The Impact of Biotechnology on Reproductive Medicine

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David Roy Meldrum ^{1 , *}

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¹ Department of Reproductive Medicine, Division of Reproductive Endocrinology and Infertility, University of California San Diego, La Jolla, U.S.A.

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Biotechnology and Health Sciences: February 2017, 4 (1); e13433
Published Online: December 12, 2016
Article Type: Editorial
Received: October 30, 2016
Accepted: November 16, 2016
DOI: 10.5812/bhs.13433

To Cite: Roy Meldrum D. The Impact of Biotechnology on Reproductive Medicine, Biotech Health Sci. 2017 ;4(1):e13433. doi: 10.5812/bhs.13433.

Copyright Â© 2016, Qazvin University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Reproductive Medicine has been at the forefront of the biotechnology revolution. Over the last three decades, a very significant proportion of abstracts at our major meetings and papers in our journals have employed molecular techniques to elucidate basic gene expression and cellular metabolic pathways in the study of reproductive processes. The resulting insights have yielded new understanding of the basic mechanisms of reproductive diseases and innovative therapeutic modalities. Specific examples will be used to illustrate this remarkable progress.

In 1988, Hollands reported the rescue of lethally irradiated rats by infusion of haemopoietic stem cells from mouse blastocysts grown in vitro (1). This remarkable study was published decades before stem cells (now induced pluripotent cells from the recipient to avoid rejection) became a clinical tool for repopulating the bone marrows of cancer patients following lethal doses of chemotherapy and or radiation.

In 1992, Lou Ignarro, who later shared a Nobel Prize for the discovery of nitric oxide (NO), showed using human penile tissue that the effect of neural NO release was enhanced by an inhibitor of cyclic GMP degradation (2), leading to the development of highly effective treatments for erectile dysfunction (ED) (3). Further elucidation of the factors influencing NO production and degradation has led to important insights into lifestyle and nutritional factors influencing erectile health (4, 5).

In the mid-1990âs, as the result of work carried out by the research group under Antonio Pellicer in Valencia, Spain and others, the etiology of increased vascular permeability and consequent extreme fluid shifts characteristic of ovarian hyperstimulation syndrome (OHSS) were shown to be due to increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor2 (VEGFR-2) (6). The incidence of OHSS was reduced by 50% by identifying and clinically utilizing the role of dopamine agonists to inhibit phosphorylation of VEGFR-2. That discovery, together with understanding and thereby avoidance of clinical factors stimulating VEGF, has now made morbid and potentially fatal OHSS a rare occurrence.

Again in the 1990âs David Gardner, along with others, defined the reproductive tract nutrients available during in vivo embryo development and the specific stage-specific requirements of embryos developing to the blastocyst stage. Those insights and clinical experience enabled the design of media specifically for embryos over the first 72 hours and the following 24 to 84 hours of culture (7), improving IVF efficiency and making accurate chromosome analysis a reality. Study of blastocyst metabolism that predicts a successful pregnancy has been progressing rapidly (8).

In the late 1990âs techniques became available to assess DNA fragmentation of sperm, first by flow cytometry and later by techniques such as TUNEL and COMET. DNA fragmentation increases with age (9) and may contribute to the low success rates in women over age 40, although the effect of male age was observed to be less with younger female age (10). The effect on IVF outcome also appears to be less for women responding normally to ovarian stimulation compared to low responders (11). These observations have suggested that cytoplasm of the better quality oocyte may be able to correct DNA fragmentation. The observation that DNA fragmentation is correlated with semen oxidative stress (12) has validated successful treatment with antioxidants (13). Because DNA fragmentation increases during transit through the male collecting system, testicular extraction of sperm has been used successfully if frequent ejaculation and antioxidants are not sufficient (14). Decreased coital frequency with age, in part due to decreased erectile function, contributes to infertility in older couples (15).

In the late 1990âs the importance of omega-3 fatty acids in the function of sperm membranes was being elucidated and correlated with indices of sperm quality and male infertility (16). Safarinejad reported a randomized trial showing highly significant benefits of omega-3 supplementation on sperm density, motility, and strict morphology (16). Semen concentrations of omega-3âs correlated with those improvements and also with semen endogenous antioxidants. Supplementation with omega-3âs is now a routine recommendation for infertile men (www.lifechoicesandfertility.com).

