Reproductive Health Research

Reproductive health research in CDRI focuses on female and male contraception and infertility, spermicides with anti-STI properties, agents for the management of osteoporosis, uterine & prostatic hyperplasia, endometriosis and polycystic ovarian syndrome.

Global population is projected to rise exponentially from the current ~7.3 billion to 9.7 billion in 2050. Indian population, which contributes to 18% of present world population, is expected to touch 1389 million in 2020. According to the World Health Organization, the family planning needs of more than 120 million couples goes unmet every year resulting in an annual abortion rate of ~46 million. On the other hand, curable sexually transmitted infections, which increase the risk of contracting viral STDs and HIV, are a major health problem in developing countries like India. Conversely, infertility affects about 50 million (15%) couples worldwide, and India shares a high percentage of these infertile couples whose population has increased significantly over the last several years. Childlessness has serious demographic, social, personal and emotional issues. In addition, given increased longevity, endocrine disorders including osteoporosis, uterine and prostatic hyperplasia, occur more frequently. In India, 1 out of 8 males and 1 out of 3 females suffers from osteoporosis, making India one of the largest affected countries in the world. The overall objectives of the program are to design and synthesize novel molecules/isolate from natural sources and bio-evaluate them for generating new leads and to develop them as female or male contraceptives, spermicides with anti-STI properties, agents for the management of infertility, osteoporosis, uterine and prostatic hyperplasia, evaluate traditional remedies for infertility management and endocrine disorders, understand mode of action of promising agents and undertake basic research to generate new knowledge on male and female reproductive endocrinology relevant to fertility regulation and endocrine disorders.

BASIC RESEARCH

Objective: To generate new knowledge on male and female reproductive endocrinology relevant to fertility regulation and endocrine disorders due to menopause and andropause.

image01 Identification of new targets for contraception – Study of basic mechanisms governing the temperature sensitivity of spermatogenesis in testis, sperm motility suppression in cauda epididymis and sperm motility activation post ejaculation in female reproductive tract.
image01Mimicking the natural barriers to conception during safe-period of menstrual cycle – a proof-of-concept-study.
image01To understand the genetic and epigenetic causes of male and female infertility.
image01Understanding the cellular signaling of endometrial receptivity for blastocyst implantation in addition to endometriosis, premature ovarian failure and polycystic ovary in PCOS conditions.
To identify the oviductal factors playing role in sperm capacitation, fertilization, early embryonic development and to explore the non-genomic signalling mechanisms involved in oviductal transport of ova
image01To understand novel pathways that play critical role in osteoporosis, and to identify and characterize novel miRNAs involved in osteoblast differentiation.
image01To understand and impart new knowledge on metabolic bone disorders like osteoporosis as well as on fractures.
image01Studies on antiproliferative action of 2,3-diaryl-2H-1- benzopyran derivatives against endometrial hyperplasia and the study of the epigenetic regulation of prostatic hyperplasia

DRUG DESIGN AND SYNTHESIS
image012-Methyl-4/5-nitroimidazole Dithiocarbamate hybrids are envisaged to introduce antimicrobial activity in spermicidal scaffolds for developing microbicidal contraceptives for vaginal use.
image01Bis(dialkylaminethiocarbonyl)disulfides, substituted maleimides and carbodithioic acid are being designed for selectively targeting sulfhydryl groups on human sperm surface that render membrane fluidity which is essential for motility and normal physiology.
image01Following leads from some natural products for the management of osteoporosis,novel benzofurochromene class of compounds were discovered and evaluated for fracture repairing activity. Some of the synthetic compounds showed osteogenic and anti-osteoclastogenic activity. One of the novel pterocarpans CDRI-1500 isselected for drug development as rapid fracture repairing agent with improved bone quality and strength
image01Development of treatment modalities for male and female infertility.
image01To develop osteogenic (bone forming) molecules and preparations.
image01A novel analog of medicarpin for orally active rapid fracture healing drug.
image01Exploration of contraceptive strategies for female along with management of endometriosis and ovarian follicle development in polycystic ovarian syndrome (PCOS/PCO) with the help of naturally-derived compound using rodent model.
image01A novel analog of 6-C-b-D-glucopyranosyl-(2S,3S)-(+)-3’,4’,5,7-tetrahydroxyflavanone for orally active anti-osteoporotic drug.

