Dr Nisha Bhatnagar and Dr Marcus Nitzschke

1. Infertility treatments with low
ovarian reserve
Dr. Nisha Bhatnagar, Dr. Markus Nitzschke
AVEYA Natural IVF, New Delhi, INDIA

2. Reduced Ovarian Reserve
 Diagnostics
 Clinical stages
 Impaired fertility
 Treatment approaches
 Data Nepal
 Conclusion

3. Reduced Ovarian Reserve - Diagnostics
Biochemical indicators:
• Anti-Mullerian-Hormone (AMH)
• FSH and estradiol in the early follicular phase
• LH und estradiol at the moment of ovulation
• Progesterone und estradiol in the luteal phase
Ultrasound:
• Antral follicle count (AFC)
• Observation of follicle growth during the cycle
Clinical evaluation:
• Variations in cycle length

4. Reduced Ovarian Reserve - Diagnostics
Anti-Mullerian-Hormone (AMH):
• Little variability during the cycle and between two cycles
• Global overview about the actual ovarian reserve
FSH und estradiol in the early follicular phase:
• High variability between two cycles
• Good estimation of the quality of each cycle
LH und estradiol at the moment of ovulation:
• Quality of the ovulation
Progesterone und estradiol in the luteal phase:
• Quality of the corpus luteum

5. Reduced Ovarian Reserve - Diagnostics
Antral follicle count (AFC):
• Very experience depending
• Alternative to biochemical indicators
• Good evaluation of ovarian reserve possible
Observation of follicle growth during the cycle:
• Important to detect ovulation disorders
• Pathologic cycles can be detected

6. Reduced Ovarian Reserve - Clinical
Stages
Four stages of reduced ovarian reserve:
1. Compensated stage
2. Stage of de-synchronized cycle
3. Stage of pathologic premature LH surge
4. Stage of suppressed follicle growth

7. Reduced Ovarian Reserve - Clinical
Stages
1. Compensated Stage:
• Low AMH (<1.0 µg/L)
• High FSH in the early follicular phase (10 - 30 IU/L)
• Normal E2 in the early follicular phase (20 - 60 pg/mL)
• Development of a mature follicle > 18mm
• Cycle length ≥ 26 days
Theory:
Ovarian reserve is reduced, but the endocrine compensation mechanisms are
still working

8. Reduced Ovarian Reserve - Clinical
Stages
2. Stage of de-synchronized cycle:
• Low AMH (<1.0 µg/L)
• Normal FSH in the early follicular phase (6 - 10 IU/L)
• High E2 in the early follicular phase (>60 pg/mL)
• Development of a mature follicle > 18mm
• Cycle length < 26 days
Theory:
Pathologic follicle formation during the luteal phase due to high basal FSH
levels  dominant follicle present at the beginning of cycle  shorter
follicular phase  de-synchronization of follicle growth and endometrium
maturation

9. Reduced Ovarian Reserve - Clinical
Stages
3. Stage of pathologic premature LH rise
• Low AMH (<1.0 µg/L)
• High FSH in the early follicular phase (10 - 30 IU/L)
• Normal E2 in the early follicular phase (20 - 60 pg/mL)
• Pathologic premature LH rise
• Cycle length < 26 days
Theory:
Lack of a specific inhibition of LH during follicle maturation  LH surge and
ovulation occur before final maturation of follicle development (< 17 mm,
E2 < 200 pg/mL)  poor quality of oocytes and embryos  weak corpus
luteum

10. Reduced Ovarian Reserve - Clinical
Stages
4. Stage of suppressed follicle growth
• Very low AMH(<0.5 µg/L)
• Very high FSH (>30 IU/L)
• Low E2 (<20 pg/mL)
• Suppressed follicle growth
• Long and irregular cycles
Theory:
High FSH and LH suppress follicular growth by down regulation oft their
receptors on the follicle  ovarian reserve is able to recover from time to
time  falling FSH and LH levels enable new follicular growth  long and
irregular cycles

11. Reduced Ovarian Reserve - Impaired
fertility
1. Compensated stage:
• Probably no direct impact on female fertility
• „Low responder“ in ovarian stimulation
2. Stage of de-synchronized cycle:
• Possibility of implantation disorders, if ovulation occurs “too early”
because of an immature endometrium
3. Stage of pathologic premature LH surge:
• Poor egg and embryo quality, if ovulation occurs from immature follicles
• Luteal phase defect
4. Stage of suppressed follicle growth:
• Long periods without ovulation
• All other reasons of the other stages together

12. Reduced Ovarian Reserve - Treatment
approaches
DHEA treatment (Barad D, Gleicher N., Hum Reprod 2006)
• Improvement of ovarian function in some patients with low ovarian reserve
• Two to three pills of 25 mg per day during several months
• Reduced abortion and aneuploidy rate reported
Theory: As a pre-hormone of Estradiol and Testosterone, DHEA compensates
the lack of androgens in ovarian insufficiency
Our experience: Strong improvement of ovarian function in some patients
during several weeks

