بسم الله الرحمن الرحیم
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بسم الله الرحمن الرحیم. به کانفرانس علمی عقامت خوش آمدید ترتیب کننده : پوهنمل دوکتور محمد حسن فرید. In the name of god.

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بسم الله الرحمن الرحیم

  • به کانفرانس علمی عقامت خوش آمدید

  • ترتیب کننده : پوهنمل دوکتور محمد حسن فرید


In the name of god

In the name of god

Definition : if a young couple did not get pregnancy during one year with at least two time intercourse per week ،without using any contraception method ، means infertility

75 - 80 % of couple got pregnancy in 1 year , 20 - 25 % needs more intervention , but around 10 % of these remained infertile.


Most important things for fertility are
Most important things for fertility are ..

In Men

  • Normal spermatogenesis production .

  • Open way for the passage of spermatozoa from testes to the orifice of urethral ( epidydemes , ductus deferent and ductus ejaculatory ).

    In Women

  • Normal oovogenesis.

  • Open way .

  • Normal development of functional endometrial layer ( compact , spongiosa and basal ) .

    Any problems interfere in this 5 maintained procedure can change the condition form fertility to infertility . it is effective from 1 - 100 %. absolutely belongs to the intensity ,location , kind of pathology duration and kind of treatment .


Percentage of getting pregnancy
Percentage of getting pregnancy

  • 25 % in 1 month after marriage

  • 63 % in 6 month after marriage

  • 75 % in 9 “ ‘” “

  • 80 % in 12 “ “ “

  • 90 % in 18 “ “ “

  • 10% rest infertil .

  • 1/3 cases belongs to the men .

  • 1/3 = = = women.

    1/3 = = = both partner (treatment is verey dificult )


Normal semen analysis
Normal semen analysis

  • Volume 2 - 5 ml ( greish , white or yellow ).

  • PH 7.2 - 7 .8 .

  • Sperm count > 20 mil / ml ( 80 - 100 favorable ).

  • Viability > 50 %.

  • Morphology > 50 % normal.

  • Leukocyte < 10 pus cell / ml.

  • Fructose 13 μ mol per ejaculation .


Terminology
Terminology

  • Aspermia : No semen.

  • Azoospermia : Not sperm in the semen.

  • Oligospermia : Low sperm count .

  • Asthenospermia : No motile sperm.

  • Teratospermia : Abnormal sperms .


Favorable condition to take semen
Favorable condition to take semen.

  • 2 -3 days abstinence intercourse.

  • Semen take with masturbation .

  • Within ½ - 2 h must be exam .

  • Don’t use condom .

  • 2-3 time should be exam .

  • Collecting in clean container ( jar )


Male infertility factor
Male infertility factor

A – Defective spermatogenesis

  • Hypothalamus Pituitary failure .

  • Testicular failure: undesending TesTes, agenesis , cryptorachidism , Damage of the T T by radiation, chemotherapy,orchitis (Mumps,T B,Syphlis)& tumors .

  • Exposure of T T to heat (NL<2c ).

  • The T TVaricocle , trauma ,androgen receptor abnormality ,chromosomal abnormality . Enzyme deficiency

    B - Obstruction in the passage :

  • Congenital absents of vas .

  • Block vas due to infection .

  • Block vas due to herniorrhaphy .


C-- Ejaculatory problems

  • Frequency and timing of intercourse .

  • Hypospadiasis and phymosis .

  • Impotence ( erectile dysfunction ).

  • Premature or retrograde ejaculation.

    D – immunological problems

  • Spermal ab.

  • Cervical mucosa ab.


E - Medical diseases

  • Diabetes , Thyroid disorders

  • TB , Mumps .

  • Hypertension.

  • Intoxication .

  • Deficiency of vitamins and minerals.

    F – Other factor

  • Smoking .

  • Alcohol.

  • Drugs .

  • Environmental.

  • Age >40 year for male , age > 30 year for female.

  • Cirrhosis.


  • History

  • Examination

  • Semen analysis

    I-- History

  • Time of ovulation and frequent coitus on that time.

