Delfi Lutan Induksi Ovulasi

8/12/2019 Delfi Lutan Induksi Ovulasi

1/57

Induction ovulation with

gonadotrophins

Delfi Lutan

Department of Obstetrics & Gynecology

Medical School. University of SumateraUtara.

MEDAN, 15 September 2013


2/57


3/57


4/57

Hypothalamic-Pituitary-Ovary Axis (HPO)

Hypothalamus

Pituitary Gland (Anterior)

LH FSH

Ovaries

GnRH

E2

P4

Androgens

Prolactin

F

ER

TILIT

Y


5/57

WHO Classification of Anovulatory Patients

Serum gonadotrophins

and

serum E2 levels

FSH and LH

and

E2

FSH ~and

E2 ~

FSH and LHand

E2

WHO I WHO II WHO III

OI

IVF

OI

IVF

OI?

IVF?

egg donation

(~80%)(510%) (510%)

PCOS

Insler & Lunenfeld. New York: Churchill Livingston, 1972; WHO. Cambridge, Cambridge University

Press, 1993; ESHRE Capri Workshop. Hum Reprod 1996;11:1779807

E2, oestradiol; FSH, follicle-stimulating hormone; IVF, in v i t rofertilization; LH, luteinizing

hormone; OI, ovulation induction; PCOS, polycystic ovary syndrome


6/57


7/57


8/57


9/57


10/57


11/57


12/57


13/57


14/57


15/57


16/57


17/57


18/57

Chronic Low Dose Protocol


19/57

Merck Serono has led the development of

gonadotrophins for therapeutic use

Follicle-

stimulatinghormone

0

10

20

30

40

50

60

70

80

90

100

%

Pergonal

(menotrophins)

Metrodin

(urofollitrophin)

Metrodin HP

(highly purifiedurofollitrophin)

Gonal-F

(recombinanthFSH)

Luveris

(recombinanthLH)

Ovidrel

(recombinanthCG)

1960s Mid-1980s 1990s developments 2000

U-LH

Urinaryproteins

R-hLH

R-hCG

BIOLOGICALEXTRACTS

PURE MONO-

THERAPEUTICS


20/57

Improved Ovarian Response

r-hFSH vs u-FSH in WHO Group II PatientsBalasch et al, 1998, J. Assisted Reprod. & Genetics

HP-FSH

20

15.8 1.8

17.2 2.81290 210

85.4 7.9

275 34

22.3 3.0

1.0 0.3

0.2 0.11.1 0.07

P Value

0.01

0.0030.003

0.05

0.009

0.002

NS

NSNS

Parameter

Cycles

FSH required

- Days of treatment

- Ampoules- IU

- Daily effective dose

Estradiol on hCG day (pg/ml)

Inhibin A on hCG day (pg/ml)

No of follicles on hCG day

11-13 mm

> 13-17 mm> 17 mm

rFSH

20

11.5 0.9

10.5 1.1787 90

73.9 6.1

473 82

48.2 7.0

0.8 0.2

0.4 0.31.2 0.1

%

-28%

-39%

N.S. = not s ign if icant


21/57

Pregnancy Rates in IUI by

Different Treatment Methods(Buhler 2004 from 21 German Fertility Centres)

no stimulation

n=2150

Clomiphenen=5775

hMG

n=3298

FSH

n=18834

FSH+Antagonist

n=409

7,2 7,3

8,9

10,1

11,7

0

2

4

6

8

10

12

14

[%]


22/57

What Dose of hCG Should be Used to Trigger

Final Follicular Maturation and Ovulation?

Typical criteria for hCG administration is when onefollicle >= 18mm no more than 3 in total >=16mm

(International rhCG OI study group Fertil Steril 2001)

Studies in WHO II patients used either 5 or 10000

IU u-hCG (Hedon et al 1998: Balasch et al 2000,2001: Hugues et al 2001)

With the availability of r-hCG it has beendemonstrated that 250 mcg r-hCG (Ovidrel) is aseffective as 5000 IU u-hCG with a lower incidence

of local adverse reactions


23/57

Identities of contaminating molecules in

urine-derived human gonadotrophins

Transferrin1

Tumournecrosis factor-

binding protein1

Immunoglobulin derivatives1

Urokinase1

Epidermal growth factor1

Leukocyte elastase inhibitor

2

Protein C inhibitor2

Zinc-2-glycoprotein2

1. Giudice et al. Hum Reprod 1994;9:229122992. van de Weijer et al. Reprod Biomed Online 2003;7:547557

All are biologically

active proteins


24/57

Induction of Ovulation in WHO Group II

Anovulatory Women Undergoing Follicular Stimulation with

Recombinant Human Follicle-stimulating Hormone: A Comparison of

Recombinant Human Chorionic Gonadotropin (rhCG) and Urinary hCGFert i l i ty and Steri l i ty Vol. 75, NO. 6, Jun e 2001

