Progesterone: uses in ART and prevention of pregnancy loss.
Luteal-phase defect and progesterone
Progesterone, as well as clomiphene citrate, aromatase inhibitors, and gonadotropin, is often used to improve luteal function, with potential benefits for fertility and prevention of recurrent pregnancy loss. This agent has specific effects on hormonal levels at the follicular phase or the luteal phase, or both, through a variety of actions. Luteal-phase defect is, essentially, a progesterone-deficiency defect that is best characterized as a subtle form of ovulatory dysfunction. This description is particularly meaningful as it applies to the typical patient who is subfertile and demonstrates clinical characteristics that suggest deficient progesterone production: advanced age, low body weight, and/or shortened menstrual cycles that are often accompanied by premenstrual spotting. Additionally, it should be noted that the use of ovulation-induction methods may compromise the luteal phase.
The impact of a patient's age on luteal function is clear. The relationship between age and luteal function also sheds light on the entire process by which luteal-phase defect, or insufficiency, occurs: In older women, the levels of progesterone metabolites are reduced significantly during the luteal phase, even in women with "regular" cycles. (1) Women who have regular menstrual cycles should be suspected of having luteal-phase defect if they have a history of shortened intermenstrual intervals and premenstrual spotting, characteristics that suggest premature breakdown of the endometrium because of lack of support from progesterone. This population also may show an increase in premenstrual symptoms that may be characterized as new-onset symptoms.
Estrogen levels in this older group also may not have the pronounced luteal-phase peak that occurs in younger women (preliminary data, Cedars). This change in estrogen secretion levels actually may initiate much of the luteal-phase deficiency process by promoting defective folliculogenesis. Therefore, luteal-phase defect may actually be viewed best as a continuum of defective ovulation.
Strategies to extend the luteal phase
Various agents are used to extend the luteal phase and increase the likelihood of implantation. Clomiphene citrate (CC), a selective estrogen-receptor modulator, is administered to establish a normal ovulatory cycle and extend the luteal phase by increasing levels of endogenous progesterone. It also increases the levels of endogenous estradiol, perhaps as a result of its effects on multifollicular development. Thus, it is an effective agent for improving fertility in specific groups of patients who have normogonadotrophic and normoestrogenic ovulatory dysfunction.
Several small studies provide important clues to guide clinicians in the use of this agent. An early study by Daly and Riddick (2) evaluated the effects of CC administered during the follicular phase compared with the use of luteal-phase progesterone in women with biopsy-diagnosed luteal-phase defect. The more severe the defect, the greater benefit seen with CC compared with the benefits of luteal-phase progesterone. This supports the theory that the actual defect began in the follicular phase. Creus (3) and Ordi (4) reported no adverse effect on integrin, leukemia inhibitory factor, or E-cadherin with CC. A reduction in pinopode formation was noted. The work by Ordi (4) suggests reproducibility of these markers is poor, thus limiting their usefulness.
In a 2005 study, Palomino et al (5) evaluated CC's effect on estradiol and progesterone levels, as well as on endometrial epithelial integrins and progesterone receptors during the luteal phase of 31 fertile women. The investigators noted that this agent was associated with [beta] (3)integrin abnormalities, although no differences were associated with in-phase biopsies. Thus, CC may affect the expression of markers of endometrial receptivity and cause a failure in the luteal function, despite high plasma levels of progesterone. Randomized controlled trials have not been conducted to confirm this.
Aromatase inhibitors also are used to treat luteal-phase dysfunction and recurrent pregnancy loss; small trials have compared the effects of CC and these agents on pregnancy rates. Recently, 15 patients having intrauterine insemination received either letrozole, 2.5 mg (n = 7), or CC, 100 mg (n = 8), from day 3 to day 7 of the cycle. (6) Intrauterine insemination was performed 1 day after confirmation of LH peak. No luteal support was administered. Significantly higher levels of estradiol and progesterone--as well as a higher number of dominant follicles--developed in patients in the CC group compared with those in the letrozole group.
