ADVANCES IN REPRODUCTIVE ENDOCRINOLOGY

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ADVANCES IN REPRODUCTIVE ENDOCRINOLOGY

• DR. CHRIS O. AIMAKHU (MBBS,FWACS,FMCOG)
• CONSULTANT OBSTETRICIAN AND
• GYNAECOLOGIST,
• CATHOLIC HOSPITAL, OLUYORO, IBADAN.

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REPRODUCTIVE ENDOCRINOLOGY

• ---Provides comprehensive care for a wide range
  of reproductive problems.
• ---Common problems evaluated and treated
  include-
• Infertility (primary and secondary)
• Pregnancy loss
• General female hormonal disorders
• Hirsutism (excessive hair growth)
• Menopausal symptoms
• Endometriosis

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REPRODUCTIVE ENDOCRINOLOGY

• Menstrual disorders/problems
• Osteoporosis
• Pelvic pain
• Polycystic Ovarian Syndrome (PCOS)
• Premenstrual Syndrome
• Uterine abnormalities
• Sexual dysfunction

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WHO IS A REPRODUCTIVE ENDOCRINOLOGIST?

• A reproductive endocrinologist is a sub
  specialist physician who has received training (a
  residency) in Obstetrics and Gynaecology, and
  advanced training (a fellowship) in the treatment
  of INFERTILITY, RECURRENT MISCARRIAGES and
  HORMONAL DISORDERS in women.

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WHAT TREATMENT DO REPRODUCTIVE ENDOCRINOLOGISTS
OFFER?

• Reproductive endocrinologist can perform a wide
  variety of treatments for infertility.
• A variety of fertility tests are run in order to
  determine the cause of infertility.
• Reproductive endocrinologists are trained in
  advanced procedures that can increase a couples
  chances of conceiving such as
• ---Infertility Surgeries,
• ---Procedures to reverse tubal ligation,
• ---Use of fertility drugs (e.g. Clomid,Pergonal,
  Follistim, Repronox) and
• ---Assisted Reproductive Techniques (ART).

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ADVANCES IN REPRODUCTIVE ENDOCRINOLOGY

• Assisted Reproductive Techniques (ART).
• Minimal invasive surgeries.
• Cloning.
• Embryonic stem cells.

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A) ASSISTED REPRODUCTIVE TECHNIQUES (ART)

• Any procedure where the gamete is manipulated or
  removed from the body and returned either as an
  oocyte or as an embryo.
• The aim is to approximate the eggs and sperms at
  the same time whether within or outside the body.

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A) ASSISTED REPRODUCTIVE TECHNIQUES (ART)(CONTD)

• Reproductive technologies have undergone a rapid
  evolution from simple procedures like the first
  insemination of fresh donor semen almost half a
  century ago to a position where we now have the
  ability to collect epididymal sperm for micro
  injection into oocytes freeze, thaw, and
  transfer donor gametes and embryos, create
  pregnancies in menopausal women, and in the near
  future may be able to harvest and store eggs from
  ovarian biopsies.

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INDICATIONS FOR ART

• ART is indicated for the management of
  infertility for which conventional care is
  INAPPROPRIATE or has FAILED.
• These include
• ---Tubal damage
• ---Oligospermia --- lt 20 million sperms/ml.
• ---Azoospermia
• ---Unexplained infertility

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INDICATIONS FOR ART(CONTD)

• Most recently, ART has made possible the
• Preimplantation diagnosis of genetic disease.
• Removal and subsequent chromosomal analysis of a
  single blastomere allows, prior to implantation,
  for the diagnosis of certain disorders e.g.
  Homozygous sickle cell disease and Duchene
  muscular dystrophy.
• It is appropriate that ART is increasingly
  attracting the attention of doctors ,nurses,
  scientists and the general public,but it must be
  realized that high-tech ART are only necessary
  when other simpler and cheaper measures have been
  tried without success.
• It is therefore necessary to fully
  investigate both the male and female partners and
  to take into account all available options.

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FACTS ABOUT INFERTILITY

• Accounts for 50 of cases in the gynaecological
  clinics in developing countries.
• Numbers of consultations have risen
  significantly.
• It affects 1 in 10 couples.

