Luteal phase events are dependent on follicular recruitment and

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D.G.F CME on
11th April 2018
at Hotel Leela Ambiance Delhi
Luteal Phase Defect
Contributors
Dr.Shweta Mittal Gupta & DGF Team Experts

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Dr.Shweta Mittal Gupta
Senior Consultant , Centre of IVF and
Human Reproduction, Sir Ganga Ram
Hospital
Luteal Phase Defect

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Luteal phase events are dependent
on follicular recruitment and
folliculogenesis

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There is a shift of FSH dominance
to LH dominance in luteal phase
 Normal length of luteal phase
in a non-fertile cycle is 14-16
days
 After ovulation, luteinization of
granulosa and theca cells
occurs, progesterone is
produced which maintains
luteal phase

5. + Theca cells derived from lutein cells are
responsive to LH and produce progesterone in
late luteal phase.

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Definition
 1949, Jones defined as corpus luteum defects in progesterone
secretion
 Luteal phase defect: is defined as luteal phase not capable of
implantation or maintenance of pregnancy.
• Luteal phase shorter than 12 days (duration between ovulation and
menses) with relatively normal progesterone levels
Hyashi et al, J endocrinology,1993
• A normal length luteal phase with inadequate progesterone
production or inadequate response of endometrium to normal
progesterone production

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LPD (Endometrial out of phase >3
days) (Jones/ Balash and Vanrell)
4.4% in fertile population (Li and colleagues)
3.5-13 % % in infertile patients
32-35% recurrent miscarriages

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Preparation
Production
Response
Inadequate FSH nd estradiol levels will make corpus luteum less responsive to LH
and hCG
Defects in

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Causes
 Abnormal folliculogenesis
 Inadequate LH surge
 Inadequate progesterone by corpus luteum
 Aberrant end organ response by the endometrium
Hyperprolactinemia and hypothyroidism

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Pathophysiology
 Follicular phase FSH has been implicated as a crucial factor in
corpus luteum function
 Others have focused on LH patterns of pulsatile secretion.
 An increased follicular LH frequency in follicular phase will
leads to stunted luteal phase amplitude in luteal phase.

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How hyperprolactinemia can cause
LPD?
 Both hyperprolactinemia as well as oversuppressed
prolactin levels effect progesterone production from
corpus luteum
 Possibly due to altered GnRH pulsatility as an effect
due to dopamine levels
 A cut off of 20 ng/ml with LPD could be explained

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Clomiphene and LPD
 Ovulation induction with clomiphene in anovulation/unexplained
infertility has been associated with as high as 25-50 % out of
phase endometrium
• Increased FSH to LH ratio
• Inadequate midcycle surge
• Imbalance of oestradiol to progesterone ratio
• Antioestrogenic effect on endometrium

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Do gonadotropins causes LPD ?
As high as 30% LPD have been observed in
gonadotropin induced cycles
Supraphysiological levels of estradiol leads
to stromal glandular dyssynchrony

14. Peri & post
ovulatory period
endometrial
advancement in
high responders
Frequent
glandular and
stromal
dyssynchrony in
mid & late
luteal phase
(De Ziegler et al 1994, Toner et al 1993)
Luteal phase defects in
gonadotropin stimulated cycle

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Exercise and LPD
 Women undertaking moderate to heavy forms of exercise (2
hours or more per day or 16 km per week), upto 50 % showed
prolonged follicular phase, short luteal phase amounting to LPD
 Complex opiopd compounds are responsible in CNS to inhibit
GnRH pulse generator thereby reducing LH pulse frequency in
follicular and luteal phase.

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Recurrent spontaneous abortions
 Women with RPL can show LPD in as high as 32.5-60% of
cycles in non conception cycles.
 Horta and colleagues sowed lower serum progesterone levels
in luteal phase (day 3-12 post ovulation, samples taken daily) in
women with RPL.
 Babalioglu et al took timed endometrial biopsy and multiple
luteal phase progesterone levels and results were same as
above.