  • Coital difficulty like premature and retrograde ejaculation .

  • Taking drugs like : antihypertensive , antipsychotic , cimetidine ,spirinolacton , oestrogen , excess ( testosterone , smoking , alcohol) and working in hot place can interfere or diminish sperms .

    4 Medical illnesses ( D.M , hypertension , thyroid disease , mumps etc ).


Ii examination a general
II - ExaminationA - General

  • Height : Excess height ( kallman & kalinfelters syndrome ) .

  • Obesity : Hormonal disorder .

  • Secondry sex characters examined any abnormality must be noted .

  • Thyroid gland enlargement .

  • Medical diseases ( D.M , HP , ect ). Must be palpated by special examination to identify it .


B local examination
B - local examination

  • Volume of the T.T ( normal 15 – 35 ml) .

  • Hernia or herniorrhaphy scar .

  • Hydrocele .

  • Testicular , descent , volume ,mobility & consistency.

  • Epididymis ,vas deferent ,Prostate by TR.


C psychological factor
C - Psychological factor

Psychological distress

a -fallopian tube

spasm

Exacerbate angry b –deficiency of g gammete

c – decreased coital f frequency

d – impotence

e - ejaculation p problems

Infertility


Fertilization
Fertilization

  • Sperm passes C.R.

  • Sperm penetrates Z.P by acrosomal reaction & release hyaloronidase ( zonal reaction = ZR ).

  • Z.R inhibits the entry of other sperm .

  • Secondary oocyte is formed by second meiotic division mature ovum come out , called female pronucleous .

  • Within the oocyte the sperm tail degenerated and male pronucleous formed.

  • pronuclie of male and female mixed and zygote formed with 46 chromosome ( sex belongs to the Y chromosome).


Different tests
Different tests

  • PCT (Post coital test) : gives information on immunological aspects and cervical mucosa quality .

    Procedure :

    Intercourse abstinence 2 -3 days . after intercourse specimen aspirated form cervical canal and posterior fornix separately . 10 or > motile sperm forward movement PCT is ok .abnormal PCT 3 - 5 % .

    Another specimen collected from posterior fornix acts as a control .


  • Sperm cervical mucus penetration test (S.C.P.T): the semen and C.M placed side by side to form interface . the sperm should penetrated > 3 cm of cervical mucus at the end of 2h (ok )

    3 – sperm cervical mucus contact test (S.C.C.T) : Equal amount of semen and C.M mixed. if > 25 % of sperm show jerky movement after 30 min immunological factor is positive (we need control specimen from the semen) .


4 other new tests
4 Other new tests

When above 3 mintioned test & semen count are normal the problem may be on fertilization process must be do it:

  • Zona free egg penetration test : depends upon ability of the sperm to penetrate the zona . free hamster egg more than 10 % penetration considered normal . this test is vary expensive

  • Acrosin reaction ,sperm zona binding are the new technique to study the fertilizing potential of the sperm.

  • U/S & Doppler study show scrotal volum and varicocele

  • Testicular biopsy is indicated in :

    A - In high F.S.H level primary T.T failure is suspected.

    B - when TB of the T.T is suspected .

    C - To study histopathology in presence of oligospermia & abnormal semen parameter .

    D- In azoospermia to distinguish testicular failure from blockage of the vas deferent or unability of the T T.


Advantage of t t biopsy
Advantage of T.T Biopsy

  • Chromosomal study .

  • Cryopreservation of spermatids & sperms can be useful in therapeutic.

  • 5 - intracytoplasmic sperm insemination

  • ( I.C.S.I ) technology .


  • Management
    Management

    • General .

    • Hormonal.

    • Surgical .

    • New teqnique.


    1 general
    1 - General

    • Treat the cause .

    • Improve time & frequency of coitus in the ovulation phase .

    • Scrotal hyperthermia avoided & use ( cold bath & loose undergarment ).

    • Limited alcohol and smoking.

    • Treated medical disorders .

