A Deficiency and Estrogen to Induction of Keratinizing Metaplasia

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A Deficiency and Estrogen to Induction of Keratinizing Metaplasia Powered By Docstoc
					                            Relation                                                                       of                        Vitamin                                           A              Deficiency                                                                                and
                            Estrogen                                                                        to                        Induction                                                                       of                    Keratinizing
                                    Metaplasia                                                                                        in                      the                          Uterus                                                      of                   the                            Rat
                                                                                                                                By          \\ALTER                       J.         Bo,      PH.D.

I      T             IS              WELL                  known                           that                    a          deficiency                                  of the                 uterine                        epithelium                                       can                 be               inducedin
              vitamin                               A        and                also               overstimulation                                    with                      experimental                              animals                           by          overstimulation                                    with
estrogen                            causes                   a keratinizing                                            metaplasia                                  of     the estrogen,                             there                       is          no              agreement                                     about                  the
epithelium                                      of           the               rat            uterus.                                Wolbach                                manner
                                                                                                                                                                          and                                  of           origin                          and               development                            of       the

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Howe’                           were                the               first            to              carry                        out                detailed                 abnormal                         epithelium.
studies                        of        the             morphologic                                   changes                            produced                         by          From                the             data                 available                           in         the             literature                        on
the           withdrawl                                    of         vitamin                          A          from                experimental                              keratinizing                          metaplasia                                    of            the               epithelium                              of
animals.                                  They                           observed                           that                          stratified                            the          rat           uterus,                         it          is        not             clear                whether                           avita-
squamous                                       keratinizing                          metaplasia                                       developed                                 minosis                    A        exerts                       its          influence                            directly                       on         the
in          all           types                     of      epithelia                             through                            the               following                epithelium                          independent                                        of        estrogen                        stimulation
sequence                             of             histologic                        changes                           :       atrophy                            of     theor            whether                    it         is        dependent                                on          estrogen                          for        the
original                            epithelium,                                  proliferation                          of           the               basal                    induction                        of        the             keratinizing                                       metaplasia.                   The
cells                    which                      displaced                              the              original                             epithelium                     experiments                                to         be             described                           in        this              paper               were
and                  finally                        a       differentiation                            into                   a           stratified                            designed                    to        provide                           information                                  on              the      manner
squamous                                        keratinizing                           epithelium.                                        In                the                 of         origin                and              development                               of         stratified                           squa-
rat           the               uterine                         changes                           were                  first              observed                             mous
                                                                                                                                                                                to                  epithelium                                   in          the             uterus                       of          the         rat            by
occur                     in         the                 endometrial                                   glands.                                 Metaplasia                       overstimulation                                   with                  estrogen                          and                   to         provide
of          the             epithelium                                    of         the            uterus                           of          the              guinea information                                       on          the                  relationship                                  of          avitamino-
pig                is          more                       marked                           than                    for               the                rat.’                   sis
                                                                                                                                                                                 In          A        to            estrogen                                in          producing                                    keratinizing
vitamin                              A-deficient                                     mice                    metaplasia                                        of          the
                                                                                                                                                                             metaplasia                             of          the             epithelium                               of        the           rat          uterus.
uterine                         epithelium                                     has               not               been                    observed                             to
                                                                                                                                                                                                                 MATERIALS                             AND              METHODS
       Selye,                       Thompson,                                   and                Collip4                          were                the             first
among                          many                       investigators’’4                                  to           observe                            that                       Three               separate                             experiments                                   were               carried                  out
prolonged                                  treatment                                   with                      estrogen                               produces                to           study                     the                      problems                                 mentioned                   above.
metaplasia                                      of           the               epithelium                                       of           the                uterus. Rats       of                      the             Wistar                       strain                   were                used all in the
Although                                 all             authors                      agree                      that                metaplasia                         of
                                                                                                                                                                        experiments.                                        The                      animals                        were                       killed               with
                                                                                                                                                                                ether               and             the           uteri                     fixed             for             12          to         24       hours                in
                                                                                                                                                                                Zenker’s                       or           Helly’s                          solution.                               Serial                   sections
       Frommi               I)cpartnicmit                        of     Amiatoniv,                     School                 (if     Medicine,
Umiivcrsity                         of          North                    Dakota,                       Gramid                        Forks,                     North           were                made                   of          each                      uterus                       and                every                   tenth
I)ak              ita.                                                                                                                                                          section               was             mounted                               and          stained                     with                  Weigert’s
       This              iiivcstigatioim                              s’as       supported                 iii         part           by              a
                                                                                                                                                      gramit                    heniatoxylin                               and              eosin.
fr(    on          The         National                         \‘itaniin                   F( )undat                    ion,             Inc.
                                                                                                                                                                                       Specific                  information                                       on         the              execution                          of        the
       Presemited                              at           the               Symposium                    omi              Some                      Recemit
                                                                                                                                                                                experiments                                along                     with               the            observations                                    nmade
Observations                             on          Biological                       Relationships                           held               in         New
York                City,             March                     5,      1957,with            the            cooperation                                of       The             will          be          presented                                  under                  appropriate                                     headings
Nat         i nial              \‘itani                  inF ‘umidati                ni,     I mic.                                                                             below.

