The purpose of this study is to determine the differences that exist in RNA molecules, the biochemical process of methylation, and estrogen receptor binding in patients that have failed to produce adequate endometrium in synthetic embryo transfer cycles when compared to patients whose endometrium thickness is within normal limits.

The purpose of this study is to determine the differences that may exist in RNA molecules, the biochemical process of methylation, and estrogen receptor binding (this is a group of proteins in the cell that are activated by the hormone estrogen) in patients that have failed to produce adequate endometrium (uterine lining) in synthetic embryo transfer cycles when compared to patients whose endometrium thickness is within normal limits.

Appropriate embryo development and luteal phase (when fertilization and implantation occur) transformation of the endometrium create a small window of opportunity where successful implantation can occur. The interaction between the embryo and the endometrium is complex and poorly understood.

The endometrium, which consists of two layers called the functionalis and basalis, goes through changes during the menstrual cycle. The changes that occur are needed for successful implantation of an embryo. The proliferative phase of the menstrual cycle is primarily governed by estrogen and is responsible for the thickening of the endometrium. Progesterone primarily controls the last half of the menstrual cycle and causes changes which allows for embryo implantation.

Through in vitro fertilization (IVF), the investigators have seen that the correct thickness of endometrium is a marker of successful implantation and ongoing pregnancy, although the reason for this is not entirely clear. In order to better understand the processes that may occur in the endometrium, the investigators are conducting a study which evaluates biochemical markers of those patients who have shown a failure to proliferate during previous synthetic IVF frozen cycles and biochemical markers of control patients who have no known endometrial pathology.

Inclusion Criteria for Case Group:

• Diagnosis of endometrial insufficiency- prior cycle with maximal endometrial thickness ≤ 6mm, abnormal endometrial pattern (failure to attain a trilaminar appearance), persistent endometrial fluid.

Exclusion Criteria for Case and Control Groups:

• Any evidence for surgically induced endometrial insufficiency (Asherman's syndrome)

• Presence of hydrosalpinges that communicate with endometrial cavity

• Any contraindications to undergoing estrogen stimulation of the endometrium

  • Age ≥35 years and smoking ≥15 cigarettes per day
  • Multiple risk factors for arterial cardiovascular disease (smoking, diabetes, and hypertension)
  • Hypertension (systolic ≥140 mmHg or diastolic ≥90 mmHg)
  • Venous thromboembolism (current or history of)
  • Known thrombogenic mutations
  • Known ischemic heart disease
  • History of stroke
  • Complicated valvular heart disease (pulmonary hypertension, risk for atrial fibrillation, history of subacute bacterial endocarditis)
  • Systemic lupus erythematosus (positive or unknown antiphospholipid antibodies)
  • Migraine with aura at any age
  • Breast cancer
  • Cirrhosis
  • Hepatocellular adenoma or malignant hepatoma
  • History of undiagnosed abnormal uterine bleeding.
  • Allergic reaction to estradiol valerate, progesterone in oil, leuprolide acetate
  • Known pregnancy or delivery within the past 6 months
  • Breastfeeding
  • Obesity >35 kg/m2

Patients who have undergone a synthetic endometrial proliferation cycle in preparation for an embryo transfer that were identified as having a proliferative phase defect will serve as the subjects. Normal, healthy patients who are undergoing infertility treatment for single gene disorder, family balancing, or male factor infertility will serve as controls. The study will occur as part of a cryosynthetic preparatory cycle prior to embryo transfer. There will be 10 cases and 10 controls recruited for participation in the study.