Will Exploration for Role of Kisspeptins Answer the Modes by which Transgenerational Transmission of Polycystic Ovary syndrome (PCOS) Occursto find a way of Avoidance of Inheritance of PCOS?-
 A Short Communication

Dr Kulvinder Kochar Kaur ¹*, DR Gautam Nand K Allahbadia ²,
DR Mandeep Singh M.D.DM ³

1. Obstt & Gynae, Specialist Reproductive Endocrinology & Infertility Specialist.

2. M.D. (Obstt & Gynae), D.N.B, Scientific Director, Ex-Rotunda-A Centre for Human Reproduction 672, Kalpak Garden, Perry Cross Road, Near Otter’s Club, Bandra (W)-400040MUMBAI, INDIA.

3. (Std) (Neurology), Consultant Neurologist, Swami Satyanand Hospital Near Nawi Kachehri, Baradri, Ladowali road, Jalandhar-144001, Punjab, India, JALANDHARPUNJAB.

Corresponding Author: Dr Kulvinder Kochar Kaur, M.D, Obstt & Gynae, Specialist Reproductive Endocrinology & Infertility Specialist.

Copy Right: © 2023 Dr Kulvinder Kochar Kaur, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received Date: February 15, 2023

Published Date: March 01, 2023

Introduction

Polycystic ovary syndrome (PCOS) possesses a minimum of the following 2 components;namely  hyperandrogenism(HA),irregular or absence of menstrual cycles( alias oligomenorrhea/ amenorrhea) or ovaries with polycystic morphology.It impacts 15-20% women in the reproductive period that impacts their fertility along with cardiometabolic health[1]. Regarding escalating fecundity assisted reproductive technology(ART) is the usual requirement; however,irrespective of the mode of conception women undergoing pregnancy usually encounter escalated risk of pregnancy induced hypertension (PIH),preeclampsia , maternal gestational diabetes mellitus(GDM) , spontaneous preterm birth, requirement for lower segment caesarean section (LSCS )delivery hence robust maternal morbidity.In total 60-70% of PCOS  mother’s daughters go on to have a hereditary acquisition of PCOS in view of genetic ,epigenetic along with generational aid that influences fetal HA generation;that is a generational characteristic shared as a precedence for all PCO phenotypes[1]. It is not astonishing that in view of PCOS multi billion dollars expenditure is placed on the United States government alone; however, it has not been feasible to attain a cure in view of its complicated generational etiopathogenesis.

The placenta of neonates born to PCOS women have been believed for considerable time to be implicated in contribution to the generational initiation of PCOS in addition to morphological along with functional intactness that gets influenced by maternal HA, obesity, GDM along with chronic low grade inflammation resulting in the reduction of uteroplacental perfusion, placental inadaequacy along with insufficient aromatization of androgens[1,2]. Animal model studies have provided direct validation regarding how maternal HA is implicated in inducing placental inadaequacy formed by maternal gestational testosterone (T) escalation [1]. Female rhesus monkeys progeny receiving exposure to gestational T display the maximum detailed PCOS-like adult phenotypes inclusive of numerous metabolic dysfunctions like diseases type2  diabetes mellitus (T2DM) which  are correlated with PCOS[ 1]. Male monkeys belonging to the same species (spp), having akin exposure to maternal HA  further display equivalent insulin resistance (IR) along with pancreatic beta βcell dysfunction equivalent to T exposed females along with simulate glucocontrolling dysfunctions illustrated by male relatives of PCOS women[1].

At the time of hyperandrogenic pregnancies in monkeys the villous hemochorial placenta displays decreased placental blood volume [3] along with probably placental blood  flow,aiding in  a comparatively hypoxic fetal milieu[3,4]. Adding diet induced maternal obesity (DIO) to the hyperandrogenic pregnancies in monkeys results  in escalated maternal gestational weight accrual as well as body fat [3,4], in addition to maternal hyperglycemia, along with IR[3], besides reduction in maternal expression of placental glucose transporters as well as diminished placental angiogenesis[4]. At the time of latter part of gestation, female rhesus monkey fetuses are hypolipidemic[1], lesser in size along with possess greater fat  accrual[3], while male fetuses are longer as well as  possess greater weight accrual[3]. Regarding the gestational T exposed neonates female rhesus monkeys, 50% are hypoglycemic ; despite equal birth weight for both sexes[1,4], as well as infant females display  exacerbated weight accrual in addition to epigenetic alterations in white adipocytes which take place prior to besides being correlated with impaired adipogenesis along with hyperlipidemia[1].

