The clinical relevance of luteal phase deficiency: a committee opinion Fertility and Sterility Vol. 98, No. 5, November 2012 Presenter: R4 孫怡虹 Advisor: VS 鍾明廷

INTRODUCTION

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

- Ovarian inadequacy As a cause of infertility or pregnancy failure ?  Cycles ( Conception occurs vs. no conception ): More rapid rise of progesterone ↑ mid - luteal estrogen and progesterone levels  Cycles ( Normal vs. biochemical pregnancies ): Similarly luteal phase progesterone levels Pregnancy losses do not always result from ovarian insufficiencyPregnancy losses do not always result from ovarian insufficiency

- Delayed implantation Associated with ↑P regnancy loss More likely a result of an embryonic problem with inadequate early hCG production Rather than an inappropriate ovarian response

Luteal phase deficiency (LPD) Endogenous progesterone is not sufficient to –Maintain a functional secretory endometrium –Allow normal embryo implantation and growth – 1 st described in 1949

Luteal Phase Deficiency (LPD) Purportedly been associated with : 1. Infertility 2.1 st trimester pregnancy loss 3. Short cycles 4. Premenstrual spotting 5. Anorexia 6. Starvation 7. Eating disorders 8. Excessive exercise 9. Stress 10. Obesity & PCOS 11. Endometriosis 12. Aging 13. Inadequately treated 21- hydroxylase deficiency 14. Thyroid dysfunction & hyperprolactinemia 15. Ovulation stimulation alone 16. Ovulation induction with or without GnRH agonists 17. ART

Luteal Phase Deficiency (LPD) Has been shown to occur : During the postpartum period With significant weight loss or exercise In random cycles of normally menstruating women

Luteal phase deficiency (LPD) Clinical significance : Controversy –Lack of a reliable test to diagnose –Only clinically relevant if it is consistently present in most cycles –Appears to be an association with infertility –Not been established as a cause of infertility This report : Address controversies regarding the diagnosis & potential treatment of luteal inadequacy

MEDICAL CONDITIONS WITH POTENTIAL IMPACT ON LUTEAL PHASE FUNCTION

In women with hypothalamic amenorrhea Abnormalities in GnRH, FSH, LH pulsatility  ↓ Luteal estrogen & progesterone secretion ↓ LH pulsatility  abnormal progesterone secretion : –Problematic in ovulation induction cycles

Thyroid & prolactin disorders Disrupt GnRH secretion Alter the hypothalamic - pituitary - ovarian axis ( HPO - axis ) –Hypothyroidism Hyperprolactinemia –Hypothyroidism  ↑ T hyrotropin - releasing hormone  ↑ lactotrope prolactin production & secretion  Hyperprolactinemia –Hyperprolactinemia –Hyperprolactinemia  Inhibit GnRH secretion ( Direct ): On GnRH neuronal prolactin receptors ( Indirect ): ↑ H ypothalamic dopamine & opioid peptide levels

Conditions that have been associated with altered luteal progesterone levels Renal transplantation ↑ beta - endorphin lactation Conditions that alter normal gonadotropin secretion  Impair follicular development & ultimately corpus luteum function  Changes in the amount and duration of luteal sex steroid secretion  Compromise endometrial development Correcting these underlying conditions  correct the abnormal luteal estrogen & progesterone secretion

Obesity Negative impact : ↓ Fertility & ↑P regnancy loss rate Particularly evident in the morbidly obese ObeseA recent study ( Obese  Normal weight women ) As with anorexic women LH pulsatilityAlteration of LH pulsatility ( ↓P ulse amplitude ) metabolite of progesterone ↓↓ luteal phase pregnanediol glucuronide ( the major metabolite of progesterone ) fecundity ratesThe contribution to ↓ fecundity rates : Unknown

Ovarian Aging Abnormalities in luteal phase function –Deficiencies in luteal phase progesterone ( in early study ) –Deficiencies in both luteal phase progesterone & estradiol metabolites ( in recent study ) The contribution to ↓ pregnancy rates & ↑ loss rates : Unclear

