Pregnancies that occur after therapy do not necessarily imply treatment benefit, but may reflect natural intercycle variation.
For example, Balasch and colleagues52 evaluated treatment with vaginal progesterone suppositories, dehydrogesterone, and no treatment. Although there was a higher pregnancy rate in the treatment groups, it was not statistically significant. However, the power of this trial to detect any differences in pregnancy rates was very low.
Investigating recurrent pregnancy loss. We also lack properly designed studies assessing the role of luteal phase support in women with recurrent miscarriages due to LPD. Two meta-analyses reached different conclusions on the role of progesterone supplementation in patients with recurrent miscarriages.34,54 Studies included in these analyses used various inclusion criteria. Moreover, diagnosis was not based on currently accepted criteria, and the treatment of choice was either 17-OH progesterone or medroxyprogesterone. The trials also included patients at more than 8 weeks’ gestation.
One multicenter randomized study evaluating luteal support with human chorionic gonadotropin (hCG) or placebo found no significant difference in pregnancy rates.55
Targeting the underlying cause. Steroidogenic cells consist of 2 main types: large and small luteal cells. Large luteal cells derive from follicular granulosa cells and secrete autocrine-acting and paracrine-acting peptides and eicosanoids but are not LH-receptive.56 They ensure basal progesterone and estradiol production from the corpus luteum. Small luteal cells derive from follicular thecal cells and acquire LH receptivity; thus, they respond to regularly occurring LH pulses, leading to increased progesterone and estradiol production.15
Only expert histopathologists or reproductive endocrinologists with special training should evaluate samples.
In a series of excellent experiments, Wuttke and colleagues15 studied corpus luteum function by measuring serial LH, progesterone, and estradiol levels. They suggested that, if the underlying cause of LPD can be determined, therapy can be appropriately directed, depending on whether the deficiency is hypothalamic LPD or a defect of small luteal cells or large luteal cells.
In hypothalamic LPD, LH pulses are absent and the hypothalamic gonadotropin-releasing hormone pulse generator appears to be oversuppressed, even though serum progesterone levels are lower than normal. However, during the follicular phase, the pulse generator functions normally.15
When there is a defect of small luteal cells, the corpus luteum responds poorly to normal LH pulses during the luteal phase, resulting in subnormal basal progesterone. Wuttke et al postulated that a defect of small luteal cells occurs because the cells do not differentiate well or fail to acquire LH receptivity.15
A defect of large luteal cells—which ensure the release of basal LH and unstimulated progesterone—occurred in 21% of cases studied. In these cases there was normal corpus luteum response to normal LH pulses, but progesterone secretion decreased to very low levels between LH pulses.15 The follicular-phase LH pulsatility, follicular development, and serum estradiol were all normal.15
Theoretically, stimulation of luteal progesterone secretion by hCG administration should be an effective therapy for hypothalamic LPD as well as a defect of large luteal cells. If the defect involves the small luteal cells, however, hCG therapy will be ineffective, since the corpus luteum is unresponsive to gonadotropins.15 In such patients, progesterone may be the treatment of choice. This may explain, at least in part, the differences in outcomes in the literature, since the underlying causative category has not been identified.
A well-designed, multicenter trial is essential to address remaining questions about LPD, not to mention a clear and uniform definition.
Clinical management
For those who believe, as we do, that LPD is a real and potential cause of reproductive disorders, we recommend that:
- its diagnosis be standardized,
- only expert histopathologists or reproductive endocrinologists with special training and skills in endometrial dating evaluate histologic samples, and
- once a “proper” diagnosis is made, treatment be multifold and as minimally invasive as possible.
Our practice generally is to give patients gonadotropins or clomiphene to improve folliculogenesis and corpus luteum function, and to induce multiple ovulations, which increase serum progesterone levels as well as the chance of pregnancy.
In patients at high risk for multiple gestation, progesterone supplementation as oral tablets or vaginal cream is relatively safe, inexpensive, and well tolerated. There is no need to monitor effects of progesterone treatment, since this natural substance has no known side effects or teratogenicity.
Dr. Engman reports no financial relationship with any companies whose products are mentioned in this article. Dr. Luciano reports that he serves on the speakers bureau and as a consultant for Eli Lilly, and receives research grants from Chitogenics, ML Laboratories, Proctor & Gamble, and Tap Pharmaceuticals.