Again in the 1990âs, techniques were introduced to evaluate individual embryo blastomeres for chromosome abnormalities. The initial technique, fluorescence in-situ hybridization (FISH) of a limited number of chromosomes proved to not be sufficiently accurate and biopsy of the embryo at the cleavage stage decreases embryo viability, together resulting in impaired IVF success (17). However, current techniques using trophectoderm biopsy of blastocysts and comprehensive chromosome screening (CCS) of all chromosomes in high quality, experienced laboratories appear to be highly successful. Elective single embryo transfer of a euploid embryo then avoids the very significant morbidity and perinatal mortality accompanying twin births while also reducing miscarriage (18). Newer CCS platforms allowing greater resolution (particularly next generation sequencing, NGS) have highlighted the importance of a high quality laboratory in producing blastocysts with fewer mitotic errors that result in embryo mosaicism (19). By avoiding the stress of twins, futile transfers, and preventable miscarriages, fewer couples may further compromise their success by dropping out of treatment (20). It is important to point out that data generated from registries that include a broad range of IVF laboratory quality and data collected before full optimization of the embryo culture environment must not be used to cast doubt on the importance of this breakthrough in IVF treatment (19).

Uterine leiomyomas have long been a major reproductive obstacle and a source for gynecologic morbidity and need for major surgery. Until recently, non-invasive techniques have had limited success, with ovarian estrogen suppression having transient benefits and bothersome side effects, and uterine artery embolization not being applicable to women planning to conceive. Molecular techniques have shown that progesterone (P) is a key stimulator of myomas and activation of myoma P receptors may express the effect of estrogen on myoma growth. Repeated 12 week courses of 5 and 10 mg of ulipristal, a selective progesterone receptor modulator, achieved amenorrhea in 62% – 73%, shrinkage of myoma volume by 54% – 58%, and relieved pain and improved quality of life (21). The place of this and other non-invasive oral treatments, for example, the oral gonadotropin-releasing hormone antagonist, Elagolix, and newer even more potent molecules, have yet to be fully explored (22).

Implantation has always been the âblack boxâ of reproduction. Endometrial gene arrays have been carried out during natural and ovarian stimulation cycles. During ovarian stimulation, expression of genes involved in implantation is disrupted (23), leading to the suggestion that embryo transfer might be more successful during natural cycles or with hormone replacement to mimic the normal menstrual cycle. Results from a randomized study showed an increase of ongoing pregnancy from 51% to 78% (P 0.007) (24). The development of cryopreservation by vitrification, which has minimal effects on embryo capacity, has spurred a âsea changeâ toward deferred transfer of embryos, also promoted due to some evidence pointing to better perinatal outcomes, clear evidence for a reduced rate of ectopic pregnancy, and the ability to send out biopsies from day 5 to 7 blastocysts to reference laboratories. More recently, gene array has been used to identify individual women whose endometrial âwindow of implantationâ is shifted, resulting in capable embryos failing to implant. Thus, a personalized approach to the timing of embryo transfer has recently been reported in a multicenter randomized trial to improve outcome in women with recurrent implantation failure (25).

New approaches are emerging for women who have lost their ovarian function due to chemotherapy or premature ovarian failure. By cryopreserving ovarian tissue prior to cancer treatment, replacement of that tissue at a later time into or adjacent to the ovary has now resulted in natural and IVF pregnancies as well as hormonal function and menses. Globally over 70 births have been achieved (26). For premature ovarian failure various approaches are being explored based on knowledge of the molecular pathways controlling follicle growth. U.S. and Japanese researchers have activated follicles in ovarian cortex biopsies by disrupting Hippo signaling by fragmenting the tissue, followed by enhanced Akt signaling and autografting. IVF then resulted in a normal birth (27). Others have been experimenting with infusion of various stem cells and their derivatives from bone marrow or umbilical cord tissues into the ovaries. Recently chemotherapy treated mice had rescue of ovarian function and fertility by intra-ovarian injection of umbilical cord mesenchymal stem cells (28).

