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O  dPresenter DisclosurezJerome H. Check, M.D., Ph.D. I have no current or past relationships with commercial entities Speaking fees for current program: I have received no speaker s fee for this learning activity.>=A#=Commercial Support DisclosuredThis program has received no financial or in-kind support from any commercial or other organization.   It is a protein not found in the cells of normal tissue but is present in mesenchymal, embryonic, and trophoblast cells of the fetal-placental unit.( {One exception may be circulating gamma/delta T-cells which make this protein when exposed to progesterone (male or female).Two forms of PIBFJ Parent form  has a molecular mass of 90 kDa (757 amino acid residues) and is associated with the centrosome. The PIBF gene has been identified in chromosome 13 in the vicinity of BRCA1 and 2 and p53 genes. Splice variants of the nuclear protein are found in the cytoplasm and these have a smaller molecular mass, e.g., 35 kDa found in the cytoplasm of leukemia cells and 57 kDa and 67 kDa found in glioblastoma multiforme cells. The 34-35 kDa splice variant is found in mensenchimal, embryonic, and trophoblast cells of the fetal-placental unit.&Z&+6 1   @0 !e"8It is hoped that this talk could stimulate some OB/GYN s or perinatologists to conduct studies:`` ,3On measuring PIBF in patients at risk for pre-term delivery to see if low PIBF levels are responsible for this condition. Comparison studies of P vs. 17-OHP to see which treatment is more effective in preventing pre-term delivery." $<%>&?'@(f)g*C+D,F-H/N0h2P#What is a mature dominant follicle?$$(We define it as attaining an 18-24 mm average diameter with a serum estradiol (E2) >200 pg/mL. This definition was based on a previous study we did on fertile women where almost all of them achieved these parameters.$S,D |3RCheck JH: Progesterone therapy versus follicle maturing drugs - possible opposite effects on embryo implantation. Clin Exp Obst Gyn 2002;29:5-10. (>s;58 infertile women diagnosed by out-of-phase endometrial biopsy: Randomly assigned to follicular phase clomiphene citrate or human menopausal gonadotropin (to allow normal post-coital test if poor on clomiphene) vs luteal phase progesterone. Normal follicle maturation (dominant follicle >18mm, serum E2 >200 pg/mL.>AZZAbg W [( 25 failing on follicular maturing drugs given luteal P during second 6 months  10 of 25 conceived only 1 miscarriage.PP&PP&.B gThus, the live delivered 6 month pregnancy rate was 3.7% with follicle maturing drugs vs. 74.2% with P. 8Because a late luteal phase endometrial biopsy that was in phase showing histologically that there was adequate P effect would not necessarily determine that an adequate amount of intracytoplasmic PIBF was being made, we decided to change our policy and provide luteal phase support to all women aged 30 or over.P4]B- Because pelvic pain may be associated with increased NK cells, and then a need for a higher level of intracytoplasmic PIBF to suppress these NK cells, P support was also given to women under 30 with pelvic pain.e_ kEmpirical use of P for all infertile women over age 30 or under age 30 but with pelvic pain: 80% live delivered pregnancy rate 6 months. Check JH, Cohen R: The role of progesterone and the progesterone receptor in human reproduction and cancer. Exp Rev Endocrinol Metab 2013;8:469-484. This article was published in 2013 and analyzed data from 10 years before.>]," ], ]8[ The beneficial effect of luteal phase support on pregnancy rates in women with unexplained infertility. Clin Exp Obst Gyn 2019;46:447-449. Check JH, Liss J, Check D&PJ,Patient CharacteristicsAge <39 Unexplained infertility  regular menses, attained a mature follicle, normal semen analysis, normal post-coital test, patent fallopian tubes by HSG. Minimum 1.5 years of infertility. Treatment exclusive vaginal P (endometrin, Crinone vaginal gel, or P suppositories according to insurance coverage) and 200mg oral micronized P hs on empty stomach. Women treated were >30 or <30 if pelvic pain present. Maximum of 6 cycles of treatment No hCG