    • Treated infection with antibiotic

    • Immunological factor:

      a – Corticosteroid : 50 mg/d prednisolon.

      b – use condom 3 - 6 months .

      the above 2 mentioned things eliminate antibodies 30 - 40 % .

      c -- Sildenafil ( Viagra ) 25 -100 mg one hour before intercourse, improve erectile function .other method of treatment vacuum pump , local penile implants and local injection . ( have own disadvantage ).


    2 hormonal therapy
    2 - Hormonal therapy

    • low dose testosterone 25 m g / day improve spermatogenesis ( height dose suppresses ).

    • Clomiphene citrate 25 mg /d for 25 days in each month for 6 month .

    • F.S.H / hCG :in pituitary hypofunction. ( FSH 37,5 iu /im twice weekly & increase to 75 iu / im .hCG 2000 iu /im 1 -2 time / weekly continues 6 –12 month ( improvement 60 to 70 %. ( pregnancy 50 - 60 %) .

    • GnRH 50 ng / kg by intervals within infusion pump or 200 mg / day intranasally in hypothalamus dysfunction.

    • Thyroid hormones in hypothyroidism.

    • Bromocryptin in hyper prolactinaemia .

      Note : these drugs must be used at least for 3 month because spermatogenesis process take 72 days time and passage from the T.T takes 2 weeks more time .


    3 surgical
    3 - Surgical

    • Vas vasostomy.

    • Rectified undescended T.T in child hood (in adult results is not good) .

    • Surgery of varicocele ( if the sperm count is abnormal ).

    • Herniorrhaphy .


    4 newer technologies
    4 - Newer technologies

    • Aspermia due to retrograde ejaculation is corrected by giving alpha adrenergic & anticholinergic drugs . Note : urine can be centrifuged & sperm insemination at ovulation time

    • Artificial insemination ( AI ).

    • In vitro fertilization ( IVF )

    • ICSI ,GIFT , ZIFT & IUI

    • Micromanipulation technique : such as zona pilloceda dissection , drilling .

    • Testicular and epidydimal aspiration of sperms when vas is blocked

    • Donor insemination


    Detail the newer therapeutic technology in male infertility

    • AI

    • IVF.

    • GIFT.

    • ZIFT.

    • Micromanipulation such as zona pillucida dissection drilling .

    • ICSI.

    • IUI.

      Testicular and epididymal aspiration of sperm when vas is blocked .


    Artificial insemination ai indication
    Artificial insemination ( AI) indication:

    • Impotence & hypospadia .

    • Premature & retrograde ejaculation .

    • CMA ( cervical mucosa antibodies) & spermal antibodies .

    • Oligospermia .

    • Unexplained infertility .


    Important factor in female infertility
    Important factor in female infertility

    • H.P.O axis factor .(schedul )

    • Ovarian factor .

    • Tubal factor .

    • Uterine factor.

    • Cervical mucosal factor .

    • Vaginal factor .

    • General factor .

      8. Pshycological factor .


    Ovarian factor

    • Ovarian agenesis & hypoplasia .

    • Ovarectomy .

    • Impaired ovaries function by radiation , infection etc.

    • Ovarian , cyst.

    • O.Tumor ( granulosal C T & theaca C T).

    • Intractable ovaries to effect of GhRH .


    Suspected ovulation

    • Monophasic BBT ( must be biphasic ).

    • Vaginal cytology .

    • Vaginal PH .

    • Cervical mucus changes ( fern test +).

    • Endometrial biopsy ( secretary phase + ).

    • Level of progesterone in luteal phase .( high + )

    • Level of pregnandiol in urine

    • Level of 17 hydroxy progesterone .

    • Ostradiol level of plasma.

    • Saliva glucose level .

    • Saliva esterase level.

    • Alkaline phosphates .

    • Normal and regular cycle ( + ).

    • Collapse and shrinking follicle . u/s

    • Collection of fluid in D.G pouch .u/s

    • Corpus luteum formed. u/s


    Tubal factor

    Important function of the tube are :

    • Transfer released ovum from ovaries to the uterine cavity

    • Permit entry of the sperm from uterus to the tube .

    • Transportation zygote onward the uterus .

