Genetics of female infertility: A review

Transcription

1 (International Journal for Biology, Ecology and Allied Sciences) ABSTRACT Genetics of female infertility: A review S. Das* and B. Deb Bioinformatics Centre, Gurucharan College, Silchar, , Assam The world s population is increasing at an alarming rate. Despite this, 15% of couples world-wide remain childless because of infertility. We are focusing specially on female infertility. Infertility can be referred as the inability to carry a pregnancy to the delivery of a baby. It is due to delayed follicular development, large oocytes, absent or abnormal granulosa proliferation, and faulty theca cell. Somatic defects affecting infertility, meiotic recombination errors are another cause of infertility. Some genes regulating the female infertility are GDF9, BMP15, BMPR1B, CBX2; M33, CHD7, DIAPH2, FGF8, POF1B, PROK2, SRY, PROKR2. These genes plays a important role in ovarian function, actions in follicle growth and development at all stages of folliculogenesis, also plays a role during in vitro maturation of oocytes. Genetic disorders of the female reproductive system includes infertility can be observed in 10% of female infertile patient including chromosome aberrations and single gene mutations, pelvic inflammatory disease, endometriosis, polycystic ovarian syndrome (PCOS), premature ovarian failure (POF), uterine fibroids. Other causes of infertility in females include ovulation problems, tubal blockage. Genetic tests are now available to explore the cause of the infertility and assess the risk of couples to transmit its genetic characteristics. Some clinical testes like in vitro fertilization technique (IVF), assisted reproductive technology (ART), artificial Insemination (AI), peripheral blood karyotype analysis. In this case the cytogenetic screening is required. Clinical application of fluorescent in situ hybridization (FISH) for the analysis of chromosome content in individual spermatozoa. A careful genetic counseling should be offered to patients. In these cases, pre-implantation diagnosis for fragile X syndrome should be offered. Keywords: Genetics, infertility, endometriosis, female. * snghtdas@gmail.com Published by The Society for Biometry, Ecology & Econometrics (BEES), Karimganj, Assam, India 25

2 INTRODUCTION Infertility may also be referred to as the inability to carry a pregnancy to the delivery of a baby. Infertility is due to delayed follicular development and histological examination reveals large oocytes, absent or abnormal granulosa proliferation, and faulty theca cell 1. Infertility can be caused by defects in the development of the urogenital system and in its function, by genetic defects of the endocrine system, including the hypothalamic-pituitary-gonadal axis, and by defects in gametogenesis, gamete function, fertilization or early embryonic development. Secondary or acquired infertility, such as after tubal disease, vasectomy or exposure to gonadotoxins 2. Genetic disorders can be chromosomal, involve single genes or be multifunctional. Infertility can be hormonal, related to age, exercise, obesity or infectious disease; it can be immunological, psychological, result from surgery or blockage, or be associated with defined abnormalities in the gametes (for example aberrant semen parameters). CAUSES OF INFERTILITY Infertility may be caused by medical condition that may damage the fallopian tubes, interferes with ovulation, or causes hormonal complications. These medical conditions. Infertility is a broad term used to define a range of different phenotypes. The genetics of infertility is very complex and is dependent on different factors. Genetic factors can affect the production of the germ cells, the ability of the gametes to meet or embryonic development. Table 1: Different genes regulating the causes of female infertility Genes Bone morphogenetic protein 15 (BMP15) Bone morphogenetic protein receptor 1B (BMPR1B) Chromobox homolog 2, Drosophila polycomb class (CBX2; M33) Phenotype Hypergonadotrophic ovarian failure (POF4) Ovarian dysfunction, hypergonadotrophichypogonadism and acromesomelicchondrodysplasia Autosomal 46,XY, male-to-female sex reversal (phenotypically perfect females) ECOBIOS, Vol. V (I&II)