SCREENING AND DRUG DEVELOPMENT
image01Design and synthesis of new and novel non-steroidal molecules for post-coital contraceptive efficacy; collection and bioevaluation of medicinal plants for anti-implantation activity and follow-up studies on promising agents.
image01Development of safe and effective contraceptives that exert action on testis (spermiogenesis), epididymis (sperm maturation/fertilization) or on sperm (spermicidal).
image01Designing novel drugs and formulations for use as dual protection vaginal contraceptives for protection against unwanted pregnancy and STDs/STIs.
image01Screening and development of natural and synthetic compounds having osteoblast promoting functions in vitro and bone anabolic effect in vivo.
image01Developing agents exhibiting potent anti-proliferative activity, but being free from estrogen-related health hazards, for the management of breast cancer.
image01Establishment of test systems for screening of synthetic compounds/natural products against BPH and mechanism of action studies with active agents on proliferative and apoptotic indices and other parameters in prostatic tissue.
image01Developing agents for prevention of estrogen deficiency and age related bone loss, but lacking carcinogenic effect of estrogen on the endometrium and breast, in addition to being free from other estrogen-related health hazards

SIGNIFICANT ACHIEVEMENTS
image01Centchroman, the world's first non-steroidal weekly oral contraceptive.- Sold under brand name ‘Saheli’ by HLL Lifecare Ltd., Thiruvananthapuram.
image01Consap, a herbal intravaginal contraceptive cream containing "Reetha" saponins as spermicide.- Licensed to Industry
image01Isaptent, an aid for medical termination of pregnancy developed by utilizing "Isapgol" seed husk.
image01Centchroman for the management of dysfunctional uterine bleeding. – Sold under brand name Novex D.S. by HLL Lifecare Ltd., Thiruvananthapuram (>100 mn strips sold)
image01Compound CDRI-99/373 (a new antiosteoporosis/anti-resorptive agent) – Ready for licensing
image01The standardized extract of Dalbergia sissoo (4744/F004) a rapid fracture-healing agent - licensed to Pharmanza Herbal Pvt. Ltd., Kania, Gujarat.
image01CDR-F147 (OsteoJuvenate) for optimal bone health as nutraceutical supplement - Licensed to Natural Remedies, Bengaluru
image01Compound CDRI-1500 (Pteroheal), a rapid fracture-healing agent (Regulatory Toxicology and Safety Pharmacology completed as per Schedule Y) – Ready for Licensing
image01A few other promising new drug candidates for osteoporosis (osteogenic agents) and vaginal contraception are under pre-clinical development.