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DEFINITIONS IN INFERTILITY

• INFERTILITY Inability of a couple to achieve
  pregnancy (conception) after 12 months (1 year)
  of unprotected regular sexual intercourse
  (Involuntary failure to conceive).
• There are 2 types of Infertility
• PRIMARY INFERTILITY - No previous pregnancy.
• SECONDARY INFERTILITY- Previous pregnancy
  (irrespective of the outcome).

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DEFINITIONS IN INFERTILITY(CONTD)

• INFECUNDABILITY- Inability of a couple to achieve
  a live birth after 12 months of regular
  unprotected intercourse.
• VOLUNTARY INFERTILITY- has never tried for a
  pregnancy and has taken contraception to avoid
  pregnancy.
• FERCUNDITY- is the capacity to participate in the
  production of a child.
• FECUNDABILITY- is the likelihood of pregnancy per
  month of exposure.

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DEFINITIONS IN INFERTILITY(CONTD)

• STERILITY- An intrinsic inability to achieve
  pregnancy. (Total inability to get pregnant).
  (Infertility is Relative).
• CHILDLESSNESS- No child at the end of
  reproductive life.
• The chances of conception should be expressed
  in terms of fertility of the couple rather than
  the individual partner.
• Infertility is associated with emotional and
  social distress.
• The longer the couple have been trying to
  conceive without success, the greater the
  decline in conception rate.

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CONTRIBUTION OF THE PARTNERS TO INFERTILITY

• Male ---- 30 - 40
• Female ---- 30 - 40
• Both ---- 15
• Unexplained ---- 5 -10

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CHANCES OF PREGNANCY

• 60 of couples conceive ----- 6 months.
• 80-85 conceive ----- 1yr.
• 90 conceive ----2yrs
• 10-15 ----Infertile

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WHAT IS THE MAGNITUDE OF INFERTILITY IN NIGERIA

• It is estimated that 15-20 of couples are facing
  this problem at any given time.
• In Nigeria, this translates to 2 million couples
  (i.e. 4 million individuals) that are
  experiencing infertility at any given time.

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PROBLEMS OF INFERTILITY IN OUR ENVIROMENT

• Social Stigma.
• Marital instability and social neglect.
• Exploitation and economic deprivation of female
  partners.
• Emotional stress / frustration / strained
  relationships/ guilt feelings/ unhappiness and
  unfulfilled lives / Psychological consequences.
• Male ego.
• Divorce.

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FACTORS CONTRIBUTING TO THE INCREASED DEMAND OF
TREATMENT

• Increased numbers of women in the reproductive
  age group.
• A trend towards a later age of child bearing,
  with more years of exposure to infections or
  toxins as well as age- specific reduction in
  fertility.
• Greater public awareness of the availability and
  scope of such services.
• Availability of new technology and drugs for
  treatment of previously hopeless cases.

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COMMON CAUSES OF INFERTILITY IN OUR ENVIRONMENT

• Male Infertility ------Infections -----
  Gonococcal
• 
  ------Chlamydia
• Female Infertility -------Tubo Peritoneal
  factors
• (Bilateral
  blockage/pelvic-
• adhesions are
  the commonest)
• --------S T I
• --------Post
  abortal sepsis
• 
  --------Puerperal sepsis

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WHEN TO INVESTIGATE INFERTILE COUPLES

• When conception does not occur within 1 year of
  unprotected regular coitus.
• This period could be shortened in certain
  individuals.
• It is good to complete investigations within 1
  menstrual cycle at least the initial evaluation.

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PRINCIPLES OF MANAGEMENT

• Deal with the infertile couple together.
• No one is at fault or to blame
• Carry out investigations and treatment
  consistently in proper sequence.

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HISTORICAL DEVELOPMNTS OF ART

• 1970s -----Experiments in ovum
  retrieval IVF ET.
• 1978 -----1st IVF ET baby born at
• 
  Oldham,Manchester,U.K---- Steptoe and
• Edwards who were
  the IVF pioneers.
• (Louise Brown
  born on 25th July, 1978 and is
• presently
  expecting her first baby which was
• conceived by
  natural means).
• (The Worlds first
  Test tube baby).
• 1983 -----1st Successful human
  pregnancy following
• cryopreservation.
• 1984 ----- 1st live birth via GIFT.