85 patients randomised received 250 mcg Ovidrel and 92receieved uhCG (5000 IU)

95% ovulated with Ovidrel

88% ovulated with uhCG Serum Progesterone levels luteal phase days 5-7 significantly

higher (P= 0.036) after Ovidrel administration

Clinical Pregnancy rate was 26%

Significantly higher incidence of local adverse reactions (P=0.039) including pain and inflammation with uhCG vs rhCG


25/57

Is Luteal Phase Support Necessary in

Anovulatory Patients?

Routine luteal support is not normally applied in

OI cycles however some pateints who have a

history of a short luteal phase may benefit

from some form of support.

Low dose hCG is an effective form of luteal phase

support, but it has been associated with a higher

incidence of OHSS in FSH stimulated patients(Daya 2004)

Vaginal gel progesterone is easy for the patient to

self administer without above complications.


26/57

Efficacy and Safety of Recombinant

Gonadotrophins

Summary

Urinary Gonadotrophins

No control on UrineDonors

Contain uncharacterizedhuman proteins

Poor batch-to-batchconsistency

Low specific activity

Recombinant FSH

Constant and fullycharacterised mammalian cell

Only contains human FSHprotein

Improved batch-to-batchconsistency

Increased specific activity

Increased purity Optimal approach for risk

reduction


27/57

The Shape of Theraupeutics in Reproductive Health

Cetrotide

GnRH

Antagonist

Luveris

r-hLH

OvidrelR-hCG

Gonalf FbM

r-hFSH

Crinone

Vaginal

P4


28/57

- 3 to 12 hours of the LH surge in dramatic change of

oocyte nucleus with breakdown of dictyatechromosomes and termination of the arrested meiotic

prophase

- The first meiotic division is completed with expulsion

from first polar body

- Preovulatory changes in the follicule include thinning

of its peripheral wall, increase of volume follicle and

finally follicle rupture

- Expulsion of the oocyte and cumulus through the

stigma of the follicle in known as ovulation


29/57

Ovulation cont

This ovulation process occurs 10-12 hours after theLH peak, between 24-36 hours after the E2 peak.

LH surge is a more precise indicator to predictovulation.

LH surge occurs between 28 to 32 hours prior tofollicle rupture

Thirdly synthesis of prostaglandin have alson beeninplicated in ovulaton


30/57

Ovulation cont 1

Followed endocrinological modification of follicular

cells the formation of corpus luteum

Follicle wall becomes convuluted

Granulosa cells enlarge

LH promotes luteinization from gralunosa whichresults in progesterone production


31/57

Ovulation cont 2

The steroidogenic capacity of the corpus luteum

depend on the tonic LH levels

Progesterone production increases and reaches the

peak after 8 days of LH surge

Gonadotrophins levels decline rapidly to the basal

level as a result of negative feedback


32/57

Ovulation cont 3

Oocytes were classified as

Preovulatory (fully mature)

Immature (viable eggs with the possiability ofmaturing)

Atretic (including oocyte with fracture of thezonal)


33/57

Critical factors for high quality oocyte

production include

Patient age

Totat amount of gonadotrophins used

Time of hCG administration

Type of gonadotrophins used

Type of protocol used


34/57

Various Ovarian Stimulation Regimes

Oral anti-estrogen medications

Gonadotropins

Gonadotrophin-releasing hormone (GnRH)

analogues (medical oophorectomy)

Pulsatile GnRH


35/57

Are known by reproductive biologists since themiddle of 1920, in brief there are 3 gonadotrophins

The first is follicular stimulating hormone (FSH), to

stimulate follicular growth and ripening

The second is luteinizing Hormone (LH), with results

in follicle maturation leading to ovulation it also

regulates transformation of follicular remnants intofunctional corpora luteal


36/57

Gonadotrophins cont 1

The third gonadotrophins is Human

Chorionic Gonadotrophin (hCG) and its

produced by trophoblastic cells; its

biological action similar to LH

Are glycoproteins with molecular weight

around 30,000 daltons.