RECENT PUBLICATIONS
image01Lal N, Jangir S, Bala V, Mandalapu D, Sarswat A, Kumar L, Jain A, Kumar L, Kushwaha B, Pandey AK, Krishna S, Rawat T, Shukla PK, Maikhuri JP, Siddiqi MI, Gupta G, Sharma VL. Role of disulfide linkage in action of bis(dialkylaminethiocarbonyl)disulfides as potent double-Edged microbicidal spermicide: Design, synthesis and biology. Eur J Med Chem. 2016; 10:115:275-90.
image01Kumar L, Yadav SK, Kushwaha B, Pandey A, Sharma V, Verma V, Maikhuri JP, Rajender S, Sharma VL, Gupta G. Energy Utilization for Survival and Fertilization--Parsimonious Quiescent Sperm Turn Extravagant on Motility Activation in Rat. Biol Reprod. 2016, March 16. pii: biolreprod.115.137752. [Epub ahead of print] PMID: 26984998
image01Kushwaha B, Mandalapu D, Bala V, Kumar L, Pandey A, Pandey D, Yadav SK, Singh P, Shukla PK, Maikhuri JP, Sankhwar SN, Sharma VL, Gupta G. Ammonium salts of carbamodithioic acid as potent vaginal trichomonacides and fungicides. Int J Antimicrob Agents. 2016; 47:36-47.
image01Mandalapu D, Lal N, Kumar L, Kushwaha B, Gupta S, Kumar L, Bala V, Yadav SK, Singh P, Singh N, Maikhuri JP, Sankhwar SN, Shukla PK, Siddiqi I, Gupta G, Sharma VL. Innovative Disulfide Esters of Dithiocarbamic Acid as Women-Controlled Contraceptive Microbicides: A Bioisosterism Approach. ChemMedChem. 2015;10(10):1739-53. doi: 10.1002/cmdc.201500291. Epub 2015 Sep 4.
image01Medicarpin, a Natural Pterocarpan, Heals Cortical Bone Defect by Activation of Notch and Wnt Canonical Signaling Pathways. Dixit M, Raghuvanshi A, Gupta CP, Kureel J, Mansoori MN, Shukla P, John AA, Singh K, Purohit D, Awasthi P, Singh D, Goel A. PLoS One. 2015 Dec 11;10(12):e0144541. doi: 10.1371/journal.pone.0144541. eCollection 2015.
image01Methoxyisoflavones formononetin and isoformononetin inhibit the differentiation of Th17 cells and B-cell lymphopoesis to promote osteogenesis in estrogen deficient bone loss conditions. Mansoori MN, Tyagi AM, Shukla P, Srivastava K, Dev K, Chillara R, Maurya R, Singh D. Menopause. 2016 Apr 11. [Epub ahead of print].
image01Induction of targeted osteogenesis with 3-aryl-2H-benzopyrans and 3-aryl-3H-benzopyrans: Novel osteogenic agents. Gupta A, Ahmad I, Kureel J, Hasanain M, Pandey P, Singh S, John AA, Sarkar J, Singh D. J Steroid Biochem Mol Biol. 2016; 158:63-75.
image01M. Manohar, H. Khan, V. K. Sirohi, V. Das, A.Agarwal, A. Pandey, W. A. Siddiqui, A. Dwivedi . Alteration in endometrial proteins during early- and mid-secretory phases of the cycle in women with unexplained infertility PLoS One. 2014 Nov 18; 9(11):e111687.
image01P. Popli, V. K.Sirohi, M. Manohar, V.Shukla, J. B.Kaushal, K.Gupta, A.Dwivedi. Regulation of cyclooxygenase-2 expression in rat oviductal epithelial cells: Evidence for involvement of GPR30/Src kinase- mediated EGFR signaling. J Steroid Biochem Mol Biol, 154, 130–141, (2015)
image01V Chandra, I Fatima, M Manohar, P Popli, VK Sirohi, MK Hussain, K Hajela, P Sankhwar, A Dwivedi. Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway. Cell Death Dis. 2014 Aug 21;5: e1380.