November-December                                                19571                                                                                         BO                                                                                                                                                                                  667

                                                                                                                                                                            kept                 intact                              and                  l)laced            OI             a          vitamin                                 A-de-
I.         The      Manner        of                                         Development                                       of            Squamous                       ficient                  diet.*                                   The                    rates                      in               group                            II           were
        Metajilasia       Induced                                             by Estrogen”                                                                                  treated                        as         those                     in         group           I except                              that                   they              re-
                                                                                                                                                                            ceived                   a dietary                                 supplement                                         of         vitamin                              A.             The
        Starting                          on          the              seventh                       day               of          age             the               rats
                                                                                                                                                                            animals                             in             group                       III                were                          bilaterally                                       ovari-
were                treated                     weekly                     with               a single                      subcutaneous
                                                                                                                                                                            ectomized                                  and                    placed                       on              a vitamin                                     A-deficient
ill     jection                       of               2          mg               estradiol                                dipropionate.*
                                                                                                                                                                            diet.                    In           group                         IV              the              rats                 were                      treated                        as          in
Animals                            were               autopsied                              every                  three                  days                from
                                                                                                                                                                            group                    III              except                         that                   they                      received                                a         dietary
the               3rd         to          the          27th                  day                  after                receiving                               the
                                                                                                                                                                            supplement                                         of              vitamin                                     A.                     Animals                                 were
first              injection.                               Others                    were                  killed                    on           the           33rd
                                                                                                                                                                            autopsied                                 from                     the          8th                  to          the                 13th               week                  of         the
and                the              39th               day                 after                  initial                   injection                                with
                                                                                                                                                                                    In        order                    to            determine                                    whether                                 the             daily                food
         Uterine                      metaplasia                                   was               first             evident                           in           the
                                                                                                                                                                            intake                    of          the                vitamin-deficient                                            animals                               was              an
animals                            autopsied                            on          the                 lSth                day               after                   the
                                                                                                                                                                            important                                  factor                              in                 producing                                   symptoms
first              injection                          of         estrogen,                           (Table                     I).                  Epithe-
                                                                                                                                                                            of          avitaminosis                                           A      rats                  of             Group                          III            and             Group
                                                                 TABLE                        I                                                                             IV           were               pair-fed.

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Imiductiomi                   of      Epithelial                        Metaplasia                             in      the             Rat           Uterus                         Metaplasia                                           of         the               uterine                          epithehium                                        of         the
by           Weekly                 Administration                             of            2.0           mg              Estradiol                          I)i-          vitamin                             A-deficient                                          intact                     rats                  was                 similar                      to
                  propionate                      Beginning                         at        Seven                  Days               of     Age                          that                previously                                           reported,’                                            (Figs.                        2c,              d,           e).
                                              Days                             Number                                                                                       However,                                    no                    metaplasia                                        of               the                    uterus                      was
                                          after            1st               of animals                                 Extent                of
        Number                            injection                            showing                                 squamous                                             observed                                   in                     the                    vitamin                                     A-deficient                   rats
      of animals                         autopsied                           metaplasia                                metaplasia
                                                                                                                                                                            following                                  ovariectomy                                          (Table                     .    II        ;            Fig.                  2).
             25                                3-15                                      0                                        -
               5                                 18                                      4                                    +                                                                                                                 TABLE                                 II
               5                                21                                       4                                  +++                                             Imifluemice                     of             Ovariectomy                                on           \‘itamin                               A         I)eficiency
               5                                24                                       4                                  +++                                             Induction                           of             Epithehial                             Metaplasia                                 in         the           Rat             Uterus
               5                                27                                       4                                   ++
               5                                :33                                      2                                  +++                                                                      Num-                                                                                                                             Pres-
                                                                                                                                                                                                     ber    of                         Intact              or                                                                       ence    of
               5                                39                                       4                                    ++                                                                       ani-                           overiecto-                                           Vitamin                               squamous
                                                                                                                                                                             Group                    mals                                mized                                                   A                              metaplasia