Sun et al.[ 5], in a recent clinical observational study escalated our insight regarding placental  function inadaequacy along with  morphology at the time of hyperandrogenic PCOS pregnancies and advanced it further.This illustration besides validating PCOS placental morphological in addition to steroidal pathophysiology, further illustrated hormonal as well as metabolic reprogramming of the infants having exposure[5]. Clinical reference of Chinese women having pregnancy with a single fetus,no correlated pregnancy induced hypertension, GDM or any other endocrine conditions along with delivered by LSCS at term were enrolled from the prior to the pregnancy utilizing  Rotterdham’s  PCOS criteria with exclusion of other endocrine conditions [5].

The age matching of PCOS women was carried out in women without PCOS , however they possessed mean overweight before pregnancy in contrast to controls. Nevertheless, indications for LSCS were not  provided along with histories regarding utilization of ART, parity, prior pregnancy complications smoking along with medicines were not available. Canonical of the hyperandrogenic PCOS women with pregnancy along with as compared to control women, weight accrual was much greater in contrast to advocated guidelines as well as was equivalent to 40% higher in case of PCOS women[5]. On attainment of term gestational age (GA) PCOS women possessed escalated quantities of circulating cholesterol along with apolipotropin B, along with controls- with equivalent glucocontrolling paradigm quantities of circulating cytokines, other than decreased quantities of anti inflammatory interleukin-10 ( IL-10) [5].In toto these blood paradigm pointed to a hyperlipidemic, proinflammatory maternal milieu [see figures 1-3].

Schematic representation of the different developmental stages in which metabolic factors might affect the expression of the Kiss1 gene. First, epigenetic effects (DNA methylation, histone modification and non-coding RNAs) might permanently affect the expression of Kiss1. This effect can occur transgenerationally or at any stage of development. Second, during the perinatal period there is a critical window in which conformational changes in kisspeptin neurons might happen as a consequence of the exposure to metabolic factors. These pre-existing modifications (epigenetic and conformational during development) might determine the timing of the activation of kisspeptin neurons (puberty onset) and their function in adulthood (luteinizing hormone (LH) pulses and surge). Nonetheless, during and after development, kisspeptin neurons can still be regulated by metabolic factors at different levels: epigenetic, nutrient sensing and central and peripheral factors. AMPK, 5'-AMP-activated protein kinase; E13.5, embryonic day 13.5; GnRH, gonadotropin-releasing hormone; mTOR, mammalian target of rapamycin.

In view of maximum of the offsprings  born were male infants in women with as well as without PCOS in addition tooverall study people were comparatively few ,the sex bias of the progeny prevented statistical evaluation for daughters only. Placental weights, birth weights along with birth lengths were parallel with the latter being canonical for GA[5].

Fetal umbilical cord blood paradigms pointed to hyperlipidemia in progeny of PCOS women in the context of escalated quantities of cholesterol along with high density lipoprotein (HDL) , along with adrenal HA[5]. On restricting evaluation to male progeny, sex hormone binding globulin (SHBG) was decreased, whereas Dehydroepiandrosteronesulphate (DHEAS)was escalated in infants of PCOS women in contrast to babies born to control women.The way predicted from prior display[1,2] placentae from term GA hyperandrogenic PCOS pregnancies exhibited infarction along with intravillous fibrin deposits,calcification as well as intervillous space in view of requirement for adapting to hypoxic fetal milieu[5]. Clarification was not there  regarding which placental areas got sampled . In view of remarkable variation regarding intraplacental intactness besides functionality is of  botheration. Placentas which got sampled from PCOS women in contrast to controls, however illustrated escalated protein expression of estrogen receptor β; nevertheless showed corresponding  quantities of estrogen receptor-α(ER-α), androgen receptor, aromatase, 17βhydroxyteroid dehydrogenase2 along with toll like receptor 4 ( TLR4) [5].

