Lec 40- Drugs to treat infertility Flashcards
The problem
-57% healthy young women conceive within 3 months
-After 1 year, 80-90% of normal couples conceive
-After 2 years 95%
-Subfertility= a failure to conveive after 2 years without contraception
-Infertility: A complete inobility to conveive
+30% no explanation
+Male factor 19%
+Ovulatory failure 27%
+Tubal damage 14%
+Endometriosis or other 5%
Investigation of infertile couple
1) Performed by the GP \+Full medical history of BOTH partners \+Semen analysis -Genral medical advice \+Timing of intercourse \+Avoid hot baths and tight underwear in males \+Both stop drinking and smoking -If technique and semen is normal then ovulatory performance is measured
Inital therapy
- Hormonal: Mid leuteal phase progesterone levels (confirms lutenisation of follicle NOT ovulation)
- Ultrasound: direct visulisation of ovaries, measurement of number and size of follicle
- If anovulation confirmed: Anti-oestrogen prascribed by the GP
- If an anti-oestrogen therapy fails after 2-3 cycles: refer to speacalist clinic
- Full endocrine screen and pelvic ultrasound to enable diagnosis
Available treatment
-Induction of ovulation \+Anti-oestrogens \+Gonadotrophin therapy \+GnRH -Assisted reproduction \+IVF, GIFT, ICSI
Induction of ovulation
1) Anti-oestrogen therapy
-Blocks physiological negative feedback of E2 on the hypothalamus and pituitary
+Displaces endogenous E2 from hypo receptors
+Acts on Hypo, increase pulse frequency of GnRH secretion
+Acts on pituitary to decrease sensitivity of gondaotrophs to inhibition by E2 (prolonged follicular phase)
+May have direct effect on ovary to increase effects of FSH
-FSH levels increase, stimulates follicle developmen , leading to ovulation
-CLOMIPHENE: first line therapy
When to use clomiphene
-Infertility due to anovulation
-Unexplained infertility where intact HPG axis exists
-Will be ineffective in women with too low E2 levels as require the +ve feedback of Ew during follicular phase
+Can be used alone to promote ovulation and conveption naturally
+Or can be used with hCG in assisted reproduction
Clomiphene alone
-50mg daily for 5 days, starting within 5 days of onset of menstruation
+Days 2-6,3-7,4-8,5-9 etc
-Second course of 100mg dd for 5days in absence of ovulation
+Doses up to 200mg have been used
-3 courses are an adequate therapeutic trial
+Long term cyclical therapy not recommended bvecause of risk of ovarian cancer
Clomiphene + hCG
-Can use hCG injection to
+Ensure follicular rupture
+Time intercourse accuralety w/ovulation
+Ovulation 24-36 hours after 5000 units hCG
-Must use ultrasound to assess follicles
+Not used when ovaries enlarged or multiple follicles developed
+Ovulation rates 70% pregnancy rate 30%
+Due to clomiphene effect on cervical mucous
-Adverse effects:Dose and duration related
+Ovarian enlargement, vasomotor symptoms, abdominal distension: Generally well tolerated
2) Gonadotrophin therapy
-Used in acquired or congenital gonadotrophin deficiency (HPG axis not intact)
+Usually in clomiphene failures or in women who have failed to respond to pulsatile GnRH therapy
-Aim to simulate pituitary gonadotrophin secretion
+hMG for FSH erffects, hCG for LH effects
+hMG promotes follicular development
+If follicular response good (Ultrasound) can give hCG to induce follicular rupture and ovulation
Gonadotrophin treatment regimes
-Daily injection (Sc or IM) hMG, increasing dose depending on follicular response
+Or alternate day injection of hMG using higher doses
-Ovarian response must be assessed: Urinary E2
+Want to avoid multiple births, intercourse avoided if E2 levels excessive
+Monitor to determine time to inject hCG
+Avoid using hCG when E2 levels high, can induce OHSS (ovarian hyperstimulation syndrome)
-Continue therapy for 6 cycles
Results gonadotrophin therapy
-Very variable, often disappointing due to non-physiological nature of treatment
+Pregnancy rate between 9-14%
+Lower if >34 or obese
-hMG contains FSH activity and LH activity, LH component might inhibit oocyte development
+Purified FSH develope : No evidence of improvement
-Normal feedback mechanisms bypassed: Multiple follicular denvelopment, multiple births, OHSS
+Multiple birthse.g. 19.3% of one study: 14 twins, 7 triples; 5 quads, 1 sextuplets: 75 children
3) pulsatile GnRH therapy
-SHould produce physiological secretion of gonadotrophins and maintain normal feedback mechanisms
+Fewer multiple pregnancies nd reduced rate of OHSS
-Indication: Absolute or relative deficiency of endogenous GnRH
+Congenital
+Or amenorrhoea due to low body weight, stress intensive exercise, hypothalamic disease, surgery and trauma
-Endocrine tests: low or normal levels of FSH, LH and E2 depending on degree of GnRH deficiency
Pulsatile vs continuous GnRH
-Continuous GnRH inhibits FSH and LH release
-Pulsed GnRH mimics physiological release stimulates FSH and LH
+Syringe pump, IV/Sc
+Expensive, time consuming, used as last resort: Frequency of therapy not as vital as time during cycle
+Monitor ovarian response: time response
+Gonadotrophin and E estimatations used to monitor pituitary responsel, Progesterone indicates luteal function= RESULTS- 52-98% ovulation w/25-30% pregnancy
Assisted reproduction (AR)
-In vitro fertilisation (test tube babies)
+Sperm and egg mixed in vitro
+Embryos selected and 2-3 (2) implanted originally to treat tubal blockages
-GIFT: gamete intrafallopian transfer
+Egg collecte , spem and egg injected together into fallopian tubes: fertilisation in vivo
-ICSI: intracellular sperm injection
-All NEED EGGS
+Use stimulated cycles so many oocytes collected
Ovarian stimulation for AR
1) Anti-oestrogens: Clomiphene +/- hCG have been used, but ovarian response not predictable
2)Gonadotrophins: increase no oocytes available for AR. Use higher gonadotrophin levels than for simple induction of ovulatio. Each clinic has own regime
+Daily injection hMG (Or purified FSH) until ovarian response satisfactory
+Monitored with ultrasound and E2 assay
+Stimulation continued until 3 mature follicles seen
+hCG used to induce ovulation: eggs collected transvaginally
Problem
-The patients own pituitary secretes fsH and LH in response to endogenous GnRH in an unreliable fashion
+Might get spontaneous ovulation when not ready to collect eggs
-Pituitary DESENSITISATION used to overcome this
+Continous administration of GnRH analogues will desensitise the pituitary to GnRH from the hypothalamus
-NOW cycle is under control fo exogenous hormones only (Control ovulation with hCG)
Pituitary desensitisation: GnRH agonist
NAFERULIN: GnRH analogue: Nasal spray
-One spray up each nostril daily (400 mcg)
-Start day 2 or mild luteal phase if pregnancy excluded
-Continue for 4 weeks, until pituitary desensitised
-Maintain during hMG (or purified FSH) adminstration
-STOP when hCG given
+Increase pregnancy rates
Results IVF treatment protocols
-No pituitary desensitsation
+Recombinant FSH gave higher birth rates than hMG
-Pituitary desensitsation with GnRH
+More effective
+FSH and hMG equally effective
-The future GnRH antagonist; more potent pituitary desensitisation
Complications of ovarian hyperstimulation
-Multiple pregnancy
-Foetal abnormality
+No increased risk c.f. normal conceptions
-Ovarian cancer: concerns but no firm evidence yet