given or IUI.L" PrX> ^ResultsJClinical pregnancies in 27 of 32 (84.3%) in an average of 4.5 treatment cycles. There were 4 miscarriages (15%). Live delivered pregnancy rate of 70%. Most of these patients had been seen in other infertility clinics and had been treated with follicle maturing drugs (clomiphene, letrozole, or gonadotropins) with IUI or even IVF.KK>     What if a woman with regular menses releases the egg before the follicle is mature? In a study conducted by our practice over 30 years ago we found the following results:(  Thus though a follicle maturing drug seemed superior to luteal phase P alone, the group treated with exclusive follicle maturing drugs seemed to have a much higher miscarriage rate without supplemental luteal phase support with P.,8 Both letrozole and clomiphene citrate may have an adverse effect on the cervical mucus thus requiring an IUI. Check JH, Adelson HG, Davies E: Effect of clomiphene citrate therapy on post coital tests in successive treatment cycles including response to supplemental estrogen therapy. Arch Androl, 32:69 76, 1994. Check JH, Liss JR, Vaniver J: The effect of clomiphene citrate vs. letrozole on post-coital tests. Clin Exp Obst Gynecol 2016;43:184-185. P  [ ?   ZThus, for today s audience it would be more prudent to begin a low dosage of gonadotropins as a boost to attain a mature follicle to prevent creating hostile cervical mucus.M T Similarly, we use P supplementation for anovulatory women taking follicle maturing drugs based on the hypothesis that these drugs do not fully create the proper luteal phase endometrium. Check JH, Chase JS, Adelson HG, Teichman M, Rankin A: The efficacy of progesterone in achieving successful pregnancy: I. Prophylactic use during luteal phase in anovulatory women. Int J Fertil 32:135 138, 1987. Check JH, Wu CH, Adelson HG: Decreased abortions in hMG induced pregnancies with prophylactic progesterone therapy (Progesterone added to hMG to reduce abortions). Int J Fertil 30:45 57, 1985. .ZZ( n(i $S HThough supplemental P may help to establish a pregnancy in infertile women, and lower the risk of miscarriage in those who conceive as evidenced by the studies presented above, the possibility exists that women who have no trouble conceiving but have miscarriages, may have a different etiology than merely the need for extra P. Check JH, Chase JS, Nowroozi K, Wu CH, Adelson HG: Progesterone therapy to decrease first trimester spontaneous abortions in previous aborters. Int J Fertil 32:192 193, 197-199, 1987. Based on this study that we published in 1987, and based on our patient population it has been our policy to treat all women with a history of previous miscarriage not documented to be of genetic origin with P from the early luteal phase throughout the first trimester.Zt X' fNevertheless, the importance of P as a method to reduce miscarriage risk has been a subject of debate.  Small series can sometimes lead to erroneous conclusions. Most researchers would agree that a proper randomized prospective study that has a great deal of power that is multi-centered and published in an extremely well respected journal may produce the final word.vSuch a study was published in the NEJM  The PROMISE study.<<(JCoomarasamy et al: A randomized trial of progesterone in women with recurrent miscarriages. NEJM 2015;373:2141-2148. There were 35 authors and the last 2 were Drs. Regan and Rai. Though published in 2015, it was recently mentioned again in an issue of the NEJM that features new studies that refute old concepts. It was featured on CNN News in May, 2019 with the title  Progesterone therapy prevents miscarriage for only some women, study finds: 75% of the P group had a live baby vs. 72% of the controls  and more than 4000 women were recruited.FvZJZfZvJf$ tGo Based on our experimental model the most critical time to suppress immune damage to the fetal placental unit is after invasion of the fetal placental unit at mid-luteal phase. Thus the most critical time to start P therapy is immediately after ovulation.WIq Other clinicians have subsequently to the PROMISE study found that supplemental P in the early luteal phase decreases miscarriage rates. Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss. Fertil Steril 2017;107:684-690. Stephenson MD, McQueen D, Winter M, Kliman HJ, had the same criticism of the PROMISE study, i.e., the late use of P..ZuZub_$k7K Stephenson s study was an observational cohort study using prospectively collected data. Possibly women with elevated glandular nuclear cyclin E expression (>70%) as determined by endometrial biopsy may be more prone to repeat miscarriage. This was the group receiving supplemental P in the early luteal phase. Controls were those with normal glandular nuclear cystin E (<20%). Most did not receive P but some insisted on it so they were in the treated group.,ZtX>:] Overall 68.5% were successful using P vs. 51% not using it. They stated that they are planning a randomized controlled  well-designed study to further evaluate the efficacy of P in reducing miscarriage.Mu Timothy Yeko found that 17 of 18 whose serum P was less than 15 ng/mL had a miscarriage. Yeko TR, Gorrill MJ, Hughes LH, et al. Timely diagnosis of early ectopic pregnancy using a single blood progesterone measurement. Fertil Steril 1987;48:1048-50. bMt ~However, we found that with aggressive P (IM and vaginal) that we could get live births in 70% of pregnant women whose serum P was <15 ng/mL and 60% of women whose serum P was <8 ng/mL Check JH, Winkel CA, Check ML: Abortion rate in progesterone treated women presenting initially with low first trimester serum progesterone levels. The Am J Gyn Health IV(2):63/33 34/64, March April, 1990. Choe JK, Check JH, Nowroozi K, Benveniste R, Barnea ER: Serum progesterone and 17 hydroxyprogesterone in the diagnosis of ectopic pregnancies and the value of progesterone replacement in intrauterine pregnancies when serum progesterone levels are low. Gynecologic and Obstetric Investigation. 34:133 138, 1992. .ZZbB  Our policy is to use follicular maturation drugs in women with infertility or recurrent miscarriage if they release the egg before the follicle attains a 200 pg/mL level (E2 important in inducing P receptors in the endometrium).B ;Not only is the PIBF protein found in the cytoplasm of fetal embryonic cells, mesenchymal cells, and trophoblast cells, it is also found in the cytoplasm of many different types of cancer cells. Check JH: The role of progesterone and the progesterone receptor in cancer. Expert Review Endo Metab 2017;12:187-197. $QyRzS{T|V~WXY The beneficial effect of suppressing intracytoplasmic PIBF in cancer cells may be available not just for one type of cancer but for most, if not all.%amPalliative benefits of mifepristone has been found in patients with a variety of different cancers including nl(Colon cancer Thymic cell epithelial cancer Transitional cell carcinoma of the renal pelvis Renal cell carcinoma Breast cancer Glioblastoma multi-formeZ> k  Non-small cell lung cancer Small-cell lung cancer Leiomyosarcoma Osteogenic sarcoma Malignant fibrous histiocytomia Rapidly growing thyroid cancer Pancreatic cancerZ>2  2 HMifepristone is extremely well tolerated and in some countries costs only 50 cents a pill. Unfortunately, because we published this concept in 2001 and thus the information became part of scientific domain, pharmaceutical companies cannot patent P receptor antagonists or modulators, and without profit, no one seems interested. Check JH, Nazari P, Goldberg J, Yuen W, Angotti D: A model for potential tumor immunotherapy based on knowledge of immune mechanisms responsible for spontaneous abortion. Med Hypoth 57:337-343, 2001. >  For those more interested in the role of progesterone receptors especially membrane receptors rather than nuclear P receptors for both the fetus and cancer cells escaping immune surveillance I would recommend these 2 articles: Check JH, Cohen R: The role of progesterone and the progesterone receptor in human reproduction and cancer. Exp Rev Endocrinol Metab 2013;8:469-484. Check JH: The role of progesterone and the progesterone receptor in cancer. 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BĔh%@ R8wedE\v| <"܏Tn[=hq 3I螜OMC\s(ܝN s %8S!