Escalated placental estrogen receptor β has been correlated with enhanced placental generation of vasoconstrictive prostanoids along with calcification correlated vascular damage,hence might point to aberrant vascular structure as well as working hence placental working is decreased .Additionally, proteomic isolation of decreased placental fibronectin generation in placentas of PCOS women[5], points to decreased intercellular cell adhesion along with villous remodelling amongst PCOS placentas along with little involvement with uterine endometrium. Hence on coincidental with escalated placental expression of estrogen receptor β, decreased placental fibronectin expression might aid in the common occurrence of PIH,preeclampsia, decreased placental oxygen along with nutrients exchange in PCOS women with pregnancy[1,2]. These kinds of placental molecular foundation might provide innovative understanding in the context of differential metabolic fetal reprogramming of the  male as well as females progeny that induces adult metabolic phenotype correlated with familial PCOS[1]. Nevertheless, without the extra  insight regarding placental impairment at the time of pregnancy it is tough to gather the way structural  metabolically disturbances bring about fetal hyperandrogenism(HA). Still the strong points validating this work is no main pregnancy associated in addition to LSCS complications occured uniformly, that probably provides  insight regarding occasional  placental function inadaequacy [6].

Earlier we had reviewed the roles of PRDM, EBS/Y box protein 1 (YBX1) to control  Bone morphogenetic protein7 (BMP7) inobesity &IR showing that PR (PRD1?BF?RIZ1 homologous) domain containing 16(PRDM16) binding is highly abundant at a broad set of brown fat selective genes. PRDM16 physically binds to MED1 a component of the Mediator complex and recruits it to superenhancers at brown fat selective genes.

Deficiency in PRDM in BAT reduces MED1 binding at PDRM16 target sites along with results in an elemental alteration in chromatin architecture at key brown fat selective genes. Thus PRDM controls chromatin architecture and superenhancers activity in BAT. PRDM16 interacts with MED1 at brown fat specific genes to facilitate gene transcription .The binding of MED1 to PRDM16 is apparently  direct in view of these factors possess the capacity of binding together in vitro as purified proteins. MED 1 is a component of the Mediator complex which plays a crucial part in regulatory genes expression via various modes . Mediator bridges enhancer regions along with correlated transcription factor complexes with RNAII polymerase and the transcriptional machinery at the promoters.Harms et al. suggest that PRDM16/PRDM3 binds to chromatin at enhancers, many of which are super enhancers(SE) in BAT selective genes via peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBP β) along with other factors. At these areas PRDM16 recruits MED1/Mediator and by doing this organizes higher order chromatin architecture along with facilitate some brown specific target genes without impeding the chromatin binding of other transcription factors, including PRDM16 crosstalking partners like PPAR γ and C/EBP β[7]. The result of Harms et al.[8] indicated that AT ppargac α PRDM16 facilitates an active chromatin hub that links at least two enhancer elements of the promoter area, differentiation of at certain brown fat specific target genes without impeding the chromatin binding of other transcription factors, including prdm16 interacting partners PPARγ and C/EBP and likely other factors. At these regions PRDM16 along with MED1disrupts a higher order chromatin architecture. Furthermore Lida et al.[9] demonstrated a direct interaction of PRDM16 with MED1 subunit of the Mediator complex through the zinc finger domains. This gets recruited by enhancer of brown fat specific UCP1 genes through this crosstalkwith the enhancer of the thyroid hormone receptor (TR) driven transcription in a biochemically defined system in a mediator based manner[9,reviewed in 10,11]..

Further recently we had reviewed if any role of flutamide is existent in identification of PCOS women.This androgen effect in PCOS correlated with changed  newly generated s/c abdominal adipocytes in vitro,that gets augmented  more in s/c adipose by intracellular alpha keto reductase (AKK IC3) modulated  testosterone (T) formation from androstenedione (A4)that facilitates storage of TG,as observed in case of women with normal weight PCOS by an inverse association amongst serum total T/ A4 ratio along with fasting serum TG quantities. This observation takes place in parallel  with catecholamines stimulated lipolysis in case of s/c abdominal adipose tissue represents another property of PCOS in fat depot[12].

Recently DumesicDA group[14] that has been actively working on how the PCOS transmission from PCOS mothers to their offsprings takes place be it male or female gender resulting in metabolic dysfunction, further postulated how overexpression of PPARγ and CEBPa in certain PCOS s/c abdominal stem cells are associated with upregulation of AKR1C3 at the time of adipocyte maturation in vitro.These findings are parallel with an inverse association of serum total T/A4 ratio with serum TG quantities in normal weight PCOS women [rev in 12],  along with pointed to  decreased TG turnover in S/C adipose of these individuals facilitates insulin sensitivity [rev in 12]. AKR1C3 gene expression along with  activity  are normally greater in preadipocytes along with adipose of  gluteal in contrast to omental fat, with gluteal fat facilitating androgen activation (i.e., AKR1C3), and omental cells  favoring androgen inactivation (i.e., aldo-ketoreductase AKR1C3-mediated androgen activation by fat depot, combined with  hyperandrogenemia along with  and preferential  intra-abdominal fat accrual , probably impact bodyfat distribution along with function in normal-weight PCOSwomen via a programmedmode to balance glucose-insulin homeostasis with fat accretion [13].