                                                                                                                                                                                        I              30                           Intact                                            Deficient                                          Yes
hal                 metaplasia                             was                observed                                 to               begin                        as
                                                                                                                                                                                    II                     10                       Intact                                            Supplied                                           No
multiple                            foci               which                       were                   located                            along                     the
                                                                                                                                                                                   111                 30                           Ovariect                    )-                    Deficient                                          No
horns                   of         the           uterus,                     (Fig.                  la).                    The               abnormal                                                                                     mized
epithelium                                was formed                           by              proliferation                            of         the                             I\                      10                       Ovariecto-                                        Supplied                                           No
luminal                        epithelial                           cells.                     The                  foci           of         epithelial                                                                                   inized

metaplasia                                 grow                  by          continual                               division,                           under-
mine                    the              original                        epithelium                                   and                  eventually                       The               results                           indicate                              that                  the              ovaries                          also             have
separate                             the                   original                          epithelium                    from                     the                     an              important                                      role                 in          producing                                         metaplasia                                  in
underlying                                     connective                                    tissue.                          In              advanced                      the              uteri                    of            vitamin                             A-deficient                                             rats.                    Of          the
conditions                                keratin                   ized            epithelium                                wa             s present,                     ovarian                         hormones,                                      it          is         probably                                    estrogen                          that
 (Fig.                ib).                   Destruction                                     of         the            luminal                           epithe-            is           concerned                                            with                     the                   mnetaplastic                                              changes
hum                 was             not          observed                           to        precede                        the             formation                      that                occur                               in          the                    uterine                              epithehium,                                         since
of           squamous                            mnetaplasia.
                                                                                                                                                                            rogestero1ie                                            is               primarily                              concerned       with
                                                                                                                                                                            secretory                             activity                             of the                     epitliehial         cells    whereas
 II.                Influence                              of          Ovariectomy                                    on              Vitamiti                            A-
                                                                                                                                                                            estrogen                             is            primimarily                  COIiCcrne(l                               with                       stimiiulat-
        Deficiency                             induction                      of Epitbelial                                   Metaplasia’6
                                                                                                                                                                            ilig         niitosis                          amid               cell          growth.
         Rats             20         to          22             days           of            age            were               divided                          into          Since                         the                     rats              of              group                       Iin I the
                                                                                                                                                                                                                                                                                                    I                              pair-fed
four                 groups.                                In           group                      I          the             animals                               wereseries                      showed                                external                              manifestations                                   of          vita-
         *   The             estradiol                     dipropionate                             used              in      this            study                   was
                                                                                                                                                                                    *    \‘itamnin                         A          Test                I)iet                 U.S.P.                       XIV,                   (;eiier’tl                      Bin-
 supplied                      through                      the            courtesy                       of         the           Ciba              Pharma-
 ceutical                    Products,                      Inc.,           Summit,                       New              Jersey.                                          chetnicals,                          Inc.      ,    Chagrin                         Falls,                 Ohio.
668                                                    THE                AMERICAN                                            JOURNAL               OF       CLINICAL                           NUTRITION                                  IVol. 5, No         6


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                                        -L,.-”                                      -

                                    (a)    Photomicrograph             of a portion              of the     uterus                                            showing           the         start      of    squamous            keratiniz-
                               ing      metaplasia           following        estrogen         stimulation                                               (hematoxylin                  and        eosin)       X     160.      (b) Photo-
                               micrograph           of     a portion          of  the      uterus        showing                                                extensive              stratified           squamous            keratinizing
                               epithelium          following         estrogen          stimulation      (giemsa                                              stain)         X         160.

mimi    A deficiency                    and                  nietaplasia                                   of                the        limiing     vitamin                 A            deficiency,              it        could          be    concluded
epithehium               of     the                    trachea                      while                                the            animals     that
                                                                                                                                                     of            the          changes                     observed                were        due       to   avita-
group           IV       on           the                    supplemented                                   diet,                       which       minosis                 A            and           not         to        indirect           effects        of       the
were         pair-fed,                exhibited                                 no                   manifestations                            of   deficiency.
                                                                                                                                                  :     -        .       ...   1

                                                                                                                                             -   .

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                                                              -                .       I           1.:.                         ‘

                                 I.                 :#.           ..               .                                            ...,.
                                         I                             -                                  -       ...   ,
                                               .1         -   (            -                :.-   --          :             -


                                                                                                                                                 Fig.       2.