13. Reduced Ovarian Reserve - Treatment
approaches
1. Compensated stage:
• No special treatment necessary, if no other reason for infertility
2. Stage of de-synchronized cycle:
• Re-synchronisation of the cycle with COCP in the luteal phase
3. Stage of pathologic premature LH rise:
• Inhibition of the premature LH rise with Clomifen citrate
4. Stage of suppressed follicle growth
• FSH and LH suppression with Ethinyl-Estradiol

14. Reduced Ovarian Reserve - Treatment
approaches
Stage of de-synchronized cycle:
 High serum FSH levels during the luteal phase due to lower serum inhibin
concentrations as a result of low ovarian reserve (Robertson et al. 1985).
 Without inhibin from the ovary, the hormones produced by the corpus
luteum alone are not able to suppress FSH sufficiently. The result is a
pathologic follicle formation during the luteal phase and a shorter follicular
phase in the following cycle.
 The treatment with COCP for 10 days during the luteal phase (e.g. day 16 -
26) can prevent pathologic follicle formation and help to re-synchronize the
cycle again.

15. Reduced Ovarian Reserve - Treatment
approaches
Stage of pathologic premature LH rise:
 The anti-estrogenic effect of Clomifen citrate can be used to delay LH surge
or to block it completely (Teramoto und Kato 2007).
 In women, LH surge is normally triggered by high serum estradiol levels
activating E2-receptors in the hypothalamus. As a competitive inhibitor of
E2-receptors, Clomifen citrate is able to block LH surge, if given before
reaching the critical serum estradiol concentration.
 In patients with reduced ovarian reserve in this stage, normal follicle
maturation can be achieved using Clomifen citrate.

16. Reduced Ovarian Reserve - Treatment
approaches
Stage of suppressed follicle growth:
 Serum FSH levels of >30 IU/L can block follicle growth by down regulation
of the FSH-receptors on the follicle. Ethinyl-Estradiol treatment can bring
FSH down to normal levels and enables follicle growth again. (Check et al.
1990).
 Ethinyl-Estradiol treatment can only be successful, if at least one antral
follicle can be seen in ultrasound and serum estradiol levels are >20 pg/mL.
 After only a few days of Ethinyl-Estradiol follicle growth can be observed,
even if the patient had a long amenorrhea before.

17. Reduced Ovarian Reserve - Treatment
protocol
Combined OCP (COCP), Ethinyl-Estradiol (EE), Clomifen citrate (CC) +
ovulation induction with GnRH agonists (stage 2 - 4):
⇒ COCP for 10 days from day 16 - 26 (if patient is cycling)
⇒ Hormonal essay on day 2 (or any time, if amenorrhea): FSH, E2
⇒ If FSH >25 IU/L + E2 >20 pg/mL: EE 25µg / day until ovulation induction
⇒ If FSH <25 IU/L: no EE necessary
⇒ 50mg CC / day from day 7 until ovulation induction
⇒ Hormonal essay on day 10: E2 + LH
⇒ If E2 < 300 pg/mL on day 10, repeat E2 + LH daily, till E2 > 300 pg/mL
⇒ Trigger ovulation with 1 injection Decapeptyl 0,1mg
⇒ Timed intercourse on the following evening or egg retrieval 36h later
⇒ In the case of IVF, ET 2-3 days later
⇒ Vaginal progesterone for luteal phase support until pregnancy test

18. Reduced Ovarian Reserve - Data
Check, 1990 361 19.0% 5.2%
100 patients with hypergonadotrophic amenorrhea with EE and HMG treatment
Zhang, 2010 1267 236 3.3% 18.2%
Natural Cycle IVF and CC Stimulation in patients with day 3 FSH >15 IU/L
AVEYA Nepal 2014 30 100.0% 10.0%
15 patients with AMH <1.0 and cycle disorders stage 2 - 4
cycles ET ovulation clinical preg-rate/ clinical preg-rate/
cycle ET
30 oocyte retrievals
21 (70.0%) oocytes
11 (36.6% per retrieval) MII
ICSI: 8 (72.7% per mature oocyte) fertilizations = 8 transfers
3 (37.5%) biochemical pregnancies. 2 (25.0%) deliveries
1 miscarriage at 8 weeks of pregnancy

19. Reduced Ovarian Reserve - Conclusion
 There are four different stages of reduced ovarian reserve
 The cycle disorders of the stages 2 - 4 may have a negative
impact on female fertility
 It is possible to treat the cycle disorders with a simple
medical treatment
 Randomized controlled studies are needed to confirm the
efficiency of this treatment approach

20. Thank you!
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