WC_LPO4O 5958
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`WC Ex. 2004, Pg. 1
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`

`
`WC_LP0405959
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`

`
`-T
`
`14
`
`ftiiLjYi
`
`Special Uses of Oral Contraception
`The Progestin Only Minipill
`
`Emergency Contraception
`
`Vaginal and Transdermal
`
`Estrogen-Progestin Contraception
`
`Implant Contraception
`
`Injectable Contraception
`
`Intrauterine Contraception
`
`Barrier Methods of Contraception
`
`Periodic Abstinence
`
`10 The Postpartum Period
`Breastfeeding and Contraception
`11 Clinical Guidelines for Contraception
`at Different Ages Early and Late
`
`12 Sterilization
`
`ri
`
`WC_LP0405960
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`

`
`CLINIcAL GUIDE
`FOR
`CONTRACEPTION
`
`FOURTH EDITION
`
`WC_LP0405961
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`WC Ex. 2004, Pg. 4
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`

`
`CuNlcsl GUIDE
`FOR
`CONTRACEPTION
`
`FOURTH EDITION
`
`Leon Speroff M.D
`
`Professor of Obstetrics
`and Gynecology
`Oregon Health
`Science University
`Portland Orcgon
`
`Philip
`Profcssor and Chief
`
`Darney M.D M.Sc
`
`and Reproductive Sciences
`Obstetrics Gynecology
`San Francisco
`General Hospital
`of California San Francisco
`
`University
`San Francisco California
`
`illustration by Becky Slemmons and Daniyel Hicks
`by Daniyel Hicks
`
`Page Design
`Poitland Oregon
`
`Wolters Kiuwer Company
`
`Phiadephia
`Buenos Aires
`
`Bdltimole
`
`Hong
`
`Kong
`
`New York
`Syaney
`
`London
`
`Tokyo
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`

`
`Acquisition
`
`Managing
`
`Production
`
`Editor Anne
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`2005 by LIPPINCOTT WILLIAMS
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`LWWcom
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`WILKINS
`
`in critical
`
`articles
`
`owner
`
`appearing
`
`prepared
`
`of this book may be
`by copyright No part
`All rights reserved This book
`is protected
`reproduced in any form or by any means including
`or utilized by any
`photocopying
`from the copyright
`without written permission
`information
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`system
`embodied
`and reviews Materials
`for brief quotations
`except
`as U.S
`in this book
`
`by individuals
`by the above-mentioned copyright
`
`as part of their official
`
`duties
`
`government employees are not
`
`Printed
`
`in the USA
`
`covered
`
`Library of Congress Cataloging-in-Publication
`Leon 193
`
`Speroff
`
`Data
`
`clinical
`
`Leon Speroff
`guide for contraception
`and Daniyel Hicks4th ed
`illustration by Becky Slemmons
`cm
`
`Philip
`
`Darney
`
`Includes
`
`bibliographical
`ISBN 0-7817-6488-2
`
`references
`
`and index
`
`Contraception
`
`Contraceptionmerhods
`
`Darney Philip
`Wi 630 S749c 2006
`
`II Title
`
`2006
`RG136.563
`61394dc22
`
`2005045188
`
`Care has been taken
`
`generally
`
`accepted
`
`practices
`
`of the information
`
`presented
`
`and to describe
`
`are not
`
`responsi
`
`ble for errors or omissions
`
`this book
`
`pleteness
`
`or accuracy
`
`of the information
`
`in
`
`respect
`
`to the currency com
`
`Application
`
`of this information
`
`in
`
`to confirm the accuracy
`However
`the authors editors and publisher
`from application
`or for any consequences
`and make no warranty expressed or implied with
`of the publication
`of
`the contents
`responsibility of the practitioner
`
`situation remains
`particular
`The authors editors
`
`the professional
`and publisher
`
`have
`
`exerted
`
`every effort
`
`and dosage
`
`set
`
`forth in this text are in accordance
`
`with
`
`current
`
`tice
`
`at
`
`the time of publication
`
`However
`
`in view of ongoing research
`
`changes
`
`ment
`
`regulations
`
`and the constant
`
`flow of information
`
`relating to drug therapy
`
`to ensure that drug selection
`recommen-dations
`and prac
`in govern
`and drug
`
`reactions
`
`the reader
`
`indications
`
`in
`
`agent
`
`is
`
`in this publication
`
`employed drug
`have Fond
`
`and Drug
`
`is urged to check
`for each drug for any change
`the package insert
`and for added warnings
`and precautions
`This is particularly
`and dosage
`impor
`tant when the recommended
`new or infrequently
`Some drugs and medical
`devices presented
`FDA clearance
`care provider
`
`Administration
`
`for limited use
`
`responsibility of
`
`the health
`
`in restricted research
`the
`settings It
`the FDA status of each drug or device
