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Ovulatory infertility and ovulation induction by the endocrinologist

Clare Boothroyd
MB BS (Hons)  M Med Sci FRACP FRANZCOG CREI GAICD
4th August 2012
Queensland Endocrine Group, Mooloolaba.

The rise and rise of assisted reproduction

July 25 1978
Louise Brown born
First IVF baby
Born to Lesley Brown, bilateral tubal blockage
Natural cycle, single egg fertilization

History of IVF

1878 - first reported attempts at IVF
1959 - IVF births in rabbits in USA
1968 - first human IVF (Edwards, Bavister)
1978 - Birth of first IVF baby (Steptoe, Edwards)
1992 - Birth of first baby after ICSI     (intracytoplasmic sperm injection) (Palermo)

ANZ ART statistics 2008

61,000 IVF/ICSI cycles  (Wang et al 2008 NPSU)
~15,000 babies born
One child in every classroom is from ART and set to rise
Fertility preservation/ reproductive life planning is now essential
How many IVF/ICSI cycles could be OI cycles?

                                                             

Schema

Ovulatory disorders
Hyperprolactinemia
PCOS
Hypogonadotrophic hypogonadism
Oral agents in PCOS
Clomiphene, metformin, dexamethazone
Hypogonadotrophic hypogonadism
rFSH, menotrophins

 

Ovulatory defects

Infertility due to ovulatory defect has best  reproductive prognosis of all causes of  infertility

Ovulation induction  is, a physiological event in which the growth of  one or two fertilizable oocytes  is stimulated,  ovulated and fertilized within the female reproductive tract vs superovulation which is the stimulation of a large cohort of ovarian follicles (supraphysiological).

Success rate per OI cycle ~15-22% (live birth)  compared with IVF and fresh transfer ~30% live birth  in women aged 30 and below.

Hyperprolactinemia

Significant hyperprolactinemia with or without microadenoma

Effective treatment with dopamine agonists such as bromocriptine, cabergoline, quinagolide

Preparation for OI

1. Ovulatory defect

2. Relies on normal seminal analysis (~2.7million morphologically normal motile sperm per ejaculate)

3. Normal fallopian tube function

4. Evaluation for risk factors for tubal disease (surgery, past severe endometriosis, PID)

5. Tubal evaluation: HSG, SIS, laparoscopy and dye studies : not required if low risk

6. Preconception: folic acid 0.5mg vs 5 mg, iodine, vitamin D, screen for rubella, varicella etc.

 

Tubal evaluation

HSG  (day 5-12 of menstrual cycle or at “quiet” phase), antibiotic cover
Laparoscopy
Saline instilled sonohysterography +/- salpingography with Echovist™ as HSG

OI in PCOS

 

Confirm diagnosis

Rotterdam ESHRE/ASRM PCOS consensus on diagnostic criteria

Revised 2003 criteria (2 out of 3)

1.         Oligo or anovulation

2.         Clinical and/or biochemical signs of   hyperandrogenism

3.         Polycystic ovaries

and exclusion of other aetiologies (CAH, androgen secreting tumours, Cushing’s syndrome)

                                                 

 

PCO:  “presence of 12 or more follicles in each ovary measuring 2-9mm in diameter and/or increased ovarian volume (>10 mls - prolate ellipsoid 0.5x length x width x thickness)”

Not subjective appearance of PCO

Follicle distribution, stromal echogenicity and stromal volume not part of definition                                  

                                                 

Follicle number estimated both in longitudinal and antero-posterior cross-sections of the ovaries (size of follicles <10mm should be expressed as the mean of the diameters on the two sections)                              

                                                             

Definition does not apply to women on combined oral contraceptives

If unilateral- sufficient for PCO

If a dominant follicle (>10mm) or corpus luteum - rescan in next cycle

Scanning should be transvaginal  where possible

Scan D3-5 of spontaneous or induced menstrual cycle or random if anovulatory                            

Screening for endometrial hyperplasia???

PCO in women undergoing IVF regardless of clinical manifestations predicts increased risk of OHSS

            Fertil Steril vol 81 Jan 2004

How common is PCOS/PCO?

PCOS = 9% of women

PCO = 25% of women

 

 

Ovulation induction in PCOS

Weight reduction to BMI 30 or less

Clomiphene alone

Clomiphene + metformin

Metformin alone

Clomiphene + dexamethasone

Clomiphene +metformin + dexamethasone

FSH ovulation induction

LOD + all/any of the above

Uncertain role of tamoxifen

Uncertain role of letrazole

 

 

Weight loss

1. Lifestyle intervention:
“Fertility Fitness” 4-6/12, weekly exercise programme.  90%  will lose 5% body weight.  90% ovulate.  60% will be pregnant within 18/12.  Cost per baby $5000.  Majority continued weight loss.  All reduced markers of risk for DM.

