Pre­ma­ture Ovar­ian Fail­ure: The New Epi­demic

IVF India - - Inside - By Dr. Shi­uli Mukher­jee

Riya was quiet happy till last six month when she joined her new job as HR con­sul­tant. She was at her 32 and was about to start a fam­ily since her hus­band also set­tled as a branch man­ager at a pri­vate bank near Kasba. Prob­lem arises as she missed her pe­riod for con­sec­u­tive three months. Ini­tially she thought of good news in the form of preg­nancy. But her ela­tion was re­placed by me­lan­cho­lia when her gy­nae­col­o­gist de­clared her to be non-preg­nant and did some hor­monal as­say. It was shock­ing for her to know that she is at her fag end of re­pro­duc­tive car­rier with a FSH re­port of 15.7mIU/ml. Riya was at a loss. Ques­tions haunted in her mind like weapon shower. Is she head­ing for a pre­ma­ture menopause? Is 32 too late an age to con­ceive? Is the con­tra­cep­tive prac­tices has taken its toll? At all she can mother a child or not? Tears rolls down her fair toned chick. She felt her ovar­ian age has sur­passed her facial/skin age by al­most 20 years! As per her gy­ne­col­o­gist’s ver­sion she was suf­fer­ing from pre­ma­ture ovar­ian fail­ure. Pre­ma­ture Ovar­ian fail­ure: This is an enig­matic dis­or­der which de­scribes a stop in the nor­mal func­tion­ing of the ovaries in a woman younger than age 40. Some peo­ple also use the term pri­mary ovar­ian in­suf­fi­ciency to de­scribe this con­di­tion. It is also known as hy­per­g­onadotropic hy­pog­o­nadism. It com­monly presents with triad of amen­or­rhoea (mainly sec­ondary), hy­per­g­onadotropin­ism and hy­poe­stro­genism in young women of re­pro­duc­tive age. Though there is greatly re­duced chance of get­ting preg­nant, but women with this di­ag­no­sis can ovu­late and even can con­ceive. The in­ci­dence has in­creased from 0.3% to 1 % in last decades and show­ing an in­creas­ing trend es­pe­cially in Asian coun­tries. Th­ese women may even com­plain of hot flushes and dys­pare­u­nia at much early age mak­ing con­ju­gal life at stake. Though the most com­mon first symp­tom of pre­ma­ture ovar­ian fail­ure is skip­ping or hav­ing ir­reg­u­lar pe­ri­ods, in­fer­til­ity could have been the first pre­sent­ing com­plains. Pre­ma­ture ovar­ian fail­ure also puts women at risk for some other health con­di­tions; some of them are se­ri­ous, like loss Women with Pre­ma­ture Ovar­ian fail­ure (POF) can ovu­late and even can con­ceive. of bone strength, low thy­roid func­tion caus­ing low en­ergy, quick tired­ness even heart dis­eases. Causative fac­tors: Women with pre­ma­ture ovar­ian fail­ure mainly fall into one of the two groups: 1. Women with fol­li­cle de­ple­tion who has no fol­li­cles left in her ovaries and there is no way to make more. 2. Women with fol­li­cle dys­func­tion may have fol­li­cles in her ovaries, but they are not work­ing prop­erly. Still the largest cat­e­gory is id­io­pathic. Cy­to­ge­netic ab­nor­mal­i­ties in­volv­ing the X chro­mo­some share a good bulk of the eti­ol­ogy of POF. It’s manda­tory to have two in­tact X chro­mo­some (struc­turally and func­tion­ally) to main­tain nor­mal ovar­ian func­tion. Dele­tion of short or long arm of X chro­mo­some causes rapid atre­sia of oocytes lead­ing to poor ovar­ian re­serve at very early age. 45 XO/XX mo­saic Turner are an­other ex­am­ple of sec­ondary amen­or­rhoea and POF. Thus kary­otype is manda­tory in women sus­pi­cious of suf­fer­ing from POF be­low 35 years of age. Even ex­tra X chro­mo­some in the form of 47XXX is a po­ten­tial can­di­date for POF. Per­haps the most im­por­tant as­so­ci­a­tion with POF is pre-mu­ta­tion of FMR1 gene. This gene is lo­cated at long arm of X chro­mo­some,Xq27. Triple re­peat mu­ta­tion of CGG(cy­to­sine-gua­ninegua­nine) se­quence re­sults in POF. They gen­er­ally have strong fa­mil­ial his­tory of men­tal re­tar­da­tion lead­ing to Frag­ile X Syn­drome. Emo­tion­ally la­bile women with fea­tures of ex­ces­sive anx­i­ety, emo­tional out­burst, short at­ten­tion span, im­pul­siv­ity and hy­per­ac­tiv­ity along with fea­tures of POF are can­di­dates of FMR1 gene de­fect. 6-10% of women with POF have frag­ile X syn­drome. Kary­otype is manda­tory in women sus­pi­cious of suf­fer­ing from POF be­low 35 years Emo­tion­ally la­bile women with fea­tures of ex­ces­sive anx­i­ety, emo­tional out­burst, short at­ten­tion span, im­pul­siv­ity and hy­per­ac­tiv­ity along with fea­tures of Pre­ma­ture Ovar­ian Fail­ure are strongly suf­fer-