Ǝ=!IJr&XzOFiٷi)CbEmffԵ>n ?2-4(vE2ruO2;BdsXfnߣFrI]:wc&O{ 7D݃Pݏ }z6x֤ d#J5-[)ʼn3: ]):F#G lb|INYecU'X@J$DX!!goxf(ߤxݴyJ] txh ^F/@>UԽp[;;E %s@b7e>jˀ 2\D,/ETqbS~injzb>q [)Φl­6#64M`&Ugsf|l:~&b~f@w=oJrF?jF=Trz7/'\2X#-q& 2Gh{DELu( u4ct7XT{sieH. 8lW]?[ |5Po (0&I$惧+ R?w՚)+zӯV@`WZSwsחMƤf@=եvO[$pIhOD1E= tEOB񽤱UVsMLAU!41le< NU/E2˄ A"J N b"1(Z 49Ds+ !|V>5rtxBUT'Ԛ#Dt]ǹ Ib&ɂ[ 5LPXӨV5]ƪ{Z45*j5å~Đ Քۘ:Tg/woP[NfQSӰ٨MmSHY6WbEpN 04D\8{^sy@yV+Fk[\ӮAԂNTs;JTjzV \VPVTjUZn   (   r0e0eRectangle 3  bPossibility 3  Inadequate production of immunosuppressive factors to neutralize a normal post-ovulatory cellular immune response. &_       H  0޽h ? ̙3380___PPT10. " YQ@ (      r,0e0eRectangle 2   >      rT0e0eRectangle 3 @   My Ph.D. thesis focused on one specific immunomodulatory protein which we called the progesterone induced blocking factor (PIBF). &(    J  H  0޽h ? ̙3380___PPT10.Xh"} P$m(  $M $  x0e0eRectangle 2P   ;Facts about the progesterone induced blocking factor (PIBF)< <( <   $  x0e0eRectangle 3  We believe this is the most important immunomodulatory protein made post-ovulation to help neutralize the increase in cellular immune factors from attacking the fetal semi-allograft. &&      H $ 0޽h ? ̙3380___PPT10.p['"0   0(  x  c $P   x  c $H  H  0޽h ? ̙3380___PPT10.0CԚF   F(  x  c $X     c $  "p`PpH  0޽h ? ̙3380___PPT10. L0  0 0(  x  c $P   x  c $  H  0޽h ? ̙3380___PPT10.pP; 3+4(  4  4  x0e0eRectangle 2P   >   y 4  r$ 0e0eRectangle 3  ;Using leukemia cell lines which contain the 35 kDa intracytoplasmic splice variant of PIBF that is similar size to the one found in embryonic, mesenchymal, and trophoblast cells, we found that all 10 cell lines tested had more messenger RNA for the PIBF protein than any other known protein these cancer cells make.< <@/          H 4 0޽h ? ̙3380___PPT10.H" 8(  82 8  xL0e0eRectangle 2P   f Adding progesterone to the media! !( !   8  rt0e0eRectangle 3  UThere was an up-regulation of the mRNA for the nuclear parent form of PIBF measuring 90 kDa There was far more mRNA dedicated to making the PIBF protein than any other mRNA dedicated to production of other proteins in these 10 leukemia cell lines. &X      H 8 0޽h ? ̙3380___PPT10.P<"  <(  < <  r0e0eRectangle 2`   >   U <  rE0e0eRectangle 3  Progesterone was added to the media of 4 cell lines in which the intracytoplasmic 35 kDa splice variant protein had been identified. Adding progesterone to the media significantly increased the amount intracytoplasmic PIBF in all 4 cell lines. ZA        q      H < 0޽h ? ̙3380___PPT10." 3+@(  @ @  rM0e0eRectangle 2   @ $  } @  rP0e0eRectangle 3  sMifepristone is a progesterone receptor modulator. It interferes or blocks some progesterone receptors but not all.t t t  H @ 0޽h ? ̙3380___PPT10.(" MED(  D  D  xd\0e0eRectangle 2   @ (   D  (`0e0e,Content Placeholder 2`   Adding mifepristone to the media of 4 leukemia cell lines making PIBF protein caused a significant decrease in intracytoplasmic PIBF. Mifepristone also decreased the 57 kDa intrcytoplasmic PIBF in glioblastoma multiforme cells.o    *                     H D 0޽h ? ̙3380___PPT10.*D" YQH(  H  H  xm0e0eRectangle 2@P   @ (   H  Ts0e0e,Content Placeholder 2  Not only does serum PIBF significantly rise after ovulation but it will precipitously rise in menopausal women or males given IM or oral progesterone   H H 0޽h ? ̙3380___PPT10.*b"l P\(  Pl P  x}0e0eRectangle 2P   @In contrast, the following progestins do not increase serum PIBFA A(&        P  0e0e,Content Placeholder 2  fDidrogesterone 17-OH progesterone (Makena) Medroxyprogesterone acetate 19 nor-testosterone derivativesN          )  H P 0޽h ? ̙3380___PPT10.85A" T(  T T  rl0e0eRectangle 2P   >   k T  r0e0eRectangle 3  aMifepristone administration does not decrease the serum PIBF as long as the serum P is increased.b b b  H T 0޽h ? ̙3380___PPT10.800B"  X(  X  X  x0e0eRectangle 2   >   c X  r0e0eRectangle 3  ITaking mifepristone just one day has a high rate of causing fetal demise.J J J  H X 0޽h ? ̙3380___PPT10.8φ" =50\(  \ \  x0e0eRectangle 2P   N Conclusion     s \  r0e0eRectangle 3  5If inadequate production of PIBF plays a role in first trimester miscarriage or