     (c)       Photomicrograph                      of a portion               of       the      uterus        of an          intact         vitamin            A-deficient              rat                  stratification
                                                                                                                                                                                                  demonstratifig                          and       keratinization
of the          glandular                epithelium.            The      animal             was      autopsied             during           the       12th      week         of the       deficiency                         and
                                                                                                                                                                                                                  (hematoxylin        eosin)        X 70.            (d) and
(e).          Photomicrograph                      of     a portion            of      the       endometrium         of an          intact         vitamin           A-deficient              rat     demonstrating        extensive            keratinization            of
the       glandular                epithelium.            The       animal          was        autopsied            during           the      12th        week       of the deficiency                    (hematoxylin
                                                                                                                                                                                                                    and       eosin)         X 175.         (f) Photo-
micrograph                     of     the       uterus          of    an     ovariectomized          vitamin            A-deficient                rat.         No        evidence            of     uterine           metaplasia                       The
                                                                                                                                                                                                                                                is present.       animal
was        autopsied                 during          the      13th      week         of the         deficiency              (hematoxylin  and       eosin)        X 55.            (g)     Photomicrograph              of the          uterus         of an        ovariec-
tomized               vitamin             A-deficient               animal          treated            with      estrogen. Many            foci      of uterine             metaplasia              are demonstrated.                The      rat    was       autopsied
during            the       6th       week        of the          experiment                 (hematoxylin and         eosin)            X 45.            (h)      Photomicrograph            of the        uterus          of an osariectomized                  animal
on       an        adequate                diet       and       treated           with         estrogen. No       evidence            of    uterine            metaplasia             The         animal            was         autopsied               during           the 9th
week           of       the       experiment          (liematoxylin             and          eosin)         X 30.
  67()                                                                       THE              AMERICAN                             JOURNAL                                     OF CLINICAL                                 NUTRiTION                                                             IVol.       5,     No.           6

     Ill.                    Relation                            of           Vitamin                          A           Deficiency                                   and
            Estrogen                             in            Production                             of             Epithelial                                Meta-                 The           observations                                   made                 in             the           present                   study
                                   7                                                                                                                                           demonstrate           that                                     keratinizing                                        metaplasia                            in-
                                                                                                                                                                               duced       by estrogen                                             begins                            as            multiple                       foci
            Rats                   20         to           22         days              of          age          were                  divided                         into
  four                   groups.                                 In          group                    I         the               animals                              were
                                                                                                                                                                               which                are               located                          along                 the                   uterine                    horns.
                                                                                                                                                                          These                   foci           of        epithelial                          cells                 extend                       t
  kept                   intact                         while                 the             rats              in          group                         II           were
                                                                                                                                                                              lumen                of           the             uterus                        and            also                   laterally                     from
  bilaterally                                  ovariectomizecl                                and              all         the               animals
                                                                                                                                                                              point                of            origin                      to              undermine                      the            original
  were                   placed                         on            the          vitamin                         A-free                     diet                  men-
                                                                                                                                                                              luminal                    epithelium.                              The                superficial                              cells               of
  tioned                           heretofor.                          In           group             III                 the             animals
                                                                                                                                                                              this          new               cell         growth                           become                         keratinized.              By
  were                  bilaterally                               ovariectomized,                              maintained                                      on
                                                                                                                                                                              this           process                      the           entire                      luminal                          epithehiumn                              is
 a           vitamin                               A-deficient                               diet              and                treated                             with
                                                                                                                                                                             replaced                    by           a        keratinizing                                epithelium.
  1 g                  estrogen                          every                third                 day.                  The                 animals                        in
                                                                                                                                                                                     The        origin                    of epithehial                               nietaplasia                              produced
 group                        IV              were                 treated                     as           those                 in                group                III
                                                                                                                                                                           by               estrogen                             stimulation                         differs                         from                   the
 except                       that                 they               received                       a dietary                          supplement
                                                                                                                                                                              metaplasia                              which                       occurs                     in                  vitamin                      A         de-
 of              vitamin                              A.               Animals                            in          group                         I       and                 II
                                                                                                                                                                              ficiency                   in           that              in              the            estrogen-induced                              the
 were                   autopsied                                from                 the           7th          to         the               13th                   week

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                                                                                                                                                                             change                  takes                   origin                    in      the           luminal                         epithelium
 of              the           vitamin                            deficiency                          while                     rats                 of         group
                                                                                                                                                                             wtiile            in that                     following                           nutritional                                  deficiency
 III              and                  IV          were autopsied                                   from              the 5th                to           the
                                                                                                                                                                              the            changes                          originate                            in      the                             endometrail
  10th                 week                   of         the           experiment.
                                                                                                                                                                             glands.                      The                  epithelial                           metaplasia                                in         the            rat
            Uterine                              metaplasia                           was                  present                            in                the
                                                                                                                                                                             uterus                produced                             by             estrogen                            stimulation                                was
 uteri                   of             intact                   vitamin                        A-deficient                                   rats                  while
                                                                                                                                                                             more                 pronounced                            than                        that                     produced                             by
 in              the                   ovariectomnized                                      vitamin                         A-deficient
 animals                               metaphasia                                of          the            uterine                       epithelium                         avitaminosis                                 A.