Al-Fozan et al (7) compared the effects of letrozole and CC on pregnancy outcomes in women with idiopathic infertility who were undergoing super-ovulation and intrauterine insemination over a total of 238 cycles. No significant differences were reported in the total number of developing follicles and endometrial thickness. Pregnancy rates per cycle associated with the use of CC and letrozole were similar (8.9% and 11.5%, respectively); however, 4 of the 11 pregnancies in the CC group resulted in a spontaneous abortion (36.6%) (TABLE 1). It is unclear whether the results of such a small study can be applied broadly; clinicians, therefore, should assume that there are no differences between treatment with CC and with letrozole.
Exogenous progesterone and hCG inhibit cell apoptosis
The use of human chorionic gonadotropin (hCG) and exogenous progesterone may prolong the health of the luteal phase in women with infertility or recurrent pregnancy loss. Significantly, the use of these agents has been associated with decreased cellular apoptosis, which may be important in preserving endometrial function, prolonging the health of luteal phase, and thus promoting implantation. In a 2005 controlled, prospective, and randomized study, Lovely et al (8) examined the effects of exogenous hCG and progesterone on apoptosis in late luteal-phase endometrial biopsies of 12 healthy fertile women (aged 20 to 34 years) with regular menstrual cycles. The women received luteal doses of either intravaginal progesterone, 200 mg (on days 18 to 27), or a single IM injection of hCG, 10,000 IU, on day 19. At 26 days, a second endometrial biopsy was performed and serum was collected. Evidence of apoptosis was reduced significantly with both luteal-phase treatments. Serum progesterone levels were higher in the hCG-treated group; however, the difference between groups was not statistically significant. These findings suggest that luteal-phase support may prolong the health of the luteal phase in part by preventing programmed cell death.
Progesterone: Route of administration
Progesterone can be administered by the oral, vaginal, or IM route. Absorption based on route of administration was evaluated in 2 very small studies conducted in the early 1990s (FIGURE 1). In the study shown on the left panel, Nahoul et al (9) evaluated plasma progesterone after oral or vaginal administration of progesterone in 6 premenopausal women. Micronized progesterone, 100 mg, was administered vaginally and orally in the luteal phase of the menstrual cycle. In the second cycle, the same doses were administered, but by different routes. As shown in FIGURE 1, circulating progesterone levels were higher after vaginal administration than after oral administration. Miles et al (10) enrolled 4 normally ovulating women and 20 functionally agonadal women receiving estrogen replacement. Participants received micronized progesterone administered either vaginally or by twice-daily IM injections. Although serum levels were higher with IM administration, vaginal administration demonstrated higher levels in the target tissue.
[FIGURE 1 OMITTED]
Progesterone and recurrent pregnancy loss: Immunologic effects
Certainly, endogenous progesterone, as has been discussed, is essential for supporting a pregnancy and has significant direct effects. A pregnancy will fail if a progestogen antagonist is administered or if surgery is performed to remove a hemorrhagic corpus luteum. However, it is likely that progesterone also exerts nonhormonal immunologic effects. We know that progesterone induces an immunomodulatory-blocking factor critical in suppressing T-helper 1 cytokines and thus exerting anti-abortive effects. In the first trimester of pregnancy, the ratio of T-helper 1 to T-helper 2 cytokines is critical. The relation between these cytokines, and potential effects on spontaneous abortion, has been examined.
Raghupathy (11) studied the associations of cytokine expression of T-helper 1, 2, and 3 cytokines and the mechanisms that may be associated with immunologically mediated pregnancy failure. Secretion of transforming growth factor- [beta] by T-helper 3 cells also may play a role. A strong association between maternal Thelper 2-type immunity and successful pregnancy was reported in this study, as was an association between Thelper 1-type and pregnancy loss.
To underscore this point, the ratio of mean cytokine levels between these 2 cytokines in women who have normal pregnancies or recurrent loss is shown in FIGURE 2.