`
`is
`
`to ascertain
`
`planned for use
`
`in their clinical
`
`practice
`
`10
`
`WC_LP0405963
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`

`
`Dedication
`
`This book
`and
`to our children one son seven
`daughters
`grandchildren As Sherlock Holmes said You know my methods use them
`
`is dedicated
`
`three
`
`WC_LP0405964
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`

`
`Contents
`
`Preface
`
`Contraception
`
`in the U.S.A
`
`Oral Contaception
`
`Special Uses of Oral Contraception
`
`Emergency Contraception
`
`The Progestin-Only Minipill
`
`Vaginal and Transdermal
`
`Estrogen-Progestin
`
`Contraception
`
`Implant Contraception
`
`Injectable Contraception
`
`Intrauterine Contraception The IUD
`
`Barrier Methods of Contraception
`
`Periodic Abstinence
`
`10 The Postpartum Period
`Breastfeeding and Contraception
`
`11 Clinical Guidelines
`
`for Contraception
`at Different Ages Early and Late
`
`12
`
`Sterilization
`
`13
`
`Induced Abortion
`
`14
`
`Interpreting Epidemiologic
`
`Reports
`
`Epilogue
`
`Index
`
`ix
`
`21
`
`139
`
`153
`
`165
`
`201
`
`221
`
`259
`
`293
`
`305
`
`329
`
`359
`
`387
`
`417
`
`423
`
`425
`
`ix
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`

`
`Oral
`
`Contraception
`
`ontraception
`
`development
`
`viewed
`is commonly
`in human history On the
`contrary
`reproduction predate our bilirv to write about
`
`as
`
`modern event
`
`recent
`
`efforts
`
`to limit
`
`is only contra
`
`it It
`
`ception with synthetic
`
`sex stejoids
`
`that
`
`is recert
`
`History1-4
`
`It wasnt until
`
`the early 1900s
`
`that
`
`inhibition
`
`of ovulation was observed to
`
`physiology at
`to demonstrate
`
`he
`
`linked
`
`to pregnancy
`proessor of
`
`and the
`
`corpus
`the University of
`
`luteum
`
`Ludwig Haberiandt
`
`Innsbruck
`
`Austria
`
`was
`
`the
`
`first
`
`that ovarian
`
`extracts
`
`given orally could
`
`prevent
`
`fertil
`
`iry in mice In the 1920s Haberlandt
`Otfried Otto Feliner were
`
`administering
`
`and
`
`Viennese
`
`gynecologist
`
`steroid
`
`extracts
`
`to
`
`variety
`
`of
`
`animals and
`
`repoiting
`
`the inhibition
`
`of fertility By 1931 Haberlandt
`was
`of hormones for birth control An extract
`
`ready to be used but Haherlandrs
`
`early
`
`an end to ibis effort Feilner disappeared
`
`the administration
`
`after
`
`proposing
`was produced named Infecundin
`at age 47 brought
`death in 1932
`the annexation
`of Austria to Hitlers Germany
`
`The concept was annunciated
`ready The extraction
`
`arid isolation
`
`of
`
`by Haherlandr
`
`but steroid chemistry wasnt
`Few milligrams of
`
`the sex stetoids
`
`or urine or
`
`thousands
`
`of
`
`in gallons
`required starting
`points
`organs Edward Doisy ptocessed
`pounds of
`12 mg of estradiol
`
`measured
`
`80000
`
`sow ovaries
`
`to produce
`
`21
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`
`Clinical Guide for Contraception
`
`Russell Marker
`
`The supply problem was solved
`who completed
`his thesis but
`born in 1902 near Hagerstown Maryland
`organic chemistry and his masters
`chemistry from the
`degree in colloidal
`thr University of Maryland Marker
`University of Maryland After
`leaving
`with the Ethyl Gasoline Corporation and in 1926
`of octane rating based
`
`Marker
`by an eccentric
`Russell
`chemist
`his course work for his Ph.D Markci
`
`riot
`
`received
`
`his bachelors
`
`degree in
`
`developed
`
`the
`
`on
`
`the discovery
`
`that knocking
`number of carbons
`
`in gasoline
`
`with an uneven
`
`worked
`
`process
`was due to hydrocarbons
`
`abundant
`
`and cheap amounts
`his work in optical
`
`From 1927
`
`no 1935 Marker worked
`
`at
`
`the Rockefeller
`
`and optical
`
`rotation
`
`Institute
`
`publishing
`as method of identi
`
`total of 32 papers on configuration
`He hu-amne
`
`lying compounds
`
`interested
`
`in solving
`
`the problem of producing
`
`of
`
`progesterone
`
`but he wa.s
`
`told to continue with
`
`to Pennsylvania
`technoloy
`reduced salary but with the freedom to pursue any field
`2500
`time the ovaries
`pigs were
`required
`the method called
`
`In
`
`1935
`
`he moved
`
`from
`
`pregnant
`
`En 1939 Marker
`
`devised
`
`State
`
`of
`
`to
`
`the
`
`University
`
`at
`
`research At that
`
`produce
`
`mg of
`progesterone
`Marker degradation
`
`to convert
`
`sapogenin molecule into
`
`progestin Marker
`
`became
`
`convinced
`
`that
`
`the solution
`
`to the problem of obtaining large quanti
`
`ties of steroid hormones
`
`was to find plants
`
`liii
`
`the family
`
`ihat
`
`includes