    • Creation favorable environment for growth ,development and division of zygote

      The most important defect of the tube are :

    • Tubal aplasia & dysplasia .

    • Tubal blockage congenitally.

    • Tubal complete or incomplete block by infection disease ,XR & etc .

    • Bilateral tuballigation .

    • Tubal adhesion by TB & Chronic PID .


    Endometrial or uterus factor

    Rule of the uterus in productive process

    • Favorable & appropriate environment for zygote , implantation & development .

    • Protection embryo & fetus from external effect ( trauma , etc ).

      these following factors are interfere in the process of infertility

    • Uterus aplasia .

    • Uterus hypoplasia .

    • Rudimentary uterus.

    • Infantile uterus .

    • Small uterus .

    • Over retroverted or anteflexed uterus.

    • Sub mucosal polyps and fibroma .

    • Acute and specially chronic endometritis.

    • Destroyed endometrium by radiation ,curettage , chemical or burned material.

    • Dfd…..

    • Hysterectomy


    Cervical factor

    • Absence of mucus by operation procedure like: amputation of cervix ,cone biopsy & diathermy etc &polyps.

    • Miss direction like : Retroversion prolapsus of cervix or uterus .

    • Closed or pin hole cervix .


    Vaginal factor
    Vaginal factor

    • Vaginal aplasia .

    • Vaginal displasia .

    • Vaginal atrophy .

    • Vaginal prolapsus &Tomurs .

    • All kind of vaginitis .

      General factor

      Most of medical diseases ( DM , aneamia , vitamins deficiency , hormonal problems .etc ) have own effects on infertility in both partners.


    Examination
    Examination

    • Height and weight .

    • Secondary sexual organs development.

    • Hirsutisum and PCOD .

    • Presence of glactorrhea .

    • Pelvic examination :( size ,mobility, consistency, location , tenderness , position of the uterus .adnexal masses .

      Investigation

    • Menstrual history .

    • BBT .

    • Cervical Mucosa Test.

    • Progestin level .

    • Endometrial study .

    • U/S.

    • Hormonal assay: FSH , LH , Prolactin , thyroid profile.


    • U/S

      a – Safe ,non invasive & reliable methods .

      b – Serial u/s monitoring shows growth ,development & rupture of F.du .Graff

      c – Endometrial growth : Normal endometrial growth before ovulation 8- 10 mm thick. normal growth rate 1 -2 mm /d , reaches around 20 mm or more at ovulation time. After ovulation follicle du graff shrink and fluid can be found in Douglas pouch.

      d – By u/s we can precise ovulation days .

      e – dictate administration of hCG .

      f – Retrieval of ova in IVF process.

      g – Also recognized PCOD.


    Explaination

    • Regular mucus suggest intact H.P.O axis .

    • BBT explained before .

    • Serum progesterone level in 22 – 23 days of the cycle 10 - 15 ng / ml < 5 ng / ml CLPD ( corpus Luteal phase defect )

    • Endometrial biopsy for histopathology examination( TB CLPD, ovulatory phase ) & invasive process.

    • Cervical mucus ( C.M).: Examine for spinnbarkeit test (10 cm stretching in proliferation phase . but in secretary phase cervical mucosa become tenacious and thick. it is unfavorable for sperm to pass it.


    • Hormonal level

      FSH,LH & prolactine levels can indicates normal or HPO axise dysfunction & or primary ovarian failure.

      A – high LH level in PCOD.

      B – High FSH level inhypothyroidism &hyperprolactenemia.

      C – Low estrogen level in ovarian failure

      D - low progesterone level in L Phase , shows CLP Dificiency.

      E - prolactine more than 25 ng /ml is high.

      schedual


    Tubal test
    Tubal test

    • HSG.

    • Laparoscopic chromotubation .

    • Sonosalpingography .

    • Falloscopy .

    • Salpingoscopy.

    • Insufflation test.

      I - HSG

      I - HSG

      thefirst important diagnostic method for evaluation of tubes. its must be done in 8 – 10 days of cycle .