 was                   not               observed                             (Table                      III). Keratinizing                                                     It         has been                        suggested        by other        investigators
                                                                                                                                                                            that            squamous                           keratinizing         metaplasia            of the
                                                                                                                                                                            uterus             results                     from      a local   vitamin         A deficiency
                                                                 TABLE                        III                                                                           regardless                         of         any            other                                   ,           The             results
 Relatiomi                         of         Vitamin                        A         1)eficieney                        and              Estrogenin                       obtained                          from                the              present                            investigations                 do
 Production                             of         Epithehial                         Metaplasia                     in          Uterus                         of          not            support                     that             conclusion.                         If             all       keratiniz-
                                                                       the        Rat                                                                                       ing            metaplasia                             is          due               to          a              local             vitamin                          A

                                                                                                                                  i;;;;;;e                                  deficiency                        regardless                           of        any        other    factors,         then
                         ber of                     Intact    or                                                                       ofsqu:-                              such changes                            would                         be         present          in the      uteri        of
                                                                                                                                         ;:;                                ovariectomized                            vitamin                               A-deficient           rats.         The
                                                                                                                                              ---                           observations                              made                        in           the                    present                       studies
             1                     15            Intact                               Deficient                      No
                                                                                                                                          s                                 demonstrate                                rather                     clearly                   that                   uterine                 meta-
        II                         15          Ovariecto-                             I)eficient                     No
                                                                                                                                                                            plasia              following                              avitaminosis                                         A            occurs                only
      III                          30          Ovariecto-                           Deficient                        Yes                  Yes                               when        the    epithehial           cells                                              are      under                               the               in-
                                                        mized                                                                                                               fluence         of   estrogen.        The                                                synergistic                                   action
                              jo               Ovariecto-                           Supplied                         Yes                   No                               of     vitamin          A      deficiency                                                                and                 estrogen                        in
                                                                                                                                                                            producing                         uterine                   metaplasia                                    is         evident                 by           the
                                                                                                                                                                            pronounced                               metaplastic                                    changes                          observed                          in
                                                                                                                                                                            the         ovariectoinized                                           rats               on               a          vitamin                      A-de-
nietaplasia                                      occurred                              inthe                ovariectonmized                                               ficient              diet              amid            treated                       with                   estrogen                      as         com-
vitamnin                           A-deficient                               rats             treated                      with                     estrogen             pared                to         the  absence                            of changes    in the      ovari-
(Fig.                    2g).                       The                     changes                        were                   observed                                to
                                                                                                                                                                         ectomized                      animiials on                          a vitamin     A free    diet    or
occur                    in             the             glandular                            epithehium                                before                         the in          the          ovariectomized                               rats    on  an    adequate
lining                       epithelium.                                Uterine                           metaplasia                       was                           diet           treated        with                         estrogen.
not               present                          in        the             ovariectomized                           animals                             on                      No          definite                            relationship                                            exists                   between
an           adequate                                 diet             and             also               treated                      with                    estro- vitamin                      A deficiency                                   and           estrogen                            in      producing
gen              (Fig.                 2h).                                                                                                                              abnormal                             cornification                                    of          the                    vagina.                         The
 November-December                                           19571                                                                                                130                                                                                                                                                           671

 change                    occurs                       imi the                    intact                   as              well             as              in          the
                                                                                                                                                                           be            considered                                    to           be             the                primary                              factor                      in
 ovariectomized                                     vitamin                          A-deficient                                                 9      21
                                                                                                                                                                           inducing                        keratinizing                                      metaplasia                                   in       the             uterus
 It       has              been               reported                            that             cornification                                            of          theof the                   rat.                    Estrogen                              seems                     to         have                  an             equal
 vagina                    following                          estrogen                           treatment                                  is         altered             role           in          producing                                    the             change.                                On              the              other
 by         excess                          vitamin                          A.2223                             Recently,                                     tissue hand,                         from                     the               experimental                            data                      that                are
 culture                    technics                         have                  been               used                     to          study                  thisavailable                                 on               the              rat              vagina,                            vitamin                          A            de-
 relationship                                between                          vitamin                             A            and                   estrogen              ficiency                        seems                       to           be             the                primary                              factor                      in
 in         producing                                   keratinized                           epithehium.                                    The                           producing                             abnormal                                cornification.
 vagina                    has          primarily                             been                used                    for             this              study.               Although                              vitamin                           A         supresses                              the              cornifica-
 It        has              been                  demonstrated                                         that                     estrogen                               cantion             of              the               vagina                           induced                             by             estrogen,                                 it
 produce                         cornification                           of              the               mouse                            vaginal                        cannot                   be           definitely                              concluded                                that                 vitamin                         A
 epithehium                       in         zritro.24               Also,               in       vitro,               keratiniza-                                         plays               a         general                            role              in           the              prevention                                     of         all
 tion            of         the              rat             vagina                       was               observed                                   to              takekeratin                    formation.                                  In             the             epidermis                                  of         the
 place                in          cultures                           that                contained                                    a          standard                 male             rat,             topically                              applied                       vitamin                         A         dissolved
medium.2’                                   The                keratinization                              that                  occurred                                  in          sesame                          oil              did                   not                 interfere                                with                     the
was         probably                              due          to        a hack                  of         available                                vitamin              keratinization                                     process.26                                  Likewise,                                   in               the

