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The human genome project will result in many new diagnostic techniques applicable to assisted reproduction. These may be directed both at infertile patients as well as at patients who seek ART because they carry a deleterious genetic disease. There are many potential advantages to the use of preprocedural testing as a means of obtaining additional preliminary information that might allow patients to make a more informed choice, either when deciding between ART and adoption or when comparing the benefits of various ART procedures. The cost of testing is relatively low when compared with the cost of additional IVF or ICSI cycles. In the case of genetic screening protocols, the results may be useful not only to the patient but also to the next generation. Genetic counseling should be made available in concert with expanded opportunities, both for diagnosing infertility and for making preimplantation genetic diagnoses. Already some of the genetic screening that has occurred because of discoveries made during the human genome initiative has become a regulatory concern with regard to insurance availability and other issues. When counseling patients, it is important to point out that certain tests hold far more prognostic value and/or serious health implications than others. A test to diagnose breast cancer susceptibility, for example, holds more serious ramifications than the less predictive test that detects the phenotype for Klinefelter's syndrome. Presymptomatic prognostic screening systems, such as the tests currently used to detect genetic mutations related to breast and prostate cancer and cystic fibrosis, provide diagnostic clues but also have serious societal implications. We are on a rather slippery slope when we attempt to determine which tests actually might prove beneficial to patients, both individually and collectively. Therefore, as part of patient counseling, cost-benefit ratios, in addition to clinical and preventive implications, should be weighed.
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PMID:Panel One: marketing strategies and informing the patient/consumer. Infertility diagnostic techniques: the rush to market. 920 65

Recent discoveries on endocrine, paracrine and autocrine involvement of insulin-like growth factor-1 (IGF-1) in the proliferation of many tissues raised the attention of its role in reproduction and in the growth of various cancers as well as of benign proliferations. The intention of this article is to focus on IGF-1 in the field of gynaecology. Perimenopausal women who exhibit high IGF-1 and low IGF binding protein (IGFBP) levels, like IGFBG-3, have an increased risk of developing breast cancer. A higher risk for cervical, ovarian and endometrial cancer is related to high IGF-1 levels in post- and premenopausal women. It has been shown that myomas, by far the most common benign uterine tumor in women, grow in the presence of IGF-1, in vitro as well as in vivo. Studies show that IGF-1 is involved in the differentiation of various reproductive tissues, like endometrium and ovarian tissues. Patients suffering from polycystic ovary syndrome (PCO) frequently show insulin resistance accompanied by an increase of IGF-1 in plasma. Plasma IGF-1 levels are higher in cases of severe endometriosis, however, in endometriosis and in PCO IGF levels locally in the endometrium are reduced, what might explain infertility. Recently, it was shown that IGF facilitates the implantation of the human embryo in the endometrium during IVF. Implantation is a paradox where different immune systems have to collaborate to make implantation and survival of the pregnancy possible. IGF seems to be the starter molecule so that the two epithelia can fuse. A disturbance can result in complications during pregnancy i.e. spontaneous miscarriage, preeclampsia as well as defects of the embryo. Therefore, IGF is a useful marker in successful pregnancy as well. A better mechanistic understanding of IGF-1 action on the cellular level not only provides more elegant mechanistic explanations for the scientist, but the practitioner might find it interesting to utilize its diagnostic potential as a marker for various diseases. The relation between systemic IGF levels and local tissue IGF-1 levels has not yet been determined for all conditions.
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PMID:IGF-1 in gynaecology and obstetrics: update 2002. 1195 96

Incubation of gradient purified human spermatozoa, which are routinely maintained in media prior to IVF and intracytoplasmic sperm injection (ICSI), induced DNA strand breaks (up to 89 nicks x 10(-3) bp) and chromatin release. Unlike highly dispersed Alu repeat sequences, the centromeric heterochromatin was much less susceptible to endonuclease attack. In addition to chromatin release, the permeability of the sperm membrane was altered as evidenced by reduced accessibility of sperm nuclei to decondensation factors in mouse embryo extracts. Hybridization of cDNA microarrays with DNA released from spermatozoa revealed a consistent hypersensitivity of certain genes to endogenous cleavage including TP53, VHL (tumour suppressors), BRCA1 (breast cancer), NOS1 (neurotransmitter), PECAM1, FLT1 (angiogenesis) and CDKN1C (cell cycle/imprinted). N-tert-butyl hydroxylamine (NTBH), a derivative of the anti-teratogenic alpha-phenyl-N-t-butyl nitrone (PBN) and synthetic superoxide dismutase (SOD)/catalase mimetics inhibited chromatin release and sustained or dissipated relative mitochondrial membrane potential. Together, these results show a link between the hyperactivation of sperm mitochondria and chromosomal damage of specific genes in vitro, and that the potential risk of disruption of paternally contributed genes can be circumvented by antioxidants which are known to target mitochondria.
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PMID:Gene-specific chromatin damage in human spermatozoa can be blocked by antioxidants that target mitochondria. 1465 2