3 Chromo domain helicase DNAbinding protein 7 (CHD7) Diaphanous homolog 2 (DIAPH2) Fibroblast growth factor 8 (FGF8) Fibroblast growth factor receptor 1 (FGFR1) Premature ovarian failure 1B (POF1B) Prokineticin (PROK2) Sex-determining region Y (SRY) Prokineticin receptor 2 (PROKR2) Growth differentiation factor 9 (GDF9) CHARGE syndrome and Kallmann syndrome (KAL5) Hypergonadotrophic, premature ovarian failure (POF2A) Normosmichypogonadotrophichypogonadism and Kallmann syndrome (KAL6) Kallmann syndrome (KAL2) Hypergonadotrophic, primary amenorrhea (POF2B). Normosmichypogonadotrophichypogonadism and Kallmann syndrome (KAL4) Mutations lead to 46,XY females; translocations lead to 46,XX males Kallmann syndrome (KAL3) Endometriosis, POS, folliculogenesis. ENVIRONMENTAL FACTORS AND INFERTILITY Environmental factors such as chlorinated hydrocarbons and fumicides have also been discovered to be associated with the increased link of spontaneous miscarriage in women. Toxins such as glues, volatile organic solvents or silicones, physical agents, chemical dusts, and pesticides are responsible for infertility 3. Weight changes and infertility Infertility can be caused by weight loss and excessive weight gain with body mass index (BMI) greater than 27 kg/m 2(3). Excess weight has also been found to have effect on infertility. Estrogen is produced by the fat cells and primary sex organ and thus, state of high body fat or obesity causes increase in estrogen production which the body interprets as birth control, limiting the chances of getting pregnant. Age and Infertility Infertility relates with age. Female fertility is at its peak between the ages of 18 and 24 years. While, it begins to decline after age 27 and drops at a somewhat greater rate after age. ECOBIOS, Vol. V (I&II)

4 Human gene mutations causing infertility Mutations in pituitary genes causing infertility result either in deficiency of all or some of the pituitary hormones, thyroid stimulating hormone (TSH), prolactin, growth hormone, FSH, and LH. Gonadal causes of infertility constitute the largest group of disorders for which mutations affecting gonadal function include gonadotrophin receptors, steroid hormone receptors, steroid synthesis defects. Mutations of genes expressed in the hypothalamus generally result in hypo gonadotrophic hypogonadism 4. Tubal factors and infertility Tubal (ectopic) and peritoneal factors importance for the cause of infertility include endometriosis, pelvic adhesions, pelvic inflammatory diseases usually due to Chlamydia, tubal occlusion, and tubal dysfunction. Uterine factors and infertility Uterine factors are uterine malformation such as abnormal uterine shape and intrauterine septum; polyps, leiomyoma, and Asherman s syndrome. Fibroid in the uterus are extremely common in women in their 30s. Large fibroids may cause infertility by impairing the uterine lining, blocking the fallopian tube, distorting the shape of the uterine cavity. Genetics of disorders of the female reproductive system (includes infertility) Premature ovarian failure Premature ovarian failure, including abnormal apoptosis, an abnormal number of primordial follicles and/or abnormal follicular maturation. POF has been linked with several X chromosome-linked defects. and it has been suggested that GDF9 and BMP15 mutations are involved in POI. In humans, a natural heterozygous mutation in the propertied region of the BMP15 gene has been associated with hyper gonadotrophic ovarian failure due to ovarian dysgenesis. The mutation appeared to be associated with reduced granulosa cell growth. 5 Endometriosis Endometriosis is an oestrogen-dependent condition that is characterized by the presence of endometrium-like tissue at ectopic sites such as the pelvic peritoneum and ovaries. Pelvic pain and infertility are the most common features of endometriosis. an abnormal immune response and a genetic predisposition to ECOBIOS, Vol. V (I&II)

5 developing endometriotic lesions. The initial mutation may be either somatic or heritable endometriosis has focused mainly on genes involved in inflammation, steroid hormone regulation, metabolism, biosynthesis. 5 Polycystic ovary syndrome In PCOS, the genes implicated in folliculogenesis, such as follistatin, genes involved in the androgen biosynthetic pathway (such as CYP11A, CYP17 and CYP19). PCOS also manifests clinically as obesity, infertility, impaired glucose tolerance (IGT), insulin resistance and an increased risk of endometrial cancer, metabolic syndrome. Diagnosis and genetic test of infertility Treatment for infertility is unique in medicine as it offers individuals radical invasive treatment that are of little or no benefit to the health of the individual being treated. Clearly the hope is that a greater understanding of the genetic control of infertility will bring low-risk treatments that are effective and easy to administer. 6 Karyotype analysis Peripheral blood karyotype analysis is strongly recommended during the diagnostic workup of patients with azoospermia andsevere oligozoospermia. In these case the cytogenetic screening is mandatory. some karyotype abnomalies (for example 47, XYY, some translocations and other structural aberrations) may cause male as well as female infertility. 7 Micro deletions of the long arm of the Y chromosome Y chromosome micro deletion screening is strongly recommended during the diagnostic workup of infertile patients with non-obstructivea zoospermia and severe oligozoospermia. Fluorescent in situ hybridization (FISH) analysis in spermatozoa Clinical application of fluorescent in situ hybridization (FISH) for the analysis of chromosome content in individual spermatozoa, FISH analysis could be indicated in primary severe testiculopathies and after chemo-radiotherapy. Fragile X syndrome This test is strongly recommended during the diagnostic workup of women with oligo-amenorrhoea caused by primary ovarian dysfunction (including premature ovarian failure, POF), especially when ECOBIOS, Vol. V (I&II)