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A.           The                  uterus,                      up             to           the              present                          time,                       has
                                                                                                                                                                          guinea                       pig,                      vitamin                               A              dissolved                               in                oheic
not        been                  used              forin        vitro              studies.                            However,                                   if      acid,            hinoleic                     acid                 or         alcohol                       did             not            inhibit                    the
such                  studies                            were                      undertaken                          interesting                                        formation                             of      the             stratum                            corneum                          of         the            skin.’7
observations                            would                       be            made                 on                 this              problem                       Also,           vitamin                            A         did              not             prevent                           the           estrogen-
of         the              relationship                            between                            vitamin                                   A           de-          induced                     hyperkeratosis                                     of        the            nipple                        epidermis
ficiency                   and              estrogen                         in       producing                                  keratinizing                             in       the         guinea                       pig.’6
metaplasia                             in         the         uterus                     of      the              rat.                                                           The           mode                    of        action                     of      vitamin                           A in             maintain-
       These                     observations                                      indicate                               that                   the                   ab-ing            normal                          uterine                            epithehium                                     is          not                 clear.
normal                     growth                       that                occurs                     in            the              uterus                           andSince                vitamin                             A          has                 not             been                    demonstrated
that             which                  has              been                reported                             to            occur                   in             theby        fluorescence                                      microscopy                                 in      epithehia                           that               are
vagina                      following                               avitaminosis                       A               cannot                               be            known                     to           undergo                                keratinization                           in          depleted
considered                             to         be          the            same.                      Although                                      the              endanimals,                         it         has              been                 suggested                             that                 vitamin                        A
result,                a          keratinized                                  epithelium,                                       is         the                  same per              se is not                     responsible                                  for          maintaining                                    normal
the        cytological                                 processes                         involved                              in         producing                       epithehia                        but               a         metabolite                                 of             vitamin                          A          may
the        change                      are             different                      in         the              two                organs.                              In
                                                                                                                                                                          be.”                 It           seems                      that                  in         order                    to         maintain                              the
the         vagina                          the              abnormal                             growth                              is             more                  of
                                                                                                                                                                          integrity                             of          the               uterine                           epithehia                              a          balance
a         hyperplastic                                 change                        and,                       as               mentioned                                exists                between                                vitamin                             A           and                estrogen                              and
above,       occurs                            in the    intact                                  and           ovariectomized                                          when       this                           balance                           is         disrupted                               a         keratinizing
rat    while        in                        the   uterus                                the               growth        is a                                     truemetaplasia                                    occurs.
metaplasia                         and                   occurs                          only                     in                the                intact
animal.                           This                  difference                               in             response                                of              the                                                             SUMMARY
uterus                and              vagina                   to       vitamin                            A          deficiency                                 may            I’vletaplasia                                   of           the                  uterine                            epithelium                 of
result            from                      the           difference                             in          the                 embryology,                              estrogen-treated                                              rats                           begins                               as                   many
morphology                                  and              physiology                               of         the                two               organs.             independent                                   centers                         that               grow                  and              coalesce                        to
The         conclusions                                 drawn                  from               observations                                          made produce                                        a            keratinized                              stratified                                squamous
on        the              vagina                       in          avitaminosis                       A             or          between                     epithehium                                              which                   replaces                          the               original                        uterine
vitamin                     A          and              estrogen                         cannot                        be             generalized                         epithehium.
to      include                   the             uterus.                                                                                                                        The            origin                      of         epithehial                          metaplasia                                   produced
    The                question                               which                     arises                            in        regard                            to
                                                                                                                                                                      by     estrogen                                  stimulation                                      differs                  from                  the            meta-
keratinized                                 epithelium                                is which                                   of    the                         twoplasia        which                               occurs                         in         vitamin                         A         deficiency                                in
causes,               estrogen                          or          vitamin           A deficiency,                                         is         the                that            in         the               former                       the             change                         takes                    origin                  in
primary                      factor                     in          producing                               the                 change.                                 On
                                                                                                                                                                         the             luminal                        epithehium                                      and              the                latter                    in         the
the        basis                  of         the              present                         work                     it        be con-
                                                                                                                                  can                                     endometrial                                  glands.                              The             epithelium                                     produced
cluded                that              vitamin                          A         deficiency              per              se cannot                                     by           estrogen                          stimulation                                       is          thicker                          and                 more
672                                                                          THE             AMERICAN                                        JOURNAL                            OF           CLINICAL                                      NUTRITION                                                                            [Vol.             5,         No.              6

