Clinical Cohort Study on the Endocrinology and Vaginal/Endometrial Microbiome of the Luteal Phase in Assisted Reproduction

NCT03507673 | Recruiting

• 1 other identifier: Aktenzeichen: 18-005
• Study Type: observational
• Target: 1,200
• Locations: 1 country
• Sites: 5

Brief Summary

Rationale: The hormone progesterone has different functions. In pregnancy, it is vital for maintenance thereof. In early pregnancy, progesterone is synthesized by the Corpus luteum (CL). Its production shifts from the CL to the placenta after several gestational weeks. This process is termed luteoplacental shift. Still, the exact time point of the luteoplacental shift remains unknown. Furthermore, the characteristics of placental progesterone increase and its relevance for the course of pregnancy has not been studied so far. Furthermore, recent studies have shown an influence of abnormal vaginal microbiota on the likelihood to achieve and maintain pregnancy. Little is known about possible crosslinks between endocrinology and vaginal/endometrial microbiota which is why this study aims to investigate possible associations of such kind. Objective: The primary objective of this study is to evaluate the time point of the luteoplacental shift in patients achieving pregnancy after transfer of cryopreserved embryos subsequently to IVF/ICSI cycles. Secondary objectives are to study the characteristics of the placental progesterone increase and its function as a predictor of the course and development of pregnancies and to study vaginal/endometrial microbiota at baseline and changes associated with shift into luteal phase and early pregnancy and how this potentially relates to pregnancy outcome. Study Design: Prospective, multi-center, observational clinical cohort study. For the primary objective, data from a single center will be also be retrospectively analyzed. Study population: Female patients aged 18 to 45 years undergoing transfer of embryos after freezing and thawing 2PN oocytes or embryos. Interventions: Blood withdrawal, vaginal/endometrial swabs and endocrine and microbiom analyses. Study parameters/endpoints: The main parameter is time point of progesterone increase in pregnancy in relation to initial progesterone levels by pregnancy status. Secondary, slope and magnitude of placental progesterone increase and its relevance as a predictor for the course and development of pregnancies/babies. Furthermore, vaginal microbiota of women undergoing embryo transfer and of women in early pregnancy are parameter of this study.

Conditions

Infertility

Outcome Measures

Primary Outcomes (1)

• Serum progesterone (microgram/Liter) levels.

  31.12. 2020

Secondary Outcomes (3)

• Change of vaginal microbiome between follicular phase, luteal phase and early pregnancy

  31.12.2022

• Vaginal bleeding pattern in the luteal phase and early pregnancy in frozen-thawed embryo transfer cycles

  31.12.2022

• Association of endocrine values and bleeding, microbiome status and treatment outcome

  31.12.2022

Study Arms (4)

Progynova/Dydrogesterone

Diagnostic Test: Blood samples and microbiological swaps

Spontaneous cycle

Diagnostic Test: Blood samples and microbiological swaps

Progynova/Crinone

Diagnostic Test: Blood samples and microbiological swaps

Others Medication

Diagnostic Test: Blood samples and microbiological swaps

Interventions

Blood samples and microbiological swaps DIAGNOSTIC_TEST

Blood analysis and analysis of vaginal microbiota.

Others Medication; Progynova/Crinone; Progynova/Dydrogesterone; Spontaneous cycle

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Patients attending infertility clinic.

You may qualify if:

• Patients aged 18 to 45 years
• Transfer of cryopreserved embryos

You may not qualify if:

• Fresh IVF/ICSI embryo transfer cycle
• Evidence for ovulation on ultrasound previous to embryo transfer confirmed by a follicle ≥14mm or by a progesterone ≥1.0 µg/l in programmed cycles
• Uterus malformations, endometrial abnormalities (on ultrasound or diagnosed by previous hysteroscopy)

Sponsors & Collaborators

• University of Luebeck: lead

Study Sites (5)

IVF-SAAR

Saarbrücken, Saarland, 66113, Germany

RECRUITING

Universitäres Kinderwunschzentrum Lübeck

Lübeck, Schleswig-Holstein, 23562, Germany

RECRUITING

Universitätsklinikum Düsseldorf,UniKiD

Düsseldorf, 40225, Germany

RECRUITING

Universitäres Kinderwunschzentrum

Kiel, 24105, Germany

RECRUITING

University of Luebeck

Lübeck, Germany

RECRUITING

Related Publications (17)

• Rommler A, Kreuzer E. [Endocrinologic aspects of habitual abortion]. Zentralbl Gynakol. 2001 Jun;123(6):344-52. doi: 10.1055/s-2001-16284. German.

  PMID: 11488162 BACKGROUND

• Csapo AI, Pulkkinen MO, Ruttner B, Sauvage JP, Wiest WG. The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary studies. Am J Obstet Gynecol. 1972 Apr 15;112(8):1061-7. doi: 10.1016/0002-9378(72)90181-0.

  PMID: 5017636 BACKGROUND

• Ogino M. Productivity of estrogens by human placental organ culture at different stages of gestation. Endocrinol Jpn. 1985 Oct;32(5):607-13. doi: 10.1507/endocrj1954.32.607.