                                     (Clark et al, 1998, Hum Rep.  13:1502-5)
2. Weight loss (2)
RCT of  overweight and infertile women
intensive treatment”fertility fitness” vs dietary advice, occasional phone call
Pregnancy results at 18/12
control 21%                 -intervention 61%
spontaneous 10           - 21
ART 8                         -32

                                                (Marks et al, FSA, 2000)

Weight loss (3)
RCT of  90 women with PCOS (263 recruited)
low protein diet vs high protein diet (isocaloric, energy restriction 12/52, then weight maintenance)
No difference in weight loss

                                                (Unpublished, Norman, personal communication)

Definition “quiet” ovaries

E2 <300pmol/dl

Progesterone in non luteal range

LH  not high

On USS no follicles >10-12mm and thin EM

= no impending or recent ovulation

 

 

Clomiphene

Used since 1961

6-14% risk of dichorionic twinning

<1% risk of triplets

Anti –oestrogenic side effects – flushes, reduced cervical mucous, endometrial thinning

Cohort data suggests increased risk of ovarian cancer after 9 cycles cc with no pregnancy

Monitoring and management of OI in PCOS

Arbitrarily set Day 1 by “quiet” bloods and USS or by day of normal menstruation in morning

Start cc on day 3 (established menses are normal but early enough for effect), 5 days of use

Alternate day coitus from day 10 - day 23

Serum progesterone day 21-23, phone for results, if luteal advised will get menses or be pregnant (review after day 28) (rarely cyst), if not luteal for bloods day 28-30  serum oestradiol, progesterone and LH and see within 2-3 days of second set of bloods

Monitoring OI cycle (telephone)

Monitoring OI cycle (consultation)

Review of cycle

Low serum progesterone on day 21 can be ovulatory, but will have luteal serum progesterone on day 28 so defer next cycle until menses

If low serum progesterone and low serum oestradiol (<300pmol/dl) on day 28 – cycle failure and proceed to next cycle with or without scan at higher dose or with adjuvant agents/interventions (e.g weight)

ovul1


ovul2 INSERT FLOW Chart

Success rate of clomiphene alone

If ovulatory 10-15% per cent per cycle

Cumulative pregnancy rate 50-60% for 6 cycles of clomiphene with cumulative ovulation rate of 75% (Laven 2006)

Cumulative pregnancy rate normal couples 76% over six months

Clomiphene vs placebo ovulation rate

Forest plot from Cochrane review

Metformin vs placebo ovulation rate

Forest plot from Cochrane review

 

Practicalities of metformin alone for OI

Oligoovulation/anovulation  - takes metformin alone, ovulates, conceives, does not recognise pregnancy and inadvertent first trimester exposure.

?significant

 

Clomiphene plus dexamethasone vs clomiphene ovulation rate

Forest plot from Cochrane review

 

 

LOD + oral  vs FSH ovulation rate

Forest plot from Cochrane review

 

 

FSH OI

PCOS

Hypogonadotrophic hypogonadism

Preparation for FSH OI

Tubal patency (at least one)

Age <41 (CVB <35)

Awareness of cycle cancellation if 4 or more fertilizable follicles

Twinning acceptable

Baseline formal USS (borderline tumours)

Breast examination

FSH OI

Quiet bloods and scan

Low dose FSH

Step up regimen (vs step down)

Scan after 7 doses of FSH to detect over-responders

No coitus for 2 days prior to USS as may ovulate spontaneously

Scan every two days once follicle recruited ie at 12 mm diameter

Match with bloods to confirm surge and rising E2

FSH OI

If no response after 10-14 days, increase dose

Once  1-2 x18 mm or more  follicles  – can induce ovulation with 5000IU hCG  (3 follicles depends on couple and number of past attempts)

Coitus 36 hrs later

Luteal phase support with hCG 1500 every 4 days (2 doses), pregnancy test one week after last hCG

FSH OI in hypo hypo

Not good ones to start gaining experience

May be stimulating ovary for first time (IHH)

Often LH deficient – low oestradiol for follicular size and thin endometrium

Need rLH (Luveris), expensive, or   hCG (50IU)  (wasteful) or Menopur (urinary derived products)

FSH OI - cons

Higher order multiples if not careful/cooperative

Uncertainty about prions with urinary derived products

Requires patience and time

In summary:

  1. OI, particularly with oral agents is an important part of management of ovulatory disorders which often exist in isolation (in contrast to other causes of infertility)
  2. PCOS is particularly at risk of OHSS and therefore superovulation undesirable
  3. Well conducted OI is associated with acceptable twinning rate and low higher multiples and is much cheaper than ART
  4. Many options other than clomiphene alone.
 
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