ENDOCRINE CAUSES OF RPL

Endocrine factors may contribute to 8-12 percent of recurrent pregnancy loss. Therefore, an endocrine evaluation is a critical component of the RPL workup.

Luteal phase deficiency

Maintenance of early pregnancy depends on the production of progesterone by the corpus luteum. Between 7 and 9 weeks of gestation the developing placenta takes over the progesterone production. Luteal phase deficiency (LPD) is defined as an inability of the corpus luteum to secrete progesterone in high enough amounts or for too short a duration. The preponderance of evidence suggests that LPD is a preovulatory event most likely linked to an alteration in the preovulatory estrogen stimulation that may indicate poor oocyte quality and a poorly functioning corpus luteum. Most authors advocate the measurement of serum progesterone levels in the luteal phase for the diagnosis of LPD with levels below 10ng/ml considered abnormal. However, progesterone levels are subject to large fluctuations because of pulsatile release of the LH hormone. Moreover, there is a lack of correlation between serum levels of progesterone and endometrial histology.. While conflicting data exist, a recent Cochrane review evaluating 15 trials concluded that there was a benefit to the routine administration of progesterone to all women with a history of RPL. Progesterone is available either as intravaginal supplements (50 to 100mg twice daily starting the third day after LH surge and continuing for 8–10 weeks) or as intramuscular injections (50mg IM daily).

Untreated hypothyroidism

Untreated hypothyroidism may increase the risk of miscarriage. Our Center for Recurrent Pregnancy Loss published a study of over 700 patients with RPL and  identified 7.6% with hypothyroidism. Hypothyroidism is easily diagnosed with a sensitive TSH test and patients should be treated to become euthyroid (defined for the purposes of RPL as between 1.0 and 2.5 uIU/mL) before attempting a next pregnancy. It has also been suggested that thyroid antibodies are elevated in women with recurrent pregnancy loss. A retrospective study of 700 patients with RPL demonstrated that 158 women had antithyroid antibodies but only 23 of those women had clinical hypothyroidism on the basis of an abnormal TSH value. The presence of antithyroid antibodies may imply abnormal T-cell function, and therefore, more of an immune dysfunction rather than an endocrine disorder may be responsible for the pregnancy losses. The Endocrine Society recommends that patients with RPL be treated to keep a TSH level of between 1.0 and 2.5 uIU/mL in the first trimester [30]. For TSH levels found to be between 2.5-10 mIU/mL, a starting levothyroxine dose of at least 50 μg/d is recommended.

 

Abnormal Glucose Metabolism

Patients with poorly controlled diabetes are known to have an increased risk of spontaneous miscarriage, which is reduced to normal spontaneous loss rates when women are euglycemic preconceptually. Testing for fasting insulin and glucose is simple and treatment with insulin-sensitizing agents can reduce the risk of recurrent miscarriage. More recently, determining the average load of blood glucose through testing of hemoglobin A1C has become an increasingly utilized modality to evaluate insulin resistance. Because there is strong evidence that obesity and/or insulin resistance are associated with an increased risk of miscarriage, weight reduction in obese women is a first step in the treatment. Metformin seems to improve pregnancy outcome, but the evidence for this treatment is limited to a few cohort studies. Metformin is a Category B medication in the first trimester of pregnancy and appears to be safe.

Hyperprolactinemia

Normal circulating levels of prolactin may play an important role in maintaining early pregnancy. Data from animal studies suggest that elevated prolactin levels may adversely affect corpus luteal function; however, this concept has not been proven in humans. One study of 64 hyperprolactinemic women showed that bromocriptine therapy was associated with a higher rate of successful pregnancy and that prolactin levels were significantly higher in women who miscarried.

 

Diminished Ovarian Reserve

Follicle stimulating hormone (FSH) is inversely correlated with the number of follicles available for recruitment on any given menstrual cycle. Therefore, elevated levels of FSH in the early follicular phase of the menstrual cycle are representative of diminished ovarian reserve. More recently, decreased levels of anti-Müllerian (AMH) hormone have been used to identify diminished ovarian reserve. Although the frequency of elevated day 3 FSH levels in women with recurrent miscarriage is similar to the frequency in the infertile population, the prognosis is worsened with increased day 3 FSH levels. Similar studies with low AMH in women with RPL have suggested that oocyte quality may be reduced as a possible explanation for RPL. Testing of AMH and day 3 FSH may be helpful in women over the age of 35 with recurrent pregnancy loss, and appropriate counseling should follow.