implantation failure by early immune rejection of the conceptus, it would seem that it is inadequate intracytoplasmic levels that may be more important than circulating levels in women who have adequate serum progesterone levels.6 6@     &    q  H \ 0޽h ? ̙3380___PPT10.8 oɴ" @`(  `  `  xĵ0e0eRectangle 2P   @ (  Z `  d¹0e0e,Content Placeholder 2  zRCertainly low serum levels may play a role in miscarriage when the serum P is low. S  H ` 0޽h ? ̙3380___PPT10.9?"j PdZ(  d> d  x˹0e0eRectangle 2P   r,Theoretically, a miscarriage might occur if:- -( -   d  x<ܹ0e0eRectangle 3` <4___PPT9 "There is a normal early luteal phase inflammatory response but inadequate intracytoplasmic PIBF to neutralize it. Treatment  supplemental P  vaginal and/or IM because oral P is metabolized through first pass through the liver and may not concentrate in the endometrium.0r " Z " Z@    ,      p`PpH d 0޽h ? ̙3380___PPT10.9@r"s `hc(  h+ h  x0e0eRectangle 2P   _Miscarriage may occur if: (    h  rl0e0eRectangle 3d @8___PPT9 There is excessive inflammation but normal PIBF response for normal inflammation. Treatment  increasing the P level may increase intracytoplasmic supranormal levels which may be adequate to negate the excessive inflammatory response. OR One may need to add dextroamphetamine sulfate to release more dopamine from sympathetic nerve fibers to diminish excessive cellular permeability.lR " P " P " P " P@           p`PpH h 0޽h ? ̙3380___PPT10.9Ё"U ppE(  p  p  x0e0eRectangle 2P   >    p  r 0e0eRectangle 3` <4___PPT9 One could also face both excessive inflammation and diminished PIBF expression. Ideal therapy would be both supplemental P and dextroamphetamine sulfate. "    DH p 0޽h ? ̙3380___PPT10.:0)"a tQ(  t  t  x0e0eRectangle 2P   >    t  r0e0eRectangle 3` <4___PPT9 oIs there a method to determine if despite adequate serum progesterone levels or histologic changes on endometrial biopsy there is insufficient PIBF secretion to suppress cellular immune rejection? Unfortunately, no. Serum PIBF only correlates with serum P and the important area is to measure intractyoplasmic PIBF but that would not be possible in the intact human.p " p@P         :  DH t 0޽h ? ̙3380___PPT10.:Е" SKx(  x  x  x.0e0eRectangle 2P   >    x  r 60e0eRectangle 3  We are still searching for the role that circulating PIBF made from gamma/delta T cells plays. One possibility is that it prevents early parturition.ZDH x 0޽h ? ̙3380___PPT10.:<"C |3(  |  |  rDF0e0eRectangle 3@ ` <4___PPT9 In animals a drop in P would also cause a drop in PIBF, which immediately precedes parturition. In humans, a drop in serum P does not precede parturition. 6" P" Pp`Pp |  p8Q0e0eTitle 2`   "  H | 0޽h ? ̙3380___PPT10.;`W#" rj(      x,Y0e0eRectangle 2   @ (     r]0e0eRectangle 3P  However, sensitivity of the gamma/delta T cells to produce PIBF seems to wane even when exposed to normal progesterone levels since a drop in serum PIBF precedes labor and delivery in humans.   H  0޽h ? ̙3380___PPT10.4" #(      x|f0e0eRectangle 2@   @ (  g   rxv0e0eRectangle 3@b >6___PPT9 [One must recall that 17 hydroxyprogesterone (17-OHP) does not increase PIBF secretion from gamma/delta T cells. Thus one must give some thought as to whether progesterone may be superior to 17-OHP in preventing pre-term deliveries. " &      DH  0޽h ? ̙3380___PPT10.]~":  @ P:(  Pr P S <~P    P S x  "p`PpH P 0޽h ? ̙3380___PPT10.3Q`I bZ(      xБ0e0eRectangle 2P   @ (     r@0e0eRectangle 3  Intramuscular P raises serum PIBF and also gets into the endometrium. But IM P can be nasty. If used, daily injections are needed or can it be used 2x/week?    H  0޽h ? ̙3380___PPT10.^Pl 1" v(     r$w0e0eRectangle 2   @ (  0   rl0e0eRectangle 3@  jOral progesterone raises serum PIBF very well but does get into the endometrium. If serum PIBF levels are all that is needed to inhibit parturition how would oral micronized progesterone compare to IM P or to 17-OHP in preventing pre-term delivery? Could be another interesting study. $  H  0޽h ? ̙3380___PPT10.^&8I" 7/(     pа0e0eTitle 1`   >      ط0e0e,Content Placeholder 2`  [Can merely an inadequate secretion of P be a cause of infertility? If so, how common is it?