Different Routes of Progesterone For ET – Dr. Ira Biswas


During assisted reproductive technology (ART) treatment, the use of gonadotropin-releasing hormone (GnRH) agonists and the aspiration of follicular fluid can lead to a relative progesterone deficit and inappropriate preparation of the endometrium for embryo implantation. Defective production of progesterone (P4) may impair implantation and pregnancy rates.

Different routes of natural progesterone supplementation have been tried . Orally administered progesterone is rapidly metabolized in the gastrointestinal tract and its use has proved to be inferior to i.m. and vaginal routes. Progesterone i.m. achieves serum progesterone values that are within the range of luteal phase and results in sufficient secretory transformation of the endometrium and satisfactory pregnancy rates. The comparison between i.m. and vaginal progesterone has led to controversial results as regards the superiority of one or the other in inducing secretory endometrial transformation. However, there is increasing evidence in the literature to favour the use of vaginal progesterone. Vaginally administered progesterone achieves adequate endometrial secretory transformation but its pharmacokinetic properties are greatly dependent on the formulation used. After vaginal progesterone application, discrepancies have been detected between serum progesterone values and histological endometrial features. Vaginally administered progesterone results in adequate secretory endometrial transformation, despite serum progesterone values lower than those observed after i.m. administration, even if they are lower than those observed during the luteal phase of the natural cycle. This discrepancy is indicative of the first uterine pass effect and therefore of a better bioavailability of progesterone in the uterus, with minimal systematic undesirable effects.

Preparation of an artificial endometrium for FET has evolved dramatically over the past 15 years. The initial regimens involved the use of GnRH analogues for pituitary suppression followed by the administration of exogenous estrogens to stimulate the endometrium. This was followed by progesterone (P4) supplementation for 3 to 6 days before ET. Several studies have questioned the need for GnRH analogues for the pituitary suppression of endogenous ovulation. Indeed, “natural cycle over-ride” regimens have been used in which high doses of exogenous estrogens are administered during the follicular phase of the natural cycle to prevent a premature LH surge followed by progesterone supplementation for luteal phase support when the endometrium is of adequate thickness. Both regimens have been shown to have comparable pregnancy rates.

Progesterone used for luteal phase support can be administered using any one of three main routes: oral, intramuscular (IM), and vaginal. The oral route of administration has been clearly shown to be inferior to the other routes in the promotion of a secretory endometrium favorable to implantation. The comparison between the intramuscular and vaginal routes has been more controversial. Although several studies have shown that cycles in which vaginal progesterone was used had comparable outcomes to IM progesterone in both fresh IVF and FET cycles, other researchers have recommended IM progesterone based on better outcome compared to vaginal progesterone in IVF cycles.

The goal has been to find an optimal route of P4 administration for luteal phase support that maintains good pregnancy rates while limiting side effects and increasing the ease of administration for the patient. Disadvantages seen in oral administration include alterations in absorption influenced by food intake, metabolic inactivation due to the hepatic first-pass effect, and drowsiness. Intramuscular P4 is uncomfortable to administer, requires daily injections to maintain appropriate serum concentration, and can lead to inflammation of the injection site. Therefore, much research has been done to evaluate the efficacy and side effect profile of vaginal progesterone since this form is easy to administer and has few side effects with minimal systemic absorption.

Vaginal P4 has been shown to be superior to oral progesterone in producing in-phase secretory endometrium and having greater bioavailability. The comparison between vaginal and IM progesterone has been more controversial. Similar pregnancy outcomes have been found in one prospective randomized study comparing the two routes in FET cycles.

IM progesterone has been demonstrated to have greater pregnancy outcomes in comparison to PV progesterone in fresh IVF cycles It has been postulated that higher local endometrial levels of progesterone seen with vaginal progesterone compared to IM progesterone (although serum levels do not reflect this) are the culprit. Whether this difference plays a role in the relative implantation inhibition seen with the use of PV remains to be determined.
Although both routes of P4 administration result in acceptable pregnancy rates, IM progesterone use results in significantly higher clinical pregnancy and live birth rates compared to PV. Therefore, consideration should be given to preferentially using IM progesterone in FET cycles and restricting the use of PV to patients who are intolerant to the IM route of administration.

Oral progesterone as luteal support is, of course, appealing due to its simplicity of administration. However, of many modes of progesterone administration, the oral route is associated with the lowest efficacy and largest number of side-effects. Moreover, the breakdown products from the metabolism of oral progesterone have been associated with sedation, drowsiness and other hypnotic effects, as well as flushing, nausea, and fluid retention. The most common form of progesterone supplementation in Italy is daily IM progesterone in-oil administration. This may lead to severe inflammation reactions, sterile abscesses, and significant patient discomfort. Another route of progesterone supplementation is the vaginal one. Nevertheless, some Authors report no statistically differences in terms of pregnancy outcomes comparing with the intramuscular progesterone. On the contrary, Cochrane database noted an evidence of benefit of the intramuscular over the vaginal route for the outcomes of ongoing pregnancy and live birth, while no significant difference in pregnancy rate was observed between vaginal progesterone gel and other types of vaginal progesterone. Authors concluded that the optimal route of progesterone administration has not yet been established.



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