Infertility treatments with low ovarian reserve

Dr. Nisha Bhatnagar, Dr. Markus Nitzschke AVEYA Natural IVF, New Delhi, INDIA

Reduced Ovarian Reserve

Diagnostics Clinical stages Impaired fertility Treatment approaches Data Nepal Conclusion

Reduced Ovarian Reserve - DiagnosticsBiochemical 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

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

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

Reduced Ovarian Reserve - Clinical Stages

Four stages of reduced ovarian reserve: 1. Compensated stage2. Stage of de-synchronized cycle3. Stage of pathologic premature LH surge4. Stage of suppressed follicle growth

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

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

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

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

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

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

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

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.

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.

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.

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

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%) deliveries1 miscarriage at 8 weeks of pregnancy

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

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