37/57

Gonadotrophins cont 2

Have been extracted from various sources

including human pituitary glands, pregnant

mare serum, urine of pregnant women, post-

mortem human hypophyses, human postmenopausal urine, from genetically

engineered hamster ovary cells


38/57

1) those who do not ovulate regularly

and/or have failed to ovulate and/or

conceive with clomiphene

2) women who ovulate on their own but

may benefit from simultaneous ovulation of

multiple eggs and the accompanyingenhanced hormonal environment

Gonadotropins are used primarily in

two groups of women


39/57

Gonadotrophin preparation available

Follicular Stimulating Hormone (FSH)

Human menopausal gonadotrophin (hMG)

Human Chorionic Gonadotrophin (hCG)


40/57

Follicular Stimulating Hormone (FSH)

Urofollitrophin (pure FSH)

Recombinant human FSH

One ampoule consists of 75 iu or 150 iu

FSH (containing FSH, LH the ratio of

100:1)


41/57

Human Menopausal Gonadotrophin

(hMG)

This is produced from post menopausal

urine.

Each ampoule contains 75 iu of LH and 75 iu

of FSH activity


42/57

When ovulation is to be triggered

Administered, usually 24 to 48 hours after the

last dosage of hMG or FSH

The dose is either 5000 or 10,000 iu

The hCG has similar effects with LH but has

longer half life

Human Chorionic Gonadotrophin

(hCG)

R i G d t hi


43/57

Regimes Gonadotrophins(Thomson and Hansen, 1970)

- Daily hMG is given overlapping with hCG for

the last 1 to 3 days, occasionally given

continously for 1 to 2 days after stopping

hMG

- Daily hMG followed by hCG from one to three

days, starting from 1 to 2 days after the last

hMG dose (not overlapping)

Regimes Gonadotrophins


44/57

Regimes Gonadotrophins

(Thomson and Hansen, 1970)

- hMG on day 1,4, and 8 followed by hCG onday 11

- hMG with hCG administration at the end,either overlapping or not

- hMG alone

- hMG in a single large dose followed by hCGin day 11

- hMG combined with CC

Regimes gonadotrophins


45/57

Regimes gonadotrophins(Jones et al, 1990)

Two ampoules of hMG were given beginning on day three of themenstrual cycle, and continued until a satisfactory response

Combo I, two ampoules of hMG were given beginning on day threeof the menstrual cycle, supplemented by two ampoules of FSH ondays three and four, until satisfactory response

Combo II, two ampoules of hMG were given beginning on daythree of the menstrual cycle, supplement by two ampoules of FSHon day three and four, with further supplementation FSH onsubsequent days, until a sastifactory response

4-4 FSH two ampoules of FSH were given beginning on day

three of the menstrual cycle, supplemented by two ampoules ofFSH on days three and four, until a sastifactory response wasobtained

Two ampoules of FSH were given beginning on day three of themenstrual cycle, supplemented by other FSH beginning on day

three, until a satisfactory response.


46/57

Regimes gonadotrophins(Serono, adopted from drug information)

Alternate day therapy. Treatment with hMG on threeanternate days followed by hCG on day 8 of thecycle

Daily therapy, hMG given daily with treatment for 7days, followed by hCG 24 to 48 hours after the lastdose of hMG

Treatment with pure FSH. Is given 8 to 10 days, alsothrough combination of FSH and hMG can be given.Once adequate E2 concentration is reached, hCGcan be administration


47/57

Regimes gonadotrophins(Lutan D, 1993)

Combination of CC+hMG, 50-100 mg cc and 1 ampoule hMGdaily from day 2 until hCG (5000 IU) administration

Combination of CC+FSH, 50-100 mg cc and 75 IU (1 ampoule)FSH daily from day 2 until hCG (5000 IU) adminstered

Human menopausal gonadotrophin (hMG) alone, 225 IU FSH and225 IU LH (3 ampoules) daily from day 2 until hCG (5000 IU)adminstration

Pure follicular stimulating hormone (FSH), 225 IU (3 ampoulesFSH) daily from day 2 until hCG (5000 IU) administered

Combination of FSH + hMG, 2:1, 2 ampoules of FSH and 1ampoules of hMG were administered daily from day 2 of thecycle for 5 days, thereafter only hMG was given and the dosedepended on the response of the patients until hCG (5000 IU)administration