      Action mechanism

    • Atropine injection to avoid tubal spasm .

    • Folli catheter must be use .

    • Wilkenson or Rubin cannules is used.

    • Water soluble dye better from oil media because of ( chemical peritonitis , granuloma and delayed spillage ) .


    With hsg we can recognized
    With HSG we can recognized

    • Septet uterus .

    • Bicornuate uterus.

    • Unicornuate uterus.

    • Asheerman syndrome.

    • Sub mucosal fibroid .

    • Patency or blockage of tubes .

      falls negative : Tubal spasm like block .

      falls positive : Hydrosalpinx like spellage .

      Tubercular salpingitis : it is cause extravasations of the

      dye and show bilateral corneal block .

      Complication

    • PID.

    • Allergic reaction .

    • Dislodgment of pregnancy.

      Advantages

    • Its a permanent record.

    • Its shows the site of blockage .


    Laparoscopy
    Laparoscopy

    Laparoscopy is indicated if :

    • HSG reported abnormal .

    • Pelvic adhesion suspected .

    • Endometriosis suspected .

      Show that

    • Patency of tube tested ( chromotubation ).

    • External adhesion of tubes.

    • Position of tubo ovarian fimberia.

      We can help these therapy processes

    • Adhisiolysis .

    • Endometriosis ablation.

    • Fimberioplasty .

    • LSC + salpingoscopy.


    Sonosalpingography ssg
    Sonosalpingography ( SSG)

    100 cc serum saline + small amount of air injected transcervical in the cavity of uterus .U/S can screen the movement of the bubble & determined blockage of tube (free fluid in the Douglas pouch indicated patency of the tube in this procedure no risk of x ray & allergic reaction)

    Hysteroscopy falloscopy ( HF)

    • For uterine abnormality pathology of corneal end of fallopian tube .

    • Tubal polyp detection .

    • In this procedure we can do it cannulation & breaking of flimsy adhesions within the lumen

      Salpingoscopy

    • Visualized the fimberial & ampullary portion of the F.T laparascopically.

    • Peritoneal infertility causes can be detected during salpingoscopy .


    Treatment
    Treatment

    A-Treat an ovulation

    • Clomephine citrate 50 mg /d from second day of the cycle . monitoring growth of F Du Graff by U/S until the follicular size reaches 20 m m .the dose may have to increased gradually up to 200mg/d in the non responders. From hyper stimulation syndrome with hCG &antiostrogenic side effect by changing over to letrozal 2.5 mg / d instead of clomephine .When follicular size reaches 20 mm , hCG 5000 iu / im give it. after 36 - 40 hour the follicular ruptured . intercourse must be arranged timely. this regime is given for 6 - 8 month .if the above regime fails following the :


    • Human menopausal gonadotrophin ( containing FSH) is given in a dose of 75 - 150 iu onward . recombination HMG is expensive but more effective .

    • GnRh sub cutaneous or intranasal in hypothalamic disorder

      Multiple pregnancy (MP)with clomephin & FSH 10 %.

      MP with GnRH 1 % .

      If failed medical therapy , donor egg or adopts with this condition .


    POCD responds to clomephen or gonadotrophin stimulation , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    • Hyperprolactemia : Hypothyroidism & pituitary adenoma should be excluded or threaded .bromocryptine 1.25 mg TID & increased to 5 mg TID.

    • (CLPD) corpus luteal phase deficiency is rectified by progesterone or hCG in the leuteal phase .


    Tubal infertility treatment
    Tubal infertility treatment , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    • Tubal microsurgery ( tubo plasty ).

    • Laparoscopic T adhesiolysis and fimberioplasty .

    • Balloon tuboplasty and canulation through hysteroscopy ( HBT ).

    • IVF ( In Vetro Fertilization ).

      I - Tuboplasty : Excising the blocked portion & anastomosis. success depending on the sit of blockage. ( fimb 25 % , cornual end 50 % , isthemic isthmus anastomosis 60 - 70 %).

      Risk

    • Failure to restore the patency of tube.

    • Reblockage .