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HISTORICAL DEVELOPMNTS OF ART(CONTD)

• 1984 ------ 1st live birth via GIFT.
• 1988 ------1st human pregnancy via PZD.
• ------1st pregnancy via SUZI.
• 1992 ----- 1st pregnancy and birth following
• ICSI.
• 1997 till date ----Experimentation and reports on
  mammalian and human cloning.
• 1997 till date ----Stem cell research.

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TYPES OF ASSISTED REPRODUCTIVE TECHNIQUES

• Many procedures and many acronyms which are
  rapidly changing.
• Variations of the same standard techniques.
• 1). Timed Intercourse (T.I.)
• 2). Intra-Uterine Insemination (IUI)
• 3). In - Vitro Fertilization and Embryo Transfer
  (IVF - ET)
• 4). Gamete Intra Fallopian Transfer (GIFT)
• 5). Zygote Intra Fallopian Transfer (ZIFT)
• 6).Subzonal Insemination (SUZI)

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TYPES OF ASSISTED REPRODUCTIVE TECHNIQUES(CONTD)

• 7). Intra Cytoplasmic Sperm Injection (ICSI)
• 8). Direct Oocyte Sperm Transfer (DOST)
• 9). Sperm Aspiration Techniques.
• TESA --- Testicular Sperm Aspiration
• PESA --- Percutaneous Sperm Aspiration
• MESA --- Micro Epididymal Sperm Aspirations.
• 10). Embryo Freezing.
• 11).Third Party ART(Donor Eggs, Donor Sperms or
  Surrogacy).

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SOME ART PROCEDURES

• 1).TIMED INTERCOURSE
• Medications are administered to promote
  ovulation.
• Treatment monitored by ultrasound scanning to
  determine the precise timing of the egg release.
• The couples are then advised on the best timing
  of intercourse.

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ART PROCEDURES (CONTD)

• 2). INTRA UTERINE INSEMINATION
• Treatment and monitoring is like in timed
  intercourse.
• The sperms are specially prepared and introduced
  into the uterine cavity via a catheter.
• This can help to overcome cervical mucus
  hostility.

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ART PROCEDURES (CONTD)

• 3).IN-VITRO FERTILIZATION AND EMBRYO TRANSFER
  (IVF- ET)
• A)---- Unlike the standard ovulation induction
  regimes, most IVF programs follow the super
  ovulation regime as this ensures a greater number
  of harvestable eggs.
• ---- This consists of an initial pituitary down
  regulation (desensitization of the pituitary)
  with a resultant complete suppression of ovarian
  activity.
• Drugs used include the subcutaneous or intranasal
  GnRH(Gonadotrophin-releasing hormone)
  analogues(Buserelin,Naferelin,Triptorelin) from
  Day
• 1 to 14 of the menstrual cycle.

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ART PROCEDURES (CONTD)

• This is followed by the standard Human chorionic
  gonadotrophin (FSH, LH) and Human menopausal
  gonadotrophin regime (LH).
• B) -----HCG is given when there are at least 3
  follicles 17-20 mm in diameter.
• C) -----Laparoscopic or preferably transvaginal
  ultrasound guided follicular aspiration
  approximately 36 hours after HCG injection.
• D) -----Incubation of aspirated eggs (under
  strict temperature, gas and aseptic control) for
  4-6hrs.This allows development to stage two
  metaphase. This is followed by addition of about
  200,000 capacitated sperms per egg.

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ART PROCEDURES (CONTD)

• E) ----- Regular stereoscopic microscopic
  evaluation is done to determine progress of
  fertilization etc
• F) ----- Usually after 48 - 72hrs, the resultant
  embryos (2-8 cell stage) are aspirated into a
  small catheter and transcervically placed in the
  uterine cavity. Usually two are placed while the
  remaining may be cryopreserved for future use or
  donated.
• G) ----Luteal support is provided by the
  administration of low dose hCG or progesterone.