The aging oocyte has reduced capacity and is prone to chromosomal segregation errors due in part to impaired mitochondrial energy production. In a very detailed study in aging mice, co-enzyme Q-10, a key enzyme in mitochondrial energy production, was shown to largely reverse those aging changes, resulting in improved ovarian reserve and spindle formation and increased litter sizes (29). A limited study in the human showed improved outcomes that were not statistically significant but the numbers were small and the CoQ-10 was taken for only 2 months (30). Poor mitochondrial function is also associated with overproduction of mitochondrial DNA copy number, which is now used clinically to identify embryos that are unlikely to implant (31, 32).

The ultimate biotechnology goal in reproduction is the generation of oocytes and sperm from pluripotent stem cells. Oocytes have been produced from pluripotent germ cell-like cells developed from the animalâs own induced pluripotent cells resulting in births of normal, fertile mice, although requiring some assistance during development by ovarian supporting cells in vivo (33). Sperm have been produced from mouse embryonic stem cells using in vitro co-culture with neonatal testicular cells, resulting in viable, fertile offspring (34). Also encouraging is the identification and maturation of pluripotent germ cell-like cells from testicles lacking mature sperm. Extensive efforts by groups around the world were recently detailed in a systematic review (35). Clinical use of stem cell-derived gametes will require detailed research using animal models because of the genetic and epigenetic/developmental risks involved in assuring that such cells are fully normal.

In summary, a dozen examples have been given of the remarkable progress in understanding and treating disorders of reproduction. Researchers in reproductive medicine have earned their place as pioneers in the application of biotechnology to the health sciences.