\ \p`PpH  0޽h ? ̙3380___PPT10.^ ,y_"  (     p0e0eTitle 1   @ (  `    0e0e,Content Placeholder 2p  Over 40 years ago Georgeanna Jones coined the term luteal phase defect and considered this a cause of infertility. For over 40 years right up to the present there are some who believe P insufficiency can cause infertility whereas others do not agree. @           DH  0޽h ? ̙3380___PPT10.^("  (     p00e0eTitle 1P   "  q   0e0e,Content Placeholder 2  5Probably no one challenges the concept that at least some progesterone is needed to allow a pregnancy to proceed to a live birth. However, various studies have failed to find any molecular marker that is found in the luteal phase that becomes subnormal as long as the mid-luteal phase serum P exceeds 5 ng/mL.@    1       H  0޽h ? ̙3380___PPT10."r 0b(     ph0e0eTitle 1`0   >       0e0e,Content Placeholder 2   @Based on inconsistent clinical studies, but especially because not one study found a putative luteal phase molecule, which, a prior would be needed for implantation, to be deficient with what seemingly is adequate serum P levels led to the conclusion by the practice committee of the ASRM that  there is no evidence that luteal phase defects are a cause of infertility .@^        ,  H  0޽h ? ̙3380___PPT10.`j" @(     j0e0eTitle 1   >   E   0e0e,Content Placeholder 2  eOf nearly 100 molecule markers evaluated in various studies not one evaluated if a lack of intracytoplasmic PIBF can be a cause of infertility. Of course there is no practical method at the present time to evaluate intracytoplasmic PIBF. @[    l      H  0޽h ? ̙3380___PPT10.aA" P(     j 0e0eTitle 1P   >   \   D0e0e,Content Placeholder 2  |What is a clinician supposed to do when faced with an infertility couple that has patent fallopian tubes, apparent normal ovulation based on regular menses, adequate mid-luteal serum P, demonstration of oocyte release by ultrasound, normal semen parameters and normal post-coital tests? &    o  H  0޽h ? ̙3380___PPT10.a$" aY`(      x0e0eRectangle 2P   @       r 0e0eRectangle 3   Patients do not want to wait until the one study is finally performed that is uncontroversial and there is universal agreement on the efficacy of therapy.    H  0޽h ? ̙3380___PPT10.aЍ"U pE(     r-0e0eRectangle 2`   >      r000e0eRectangle 3  ;The treating physician must decide based on the literature, lectures at meetings, and teaching from more experienced mentors on a treatment plan that makes sense to them and would be the appropriate therapy that best fits their patient population.    H  0޽h ? ̙3380___PPT10.b`M+"f V(      x;0e0eRectangle 2    @        rP?0e0eRectangle 3P  DFor example, a good percentage of REI s may recommend IVF-ET for unexplained infertility for economic reasons that would be best for the treating physician rather than the patient. There is no question that IVF-ET will be an effective treatment for many patients that fit the above therapy. However, its success could merely be related to providing a very expensive way to provide P.    H  0޽h ? ̙3380___PPT10.bJ"# {(     r T0e0eRectangle 2P   "     rU0e0eRectangle 3  %Obviously, IVF-ET would not be a reasonable choice for patients of treating physicians at this meeting. Nor for poor patients who cannot afford this expensive procedure. It certainly would be a crying shame if all the patient needed was supplemental P!!   H  0޽h ? ̙3380___PPT10.fp" w(      x`0e0eRectangle 2P   @ (  +   rLd0e0eRectangle 3  eWe performed a study conducted about 30 years ago in 100 women who also had unexplained infertility of at least one year duration and who had an out-of-phase late luteal phase endometrial biopsy. We found that 58 of these patients made a mature dominant follicle. &    _  H  0޽h ? ̙3380___PPT10.bU"0  ` X0(  Xx X c $rP   x X c $r  H X 0޽h ? ̙3380___PPT10.P  (      x{0e0eRectangle 2PP   @ (  U   r\0e0eRectangle 3  /In the time era that we started this study the pervading concept was that the progesterone deficiency was the result of not attaining a mature follicle. Thus the most common suggested treatment for women with out-of-phase endometrial biopsies were follicle