`
`the lily
`
`amounts
`
`with his discovery
`production This conviction
`was strengthened
`of Trillium known locally as Bedis root was collected
`used in th preparation
`relieve menstrual
`
`of Lydia Pinkhams
`
`Compound popular -at
`in Beths root was diosgerrin
`
`the time to
`
`the agave
`
`steroid
`
`and the yam that contained sufficient
`that could be used as
`
`sapogenin
`
`starting point
`
`of diosgenin
`thr steroid hormone
`
`plant
`
`that
`
`species
`
`in North Carolina and
`
`troubles
`
`principal
`
`ingredient
`
`but
`
`the rhizome was
`
`too small
`
`to provide
`
`sufficient
`
`amounts
`
`for commercial
`
`production Markers
`
`search
`
`for an appropriate
`
`plant
`
`took him to California
`
`Arizona and Trxas
`
`On
`
`visit
`
`to Texas
`
`dioscorea Dioscorea ncxicala in
`
`found
`
`of
`
`large
`
`University Marker
`picture
`book that he just happened
`no pick up
`the home of
`
`and browse
`
`through while spending
`
`the night at
`
`retired
`
`botanist After
`
`returning to Pennsylvania
`
`he decided
`
`to go
`
`Mexico
`
`it rook
`
`day-s by train to search
`
`for
`
`this dioscorea
`
`to VŁracruz
`He made
`
`several attempts in 1941
`
`plant-collecting
`
`tubers
`
`like
`
`and early 1942 but was
`from the Mexician
`of
`permit
`failure to find the plant He remembered that
`this dioscorea was known
`reported that
`locally
`that grew near Onizaba arid cordoba Marker
`and near Onizaha
`an Indian who ovned
`small store
`plants Each tuber v-as 912 inches
`high and
`turnip used by local Mexk am as
`
`frustrated
`
`first by the lack
`and then by his
`government
`the book with the picture
`
`as cabeza
`
`took
`
`consisted
`
`de negro black
`bus to Gordoba
`
`brought
`
`him two
`
`of white material
`
`poison to catch fish
`
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`

`
`Oral Contraception
`
`University
`
`maceutical
`
`collected
`
`arrested
`
`tubers
`
`ba
`
`to Pennsylvania
`
`State
`
`to obtain
`
`from the phar
`
`and
`
`he returned
`
`srup
`the
`
`their yarns
`
`Marker managed
`bag of
`one
`to gel
`and isolated dxosgenin Unable
`support
`industry Marker
`used his life savings
`in 1942
`the roots of the Mexican yam and prepared
`to Vecacruz
`from the roots Marker paid Mesican medical
`students to collect
`when farmers reported that
`yams The students were
`being stolen but not before Market hd enough
`to prepare
`syrup
`Back in Pennsylvania
`ith his 5-gallon cans of syrup Marker worked out
`One 5-gallon can yielded
`the degradation
`of diosgenin to progesterone
`kg of progetcrone United
`reRiscd
`and even
`to back Marker
`
`States
`
`pharmaceutical
`companies
`the University refused despite Markers urging
`
`still
`
`to patent
`
`the
`
`process
`
`In 1943 Marker
`
`resigned
`
`Mexico where
`
`he collected
`
`looking
`
`through
`
`the
`
`Markci
`
`found
`
`from Pennsylvania
`
`to
`
`State University and went
`10 tons worth
`the roola of Dio5cwea
`
`mexzcana
`
`directory
`
`lawyer
`
`ing and
`
`the three agreed to forrri
`
`in Mexico City relephone
`yellow
`pages
`called Laborarorios Hormona owned by
`company
`physician Frederick Lehman Marker
`Erneric Sonilo and
`arranged meet
`to produce hormones
`Mexican
`company
`of Laboratorios
`in Mexico City the laboratories
`in an old pottery shed
`in months he prepared several pounds of
`Hormonal
`progesterone worth
`300000i with the help of four young women who had
`little education
`and
`two rm11 arid
`The
`did riot
`no F.nglish Marker
`speak Spanish
`spoke
`Marker
`formed
`in 1944
`they called Snrex from synthesis
`company
`and Mcxico In 1944 Marker produced
`The
`fll from $200 to $50
`price of progesterone
`
`that
`
`over 30 kg of
`
`progesterone
`
`gram
`
`During tIlts time Marker
`expenses
`the 40% share otstock due
`
`of the profits or
`
`received
`
`but he was not given his share
`to him Failing
`and started
`
`to reaLh
`
`settle-
`
`in
`
`rnenr Marker
`
`year
`
`Texcoco
`
`called Botanica--Mex
`
`to Dioscorea
`
`new company
`barbasco hich gave
`to $10
`dropped
`
`progesterone
`
`lefi Synrex after only
`He changed
`the price of
`yield of diosgenin and
`to $5 This
`
`greater
`gram and
`1w Svntex
`
`later
`
`callyi
`
`comiiaiiy was allegedly harassed
`and in 1946 was sold eventually
`coming under
`
`legally
`
`arid physi
`
`the ownership
`
`of Orgarion of Holland
`
`which still uses
`
`it
`
`in 1949 Marker
`
`retired to Pennsylvania
`
`to devote the nat of his life to making
`that allowed him in the
`
`replicas of antique works in silverasticcessl business