Aromatase inhibitors (AI) block the last enzymatic step of estrogen production, the aromatization of the A-cycle of aromatizable androgens and particularly, androstenedione (D4) and testosterone (T). Molecules designed for interfering with aromatase activity have existed for many years. Yet the activity of products of the aminogluthetimide era was too unspecific and these substances carried too many side effects for being used clinically. Today, however, 3rd generation AIs have become available that are highly specific and essentially devoid of side effects. These molecules have recently been approved for treating breast cancer in post-menopausal women, either in advanced forms, or as part of adjuvant therapy. In women whose ovaries are active, a temporary inhibition of E2 production will activate gonadotropins and in turn, stimulate follicular growth. In cancer patients, this property precludes the use of AIs in women whose ovaries are still active, unless gonadotropins are blocked. In infertile patients, this property of AIs has been put to play for inducing ovulation. AIs have been used both in women who do not ovulate but whose hypothalamo-pituitary-gonadal (HPG) axis is active (oligo-anovulators of PCOD type) and in those who ovulate regularly but in whom multiple ovulation is sought for treating infertility or as part of IVF. Like CC, AIs are not usable in women whose gonadotropins are suppressed, as in the case of hypothalamic amenorrhea. The sum of data available on the use of AI for inducing ovulation remains however meager to this date and is mainly constituted of pilot and non-randomized trials. Yet mounting evidence tends to support AIs' advantages over CC for induction of ovulation. Hence, we think that these drugs will play a key role for the induction of ovulation in the future.
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PMID:[Use of aromatase inhibitors in infertile women]. 1614 May 57

Aromatase inhibitors (AI) block the last enzymatic step of estrogen production, the aromatization of the A-cycle of aromatizable androgens and particularly, androstenedione (delta4) and testosterone (T). Molecules designed for interfering with aromatase activity have existed for many years. Yet the activity of products of the aminogluthetimide era was unspecific and these substances carried too many side effects for being used clinically. Newer third generation AIs, however, are highly specific and essentially devoid of side effects. These molecules have recently been approved for treating breast cancer in postmenopausal women either, in advanced forms or, as part of adjuvant therapy. In women whose ovaries are active, a temporary inhibition of E2 production will raise gonadotropins and in turn, stimulate follicular growth. In cancer patients, this property precludes the use of AIs in women whose ovaries are still active, unless gonadotropins are blocked. But in infertility patients, this property of AIs has been put to play for inducing ovulation. AIs have been used both in women who do not ovulate but whose hypothalamo-pituitary-gonadal (HPG) axis is active (oligo-anovulators of PCOD type) and those who ovulate regularly but in whom multiple ovulation is sought for treating unexplained infertility or as part of IVF. Like clomiphene citrate (CC), AIs are not usable in women whose gonadotropins are suppressed, as in the case of hypothalamic amenorrhea. The sum of data available on the use of AI for inducing ovulation remains however meager to this date and is mainly constituted of pilot and non-randomized trials. Yet mounting evidence tends to support AIs' advantages over CC for induction of ovulation. Hence, we think that the likelihood that these drugs will play a key role in induction of ovulation in the future is high. AIs appear particularly interesting for treating unexplained infertility because AI-FSH/hMG regimens are lighter than FSH-only regimens while retaining the high pregnancy rates of these latter treatments.
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PMID:Clinical use of aromatase inhibitors (AI) in premenopausal women. 1868 52

Although nulliparity has been extensively related to the risk of ovarian, breast and endometrial cancers, with many studies showing the relationship largely attributable to infertility, treatment effects on cancer risk are poorly understood. Two early studies raised substantial concern when ovulation-stimulating drugs were linked with large increases in ovarian cancer, supporting the notion of an important aetiological role of incessant ovulation. Subsequent studies have been mainly reassuring, although some have suggested possible risk increases among nulligravid women, those with extensive follow-up, and those developing borderline tumours. Results regarding effects of fertility drugs on breast cancer risk are conflicting, with some showing no associations and others demonstrating possible risk increases, although for varying subgroups. In contrast, endometrial cancer results are more consistent, with two recent studies showing increased risks related to clomiphene usage. This is of interest given that clomiphene is structurally similar to tamoxifen, a drug extensively linked with this cancer. Given the recent marketing of fertility drugs and the fact that exposed women are only beginning to reach the cancer age range, further follow-up is necessary. This will also be important to fully resolve effects of exposures such as gonadotrophins, used more recently in conjunction with IVF.
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PMID:Long-term effects of ovulation-stimulating drugs on cancer risk. 1762 33