17. Aspiration of granulosa cells that surround oocyte
can interfere with production of progesterone, which
is necessary for successful implantation of the embryo
Daya et al, Cochrane 2004 systematic review (updated in 2008)
LPD specific in IVF cycles

18. Aspiration of
granulosa cells of
follicles may
interfere with P
production in IVF
cycles
GnRH agonist
directly have anti
proliferative
effects on the
endometrium
Stimulated cycles may lead
to early and increased
exposure to progesterone
Elevated S.E2 may lead
to glandular-stromal
dys-synchrony &
endometrial
advancement
Trigger for oocyte
maturation may
lead to disrupted
endometrial
morphology
IVF CYCLES

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Trigger for final oocyte maturation
Luteal phase insufficiency also depends on
the trigger used for final oocyte maturation:
 GnRH agonist – profound LPD
 Rec. LH- intermediate LPD
 hCG- least LPD
(Beckers et al, 2003)

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In diagnosis LPD few factors to be
considered are:
 Patient selection
 Test sensitivity and specificity
 Invasiveness
 Convenience
 cost

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In Whom to suspect and offer ?
 Patients of unexplained infertility
 advanced maternal age
 recurrent abortions
 strenuous exercise
 underweight or recent sudden weight loss
sec.amenorrohoe
 Hyperprolactinemia/hypothroidism

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Diagnoses
 Diagnosis LPD is a challenge.
 Timed endometrial biopsy (>2->3 days out of phase) should
help in diagnosing LPD
 Preferred time of endometrial biopsy would be between 6-10
days post ovulation as it coincides with window of implantation
 In order not to over diagnose LPD two biopsies should reveal
similar picture histologically.
 Future would be identifying integrin molecules and
glycoprotiens may indicate uterine receptivity.

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Serum progesterone
 Since progesterone is secreted in a pulsatile manner, single
estimation hold little value done in luteal phase.
 Jordan and colleagues suggested pooling of three
progesterone values (between luteal day 5 and 9), and values
cut offs of 30 ng/ml had a sensitivity of 100% and specificity of
80%
 Ultrasound can be used to trac follicle, follicular rupture at <17
mm size could suggest LPD.

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Points
 LPD is relevant if present in most of the menstrual cycles.
 LPD can only be diagnosed after repeat testing
 Requirement for two consecutive menstrual cycles is also
arbitrary

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Treatment approach to LPD
 Treat two important cause of LP : Hyperprolactinemia or
abnormal thyroid function
 Clomiphene (CC) is not used as first line treatment modality for
LPD as it can potentially cause LPD
• However CC can be used in cases of LPD who have short or abnormally long
follicular phase, who ovulate at follicles < 18 mm
• These are cases of abnormal folliculogenesis

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Progesterone supplementation
 Progesterone supplementation in the luteal phase is the
commonest form of treating LPD as first line management
 4 days after detection of urine LH, progesterone can be started
(200-400 mg in divided doses, vaginally)
 Very early introduction of progesterone can suppress
periovulatory cervical mucous and to maximize effect of
progesterone at time of nidation.

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Why Progesterone for LPS??
 This recognition of pregnancy results in an upregulation of
progesterone receptors on activated lymphocytes amongst
placental cells and decidual CD56+ cells.
 In the presence of sufficient progesterone, these cells
synthesise a 34-kDa protein named progesterone-induced
blocking factor (PIBF), a mediator that exerts substantial anti-
abortive activities.
Source: Szekeres-Bartho J et al. Chem Immunol Allergy. 2005;89:118-25.
Druckmann R, Druckmann MA. J Steroid Biochem Mol Biol. 2005;97(5):389-96.
27

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Chemical structure of
progesterone
Natural Progesterone
 Identical structure and similar
actions as that of endogenous
progesterone
 Micronized particles
(<10 microns)
 Capsule, pessary/ suppository,
gel, ampoule; VT (100 / 200 /
300)
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0
CH3
CH3
C=0
CH3

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Structural Modification of
Progesterone
 Dydrogesterone is retroprogesterone, stereoisomer of progesterone, with additional double
bond between carbons 6 and 71
 Dydrogesterone, shaped by light, enhances progestogenic effects (improved bioavailability,
and specificity and affinity for progesterone receptor)2
1. Kuhl H. Climacteric 2005; 8(Suppl 1): 3-63.
2. Schindler AE et al. Maturitas 2009; 65(Suppl 1): S3-S11.
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Progesterone Dydrogesterone

30. Routes and doses of administration
 Vaginal : Suppositories 200 to 800 mg/day in 2-
3 times/day and Gel (crinone 8% 90mg daily
once) SR
Prospective RCT: gel vs suppository n=126; comparable
results in terms of PR, abortion rate and ongoing PR
(Ludwig et al., 2002)
Ease and side effects less of gel (Simunic et al 2007)
 Intramuscular: 25 to 100 mg once daily
 Rectal suppositories: 200 to 600mg 2-3
times/day
 Oral tablets: 200-800 mg 3 to 4 times/day
Progesterone as luteal support
(micronized )

