endometrial thickness in individuals with thin endometrium, yielding mixed results across studies. Direct infusion of drugs into the uterine cavity presents a potential route for localized treatment, thereby minimizing systemic effects under specific circumstances. Thus, different studies explored the possible intra-uterine effect of drugs such as Granulocyte colony stimulating factor (GCSF), and Human chorionic gonadotropin (hCG). To date, only an animal study and two small studies without control group have investigated the efficacy of direct intrauterine infusion of growth hormone in increasing endometrial thickness among patients with thin endometrium. However, the absence of randomized controlled trials with placebo groups limits our understanding of the effectiveness of intrauterine growth hormone therapy in this patient population. Thus, we aimed to design an exploratory randomized clinical trial with parallel placebo group to evaluate the effectiveness of intrauterine Growth Hormone infusion as an add-on therapy to conventional hormone therapy compared to placebo in patients with thin endometrium undergoing frozen thawed embryo transfer

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Isfahan, Iran, Islamic Republic of, 8174673461
    • Isfahan Shahid Beheshti hospital, Hazrat e Maryam Fertility Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least a history of cycle cancellation due to a thin endometrium less than 7 mm following standard hormonal treatment
• Availability of ≥1 embryo with good quality
• Normal baseline hormones value including: Testosterone, Progesterone, Prolactin, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH)

Exclusion Criteria:

• Internal genital anomalies
• Active intrauterine infection Endometrial thickness≥7 on the 10th day of menstrual cycle
• History of Asherman syndrome
• History of cancer
• History of uterine surgery in past 3 months
• Intrauterine polyps visible in Transvaginal Ultrasonography
• Visible intrauterine adhesion
• Pathospermia in partner
• Premature ovarian failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Similar to the intervention group, from cycle day 10, an equal volume of 0.9% saline solution (normal saline) will be administered in addition to standard hormonal therapy. Treatment sessions will be conducted at two-day intervals. In case of non-response to treatment (failure to reach a minimum endometrial thickness of 7 millimeters in the subsequent assessment), the patient will receive a maximum of 4 doses, and if response to treatment is observed, placebo infusion will be discontinued. All infusions will be administered intrauterinely via an Intrauterine Insemination (IUI) catheter.
Active Comparator: Growth hormone	Drug: Growh hormone; In this group, patients will receive growth hormone solution containing 1.99 milligrams of the drug dissolved in 1.5 milliliters of 0.9% saline solution (normal saline), in addition to standard hormonal therapy, starting from cycle day 10. Treatment sessions will be conducted at two-day intervals. In case of non-response to treatment (failure to reach a minimum endometrial thickness of 7 millimeters in the subsequent assessment), the patient will receive a maximum of 4 doses, and if response to treatment is observed, growth hormone infusion will be discontinued. All infusions will be administered intrauterinely via an Intrauterine Insemination (IUI) catheter.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endometrial thickness	Measurement of endometrial thickness will be performed utilizing transvaginal sonography due to its closer proximity to the endometrium and with an empty bladder. To minimize the potential bias of measuring endometrial thickness during uterus contraction, occur during contractions, measurements will be taken only after the patient's contractions have ceased.	Baseline (On the 10th day of menstrual cycle), and On the day of response to treatment (in case of response) and in case of non-response to treatment on the 18th day of the mesntrual cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Pregnancy Rate	The number of fetuses that have a heartbeat and are not ectopic evaluated by Transvaginal Ultrasonography	6-8 of gestational week
Response to treatment	The number of patients that reach at least 7 mm of endometrial thickness	2 days following the last dose of placebo or growth hormone
Implantation rate	The number of gestational sacs to the number of transferred embryos evaluated by Transvaginal ultrasonography	6-8 of gestational week
IVF cancellation rate	The number of patients who do not reach enough endometrial thickness for transferring despite maximum treatment	2 days following the last dose of placebo or growth hormone
Early pregnancy complications	Including early miscarriage (miscarriage in less than 12th gestational week) and Ectopic pregnancy	During the first 12 weeks of pregnancy

Collaborators and Investigators

• Sponsor: Isfahan University of Medical Sciences

Publications and helpful links

General Publications

• Yu H, Gao S, Tang H, Chen H, Deng Z, Yang L, et al. Growth hormone intrauterine perfusion combined with replacement cycle in the treatment of non-response thin endometrium: report of 5 cases. Int J Clin Exp Med. 2016;9(6):11982-9
• Hosseini Aghdam S, Ghasemzadeh A, Farzadi L, Hamdi K, Baradaran-Binazir M, Nouri M, Fattahi A, Dttrich R. Growth Hormone: A Potential Treatment of Patients with Refractory Thin Endometrium: A Clinical Trial Study. Int J Fertil Steril. 2022 Oct 9;16(4):251-255. doi: 10.22074/ijfs.2022.541389.1210.
• Li W, Cao Z, Yu X, Hu W. Effect of growth hormone on thin endometrium via intrauterine infusion. Ann Transl Med. 2021 Aug;9(16):1325. doi: 10.21037/atm-21-3583.
• Altmae S, Aghajanova L. Growth Hormone and Endometrial Receptivity. Front Endocrinol (Lausanne). 2019 Sep 24;10:653. doi: 10.3389/fendo.2019.00653. eCollection 2019.
• Liu KE, Hartman M, Hartman A. Management of thin endometrium in assisted reproduction: a clinical practice guideline from the Canadian Fertility and Andrology Society. Reprod Biomed Online. 2019 Jul;39(1):49-62. doi: 10.1016/j.rbmo.2019.02.013. Epub 2019 Mar 20.
• Fu LL, Xu Y, Yan J, Zhang XY, Li DD, Zheng LW. Efficacy of granulocyte colony-stimulating factor for infertility undergoing IVF: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2023 Apr 3;21(1):34. doi: 10.1186/s12958-023-01063-z.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2024
• Primary Completion (Actual): July 29, 2024
• Study Completion (Actual): September 14, 2024

Study Registration Dates

• First Submitted: April 11, 2024
• First Submitted That Met QC Criteria: April 19, 2024
• First Posted (Actual): April 23, 2024

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 14, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Infertility; Growth Hormone; Infertility, Female; Human Growth Hormone; Somatropin; endometrial thickness; Thin Endoetrium; Intra-uterine infusion
• Additional Relevant MeSH Terms: Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Infertility; Infertility, Female; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: IR.MUI.MED.REC.1402.449; IRCT20110908007513N18 (Registry Identifier: IRAN registry of clinical trials (IRCT))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual Participant Data (IPD) may be shared following the publication of the study, as per specific requests from the researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No