Maintenance of pregnancy
Corpus luteum Progesterone
After ovulation ~ during the early first trimester ~ until placental function established
Removal of the corpus luteum spontaneous pregnancy loss
Ovarian progesterone production implantation & early pregnancy
2. Maintenance of pregnancy
• Cor pus lut eum Progest er one
– Af t er ovulat ion ~ dur ing t he ear ly f ir st
t rimest er ~ unt il placent al f unct ion
est ablished
– Removal of t he cor pus lut eum
spont aneous pregnancy loss
• Ovarian pr ogest er one pr oduct ion
implant at ion & early pr egnancy
3. - Ovarian inadequacy
• As a cause of inf er t ilit y or pr egnancy
f ailur e ?
Cycles (Concept ion occurs vs. no
concept ion):
• More r apid rise of progest erone
• ↑ mid-lut eal est rogen and pr ogest er one
levels
Cycles (Nor mal vs. biochemical
pr egnancies):
• Similar ly lut eal phase pr ogest erone levels
4. - Delayed implantation
• Associat ed wit h ↑Pregnancy loss
• More likely a r esult of an embryonic
pr oblem wit h inadequat e early hCG
production
• Rat her t han an inappropriat e ovarian
response
5. Luteal phase deficiency (LPD)
• Endogenous progest er one is not suf f icient t o
– Maint ain a f unct ional secr et ory
endomet rium
– Allow normal embryo implant at ion and
growt h
– 1st descr ibed in 1949
6. Luteal Phase Deficiency (LPD)
Pur port edly been associat ed wit h:
1. I nf ert ilit y
2. 1st
t rimest er pregnancy loss
3. Short cycles
4. Premenst rual spot t ing
5. Anorexia
6. St arvat ion
7. Eat ing disorders
8. Excessive exercise
9. St ress
10. Obesit y & PCOS
11. Endomet riosis
12. Aging
13. I nadequat ely t reat ed 21-
hydroxylase def iciency
14. Thyroid dysf unct ion &
hyperprolact inemia
15. Ovulat ion st imulat ion alone
16. Ovulat ion induct ion wit h or
wit hout GnRH agonist s
17. ART
7. Luteal Phase Deficiency (LPD)
Has been shown t o occur:
• During t he post par t um period
• Wit h signif icant weight loss or exercise
• I n random cycles of nor mally menst r uat ing
women
8. Luteal phase deficiency (LPD)
• Clinical signif icance: Cont rover sy
– Lack of a r eliable t est t o diagnose
– Only clinically r elevant if it is consist ent ly
pr esent in most cycles
– Appear s t o be an associat ion wit h
inf er t ilit y
– Not been est ablished as a cause of
inf er t ilit y
• This r epor t : Addr ess cont rover sies regarding
t he diagnosis & pot ent ial t r eat ment of lut eal
10. In women with hypothalamic amenorrhea
• Abnormalit ies in GnRH, FSH, LH pulsat ilit y
↓ Lut eal est rogen & pr ogest erone
secr et ion
• ↓ LH pulsat ilit y abnormal pr ogest erone
secr et ion:
– Pr oblemat ic in ovulat ion induct ion cycles
11. Thyroid & prolactin disorders
• Disrupt GnRH secret ion
• Alt er t he hypot halamic-pit uit ary-ovarian axis (HPO-
axis)
– HypothyroidismHypothyroidism
↑ Thyrot ropin-releasing hormone
↑ lact ot rope prolact in product ion & secret ion
HyperprolactinemiaHyperprolactinemia
– HyperprolactinemiaHyperprolactinemia I nhibit GnRH secret ion
• (Direct ): On GnRH neuronal prolact in recept ors
• (I ndirect ): ↑ Hypot halamic dopamine & opioid
pept ide levels
12. Conditions that have been associated with
altered luteal progesterone levels
• Renal t ransplant at ion
• ↑ bet a-endor phin
• lact at ion
• Condit ions t hat alt er normal gonadot ropin secret ion
I mpair f ollicular development & ult imat ely corpus lut eum
f unct ion
Changes in t he amount and durat ion of lut eal sex st eroid
secret ion
Compromise endomet rial development
• Correct i ng t hes e underl yi ng condi t i ons
correct t he abnormal l ut eal es t rogen &
proges t erone s ecret i on
13. Obesity
• Negat ive impact :
• ↓Fert ilit y & ↑Pregnancy loss rat e
• Part icularly evident in t he morbidly obese
• A recent st udy (ObeseObese Normal weight women)
• As wit h anorexic women
• Alt erat ion of LH pulsatilityLH pulsatility (↓Pulse amplit ude)
• ↓↓ lut eal phase pregnanediol glucuronide (t he
maj or metabolite of progesteronemetabolite of progesterone)
• The cont ribut ion t o ↓ fecundity ratesfecundity rates: Unknown
14. Ovarian Aging
• Abnormalit ies in lut eal phase f unct ion
– Def iciencies in lut eal phase pr ogest er one (in
earlystudy)
– Def iciencies in bot h lut eal phase
pr ogest erone & est radiol met abolit es (inrecent