Additionally, certain PCOS candidate genes, like thyroid adenoma associated (THADA) along with insulin receptor(INSR), have been correlated with metabolic syndrome(MetS) along with dysfunctional glucose regulation in PCOS along with and type 2 diabetes[rev in 14].Thus summarizing along with  positing how in the last 2 millenia , menstrual irregularity, male-kind phenotype and decreased fertility have been detailed in women validate how these clinical characteristics were frequent in the earlier era. Recent observations in normal weight hyperandrogenic PCOS women illustrated that escalated lipid accrual by the s/c abdominal adipose stem cells(ASC’s) at the time of generation of in vitro adipocytes in vitro takes place combined with diminished insulin sensitivity along with favoured  accrual of considerable lipolytic intraabdominal fat in vivo . This kind of PCOS phenotype might be an evolutionary metabolic adaptability regarding balancing energy with  storage with glucoseat disposal besides fatty acids oxidation(FAO) regarding ideal energy use at the time of  reproduction. They tried to incorporate foundational endocrine-metabolic alterations in healthy, normal-weight PCOS women with akin PCOS-like traits existent in animal models where tissue differentiation finishes at the time of fetal life in humans for validation of the  evolutionary posit that PCOS possesses  ancient along with generational origins[see figure 4].

We had further reviewed earlier the part  of AMH as an early predictor of PCOS in perimenarchal girls in preventing associated comorbidities[24].Furthermore Ibanez et al.[ 25], illustrated that if early insulin sensitization was done it avoided the conversion of precocious pubarche to PCOS[25]. Although weight loss in overweight/obese women with PCOS through lifestyle intervention  medication use and/or bariatric surgery can improve their metabolic-reproductive function [rev in 14], long-term effects of these clinical therapies remains uncertain, while gestational use of some medications are either contraindicated (i.e., antiandrogens) or associated with childhood adiposity and insulin resistance (i.e., metformin) [rev in 14]. A more efficacious approach might be to identification of young girls at risk for PCOS, probably by determining facial sebum quantities[rev in 14], anogenitaldistance [rev in 14] as well as /or circulating AMH quantities [rev in 14] in early life, and then initiate relevant interventions before puberty. This kind of clinical approach  for the treatment of  PCOS shifts the approach from disease treatment to preventive intervening , emphasizingon early along with  proper lifestyle choices besides the generation of innovative therapies; however  long-termactiond of these clinical therapies remains unsure.

Conclusion

Recently we had reviewed role of  glucose transporter GLUT4, along with endoplasmic reticulum (ER) as well as inflammatory stress,in DMgeneration[26] . Uptake of glucose in muscles along with ATs are based  on the insulin responsive glucose transporter GLUT4 that gets encoded by the soluble carrier family 2 member 4 (SLC2A4)gene,that got cloned 3decades back[27]. Subsequently it got clarified that GLUT4 possesses a foundational part in plasma glucose clearance dysfunction along with glycemia homeostasis[27]. Moreover, alterations in expression of GLUT4 have been correlated with glycemic regulation,with diminished GLUT4 taking part in susceptibility to hyperglycemia.In view of that here SLC2A4/ GLUT4 control of  muscles GLUT4 along with ATs glycemic regulation in DM. Conversely, combinations of IR along with compensatory hyperinsulinemia (in case of T2D)or hyperinsulinemia induction by insulin therapy(in case of T1D) have further been revealed as possessing the capacity of resulting in injury to different organ systems.As early as 1993 Robenaum etal.[19] had presented regarding diminished GLUT4 transporters existed in PCOS[19],despite that we still do not have answers till date for IR correlated with PCOS.Thus we had reviewed how till date it has become clear in DM regarding the dysfunctional glucose homeostasis along with generation of neurodegenerative conditions take place secondary to AGEs stimulated  ER stress along with inflammatory stress.Blockade of stimulated  ER stress along with inflammatory stress under certain experimental conditions in particular tissues have shown remarkable improvement of glycemic regulation or avoidance of CVD generation or its propagation.Hence dependent on hampering of ER along with inflammatory stress greater work was needed regarding small molecule hampering agents acting in the form of probable targets for the avoidance of  along with generation of therapies for DM or its complications. Furthermore roles of melatonin, nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain- containing 3 (NLRP3) ,nutraceuticals were needed for DM complications both micro as well as macrovascular. Similarly we had further reviewed role of therapeutic targeting of  macrophages polarization status in the treatment of obesity induced insulin resistance ,chronic inflammation[28]. Studying macrophages polarization status in utero might give more insight regarding avoidance of metabolic programming for IR generation in later life. Furthermore, considering the role of kisspeptins in reproduction along with  nutritional control in view of their particular roleon control of GnRH secretion along with nutritional control,the former via estrogen receptor(ER)-α receptors present in various hypothalamic nuclei[[28,29],latterin rodents [rev in ref 30] (see figure5) and this part needs to be explored in human &neonatesof monkeys programmed in utero if the evolutionary theory of metabolic adaptation  is correct.