References

1. Hollands P. Differentiation of embryonic haemopoietic stem cells from mouse blastocysts grown in vitro. Development. 1988; 102(1): 135-41[PubMed]
2. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med. 1992; 326(2): 90-4[DOI][PubMed]
3. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998; 338(20): 1397-404[DOI][PubMed]
4. Meldrum DR, Gambone JC, Morris MA, Ignarro LJ. A multifaceted approach to maximize erectile function and vascular health. Fertil Steril. 2010; 94(7): 2514-20[DOI][PubMed]
5. Meldrum DR, Burnett AL, Dorey G, Esposito K, Ignarro LJ. Erectile hydraulics: maximizing inflow while minimizing outflow. J Sex Med. 2014; 11(5): 1208-20[DOI][PubMed]
6. Soares SR, Gomez R, Simon C, Garcia-Velasco JA, Pellicer A. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Hum Reprod Update. 2008; 14(4): 321-33[DOI][PubMed]
7. Gardner DK, Lane M, Schoolcraft WB. Physiology and culture of the human blastocyst. J Reprod Immunol. 2002; 55(1-2): 85-100[PubMed]
8. Gardner DK, Meseguer M, Rubio C, Treff NR. Diagnosis of human preimplantation embryo viability. Hum Reprod Update. 2015; 21(6): 727-47[DOI][PubMed]
9. Schmid TE, Eskenazi B, Baumgartner A, Marchetti F, Young S, Weldon R, et al. The effects of male age on sperm DNA damage in healthy non-smokers. Hum Reprod. 2007; 22(1): 180-7[DOI][PubMed]
10. de La Rochebrochard E, de Mouzon J, Thepot F, Thonneau P, French National IA. Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in France. Fertil Steril. 2006; 85(5): 1420-4[DOI][PubMed]
11. Jin J, Pan C, Fei Q, Ni W, Yang X, Zhang L, et al. Effect of sperm DNA fragmentation on the clinical outcomes for in vitro fertilization and intracytoplasmic sperm injection in women with different ovarian reserves. Fertil Steril. 2015; 103(4): 910-6[DOI][PubMed]
12. Mahfouz R, Sharma R, Thiyagarajan A, Kale V, Gupta S, Sabanegh E, et al. Semen characteristics and sperm DNA fragmentation in infertile men with low and high levels of seminal reactive oxygen species. Fertil Steril. 2010; 94(6): 2141-6[DOI][PubMed]
13. Greco E, Iacobelli M, Rienzi L, Ubaldi F, Ferrero S, Tesarik J. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J Androl. 2005; 26(3): 349-53[DOI][PubMed]
14. Greco E, Scarselli F, Iacobelli M, Rienzi L, Ubaldi F, Ferrero S, et al. Efficient treatment of infertility due to sperm DNA damage by ICSI with testicular spermatozoa. Hum Reprod. 2005; 20(1): 226-30[DOI][PubMed]
15. Brewis A, Meyer M. Marital coitus across the life course. J Biosoc Sci. 2005; 37(4): 499-518[PubMed]
16. Safarinejad MR. Effect of omega-3 polyunsaturated fatty acid supplementation on semen profile and enzymatic anti-oxidant capacity of seminal plasma in infertile men with idiopathic oligoasthenoteratospermia: a double-blind, placebo-controlled, randomised study. Andrologia. 2011; 43(1): 38-47[DOI][PubMed]
17. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007; 357(1): 9-17[DOI][PubMed]
18. Werner MD, Scott RJ, Treff NR. 24-chromosome PCR for aneuploidy screening. Curr Opin Obstet Gynecol. 2015; 27(3): 201-5[DOI][PubMed]
19. Meldrum DR, Su HI, Katz-Jaffe MG, Schoolcraft WB. Preimplantation genetic screening 2.0: an evolving and promising technique. Fertil Steril. 2016; 106(1): 64-5[DOI][PubMed]
20. Meldrum DR. Lightening the burden of care in assisted reproductive technology. Fertil Steril. 2016; 105(5): 1144-5[DOI][PubMed]
21. Donnez J, Hudecek R, Donnez O, Matule D, Arhendt HJ, Zatik J, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril. 2015; 103(2): 519-27 e3[DOI][PubMed]
22. Kim SM, Lee M, Lee SY, Park E, Lee SM, Kim EJ, et al. Discovery of an Orally Bioavailable Gonadotropin-Releasing Hormone Receptor Antagonist. J Med Chem. 2016; 59(19): 9150-72[DOI][PubMed]
23. Haouzi D, Assou S, Mahmoud K, Tondeur S, Reme T, Hedon B, et al. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009; 24(6): 1436-45[DOI][PubMed]
24. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril. 2011; 96(2): 344-8[DOI][PubMed]
25. Simon C, Vladimirov IK, Castillon Cortes G, Ortega I, Cabanillas S, Vidal C, et al. Prospective, randomized study of the endometrial receptivity analysis (ERA) test in the infertility work-up to guide personalized embryo transfer versus fresh transfer or deferred embryo transfer. Fertil Steril. 2016; 106(3): 46-7[DOI]
26. Oktay KH, Pacheco FS. Current succes and efficiency of autologous ovarian transplantation with cryopreserved tissue: a meta-analysis. Fertil Steril. 2016; 106(3): 131-2[DOI]
27. Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013; 110(43): 17474-9[DOI][PubMed]
28. Mohamed SA, Shalaby SM, Brakta S, Stone L, Ellakany M, Al-Hendy A. Umbilical cord blood mesenchymal stem cells as an infertility treatment for chemotherapy induced premature ovarian failure. Fertil Steril. 2016; 106(3): 128[DOI]
29. Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015; 14(5): 887-95[DOI][PubMed]
30. Bentov Y, Hannam T, Jurisicova A, Esfandiari N, Casper RF. Coenzyme Q10 Supplementation and Oocyte Aneuploidy in Women Undergoing IVF-ICSI Treatment. Clin Med Insights Reprod Health. 2014; 8: 31-6[DOI][PubMed]
31. Fragouli E, Spath K, Alfarawati S, Kaper F, Craig A, Michel CE, et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. PLoS Genet. 2015; 11(6)[DOI][PubMed]
32. Diez-Juan A, Rubio C, Marin C, Martinez S, Al-Asmar N, Riboldi M, et al. Mitochondrial DNA content as a viability score in human euploid embryos: less is better. Fertil Steril. 2015; 104(3): 534-41 e1[DOI][PubMed]
33. Hayashi K, Ogushi S, Kurimoto K, Shimamoto S, Ohta H, Saitou M. Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice. Science. 2012; 338(6109): 971-5[DOI][PubMed]
34. Zhou Q, Wang M, Yuan Y, Wang X, Fu R, Wan H, et al. Complete Meiosis from Embryonic Stem Cell-Derived Germ Cells In Vitro. Cell Stem Cell. 2016; 18(3): 330-40[DOI][PubMed]
35. Hendriks S, Dancet EA, van Pelt AM, Hamer G, Repping S. Artificial gametes: a systematic review of biological progress towards clinical application. Hum Reprod Update. 2015; 21(3): 285-96[DOI][PubMed]

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