image01Ruchi Saxena, Garima Gupta, Murli Manohar, Utsab Debnath, Pooja Popli, Yenamandra S Prabhakar, Rituraj Konwar, Sandeep Kumar, Atul Kumar, Anila Dwivedi, Spiro-oxindole derivative 5-chloro-4',5'-diphenyl-3'-(4-(2-(piperidin-1-yl) ethoxy) benzoyl) spiro[indoline-3,2'-pyrrolidin]-2-one triggers apoptosis in breast cancer cells via restoration of p53 function. Int J Biochem Cell Biol. ;70:105-17. (2016)
image01Kumar Vijay, Maurya Vineet Kumar, Joshi Anubha, Meeran Syed Mustapha, Jha Rajesh Kumar. Integrin beta 8 (ITGB8) regulates embryo implantation potentially via controlling the activity of TGF-B1 in mice. Biol Reprod. 2015;92(4):109. doi: 10.1095/biolreprod.114.122838. Epub 2015 Mar 18. PMID:25788663
image01Chadchan SB, Kumar V, Maurya VK, Soni UK, Jha RK. Endoglin (CD105) coordinates the process of endometrial receptivity for embryo implantation. Mol Cell Endocrinol. 2016 Apr 15;425:69-83.
image01Carlus SJ, Sarkar S, Bansal SK, Singh V, Singh K, Jha RK, Sadasivam N, Sadasivam SR, Gireesha PS, Thangaraj K, Rajender S. Is MTHFR 677 C>T Polymorphism Clinically Important in Polycystic Ovarian Syndrome (PCOS)? A Case-Control Study, Meta-Analysis and Trial Sequential Analysis. PLoS One. 2016 Mar 16;11(3):e0151510. doi: 10.1371/journal.pone.0151510. eCollection 2016. PMID: 26983014
image01Maurya Vineet Kumar, Sangappa Chadchan, Kumar Vijay, Mahfooz Sahil, Singh Archana, Rajender Singh, Jha Rajesh Kumar. Expression and activity of Rac1 is negatively affected in the dehydroepiandrosterone induced polycystic ovary of mouse. J Ovarian Res. 2014; 14;7:32.
image01Sandeep Kumar Bansal, Gopal Gupta, Singh Rajender. Y chromosome b2/b3 deletions and male infertility: a comprehensive meta-analysis, trial sequential analysis and systematic review. Mutation Research Reviews (in press).
image01Bansal SK, Jaiswal D, Gupta N, Singh K, Dada R, Sankhwar SN, Gupta G, Rajender S. Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses, and trial sequential analyses. Sci Rep. 2016 Feb 15;6:19798. doi: 10.1038/srep19798.
image01Bansal SK, Gupta N, Sankhwar SN, Rajender S. Differential Genes Expression between Fertile and Infertile Spermatozoa Revealed by Transcriptome Analysis. PLoS One. 2015 May 14;10(5):e0127007. doi: 10.1371/journal.pone.0127007. eCollection 2015.
image01Carlus SJ, Sarkar S, Bansal SK, Singh V, Singh K, Jha RK, Sadasivam N, Sadasivam SR, Gireesha PS, Thangaraj K, Rajender S. Is MTHFR 677 C>T Polymorphism Clinically Important in Polycystic Ovarian Syndrome (PCOS)? A Case-Control Study, Meta-Analysis and Trial Sequential Analysis. PLoS One. 2016 Mar 16;11(3):e0151510. doi: 10.1371/journal.pone.0151510. eCollection 2016.

SCIENTISTS ASSOCIATED WITH THE PROJECT


image01 Dr. Gopal Gupta
image01 Dr S Sanyal
image01 Dr Atul Goel

image01Dr. Naibedya Chattopadhyay image01Dr (Ms.) Kanchan Hazela
image01Dr. (Mrs.) Anila Dwivedi image01Dr V L Sharma
image01 Dr. Gopal Guptaimage01Dr. Atul Kumar
image01Dr. F W Bansode image01Dr Atul Goel
image01Dr D P Mishra image01Dr R P Tripathi
image01Dr Rajender Singh image01Dr Gautam Panda
image01Dr. (Mrs.) Divya Singh
image01Dr (Mrs.) Ritu Trivedi   
image01Dr Rituraj Konwar
image01Dr M Sachdev image01Dr A K Dwivedi
image01Dr S Sanyal image01Dr Amit Misra
image01Dr K R Arya image01Dr Prabhat R Mishra
image01Dr JR Gayen
image01Dr Rajesh Jha image01Dr Wahajuddin
image01Dr Syed Musthapa