6 Assisted reproductive system is considered. A careful genetic counseling should be offered to patients. In these cases, preimplantation diagnosis for fragile X syndrome should be offered. 7 Invitro fertilization technique (IVF) In Vitro Fertilization also known as the "Test-tube baby" technique IVF is the advanced clinical treatment for infertility. In-vitro fertilization is very helpful for women with blocked fallopian tubes or for men with a low sperm count lead to conceiving of babies. In-vitro fertilization which involves the fertilization of eggs and sperm outside the body in a laboratory and once, an embryo or embryos form; they are then placed in the uterus. 8 Fig. 1: Causes of infertility in couples having IVF. ( ECOBIOS, Vol. V (I&II)

7 Fig. 2: Flow chart illustrating the diagnostic approach of an infertility workup for women ( Assisted reproductive technology(art) Assisted reproductive technologies include any fertilization involving manipulation of gametes/ embryos outside the human body and transfer of gametes/embryos into the body. The new reproductive technologies give great help and offer biomedical parenthood to various infertile couples who have exhausted all other avenues to have a child of their own. Artificial Insemination (AI) It involves manipulation of fertilization by injecting of a sperm artificially through a needle into the vagina /cervix/ uterus/ fallopian tubes of the patients directly without sexual intercourse. Success rate of AI is 70 75% within three to four months while it is done successively for four five days in each cycle. 9 CONCLUSION Female infertility is now a days a major health problem as in many countries it affects about 15% of couples trying for a ECOBIOS, Vol. V (I&II)

8 child. We have concluded that 10% of female infertile patient s genetic abnormalities could be present and it can be diagnosed by different genetic tests. Acknowledgement The authors wish to extend their grateful thanks to Department of Biotechnology (DBT), Government of India, New Delhi for the establishment of Institutional Level Biotech Hub and Bioinformatics Centre in Gurucharan College, Silchar, India. I am also very thankful to my guide Dr. Bibhas Deb, Head and associate professor of Dept. of Botany, Gurucharan College, Silchar. REFERENCES [1] Matzuk, M. M., & Lamb, D. J. (2002). Genetic dissection of mammalian fertility pathways. [Research Support, U.S. Gov't, P.H.S.Review]. Nat Cell Biol, 4 Suppl, s doi: /ncb-nmfertilityS41. [2] Shah, K., Sivapalan, G., Gibbons, N., Tempest, H., & Griffin, D. K. (2003). The genetic basis of infertility. [Review]. Reproduction, 126(1), [3] Olooto, W. E., Amballi, A. A., & Banjo, T. A. (2012). A review of Female Infertility; important etiological factors and management. J Microbiol Biotech Res, 2(3), [4] Layman, L. (2002). Human gene mutations causing infertility. Journal of medical genetics, 39(3), [5] Martin, E. (2001). The woman in the body: A cultural analysis of reproduction: Beacon Press. [6] Karlberg, S. (2012). Mulibrey nanism: Characterization of hypogonadism, infertility and tumors. [7] Foresta, C., Ferlin, A., Gianaroli, L., & Dallapiccola, B. (2002). Guidelines for the appropriate use of genetic tests in infertile couples. European journal of human genetics: EJHG, 10(5), [8] Rani, K. and Paliwal, S. (2014) A brief review on in-vitro fertilization (ivf): an advanced and miraculous gateway for infertility treatments. World journal of pharmacy and pharmaceutical sciences, 3(4), [9] Chaudhary, B. L., (2012) Assisted Reproductive Techniques Ethical and Legal Issues. J Indian Acad Forensic Med, 34(4), ECOBIOS, Vol. V (I&II)