Improving Implantation – Endometrium & Pregnancy

by The SOFT Blogger on March 31, 2011

The SOFT Fertility Blog is proud to introduce a new Fertility Information Sheet titled: Improving Implantation – Endometrium & Pregnancy

Patients of Southern Ontario Fertility Technologies (S.O.F.T.) will often become concerned during monitoring of their cycles with the measured thickness of the endometrium prior to ovulation and during their luteal phase.  Dr. Martin takes some time to discuss the various concerns about endometrial thickness, factors that impact pregnancy rates and our treatment options at S.O.F.T..

To download a PDF version of the Improving Implantation – Endometrium & Pregnancy information sheet click here

Introduction

Implantation - Endometrium & Pregnancy

Implantation is the attachment of the early embryo to the endometrium or lining of the uterus. It is the limiting factor of all human fertility.  Humans, in general, are the most infertile species on earth. The difference in our fertility and other species is thought to be the implantation step.
If a young fertile couple has intercourse at the time of ovulation, only about 25% will get pregnant in any given month. The egg probably becomes fertilized in most instances but the fertilized egg or embryo does not implant. The problem compounds when fertility issues are present. This is usually why a perfect intrauterine insemination (IUI) cycle or in vitro fertilization (IVF) cycle does not always work.
Despite the fact that understanding and improving implantation would be the next great scientific hurdle in improving our infertility treatment, little is known about it.  We do believe that progesterone given in the luteal phase of the cycle may be helpful in some circumstances.  Besides this, nothing else is proven but I will go over some of the intriguing possibilities for the future.

Progesterone
            Progesterone is produced by the ovary (corpus luteum) once ovulation occurs. This is referred to as the luteal phase of the cycle because the follicle that produced the egg becomes luteinized and produces progesterone. At the endometrial level, progesterone tends to mature the lining cells and increases their secretions. The use of progesterone to improve implantation has never been absolutely proven but has become the standard of care in many situations.
Synthetic forms of progesterone, such as progestin, used in the past have led to some problems. However, modern progesterone is probably very safe as it is bioidentical. This means it has exactly the same chemical structure as the progesterone made by the body.
Bioidentical progesterone is available in many forms.  It can be taken as oral medication, intramuscular injections or locally in the vagina either as oral pills, vaginal suppositories or vaginal cream.  Many recent investigations have looked into what form is best.  Generally, oral administration has been shown to be inferior to the other methods of administration due to the process of metabolism in the liver.  Intramuscular and vaginal preparations appear to be equally effective and vaginal pills (suppositories and creams) appear to be equally effective.  However, patients much prefer vaginal administration and it tends to produce higher levels at the uterus and lower levels throughout the rest of the body and therefore fewer side effects.
Oral pills (Prometrium ®), which are widely available, can be inserted vaginally or progesterone can be compounded into vaginal suppositories.  A vaginal cream is available. Pills have the disadvantage of being limited to two (100 mg and 200 mg) doses. All of these show similar absorption efficacy and similar positive results.
In the past, one way if increasing progesterone production in the luteal phase of the cycle was to inject HCG after ovulation.  When this was performed in IVF cycles, any improved implantation could not be demonstrated but more ovarian hyperstimulation syndrome was promoted.  Despite these negative findings HCG could improve the luteal phase and implantation by promoting endogenous progesterone production. This could theoretically involve the production of other growth factors, which have not yet been discovered.  Our limited experience at S.O.F.T. has been somewhat positive. The medical literature on this subject is divided.

Other Non-proven Possibilities Medications

Ovulation induction
The quality of the endometrium for implantation may be directly related to the quality of the follicular phase of the cycle as it progresses towards ovulation and also the quality of the ovulation.  Syndromes such as luteinized unruptured follicle syndrome or inadequate luteal phase have been treated for some time with ovulation induction using clomiphene citrate.  Theoretically, if the clomiphene improves the cycle it may improve the endometrium for implantation.  The major difficulty of this has been that clomiphene citrate, due to blocking estrogen, often negatively affects the endometrium.
A newer form of ovulation induction, letrozole (Femara ©), induces ovulation but often (especially in its lower doses) does not seem to cause multiple follicles to develop.  In most studies it has been shown to be as effective as clomiphene at improving the pregnancy rate.  Although unproven, it is thought by many to improve pregnancy rates by improving implantation.  Indirect evidence of this is that ultrasound evidence shows that it improves the ultrasound appearance of the endometrium. Dr. Martin hopes to be presenting additional evidence for this concept at the annual meeting of the Canadian Fertility and Andrology Society this year (2011). I have included the proposed abstract for this presentation below.