[FIGURE 2 OMITTED]
In 2005, Gruber and Huber (12) reviewed the evidence regarding the administration of progesterone and dydrogesterone in the prevention of habitual abortion. When peripheral mononuclear cells from women who have recurrent pregnancy loss were incubated with progesterone or dydrogesterone in vitro, T-helper 1 cytokine interferon-gamma decreased, while T-helper 2 cytokines such as interleukin-4 and interleukin-6 markedly increased, further documenting the importance of this cytokine ratio.
The literature regarding recurrent pregnancy loss and the efficacy of progesterone was evaluated in a 2003 Cochrane collaboration review by Oates-Whitehead et al. (13) The investigators reviewed 30 original studies, of which 14 met criteria for further review. Overall, the data showed that progesterone reduced the risk of miscarriage in women with recurrent losses, not in threatened loss.
Progesterone in assisted reproduction technologies: Luteal-phase support
Finally, progesterone is used in fertility care with ART. Certainly, adequate levels of progesterone are essential to support implantation and early pregnancy. However, both the procedures used in ART and the agents administered to induce ovulation and stimulate the ovaries may interfere with progesterone production. How critical is administration of exogenous progesterone? Are the route of administration and the specific properties of available agents of consequence?
Endogenous levels of progesterone may well be insufficient: at the time of oocyte retrieval, aspiration of follicles may result in the removal of granulosa cells. Therefore, levels of luteal-phase progesterone may not be adequate to support the endometrium and early pregnancy. Administration of other agents, such as gonadotropin agonists alone or with CC, also may be associated with diminished or defective progesterone production during the luteal phase. The reasons for this effect remain unclear; however, possible causes may include excessively high estradiol levels during the follicular phase and suppression of endogenous luteinizing hormone following administration of hCG, early induction of progesterone receptors, or negative impact on cytosolic progesterone receptors. Conversely, gonadotropin-releasing hormone (GnRH) antagonists are shorter-acting and it has been thought that they will not result in defective luteal function. The lower levels of follicular phase estrogen also might be a benefit.
Early studies suggested that progesterone support in the luteal phase was unnecessary. (14) In these investigations, addition of agonists led to a fall in luteal-phase progesterone and premature luteolysis. However, since it has been shown that without luteal-phase support, either through hCG (increasing endogenous progesterone) or administration of exogenous progesterone, pregnancy rates are reduced. A recent study by Beckers et al (15) looked at GnRH antagonist cycles to evaluate premature luteal phase in patients with ovulation induction with recombinant follicle-stimulating hormone combined with a GnRH antagonist. Ovulatory trigger was initiated by recombinant-hCG (r-hCG), recombinant luteinizing hormone, or GnRH agonist. No luteal support was provided, and the median duration of the luteal phase was 13, 10, and 9 days, respectively. The least disruption to the luteal phase was seen in the r-hCG group, probably because of slow clearance of hCG from the circulation, which extended luteal support of the corpus luteum. Despite high progesterone and estradiol concentrations in the early luteal phase, luteolysis began prematurely, probably as a result of excessive negative feedback stemming from suppressed release of pituitary LH. The study was stopped early because of the low pregnancy rate and very obvious premature luteolysis. Clearly, luteal-phase support of ART cycles is critical to success.
The question remains: What is the best method for providing luteal-phase support during an ART cycle? In the Cochrane Database review by Daya et al, (14) a comparison of placebo versus hCG demonstrated the importance of luteal-phase support. A comparison of studies revealed no difference in efficacy between hCG, which stimulates the production of progesterone, and the administration of exogenous progesterone for luteal-phase support. Given the higher risk of ovarian hyperstimulation syndrome associated with luteal-phase hCG support, progesterone support is preferable (TABLE 2).
[TABLE 2 OMITTED]
Progesterone: Route of administration
A study by Chakravarty et al (16) compared vaginal administration of micronized progesterone to oral delivery of dihydrogesterone, a form of progesterone not available in the United States. The study results indicate that the viable delivery rates (22.8% and 24.1%, respectively), and the spontaneous abortion rates (8.3% and 7.6%, respectively) were similar in both groups.