Pathophysiology of luteal inadequacy endometrial developmentMay include several different mechanisms that ultimately affect endometrial development

Short luteal phase ( LH peak ~ Onset of menstrual flow ): Interval ≤ 8 days  11–13 days  Considered normal  Follicular phase abnormalities Low follicular FSH levels Altered follicular FSH / LH ratios Abnormal FSH & LH pulsatility  ↓ Luteal estrogen & progesterone levels May occur in young healthy♀ with regular cycle length  Clinical consequences : unclear

During cycles with IVF Luteal phase may be abnormal Cycle with GnRH agonists –Prolonged suppression of pituitary LH secretion (3 weeks after down regulation ) –Luteal phase inadequacy and subfertility Cycle with GnRH antagonists –Recovery of LH production from the pituitary is quite rapid following cessation –Still have significant reductions in pregnancy rates / clear negative clinical impact in the luteal phase

During cycles with IVF Hypothesis : In the stimulatory phase : High gonadotropin levels  Suppress endogenous LH  ↓ progesterone secretion & premature luteolysis  In Superovulation & intrauterine insemination ( SO - IUI ) cycles or Gonadotropin ovulation induction ( OI ) cycles for PCOS : –Adding GnRH agonists Did not ↓ the pregnancy rate, luteal estrogen or progesterone levels Did not alter endometrial dating

ARE THERE DIAGNOSTIC CRITERIA FOR INADEQUATE LUTEAL FUNCTION?

Diagnostic tests are influenced by and based upon the following physiologic observations: 1. Normal luteal phase length : 12–14 days 2.[ Progesterone ] peak in non - pregnancy cycles : 6 ~ 8 days after ovulation 3. Progesterone is secreted in pulses 4. Endometrial response : A reflection of the follicular phase estrogen & the luteal phase estrogen & progesterone

5. Once implantation occurs, progesterone secretion by the corpus luteum : Dependent upon ↑ [ hCG ] 6. Failure of [ hCG ] ↑  directly causes corpus luteum failure  ↓ progesterone levels

Methods proposed for diagnosing LPD Basal body temperature ( BBT ) charting : Inaccuracy, inconvenience, should be discouraged Serum progesterone levels Endometrial biopsy Ovulation & adequate luteal length : Urinary LH surge detection & Monitoring of luteal length

Progesterone Levels Secreted in pulses ( Reflect LH pulses ) Within 90 minutes : Fluctuate up to 8- fold After ovulation (- pregnancy ): Peak 6 ~ 8 days –Determine peak progesterone levels  Need determine the time of ovulation  Urine LH  false - positive LH surge

Progesterone Levels During the luteal phase : No standard characterization No minimum conc.  ‘‘ fertile ’’ luteal function Corpus luteum function in normal fertile women : varies from cycle to cycle luteal phase adequacy  Random levels : Not a valid clinical diagnostic tool to evaluate luteal phase adequacy

Progesterone Levels Pregnancy  hCG  Corpus luteum  Progesterone  ↓ Progesterone levels in early pregnancy :  Nonviable or extra - uterine pregnancy  Abnormal hCG stimulation  Should not be used to initiate therapy with exogenous progesterone

Endometrial Biopsy Abnormalities of endometrial maturation : Inadequate ovarian hormone secretion Intrinsic endometrial abnormality ‘‘ Gold standard ’’ to diagnose luteal inadequacy

Endometrial Biopsy luteal inadequacy Identify : Microscopic appearance of luteal phase endometrial development Prevent : Normal implantation or early placental development Associated with : Changes in steroid receptors, structural proteins, growth factors, cytokines, receptors, pinopodes Normal luteal phase endometrial development :Normal luteal phase endometrial development : Clinically applicable criteria is complex & evolving

Endometrial Biopsy For histologic endometrial dating  Not a valid clinical diagnostic tool for The identification of an infertile population The diagnosis or treatment of LPD Low progesterone levels  Inadequate endometrial development ? ↓ Progesterone to 3–10 ng / mL  No evident impact with histological dating