  PMID: 4092668 BACKGROUND

• Devroey P, Camus M, Palermo G, Smitz J, Van Waesberghe L, Wisanto A, Wijbo I, Van Steirteghem AC. Placental production of estradiol and progesterone after oocyte donation in patients with primary ovarian failure. Am J Obstet Gynecol. 1990 Jan;162(1):66-70. doi: 10.1016/0002-9378(90)90822-o.

  PMID: 2154102 BACKGROUND

• Scott R, Navot D, Liu HC, Rosenwaks Z. A human in vivo model for the luteoplacental shift. Fertil Steril. 1991 Sep;56(3):481-4. doi: 10.1016/s0015-0282(16)54544-0.

  PMID: 1894025 BACKGROUND

• Azuma K, Calderon I, Besanko M, MacLachlan V, Healy DL. Is the luteo-placental shift a myth? Analysis of low progesterone levels in successful art pregnancies. J Clin Endocrinol Metab. 1993 Jul;77(1):195-8. doi: 10.1210/jcem.77.1.7686913.

  PMID: 7686913 BACKGROUND

• Tulchinsky D, Simmer HH. Sources of plasma 17alpha-hydroxyprogesterone in human pregnancy. J Clin Endocrinol Metab. 1972 Dec;35(6):799-808. doi: 10.1210/jcem-35-6-799. No abstract available.

  PMID: 4634481 BACKGROUND

• Jarvela IY, Ruokonen A, Tekay A. Effect of rising hCG levels on the human corpus luteum during early pregnancy. Hum Reprod. 2008 Dec;23(12):2775-81. doi: 10.1093/humrep/den299. Epub 2008 Aug 10.

  PMID: 18694877 BACKGROUND

• Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017 May 1;32(5):1019-1027. doi: 10.1093/humrep/dex023.

  PMID: 28333318 BACKGROUND

• van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015 Jul 7;2015(7):CD009154. doi: 10.1002/14651858.CD009154.pub3.

  PMID: 26148507 BACKGROUND

• Haahr T, Jensen JS, Thomsen L, Duus L, Rygaard K, Humaidan P. Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Hum Reprod. 2016 Apr;31(4):795-803. doi: 10.1093/humrep/dew026. Epub 2016 Feb 23.

  PMID: 26911864 BACKGROUND

• van Oostrum N, De Sutter P, Meys J, Verstraelen H. Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis. Hum Reprod. 2013 Jul;28(7):1809-15. doi: 10.1093/humrep/det096. Epub 2013 Mar 29.

  PMID: 23543384 BACKGROUND

• Graspeuntner S, Bohlmann MK, Gillmann K, Speer R, Kuenzel S, Mark H, Hoellen F, Lettau R, Griesinger G, Konig IR, Baines JF, Rupp J. Microbiota-based analysis reveals specific bacterial traits and a novel strategy for the diagnosis of infectious infertility. PLoS One. 2018 Jan 9;13(1):e0191047. doi: 10.1371/journal.pone.0191047. eCollection 2018.

  PMID: 29315330 BACKGROUND

• Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014 Dec;35(6):851-905. doi: 10.1210/er.2014-1045. Epub 2014 Aug 20.

  PMID: 25141152 RESULT

• Di Renzo GC, Giardina I, Clerici G, Brillo E, Gerli S. Progesterone in normal and pathological pregnancy. Horm Mol Biol Clin Investig. 2016 Jul 1;27(1):35-48. doi: 10.1515/hmbci-2016-0038.

  PMID: 27662646 RESULT

• Eggersmann TK, Hamala N, Hiller AR, Depenbusch M, Schultze-Mosgau A, Edimiris P, Baston-Bust D, Bielfeld AP, Kruessel JS, von Otte S, Junkers W, Tauchert S, Vonthein R, Griesinger G. Live birth rates are unrelated to sex-steroid levels on ET day in a dydrogesterone-based 'programmed-ovulatory FET' protocol: a multi-centric prospective cohort study. Hum Reprod Open. 2025 Sep 15;2025(4):hoaf058. doi: 10.1093/hropen/hoaf058. eCollection 2025.

  PMID: 41221299 DERIVED

• Neumann K, Masuch A, Vonthein R, Depenbusch M, Schultze-Mosgau A, Eggersmann TK, Griesinger G. Dydrogesterone and 20alpha-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study. Hum Reprod. 2022 May 30;37(6):1183-1193. doi: 10.1093/humrep/deac045.

  PMID: 35323905 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood samples and Microbiological swaps (cervix uteri and endometrial sampling)

MeSH Terms

Conditions

Infertility

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Georg Griesinger, MD

  Sektion für gynäkologische Endokrinologie und Reproduktionsmedizin

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Georg Griesinger, MD

CONTACT

+49451 50577810; georg.griesinger@uni-luebeck.de

Tanja Eggersmann, MD

CONTACT

+49451 50577810; tanja.eggersmann@uksh.de

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 14, 2018
• First Posted: April 25, 2018
• Study Start: May 2, 2018
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): June 30, 2028
• Last Updated: May 22, 2025

Record last verified: 2025-05

Locations

DE (5)