Follicular Development, Implantation, Pregnancies, and Multiple Pregnancies In IUI Cycles Using Clomiphene Citrate and Femara (Letrozole)
James S.B. Martin*, Cathy S. Frank. Southern Ontario Fertility Technologies, London, Ontario, Canada
Objective: To investigate follicular development, implantation and multiple pregnancies in IUI cycles using clomiphene citrate and femara.
Methods: All first IUI cycles performed at a single infertility clinic from January 2001 to December 2010 using clomiphene citrate (cc) 50 mg/day from day 3 to 7 of the cycle and Femara 2.5 mg/day from day 3 to 7 of the cycle were analyzed. All diagnostic categories were included. Women older than 40 years old were excluded. Cycles where an ultrasound was not performed within 48 hours of insemination could not be included. Follicles over 15 mm, implantation rates (positive fetal hearts on early viability ultrasound divided by the number of follicles with a maximum diameter of over 15 millimeters at the time of LH surge or HCG injection), pregnancies and multiple pregnancies were recorded and compared.
Results: The results are presented in the table.

Drug Cycles Total Follicles(Follicles/Cycle) Pregnancies(Pregnancies/Cycle) Twins(% Twins) % Implantation / Follicle
cc 864 2042 (2.04) 118 (13.7) 7 (6.3) 5.8
Femara 399 537 (1.35) 59 (14.8) 1 (1.7) 10.4
Conclusions: Pregnancy rates in first IUI cycles using clomiphene citrate and Femara are very similar (13.7% vs. 14.8%). Clomiphene citrate causes more twin pregnancies (6.3% vs. 1.7%). This might be explained by the other two findings in this study. Clomiphene citrate produces more mature follicles per cycle (2.04 vs. 1.35) while Femara has a higher implantation rate (10.4% vs. 5.8%).

Endometrial Thickness and Implantation
Many patients will pay great attention to their endometrial thickness during fertility treatments. It is generally thought that the thicker the endometrium, the better the chance of pregnancy. This may be true in some circumstances but has to be considered in the correct context.  Endometrial thickness has gained such importance because we can measure it so easily with a vaginal ultrasound. Endometrial pattern is important too (see illustration on the next page). Also important are changes in different factors excreted by the endometrium.  So far measuring these factors has not given us a good test of endometrial receptivity but it may in the future.
In general, as endometrial thickness after IVF stimulation increases so does the pregnancy rate.  Endometrial thickness between 6mm-14mm is ideal.  Pregnancies do occur when the endometrial thickness is <6mm or >14mm but it does not happen as often.  A study completed in 2008 found a correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome. Pregnancy rate (PR) was 35.8% and increased linearly (r = 0.864) from 29.4% among patients with a lining of less than or equal to 6 mm, to 44.4% among patients with a lining of greater than or equal to 17 mm. However, other studies have not found such a direct correlation. One study, found a decreasing pregnancy rate if the endometrium became too thick (>14 mm).
One study of 768 frozen embryo transfers (FET) cycles found that live birth rates were 1.9 times lower in women with endometrial thickness of 7-8 mm compared to women with thickness of 9-14 mm, after adjusting for confounding variables. However, these were all medicated transfers and may not relate to normal cycles.
Endometrial thickness in non-medicated cycles has been poorly studied and the thicknesses in these cycles may not be the same as in IVF cycles or even medicated IUI cycles. In a study completed this year we tried to look at endometrial thicknesses in spontaneous cycles. The abstract below will be submitted for possible presentation at the annual meeting of the Canadian Fertility and Andrology meeting this year (2011). It is included here for your interest.

