This Open label, prospective, Investigator Initiated observational surveillance study conducted between observation period of January to May 2014 in five out-patient settings across India with approval from an Independent Ethics Committee. The study was conducted as per International Conference for Harmonisation -Good Clinical Practise (ICH GCP) Guidelines, Schedule Y of Drugs and Cosmetic Act with written informed consent from patients.

The study population consisted of females aged 22 to 40 years with at least 1 year history of unexplained infertility. A total of 120 cases of unexplained infertility were evaluated in the study. Exclusion criteria included women with history of Progesterone (Natural or synthetic) use in the last cycle, history of tubal insufficiency or obstruction including Endometriosis or Polycystic Ovarian Syndrome, AST and/or ALT > 2.5 x ULN (active liver disease), Serum creatinine >1.5 mg/dl (active renal disease), Uncontrolled hypertension, hypercholesterolemia or diabetes, oral anticoagulants or prolonged use of high doses of NSAIDs, Hypersensitivity to Natural micronized progesterone, Spouse with Male factor infertility.

At baseline visit, detailed history, physical examination and medications of the subjects were recorded. Patients with baseline FSH <10mIU/ml or E (2) levels <80 pg/ml on Day 0+/-2 day of cycle with sr. progesterone levels were assessed on the day of IUI procedure respectively were included for the analyses.

In the next cycle, ovalogens including Clomiphene citrate (100 to 150 mg) was administered from 2^nd to 6^th day of cycle for 5 days. Each of the cycles was further stimulated with HMG for 3 to 5 days from Day 4 with regular monitoring of mono- or bi-follicular growth by ultrasound. The injections were continued till the ovarian follicles were large enough (≈16 to 18 mm) for HCG 5000-10000 IU trigger on 12^th or 13^th day to release the eggs. IUI procedure was conducted within the next 48 hours while assessing the baseline sr. progesterone levels. On the same day of HCG trigger, patients were prescribed Progesterone supplement i.e oral NMP SR 200/300mg OD or Dydrogesterone 10mg BD for 2 weeks. Serum progesterone levels were repeated on Day 21+/-2 of the stimulated cycles with pregnancy confirmation by biochemical and urinary estimation of beta-HCG subsequently after the ‘First’ IUI cycle.

In case of pregnancy being confirmed, the progesterone regimen was continued for upto 8 to 12 weeks further. Otherwise the drug regimen was discontinued after 2 weeks and appropriate therapy as justified by the doctor was followed.

Any side effects or serious adverse events including death, life-threatening (real risk of dying), hospitalization (initial or prolonged), disability (significant, persistent or permanent), congenital anomaly, required intervention to prevent permanent impairment or damage arising during the course of the study were documented and notified to Drug Controller General of India (DCGI) on the Suspected Adverse Drug Reaction reporting form of Central Drug Standard Control Organization (CDSCO). A post-hoc statistical analysis involving descriptive statistics and paired-t test utilizing IBM SPSS statistics v.21 software package was carried out to assess the level of significance with p< 0.05 considered as significant.

Data records from 120 patients who underwent IUI procedure for unexplained infertility between the observation period was collated for analyses. Twelve of these patients had confounding Male factor subfertility or intermediate infertility amongst their partners and excluded from analyses. Amongst the rest, baseline sr. progesterone assessment records were available in 78 patients as highlighted in [Table/Fig-1].

[Table/Fig-1]:

Patient disposition chart at the end of the study.

Of the 42 cases, 12 couples did not fulfill the exclusion criteria for Male factor infertility as suggested by WHO guidelines (2010) since the objective data on sperm motility (progressive or total) was missing. In the rest of the thirty (30) cases, baseline sr. progesterone levels were not available for analyses and therefore excluded from the Per Protocol analyses.

Baseline demographics showed mean age, weight and cycle duration distribution of 29.5 years, 57.3 kg & 28.6 days respectively. Progesterone was supplemented as Oral NMP SR 200/300 mg OD or Dydrogesterone 10 mg bid in 22, 23 and 33 patients respectively. In all cases ovulation was triggered with HCG Injection followed by IUI within the next 48 hours while baseline sr. progesterone levels were being assessed. The baseline demographics are presented in [Table/Fig-2].

Ovulation Induction was done with Clomiphene citrate 100 mg for 5 days in 95% of patients and Inj HMG 75/150 mg for 3days in 98% of patients. Luteal phase support given with Dydrogesterone 10 mg BD in 33 patients and oral NMP SR 200mg OD in 22 patients and Oral NMPSR 300mg OD in 23 patients respectively.

The obstetric history was not significant with Secondary infertility noted in 13 (0.4%) and 7 (0.2%) patients for Dydrogesterone and oral NMP SR groups respectively. Amongst the cases of secondary infertility in oral NMP SR, 10% cases had history of stillbirth.

Mid-luteal sr. progesterone levels assessed in both groups on Day 21+/-2 showed mean levels of 30.7 and 28.5 ng/ml in both the groups for Dydrogesterone and oral NMP SR group respectively [Table/Fig-3].

Adverse events: Oral NMP SR and Dydrogesterone were both found to be safe and well tolerated. Only 3 cases of drowsiness and 1 case of nausea were seen with OMP SR while 4 cases of nausea and 1 case of drowsiness reported with Dydrogesterone.

Unexplained infertility continues to be an important cause of infertility with few treatment options available at the disposal of the clinician. Despite the varied aetiology involving immunologic, endocrinological or genetic reasons, the over-reliance on the use of ART techniques has never been underemphasized. In this line the clinical benefits and utility of Controlled ovarian Hyperstimulation plus intrauterine insemination as strategy has often been shown to be more effective than intrauterine insemination especially in terms of fecundity or pregnancy rates.

Success rate for patients undergoing IUI has been found to be varied. IUI in the spontaneous cycle among women with unexplained infertility yields pregnancy rates of 2.4-7.4% per cycle [7,8] which is similar to pregnancy rates of expectant management [8]. If CC is used without IUI, the pregnancy rate per cycle is 4-5.6% among women with unexplained infertility [7,9]. The use of gonadotropins (hMG) alone is associated with a pregnancy rate of 7.7% [7]. If CC is used in combination with IUI, the pregnancy rate per cycle is approximately 8.3% [7]. However, in case of COH + IUI, the pregnancy rate per cycle varies from 3.8 to 14.3% [10–13]. Though several factors could explain the divergent success rates reported for First cycle IUI procedure following Controlled Ovarian Hyperstimulation (COH) with CC/HMG stimulation protocol, LPS with progesterone has often been recommended for better ‘implantation’ and therefore successful ‘ongoing’ pregnancy. In this line, MHRA has recommended mid-luteal sr. progesterone levels as ≥14 ng/ml to adequately ‘sustain’ pregnancy especially in documented cases of luteal phase deficiency

A recently concluded open-label observational study conducted by Gopinath [6], to determine the success of first cycle IUI that was unstimulated or CC regulated involving LPS with oral natural or synthetic progesterone showed promising results. 93.3% of the patients in both the groups achieved ‘therapeutic’ mid-luteal sr. progesterone levels especially with oral NMP SR 400 mg group. Similarly pregnancy rate of 3.3 & 6.6% were noted in with Dydrogesterone and Oral NMP SR group respectively [6]. While in the present study, 82.2% of the patients achieved achieved mid luteal Serum. Progesterone levels ≥ 14 ng/ml with pregnancy rate of 11% (n=5) for Oral NMP SR group receiving 200 or 300 mg once a day for the ‘First’ cycle of Controlled Ovarian Hyperstimulation (COH) + IUI.

These results with oral NMP SR are similar to those reported by Jang et al., for women with unexplained infertility [14]. Jang reported pregnancy rates of 7.8% and 12% for women undergoing Natural or COH+IUI cycle compared with 6.6% and 11% reported by Gopinath et al., and current study respectively [6]. This open label, observational study further compliment the findings by Gopinath et al., regarding the clinical role of oral NMP SR in women with iatrogenic progesterone insufficiency due to CC/HMG cycles unlike the natural cycles that was earlier reported [6]. These clinical findings for the first cycle however need to be further confirmed in a reproducible, double blind, randomized clinical trial setting.

Clinical supplementation with oral NMP SR suggests therapeutic compliance and alternative strategy to conventional formulations while offering dosing convenience with minimal side effects.