Young female cancer patients are still being poorly counseled with regard to the negative impact of treatment on their fertility and on their options for fertility preservation. Today, many possibilities exist for fertility preservation, such as ovarian suppression with GnRH analogues, ovarian tissue cryopreservation, in vitro maturation or IVF after ovulation induction with aromatase inhibitors. A pregnancy after cancer treatment does not seem to limit the prognosis. This review focuses on both the effect of cancer treatments on fertility and on the various assisted-reproduction innovations that are available to provide the cancer patient with the option of future pregnancies. It is currently a time of uncertainty and revolution concerning the role of ovarian suppression and other fertility preservation measures in the management of early breast cancer, but developments in the near future promise to be very exciting.
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PMID:Review. Fertility preservation for young female cancer patients. 1936 36

Transplantation of cryopreserved tissue from patients with cancer may carry the risk of reactivation or redissemination of micrometastases. This prospective study was conducted to evaluate the potential involvement of micrometastases in ovarian tissue in cancer patients. Ovarian biopsies were collected from patients who underwent ovarian tissue cryopreservation, in our IVF unit before chemotherapy between 2000 and 2008. Indications for cryopreservation included breast cancer (n=13), osteosarcoma (n=13), hematologic malignancies (n=13), uterine cervix carcinoma (n=2), endometrial carcinoma (n=1), colon cancer (n=1), and brain medulloblastoma (n=1). The samples were stained with hematoxylin and eosin, and examined histologically. Immunoperoxidase broad-spectrum cytokeratin staining was also performed on specimens from breast cancer patients. There were 44 patients (age range 5-40 yr) who yielded 40 specimens. No gross pathologic involvement was observed, and the histologic examination revealed normal histology with no evidence of metastases. Our findings showed that for the purpose of considering ovarian tissue cryopreservation in cancer patients, the likelihood of microscopic metastases within ovaries of normal appearance is apparently very low. Clarification of the actual risk of ovarian involvement and any subsequent risk of micrometastases and tumor reimplantation requires further investigation.
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PMID:Histologic evaluation of fresh human ovarian tissue before cryopreservation. 1995 43

Kristin, a 38-year-old female with breast cancer, was scheduled to begin treatment a week after receiving her diagnosis. Although she was in a four-year-long relationship, she had never thought about having kids. Kristin was told that embryo banking (IVF) was the best option for fertility preservation, and she had to decide immediately if she wanted biological children in order to start an egg-retrieval cycle. Because no other options were provided and she was uncertain about freezing embryos with her partner, she ended up foregoing fertility preservation prior to the treatments that ultimately left her infertile. Ethan, a 19-year-old male, was in the hospital for four days awaiting surgery to remove a pelvic sarcoma. The surgery required removal of his testes rendering him infertile. During those four days, no one talked to him or his family about sperm banking, even though it could hve been accomplished in a matter of minutes.
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PMID:MyOncofertility.org: a web-based patient education resource supporting decision making under severe emotional and cognitive overload. 2081 46

The purpose of the present study was to evaluate breast mammographic features, particularly mammographic density in a selected population of infertile women and to assess if these women should be considered at higher risk for breast cancer. The prevalence of female infertility in Western countries is approximately 10-15% and since causes affecting the female are involved in 35-40%, concerns have developed about the future health of these women, specifically whether infertility could represent a risk factor for future cancer development. Moreover, infertility is now often treated with medication and procedures that could modify the hormonal environment and be cofactors in the cellular changes towards cancer development. Mammographic breast density is a useful marker for breast cancer risk and breast density is considered one of the strongest risk factors for breast cancer. Breast density is associated with known breast cancer risk factors such as reproductive and menstrual factors including serum estrogen and progesterone concentrations. In Italy the National Federation for Breast Cancer (FONCAM) guidelines suggest the usefulness of mammography from 35 years of age for women who undergo infertility hormone therapy (FONCAM Guidelines, 2005). According to this recommendation 294 women aged > or = 35, with primary infertility, sent to our breast service before joining an IVF program were recruited and then underwent clinical examination and X-ray mammography. Women were divided into two groups: dense breast (DB) and non-dense breast (NDB). Univariate analysis was employed to evaluate if there was an association between mammographic density and other risk factors. Evaluation of mammographic features showed the presence of BI-RADs C and D in the sample of 200 (68%) patients with DB and in 94 (32%) patients with NDB BI-RADS A and B. Univariate analysis showed that there were no statistically significant differences between the groups BD and NDB as regards age at mammography, age at menarche, BMI and family history for breast cancer, while ovulatory etiology of infertility was found to be associated with high mammographic density (p < 0.05). In conclusion, bearing in mind that 68% of our study sample had high breast density, we can assume that patients with primary infertility might represent a group at high risk for breast cancer, particularly if infertility is due to an ovulatory factor. We suggest breast screening from the age of 35 in infertile patients who undergo treatment with fertility drugs in accordance with FONCAM recommendations. This might allow the identification of higher risk patients who need more closely monitored breast examinations.
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PMID:Mammographic features in infertile women as a potential risk for breast cancer: a preliminary study. 2243 5


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