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ART PROCEDURES (CONTD)

• IVF RESULTS
• The realistic pregnancy rate per ET in IVF is
  20-30 overall but this is influenced by age and
  the number of embryos transferred.
• Younger women lt 35 years have at least a 33
  success rate.

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ART PROCEDURES (CONTD)

• COMPLICATIONS OF IVF
• i) Multiple pregnancies
• 1 in 5 IVF pregnancies are multiple if
  transferring 3 embryos or less.
• Transferring more than 3 embryos(where available)
  results in multiple pregnancies in about 40 of
  IVF babies.

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ART PROCEDURES (CONTD)

• ii) Ovarian hyperstimulation syndrome(OHSS)
• Excess response to ovarian stimulants can lead to
  ovarian enlargement, abdominal distension and
  pains in up to 7 of IVF patients.
• However, serious OHSS involving gross ascites
  affects less than 2 of all patients.
• The prevention of OHSS is the identification of
  women at risk (polycystic ovaries, high
  responders) and either reduced hMG doses or
  electively cryopreserving all embryos to avoid
  pregnancy until the danger has been averted.

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ART PROCEDURES (CONTD)

• iii) Pelvic infection
• Serious infection is rare in IVF.
• Prophylactic antibiotics are advised.
• iv) Haemorrhage
• This can occur during egg collection.
• Usually there is a bleeding point, but this stops
  when pressure is applied for a short while.

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ART PROCEDURES (CONTD)

• v) Ectopic pregnancy
• vi) Anembryonic pregnancy (Blighted ovum)
  
• vii) Spontaneous abortion
• viii) Intrauterine growth restriction (IUGR)
• ix) Preterm delivery

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ART PROCEDURES (CONTD)

• 4).GAMETE INTRAFALLOPIAN TRANSFER (GIFT)
• Indicated in patients with at least one normal
  tube.
• Super ovulation is as above (in IVF-ET) followed
  by a laparoscopic follicular aspiration.
• Capacitated sperms and eggs are mixed and placed
  in the catheter.
• Both are then transferred into the fallopian
  tubes.
• In this case fertilization occurs naturally
  within the body.
• GIFT is not recommended if the fallopian tubes
  are blocked or the sperm quality is far below
  average.

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ART PROCEDURES (CONTD)

• 5). ZYGOTE INTRA FALLOPAIN TRANSFER (ZIFT)
• Similar to GIFT except that the sperms and eggs
  are incubated first and transferred after
  fertilization.

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ART PROCEDURES (CONTD)

• 6). INTRA CYTOPLASMIC SPERM INJECTION (ICSI)
• Indicated in patients with
• i) Severe oligospermia lt 5million/ml,
• ii) Significant sperm immotility,
• iii) Multiple sperm factors,
• iv) Failed IVF ET or
• v) Inability of the sperms to penetrate the egg
  as confirmed from the ZONA PELUCIDA PENETRATION
  TEST.

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ART PROCEDURES (CONTD)

• Steps involved are similar to IVF ET except
  that after aspiration of the eggs, (under an
  inverted microscope) the eggs and sperm are held
  by a system of two hyallically - controlled
  micropipettes.
• An egg is held in place by a micropipette while
  another micropipette picks up a single live
  sperm. The egg cell membrane is then pierced and
  the sperm injected into the cytoplasm with the
  resultant fertilization of the egg.

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ART PROCEDURES (CONTD)

• 7).SPERM ASPIRTION PROCEDURES
• Indicated in severe oligospermia.
• This may consist of
• I) Testicular Sperm Aspiration (TESA)
• II) Percutaneous Sperm Aspiration (PESA),
• III) Micro Epididymal Sperm Aspiration (MESA).

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ART PROCEDURES (CONTD)

• 8).THIRD PARTY ART
• I) Donor Sperms
• Absence of sperms in the man especially due to
  testicular failure has traditionally been treated
  with donor sperms for several decades.
• In these days, it is possible to extract directly
  from the testes in obstructive azoospermia and
  the sperms directly injected into the eggs.
• Where this procedure of sperm extraction
  (PESA/TESA) fails, the only recourse is to use
  donor sperms if the couple desires a pregnancy.

