Nasal Oxcytocin During IUI
Condition: Idiopathic Infertility
MeSH terms: Infertility
Study type: Interventional

Summary: 
      Placebo-controlled study. Application of nasal oxytocin (8 IU) during intrauterine
      insemination in 86 patients.
    

Detailed description: 
      Between 2004 and 2007, 86 patients with primary or secondary infertility were enrolled in
      this prospective, randomized, double-blinded study in our tertiary-care infertility center. A
      total of 132 homologous intrauterine insemination (IUI) cycles (mean: 1.5 cycles) was
      performed. All patients gave informed consent. The study was approved by the Human Ethics
      Committee of the Medical Faculty of the Ludwig-Maximilians-University (LMU) Munich and the
      German Federal Institute for Drugs and Medical Products (BfArM) (Bundesinstitut für
      Arzneimittel und Medizinprodukte) consented to the study.

      Inclusion criteria for couples were idiopathic infertility, polycystic ovary syndrome (PCOS)
      and / or male subfertility (table 1). Maximum female age was 42 years. Infertility workup
      included a standard gynecological examination with a transvaginal sonography using a 7.5 MHz
      probe. Patients displaying signs or symptoms of anomalies such as uterine fusion defects,
      submucosal fibroids, active endometriosis or acute inflammation were excluded from the study.
      Further prerequisites were endocrine serum parameters (FSH, LH, estradiol, testosterone,
      SHBG, DHEA-S, Prolaktin, TSH) from cycle day 2-5 within the normogonadotropic range with no
      evidence of hyperandrogenemia, thyroid dysfunction or hyperprolactinemia. 15 patients were
      diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam ESHRE/ASRM
      Consensus Workshop Group (26). In all patients fallopian tubes were documented to be patent
      by sonographic contrast hysterosalpingography (Echovist® 200, Bayer Vital GmbH, Leverkusen,
      Germany) or by chromo-laparoscopy. Infections with Hepatitis B and C and HIV were excluded in
      all couples by negative serological tests. In all patients protective titers against rubella
      virus were confirmed.

      IUI was performed in natural (n=31, 23%) or stimulated cycles (n=101, 77%). Stimulation was
      done with daily s.c. 37 IU or 50 IU of recombinant FSH (Puregon, Organon GmbH,
      Oberschleißheim, Germany) starting on day 3 to day 5 of the menstrual cycle. Cycles were
      monitored by repeated transvaginal sonography and determination of serum estradiol and LH.
      Ovulation induction (OI) was done by 5.000 IU hCG (Predalon, Organon GmbH, Oberschleißheim,
      Germany) s.c. or 250 μg recombinant hCG (Ovitrelle, Serono GmbH, Unterschleißheim, Germany)
      s.c. as soon as one of maximum three follicles reached a mean diameter of 20 mm or LH
      exceeded 10 mIU/mL in combination with a follicle mean diameter of at least 16 mm. IUI was
      done 24h-36h after OI. Data on uterine, ovarian and endocrine parameters at the time of
      ovulation induction (OI) are summarized in table 2.

      Homologous semen samples were gained by masturbation after an abstinence time of 3-5 days.
      After liquification for 30 min analysis of semen parameters were carried out according to the
      World Health Organization guidelines (27). Details on results are summarized in table 2.
      Sperm morphology was analysed according to WHO guidelines in at least one semen analysis
      preceding this study not more than 3 months. The sperm preparation was conducted utilizing
      density gradient separation as described in the WHO manual (27). Sil Select (FertiPro N.V.,
      Beernem, Belgium) was used instead of Percoll as recommended in the WHO manual (27). The
      density gradient (90%/45%) achieved separation of sperm after centrifugation at 500 g for 20
      minutes. The pellet was washed in 5.0 mL Universal IVF Medium (Medi Cult, Jyllinge, Denmark),
      centrifuged for 5 minutes at 500 g and resuspended in a total volume of 0.3 mL. After
      processing, semen was evaluated for sperm concentration and motility. Only couples with a
      total progressive motile sperm count (TPMC) of at least 1 million in the processed sperm
      suspension were included in the study. Data are summarized in table 2.

      Oxytocin and placebo, filled in identical nasal spray applicators labelled with "A" or "B",
      were delivered by the pharmacy department of LMU-Klinikum, Campus Grosshadern. Probes were
      blinded to the clinical staff and the patients. The verum consisted of Synthocinon®-Spray
      (Novartis Pharma GmbH, Nürnberg, Germany). According to the manufacturer one nasal spray pump
      consists of 4 IU of oxytocin. In addition the verum contained chlorobutanol,
      methyl-4-hydroxybenzoat and propyl-4-hydroxybenzoat for preservation. Placebo consisted of
      isotonic NaCl solution with 0.01 % benzalkoniumchloride und 0.1% Na-EDTA for preservation.
      The nasal sprays were kept at 4°C and replaced monthly. Patients were randomly assigned to
      either group A or group B (double-blinded) by using a computer generated randomization list.
      Codes for A and B were broken after the last study patient had completed the pregnancy test.
      Data on patient variables in both groups are summarized in table 2. All patients were asked
      to squeeze the spray into the air for control of the pump mechanism and then to apply two
      snuffs (=8 IU oxytocin) of nasal spray labelled with A and B respectively into one nostril
      directly after IUI.

      Ten minutes after completion of the IUI patients were asked to fill out a form documenting
      possible side effects. Each of the following complaints was asked to be quantified in a scale
      from level 1 (=no side effect) to level 10 (=maximum side effect): lower abdominal pain,
      nasal mucosal irritation, nausea, headache and vomiting.

      The primary endpoint of the study was evidence of a chorionic sac in transvaginal sonography
      21-23 days after IUI with a positive serum hCG test.

      Statistical analysis was carried out using SPSS 16.0. Binary logistic regression was applied
      for calculation of Odds ratio and likelihood ratio test. For all comparisons, p < 0.05 was
      considered significant.
    

Intervention name(s): oxytocin, placebo
Intervention type(s): Drug
Intervention description(s): intranasal oxytocin during intrauterine insemination
Other intervention name(s): Synthocinon
Intervention MeSH terms: Oxytocin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: IUI; oxytocin