`980s to endow scientific
`
`lectureships
`
`at both Pennsylvania
`State University
`his know-how with him
`
`and
`
`the Unicersity
`
`of Maryland Howe\er
`
`he took
`
`oi-tunately
`
`for Syntex
`
`he had published
`
`scientific
`
`description
`
`and
`
`there
`
`still was
`
`no
`
`patent
`
`on his discoveries
`
`Rosenkranz
`
`flungarian immigrant
`
`of his process
`reci-uited George
`Syntex
`living ill Cuba to reinstitute tile commer
`
`cial manufacture
`
`of progesterone
`and testosterone
`took him with the help of the women left behind b- Marker
`
`from Mexican
`
`that
`
`yams
`
`task
`
`years
`
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`

`
`Clinical Guide for Contraception
`
`In 1970
`
`the Mexican
`
`government
`
`honored Marker and warded him the
`
`Order of
`
`the Aztec
`
`University established
`
`the Russell
`
`he declined
`
`In
`
`1984
`
`Eagle
`the annual Marker Lectures
`
`Pennsylvania
`
`State
`
`of Natural
`
`Product
`
`an honorary
`
`doctorate in science
`
`to receive
`
`in 1926
`
`in Science and in 1987
`and Mildred Marker Professorship
`Chemistry In 1987 Marker was granted
`from the University of Maryland
`the degrce he Failed
`the age of 92 Russell Earl Marker died in Wernersville Pennsylvania
`At
`in 1995
`from complications after
`broken hip
`
`Car Djerassi5
`
`The Djerassi
`
`family lived in Bulgaria for hundreds
`
`of years after escaping
`
`Spain during the Inquisition Carl Djerassi
`Bulgarian physi
`cian was born in Vienna as was his physician mother Djerassi at the age
`of 16 and his mother emigrated
`in 1939
`to the United
`Jewish
`family in Newark New
`refugee aid organization placed Djerassi
`Jersey With
`to middle America where
`
`scholarship
`
`to Tarkio College in Tarkio Missouri
`
`he was
`
`exposed
`
`he earned his way giving talks to church
`
`the son of
`
`States
`
`with
`
`groups
`
`by another
`
`furrher
`
`supported
`
`he pursued
`
`was
`about Bulgaria and Europe His education
`scholarship from Kenyon College in Ohio where
`for CiBA Djerassi
`chemistry After
`year working
`degree from the University of Wisconsin
`somewhat
`he
`to an
`
`unhappy
`
`responded
`
`Returning
`
`invitation
`
`received
`
`his graduate
`to CIBA and being
`isit Syrmtex
`
`to
`
`Rosenkranz
`
`proposed
`
`that Djerassi
`
`head
`
`research
`
`group
`
`to concentrate
`
`on the synthesis
`
`of cortisone
`
`it was discovered
`
`that cortisone relieved
`
`arthritis
`
`In 1949
`an easy and cheap method to synthesize
`on to develop
`at age 26 joined Syntex
`to work on
`Djerassi
`Mexican yam plant
`diosgenin as
`quickly achieved in 1951 but soon
`sone
`
`and the race was
`
`cot
`
`tisone
`
`Carl
`
`this synthesis
`
`using the
`
`steroid
`
`after
`
`the
`
`starting
`
`point
`an even better method of corti
`
`Ihis was
`
`was
`
`discovered
`
`at
`
`fermentation
`
`using ni icrobiologic
`production
`Upjohn This latter method used progesterone
`found
`therefore Syrirex
`
`point and
`to other companies
`process at the rate of 10 tons of progesterone
`per year and
`this important
`of 48 cents per grain
`
`itself as the
`
`key supplier
`
`for
`
`as the starting
`
`price
`
`Dierassi
`
`and other Syntex
`
`chemists
`
`then turned their attention
`
`to the sex
`
`steroids
`
`They
`
`discovered
`
`that
`
`the removal
`
`of
`
`the 19-carbon
`
`from yam-
`
`derived progesterone
`Ethisterone had been
`
`reasoned that
`
`available
`
`for
`
`dozen
`
`increased the progestational
`activity
`years and the Syntex chemists
`removal of the 19-carbon would increase
`
`of the molecule
`
`the progesmational
`
`potency
`
`of
`
`this orally active
`
`compound
`
`In
`
`1951
`
`norethindrone
`
`was
`
`synthesized the
`for this drug is the first patent
`patent
`Inventors Hall of Fame in Akron Ohio
`
`the National
`
`for
`
`drug listed in
`
`closely
`
`related
`
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`
`Oral Contraception
`
`compound
`
`norethvnodrel
`
`tional
`agent
`G.D SearJe
`
`to receive
`
`Company
`
`the first orally active
`ss as actually
`assigned to Frank Cokon
`
`patent
`
`progesta
`
`chemist
`
`at
`
`Djerassi
`
`University
`
`eventually
`and is now
`
`left
`
`Syntex
`
`to
`
`become
`
`professor
`
`at Stanford
`
`playwright
`
`and novelist
`
`living in San Francisco
`
`Gregory Pincus
`Gregoiy Goodwin Goody lincus was born in 903 in New Jersey the son
`of Rusian Jewish immigrants who lived on
`founded
`farm colony
`philanthropic organization Pincus was
`home of iniellectuat