heavily                         keratimmied                                          than                       that                  produced                                   by 7.        NElsoN,                            \V.               0.             :               Endometrial                       and               mvometrial
                                                                                                                                                                                                   ehaliges,                          including                                   fibromnyomnatous                                              l1 )dules,
vitamin                       A deficiency.
                                                                                                                                                                                                   induced                           imi         the                  uterus                   of             the            guimiea               I)) pig the
       Keratinizing                                    nietal)laSia                             in         the              uterus                      of          the
                                                                                                                                                                                                   prolomiged                                admuinistration                                            of           oestrogenic                                    li            r-
rat            was                   observed                                        to              occur                      only                     iii           intact                      imiomie.                     -mat.                  Rec. 68:                        99,          1937.
animals                       on          a            vitamin                            A-deficient                                 diet               or          in         the    8.     ZONDEK,                    B. :                    The                  effect                  of             long-contimiued                                large

ovariectomized                                     ,               vitamin                                A-deficient                                    rats                                      doses                 of           folhicular                                  hiormnone                          upon                  the               uterus                          of
                                                                                                                                                                                                   the         rat.                   An:. J.                    Obst.                  & Gynec. 33:                                979,           1937.
treated        with                                      estrogen.                                         The                 results                         demon-
                                                                                                                                                                                       9.    LOEB,                L.,                SUNTZEFF,                                    V.,               and                    BURNS,                            E.               L.:
strate                  that                  estrogen                                has                 an           imnportant                                   role             in
                                                                                                                                                                                                   Growth                            processes                                    induced               by           oestrogenic                                  hor-
producing                             keratinized                                          epithehium                                  in         avitamin-                                        mcrnes                       in          the                   uterus                           of          the               mouse. Ant.                        J.
osis              A           and               the                     change                        cannot                          be           considered                                       Cancer               34:              413,              1938.
to       be        due              to         only                     a local                      vitamin                       A         deficiency.                              10.    KORENCHEVSKY,                                             V.    ,         HALL,                  K.,             and          BURBANK,                            R.:
                                                                                                                                                                                                   The              manifold                                 effects                          of              prolonged                            administra-
       From                   the              present                                investigation                                          it              can                be
                                                                                                                                                                                                   tion           of        sex            hormones                                     to         female                   rats.Biochem.                            J.
concluded                            that                     vitamin                            A             deficiency                           is         not              the                33:372,                       1939.
primary                        factor                        in          producing                                   keratinizing                                    meta-            1 1.    KORENcHEVSKY,                                            V.     ,        and               HALL,                      K. :            Pathological
plasia                 in           the                 uterus                        of             the              rat          since                     estrogen                              changes                           in           the                  sex              organs                         after                   prolonged                                ad-

plays               a role                    in             producing                                    the          change.                                                                     ministration                                  of              sex               hormones                                    to          female                         rats.