48/57

Regimes gonadotrophins(Jamaan T and Anwar NC,2006)

Clomifen citrate and hMG sekuensial

Flare protocol and FSH/hMG

Fixed dose regiment FSH/hMG

Protocol antagonist and FSH

R i d t hi


49/57

Regimes gonadotrophins(Speroff L and Fritz MA, 2005 )

Step-up Regimen, begin low daily dose (75 IU). After4 to 7 days of stimulation the dose ofgonadotrophins may be maintained or increaed.When the mean diameter of the lead follicle reaches15-18 mm, hCG is adminstered to trigger ovumrelease

Step-down regimen, treatment begins with a higherdose (150-225 IU daily)

Sequential treatment with clomiphene andgonadotrophins, 50-100 mg daily cc, followed bylow-dose FSH or hMG (75 IU daily)

Adjuvant treatment with GnRH


50/57

Gonadotrophin-releasing hormone (GnRH)

analogues with gonadotrophins

The potent GnRH analogues are able to reduce thelevels of endogenous gonadotrophis, to suppressthe positive LH feedback mechanism and increasethe number of follicles (medical oophorectomy)

Administered in three protocols, the long, the shortand the ultrashot

Another respectively termed as the flare-down, theflare-up and the ultra-shot

Gonadotrophins, with hMG.

M i i d hi


51/57

Monitoring gonadotrophin

therapy/prediction of ovulation

Serum oestradiol levels

Luteinizing hormone (LH) surge

Ultrasonography Basal body temperature

Cervical mucus

Mittelschmerz

Vaginal squamous epithelium



52/57


adminstration

Objectives of hCG administration are to initiate final

oocyte maturation and normal corpus luteumformation

Disadvantages encountered involve the maturity of thefollicles when the hCG is given and the time of interval

between the injection and ovulation

These two factors are closely related. Follicular growthis usually monitored by daily serum or urinaryoestradiol and ultrasonography

The time interval between the injection hCG andovulation, 32-42 hours after injection

Doses hCG, for initiating ovulation was 5000 IU.


53/57

Luteal Phase Support

First regime progesterone 25 mg im, wasgiven daily from the 5th day (day 0 being theday of preovulatory) to the 16th. Blood testB-hCG was done on the 14th and 16th day

The other luteal support regime was hCG1000IU on days 4,7,10 and 13 afterpreovulatory. Blood test was done on the16th and 18th day

C li ti f d t hi


54/57

Complication of gonadotrophin

therapy

Multiple pregnancy abortion, neonatal deathsand congenital abnormalities

The hyperstimulation syndrome, mildhyperstimulation is a common finding andhas no clinical significance

Hyperstimulation may be catagories intomild, moderate and severy

Grades of hyperstimulation


55/57

Grades of hyperstimulation(Rabau et al, 1967)

A. Mild, 1.urinary oestrogen above 150 ug and

urinary pregnandiol above 10 mg, but no palpablecyst or enlargement of ovaries. 2. Enlargement ofovaries with or without palpable cyst formation

B. Moderate, 3. enlargement of ovaries or cyst,

distention of abdomen, nausea. 4. Enlargement ofovaries of cyst, distention of abdomen, nausea,vomiting and/or diarrhea

C. Severe, 5. Enlargement of ovarian or cysts,include distention of abdomen, nausea, vomitingand/or diarrhoea, plus fluid in abdomen and/orpleura. 6. Same as group 5 plus change in bloodvolume, viscosity and coagulation time.

Grades of hyperstimulation


56/57

Grades of hyperstimulation(NG, at al, 1991 based on WHO, 1973)

Mild, oestradiol (E2) of at least 1500 pg/ml, and

ultrasonic evicence of at least 10 follicles and no lutealphase complications

Moderate, with luteal problems of enlarged, painful

ovaries, high oestradiol of at least 3000 pg/ml, ascitesof less than 1.5 liters, and without grossly distendedabdomen

Severe, with grossly distended abdomen due toexcess ascites and possible hydrothorax. May beassociated with fluid-shift problems resulting inhaemoconcentration, hyper-coagulopathy andelectrolyte changes. Requires hospitalisation and may

require paracentesis


57/57

Delfi Lutan Induksi Ovulasi

Documents

Transcript of Delfi Lutan Induksi Ovulasi