`and energy hut even his
`
`German-Jewish
`
`dren and grew up in
`regarded him as
`
`family
`
`genius
`
`curiosity
`
`by
`
`the oldest
`
`of
`
`chil
`
`Pincus
`
`to Harvard
`
`to study generics
`
`from Gornell and went
`graduated
`joining Hudson Hoagland and
`
`Skinner
`
`as graduate
`in 1927 Croziers
`in physiology
`degrees
`Loch who discovered artificial parthenogenesis
`Loch was
`eggs Most
`importantly
`human life Thus Crozier
`science to improve
`
`Croziei-
`
`Jacques
`
`urchin
`
`receiving
`
`Pincus
`
`Hoagland
`
`and Skinner
`
`iespectively
`
`neurophysiology
`
`This was
`
`students of
`
`hero was
`
`working with sea
`
`in applying
`strong believer
`influenced by Loch taught
`
`and psychology
`to be the cornerstone
`
`in reproductive
`biologv
`to human problems
`to apply science
`of Pincuss own philosophy
`
`Hoagiarid
`
`after
`
`short
`
`stay
`
`at Harvard
`
`spent
`
`in Cambridge
`
`England
`
`and
`
`then
`
`moved
`
`Massachusetts
`
`England
`
`year
`to Clark University
`in Worcester
`age of3l Pincus went
`to be the chair
`of biology at the
`to
`and Germany and returned to Harvard as an assistant professor
`of physiology
`
`Pincus performed
`
`oocyres
`
`in both rabbit
`
`In 1934
`
`of meiotic maturation in mammalian
`pioneering studies
`and human oocytes
`Pincus reported the
`eggs earning him headline
`achievement
`of in vitro fertilization of rabbit
`in the ATew York Times that alluded to Haldane and Huxley An article in
`By 93 Harvard
`him as an evil scientist
`Goiier
`had
`outstanding scientific
`denied him tenure in 1937
`
`depicted
`Pincuss work as one of the universitys
`
`of all time but Harvard
`
`cited
`
`achievements
`
`At Clark University Hudson
`
`Hoagland
`
`was
`
`in constant
`
`conflict with the
`
`president
`
`of the university
`
`\Vallace
`
`Atwood
`
`the senior author of widely
`
`used
`
`textbook
`
`of one
`
`on geography
`faculty member
`
`Fioagland
`
`Floagiand
`
`upset
`
`to his friend
`suspecring
`Pincus to join him 1loagland
`
`that
`
`In 1931 the Department of Biology consisted
`student and their chair Hudson
`and his graduate
`and angry over Harvards
`this wa because
`of anti-Semitism
`
`ieftssal
`
`to grant
`
`tenure
`
`invited
`
`secured funds for Pincus from philanthropists
`
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`Clinical Guide for Contraception
`
`in New York City enough
`impressed the two men especially
`be possible
`research with private money
`
`for
`
`laboratory
`
`and an assistant This success
`
`Hoagland planting
`
`the idea that
`
`it would
`
`to support
`
`Min-Chueh
`
`Chang
`
`received
`
`his Ph.D from Harvard on an infamous
`and thus he was forced to remain in this coun
`day December
`1941
`try He was drawn to Pincus
`book The Eggs of
`Mammals
`on biol
`that had major impact
`published in 1936
`of M-C Chang by
`time The
`successful
`recruitment
`ogists
`Hoagland and Pincus was to pay great dividends
`
`because
`
`of Pincuss
`
`book
`
`at
`
`that
`
`Soon Hoagland had put
`because
`of his on-going
`was denied
`
`faculty
`
`supported
`
`totally
`
`were
`
`but
`of outstanding
`together
`group
`antagonism with President Atwood the group
`barn they were
`converted
`status Working
`by private funds By 1943 12 of Clarks 60 faculty
`of Biology
`in the Department
`
`scientists
`
`in
`
`Frustrated by the politics of academia Hoagland and Pincus who both
`of convention had
`vision of
`stepping outside
`
`enjoyed
`
`private
`
`research center devoted
`
`to their philosophy
`
`of applied science
`
`Indeed
`
`the establishment
`
`of
`
`the Worcester
`
`Foundation for Experimental
`
`their
`
`be attributed directly
`
`their spirit
`
`that
`
`to Hoagland and Pincus
`in 1944 can
`Biology
`enthusiasm ambi
`friendship for each other and their confidence
`of
`tion and drive
`turned many members
`It was
`science
`of biologic
`to do They
`
`Worcester
`
`society
`
`into financial
`
`Hoagland
`
`and Pincus
`
`accomplished
`
`supporters
`what
`
`they set out
`
`created
`
`and
`
`which it was
`
`sustained
`vibrant
`pleasure to work
`
`productive
`
`scientific
`
`institution
`
`in
`
`Foundation for Experimental
`1945
`in the summer of
`across
`in Shrewsbury The board
`on an estate
`
`Biology
`Lake
`
`of
`
`laureates
`
`Quinsigamond
`was chaired by Harlow Shapley
`astronomer
`distinguished
`three Nobel
`vice-chaired by Rabbi Levi Olan and included
`and
`businessmen
`
`Although named
`the Foundation was
`
`the Worcester
`
`located
`
`in
`
`house
`
`trustees
`
`group of Worcester