ing from FMR1 gene de­fect. En­zy­matic de­fects: in the form of aro­matase de­fi­ciency with nor­mal 46 XX kary­otype also suf­fer from POF. They can even de­velop cliteromegaly and les­bian instinct at later life. (e.g. re­cent case of fe­male ath­lete Pinki Pra­manik ). FSH re­cep­tor gene de­fect or se­cre­tion of bi­o­log­i­cally in­ac­tive go­nadotropin are other fac­tors. En­vi­ron­men­tal in­sults: in the form of ra­di­a­tion or chemo­ther­apy and sur­gi­cal in­jury can cause POF. Vi­ral in­fec­tion mumps oophori­tis is an im­por­tant as­so­ci­a­tion in un­ex­plained POF. Even cig­a­rette smok­ing can be re­spon­si­ble for POF. Au­toim­mune dis­or­der: About 3.2 per­cent of women with pre­ma­ture ovar­ian fail­ure also have Ad­di­son’s dis­ease with de­fects in adrenal func­tion. It even can in­volve thy­roid gland in the form of au­toim­mune thy­roidi­tis. This group typ­i­cally has the wax and wane fea­tures. And they must be treated early till the ovar­ian re­serve is com­pletely lost. How is pre­ma­ture ovar­ian fail­ure di­ag­nosed? Be­cause one of the most com­mon signs of pre­ma­ture ovar­ian fail­ure is ir­reg­u­lar pe­ri­ods, women should pay close at­ten­tion to their men­strual cy­cles and if any ir­reg­u­lar­i­ties oc­cur they must con­tact to gy­nae­col­o­gist. Pri­mary in­fer­til­ity could be a first sign of POF even. Nec­es­sary in­ves­ti­ga­tions which will guide to iden­tify the cause are listed be­low:

1. Serum TSH and pro­lac­tine level.

2. Basal serum FSH and E2 (estra­diol) on at least two oc­ca­sions.

3. Kary­otype when woman is less than 35years.

4. Care­ful fam­ily his­tory and eval­u­a­tion of FMR1 pre-mu­ta­tion (by FISH tech­nique).

5. Adrenal an­ti­body test­ing and thy­roid-stim­u­lat­ing im­munoglob­u­lins. Women with other au­toim­mune dis­or­der s must be in­ves­ti­gated for POF and treated early till the ovar­ian re­serve is com­pletely lost.

