A randomized clinical trial of transdermal (gel) versus oral estrogen for endometrial preparation in frozen embryo transfer cycle

Carvalho, Mariana Oliva Cassará; Lima, Sônia Maria Rolim Rosa; Glina, Claudia Godman; Tso, Leopoldo de Oliveira; Romano, Rodrigo Sabato; Glina, Sidney; Busso, Newton Eduardo; Busso, Cristiano Eduardo

doi:10.1590/1806-9282.20231548

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Revista da Associação Médica Brasileira

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Original Article • Rev. Assoc. Med. Bras. 70 (5) • 2024 • https://doi.org/10.1590/1806-9282.20231548 copy

A randomized clinical trial of transdermal (gel) versus oral estrogen for endometrial preparation in frozen embryo transfer cycle

Authorship SCIMAGO INSTITUTIONS RANKINGS

SUMMARY

OBJECTIVE:

The aim of this study was to compare endometrial thickness with the use of transdermal estrogen (gel) versus oral estrogen (pills) for endometrial preparation in the frozen embryo transfer cycle and serum estrogen concentrations during the preparation cycle, side effects, and chemical and clinical pregnancy rates.

METHODS:

This was a prospective, randomized controlled trial of women undergoing endometrial preparation for cryopreserved blastocyst transfer. A total of 88 women were randomized, of which 82 completed the study protocol. Of this group, 44 received 6 mg/day of estradiol valerate orally (pills group) and 38 received 4.5 mg/day of estradiol hemihydrate transdermally (gel group). Endometrial thickness was measured using transvaginal ultrasound between the 7 and 10th day of the cycle. Serum estradiol concentrations were measured on the day of initiating the cycle, on control transvaginal ultrasounds, and on the day of embryo transfer. Side effects were documented at each study visit. p<0.05 were adopted as statistically significant. The groups were compared using Student's t-test for continuous variables and chi-square or Fisher's exact test for categorical variables.

RESULTS:

There were no significant group differences (p>0.05) in endometrial thickness, biochemical and clinical pregnancy rates, miscarriage rate, blood estradiol concentrations, duration of estradiol administration, or cycle cancellation rates.

CONCLUSION:

Endometrial preparation with transdermal estrogen yielded similar reproductive outcomes to oral estrogen with fewer side effects.

KEYWORDS:
Embryo transfer; Estrogens; Cutaneous administration; Oral administration; Endometrium

		Gel group	Pills group	p
		n=38	n=44
		n (%)	n (%)
Age (years)^* * Student's t-test;		37.15±5.27^◊ ◊ mean (±SD): standard deviation; p<0.05;	37.25±5.57^◊ ◊ mean (±SD): standard deviation; p<0.05;	0.939
BMI (kg/m²)^* * Student's t-test;		25.46±3.9^◊ ◊ mean (±SD): standard deviation; p<0.05;	26.48±3.73^◊ ◊ mean (±SD): standard deviation; p<0.05;	0.223
Duration of infertility (years)^* * Student's t-test;		6.78±4.83^◊ ◊ mean (±SD): standard deviation; p<0.05;	6.52±3.68^◊ ◊ mean (±SD): standard deviation; p<0.05;	0.791
Cause of infertility^ chi-square test;
	Tuboperitoneal	14 (36.8%)	8 (18.1%)	0.057
	Ovulatory + male factor	3 (7.8%)	7 (15.9%)	0.326
	Male factor	6 (15.7%)	10 (22.7%)	0.429
	Unexplained	3 (7.8%)	4 (9.0%)	1
	Same sex couple/solo parent	5 (13.15%)	3 (6.8%)	0.462
	Tubal + male factor	1 (2.63%)	3 (6.8%)	0.620
	Ovulatory + male factor	4 (10.5%)	5 (11.3%)	1
	Tubal + ovulatory factor	2 (5.26%)	4 (9.0%)	0.679
Egg and embryo donation^ chi-square test;
	Own eggs	27 (71.1%)	30 (68.2%)	0.485
	Egg or embryo donation	11 (28.9%)	14 (31.8%)	0.485
No. of embryos transferred^ chi-square test;
	1	10 (28.6%)	31 (73.8%)	0.815
	2	25 (71.4%)	11 (26.2)
At least a top-quality embryo transferred^ chi-square test;		6/35^□ □ only cycles with embryo transfer. (17.1%)	6/42^□ □ only cycles with embryo transfer. (14.3%)	0.977

