Clinical trial NCT01662180: Predicting Ovarian Response in Artificial Insemination With Low Stimulation
Official title: Predicting Ovarian Response in Artificial Insemination With Low Stimulation
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Subfertility
Keywords: subfertility, IUI, rec FSH, FSH, E2, AMH
Lead sponsor: Isala
Sponsor class: OTHER
Collaborators: name: Merck Serono International SA
First posted: 2012-08-10
Enrollment: 510
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Subfertile couples presenting at fertility clinics with an indication for IUI in stimulated cycles

Brief summary: This large prospective multi-center cohort study aims to identify patient's characteristics that significantly influence ovarian response to mild stimulation with a fixed dose of 75 IU recombinant FSH.

Detailed description: A multi-center, open-label, prospective cohorts study. Patients with a regular indication for COH/IUI (controlled ovarian stimulation/ intra uterine insemination) will be asked to participate. Patient's characteristics will be documented including age, weight, BMI, smoking status, cycle day 2 3 or 4 FSH /Estradiol levels, antral follicle count, and AMH. AMH and FSH/Estradiol will be determined centrally after completion of inclusion of all patients in the study. All patients will receive a fixed 75 IU recFSH per day conform normal stimulation protocol starting from cycle day 3, 4 or 5 after exclusion of ovarian cysts by ultrasound. Ovarian response will be documented by ultrasound only. Once the dominant follicle(s) reach a mean diameter of 16-18 mm, hCG (5000IU or 250 mcg) will be applied and insemination will be scheduled 36-42 hours later. Cancellation criteria will be defined according to the national guidelines provided by the NVOG (7).

Eligibility criteria: Inclusion Criteria:

* couples with unexplained or mild male subfertility (1-3) and a spontaneous chance of conception below 40% (Hunault score).
* Unexplained subfertility including minimal to mild endometriosis (AFS grade 1 or 2) is defined as the failure to conceive after at least one year of unprotected intercourse whereas the standard fertility work-up was unable to detect any factors that might influence fertility negatively.
* semen analysis should be normal according to the WHO guidelines (8),
* ovulation should be documented (by BBT charts, ovulation detection by ultrasound or normal luteal progesterone values),
* tubal patency should be confirmed (HSG, laparoscopy or fertiloscopy) and when a postcoital test was performed a cervical factor should have been excluded.
* Mild male subfertility is defined as abnormal semen parameters according to the WHO (8) but an average total motile sperm account before processing of at least 10 million.

Exclusion Criteria:

* Hunault score ≥ 40%
* Endometriosis AFS grade 3 or 4
* Contra-indications for the use of gonadotrophins (cysts larger than 2 cm, allergy for gonadotrophins)
* Total motile sperm count after sperm processing below 1 million
* Women aged younger than eighteen years or older than 45 years.
* Previous treatment with COH/IUI for treating current subfertility
* Unable to speak or read the Dutch language

Primary outcomes:
measure: To assess the relationship between AMH serum levels and ovarian response
timeFrame: one menstrual cycle, one month
Secondary outcomes:
measure: To assess the relationship between age, weight, BMI, smoking, AFC, FSH/E2 on CD3 and ovarian response
timeFrame: one menstrual cycle, one month
measure: Pregnancy rate per started cycle.
timeFrame: three months
measure: Multiple pregnancy rate per started cycle.
timeFrame: three months
measure: Miscarriage rate per started cycle.
timeFrame: five months
measure: Cancellation rate per stimulated cycle
timeFrame: one menstrual cycle, one month
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: OLVG
state: Po 95500
city: Zwolle
country: Netherlands
facility: Isala Klinieken
state: PO Box 10400
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
state: PO box 1350
city: Amsterdam
country: Netherlands
facility: AMC
state: PO box 22660
city: Amsterdam
country: Netherlands
facility: VUMC
state: PO box 7057
city: Utrecht
country: Netherlands
facility: UMC Utrecht
state: PO box 85500
city: Tilburg
country: Netherlands
facility: st Elizabeth Gasthuis
state: PO box 90151
Study officials:
affiliation: Isala
name: Ben Cohlen, dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bensdorp AJ, Cohlen BJ, Heineman MJ, Vandekerckhove P. Intra-uterine insemination for male subfertility. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD000360. doi: 10.1002/14651858.CD000360.pub4.
citation: Verhulst SM, Cohlen BJ, Hughes E, Te Velde E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD001838. doi: 10.1002/14651858.CD001838.pub3.
citation: Tummon IS, Asher LJ, Martin JS, Tulandi T. Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil Steril. 1997 Jul;68(1):8-12. doi: 10.1016/s0015-0282(97)81467-7.
citation: Freiesleben NL, Lossl K, Bogstad J, Bredkjaer HE, Toft B, Loft A, Bangsboll S, Pinborg A, Budtz-Jorgensen E, Andersen AN. Predictors of ovarian response in intrauterine insemination patients and development of a dosage nomogram. Reprod Biomed Online. 2008 Nov;17(5):632-41. doi: 10.1016/s1472-6483(10)60310-0.
citation: la Cour Freiesleben N, Lossl K, Bogstad J, Bredkjaer HE, Toft B, Rosendahl M, Loft A, Bangsboll S, Pinborg A, Nyboe Andersen A. Individual versus standard dose of rFSH in a mild stimulation protocol for intrauterine insemination: a randomized study. Hum Reprod. 2009 Oct;24(10):2523-30. doi: 10.1093/humrep/dep239. Epub 2009 Jul 14.
citation: Freiesleben Nl, Rosendahl M, Johannsen TH, Lossl K, Loft A, Bangsboll S, Friis-Hansen L, Pinborg A, Andersen AN. Prospective investigation of serum anti-Mullerian hormone concentration in ovulatory intrauterine insemination patients: a preliminary study. Reprod Biomed Online. 2010 May;20(5):582-7. doi: 10.1016/j.rbmo.2010.02.007. Epub 2010 Feb 12.
citation: Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010 May-Jun;16(3):231-45. doi: 10.1093/humupd/dmp048. Epub 2009 Nov 24.
citation: La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio AC, Stabile G, Volpe A. Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update. 2010 Mar-Apr;16(2):113-30. doi: 10.1093/humupd/dmp036. Epub 2009 Sep 30.
citation: Nelson SM, Anderson RA, Broekmans FJ, Raine-Fenning N, Fleming R, La Marca A. Anti-Mullerian hormone: clairvoyance or crystal clear? Hum Reprod. 2012 Mar;27(3):631-6. doi: 10.1093/humrep/der446. Epub 2012 Jan 11.
citation: Rutten A, van Ballegooijen H, Broekmans F, Cohlen B; PRORAILS study group. Insights into ovarian response with a fixed low dose FSH stimulation in an IUI programme: the PRORAILS study. Hum Reprod. 2022 Jun 30;37(7):1440-1450. doi: 10.1093/humrep/deac076.