6. Blood for AMH for as­sess­ment of Ovar­ian re­serve.

If the FSH level is greater than 30mIU/ml no oocyte can be re­trieved. A level of more than 15mIU/ml ne­ces­si­tates cross check­ing of FSH in a sep­a­rate oc­ca­sion along with E2 level es­ti­ma­tion. If E2 level re­mains greater than 50pg/ml still there is chance of get­ting few fol­li­cles on stim­u­la­tion. AMH level less than 1.5mIU/ml in­di­cate very poor ovar­ian re­serve. 35% of women with sec­ondary amen­or­rhoea be­low age 35 con­tain any kind of kary­otype ab­nor­mal­i­ties. So kary­otype is a must to rule out any fa­mil­ial trans­mis­sion of X chro­mo­so­mal dis­or­der. Fam­ily his­tory of a woman whose mother had an early menopause should be cau­tious on achiev­ing POF at early age. Treat­ments for pre­ma­ture ovar­ian fail­ure: The very first and per­haps most im­por­tant, chal­lenge in pro­vid­ing ap­pro­pri­ate treat­ment to women with POF is in­form­ing the pa­tient about di­ag­no­sis in a sen­si­tive and car­ing fash­ion. It is al­ways very shock­ing for a woman to ac­cept the truth of be­ing at a fag end of her re­pro­duc­tive car­rier es­pe­cially when she de­sires kids. It can pro­vide emo­tional trauma to such a mag­ni­tude that she can suf­fer even men­tal set back. So it is al­ways bet­ter to dis­cuss her treat­ment op­tion in a sep­a­rate visit with spend­ing qual­ity time. It is im­por­tant to coun­sel the pa­tient that spon­ta­neous preg­nancy is still pos­si­ble with the help of hor­mone re­place­ment ther­apy (HRT). HRT can also help her to get rid of the symp­toms of pre­ma­ture ovar­ian fail­ure; she can have her reg­u­lar pe­ri­ods back and lower their risk for os­teo­poro­sis. Hor­mone re­place­ment ther­apy (HRT): A con­tin­u­ous ex­oge­nous es­tro­gen in the form of estra­diol valer­ate 2mg oral daily dose or trans­der­mal skin patch of estra­diol-17• 0.1mg daily gen­er­ally suf­fices. It is im­por­tant to ex­clude thy­roid dys­func­tion, adrenal in­suf­fi­ciency and frag­ile X per­mu­ta­tion be­fore reach­ing to a fi­nal di­ag­no­sis of pre­ma­ture ovar­ian fail­ure. It is im­por­tant to coun­sel the pa­tient that spon­ta­neous preg­nancy is still pos­si­ble with the help of hor­mone re­place­ment ther­apy (HRT). Ad­di­tion of pro­ges­terone in the form of mi­cronized pro­ges­terone 200 mg daily or medrox­ypro­ges­terone ac- etate 10 mg daily for first 14 days of each month will main­tain the withdrawal bleed­ing. 25% of women ovu­late af­ter con­tin­u­ous treat­ment of 3-6 months and 10% of them even con­ceive. In­fer­til­ity ther­apy: There is no role of ovu­la­tion in­duc­tion agents in the form of clomiphane cit­rate. High dose of go­nadotropins some­times can pro­duce fol­li­cles but good qual­ity eggs are rarely achieved. Op­tions for ovum do­na­tion should be dis­cussed with the cou­ple. Oocyte do­na­tion suc­cess rates are gen­er­ally greater than tra­di­tional IVF par­tic­u­larly in th­ese cases. Some up­com­ing ther­apy of fat cell in­fu­sion in­side ovary of POF women can pro­duce eggs. This is for­mu­lated from a study which is still in trial phase and con­ducted by a group of china. Here they are tak­ing the fat cell of the same woman by li­po­suc­tion tech­nique from ab­dom­i­nal fat. Those fat cells are cen­trifuged and cul­tured at lab­o­ra­tory in tis­sue cul­ture plate. Later on th­ese fat cells are trans­ferred in­side the ovary of POF woman via la­paro­scopic tech­nique. Since ova are ba­si­cally gen­er­ated from fat cells, this tech­nique will re­gen­er­ate eggs in the ovary of a woman of pre­ma­ture ovar­ian fail­ure. Key points for clin­i­cal prac­tice: POF is suf­fi­ciently com­mon and grad­u­ally up­com­ing in an epi­demic form spe­cially among women suf­fer­ing from in­fer­til­ity. Early eval­u­a­tions are im­por­tant to ex­clude treat­able causes and as­so­ci­ated health con­cerns. It is im­por­tant to ex­clude thy­roid dys­func­tion, adrenal in­suf­fi­ciency and frag­ile X per­mu­ta­tion be­fore reach­ing to a fi­nal di­ag­no­sis of pre­ma­ture ovar­ian fail­ure. Kary­otype is manda­tory in women sus­pi­cious of suf­fer­ing from POF be­low 35 years. Af­fected pa­tients should be pro­vided with sen­si­tive care and ex­ten­sive coun­sel­ing as needed. In Vitro fer­til­iza­tion with ovum do­na­tion is the most ef­fec­tive way of pro­vid­ing th­ese women with preg­nancy.

Dr. Shi­uli Mukher­jee is an in­fer­til­ity ex­pert at Genome, Kolkata.

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