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The aim of this study was to evaluate the impact of low dose liraglutide in combination with metformin compared to metformin alone on IVF pregnancy rate (PR) and cumulatively PR (IVF and spontaneous) in infertile obese women with PCOS who had been previously poor responders regarding weight reduction with lifestyle modification and resistant to first line reproductive treatments.
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, in particular when PCOS is linked to obesity. Obese PCOS has poor IVF outcomes associated with impaired oocyte and embryo parameters and morphology. The purpose of this pilot prospective study was to investigate the effect of the novel medical therapy (combination of metformin and liraglutide (COMBI)) in the specific infertile obese PCOS population. GLP-1 has been investigated in regulation of reproductive system in animal models. Current observations suggest that it directly regulates kisspeptin and GnRH expression and that ovaries express GLP-1 mRNA. In obese PCOS, GLP-1 receptor agonist liraglutide provided positive effects on weight reduction and glucose homeostasis
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metfrormin group (MET) | Active Comparator | Drug: Metformin |
|
| COMBI group (COMBI) | Active Comparator | Drug: liraglutide |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MET | Drug | In the MET group metformin was initiated at a dose of 500 mg once per day and increased by 500 mg every 3 days up to 1000 mg BID per os for 12 weeks. After 1 month IVF was done. |
| Measure | Description | Time Frame |
|---|---|---|
| IVF pregnancy rates | Clinical pregnancy rate defined as the presence of a fetal heart beat by ultrasound | 14 days |
| BMI | Patient's BMI was defined as the patient's body mass in kilograms divided by the square of their height in meters. | Patient's BMI was measured at the beginning and every four weeks during 12 weeks of clinical trial. ] |
| Cumulative pregnancy rates | Number of all pregnancies (IVF pregnancies and spontaneous pregnancies) per patient | The pregnancies were collected by phone interview after one year |
| Measure | Description | Time Frame |
|---|---|---|
| Oocyte nuclear maturation | The number of metaphase 2 oocytes, metaphase 1 oocytes, and germinal vesicles | 2 days |
| Embryo quality | The embryo quality assessed by standard cleavage stage embryo grading system on day 3 of embryo culture. For any embryos grown to day 5, the embryo quality assessed by standard blastocyst grading system on day 5 of embryo culture |
| Measure | Description | Time Frame |
|---|---|---|
| The other outcomes was changes changes in fasting concentrations of glucose | Patient's blood was drawn between 8 and 9 a.m. Concentrations of fasting glucose was measured in mmol/L. | Patient's fasting blood was drawn at the beginning and every four weeks during the 12 weeks of clinical trial. |
| The other outcomes was changes changes in fasting concentrations of insulin |
Inclusion Criteria:
Exclusion Criteria:
type 1 or type 2 diabetes mellitus
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| Name | Affiliation | Role |
|---|---|---|
| Eda Vrtacnik Bokal, professor | UMC Ljubljana | Study Chair |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24362411 | Background | Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol. 2014 Feb 7;170(3):451-9. doi: 10.1530/EJE-13-0797. Print 2014 Mar. | |
| 35834645 |
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| ID | Term |
|---|---|
| D011085 | Polycystic Ovary Syndrome |
| D009765 | Obesity |
| D007247 | Infertility, Female |
| D007246 | Infertility |
| ID | Term |
|---|---|
| D010048 | Ovarian Cysts |
| D003560 | Cysts |
| D009369 | Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 |
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| ID | Term |
|---|---|
| D000069450 | Liraglutide |
| D012996 | Solutions |
| D007267 | Injections |
| ID | Term |
|---|---|
| D052216 | Glucagon-Like Peptide 1 |
| D004763 | Glucagon-Like Peptides |
| D052336 | Proglucagon |
| D005768 | Gastrointestinal Hormones |
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|
| COMBI | Drug | In the COMBI group the initial dose of MET was 500 mg for at least 2 wk and gradually increased to a final dose of 1000 mg BID. Liraglutide 1.2 mg QD s.c. was added after first two weeks of monotherapy with MET. After 1 month IVF was done. |
|
|
| 6 days |
Patient's blood was drawn between 8 and 9 a.m. Fasting concentrations of insulin was measured in mU/L. |
| Patient's fasting blood was drawn at the beginning and every four weeks during the 12 weeks of clinical trial. |
| Other outcome was change in blood concentration of testosterone | Patient's blood was drawn between 8 and 9 a.m. Blood concentration was measured in nmol/L. | Patient's fasting blood was drawn at the beginning and every four weeks during the 12 weeks of clinical trial. ] |
| Other outcome was change in blood concentration in androstenedione. | Patient's blood was drawn between 8 and 9 a.m. Blood concentrations of androstenedione was measured in nmol/L. | Patient's fasting blood was drawn at the beginning and every four weeks during the 12 weeks of clinical trial. |
| Other outcome was change in blood concentrations of SHBG (sex hormone-binding globulin). | Patient's blood was drawn between 8 and 9 a.m. Blood concentrations of SHBG was measured in nmol/L. | Patient's fasting blood was drawn at the beginning and every four weeks during the 12 weeks of clinical trial. ] |
| Salamun V, Rizzo M, Lovrecic L, Hocevar K, Papler Burnik T, Janez A, Jensterle M, Vrtacnik Bokal E, Peterlin B, Maver A. The Endometrial Transcriptome of Metabolic and Inflammatory Pathways During the Window of Implantation Is Deranged in Infertile Obese Polycystic Ovarian Syndrome Women. Metab Syndr Relat Disord. 2022 Sep;20(7):384-394. doi: 10.1089/met.2021.0149. Epub 2022 Jul 13. |
| Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D004364 | Pharmaceutical Preparations |
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |