Discussion

Progesterone is essential for the establishment and maintenance of pregnancy. As such, exogenous progesterone is used therapeutically for several obstetric indications associated with low progesterone levels including luteal phase support during ART, management of threatened spontaneous miscarriage, prevention of some cases of PTD, and treatment of patients with high-risk pregnancies (unexplained poor obstetric history or at risk of PTD). In regions without specialist IVF/ICSI facilities, IUI may be a practical approach to enhance fertility. It is a simpler and less intrusive procedure than other ART methods, is widely available, and can be a successful and safe option in selected patients.21Studies suggest that oral NMP and NMP-SR may be an effective and feasible option in this setting.
Route of administration is an important aspect of any therapy as it may influence treatment adherence and treatment satisfaction. In obstetric indications, natural progesterone can be administered by IM, vaginal, and oral routes. From the patient’s perspective, oral administration is less painful than IM injection and may be less embarrassing and messy than intravaginal administration. In some countries, including India, women are notably reluctant to use intravaginal medications, particularly during pregnancy, and prefer to take oral medication [personal communication, Reena J Wani]. A preference for oral progesterone over vaginal suppositories has previously been reported.45 Among oral progestogen options for use in pregnancy, NMP-SR represents an important advance, providing improved bioavailability and better tolerability than conventional oral NMP. A once-daily dose of NMP-SR maintains serum progesterone concentrations in the luteal phase range (i.e. ≥ 14 ng/mL) in contrast with the multi-dose regimens required with conventional oral NMP and dydrogesterone. A once-daily oral regimen of NMP-SR is convenient for patients, and may enhance treatment efficacy through better adherence.
In terms of safety and tolerability, oral progestogen preparations avoid the local effects associated with IM injections or intravaginal administration. The sustained-release kinetics of the NMP-SR formulation and absorption of intact progesterone in the distal part of the gastrointestinal tract avoids drug loss through first-pass metabolism and minimizes any central side effects caused by the formation of active metabolites.9 Drowsiness, the most frequent adverse event with conventional oral NMP, is much less common with NMP-SR.
NMP-SR has been available in India for more than 7 years and is increasingly becoming physicians’ treatment of choice for obstetric indications. A real-world national survey of 925 Indian gynaecologists found that 23% reported oral NMP-SR as their preferred choice for management of luteal phase defects, 11% as their preferred choice for luteal phase support during ART, 10% as their preferred choice for prevention of PTD, while 56% reported that NMP-SR was their preferred choice for all three indications.9 In women with a poor obstetric history associated with luteal phase deficiency, 58% of the clinicians preferred to use vaginal progesterone, 36% oral NMP-SR, and 6% dydrogesterone. Thus, oral NMP-SR has an important role in managing obstetric conditions in India. Given the established efficacy of oral NMP during more than 30 years’ use, and enhanced pharmacokinetics and safety profile of NMP-SR, global interest in NMP-SR might be expected in the near future.
The review is limited by the relatively small number of studies (especially studies of NMP-SR), modest sample sizes in some studies, and low evidence quality of some studies. Only about half of reviewed studies (55%) were RCTs, although observational studies also have value in terms of reflecting the real-world standard of care. As searches were limited to PubMed and Cochrane Database, it is possible that some studies of oral NMP and NMP-SR were missed. To minimize this possibility, search terms were purposely broad and all retrieved records were checked individually.