Endometrial Thickness as a Predictor of Success in Spontaneous Cycles
James S.B. Martin*, Cathy S. Frank. Southern Ontario Fertility Technologies, London, Ontario, Canada
Objective: To investigate endometrial thickness measurement at the time of LH surge in successful and non-successful spontaneous IUI cycles.
Methods: All spontaneous first IUI from Jan 2001 to December 2010 in women under 40 years old where an ultrasound evaluation of the endometrial thickness was performed within 24 hours of the LH surge were included. LH surge was defined as a doubling of the baseline LH and the presence of a follicle 16 mm or greater. The endometrial stripe was measured at its maximum anteroposterior thickness along the longitudinal axis of the uterine body. This measurement included both anterior and posterior endometrial layers. Pregnancy was defined as a normal early viability ultrasound (approximately luteal day 40).
Results: 412 cycles of IUI fit the criteria above. 47 of 412 cycles (11.4%) resulted in a pregnancy. Endometrial thickness in the pregnancies were 8.1 mm + 2.2 mm. The measurements ranged from 4.3 to 11.9 mm. Endometrial thickness in the unsuccessful cycles were 7.9 + 1.9 mm. The measurements ranged from 3.6 to 14.0 mm. Endometrial thickness were not different in successful and non-successful cycles.
Conclusions: Endometrial thickness does not appear to be a good predictor of success in spontaneous cycles. Most reports, which have correlated endometrial thickness and pregnancy success, have been in IVF or FET cycles. In general, success appears to be correlated with endometrial thicknesses greater than 6 mm and to increase with increased thickness up to about 14 mm. These IVF thicknesses may not relate to thickness reported in spontaneous cycles.

Biochemical pregnancies have been associated with a thinner endometrium but the study was very small and has not been repeated.
A triple-layer or trilaminar pattern for the endometrium would be optimal for implantation. One report documented a trilaminar pattern changing to a homogeneous pattern after ovulation was associated with the best pregnancy rate.
However, can we increase endometrial thickness and if so, does it increase and improve pregnancy outcome? Numerous possible treatments for increasing endometrial thickness have been proposed. These include aspirin, tamoxifen, sildenafil (Viagra ®) and estrogen. Low-dose aspirin (acetylsalicylic acid, 81 mg) has anti-inflammatory, vasodilatory and platelet aggregation inhibition properties and may promote uterine blood flow. Randomized clinical trials have produced conflicting results on the beneficial effects of aspirin in IVF. One meta-analysis of 10 randomized clinical studies of fresh and frozen IVF cycles found that clinical pregnancies were 1.15 times higher in low dose aspirin groups than placebo groups. However, aspirin does not appear to improve endometrial thickness and subsequent randomized placebo-controlled trials have failed to find a significant difference in pregnancy rates between aspirin-treated and non-aspirin treated groups.
There is only a single study that examined tamoxifen and the endometrium. This study compared the use of supplemental Clomid or Tamoxifen in addition to injectable gonadotropins in IUI cycles and found that patients taking tamoxifen had increased endometrial thickness and improved ongoing pregnancy rates. Women taking tamoxifen for breast cancer are prone to overgrowth of their endometrium and therefore it is thought to have a positive effect on the endometrium.  At S.O.F.T. we have had very little experience with tamoxifen but may implement this in the near future.
Sildenafil (Viagara®) has been found to improve blood flow by enhancing the release of nitric oxide and thus relaxing vascular smooth muscle. In men, it increases the blood supply to the penis but in women it appears to increase the blood supply to the endometrium. One randomized placebo-controlled study of 15 non-pregnant, nulliparous women found that sildenafil improved uterine volumetric flow during the luteal phase of their cycle. Vaginal administration of sildenafil (Viagra) for several days prior to the “hCG trigger” or progesterone administration enhances uterine blood flow and estrogen delivery to the uterine lining, and so improves endometrial thickening. Since the introduction of this form of treatment, more than 500 women have been reportedly treated and many have gone on to have babies after repeated prior failure in IVF.
Estrogen supplementation during stimulation with Clomid during IUI cycles has been shown to improve endometrial development and to result in thicker endometria and improved morphology.  Clomiphene citrate, although improving the cycle and therefore perhaps correcting any inadequate luteal phase, has negative effects on the endometrium because it physiologically blocks estrogen.  This can be theoretically overcome by supplementing estrogen in the follicular phase once clomiphene has completed its population induction.  This was confirmed in a study done here at S.O.F.T..  Below, is a presentation by S.O.F.T. from the 2006 annual meeting of the Canadian Fertility and Andrology Society which looks at vaginal estrogen to thicken the endometrium in clomiphene citrate intrauterine insemination cycles where the endometrium was found to be less than 6 mm.

