Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole
| Status: | Completed |
|---|---|
| Conditions: | Ovarian Cancer, Women's Studies |
| Therapuetic Areas: | Oncology, Reproductive |
| Healthy: | No |
| Age Range: | 20 - 40 |
| Updated: | 2/23/2018 |
| Start Date: | July 6, 2012 |
| End Date: | December 30, 2017 |
"Supplementation of the Luteal Phase With Vaginal Progesterone (Crinone 8%) in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction With Letrozole: A Prospective and Randomized Controlled Trial
Aromatase inhibitors such as letrozole are hypothesized to maintain normal hypothalamic/
pituitary feedback mechanisms and in the case of OI (ovulation induction) in women with PCOS,
may act to increase follicular sensitivity to FSH by increasing intrafollicular androgen
levels. Letrozole also may act to increase midluteal P levels presumably by induction of
follicles and corpora lutea. We are asking the question whether P supplementation with
Crinone (8%) may have an additive beneficial effect on endometrial development in those women
taking letrozole. Progesterone levels in the endometrium (tissue levels) have been documented
to be significantly higher than serum levels after vaginal administration which may lead to
higher pregnancy rates. In addition P has been shown to decrease LH pulse frequency which is
elevated in PCOS and has been shown to down regulate endometrial androgen receptors. There
have been retrospective studies showing progesterone supplementation seems to benefit both CC
and letrozole treatment groups. In fact, this study showed the only pregnancies in the
letrozole group were those in women who took P supplementation. However the number of cycles
studied was small. There is a place for a randomized controlled trial (RCT) to determine if
luteal phase P supplementation with Crinone should be used in all women using letrozole for
Ovulation Induction (OI) in combination with Intrauterine Insemination (IUI) or Timed
Intercourse (TI). This is currently not done in all clinical practices.
pituitary feedback mechanisms and in the case of OI (ovulation induction) in women with PCOS,
may act to increase follicular sensitivity to FSH by increasing intrafollicular androgen
levels. Letrozole also may act to increase midluteal P levels presumably by induction of
follicles and corpora lutea. We are asking the question whether P supplementation with
Crinone (8%) may have an additive beneficial effect on endometrial development in those women
taking letrozole. Progesterone levels in the endometrium (tissue levels) have been documented
to be significantly higher than serum levels after vaginal administration which may lead to
higher pregnancy rates. In addition P has been shown to decrease LH pulse frequency which is
elevated in PCOS and has been shown to down regulate endometrial androgen receptors. There
have been retrospective studies showing progesterone supplementation seems to benefit both CC
and letrozole treatment groups. In fact, this study showed the only pregnancies in the
letrozole group were those in women who took P supplementation. However the number of cycles
studied was small. There is a place for a randomized controlled trial (RCT) to determine if
luteal phase P supplementation with Crinone should be used in all women using letrozole for
Ovulation Induction (OI) in combination with Intrauterine Insemination (IUI) or Timed
Intercourse (TI). This is currently not done in all clinical practices.
Approval of the study was obtained from the local IRB. Prospective volunteers had had an
infertility workup including blood hormone levels (FSH, LH, E2, Progesterone, Prolactin, and
Thyroid), partner's semen analysis, HSG, laparoscopy or hydrosonogram, plus a baseline
evaluation including ultrasound of ovaries and uterus performed as standard of care. If the
results of these tests and the remaining Inclusion/Exclusion criteria were met, the study
consent was reviewed with patients and signatures were obtained. Patients contacted the
clinic at the start of their menses (spontaneous or progesterone-induced) to start the
treatment cycle. Eligibility criteria was reviewed, and Letrozole 2.5-7.5 mg day 3-7 was
initiated based on BMI and prior response. An ultrasound was performed on cycle day 11 or 12
and repeated if needed to determine response until at least 1 follicle with mean diameter >
17mm in size was observed. When the appropriate follicle size was reached, patients were
randomized into one of the two treatment groups as determined by a randomization table, and
Ovidrel (250mcg) was administered. If there was no response identified by follicle growth on
day 21, the patient was considered a letrozole failure, the cycle was stopped, and the
patient was dropped from the study and was not included in subsequent cycles.
IUI/TI was performed at 24-48 hours after the Ovidrel (hCG) injection. If the patient was
randomized to progesterone (Crinone), the luteal phase was supplemented once daily with
vaginal progesterone (Crinone 8%) starting the second day after the IUI or TI and continued
for 14 days. A urine or serum pregnancy test was performed as standard of care 16 days after
the IUI/TI. If the test was positive, a confirmatory blood level (βhCG) was performed as
standard of care X2 (1 week apart) and an ultrasound on post-hCG day 35-42 was done. Any
pregnancies occurring in either treatment group were followed for delivery outcomes.