		Gel group	Pills group	p
		n=38	n=44
		Mean±SD	Mean±SD
T0	AST (U/L)^* * Student's t-test;	17.57±4.10	21.58±9.20	0.016
	ALT (U/L)^* * Student's t-test;	17.89±6.95	20.27±12.10	0.289
	P4 (ng/mL)^* * Student's t-test;	0.25±0.15	0.33±0.25	0.086
	E2 (pg/mL)^* * Student's t-test;	41.28±32.82	42.90±21.31	0.793
T1	ET (mm)^* * Student's t-test;	7.87±1.74	8.45±2.04	0.175
	P4 (pg/mL)^* * Student's t-test;	0.22±0.21	0.25±0.16	0.569
	E2 (ng/mL)^* * Student's t-test;	275.79±193.40	224.57±83.24	0.116
	Endometrium trilinear^ chi-square test;	32/38 (84.2%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	42/44 (95.5%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	0.087
	Adverse effects^* ***** Fisher's exact test; p<0.05.	4 (10.5%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	15 (34.1%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	0.017
	Headache^* ***** Fisher's exact test; p<0.05.	1 (2.6%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	8 (18.2%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	0.033
	Gastrointestinal^* ***** Fisher's exact test; p<0.05.	0	5 (11.4%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	0.058
	Cramps^* ***** Fisher's exact test; p<0.05.	1 (2.6%)◊	1 (2.3%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	1
	Paresthesia^* ***** Fisher's exact test; p<0.05.	1 (2.6%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	1 (2.3%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	1
	Others^* ***** Fisher's exact test; p<0.05.	1 (2.6%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	3 (6.8%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	0.365
		n=12	n=8
T2	ET (mm)^* * Student's t-test;	7.68±1.79	7.35±1.00	0.64
	P4 (ng/mL)^* * Student's t-test;	0.15±0.11	0.19±0.27	0.722
	E2 (pg/mL)^* * Student's t-test;	327.94±161.22	302.33±99.72	0.736
	EE trilinear^* ***** Fisher's exact test; p<0.05.	10 (83.3%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	8 (100.0%)^◊ ◊ n (%). T0: Initial time. T1: visit 1 of the study performed between the 7 and 10th day of endometrial preparation. T2: visit 2 of the study. FET: frozen embryo transfer.	0.224
		n=35	n=42
FET	AST (U/L)^* * Student's t-test;	25.36±13.05	28.15±21.16	0.593
	ALT (U/L)^* * Student's t-test;	22.21±13.68	19.03±9.62	0.264
	E2 (pg/mL)^* * Student's t-test;	226.24±138.44	224.35±91.50	0.945

	Gel group	Pills group	p
	n=38	n=44
	n (%)	n (%)
Duration of endometrial preparation (days)^* * Student's t-test;	14.86±2.37^◊ ◊ Mean (±SD): standard deviation;	14.43±1,56^◊ ◊ Mean (±SD): standard deviation;	0.344
Cycle cancellation rate^ chi-square test; p<0.05.	3/38 (7.9%)	2/44 (4.5%)	0.527
Biochemical pregnancy^ chi-square test; p<0.05.	18/35^□ □ only cycles with embryo transfer, (51.4%)	28/42^□ □ only cycles with embryo transfer, (66.7%)	0.261
Clinical pregnancy^ chi-square test; p<0.05.	11/35^□ □ only cycles with embryo transfer, (31.4%)	16/42^□ □ only cycles with embryo transfer, (38.1%)	0.542
Multiple pregnancy^ chi-square test; p<0.05.	3/11^Δ Δ positive clinical pregnancy only. (27.3%)	3/16^Δ Δ positive clinical pregnancy only. (18.8%)	0.601
Miscarriage rate^ chi-square test; p<0.05.	7/18 (38.8%)	12/28 (42.8%)	0.070
Live births per cycle transferred^ chi-square test; p<0.05.	11 /35^□ □ only cycles with embryo transfer, (31.4%)	16/42^□ □ only cycles with embryo transfer, (38.1%)	0.542

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[1] *Corresponding author: mcassara@hotmail.com