Vaginal estrogen for endometrial thickening in clomiphene citrate intrauterine insemination cycles
James S.B. Martin*. Southern Ontario Fertility Technologies, London, Ontario, Canada
Objective: To investigate if vaginal estrogen will cause thickening of the endometrium in intrauterine insemination cycles with clomiphene citrate where the day 11 endometrial thickness is found to be less than 6 mm.
Methods: Forty consecutive intrauterine insemination cycles in which the endometrial thickness was less than 6 mm were randomized to receive vaginal estrogen consisting of 17B estradiol 0.5 mg (estrace ®) each night or no treatment. Inclusion criteria included at least one follicle on day 11 of 12 mm or greater (so that the cycle would likely be ovulatory) and an LH less than 10 and no follicle greater than 16 mm (so that ovulation had not already occurred). Endometrial thickness was measured 48 hours later and on insemination day. A pregnancy test (serum BHCG) was done 14 days after insemination and a vaginal ultrasound for early pregnancy viability was performed 40 days after insemination.
Results: Day 11 endometrial thickness was similar in the two groups (control group = 3.9 +1.1 mm and treatment group 4.0 + 1.1). Endometrial thickness measured 48 hours later was significantly different (control group = 4.4 +1.1 mm and treatment group 7.5 + 1.9). Endometrial thickness measured at insemination day (which was an average of 4.8 days later in both groups) was significantly different (control group = 5.1 +1.2 mm and treatment group 8.4 + 2.2). Two positive pregnancies (2/20 = 10%) occurred in the control group at 14 days but both of these decreased
Discussion: Endometrial thickness has been demonstrated in many studies to be a positive predictor of successful pregnancy. This small study demonstrates that vaginal estrogen causes endometrial thickening in clomiphene citrate cycles where the endometrium is found to be less than 6 mm thick.

Thin endometrium, as they are read by ultrasounds, is thought to decrease implantation and therefore pregnancy rates.  Estrogen was definitely shown to increase the endometrial thickness but this study does not demonstrate it improves the pregnancy rate.  Below, are two additional studies, which were presented in 2007. The first, demonstrates how decreased pregnancy rate in clomiphene citrate, intrauterine insemination cycles where the endometrium is found to be thinned.   The second demonstrates an improved pregnancy rate in the same cycles where the endometrium has been sickened by clomiphene citrate.  Interestingly, although the pregnancy rate is improved and is not statistically different than clomiphene citrate intrauterine insemination cycles where the endometrium appears to be unaffected; there is a trend to a decreased pregnancy rate.  Only larger numbers will sort this out.

Pregnancy rate in clomiphene citrate-intrauterine insemination (IUI) cycles with an endometrial lining less than 6 millimeters (mm)
James S.B. Martin*. Southern Ontario Fertility Technologies, London, Ontario, Canada
Objective: In 2006 we reported to this meeting that vaginal estradiol would thicken the endometrium in intrauterine insemination cycles using clomiphene citrate. The study was performed because the literature indicated lower pregnancy rates with thin endometrium. However the pregnancy rate in these cycles in our clinic was not documented prior to using estradiol. This study is to provide that documentation.
Design: retrospective cohort study
Methods: All IUI cycles using clomiphene citrate only between Oct. 2000 and Dec. 2003 were included. This included 1437 completed cycles resulting in 202 positive (14.1%) BHCGs and 176 (12.2%) normal early viability ultrasounds. These cycles were divided into those with in which the endometrial thickness was equal to or greater than 6 mm and those in which the endometrial thickness was less than 6 mm at the time of spontaneous LH surge or HCG injection. The cycles were analyzed using our computer database.
Results: .1191 cycles in which the endometrial thickness was equal to or more than 6 mm and resulted in 183 (15.4%) positive BHCGs and 165(13.6%) normal early pregnancy ultrasounds were compared to 246 cycles in which the endometrial thickness was less than 6 mm resulted in 19 (7.7%) positive BHCGs and 11 (4.5%) normal early pregnancy ultrasounds. The difference was statistically significant using a chi-squared test.
Conclusions: The results indicate a statistically significant lower pregnancy rate in clomiphene citrate and intrauterine insemination cycles where the endometrial thickness is less than 6 mm. 
References: Vaginal estrogen for endometrial thickening in clomiphene citrate intrauterine insemination cycles, James S.B. Martin, oral presentation, 2006 annual meeting C. F A. S.

