**4.2. Oral dydrogesterone vs. vaginal micronized progesterone**

In a prospective randomized study [33] a total of 430 women underwent IVF/ICSI treatment. Long protocol gonadotropin releasing hormone analogue down-regulation was followed by gonadotropin stimulation. Luteal support was initiated from the day of embryo transfer and continued for up to 14 days. Patients were randomised to luteal supplementation with either intravaginal micronised progesterone 200 mg three times daily (n = 351) or oral dydrogesterone 10mg twice daily (n = 79). In cases of a positive pregnancy test, luteal support was continued for 12 weeks. Both dydrogesterone and micronised progesterone were associated with similar rates of successful pregnancies. Vaginal discharge or irritation were reported by 10.5% of patients given micronized progesterone. Signicantly (p < 0.05), more patients given dydrogesterone than micronised progesterone were satised with the tolerability of their treatment. There were no differences between the treatments with regard to liver function tests. In agreement with this another study [34] compared oral dydrogesterone for luteal-phase support in assisted reproductive technologies with micronized vaginal progesterone. All patients underwent long-term downregulation with gonadotropin-releasing hormone agonists. In phase I, 498 patients were divided into three groups: long protocol and not at risk of OHSS (group A); long protocol and at risk of OHSS (group B); and those in a donor oocyte program (group C). All patients received micronized progesterone 600 mg/day, vaginally. They were also randomized to dydrogesterone 20 mg/day (n = 218) or placebo (n = 280). The pregnancy rate was higher with dydrogesterone than with placebo in group A (33.0% vs. 23.6%), group B (36.8% vs. 28.1%) and group C (42.9% vs. 15.6%; p < 0.001). In phase II, 675 patients were divided into the same three groups (groups D, E and F) and were randomized to dydrogesterone 30 mg/day (n = 366) or micronized progesterone 600 mg/day (n = 309). The pregnancy rate was significantly higher with dydrogesterone than with progesterone in group D (39.1% vs. 26.7%; p < 0.01), group E (41.2% vs. 35.6%; p < 0.01) and group F (48.2% vs. 33.9%; p < 0.001).Although both routes had more or less comparable cycle outcome the cited studies did not comment on sedative effects of oral synthetic dydrogesterone compared with vaginal micronized progesterone.

#### **4.3. Micronized progesterone: oral vs. vaginal routes**

158 Enhancing Success of Assisted Reproduction

(oral, 20–30 mg/day) [25].

(12.5–100 mg/day), various vaginal preparations such as creams, pessaries, sustained release gel and vaginal rings, vaginal applications of oral formulations and oral preparations including micronized progesterone (600–1200 mg/day) and dydrogesterone

Progesterone can be administered orally, vaginally, or through I.M. injection and all these routes of administration have demonstrated characteristic endometrial histological changes [26]. Oral dosing requires a higher concentration in order to compensate for "first-pass" liver metabolism. The bioavailability of the orally administered progesterone can be as low as 10% [27].Micronized dosage forms of progesterone are utilized to increase efficiency of delivery. Micronization decreases particle size and shortens its dissolution time according to the equation of Noyes–Whitney[28].However, oral administration may result in noticeable sedative and anxiolytic effects due to progesterone metabolites that enhance inhibitory

Intramuscular injections of micronized progesterone in oil result in a higher peak and longer lasting plasma concentrations when compared to aqueous solutions. But, a daily administration is required due to a rapid metabolism. Progesterone in oil (USP) is formulated with sesame oil (50 mg/ml) and 10% v/v benzyl alcohol that functions as preservative. Intramuscular injections are difficult to self-administer and are often painful. A common practice is to warm up the oil solution in order to decrease its viscosity in an

Bulletti et al[30] first described a preferential trafficking of vaginally delivered progesterone to the uterus leading to a higher progesterone concentration in the endometrial tissue compared to the blood serum. Therefore, targeted delivery of progesterone directly to the uterus is thus achievable through utilizing this 'uterine first pass effect' [31] .The anatomy of the vagina with its rich vascular plexus provides an ideal environment for absorbing drugs. The rugae of the vaginal wall increase the total available surface area. The vascular system around the vagina and the venous drainage of the vagina does not initially pass through the liver, and thus bypasses the first pass hepatic effect [32] .By avoiding the hepatic first pass effect, vaginal progesterone does not create high concentrations of metabolites that cause undesired side effects. Vaginal administration of progesterone results in more consistent serum levels, which can remain

In a prospective randomized study [33] a total of 430 women underwent IVF/ICSI treatment. Long protocol gonadotropin releasing hormone analogue down-regulation was followed by gonadotropin stimulation. Luteal support was initiated from the day of embryo transfer and continued for up to 14 days. Patients were randomised to luteal

**4.1. Comparison between routes of progesterone administration** 

neurotransmission by binding to the GABAA receptor complex [29].

**4.2. Oral dydrogesterone vs. vaginal micronized progesterone** 

attempt to reduce pain with injection [28].

elevated for up to 48

A prospective randomized small sample study [35] compared the efficacy of micronized progesterone administered as luteal support following ovulation induction for in-vitro fertilization (IVF)– embryo transfer in cycles using gonadotrophin-releasing hormone agonist, orally (200 mg×4/day) or vaginally (100 mg×2/day) and to characterize the luteal phase hormonal profile during such treatments. A total of 64 high responder patients requiring intracytoplasmic sperm injection due to male factor infertility were prospectively randomized into two treatment groups. Patients treated orally or vaginally were comparable in age, number of oocytes retrieved, and number of embryos transferred per cycle. Following low dose vaginal treatment, a significantly higher implantation rate (30.7 versus 10.7%, P < 0.01), and a tendency to higher clinical pregnancy rate (47.0 versus 33.3%) and ongoing pregnancy rate (41.1 versus 20.0%) was observed, compared with oral treatment. In conception cycles, luteal serum progesterone and oestrogen concentrations did not differ between the treatment groups. In non-conception cycles, late luteal progesterone concentrations were significantly lower following vaginal treatment. As low dose micronized progesterone administered vaginally is simple, easy and well tolerated, it could be recommended as the method of choice for luteal support.