maturing drugs, especially clomiphene citrate.0 Z0&        H  0޽h ? ̙3380___PPT10.bm"0   0(  x  c $P   x  c $\  H  0޽h ? ̙3380___PPT10.XX  VN (  x  c $ @   ~  s *      # #"t0    B ?"6@ NNN?N   G1 @`  B, ?"6@ NNN?N  O 24 (77.3%   @`  B ?"6@ NNN?N   eVaginal progesterone (n=31) @`  B ?"6@ NNN?N   G2 @`   B ?"6@ NNN?N  O 3 (11.1%)   @`"   B0 ?"6@ NNN?N  j Follicle stimulating drug (n=27)!! @`   B ?"6@ NNN?N  ]Number miscarriages @`   B ?"6@ NNN?N  f6-month clinical pregnancies @`   B< ?"6@ NNN?N P  @`B  <o ?"0@NNN?NB  61 ?"0@NNN?NB  61 ?"0@NNN?N  B  <o ?"0@NNN?N  B  <o ?"0@NNN?N B  61 ?"0@NNN?N B  61 ?"0@NNN?N  B  <o ?"0@NNN?N H  0޽h ? ̙3380___PPT10.p$  p $(  r  S H P   r  S   H  0޽h ? ̙3380___PPT10.2\'0   0(  x  c $P   x  c $  H  0޽h ? ̙3380___PPT10."0   0(  x  c $P   x  c $T  H  0޽h ? ̙3380___PPT10."@\s0   0(  x  c $%P   x  c $T&  H  0޽h ? ̙3380___PPT10.8V $ (     p30e0eTitle 1P   @ (  p   70e0e,Content Placeholder 2P  Related to continued controversy about the existence of luteal phase defects doubting benefits of exclusive P in the luteal phase as a treatment of infertility, we decided to re-evaluate the efficacy of P treatment for women with unexplained infertility (no endometrial biopsy). @8    7      H  0޽h ? ̙3380___PPT10.cJ"0   0(  x  c $EP   x  c $F  H  0޽h ? ̙3380___PPT10.}TF   F(  x  c $TKP     c $dY  "p`PpH  0޽h ? ̙3380___PPT10.0   0(  x  c $]P   x  c $^  H  0޽h ? ̙3380___PPT10.R{0   0(  x  c $nP   x  c $do  H  0޽h ? ̙3380___PPT10.@  \T ""(  x  c $4u   4 Q # #"&BACAQ   B0b ?"6@ NNN?NQ N13 (65%)   @`  Bw ?"6@ NNN?N Q I30% @`  BP ?"6@ NNN?N Q I25% @`  B ?"6@ NNN?NQ gLive delivered pregnancy rate @`  Bؚ ?"6@ NNN?N  N1 (7.1%)   @`   Bأ ?"6@ NNN?N  G4 @`   B< ?"6@ NNN?N  G0 @`   B( ?"6@ NNN?N  XNo. miscarriages @`   B ?"6@ NNN?N  N14 (70%)   @`   B ?"6@ NNN?N   M7 (70%) @`  BL ?"6@ NNN?N  M3 (25%) @`  BD ?"6@ NNN?N  gClinical pregnancy (6 months) @`  B0 ?"6@ NNN?N H20 @`  Bd ?"6@ NNN?N  H10 @`  B ?"6@ NNN?N  H12 @`  B ?"6@ NNN?N PNumber @`  B8  ?"6@ NNN?N aFollicle maturing and P @`  B0  ?"6@ NNN?N  eFollicle maturing drug only @`  B ?"6@ NNN?N  XExclusive P Rx @`  B$ ?"6@ NNN?N P  @`B  <o ?"0@NNN?NB  61 ?"0@NNN?NB  61 ?"0@NNN?NB  61 ?"0@NNN?N  B  61 ?"0@NNN?NB  <o ?"0@NNN?NQQB  <o ?"0@NNN?NQB  61 ?"0@NNN?NQB   61 ?"0@NNN?N  QB ! 61 ?"0@NNN?NQB " <o ?"0@NNN?NQH  0޽h ? ̙3380___PPT10. ;0  0 0(  x  c $P   x  c $  H  0޽h ? ̙3380___PPT10."KM$    $(   r   S DP   r   S tE  H   0޽h ? ̙3380___PPT10.3\:+$   $$(  $r $ S RP   r $ S S  H $ 0޽h ? ̙3380___PPT10.3\#t0  @ 0(  x  c $YP   x  c $Z  H  0޽h ? ̙3380___PPT10.p0  P 0(  x  c $4hP   x  c $i  H  0޽h ? ̙3380___PPT10.P){;0  ` 0(  x  c $mP   x  c $n  H  0޽h ? ̙3380___PPT10.0  p 0(  x  c $~P   x  c $  H  0޽h ? ̙3380___PPT10.Ri0   0(  x  c $ԄP   x  c $  H  0޽h ? ̙3380___PPT10.{0   0(  x  c $   x  c $|  H  0޽h ? ̙3380___PPT10.E x(      x0e0eRectangle 2P   >(  .   r0e0eRectangle 3  hBut what good is a properly randomized multi-center study with a large study population if the experimental design is flawed? Check JH: Pros and cons of the use of progesterone to reduce miscarriage rates. Clin Exp Obst Gyn 2018;45:652-655.Z              H  0޽h ? ̙3380___PPT10.lp?9"0   0(  x  c $P   x  c $  H  0޽h ? ̙3380___PPT10."pga 0 u(       x0e0eRectangle 2P   "  G    rص0e0eRectangle 3  In the Pros and Cons article I point out that the progesterone was started in the PROMISE study shortly after the first positive beta-human chorionic gonadotropin (b-hCG) level or at least within the first two weeks from confirmation of pregnancy. THEY STARTED PROGESERONE WAY TOO LATE4Z&Z&$   H   0޽h ? ̙3380___PPT10.l"0   0(  x  c $DP   x  c $   H  0޽h ? ̙3380___PPT10.0   0(  x  c $XP   x  c $4  H  0޽h ? ̙3380___PPT10.i0   0(  x  c $lP   x  c $H  H  0޽h ? ̙3380___PPT10.