study)
• The cont r ibut ion t o ↓ pr egnancy rat es & ↑
loss r at es: Unclear
15. Pathophysiology of luteal inadequacy
• May include several dif f erent
mechanisms t hat ult imat ely af f ect
endometrial developmentendometrial development
16. Short luteal phase
• (LH peak ~ Onset of menst rual f low): I nt erval ≤ 8 days
11– 13daysConsiderednormal
Follicular phase abnormalit ies
• Low f ollicular FSH levels
• Alt ered f ollicular FSH/ LH rat ios
• Abnormal FSH & LH pulsat ilit y
↓Lut eal est rogen & progest erone levels
• May occur in young healt hy♀ wit h regular cycle lengt h
Clinical consequences: unclear
17. During cycles with IVF
• Lut eal phase may be abnormal
• Cycle wit h GnRH agonist s
– Prolonged suppression of pit uit ary LH secret ion (3
weeks af t er down regulat ion)
– Lut eal phase inadequacy and subf ert ilit y
• Cycle wit h GnRH ant agonist s
– Recovery of LH product ion f rom t he pit uit ary is
quit e rapid f ollowing cessat ion
– St ill have signif icant reduct ions in pregnancy
rat es/ clear negat ive clinical impact in t he lut eal
phase
18. During cycles with IVF
• Hypot hesis: I n t he st imulat ory phase:
High gonadot ropin levels Suppress endogenous LH
↓ progest erone secret ion & premat ure lut eolysis
I n Superovulat ion & int raut erine inseminat ion (SO-
I UI ) cycles or Gonadot ropin ovulat ion induct ion (OI )
cycles f or PCOS:
– Adding GnRH agonist s
• Did not ↓ t he pregnancy rat e, lut eal est rogen
or progest erone levels
• Did not alt er endomet rial dat ing
20. Diagnostic tests are influenced by and based
upon the following physiologic observations:
1. Normal lut eal phase lengt h: 12–14 days
2. [Progest erone] peak in non-pr egnancy cycles:
6 ~ 8 days af t er ovulat ion
3. Pr ogest erone is secret ed in pulses
4. Endomet r ial response: A ref lect ion of t he
f ollicular phase est r ogen & t he lut eal phase
est r ogen & progest er one
21. 5. Once implant at ion occurs, pr ogest erone
secr et ion by t he cor pus lut eum: Dependent
upon ↑ [hCG]
6. Failure of [hCG] ↑ dir ect ly causes corpus
lut eum f ailur e ↓ pr ogest er one levels
22. Methods proposed for diagnosing LPD
• Basal body t emperat ur e (BBT) char t ing:
• I naccuracy, inconvenience, should be
discour aged
• Serum progest erone levels
• Endomet r ial biopsy
• Ovulat ion & adequat e lut eal lengt h:
• Ur inar y LH sur ge det ect ion & Monit or ing of
lut eal lengt h
23. Progesterone Levels
• Secret ed in pulses (Ref lect LH pulses)
• Wit hin 90 minut es: Fluct uat e up t o 8- fold
• Af t er ovulat ion (- pr egnancy): Peak6 ~ 8 days
– Det ermine peak pr ogest erone levels
Need det ermine t he t ime of ovulat ion
Urine LH f alse-posit ive LH surge
24. Progesterone Levels
• During t he lut eal phase: No st andar d
charact erizat ion
• No minimum conc. ‘‘f ert ile’’ lut eal f unct ion
• Cor pus lut eum f unct ion in nor mal f er t ile
women: var ies f r om cycle t o cycle
Random levels: Not a valid clinical diagnost ic
t ool t o evaluat e luteal phase adequacyluteal phase adequacy
25. Progesterone Levels
• Pr egnancy hCG Cor pus lut eum
Pr ogest erone
↓ Pr ogest er one levels in ear ly pregnancy:
Nonviable or ext r a-ut erine pr egnancy
Abnormal hCG st imulat ion
Should not be used t o init iat e t herapy wit h
exogenous progest erone
26. Endometrial Biopsy
• Abnormalit ies of endomet r ial mat urat ion:
• I nadequat e ovar ian hormone secr et ion
• I nt rinsic endomet r ial abnormalit y
• ‘‘Gold st andar d’’ t o diagnose luteal
inadequacy
27. Endometrial Biopsy
• luteal inadequacy
• I dent if y: Micr oscopic appear ance of lut eal phase
endomet rial development
• Pr event : Normal implantation or ear ly placent al
development
• Associat ed wit h: Changes in st er oid recept or s,
st r uct ural prot eins, gr owt h f act or s, cyt okines,
recept or s, pinopodes
• Normal luteal phase endometrial development:Normal luteal phase endometrial development:
Clinically applicable cr it er ia is complex & evolving
28. Endometrial Biopsy
• For hist ologic endomet rial dat ing Not a
valid clinical diagnost ic t ool f or
• The ident if icat ion of an inf ert ile populat ion
• The diagnosis or t r eat ment of LPD
• Low pr ogest erone levels I nadequat e
endomet rial development ?