`
`from 12 to
`in 1967 the staff
`From 1945 to the death of Pincus
`and support people 36 of whom were independently
`350 scientists
`fellows The annual
`funded and 45 were postdoctoral
`budget grew from
`$100000 to $4.5 million One hundred acres of
`land were
`and the campus
`grew to 11 buildings
`3000 scientific
`
`acquired
`
`approximately
`
`adjoining
`
`In its first
`
`25 years
`
`papers were published
`
`grew
`
`But in those early years Pincu was the animal keeper Mrs Hoagland
`the bookkeeper M-C Chang was the night watchman and Hoagland
`
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`
`Oral contraception
`
`ears
`
`of Wrld Wr II
`in hormones and
`
`Pincus
`
`arid
`
`neurophysiology
`
`to
`
`interests
`
`in indusuv
`
`and the military
`
`the lawn During the
`Hoagland combined their
`focus on siress and fatigue
`
`mowed
`
`discoveries
`
`that
`
`led to an oral contracepth.e
`
`can bc attributed
`
`to
`
`to describe
`
`The initial
`M-C Chang also rise first
`of sperm
`the capacitarion
`process
`the work of Makepeace
`in l937 demonstrating
`In 1951
`inhibit ovulation in rabbits When norethindrone
`
`he confirmed
`
`that progesterone
`and norethvnodre
`
`could
`
`became
`
`100% effective
`
`in inhibiting
`
`aviiiable
`
`them to be virtually
`harig found
`ovulation when administered orally to rabbits
`
`Katherine Dexter Mcorrnick
`
`1904
`
`founder
`
`woman
`
`socially
`
`18751 96 was
`very rich woman in
`she married Stanley McCormick the son of Gyrus McCormick the
`of
`Harvester
`the second
`She was
`
`international
`
`also
`
`intelligent
`
`to graduate
`and
`
`conscious
`
`from the Massachusetts
`
`Institute
`
`of Technology
`
`generous
`husband suffered
`from schi7ophrenia
`
`contributor
`
`to family planning efforts
`and she established
`
`McCormicks
`
`the Neuroendocrine
`
`nia This brought
`being done by Ghang
`
`he
`
`Research
`Foundation
`at Harvard
`to study schizophre
`together with Hoagland who wld her of the work
`and Pincus
`
`Pincus
`
`attributed
`
`his interest
`
`tion
`
`for
`
`the worlds
`
`to his growing
`in contraception
`and
`
`1951
`
`to
`
`apprecia
`
`visit with
`
`population
`
`problem
`
`time president of
`Margaret
`Sanger
`Federation of America Ar
`
`that
`
`visit
`
`Sanger
`
`at
`
`that
`
`method of contraception
`being done by Piricus and Chang
`
`could
`
`be derived from
`
`the Planned
`
`Parenthood
`
`hope
`expressed
`the laboratory work
`
`that
`
`In 1952 Margaret
`
`Sanger brought
`
`Pincus
`
`and Katherine McGormick
`
`together During this meeting Pincus
`from his mammalian
`
`iesearch I-Ic envisioned
`
`formulated
`
`his
`
`thoughts
`
`derived
`
`progestational
`
`agent
`
`in
`
`pill
`
`Sanger
`
`research
`
`research
`
`form as
`acting like progesterone
`conrraeeptive
`and MeCotmick piovided
`By the rime of her death VlcGormick
`
`in pregnancy
`further animal
`
`fbr
`
`grant
`had contributed more
`
`than
`
`left
`
`another
`
`$1
`
`$2 million to the orcester Foundation and
`The ContoI of Ferti1itj
`million in her will
`In his hook
`published in
`1965 Pincus wrote This book is dedicated
`to Mrs Stanley McCormick
`inquiry and her unswerving
`
`because
`
`of her steadfast
`
`faith in scientific
`
`encourage merit of hunsan
`
`dignity
`
`he
`
`colleagues
`
`pursued
`
`Using
`
`oocytes
`
`interest
`
`and
`
`his
`
`WC_LP0405972
`
`It was Pincus who made the decision to involve
`knew human expe meats would be
`necessary
`cology and obtetrics at Harvard met Piicus at
`in reproductive physiology Rock
`discovered
`their mutual
`Pincuss work
`from oophorectoinies
`
`physician because
`John Rock chief of gyne
`conference
`
`scientific
`
`arid
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`
`Clinical Guide for contraception
`
`in 1944
`
`the first
`
`demonstration
`
`of
`
`they reported in vitro fertilization
`of human
`
`fprtilizatioii
`
`oocytes
`with progesrationa agents not
`female sex steroids
`could
`hoped the
`
`in vitro Rock was
`
`for contraception
`
`interested
`
`in the work
`
`however but because
`
`he
`
`be used
`
`to overcome
`
`infertility
`
`Sanger and McCormick
`
`needed
`
`that Rocks Catholicism
`
`some convincing
`they were eventually won over because of his
`handicap hut
`physician who literally transformed his persona
`to uncontrolled
`in response to his recognition of the problems
`secondary
`reproduction With the help of Luigi Man roianni
`to women was
`of synthetic
`to Rocks
`to receive 1040 mg of synthetic
`progcstin
`for 20 days each month all
