The Controversy Regarding Association of Naturally Decreased Amh Quantities in Young Women Who Generate Cancer Still Persists: A Short Communication

Inspite of massive evaluation of the pathophysiological modes there is the absence of insight regarding modes of premature ovarian aging that results in diminished ovarian reserve(DOR) in addition to probably infertility in case of young women.

Inspite of massive evaluation  of  the pathophysiological modes there   is the absence of insight regarding modes of  premature  ovarian aging that results in   diminished ovarian reserve(DOR) in addition to probably infertility  in case of young  women.The well acknowledged canonical riskfactors for DOR  are aggravated ovarian surgery,endometriosis along  with cytotoxic  treatment; nevertheless, gene mutations like FregileX syndrome can further  result in premature  ovarian elimination of ovarian follicles as well as DOR.The BRCA1 along with BRCA2genes are crucial members of the kinase ataxia -telangiectasia mutated(ATM)-  deoxy ribonucleic acid(DNA) double strand break(DSB) healing pathway. Mutations of these genes are correlated with an escalated risk of breast  as well as ovarian cancer generation  [1]. At the time of generation of  ovarian  stimulation protocols with aromatase hampering agents in   women with breast  cancer(BC)the group of Oktay along   with  others the  observation was that in women with BC,the ones possessing the  BRCA mutations  generated lesser   oocytes[2,3].

Serum antimullerian hormone (AMH) gets  generated from the proliferating  granulosa cells whose destruction takes place at the time of chemotherapy.  Ovarian  reserve is comprised of primordial follicles(PF) that are quiet,thus do not produce  AMH [4]. In view of   the  population size of follicles that get produced have a direct association with the generating follicles[5]. Despite,no markeris perfect regarding quantification of PF in human ovary,noninvasively , AMH determination gives maximum precision  for identification of injury subsequent  to chemotherapy   on  ovarian reserve[6].In view of unpublished observations of Oktay group besides restricted work they determined that 3-6 mths might be the need  for the  repopulation of the generating follicles pool to AMH  quantities that are determinable.Thus  AMH  quantities that can get determined  would reach a steady state  to point to the chemotherapy stimulated ovarian injury[9].To assess if BRCA mutations in contrast to  those not possessing BRCA mutations  would  generate  greater  ovarian reserve loss they planned a study.

Thus despite diminished ovarian function that result in infertility is implicated in a robust psychological load on the  patients impacted, outcomes   pointedtowards a  probable association amongst gene mutations,dysfunctional DNA healing modes along   with  escalated risk of  generation of cancer.The probably association of infertility regarding long term health along   with   life anticipation  has been illustrated  in a new publication,that detailed a 10% escalated risk of  mortality in case of infertile patients with a 47%  escalated risk of   mortality  in view of cancer][8].

Oktay etal.[9], carried out the assessment of  prior cytotoxic ovarian reserve in addition to post cytotoxic therapy in case of patients possessing the  BRCA mutations. Oktay etal.[9], illustrated that with great clarity  that patients impacted  by BRCA gene encountered  a considerable reduction in antimullerian hormone (AMH) quantities along   with decreased recovery  subsequent to chemotherapy in contrast to non influenced women.Their observation along   with prior publications of their group corroborated the same posit that  DNAhealing deficiency  is a common mode amongst ovarian aging, infertility along with  cancer in view of  both BRCA genes  have the akin family of DNA double strand breaks(DSB) healing genes, possessing a key part  inconferring  protection  to DNA intactness(see figure1).

Courtesy ref no.9-BRCA1 deficiency results in oocyte sensitivity to chemotherapy in a mouse bioassay. FVB mice oocytes were treated with doxorubicin (100 μg/mL) for 1 hour after sham, scrambled small interfering ribonucleic acid (siRNA), or siRNA microinjection to silence BRCA1 in the oocytes. Oocyte survival was assessed 8 hours later. (A) Significant increase (P = .003) in the percentage of oocyte death was observed in the BRCA silenced group (128 oocytes from 8 mice) when compared to the sham (110 oocytes from 8 mice) and scrambled-siRNA-injected group (118 oocytes from 8 mice). Representative differential interference contrast images of the sham (B), scrambled siRNA (C) and BRCA1 siRNA-treated (D) oocytes are shown after doxorubicin exposure. White arrows point to representative viable and red arrows point to nonviable oocytes.

DNA injury can  take place secondary to endogenous as well as  exogenous processes along with might  take origin in various diversities.The  DSBs where the phosphate  backbones regarding the 2  corresponding  DNA  strands  break  at the same time,reflects the maximum cytotoxic  injury . in view of  genomic  intactness  is of  considerable significance regarding cell survival along with  in view of genomic  injury  might  result  in mutagenesis in addition to cancer  over  evolution  cells have generated particular healing pathways for tackling DNA injuries,the DNA damage  response (DDR).Working DDR is key   for health along with  subjects impacted by DDR  mutations in the DDR genes can reveal   variation of conditions of nervous, immune in addition to reproductive system along with    being prone  to premature aging as well as cancer generation[10].

DDR   further  possesses  a key part in the formation of gametes like at the  time of meiosis amongst the homologous chromosomes need interchange of  genetic matter.In this such interchange the generation of DSB is implicated along with  their following healing by homologous recombination. Deficiency in the healing system of DSBs at the time of meiosis might cause infertility.