• ↓ Pr ogest erone t o 3–10 ng/ mL No evident
impact wit h hist ological dat ing
29. Additional markers
• Biochemical, mor phological, or molecular
marker s of endomet r ial f unct ion
To det er mined when or if t he endomet r ium
is r ecept ive t o implant at ion
No mar ker validat ed in dist inguishing
nor mal f er t ile women f rom inf er t ile women
30. Molecular markers of receptivity
• I n t he subj ect s wit h ↓ progest er one
replacement : Dif f er ent endomet r ial pr ot ein
expr ession
Pot ent ially mor e subt le def iciency
• Remain experiment al and are not valid clinical
diagnost ic t ools
31. Summary
• No reproducible, physiologically relevant , and
clinically pract ical st andard
Diagnose LPD
Dist inguish f ert ile f r om inf er t ile women
• BBT, lut eal pr ogest er one levels, endomet r ial
biopsy & ot her diagnost ic st udies
Have not been est ablished
Perf ormance of t hese t est s cannot be
recommended
32. IF DIAGNOSIS IS NOT POSSIBLE, IS
TREATMENT FOR LUTEAL INADEQUACY
EVER APPROPRIATE?
33. Treatment of potential luteal inadequacy
• 1st
approach: Correct ion of any underlying condit ion
(hypothalamicorthyroiddysfunction, hyperprolactinemia)
• 2nd
: Empiric Treat ment (based on limit ed reliable dat a)
• Promot e endomet rial mat urat ion
• Enhance endomet rial r ecept ivit y
• Suppor t implant at ion and development of an early pregnancy
• St rat egies: Progest erone, progest erone + est rogen, hCG in
t he lut eal phase, Ovulat ion induct ion wit h clomiphene or
gonadot ropins
34. Ovulation Induction
• I mproved pre-ovulat ory f ollicular dynamics Should
improve corpus lut eum f unct ion
? Use of agent s t hat induce ovulat ion I mproved
corpus lut eum f unct ion & f ert ilit y out comes
• 1st
problem: Def init ion of luteal insufficiencyluteal insufficiency
• Surrogat e endpoint s: progest erone def iciency or
out -of -phase endomet rium
• Poor f ert ilit y out comes Surrogat e endpoint s
Unsuccessf ul
• 2nd
:‘‘Ovulat ion induct ion st rat egies’’ improve f ert ilit y
by inducing mult iple ovulat ion and not by correct ing
LPD
35. Progesterone
• Or ally, Vaginally, I nt r amuscular r out e
• Benef icial in nat ur al, unst imulat ed cycles: no
evidence
• Only well-document ed indicat ion: For t he
impr ovement of ART out comes in GnRH
agonist or ant agonist st imulat ion cycles
36. Progesterone supplementation
• I M Progest erone Highest serum levels
• Vaginal Progest erone ↑ Endomet rial t issue levels
• Oral progest erone
Only ~10% of micronized progest erone is absorbed
int act t hrough GI t ract
↓ Pregnancy rat es
Should not be used f or lut eal support
• Should be administ ered unt il placent al progest erone
product ion is adequat e (8–10 weeks of gest at ion)
37. hCG
• I n GnRH agonist / ant agonist ART cycles
• Lut eal supplement at ion wit h hCG
St imulat es t he ovaries (or corpora lut ea) boost product ion
of endogenous pr ogest erone & est radiol
↑ Delivery rat es
↓Spont aneous abort ion rat es
↑↑ Moderat e or severe OHSS
Low-dose hCG (500 I U every ot her day)
minimal risk of inducing OHSS
38. hCG
Clinical equivalence wit h int ramuscular progest erone
Higher incidence of side ef f ect s wit h Hcg
Lut eal progest erone is generally pref erred in GnRH
agonist / ant agonist I VF cycles
• Once pregnancy is est ablished
– Supplement al hCG is not benef icial
– RCT: hCG f or 1st
-t rimest er vaginal bleeding
Miscarriage rat e: 11% 12% (hCG)
39. SUMMARY
• Abnormal luteal function may occur as t he result of
a medical condit ion
– e.g., Elevat ed prolact in, abnormal t hyroid f unct ion
– I nf ert ile women should be invest igat ed and
t reat ed f or t hese disorders and ident if ied
condit ions
• No diagnost ic t est f or lut eal phase insuf f iciency has
been proven reliable in a clinical set t ing
– BBT, lut eal progest erone levels, endomet rial
biopsy, or ot her diagnost ic st udies
– Perf ormance cannot be recommended
40. • No t reat ment f or lut eal phase insuf f iciency
has been shown t o improve pr egnancy
out comes in nat ur al, un-st imulat ed cycles
• Lut eal suppor t af t er ART procedures
(progest erone or hCG)
– I mpr oves pr egnancy out comes
– hCG increases t he r isk of OHSS
41. • Not proven benef icial:
– Pr ogest erone or hCG f or lut eal suppor t :
Once a pregnancy has been est ablished
– Pr ogest erone in a non-ART cycle beyond
t he t ime of expect ed menses (i.e., 2 weeks
af t er ovulat ion)
42. CONCLUSIONS
• Pr ogest erone is impor t ant f or t he process of
implant at ion and early embryonic development
• LPD, as an independent ent it y causing
inf er t ilit y, has not been proven