Additional markers Biochemical, morphological, or molecular markers of endometrial function  To determined when or if the endometrium is receptive to implantation  No marker validated in distinguishing normal fertile women from infertile women

Molecular markers of receptivity In the subjects with ↓ progesterone replacement : Different endometrial protein expression  Potentially more subtle deficiency Remain experimental and are not valid clinical diagnostic tools

Summary No reproducible, physiologically relevant, and clinically practical standard  Diagnose LPD  Distinguish fertile from infertile women BBT, luteal progesterone levels, endometrial biopsy & other diagnostic studies  Have not been established  Performance of these tests cannot be recommended

IF DIAGNOSIS IS NOT POSSIBLE, IS TREATMENT FOR LUTEAL INADEQUACY EVER APPROPRIATE?

Treatment of potential luteal inadequacy 1 st approach : Correction of any underlying condition ( hypothalamic or thyroid dysfunction, hyperprolactinemia ) 2 nd : Empiric Treatment ( based on limited reliable data ) Promote endometrial maturation Enhance endometrial receptivity Support implantation and development of an early pregnancy Strategies : Progesterone, progesterone + estrogen, hCG in the luteal phase, Ovulation induction with clomiphene or gonadotropins

Ovulation Induction Improved pre - ovulatory follicular dynamics  Should improve corpus luteum function ? Use of agents that induce ovulation  Improved corpus luteum function & fertility outcomes luteal insufficiency 1 st problem : Definition of luteal insufficiency Surrogate endpoints : progesterone deficiency or out - of - phase endometrium Poor fertility outcomes  Surrogate endpoints  Unsuccessful 2 nd :‘‘ Ovulation induction strategies ’’ improve fertility by inducing multiple ovulation and not by correcting LPD

Progesterone Orally, Vaginally, Intramuscular route Beneficial in natural, unstimulated cycles : no evidence Only well - documented indication : For the improvement of ART outcomes in GnRH agonist or antagonist stimulation cycles

Progesterone supplementation IM Progesterone  Highest serum levels Vaginal Progesterone  ↑ E ndometrial tissue levels Oral progesterone  Only ~10% of micronized progesterone is absorbed intact through GI tract  ↓ P regnancy rates  Should not be used for luteal support Should be administered until placental progesterone production is adequate (8–10 weeks of gestation )

hCG In GnRH agonist / antagonist ART cycles Luteal supplementation with hCG  Stimulates the ovaries ( or corpora lutea )  boost production of endogenous progesterone & estradiol  ↑ Delivery rates  ↓ Spontaneous abortion rates  ↑↑ Moderate or severe OHSS  Low - dose hCG (500 IU every other day )  minimal risk of inducing OHSS

hCG Clinical equivalence with intramuscular progesterone Higher incidence of side effects with Hcg  Luteal progesterone is generally preferred in GnRH agonist / antagonist IVF cycles Once pregnancy is established –Supplemental hCG is not beneficial –RCT : hCG for 1 st - trimester vaginal bleeding  Miscarriage rate : 11%  12% ( hCG )

SUMMARY Abnormal luteal function may occur as the result of a medical condition –e. g., Elevated prolactin, abnormal thyroid function –Infertile women should be investigated and treated for these disorders and identified conditions No diagnostic test for luteal phase insufficiency has been proven reliable in a clinical setting –BBT, luteal progesterone levels, endometrial biopsy, or other diagnostic studies –Performance cannot be recommended

No treatment for luteal phase insufficiency has been shown to improve pregnancy outcomes in natural, un - stimulated cycles Luteal support after ART procedures ( progesterone or hCG ) –Improves pregnancy outcomes –hCG increases the risk of OHSS

Not proven beneficial : –Progesterone or hCG for luteal support : Once a pregnancy has been established –Progesterone in a non - ART cycle beyond the time of expected menses ( i. e., 2 weeks after ovulation )

CONCLUSIONS Progesterone is important for the process of implantation and early embryonic development LPD, as an independent entity causing infertility, has not been proven

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