As Dr Simon noted in his introductory comments, route of administration is important, but so are the molecular absorption dynamics and bioavailability of agents. Whereas most studies have suggested no difference between the use of IM and vaginal routes of administration on pregnancy outcome, it is hypothetically possible that the very high local levels and rapid absorption associated with vaginal administration may shorten the window of implantation by accelerating the progesterone response of the endometrium. The proper timing and dosing may not be known at this time.
There seem to be similar outcomes for ongoing pregnancy associated with both progesterone capsules and gel formulations. Kleinstein et al (17) noted similar rates of ongoing pregnancy with vaginal progesterone capsules compared with a vaginal 8% gel, with pregnancy rates of 25.2% versus 22.2%, respectively. Additionally, data suggest that patients may accept vaginal delivery versus IM delivery of agents more readily.
Some women may have inadequate amounts of progesterone and may have inadequate luteal phases, although the only means of diagnosis currently available are a patient history and assessment of hormonal factors that suggest dysfunctional folliculogenesis. At-risk women include those with diminished ovarian reserve and/or decreased estradiol levels, suggesting the importance of the follicular phase in identifying and treating defective luteal-phase function.
In the treatment of recurrent pregnancy loss, there is a suggestion that progesterone is helpful in women who have otherwise unexplained recurrent pregnancy loss; however, the indications and mechanisms are unclear.
In ART, the administration of endogenous progesterone for progesterone support is required. It appears that the use of progesterone alone is likely adequate: vaginal, IM, or oral (in the case of dydrogesterone only) administration appear to be equally effective.
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(8.) Lovely LP, Fazleabas AT, Fritz MA, McAdams DG, Lessey BA. Prevention of endometrial apoptosis: randomized prospective comparison of human chorionic gonadotropin versus progesterone treatment in the luteal phase. J Clin Endocrinol Metab. 21105;90:2351-2356.
(9.) Nahoul K, Dehennin L, Jondet M, Roger M. Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone. Maturitas. 1993;16:185-202.
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(12.) Gruber CJ, Huber JC. The role of dydrogesterone in recurrent (habitual) abortion. J Steroid Biochem Mol Biol. 2005;97:426-430.
(13.) Oates-Whitehead RM, Haas DM, Carrier JA. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2003;141:CD003511.
(14.) Daya S. Gonadotropin releasing hormone agonist protocols for pituitary desensitization in in vitro fertilization and gamete intrafallopian transfer cycles. Cochrane Database Syst Rev. 2000;(2):CD001299.
(15.) Beckers NG, Macklon NS, Eijkemans MJ, et al. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab. 2003;88:4186-4192.
(16.) Chakravarty BN, Shirazee HH, Dam P, et al. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support ill assisted reproductive technology (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol. 20115;97:416-20.
(17.) Kleinstein J; luteal Phase Study Group. Efficacy and tolerability of vaginal progesterone capsules (Utrogest 200) compared with progesterone gel (Crinone 8%) for luteal phase support during assisted reproduction. Fertil Steril. 2005;83:1641-1649.
TABLE 1 Luteal-phase function: Letrozole versus clomiphene citrate Letrozole Clomiphene Citrate Total number of follicles 5.5 [+ or -] 0.4 4.8 [+ or -] 0.3 Number of follicles larger 2.0 [+ or -] 0.1 1.7 [+ or -] 0.1 than 14 mm Number of dominant 1.3 [+ or -] 0.1 1.1 [+ or -] 0.1 follicles Pretreatment endometrial 4.4 [+ or -] 2.2 4.5 [+ or -] 0.2 thickness (mm) Endometrial thickness at 7.1 [+ or -] 0.2 8.2 [+ or -] 0.6 hCG (mm) Duration of 10.1 [+ or -] 0.3 10.8 [+ or -] 0.9 stimulation (d) Pregnancy (%) 11.5 (13/115) 8.9 (11/123) Spontaneous abortion (%) 0 (0/115) 36 (4/11) On-going (%) 9.6 (11/115) 6.5 (8/123) hCG, human chorionic gonadotropin. Al-Fozan H, et al. Fertil Steril. 2004;82:1561-1563.
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|Author:||Cedars, Marcelle I.|
|Date:||Feb 1, 2007|
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