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Pregnancy after ovarian superovulation by transdermal delivery of follicle-stimulating hormone
Pregnancy after ovarian superovulation by transdermal delivery of follicle-stimulating hormone Because of its size of 32 kDa and physicochemical properties, urinary FSH cannot permeate intact skin. We report the first pregnancy after laser microporation and transdermal delivery of FSH for ovarian superovulation as a substitute for SC or IM injections. (Fertil Steril 2011;95:2784–5. 2011 by American Society for Reproductive Medicine.) Key Words: Transdermal drug delivery, laser skin microporation, large molecular weight compound, ovarian superovulation, hyperstimulation, follicle stimulating hormone, pregnancy
For IVF, FSHs are routinely used for induction of superovulation. They are not active orally and so have to be given with 1 to 2 weeks of daily SC or IM injections. Fear of needles and concern about the discomfort associated with sharp needle injections remain significant disincentives. However, there has been no alternative because the transport of FSH across the skin is limited by its hydrophilic nature and size (32-kDa protein). We now report the first pregnancy in a recipient after superovulation of an oocyte donor enrolled in a clinical study with transdermal delivery of highly purified urinary FSH (Fostimon; Institut Biochimque SA, Lugano, Switzerland). For down-regulation of the pituitary gland the GnRH long protocol was applied in the oocyte donor. Twelve days after onset of menstrual bleeding, treatment was started using a skin patch containing FSH. Before patch application the skin was pretreated with the proprietary P.L.E.A.S.E. laser microporation device. The FSH patch dose was adjusted to correspond to 150 IU SC FSH, as demonstrated in a previous feasibility study measuring blood values of FSH. A transvaginal scan for automated measurement of follicular size in three dimensions was performed every day,
starting on day 3 of stimulation until administration of hCG (10,000 U Pregnyl; Schering-Plough) to induce final oocyte maturation (1), with transvaginal oocyte retrieval 35 hours later. The dose of FSH was titrated to the donor’s response from day 6 onward. Culture of embryos and sperm processing techniques were as described previously by our group (2, 3). Fifteen oocytes were retrieved, of which 11 were in metaphase II. Nine metaphase II oocytes fertilized, and five further developed to the blastocyst stage on day 5. The recipient received two of the donor-derived embryos in the same cycle. As of writing, the recipient has experienced 12 weeks of uneventful dichorionic– diamniotic twin pregnancy. The side effects of the patch included mild erythema on the side of patch application for up to 3 days, with spontaneous resolution. To our knowledge, this is the first pregnancy recorded after transdermal delivery of the largemolecular-weight FSH with promotion of ovarian superovulation in an oocyte donor. The twin pregnancy testifies to the quality of the retrieved oocytes. This transdermal device holds great potential for the transport of compounds of large molecular size or of hydrophilic nature across the skin.
Nicolas H. Zech, M.D.a,b Maximilian Murtinger, M.D.a Petr Uher, M.D.c a IVF Centers Prof. Zech, Bregenz, Austria b Unit of Gynecological Endocrinology and Reproductive Medicine, Department for Obstetrics and Gynecology, University of Graz, Graz, Austria c IVF Centers Prof. Zech, Pilsen, Czech Republic Received February 20, 2011; accepted March 22, 2011; published online April 16, 2011. N.H.Z. has nothing to disclose. M.M. has nothing to disclose. P.U. has nothing to disclose. Pantec Biosolutions (Ruggell, Liechtenstein) sponsored the clinical study in Pilsen, Czech Republic. Reprint requests: Nicolas H. Zech, M.D., IVF Centers Prof. Zech, Roemerstrasse 2, 6900 Bregenz, Austria (E-mail: [email protected]).
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Fertility and Sterility Vol. 95, No. 8, June 30, 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/$36.00 doi:10.1016/j.fertnstert.2011.03.073
REFERENCES 1. Murtinger M, Aburumieh A, Rubner P, Eichel V, Zech MH, Zech NH. Improved monitoring of ovarian stimulation using 3D transvaginal ultrasound plus automated volume count. Reprod Biomed Online 2009;19:695–9.
Fertility and Sterility
2. Vanderzwalmen P, Hiemer A, Rubner P, Bach M, Neyer A, Stecher A, et al. Blastocyst development after sperm selection at high magnification is associated with size and number of nuclear vacuoles. Reprod Biomed Online 2008;17:617–27.