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Dihydrogesterone (retro progesterone)
• Orally active (unlike micronized
progesterone)
• Dose: 20mg to 30mg /day orally in 3 divided
doses
• Can replace micronized progesterone
(Vaginal or intramuscular) in patients
sensitive/allergic to it with comparable results
Progesterone as luteal support

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First uterine pass effect of Vaginal P

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LPS: Clinical Evidence
 Progesterone-induced blocking factor (PIBF) modulates
cytokine production by lymphocytes from women with recurrent
miscarriage or preterm delivery.
Raghupathy R et al. J Reprod
Immunol.
2009;80(1-2):91-9.
 Production of the type 2 cytokines IL-4, IL-6 and IL-10 by
lymphocytes from the RSM and PTD groups and of IL-4 and IL-
10 by lymphocytes from healthy pregnant women was
significantly increased upon exposure to PIBF, while the levels
of type 1 cytokines were not affected; PIBF induces a type 1 to
type 2 cytokine shift.
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Balasch J et al. (1982)
 44 infertile women with LPD (diagnosed by histological
assessment) confirmed in at least 2 consecutive cycles
 Dydrogesterone (20 mg/day) or Progesterone suppositories 25mg
BD for at least 3 months & no treatment
 Success rate significantly higher with dydrogesterone (68.7%) &
progesterone (62.5%) than in control group (16.6%)
(p < 0.001)
 Equivalent to absolute treatment effect (ATE) of 45.9%, which translates
into number needed-to-treat (NNT) of 2
 Pregnancy rate - 31% in both active treatment groups, compared
with 17% in group that received no treatment
Success rate, defined as correction of the endometrial defect (i.e. normal secretory pattern in
the endometrial biopsy) during the fourth treatment cycle if pregnancy was not achieved, or term
pregnancy
Balasch J, Vanrell JA, Márquez M, Burzaco I, González-Merlo J. Dehydrogesterone versus
vaginal progesterone in the treatment of the endometrial luteal phase deficiency. Fertil Steril.
1982;37:751-4.
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Author(s) Key Findings
Malik et al.
(2000)1
• 25 patients suffering from LPD; Duration - 3 months;
Dose – Duphaston 10 mg BD from day of ovulation for 14
days for 3 cycles
• Dydrogesterone treatment resulted in 100% secretory
conversion of endometrium
• Pregnancy rate - 37.5% with no side effects observed
with dydrogesterone therapy in this study
• Of which 20.83% achieved pregnancy within first month
Malik et al. (2000)
1. Malik S et al. Obs & Gynae. 2000(8):497-501.
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36. Corpus luteum can be rescued by hCG (1980)
Advantage: hCG stimulates CL to produce
progesterone & E2 both. Also produces
placental protein 14 (Anthony et al., 1993), integrin
α√β3 (Honda et al.,1997), relaxin (Ghosh et al.,1997)
to support luteal phase and early pregnancy.
Disadvantage: Risk of OHSS increases
Dose 1500 to 2000 units on day 0/1, 3/4 and 6/7
of oocyte retrieval
Not to be given within 7 days of pregnancy test, as
may interfere with pregnancy detection
hCG as luteal support

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• Same Pregnancy rate
(meta-analysis; Pritts & Atwood 2002)
• Higher Pregnancy rate
(meta-analysis; Nosarka et al.,2005)
Evidence for hCG vs
Progesterone for luteal
support

38. Novel method of luteal support with GnRH agonist
Stimulates pituitary gonadotrops to produce more LH
Acts directly on endometrium by locally expressed
GnRH receptors
May act on the embryo with doubtful adverse effects
1 mg/day for 2 to 3 days from day 5 or 6 of OCR
Mainly effective in antagonist treated gonadotropin
stimulated cycles
Tesarik et al 2006, Pirard et al., 2005,Lambalk and Homburg 2006
Progesterone with GnRha for
luteal support

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 Luteal phase deficiency has a multifactorial cause.
 Still medical literature has failed to confirm its true existence
and investigations have failed to truly demonstrate its incidence
conclusively.
 Three pooled luteal progesterone seems to be best way to
diagnose LPD
 Progesterone is the first line treatment for support in luteal
phase
 Detecting and correcting defective follicular phase defects can
correct luteal phase defects

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 When a thing ceases to be a subject of controversy, it
ceases to be a subject of interest.
 Similarly is Luteal Phase Defect
 Thank You
9910303056, mshwets@hotmail.com

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Thank You