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ART PROCEDURES (CONTD)

• II) Donor eggs
• In menopausal or perimenopausal women desiring
  pregnancy, eggs can be obtained from willing
  donors (that may be known or unknown to the
  recipient), fertilized with the husbands sperms
  and the embryos transferred into the uterus of
  the older woman.
• III) Surrogacy
• Couples desiring their own genetic children, but
  where the woman has had a hysterectomy or severe
  damage to her uterus or endometrium, can opt for
  the use of a surrogate mothers uterus to receive
  embryos generated from the eggs and sperms of the
  genetic parents.

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PRE CONCEPTION DIAGNOSIS

• SEX SELECTION --- Sex-gene probes have been
  available for several years for embryo sexing,
  especially where there are concerns about sex
  linked diseases. Social sex selection has ethical
  implications.
• SICKLE CELL DISEASE PREVENTION --- Embryos
  selection based on the absence of genetic
  diseases (sickle cell disease is the most common
  in our environment) is more acceptable in most
  cultures or religions than selective pregnancy
  termination after antenatal diagnosis.
• Pre-conception diagnosis can be applied to just
  about any chromosomal disease, sex-linked
  disorders or inborn errors of metabolism for
  which appropriate probes have been developed.

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ISSUES IN ASSISTED REPRODUCTION

• Cost effectiveness
• Ethical / moral / legal considerations
• Emotional issues

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B)MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY

• Developments of new surgical techniques and
  advances in surgical equipments allow us to
  perform more and more surgical procedures using
  LAPAROSCOPY and HYSTEROSCOPY.
• These novel procedures have revolutionized the
  approach to the majority of gynecological
  disorders.
• We can now perform the majority of surgeries
  without the need for larger incisions in the
  abdominal wall and therefore, most often patients
  can go home on the day of surgery and recover to
  full activity in approximately two weeks after
  surgery.

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• 1) LAPAROSCOPY
• This refers to the transabdominal visualization
  of the peritoneal cavity usually after
  insuflation with gas.
• Indications for laparoscopy could be diagnostic
  or therapeutic.

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• Diagnostic Indications for Laparoscopy
• Include the evaluation of amongst others
• Chronic and acute pelvic pain of indeterminate
  origin e.g. endometriosis, acute PID, leaking
  ectopic gestation, ovarian cysts/accidents
• Causes of infertily
• Second look evaluation following treatment for
  cancer of the ovary
• Suspected endometriosis
• Uterine perforation
• Follicular growth monitoring

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• Therapeutic Indications for Laparoscopy
• Include
• Tubal sterilization either by electrical or
  insertion of bands, rings etc
• Pelvic adhesiolysis
• Retrieval of lost IUCDs
• Aspiration of ovarian cysts including ovarian
  cystectomy, wedge resection of the ovary and
  ovarian biopsy.
• Laparoscopic myomectomy

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• Metroplasty
• Laparoscopic assisted vaginal hysterectomy,LAVH
• Laparoscopic tubal surgery, which may include
  salpingectomy, salpingostomy, tubal
  re-implantation
• Laparoscopic lymphadenectomy, colposuspension
• As part of the assisted fertilization procedures
  ova collection, gamete transfer

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• 2) HYSTEROSCOPY
• Is the endoscopic evaluation of the uterine
  cavity using the Hysteroscope.
• The Hysteroscope is very much like an operating
  Laparoscope with an added channel for the
  introduction of fluids used for the distension of
  the uterine cavity.
• Distending media include high molecular weight
  dextran with normal saline,glycine, and 5
  dextrose in water or carbon dioxide.

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• With the use of the liquid media, the uterine
  pressure should not exceed 150mmHg, and with the
  use of Co2 the flow rate should also not exceed
  100ml/mixture.
• Hysterosopic evaluations may be performed either
  under local or general
• aneasthesia.