Pregnancy rate in clomiphene citrate IUI cycles with vaginal estradiol for endometrial thickening
James S.B. Martin*. Southern Ontario Fertility Technologies, London, Ontario, Canada
Objective: In 2006 we reported to this meeting that vaginal estradiol would thicken the endometrium in intrauterine insemination cycles using clomiphene citrate. However it was not known how this affected the pregnancy rate. This study was to investigate that question.
Design: retrospective cohort study
Methods: All IUI cycles using clomiphene citrate only between Jan. 2005 and Dec. 2007 were included. This included 2016 completed cycles resulting in 308 positive (15.3%) BHCGs and 258 (12.5%) normal early viability ultrasounds. These cycles were divided into those with in which the endometrial thickness was equal to or greater than 6 mm and those in which the endometrial thickness was less than 6 mm and were given vaginal estrogen consisting of 17B estradiol 0.5 mg (Estrace ®) each night The cycles were analyzed for pregnancies using our computer data base.
Results: .1760 cycles in which the endometrial thickness was equal to or more than 6 mm and resulted in 271 (16.9%) positive BHCGs and 234 (13.3%) normal early pregnancy ultrasounds were compared to 256 cycles in which the endometrial thickness was less than 6 mm and were given vaginal estrogen and resulted in 37 (14.5%) positive BHCGs and 24 (9.2%) normal early pregnancy ultrasounds. The difference was not statistically significant using a chi-squared test. However, there does seem to be a trend.
Conclusions: We will continue to monitor these cycles to see if the trend becomes significant. However, in the meantime, we switch medicines if possible, add injectable fertility medication or continue to use Estrace. 
References: Vaginal estrogen for endometrial thickening in clomiphene citrate intrauterine insemination cycles, James S.B. Martin, oral presentation, 2006 annual meeting C.F.A.S.

Similarly, a placebo-controlled randomized trial of 81 women demonstrated that oral estrogen supplementation throughout a fresh IVF cycle was associated with increased pregnancy rates. The estrogen group had significantly thicker endometrial thickness and a 1.9 times higher pregnancy rate. Supplementing progesterone with estrogen purely in the luteal phase has also been shown to increase pregnancy rates compared to progesterone-only supplementation during the luteal phase.

Mechanical Aspects of Implantation
It is likely that any surface lesion in the uterine cavity, whether an endometrial, placental or fibroid polyp (no matter how small), or intrauterine adhesions, has the potential to interfere with implantation. These small lesions may produce a local inflammatory response, not too dissimilar in nature from that which is caused by a foreign body such as an intrauterine contraceptive device (IUD). Hysterosalpingogram (HSG) will diagnose most of these. If there is any doubt about one of these lesions affecting implantation, we will advise a sonohystogram. This can identify very small lesions in the endometrial cavity. Information sheets are available on Hysterosalpingograms and Sonohystograms. Hysteroscopy can be used for definitive diagnosis and removal.

Injury to the Endometrium
In the late 1990s, researchers in the USA performed endometrial biopsies (a procedure in which a small sample is taken from the lining of the uterus) on 12 women who had failed to conceive after numerous IVF treatments and most (11 of 12) of these women then became pregnant in the cycle in which the endometrial biopsy was performed. To investigate this, in 2003, they conducted a larger study with patients who had at least four failed IVF treatments and discovered that undergoing an endometrial biopsy prior to IVF treatment improved the chances of a successful pregnancy. In 1,300 cycles it increased IVF pregnancy rates from 31% in the group who did IVF alone to 48% in the group treated with pipelle endometrial biopsy & IVF.
About the same time, a study performed at TCART, in Toronto, in frozen embryo transfer cycles (FET) was reported at the annual meeting of the Canadian Fertility and Andrology Society demonstrating an improvement in pregnancy rates in cycles in which an endometrial biopsy was performed.
A clinical trial being performed by at McGill University Health Center in Montreal is currently testing this and should be nearing completion. The clinical trial took women without tubal disease, uterine pathology, severe male factor infertility or positive cervical cultures, but did include couples with mild male factor infertility or only a single fallopian tube. In this study, they are comparing the results of IUI with and without endometrial sampling.
We have been offering endometrial biopsies in FET cycles since 2003 but have not subjected it to a clinical trial.
There have been many reports in our medical literature that a hysterosalpingogram (HSG) will increase the chance of a pregnancy in the cycle that it’s done in.  This is certainly been our experience at S.O.F.T. We obtain about 300 pregnancies per year and in most years 2 to 4 of these are in the initial investigation cycle where a HSG has been performed.
In the past, it was thought that the HSG somehow mechanically removed some minor blockage of the tubes.  However, more recently the accepted mechanism has been that the HSG dye irritates the endometrial lining, causing a healing process to occur and that this healing process improves implantation.