3. Vanderzwalmen P, Ectors F, Grobet L, Prapas Y, Panagiotidis Y, Vanderzwalmen S, et al. Aseptic vitrification of blastocysts from infertile patients, egg donors and after IVM. Reprod Biomed Online 2009;19:700–7.
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For IVF, FSHs are routinely used for induction of superovulation. They are not active orally and so have to be given with 1 to 2 weeks of daily SC or IM injections. Fear of needles and concern about the discomfort associated with sharp needle injections remain significant disincentives. However, there has been no alternative because the transport of FSH across the skin is limited by its hydrophilic nature and size (32-kDa protein). We now report the first pregnancy in a recipient after superovulation of an oocyte donor enrolled in a clinical study with transdermal delivery of highly purified urinary FSH (Fostimon; Institut Biochimque SA, Lugano, Switzerland). For down-regulation of the pituitary gland the GnRH long protocol was applied in the oocyte donor. Twelve days after onset of menstrual bleeding, treatment was started using a skin patch containing FSH. Before patch application the skin was pretreated with the proprietary P.L.E.A.S.E. laser microporation device. The FSH patch dose was adjusted to correspond to 150 IU SC FSH, as demonstrated in a previous feasibility study measuring blood values of FSH. A transvaginal scan for automated measurement of follicular size in three dimensions was performed every day,
starting on day 3 of stimulation until administration of hCG (10,000 U Pregnyl; Schering-Plough) to induce final oocyte maturation (1), with transvaginal oocyte retrieval 35 hours later. The dose of FSH was titrated to the donor’s response from day 6 onward. Culture of embryos and sperm processing techniques were as described previously by our group (2, 3). Fifteen oocytes were retrieved, of which 11 were in metaphase II. Nine metaphase II oocytes fertilized, and five further developed to the blastocyst stage on day 5. The recipient received two of the donor-derived embryos in the same cycle. As of writing, the recipient has experienced 12 weeks of uneventful dichorionic– diamniotic twin pregnancy. The side effects of the patch included mild erythema on the side of patch application for up to 3 days, with spontaneous resolution. To our knowledge, this is the first pregnancy recorded after transdermal delivery of the largemolecular-weight FSH with promotion of ovarian superovulation in an oocyte donor. The twin pregnancy testifies to the quality of the retrieved oocytes. This transdermal device holds great potential for the transport of compounds of large molecular size or of hydrophilic nature across the skin.
Nicolas H. Zech, M.D.a,b Maximilian Murtinger, M.D.a Petr Uher, M.D.c a IVF Centers Prof. Zech, Bregenz, Austria b Unit of Gynecological Endocrinology and Reproductive Medicine, Department for Obstetrics and Gynecology, University of Graz, Graz, Austria c IVF Centers Prof. Zech, Pilsen, Czech Republic Received February 20, 2011; accepted March 22, 2011; published online April 16, 2011. N.H.Z. has nothing to disclose. M.M. has nothing to disclose. P.U. has nothing to disclose. Pantec Biosolutions (Ruggell, Liechtenstein) sponsored the clinical study in Pilsen, Czech Republic. Reprint requests: Nicolas H. Zech, M.D., IVF Centers Prof. Zech, Roemerstrasse 2, 6900 Bregenz, Austria (E-mail: [email protected]).
2784
Fertility and Sterility Vol. 95, No. 8, June 30, 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/$36.00 doi:10.1016/j.fertnstert.2011.03.073
REFERENCES 1. Murtinger M, Aburumieh A, Rubner P, Eichel V, Zech MH, Zech NH. Improved monitoring of ovarian stimulation using 3D transvaginal ultrasound plus automated volume count. Reprod Biomed Online 2009;19:695–9.
Fertility and Sterility
2. Vanderzwalmen P, Hiemer A, Rubner P, Bach M, Neyer A, Stecher A, et al. Blastocyst development after sperm selection at high magnification is associated with size and number of nuclear vacuoles. Reprod Biomed Online 2008;17:617–27.
3. Vanderzwalmen P, Ectors F, Grobet L, Prapas Y, Panagiotidis Y, Vanderzwalmen S, et al. Aseptic vitrification of blastocysts from infertile patients, egg donors and after IVM. Reprod Biomed Online 2009;19:700–7.
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