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• Diagnostic and therapeutic indications for
• Hysteroscopy
• Include
• Focal biopsy for evaluation of patients with
  abnormal uterine bleeding.
• Evaluation of patients with infertility
• Hysteroscopic endometrial laser coagulation
  instead of hysterectomy in patients with
  endometrial hyperplasia or dysfunctional uterine
  bleeding
• Hysteroscopic submucous myomectomy or metroplasty
• Diagnosis and management of Ashermans syndrome

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MINIMALLY INVASIVE SURGICAL OPTIONS IN
REPRODUCTIVE ENDOCRINOLGY(CONTD)

• Identification and retrieval of lost IUCDs
• Excision of polyps
• Sterilization

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C)CLONING

• The first mammal cloned from the cell of an
  adult, DOLLY THE SHEEP,
• generated considerable interest worldwide.
• It stimulated much discussion about the ethics of
  cloning and also, in particular, the potential
  for human reproductive cloning.

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CLONING(CONTD)

• Dolly was derived from the udder( an organ shaped
  like a bag that produces milk and hangs beneath
  the body) of a six-year old FINN DORSET EWE that
  was cultured in the laboratory. The cultured
  cells were then fused with unfertilized eggs,
  from which the nuclei had been removed. The
  variable reconstituted eggs were then implanted
  into the SURROGATE BLACK EWE. One implanted egg
  resulted in the birth of DOLLY.
• An ewe is a female sheep.

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CLONING(CONTD)

• The production of DOLLY demonstrated for the
  first time that a NUCLEUS taken from an adult
  cell could be REPROGRAMMED to permit the full
  range of GENE EXPRESSIONS needed to produce a
  COMPLETE ANIMAL.
• A clear distinction should be drawn between
  REPRODUCTIVE CLONING and THERAPEUTIC (NON
  REPRODUCTIVE) CLONING.

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CLONING(CONTD)

• REPRODUCTIVE CLONING --- by either embryo
  splitting or nucleus replacement, is aimed at
  birth of genetically identical individuals.
• There are no ethical objections to
• genetically identical individuals per se,
  
• but there are serious ethical questions
  
• about instrumentation of human beings.

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CLONING(CONTD)

• THERAPEUTIC (NON- REPRODUCTIVE) CLONING --- is a
  term used to describe the use of cloning that
  does not involve the production of genetically
  identical individuals, has SCIENTIFIC and
  THERAPEUTIC applications including potential
  therapy for mitochondrial disease and research on
  EMBRYONIC STEM CELLS, which could lead to the
  development of tissue and possibly organs without
  the risk of immune rejection.

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CLONING(CONTD)

• Such cell-based therapies might be used to
  treat Parkinsons and Huntingtons disease (nerve
  cells), muscular dystrophy (striated muscle
  cells) and leukaemia(white blood cells).

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D) EMBYONIC STEM CELLS

• Researchers have been making embryonic stem cells
  from mice, hamsters and other animals for several
  years.
• They have been described as the ultimate spare
  part.
• Embryonic stem cells are found in early stages of
  the embryo, after the egg is fertilized and has
  begun dividing, but before the mass of cells
  attach itself to the wall of the uterus.
• Eventually they differentiate into the various
  cell types in the body, and disappear.

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EMBYONIC STEM CELLS(CONTD)

• Researchers have been able to capture these cells
  in their undifferentiated state and keep them in
  that state in a culture.
• They are presently working on how to direct these
  cells to become specific types of cells which
  would allow scientists to grow an unlimited
  supply of cells for transplant and other aspects
  of medicine and biology.

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EMBYONIC STEM CELLS(CONTD)

• Much of the excitement surrounding embryonic stem
  cell research focuses on their potential for
  transplantation to repair diseased organs.
• With their unique ability to differentiate into
  all cells of the body, stem cells may be used to
  treat a variety of disorders, ranging from
  diabetes to Parkinsons disease and spinal cord
  injuries.

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CONCLUSION

• The introduction of these advances has provided
  not only hope and treatment for the infertile
  couple but also stimulated continuing research in
  the field of reproduction.
• Reproductive advances will make more COUPLES
  happier.

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WOMEN MUST BE HAPPY AND HAVE CHILDREN
66
THANK YOU