    • Ectopic pregnancy.

      two weeks after do it this procedure , needs hydrotubation also .


    II -Laparoscopy : we can do it : , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    • Fimberioplasty.

    • Adhesiolysis .

    • PCOD can be dealt.

    • Endometriosis nodules cauterization .

      III_ Balloon tuboplasty & cannulation .

      Medical end blocked by flimsy adhesion ( 40 % pregnancy occured )

      IV - IVF : we don in :

    • Extensive Tubal damage.

    • Failed tuboplasty .


    Unexplained infertility
    Unexplained infertility , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    When all investigation in both male & female are normal we used this term.

    • Counseled on adoption.

    • Used newer technologies are :

      a - IUI ( AI ).

      b - IVF.

      c - ZIFT.

      d - GIFT.

      e - Cryopreservation technique .

      f - ICSI.


    1 iui or iti
    1 – IUI or ITI , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    Indication :

    • Male infertility.

    • Cervical mucus hostility with ab.

    • Unexplained infertility .

      Action mechanism :

      ovulation induction . intra uterine or fallopian insemination of washed sperms at ovulation time ( 3 - 4 cycle attempted 30 - 40 % success ).


    2 ivf
    2 - IVF , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    Indication

    • Tubal infertility.

    • Male infertility .

    • Cervical factor .

    • Unexplained infertility.

      Action mechanism

    • Induction of multiple ovulation .

    • Under u/s guidance retrieval oocyte.

    • Invitro fertilized with washed sperms .

    • 2 -3 fertilized egg or embryo transfer to uterine .

    • Success rate 20 - 30 % .

      Complication

    • High failure rate.

    • High cost of IVF.

    • High abortion rate.

    • Multiple pregnancy.

    • Ectopic pregnancy .

    • Psychological trauma to the couple if IVF fails.


    3 gift gammete intra fallopian transfer
    3 - GIFT ( , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized. gammete intra fallopian transfer )

    Action mechanism

    • Induction of multiple ovulation .

    • Oocyte retrieval .

    • Placement of two oocytes & 50 000 washed sperm in each ampullary portion laparascopically .

    • 30 - 40 % success .

      4 - Cryopreservation :

      Lately it has been possible to caryopreserve the sperm , ova and embryos .( to avoid of invasive procedure time by time and reduced cost ).


    5 insuffilation
    5 – insuffilation , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    Passage of co2 with Rubin‘s machine in the uterine cavity .

    A – complication

    • Collapse .

    • Shock in death.

    • Embolic ( interavasition ).

    • Peritoneal reaction .

    • Salpangitis .

    • Sensetivity to drugs ( if we want to use drugs instead of air).

    • Abortion ( if she is pregnant ).

      B - Contraindication

    • During of immediately after menstruation.

    • After curettage .

    • After salpangitis .

    • Active TB .

    • Cervicitis , vaginitis , etc.


    Note , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized. : counseling a couple is essential & prognosis at each treatment should be discussed the last choice of adoption should be left to their decision .


    C – Four important following criteria shows open tubes , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    • Change compression in machines .

    • Ascultation of the gas sound during passed from the tube .

    • Felling pain in the right shoulder.

    • Free air in the abdominal cavity.


    Infertility factor in woman
    Infertility factor in woman , but hyperstimulation must be watched , if it occur hCG should be withheld in the cycle. If failed medical therapy calls for laparoscopic drilling of the cyst or cauterized.

    • H.P.O axis factor .

    • Ovarian factor .

    • Tubal factor .

    • Uterine factor.

    • Cervical mucosal factor.

    • Vaginal factor .

    • General factor .

    • Dysparonia ,PID ,Endometriosis.

    • Unfrequent & untimely intercourse.

    • Duration of infertility & user of contraception.

    • History of TB or contact T B patient , D M , etc .

    • Menstrual irregularity , ovaries dysfunction & non ovulation in PCOD.

    • Previous history of PID & ectopic pregnancy suggest tubal damage.

    • In secondary infertility P.P infection , PPH (Sheehan's syndrome ) prolonged lactation is very important .


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