References

1. DumesicDA,Hoyos LR,Chazenbalk GD,Naik R,Padmanabhan V,AbbottD.Mechanisms of intergenerational transmission of Polycystic ovary syndrome. Reproduction  2019;159:R1-13.

2. KosterMP,DeWilde MA,Veltman VerhulstSM,Houben ML,Nikkels PG,VanRijnBB,etal. Placental characteristics  in women with Polycystic ovary syndrome. Hum Reprod  2016;32(1): 147-53. 

3. Bishop CV, Stouffer RL,Takahashi DL, Mishler EC, WilcoxMC,SlaydenOD,etal.Chronic hyperandrogenimia and western style diet beginning at pubertyreduces  fertility  and increases metabolic  dysfunction during pregnancy in young adult female Macaques. Hum Reprod  2018;33: 694-705.

4. KuoK, Roberts VHJ,Gaffney J, Takahashi DL, Morgan T, LoJO, etal. maternal  high  fat diet consumption and Chronic hyperandrogenimia are associated with Placental dysfunction  in female rhesus Macaques Endocrinology 2019; 160: 1937-49.

5. Sun M, Sun B, QiaoS, Feng X, Zhang S, et al. Elevated  maternal  androgen is associated with the dysfunctional placenta and lipid disordersin PCOS newborns. Fertil Steril  2020;113(6):1275-85. 

6. AbbottDH.Does a compromised placenta contribute to  transgenerational transmission of metabolic  dysfunction in Polycystic ovary syndrome. Fertil Steril  2020;113(6):1165-66.

7. Chen W, Roeder RG. Mediator dependent nuclear receptor function. Semin Cell Dev Biol. 2011;22(7):759–768.

8. Harms MJ, Lim HW, Ho Y, et al. PRDM 16 binds MED and controls chromatin architecture to determine a brown fat transcriptional program. Genes Dev. 2015;29(3):298–307.

9. Lida S, Chen W, Nakaidai T, et al. PRDM16 enhances nuclear receptor– dependent transcription of brown fat–specific Ucp1 gene through interactions with Mediator subunit MED1. Genes Dev. 2015;29(3):308– 324.

10. Seale P. Transcriptional Regulatory circuits Controlling Brown fat Development and Activation. Diabetes. 2015;64(7):2369–2375.

11. Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Advances in BAT physiology for understanding and translating into Pharmacotherapies for obesity and comorbidities. MOJ Drug Des Develop Ther. 2018;2(5):166?176.

12. Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Identification of Women of Polycystic Ovary Syndrome (PCOS) AtRisk for Generation of Metabolic Disease in Normal Weight PCOS: Is There a  Role of Flutamide?- AShort Communication. CPQ Medicine, (2023); 14(2), 01-06.

13. Cole B, Hensinger K, Maciel GA, Chang RJ, Erickson GF. Human fetal  ovary development involves the spatiotemporal expression of p450c17  protein. J Clin Endocrinol Metab. 2006;91(9):3654–61

14. DumesicDA, Chazenbalk GD ,Padmanabhan V,AbbottD. Polycystic ovary syndrome as a plausible outcomes of  evolutionary metabolic adaptation. Reprod  Biol   Endocrinol 2022;20:12.