`the animal data
`
`would not he
`
`stature Rock was
`
`progestins
`
`first
`
`50 patients
`
`olated
`
`From
`
`values
`
`the first admini.rration
`
`patients
`
`in 1954 Of the
`
`dose etrap
`
`failed to ovulate
`
`during treatment causing
`to begin
`referring
`the pill and
`after discontinuing the mtdica
`of the 50 became pregnant
`tion pleasing Rock who all along was motivated
`
`Pincus
`
`to the medication
`
`as
`
`to treat
`
`infert1ity
`
`Pincus and Chang decided
`
`to announce
`
`their
`
`findings
`
`at
`
`the International
`
`Planned Parenthood meeting
`
`in Tokyo
`
`in the fall of 1955
`
`Rock
`
`refused
`
`to
`
`iOin ill
`
`this efRlrt
`
`believing
`
`Despite
`
`was done
`
`this disagreement
`and the Tok
`
`In
`
`which
`
`that Pincus and Chang were moving too
`apparently was sprited and strong it
`presentation generated worldwide
`
`fast
`
`pubiicitw
`
`working
`
`in
`
`initial
`
`Puerto Rico the
`
`products
`
`were
`
`cojitarninated
`
`progestin
`
`the amounts
`
`Iii
`
`sufficient
`
`amount
`
`jag
`
`of
`
`efforts
`
`and Edris Rice-Wray
`1956 with Celso-Ramon Garcia
`first human trial was performed The
`with about
`10/o mestrlnol
`up to 50500
`being used this added
`of mestranol
`estrogen to inhibit o7uiation by itselE When
`content
`pure progestin lowered
`
`to provide more
`and yielded breakthrough
`thus estab
`bleeding it was decided to retain the csrrogen for cclc control
`combined
`
`the
`
`estrogen
`
`lishing
`
`the principle
`
`of
`
`the
`
`estrogen-progesrin
`
`oral
`
`contraceptive Early clinical
`
`trials
`
`were
`
`conducted
`
`by
`
`Goldzieher
`
`in
`
`San Antonio
`
`and
`
`Tyler in Los Angeles
`
`Pincus
`
`longi-ime
`
`consultant
`
`to Searle picked
`
`the Searle
`
`compound
`
`for
`
`extended
`
`use and with
`
`great effort
`
`convinced
`
`Searie
`
`that
`
`the commercial
`
`potential
`
`of an oral
`
`contraceptive
`
`warranted
`
`the
`
`risk of possible
`
`negative
`
`PinLus also convinced Rock
`
`and
`
`the
`
`In
`
`they pushed
`public reaction
`together
`U.S Food and Drug Administration for acceptance of oral contraception
`and mensrrua
`1957 Enovid was approved
`for the treatment of miscarriages
`and in 960
`disorders
`for contraception Neither Pincus nor the Worcester
`got rich on the pill alas
`
`Foundation
`
`there was no royalty agreement
`
`The
`ira-d There is no doubt
`and
`pill did bring Pincus fame
`very much aware of the accompltshment
`
`and its implications
`
`that he was
`
`As he tray-
`
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`
`Oral Contraception
`
`eled and lectured
`
`in 1957
`
`he said How fey precious facts obscurely
`into the lives uf men everywhere
`come to in the laboratory
`may resonate
`bring order to disorder hone to the hopeiess
`life to die dying TI hat this is
`the magk and mystery of our time is sometimes
`hut
`is inevitable
`
`to expound it
`
`grasped and often missed
`
`Pincus
`
`world at
`
`the perfect
`time when
`
`person to bring oral contraception into the public
`
`contraception
`
`aas
`
`private
`
`suppressed
`
`subject
`
`Difficult
`
`projects
`
`require
`
`could plow through
`staff He could
`
`remain
`
`distractions
`
`fbcuced
`
`people like Pincus
`entrepreneur
`Ne could be hard and aggressive with his
`He hated to lose
`
`scientific
`
`he
`
`even
`
`in meaningless
`
`gracious charming manner
`
`games with
`
`his children Yet he combined
`He was
`
`with his competitive hardness
`
`filled with the kind of self-confi
`
`dence
`
`that permits an individual
`to fadge
`realits Pincus died in 1967 as did Katherine Mccormick
`
`ahead
`
`to translate
`
`vision
`
`into
`
`at the
`
`age
`
`of 92
`
`of aplastic
`
`anemia
`
`that
`
`some have
`
`exposute
`
`to solvents
`
`and chemicals
`
`argued was
`Rock died in 1984
`
`caused
`
`by his
`
`at
`
`long-term
`of 94
`
`Chang died in 1991
`his laboratory and close
`
`at
`
`the age
`
`to the grave
`
`of Pincus
`
`the age
`o(cid:238) 82 and was buried in Shrewshury
`
`near
`
`The contioi ofFerri1yr in 196465 only because
`Pincus wrote
`his book
`break came in the apparent dam to publication on reproductive ph si
`ology and
`its subdivisions
`concerned
`ith reproductive
`behavior
`
`conception
`
`and contraception.6
`
`particularly
`
`We have
`world seen at
`
`cordurred and
`
`lectured
`
`in man1
`
`countiies of
`
`the
`
`first hand the
`
`research
`
`needs
`
`ii almost
`
`every
`American country
`laiion
`in country
`
`European
`
`Asiatic
`
`Gentral
`
`antI South
`
`and possibilities