Embryo Implantation

Can Decreased Endometrial Thickness and Receptivity Be a Primary Fertility Issue?
This is an extremely good question!
I have done a very complete literature search and cannot find a scientific study addressing this question. However, I will review our experience at S.O.F.T.. Usually, we discover a thin endometrium in cycles where clomiphene citrate is being used. Earlier in this information sheet a study demonstrating that vaginal estrogen would thicken the endometrium in these cycles was presented. Additional retrospective studies demonstrated that this thickening of the endometrium restored most, but not all, of the pregnancy potential. We therefore will usually discontinue the clomiphene in subsequent cycles. Letrozole (Femara ®) is a very good alternative for women who are not ovulating and spontaneous cycles might be better for women who are ovulating on their own.
Sometimes we discover that the thin endometrial lining does not resolve or it is present without the use of clomiphene. I can recall seven (7) patients (so if it exists, it is very rare) who were discovered to have this problem at S.O.F.T. and I will review their outcomes.
First it is important to define normal parameters for endometrial thickness during the menstrual cycle. Day 1 of the menstrual cycle is the first day of bleeding requiring more than a panty-liner before midnight. The endometrium starts off as a thickened lining, sometimes measuring up to 15 mm but usually 10 to 13 mm in thickness. Menstruation occurs during the first week of the menstrual cycle. As the endometrium is expelled it may vary in thickness and may have an irregular appearance on ultrasound. As the week progresses, the endometrium becomes thinner. By the end of menstruation the endometrium should measure approximately 2 to 3 mm thick.
The proliferative phase begins at the end of menstruation and lasts until ovulation. During the proliferative phase, a follicle begins to grow on one of the ovaries. While this follicle grows, it secretes estradiol; an estrogen that is responsible for the thickening of the endometrium prior to ovulation. Fertility increases during this stage of the cycle. During the proliferative stage the endometrium can become as much as 8 mm thick. On ultrasound, it has the appearance of three lines (see picture earlier in this information sheet). This general consensus of 8 mm agrees very well with our study presented earlier “Endometrial Thickness as a Predictor of Success in Spontaneous Cycles”.
Ovulation marks the end of the proliferative phase and the beginning of the secretory phase. In the proliferative phase, the endometrium usually appears trilaminar. The mature follicle ruptures and releases an egg (ovulation). Fertility is greatest between five days prior to ovulation and one or two days after. Some fertility clinics like to see a 10 thick endometrium just prior to ovulation but 8 mm and above is normal. The follicle that ruptured to release the egg is now called the corpus luteum. The corpus luteum releases progesterone. Progesterone is responsible for the further thickening of the endometrium in preparation for blastocycst implantation. The endometrium usually appears homogeneous. During the secretory phase, the endometrium can thicken to as much as 15 mm but is usually 11 to 13 mm.
Of the 7 people who appeared to have this problem at S.O.F.T., 4 have had successful pregnancies. Two pregnancies occurred despite thin endometrium. One with a measurement of only 4 mm at the time of LH surge. However, she has returned for a second pregnancy and is still in treatment. Two pregnancies occurred by treating the thin endometrium. This was done by avoiding clomiphene, supplementing estrogen and progesterone and adding vaginal Viagra ®. One of the two had an endometrial biopsy in the cycle where the pregnancy occurred.  Three patients, as well as one returning patient, are currently being treated.

Conclusion
One of the fascinating but frustrating issues in infertility treatment is our lack of good diagnostic tests. Many steps in the process of creating a new pregnancy are not testable. Perhaps implantation issues are one of these untestable problems. Endometrial thickness may represent a surrogate measurement of endometrial receptivity. Better tests still elude us.

James Martin MD ©

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