History & Development of ART Flashcards
(35 cards)
Discovery of spermatozoa(Anton Van Leeuwenoek 1677)
Father of microbiology, first microbiologist.
First to observe and describe single-celled organism
(animalcules)…microorganisms, muscle fibres, bacteria, capillaries and
spermatozoa.
Artificial Insemination - AI(John Hunter 1790)
Appointed as surgeon at St George’s in 1768.
He advised a patient with severe hypospadias to collect the semen which escaped during coitus in a warmed syringe and inject the sample into the vagina. A successful pregnancy resulted.
Hypospadias
opening of the urethra develops abnormally,
usually on the underside of the penis.
Abnormal closure of the urethral fold over
the genital groove.
a birth defect in boys in which the opening of the urethra is not located at the tip of the penis.
Embryo transfer – in rabbits (Walter Heape Cambridge University 1891)
Transferred 4 cell embryos from the uterine tubes of
Angora rabbits and placed them into the tubes of a
recently mated Belgian hare.
2 Angora rabbits (and 4 Belgians) in the resulting litter.
General anaesthetic and the embryos transferred on
the point of forceps…they were not transferred to any
kind of media.
First to take pre-implantation embryos and transfer them to a gestational carrier without affecting their development.
Estrogens & sex steroids (Edward Doisy Harvard Medical School 1929)
Extracts from sow ovaries injected into ovarectomized mice, resulted in the production
of cornified cells in the vagina – a bioassay. Later isolated estradiol from pig follicular fluid.
Adolf Butenandt University of Göttingen 1929
Isolated estrogen from hundreds of gallons of human pregnancy urine.
Pituitary and gonadotrophins (Samuel Crowe 1910)
Partial pituitary ablation resulted in gonadal atrophy
in dogs and persistence of infantilism in puppies.
Bernard Aschner 1912
Postulated that pituitary function determined by
higher centres in the brain (hypothalamus) after
observing gonadal atrophy in patients with brain
injury.
Sectioned pituitary stalk which resulted in gonadal
atrophy and hypothesised that brain/pituitary
extracts might affect the gonads.
Identification of FSH & LH (Bernhard Zondek Berlin 1930)
Proposed the idea that the pituitary secretes two hormones – Prolan A stimulated follicular growth (FSH) and prolan B
stimulated ovulation and formation of the corpus luteum (LH).
He isolated these gonadotrophins from post menopausal blood and urine.
Also isolated hCG from pregnancy urine and injected into mice leading to follicular maturation and ovulation – potential pregnancy test.
Friedman test – Bioassay of pregnancy (Maurice Friedman & Maxwell Lapham Pennsylvania 1931)
Inject the tested woman’s urine into a female rabbit, then examined the rabbit’s ovaries a few days later…
presence of corpus luteum indicated pregnancy.
Hormone responsible is hCG which binds to LH receptors causing luteinisation.
Drawback that the rabbit had to be operated on to examine ovaries.
Later development used the African
clawed frog, which responds to hCG
by laying eggs and so removing the
need for surgery.
Human in-vitro fertilisation (John Rock & Miriam Menkin Harvard 1944)
Culmination of 6 years of experiments changing
conditions.
Oocytes obtained from patients around 10th day of the
menstrual cycle by laparotomy.
Oocytes washed in Locke’s solution and incubated for
27 hours in serum obtained from the egg donor;
exposure to a sperm suspension also washed in Locke’s
solution for 1 hour.
Transferred to a serum from a post-menopausal patient
and observed over the following days where they divided
into 2-4 cell embryos. No attempt to transfer the embryos
to a recipient.
Fertility treatment 1950’s - 1970’s
1st use of hyperstimulation was in mice used crude extracts of PMS, 1950’s
Hypogonadotrophic women treated with crude pituitary extracts & hCG (Gemzel,
1967).
Human menopausal gonadotrophins to treat amenorrhoeic women
(Lunenfeld, 1969).
Anovulatory PCOS patients treated using clomiphene (Kistner, 1972).
What are problems in fertility treatment 1950s- 1970
Multiple pregnancies.
Ovarian Hyperstimulation syndrome (OHSS).
Miscarriage.
Purity of preparations.
CJD…other infectious agents.
Virtually no monitoring.
Patrick Steptoe - Laparoscopy
Graduated from St George’s in 1939.
Studied obstetrics and, in 1951 learned the technique of laparoscopy from one of its pioneers Raoul Palmer and promoted its usefulness.
In 1967 he published a book on Laparoscopy
in Gynaecology.
Robert Edwards - Fertilisation
Began to study human fertilisation around 1960. Optimised culture media.
Discovered when to collect eggs after hCG trigger using ‘ovulations’ from pieces of ovary and oocyte maturation in vitro, 1965.
In-vitro matured fertilised eggs did not develop, problems with timing egg maturity and sperm capacitation, 1968.
Achieved fertilisation of a human egg in the laboratory 1969.
Next problem was obtaining follicular oocytes from selected patients.
To solve this clinical problem, an inspired collaboration was initiated with Patrick Steptoe.
Steptoe & Edwards
Measured urinary oestrogen in a
gonadotrophin stimulated cycle.
Timed collection by laparoscopy IVF and
replacement of embryos …..failure 1971.
Decided to give luteal support using
Primulot which turned out to be an
abortive agent. This wasted 3 years.
Switched to using a natural cycle and
achieved 1st pregnancy but it was ectopic,
1977.
Louise Brown 1978
Second patient Lesley Brown, here with husband John and baby Louise Brown.
25th July 1978 at Oldham General Hospital by elective Caesarean section.
Progress in IVF technology
Purer urinary FSH/LH preparations, recombinant gonadotrophins
GnRH agonists/antagonists
Better ultrasound monitoring
Micromanipulation for ICSI, MESA, TESA etc
Cryopreservation of oocytes (vitrification)
Reduction in OHSS less stimulation & GnRH agonist/Kisspeptin triggers
Sequential media for blastocyst culture
Single embryo transfer
Pre-implantation diagnosis or screening
Ovarian tissue cryopreservation
Mitochondrial donation (3 parent family)
In vitro maturation of oocytes
Preimplantation genetic testing (PGT)
PGT-A aneuploidy
PGT-SR chromosomal structural rearrangements
Screening of embryos for aneuploidy or chromosomal
translocations. Often used for advanced maternal age
risk of aneuploidy, know translocations or repeated
implantation failure.
Screening of embryos for known genetic mutations
where the parents are carriers.
PGT information used to decide which embryo to transfer to the
mother.
Screening of embryo includes…
fluorescence in situ-
hybridisation (FISH), array-based comparative genomic
hybridisation (aCGH), next-generation sequencing (NGS)
and single nucleotide polymorphism (SNP) array. Also,
whole genome amplification (WGA) based versions of
techniques for PGT-M.
Mitochondrial donation
Meiotic spindle transfer (MST)
Meiotic spindle of donor oocyte
removed during MII and replaced
by patient spindle.
Pronuclear transfer (PNT)
Pronuclei of fertilised patient
egg transferred to fertilised
donor egg which has had
pronuclei removed.
Types of cloning
- Natural cloning
- reproductive cloning
- therapeutic cloning