@p p0x(  0 0  x0e0eRectangle 2P   "  J 0  r80e0eRectangle 3  \So is it ever worth starting P during a pregnancy if the level is already low? Is it futile? ]  H 0 0޽h ? ̙3380___PPT10.mj="0   0(  x  c $P   x  c $  H  0޽h ? ̙3380___PPT10."0   0(  x  c $\P   x  c $8  H  0޽h ? ̙3380___PPT10."Q0   0(  x  c $P   x  c $p   H  0޽h ? ̙3380___PPT10.j$   ($(  (r ( S P   r ( S   H ( 0޽h ? ̙3380___PPT10.3\8A @1(  @ @  rt0e0eRectangle 2p   >(   @  r<0e0eRectangle 30  'If the PIBF protein is important in helping the fetal-placental unit and also cancer cells escape immune surveillance AND If supplementing P can successively treat infertility, miscarriage, and even pre-term delivery THEN Using a progesterone receptor antagonist to suppress intracytoplasmic PIBF in cancer cells should be able to provide increased longevity and palliation for patients with cancer.NvZZ_ZZZ&    m  H @ 0޽h ? ̙3380___PPT10.mPDr" D(  D D  r90e0eRectangle 2P   "  ^ D  xL<0e0eRectangle 3  jIndeed, oral mifepristone, the P receptor modulator, has been found to stop many cancers from progressing. k  H D 0޽h ? ̙3380___PPT10.n0hH" RJH(  H H  rC0e0eRectangle 2P   "   H  rE0e0eRectangle 3  ~Check JH, Dix E, Sansoucie L, Check D: Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon  case report. Anticancer Res 2009 May;29(5):1611-1613. Z     ?     >      H H 0޽h ? ̙3380___PPT10.n{X"- L(  L L  xP0e0eRectangle 2P   "   L  rHR0e0eRectangle 3  )Check JH, Dix E, Cohen R, Check D, Wilson C: Efficacy of the progesterone receptor antagonist mifepristone for palliative therapy of patients with a variety of advanced cancer types. Anticancer Res 2010;30:623-628. &      H L 0޽h ? ̙3380___PPT10.n9w}" .&T(  T  T  xb0e0eRectangle 2P   >(  t T  ri0e0eRectangle 3  Check JH, Wilson C, Cohen R, Sarumi M: Evidence that mifepristone, a progesterone receptor antagonist can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV. Anticancer Res 2014;34:2385-2388. Z$t                    H T 0޽h ? ̙3380___PPT10.oP&J" bZX(  X X  x|0e0eRectangle 2P   "   X  r~0e0eRectangle 3  Check JH, Check D, Wilson C, Lofberg P: Long-term high-quality survival with single-agent mifepristone treatment despite advanced cancer. Anticancer Res 2016;36:6511-6513. &      H X 0޽h ? ̙3380___PPT10.o,u"c  \S(  \  \  x0e0eRectangle 2P   >(    \  rx0e0eRectangle 3  CCheck JH, Check D, Poretta T: Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that has progressed despite chemotherapy and a check-point inhibitor. Anticancer Res 2019;39:1923-1926. &      H \ 0޽h ? ̙3380___PPT10.oPdD"< 0`,(  ` `  x0e0eRectangle 2P   "   `  r0e0eRectangle 3  8A recent summary of the role of PIBF and how suppressing this immunomodulatory protein can make a significant contribution to the fight against cancer was published in July, 2019. Check JH, Check D: Therapy aimed to suppress the production of the immunosuppressive protein progesterone induced blocking factor (PIBF) may provide palliation and/or increased longevity for patients with a variety of different advanced cancers  a review. Anticancer Res 2019;39:3365-3372.P@>    t      H ` 0޽h ? ̙3380___PPT10.op"$   |$(  |r | S XP   r | S 4  H | 0޽h ? ̙3380___PPT10.>QP   @ (  x  c $pP   r  S L   r  S (p   H  0޽h ? ̙3380___PPT10.)T)$  ` $(  r  S 0P   r  S    H  0޽h ? ̙3380___PPT10.)T$   ,$(  ,r , S P   r , S   H , 0޽h ? ̙3380___PPT10.4\po$  p $(  r  S HP   r  S   H  0޽h ? ̙3380___PPT10.)T@i$   $(  r  S P   r  S ,  H  0޽h ? ̙3380___PPT10.*T ޣ$   0$(  0r 0 S 8P   r 0 S   H 0 0޽h ? ̙3380___PPT10.4\0%0 5(  /   ~Dpmpm??Rectangle 7   p*    M   l0e0eRectangle 20K      xpmpmRectangle 3 >)   R    H  0i ? 3380___PPT10.Br0f`áGɱST`rp ~<`) 5O$\ f$(,1>6<QAF J/ gNT2 Y_8zGIM Q@qXRV@]g]پ_B  Frdfz }BF~̊<00hؿe רxhEOh+'0T `h   ( 4@HTRecombinant FSH (especially Gonal-F) May Adversely Effect the Uterine EnvironmentUnknown Userlaurie438Microsoft Office PowerPoint@0o!@$H@@SrbGSg  )'    """)))UUUMMMBBB999|PP3f333f3333f3ffffff3f̙3ff333f333333333f33333333f33f3ff3f3f3f3333f33̙33333f333333f3333f3ffffff3f33ff3f3f3f3fff3ffffffffff3ffff̙fff3fffff3fff333f3f3ff3ff33f̙̙3̙ff̙̙̙3f̙3f333f3333f3ffffff3f̙3f3f3f333f3333f3ffffff3f̙3f3ffffffffff!___www4'A x(xKʦ """)))UUUMMMBBB999|PP3f3333f333ff3fffff3f3f̙f3333f3333333333f3333333f3f33ff3f3f3f3333f3333333f3̙33333f333ff3ffffff3f33f3ff3f3f3ffff3fffffffff3fffffff3f̙ffff3ff333f3ff33fff33f3ff̙3f3f3333f333ff3fffff̙̙3̙f̙̙̙3f̙3f3f3333f333ff3fffff3f3f̙3ffffffffff!___www<_?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root EntrydO)PicturesCurrent UserSummaryInformation((UPowerPoint Document(DocumentSummaryInformation8