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    Is menses induction necessary before ovulation induction?

    New evidence suggests that progestin withdrawal may adversely affect outcomes of ovulation induction with clomiphene.


    Endometrial shedding and fertility

    Several theories have been proposed to explain the mechanism by which lack of endometrial shedding in anovulatory women could exert a positive effect on subsequent conception and live births. Potential mechanisms include the direct and indirect effect of a progestin on the hypothalamic-pituitary-ovarian axis, a direct effect on endometrial receptivity, and a direct or indirect effect related to endometrial thickness.4-6 Endometrial receptivity and morphological appearance is indicative of the functional status of the hypothalamus-pituitary-ovary axis; understanding the morphological changes and biomarkers expressed by the endometrium in response to progestin is critical in explaining potential mechanisms.7,8  Moreover, hypothalamic pituitary dysfunction (HPD) can result in luteal phase deficiency,8 which has been postulated to affect fertility, although that could not be demonstrated in an earlier RMN study.9

     The endometrium undergoes a complex series of organized proliferative and secretory changes in each menstrual cycle, leading to creation of a favorable environment for implantation.10 The window of implantation is a short period of endometrial receptivity that is primarily considered to be coordinated by estradiol and progesterone.  Human endometrial stromal decidualization is required for embryo receptivity, angiogenesis, and placentation.  The steroid hormones progesterone (P4) and estradiol (E2), through binding of estrogen and progesterone receptors (ER and PR), also play an important role in regulating decidua formation during pregnancy.  Moreover, functional studies indicate that decidual angiogenesis is mainly regulated by vascular endothelial growth factor A (VEGF-A) secreted from decidual stromal cells expressing PR; thus, greater expression of VEGF-A corresponds to high PR expression.11  In fact, first-trimester miscarriage, preeclampsia, placental failure and intrauterine growth restriction may all result from vascular disturbances when these signaling pathways and cellular coordination are disrupted.11  In addition, progesterone is one of the factors that regulate trophoblastic invasion, which is an important process in placentation and establishment of a successful pregnancy. Progesterone-induced binding factor (PIBF) and leptin were found to control trophoblastic invasion, aided by differential expression of PR.12  In fact, in the human endometrium, progestins suppresses leptin receptor mRNA expression via the PRs.13 Furthermore, Leptin receptor expression is lower in patients with PCOS and endometriosis and higher in patients with recurrent implantation failure, indicating the importance of regulation of endometrial expression.14 Expression of adipokines such as leptin and resistin is influenced by estrogen and progesterone and both have been noted to increase in the midluteal phase of the menstrual cycle during the window of implantation.15,16 Early progestin exposure may lead to altered expression of PR, or to PR resistance, resulting in disrupted vascular remodeling and placentation, and thus impact pregnancy outcome.  Moreover, a thin endometrium following a progesterone-induced withdrawal bleed may have impaired proliferation due to clomiphene citrate’s antagonistic properties at remaining endometrial ERs.  This could theoretically be in contrast to the effect of clomiphene when there has been no endometrial shedding, with a near normal endometrial thickness.  In such situations, endometrial ER antagonism by clomiphene may be less consequential, due to the pre-existing endometrial thickness.

    Current literature indicates that not only anovulation, but also endometrial dysfunction, contributes to infertility in women with PCOS.  Even when ovulation is restored, these patients exhibit a higher rate of implantation failure and spontaneous miscarriage.17 In a retrospective study, Bromer et al. evaluated the base endometrial development in a heterogeneous infertility population. Significant decrease in endometrial thickness was observed in women with PCOS despite correction for estradiol levels.  The authors also found that endometrium growth plateaus around day 9 regardless of treatment regimen, drug, underlying diagnosis or success.  This suggests that the endometrium can tolerate long estrogen exposure and optimal endometrial thickness precedes peak estradiol level.18

    Gene expression analysis indicate that patients with PCOS who are treated with clomiphene to induce ovulation show evidence of progesterone resistance in the endometrium.19 In fact, biopsies performed on women during the secretory phase of a normal cycle and in women with PCOS before and after treatment with micronized progesterone revealed a lower number of glands and thicker luminal epithelium in the secretory phase in the women with  PCOS.20 Before treatment, the endometrium of patients with PCOS exhibited a slightly increased number of glands that transformed to histological delay after treatment (less developed glands and higher concentration of stromal component).20 The authors concluded that progesterone administration for 10 days failed to correct the dysfunctional endometrium; however, progesterone in fact may have an adverse effect on the endometrium as indicated by the lower number of glands in the secretory phase after therapy.

    Moreover, androgen receptor and steroid receptor co-activators are over-expressed in the endometrium of women with PCOS, with a rise of AR expression observed in the late proliferative phase.21 AR expression is up-regulated by both circulating estrogens and androgens, and down- regulated by progesterone.21,22 In preparation for implantation, both ER and PR are down-regulated in the epithelial compartment, and AR is almost undetected in the secretory phase of normally cycling women. Also, biomarkers of endometrial receptivity such as αvβ3 integrin are down-regulated when epithelial AR is overexpressed.21 Although progesterone seems to down regulate AR expression, early exposure may alter the hypothalamic-pituitary-ovarian axis, resulting in a delay in the progesterone effect, and thereby leading to abnormal endometrial receptivity.

    In editorial remarks in response to the RMN secondary analysis4, Casper proposed that the decrease in pregnancy rate can be explained simply by the thinner endometrium in spontaneous or induced menses.6 The author argued that clomiphene, acting predominantly as an ER antagonist, is associated with thin endometrium. Thus, endometrial shedding results in a thin endometrium that is more likely to become ER depleted, and thus unresponsive after clomiphene treatment.  Consistent with this hypothesis, multiple studies have reported a positive correlation between endometrial thickness and pregnancy rates. Dickey et al. showed that endometrial thickness was negatively related to clomiphene, and an endometrium measurement of 9 mm or more was associated with higher pregnancy rates.23 These observations suggest that it is more likely that progesterone administration and endometrial shedding is able to adversely affect an anovulatory endometrium that is deregulated and unresponsive at the molecular level.  In addition, thick endometrium doesn’t always ensure successful implantation, and pregnancy can occur with thin endometrium.24 Sonographic detection of adequate endometrial thickness doesn’t always represent functional endometrium.

    NEXT: Conclusion and references

    Soumia Brakta, MD
    Dr. Brakta is a reproductive endocrine and infertility fellow at Medical College of Georgia at Augusta University, Augusta, GA.
    Michael P. Diamond, MD
    Dr. Diamond is William H. Brooks, MD, Distinguished Chair, Professor and Chair, Department of Obstetrics and Gynecology, Associate Dean ...


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