REVIEWS MINERVA ENDOCRINOL 2013;38:401-14
Luteal phase support for assisted reproductive technologies: between past, present and future
IN C ER O V P A Y R M IG E H DI T C ® A
G. LO MONTE, I. PIVA, E. BAZZAN, R. MARCI
The luteal phase is defined as the period between ovulation and either the establishment of a pregnancy or the onset of menses two weeks later. Assisted reproductive technologies (ART), and in particular controlled ovarian stimulation (COS), negatively interfere with the endocrine mechanisms normally regulating the luteal phase. Up to now, there is no generally accepted opinion as to the most appropriate therapeutic schemes for luteal phase support in ART cycles. Progesterone-based protocols are the most frequently adopted, while alternative regimens including human chorionic gonadotropin (hCG) and GnRH agonists (GnRH-a) are controversial. A GnRH-a can be used instead of hCG for ovulation triggering and the effectiveness of luteal phase support in such new protocols is the object of a growing number of experimental studies. Currently, vaginal progesterone is considered as the first line therapy for luteal phase support (LPS). The starting-time and the duration of luteal phase supplementation after the onset of pregnancy are still debated. Despite the lack of clinical or biological evidence supporting the efficacy of luteal phase support in intrauterine insemination cycles, the use of progesterone has become a wellestablished practice. Key words: Luteal phase - Reproductive techniques, assisted - Ovulation induction - Corpus luteum.
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Corresponding author: R. Marci, Department of Biomedical Sciences and Advanced Therapies, Unit of Obstetrics and Ginecology, University of Ferrara, corso Giovecca 183, 44121, Ferrara, Italy. E-mail:
[email protected]
Vol. 38 - No. 4
Department of Morphology Surgery and Experimental Medicine Section of Obstetrics and Gynecology University of Ferrara, Ferrara, Italy
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he luteal phase is defined as the period between ovulation and either the establishment of a pregnancy or the onset of menses two weeks later.1 This phase is physiologically regulated by the activity of corpus luteum (CL), a temporary endocrine gland that forms after follicle rupture and releases progesterone (P) and other steroid hormones, such as 17-β-estradiol (E2). The steroidogenic activity of CL is first regulated by hypophyseal LH, and later on by blastocyst-secreted human chorionic gonadotropin (hCG), in case conception and implantation occur. Both LH and hCG bind to a specific glycoproteic receptor on the plasmatic membrane of steroidogenic luteal cells. The binding of these hormones to the receptor activates adenylate cyclase-cAMP-protein kinase A signal transduction pathway, which has been widely recognized as the primary mechanism by which gonadotropins regulate CL steroidogenic activity.2 LH plays a major role in the control of luteal phase: it induces CL steroidogenic activity,3 it up-regulates several growth factors such as the vascular endothelial growth fac-
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Luteal phase support for assisted reproductive technologies
Although no generally accepted cause for LPD has been recognized yet, the possible mechanisms involved are two:16 inadeguate folliculogenesis due to three possible factors: reduced FSH release, altered pulsatile release of FSH, reduction in LH pre-ovulatory peak; defective P production that, in its turn, can depend on an abnormal endometrial response to the hormone. Also severe hyperprolactinemia, hyperandrogenism, quick and considerable weight loss, stress and competitive sport 17 are identified as possible causes of LPD, but they should be attributed to the aforementioned mechanisms anyway. As to the clinical manifestations, luteal phase disorders go unnoticed for a long time or they can cause shorter duration of the mestrual cycle, spotting, abnormal uterine bleeding and infertility. The diagnosis of LPD is obtained either by the dosage of P plasma mid-luteal levels or by an endometrial biopsy carried out between the 21st and 24th day of an average 28-day-long menstrual cycle. Besides being difficult to perform and hardly repeatable, endometrial biopsy does not seem to be more accurate than the determination of P plasma levels. Given the pulsatile release of P and its 20-30 minutes half-life, plasma levels of such hormone could theoretically undergo significant changes within a range of 3-20 ng/mL.18, 19 Thus, P measuring should be conducted on several samples, withdrawn on the same day during the mid-luteal phase, and repeated for two or three consecutive menstrual cycles. In this way false positive can be avoided and the diagnosis of LPD is made truly reliable. However, it has been reported that plasma mid-luteal levels of P are not linked to the degree of endometrial maturation.20 Thus, according to several authors, a reliable diagnosis of LPD should be based on the histological finding of more-than-2-days delay in endometrial maturation.21 Furthermore, transvaginal ultrasound provides indirect evidence of the immediate post-ovulatory period, such as the presence and persistence of CL, normally ≥11 days, as well as
IN C ER O V P A Y R M IG E H DI T C ® A
tor A (VEGF-A), the fibroblast growth factor type 2 (FGF-2) 4, 5 and it determines the release of some cytokines involved in blastocyst implantation.6 Additionally, LH may directly stimulate extra-gonadic receptors at endometrial level.7 Several pre- and post-fecundation phenomena depend on adequate P (from Latin “pro”: favouring and “gestationis”: pregnancy) synthesis. These include: 1) the occurrence of the secretive changes in the endometrium that are necessary for blastocyst implantation; 2) the endometrial decidualization; 3) the reduction of uterine contractility after the onset of pregnancy.8 hCG acts in the same way as hypophyseal LH, thereby supporting the physiological and adequate luteal steroidogenesis from embryo implantation until the fifth gestational week, when the placenta becomes responsible for steroidogenic activity (“luteoplacental shift”).10 In case P was lacking or its action blocked by an antagonist agent (for example, mifepristone, which is commonly used in clinical practice to induce abortion), the endometrium would remain hostile, thus preventing embryo implantation.11 According to several studies published over the last decades, CL removal (lutectomy) before the seventh gestational week severely reduces P serum concentration and determines abortion.12 On the contrary, when lutectomy is performed later on (from the seventh gestational week), it does not cause pregnancy termination.13 The minimal serum concentration required for physiological maintenance of the pregnancy is still unknown. However, no pregnancy was reported with P levels