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                                                                                                                                                                                                   J.      Path.                 & Bact. 50 : 295, 1940.
       The            mode                    of             action                   of        vitamin                          A in              maintain-
                                                                                                                                                                                      12.    GREENE,                     R.       R., and BURRILL,       M.                                                                U. :                Postnatal
ing           normal                          uterine                               epithehium                                   is         not                 known,                             treatment                               of           rats                   with                 sex             hormones                            :         the                  per-
but     it seems                               that      a balance                                       may                       exist                  between                                  manent                        effects                          on              the              ovary.            Am.                  J.       Physiol.
estrogen       and                               vitamin        A                                     in order                        to                 maintain                                  133:302,                           1941.
                                                                                                                                                                                     13.     WEICHERT,                               C. K.,                       and             KERRIGAN,                                S. :                Effects                    of
the           integrity                                      of             the            uterine                            epithelium                                    and
                                                                                                                                                                                                   estrogens                              upon                        the              young                      of         injected                         lactating
when                  this           is            disrupted                                    keratinizing                                  metaplasia
                                                                                                                                                                                                   rats.               Endocrinology                                           30:            741,                1942.
occurs.                                                                                                                                                                               14.    WILSON,                     J.           G. :                  Reproductive                                       capacity                           of          adult
       The             abnormal                                    cornification                                     of the                vagina                     that                         female                rats               treated                             prepuberally                                        with               estrogenic
occurs                   in          vitamin                                 A        deficiency                                of          the                rat              was                hormone.                               Anat.                       Rec. 86:341,                                   1943.
                                                                                                                                                                                     15.      Bo,            W.     J.      :         Study                      of            metaplasia                                  in        the               uterus                      of
compared                        with                     the     uterine      changes     and     it was
                                                                                                                                                                                                   the            rat                 following                                        estrogen                            treatment.                   Anat.
concluded                       that                     the     two      are   not   the   same.       In                                                                                       Rec. 118:215,                                          1954                      (abstract).
the        vagina                  the                    change        is more     of a hyperplastic                                                                                16.      Bo,    W. J. : The                                            effect                       of             ovariectomy                        on          meta-
changewhilein                                            the uterus                                  it is a true                           metaplasia.                                            plastic               changes                            in              the          uteri                 of       vitamin                        A deficient
Therefore,                           the                  conclusions                                     drawn                              from       the                                        rats.               Anat.                 Rec.                     121:241,                           1955.
                                                                                                                                                                                     17.      Bo,            W. J. :                  The                   relationship                                        between                           vitamin                              A
observations                                   made                           on          the             vagina                      in      avitamino-
                                                                                                                                                                                                   deficiency                         and                   estrogen                                     in            producing                  uterine
sis      A         and             between                                   vitamin                           A and                  estrogen                             can-
                                                                                                                                                                                                   metaplasia                              iii          the                     rat.            Anal.                        Rec.              124:          619,
not          be        generalized                                           to       include                         the          uterus.                                                         1956.
                                                                                                                                                                                     18.     MCCULLOUGH,                                         K., and DALLDORF,       G. : Epithelial
                                                                                                                                                                                                   metaplasia.                                   A rch. Path. 24 : 486,     1937.
  1.     \VOLBACH,                       S.        B.,             and HOWE,                         P.        R.:            Tissue               changes                           19.     \AN             EEKELEN,                             M. : Action    des    preparatiomis                                                                                    de
              following                        deprivation                                      of          fat-soluble                           A          vitamin.                              carotine                          et            de                  vitamine                               A          determinee                                      par                 la
              J.         Exp.                 Med. 42:753,                                  1925.                                                                                                  colpokeratose.                                       A rch.                          neeriand.                            de            physiol.            16:
 2. WOLBACH,                              S.           B.,             and HowE,                               P.       R.:                Vitamin                         A-                      281,           1931.
              deficiency                                in             the           guinea                         pig.Arch.                Path.              5:                   20.     MASON,                    K.             E.,              and             WOLFE,                       J.            M. : Relation                                      of
              234,             1928.                                                                                                                                                               castration                              to            vitamin                                   A-deficiemicy                    iii          the              rat.
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              deficiency                           in             the             albino                  mouse.        J.      Nutrition                      4:                    21.     SHERWOOD,                               T.            C.,                BREND,                       M.               A., and                      ROPER,
              185,            1931.                                                                                                                                                                E.      A.:                  Changes                                in         the          vaginal                          epithehium                               of            the
 4.      SELVE,               H.,         THOMPSON,                                  D.         L.,        and               COLLIP,               J.          B.:                                 rat       on          an           extensive                                   vitamin                           A diet.J.                  Nutrition
              Metaplasia                                     of         uterine                      epithehium                             produced                            by                 11:593,                       1936.
              chronic                         oestrimi                        administration.                                  Nature                    135:                        22.     KAHN,                     R.            H.,               and                   BERN,                       H.            A.:                 Antifolhiculoid
              65,        1935.                                                                                                                                                                  activity                        of         vitamin                                A. Science                        111:            516, 1950.
 5.      MCEUEN,                         C.            S.,         SELYE,                  H.,             and          COLLIP,                   J. B.:                          23.        KAHN,             R.             H.:                  Effect                         of         locally                   applied                         vitamin                           A
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              produced                         in            rats             by          prolonged                           administration                   of                              produced                              by            estrogens                             in              vitro.                      Nature                  172:
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November-December                                       1957]                                                                                  BO                                                                                                                                673

25.    KAmIN,          R.    H. : Effect                            of        oestrngen                  :mmi(l of        vitamnimi              A              27.
                                                                                                                                                               MONTAGNA,                      \V. :             Pemietratinmi                       amid       local effect            of
          (iii         vaginal                      cori,ificatiomi                       ill          tissue              culture.                                 vitaniin             A       om,      the        skin     of        the          guinea          pig.     I’roc.
          iTaturc           174:             317,              1954.                                                                                                 Soc.       Exper.                Biol.          .hI(d. 86:          (1(18,        1954.
201.   BERN,           H.    A.,        ELIAs,                  J. J., PICKETT,                         P.      B.,     PowERs,
          T.       R.,      amid HARKNESS,                            M. N. :                          The        imifluence           (if               28.        LOWE,       J.    S., amid            MORTON,                  R.         A. :      Some         aspects                of
          VitamiliIi             A    1)11        the           epidermis.                        A em. J.            .1 piat.     96:                              vitarnimi                A         miietabulismn.                Iitanzins                  &       flormones
          419,         1955.                                                                                                                                         14:97,           1956.

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                                                                                                                                                  AMERICAN                           JOURNAL                         OF      CLINICAL                         NUTRI-
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