Information regarding the delivery (induced, vaginal, cesarean section), date of birth,
infant measurements (weight and length) and other important information regarding the
infant's condition was obtained. Patients were allowed to undergo up to 3 cycles of letrozole
as the pregnancy rates for the first 3 cycles have been shown to be similar. The patients
were re-randomized each cycle. If the patient was pregnant, Crinone (8%) was continued until
10 weeks gestation in both groups.
Each patient was able to proceed with up to 3 cycles (consecutively, if desired) of OI over
the next 6 months and was re-randomized each cycle.
infertility workup including blood hormone levels (FSH, LH, E2, Progesterone, Prolactin, and
Thyroid), partner's semen analysis, HSG, laparoscopy or hydrosonogram, plus a baseline
evaluation including ultrasound of ovaries and uterus performed as standard of care. If the
results of these tests and the remaining Inclusion/Exclusion criteria were met, the study
consent was reviewed with patients and signatures were obtained. Patients contacted the
clinic at the start of their menses (spontaneous or progesterone-induced) to start the
treatment cycle. Eligibility criteria was reviewed, and Letrozole 2.5-7.5 mg day 3-7 was
initiated based on BMI and prior response. An ultrasound was performed on cycle day 11 or 12
and repeated if needed to determine response until at least 1 follicle with mean diameter >
17mm in size was observed. When the appropriate follicle size was reached, patients were
randomized into one of the two treatment groups as determined by a randomization table, and
Ovidrel (250mcg) was administered. If there was no response identified by follicle growth on
day 21, the patient was considered a letrozole failure, the cycle was stopped, and the
patient was dropped from the study and was not included in subsequent cycles.
IUI/TI was performed at 24-48 hours after the Ovidrel (hCG) injection. If the patient was
randomized to progesterone (Crinone), the luteal phase was supplemented once daily with
vaginal progesterone (Crinone 8%) starting the second day after the IUI or TI and continued
for 14 days. A urine or serum pregnancy test was performed as standard of care 16 days after
the IUI/TI. If the test was positive, a confirmatory blood level (βhCG) was performed as
standard of care X2 (1 week apart) and an ultrasound on post-hCG day 35-42 was done. Any
pregnancies occurring in either treatment group were followed for delivery outcomes.
Information regarding the delivery (induced, vaginal, cesarean section), date of birth,
infant measurements (weight and length) and other important information regarding the
infant's condition was obtained. Patients were allowed to undergo up to 3 cycles of letrozole
as the pregnancy rates for the first 3 cycles have been shown to be similar. The patients
were re-randomized each cycle. If the patient was pregnant, Crinone (8%) was continued until
10 weeks gestation in both groups.
Each patient was able to proceed with up to 3 cycles (consecutively, if desired) of OI over
the next 6 months and was re-randomized each cycle.
Inclusion Criteria:
- Women who have anovulatory or oligoovulatory infertility who are undergoing ovulation
induction for infertility with TI or IUI , with or without regular cycles defined as
cycle length > 35 days, < 26 days or amenorrhea (no cycles in the past six months),
and who meet 2 out of 3 of the Rotterdam Criteria (1. Chronic anovulation or irregular
cycles, 2. Clinical or biochemical hyperandrogenism, 3. Polycystic appearing ovaries
on ultrasound.)
- Day 3 FSH(Follicle stimulating hormone)< 10 (obtained within 2 years prior to
screening
- Documented infertility for at least 1 year or documented anovulation
- Willing to participate in up to 3 cycles of OI with letrozole and IUI or TI
- Partner's or donor's SA> 5 million motile sperm within 2 years of screening
- Patients may have received clomiphene citrate or letrozole treatment in the past.
Exclusion Criteria:
- Untreated thyroid or prolactin abnormalities
- Pregnancy in the last 3 months
- BMI< 18 or >40kg/m2
- Abnormal uterine bleeding of undetermined origin
- Contraindications to pregnancy
- Progesterone sensitivity
- Uterine anomalies seen on ultrasound (performed within 6 months prior to screening)
that can affect pregnancy chances such as submucosal uterine fibroids or polyps
- Three or more previous consecutive pregnancy losses
- Blocked fallopian tubes X2 (documented by HSG, laparoscopy, or hydrosonogram completed
within past 3 years)
- More than 3 failed monitored letrozole cycles prior to enrolling
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