15. Leung KL, Sanchita S, Pham CT, Davis BA, Okhovat M, Ding X, et al. Dynamic  changes in chromatin accessibility  altered adipogenic gene   and total versus de novo fatty acids synthesis in  subcutaneous adipose stem cells of  normal weight Polycystic ovary syndrome(PCOS) women during adipogenesis: evidence of   cellular programming. Clin  Epigenet 2022; 12(1):181.

16. Arner P. Effects  of  testosterone on fat cell  lipolysis:species differences and possible role in Polycystic ovary syndrome. Biochemie 2005;87(1):39-43. 

17. Chazenbalk GD, ,SinghP, Irge D, AbbottDH, DumesicDA. Androgens inhibit adipogenesis during human adipose stem cells commitment to pre adipocyteformation. Steroids 2013;78(9):920-6.

18. Carbould A. testosterone treatment  induces  insulin resistance in subcutaneous  adipocytes in women. J Gynaecol 2007;192(3):585-94.

19. Rosenbaum D, Harber RS, Dunaif A. Insulin resistance in polycystic  ovary syndrome: decreased expression of GLUT-4 glucose transporters   in adipocytes. Am J Phys. 1993;264(2 Pt 1):E197–202.

20. O’Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN,  Allwood JW, et al. AKR1C3-mediated adipose androgen generation  drives lipotoxicity in women with polycystic ovary syndrome. J Clin  Endocrinol Metab. 2017;102(9):3327–39.

21. Dumesic DA,ObenfieldSE,StenerVictorinE,MarshalJC,LavenJS,Legro RS.Scientific statement on the diagnostic criteria , epidemiology, pathophysiology and molecular genetics of Polycystic ovary syndrome. Endocrin Rev 2015;36:487-525.

22. Manneras-Holm L, Leonhardt H, Kullberg J, Jennische E, Oden A, Holm  G, et al. Adipose tissue has aberrant morphology and function in PCOS:  enlarged adipocytes and low serum adiponectin, but not circulating  sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol  Metab. 2011;96(2):E304–11.

23. Chang RJ, Dumesic DA. Polycystic ovary syndrome and Hyperandrogenic  states. In: Strauss III JF, Barbieri RL, editors. Yen and Jaffe’s  reproductive endocrinology: physiology, pathophysiology and clinical   management. 8th ed. Philadelphia: Elsevier Saunders; 2018. p. 520–55.

24. Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Role of Antimullerian Hormone as an Early Predictor of  PCOS in Perimenarchal Girls-Role in Preventing Associated Comorbidities. J Gynecol  2019, 4(1): 000175.

25. Ibanez L, Ferrer A, Ong K, Amin R, Dunger D, et al. Insulin sensitization early after menarche prevents progression from precocious pubarche to  poly cystic ovary syndrome. J Pediatr 2004); 144(1): 23-29.

26. Kulvinder Kochar Kaur,Allahbadia GN,Singh M. ’An update on Mechanistic Modes in AGEs Stimulated & ER and  Inflammatory Stress- Modulated Control of the GLUT4 expression(SLC2A4 promoted)and  Atherogenesis in Diabetes mellitus -A Narrative review’’. Mathews J Cytol Histol. 6(1):21:1-25.

27. James DE,Strube M,Mueckler M. Molecular  cloning  ion characterization of an insulin regulatable promoted  glucose transporter. Nature 1989;338:83-7.

28. Kulvinder Kochar Kaur,Allahbadia GN,Singh M.   ’An update of use of therapeutic targeting of   macrophages polarization status  in the treatment of obesity  induced insulin resistance ,chronic  inflammation and type2 Diabetes mellitus-A Narrative Review’’

29. Kulvinder Kochar Kaur,Allahbadia GN,Singh M..Kisspeptins in human reproduction—future therapeutic potential. J Assist Reprod Genet  2012;29(10):999-1011. DOI 10.1007/s10815-012-9856-1.

30. Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Has The Enigma of Steroid Feedback Effects on GnRH Liberation Been Resolved with the Illustration of Estrogen Receptor-Α on the Hypothalamic Kisspeptins Neurons-A Narrative Review. Int Gyn & Women’s Health 5(4)- 2023. IGWHC.MS.ID.000218. DOI: 10.32474/IGWHC.2023.05.000218.

31. Navarro VM . Metabolic regulation of   Kisspeptin-the link  between energy balance and reproduction. Nat Rev Endocrinol  2020;16(8):407-20.