`
`have
`
`faced
`
`after
`
`country
`
`the hard fact of overpopu
`the bleak
`
`learned
`
`of
`
`demographic
`
`Atture assessed
`
`ihe prospects
`
`for the practice
`
`efficient
`
`fertility
`
`control
`
`This has been
`
`saddening
`
`and
`
`heartening experience
`and
`
`continuing
`
`poverty
`
`saddening
`misery heartening because
`arid workers
`to overconie
`
`because
`
`of
`
`the
`
`sight
`
`of
`
`seeking
`
`of
`
`of
`
`the
`
`the
`
`dedkated
`
`colleagues
`
`handicap
`
`of cxccss
`
`fertility
`
`and
`
`tive Rmnction Among
`found
`devoted
`students
`
`friends
`
`to promote healthy reproduc
`have made many
`these we
`
`Syntex
`
`wholesale
`
`was without marketing
`
`organization
`
`sales outlet Searle marketed Enovid
`
`experience
`with Ortho for
`
`or
`
`drug supplier
`By the time Syntex had secured
`arrangements
`in 1960 150 pg mestranol and 9.85
`from Snrex
`using noreihindrone
`
`Ortho-NovunL
`
`mg norerhynodrel
`irs 1962 Wyeth Laboratories introduced nolgestrel
`
`appeared
`
`in 1968
`
`the
`
`same year
`
`in which
`
`the
`
`first
`
`reliabe
`
`prospective
`
`studies
`
`were
`
`initiated
`
`Jr
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`
`the amount of steroids
`and pamt over
`bewildering array of different
`this clinical dilemma is
`
`between
`
`As
`
`prob
`
`result
`
`ill
`
`the
`
`pitl was appreciated
`
`the years
`
`have
`
`bcen
`
`confronted
`
`and
`
`foinulations The solution
`
`by
`
`to
`
`products
`
`Clinical Guide for Contraception
`
`was not until
`
`the late
`
`9Os that
`
`dose-response
`
`relationship
`
`lems and
`
`health care providers
`
`the theme of this chapter
`the lowest doses that provide effective contraception
`
`straightforward
`
`relatively
`
`use
`
`Pharmacology of Steroid Contraception
`
`The Estrogen Component of Combination Oral contraceptives
`
`is the most potent natural
`estrogen
`The major obsiacle
`of the compounds
`
`Estradiol
`
`secreted
`
`by the ovarie
`
`ontraception was inactivity
`
`breakthrough
`
`occurred
`
`in
`
`and is the major estrogen
`to the use of sex steroids
`when given orally
`938 when it was discovered
`the addition
`
`for
`
`major
`
`that
`
`the
`
`of an ethinyl
`
`is
`
`estradiol
`
`gerl used
`
`ether of ethinyl
`
`17 position made estradiol
`orally active Erhinyl
`group at
`very potent oral estrogen and is one of the two forms of estro
`is the 3meth1
`The other
`in every oral contraceptive
`estradiol mcttanol
`
`csttogen
`
`OH
`
`OH
`
`CH
`
`CH
`
`Ethinyl estradiol
`
`Mestranol
`
`Mestranol
`
`and ethinyl
`
`estradiol
`
`are different
`
`from
`
`natural
`
`estradiol
`
`and
`
`must be regarded
`
`as pharrnacologk
`
`that mestranol
`
`is weaker
`
`than ethinyl
`
`drugs Animal studies
`because mestranol must first
`
`have
`
`suggested
`
`estradiol
`
`be converted
`
`to ethim estradiol
`
`in the body Indeed inestrariol does not
`
`bind to the
`
`cellular
`
`estrogen
`
`receptor Therefore
`
`unconjugated
`
`ethinyl
`
`estradiol
`
`is
`
`the acti\
`
`arid ethinyl
`
`estradiol
`
`indicated
`
`in potency
`
`between
`
`ethinyl
`
`estra
`
`certainly
`
`as
`
`all of the
`
`estrogen in the blood for both mnestranol
`In the human body differences
`diol and mestranol do nor appear
`to be significant
`not as great
`in rodents This is now minor point because
`by assays
`contain ethinl
`
`low-dose
`
`olal contraceptives
`
`estradiol
`
`WC_LP0405975
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2004, Pg. 18
`
`

`
`The metabolism of ethinyl esnadiol particularl
`from individual
`
`to individual
`
`varies significantly
`
`Oral Contraception
`
`as reflected in blood levels
`
`and from one population
`of variability at different
`
`to another
`
`within the
`
`is even
`
`rangL
`same indi\idual Therefore
`
`it
`
`dose
`
`can cause
`
`side effects in one indiidual
`
`sampling
`
`times
`
`is not surprising
`and not
`
`in anothet
`
`that
`
`rhc
`
`same
`
`is of major clinical
`
`importance
`
`The estrogen Loment dosage of the pill
`Thrombosis
`
`role in the increased
`
`ety of circulatory
`
`is related to estrogen
`
`of rhe pill playing
`is one oft-he most sesious
`key
`risk of death in the past with high doses horn vari
`and it is
`problems This side effect
`
`side effect.s
`
`dose
`
`related therefore the dose of estrogen is
`
`critical
`
`issue
`
`in selecting
`
`an
`
`oral contraceptive
`
`The Progestin Cornponenl
`
`of Combination Oral Contraceptives
`
`The discovery of ethirtyl eubstirurioii
`
`and oral
`
`otency
`
`led at the end of
`
`th