The impact of mutations regarding DDR gets apparent in case of patients with Fanconi - anaemia(FA). FA  reflects an autosomal recessive  condition that  possesses the properties of propagative  bone marrow  failure as well as considerably greater incidence along  with   proneness towards  cancer generation in addition to decreased  fertility amongst other congenital aberrations . Maximum  of   patients with FA possess significantly decreased   quantities of gametes besides female patients present with premature  ovarian   insufficiency(POI).It is well acknowledged that FA  proteins  take part  in the  DSB healing model of genetic recombination  at the meiotic prophase; nevertheless,the actual association amongst their part  in DNA healing as well as  fertility has not been deeply detailed  in humans[11].

DNA healing ability is  variable amongst subjects along with association amongst decreased DNA healing ability along with proneness towards various kinds of haematological  cancers has been  acknowledged earlier. Akin to patients with BRCA1 mutations,where DOR was illustrated,girls as well as  young women  that  in with impacted by  leukaemia along with     lymphoma(Hodgkin’s as well as non Hodgkin’s) further possessed decreased  AMH quantities in theform of a marker  of ovarian reserve before cytotoxic  treatment was started  as well[12].

In  theory these decreased  AMH quantities could be attributed to dysfunctional granulosa cells working in view of  dysfunctional DNA healing mode.Thus with background of observations of  Oktay etal.[9], dysfunction of DNA healing ability might get shared for both,like besides   escalating the  chances of cancer generation, result  in enhancement of premature ovarian aging along  with  DOR.Greater work regarding association amongst  dysfunctional DNA healing system, cancer risk along  with  DOR is needed along  with   of great significance. Furthermore, in view of  AMH quantities are frequent evaluation test in infertility, particular concentration needs to be done in young patients that possesslesser ovarian reserve naturally in view of their greater susceptibility of cancer generation risk once there is presence of dysfunctional DDR system. Moreover, young cancer patients apart from being  susceptible to generation of DOR in view of cytotoxic therapy along with   decreased quantities of gametes probably secondary to dysfunctional DNA healing ability. In view of  them being prone to generation of considerable decrease of AMH quantities along   with decreased recovery  subsequent to chemotherapy fertility preservation strategies become imperative.

Once  this posit gets corroborated in further studies, patients that possess lesser ovarian reserve naturally need to get cautioned about cancer screening for earlier aim of cancer avoidance that result  in early intervening regarding long time health results[13].

 Subsequently  Verdiesen etal.[15],whose group had been earlier pursuing this research  earlier[14], assessed  longitudinal data from 3025 women in the prospective Doetinchem Cohort Study,using  Cox proportional hazards models for evaluation of baseline age- AMH tertiles with cancer.. Their results did not give  proof for a correlation amongst age-particular  AMH and age- associated projections along with    cancer risk. Nevertheless, effect estimates for breast cancer were in agreement with risk- escalating  actions  observed in prior  studies.Their results were a little paradoxical in sense that they correlated greater AMH amounts in younger women in  longitudinal studies in contrast to lower values in others but theirs was only longterm  evaluation at different time periods while others had only checked single valuedespite them finding link with BC in these  younger women[15].

Furthermore,role of diet was probed for the etiology of diet along with    the risk of ovarian, endometrial, and breast cancer  in  menopause women[16]. There is evidence that diet is significant  regardingvarious women's cancers, along with  is  correlated with cancer propagation,its  survival, in addition to its therapy.They gave emphasis on  Nutrigenetics, Nutrigenomics, as well as Nutritionalgenomics   . The ideal combination regarding cancer avoidance was a diet having enrichment of Vitamins along with  fibers as well as lesser meat ingestion,milkintake besides moderate utilization of alcohol.For that  Mediterranean diet is apparently ideal  having a greater nutritional paradigm making it ideal for prescription [17].

Recently in a  a systematic review conducted by  Anderson RA regarding Antimullerian hormone quantities in the form of  a marker of ovarian reserve as well as    premature  ovarian   insufficiency in children and women  with cancer  their observation wasthat in personalized subjects at  variable   ages inclusive of prepubertal adolescents  girls in addition to contrasting   with  variable treatment regimens,ages as well as to pre treatment AMH quantities in population of  women.They found proof regarding importance of POI following  cancer therapy,future work over broad range of diagnosis along with  treatment as well as ages of patients are  required for clarity  and quantification  of anticipation value.The biggest short comings of utilization of AMH clinically was restricted results  correlated with post therapy AMH quantities to fertility , time period  of reproductive lifespan/time to POI generation; evaluation of these clinically significant results would prove to be useful in future  evaluation[18]I(see figure2).  

Courtesy ref no.18-Putative mechanisms of impact of cancer treatment on ovarian function. (a) In premenopausal individuals, circulating AMH is produced by secondary, preantral and early antral growing follicles, and has been shown in animal models to be one of several molecules which contribute to maintenance of ovarian reserve by inhibiting folliculogenesis; (b) anticancer treatment can reduce the ovarian pool of primordial follicles either by direct or indirect DNA damage, or by overactivation and subsequent depletion of primordial follicles; (c) following treatment, a patient may experience some recovery of the number of AMH-producing growing follicles, depending on the impact of anticancer treatment, or POI. In patients who recover ovarian function, a reduced pool of primordial follicles may still lead to an increased risk of later POI and infertility. AMH, anti-Müllerian hormone; POI, premature ovarian insufficiency; ROS, reactive oxygen species

Having earlier reviewed the part of alkylating agents in particular implicated in decreasein PF pool along with methods of intervention[19-21],detailing modes implicated in decrease in PF,ORand POI   here we further tried to see the recent posit by Oktay’s groupregarding association of AMH low levels with women who are prone to generate cancer in view of correlation of DSB,DDR with normal meiotic events .Thus the dilemma persists if lesser AMH quantitiesin women with natural low AMH are predisposed to cancer forming and more probing is needed in view of correlation of DSB,DDR with normal meiotic events.