Fertility Blaze
Fertility Blaze 2011 › Fertility Blaze Vol-1, No-6, 2011

LUTEAL PHASE SUPPORT IN INFERTILITY TREATMENT

Introduction

The luteal phase of the menstrual cycle extends from ovulation to menstruation. The luteal phase is called so because it involves the process of luteinization, in which a structural transformation takes place in the luteinized cells of the collapsed follicle in response to increased vascularization.1   During the luteal phase, the corpus luteum secretes progesterone, which, along with estrogen, prepares the endometrium for the implantation of the embryo.2

The luteal phase normally lasts for at least 12 to 14 days. A luteal phase of less than 10 days’ duration will have difficulty producing an environment favorable for implantation. Thus, a luteal phase defect (LPD) can interfere with a woman’s ability to conceive, and is an important cause of infertility.3

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In LPD, there is either an insufficient production of progesterone during the luteal phase or the endometrium does not respond appropriately to the progesterone stimulation. The end result is that the endometrial lining is not sufficiently prepared for implantation.3

LPD may occur due to a problem at any stage with the follicle, the developed corpus luteum, or the endometrium. Miscarriage, then, is presumably caused by the failure of the embryo to implant, improper implantation of the embryo or unsuitable nourishment of the growing embryo and fetus.2

Pathogenesis of LPD

Insufficient progesterone production is a major factor in the pathogenesis of LPD, but is not the only one. This fact is amply borne out by the failure of attempts to treat this condition only by progesterone administration. Other factors implicated in causing LPD include defective folliculogenesis and impairment in the levels of follicle stimulating hormone (FSH) or luteinizing hormone (LH).1

Luteal phase defect can also be caused by gonadotropin releasing hormone agonists (GnRH-a) used in ovarian stimulation regimens to prevent premature LH surge. This results in persistent block of LH secretion for at least ten days after discontinuing GnRH-a, which can result in impairment of progesterone secretion by the corpus luteum. The resultant increase in the estrogen/progesterone ratio can have an inhibitory effect on embryo implantation.4

Symptoms of LPD

LPD often goes unnoticed, and the menstrual cycle appears normal because of regular periods. Sometimes, the periods may be frequent but light. However, women who are actively trying to conceive may experience the symptoms a bit sooner.3

Progesterone has a hyperthermal effect, due to which the basal body temperature rises at least four-tenths of a degree to one full degree Fahrenheit after ovulation. The temperatures and thus the progesterone levels should remain elevated for 14 days after ovulation.1   In LPD, the basal body temperature does not stay elevated during the luteal phase, and periods occur sooner than the average 14 days after ovulation.3

Luteal support

An important role is played by the corpus luteum in preparing the endometrium for implantation. This it does by secreting progesterone to induce secretory transformation of the endometrium so that implantation can occur and the necessary support can be provided for the pregnancy during the early stages of its development. In order to produce progesterone sufficiently, the corpus luteum needs to be continuously stimulated by the luteinizing hormone (LH), which, in pregnancy, is produced by the action of human chorionic gonadotropin (hCG) on LH receptors.4

Therefore, methods of luteal phase support include giving serial injections of hCG to stimulate the corpus luteum to secrete endogenous estrogen and progesterone or exogenous replacement of progesterone.  5

A meta-analysis6   of randomized trials tried to find out if luteal phase support improves the pregnancy rate in in vitro fertilization (IVF) cycles. The main outcome measure was the pregnancy rate per cycle. The investigators concluded that luteal phase support is definitely indicated in IVF treatment cycles.

Administration of hCG could be risky in a woman who inadvertently develops ovarian hyperstimulation syndrome (OHSS). In such cases, it is best to administer progesterone.7

Another situation where progesterone is preferred to hCG supplementation is when the woman is an embryo recipient (i.e., ovum donation, embryo adoption, gestational surrogacy and frozen embryo transfers). In these cases, ovarian hormonal activity is dormant, rendering any attempt to try to promote ovarian steroid production with hCG, futile.7

Once the placental trophoblast takes over the job of maintaining the pregnancy, supplementation with either progesterone or hCG is not needed. Therefore, after the completion of the 9th week of pregnancy, supplemental hormonal ther  apy is discontinued.7

Use of micronized progesterone for luteal support

Considering the important role played by progesterone in human reproduction, this hormone is commonly administered exogenously in the treatment of infertility, especially when assisted reproductive technologies (ART) are being employed.

Progesterone can be administered by several routes. The oral, intramuscular (IM) and vaginal routes are the most frequently chosen routes. The oral route is less effective, since progesterone has a low oral bioavailability (<10%), and a high rate of metabolites, which may result in side effects, such as somnolence etc. Intramuscular administration produces very high serum levels of progesterone and this route is effective with regard to pregnancy rates. However, injection of progesterone is painful and the patient has to depend on others to get it.8   Transdermal administration of progesterone is also not feasible,9   as progesterone is not able to penetrate the skin in sufficient amounts, and even the small amount that can get through is inactivated by the enzyme 5-∝-reductase, which is abundantly present in the skin. Hence, the vaginal route is the only remaining practical option for administration of progesterone for luteal support.

The vaginal route is as effective as the IM route, and also conducive to self-administration by the patient herself. Moreover, progesterone is delivered directly to the uterus, where high levels are achieved (first uterine pass effect). There is ample evidence that the vaginal administration of progesterone is effective also with regard to the downregulation of uterine contractions.8   A study by Penzias and Alper10   found that luteal support with exogenous progesterone significantly improves implantation and pregnancy rates after IVF. Vaginal administration was more convenient and tolerable than intramuscular injection.

Bulletti and colleagues11   found that vaginal application of progesterone resulted in its diffusion into the entire uterus within 4-5 hours; 4 hours after application, progesterone concentrations reached 185 ± 155 ng/100 mg of endometrial and 254 ± 305 ng/100 mg of myometrial tissue. Endometrial extraction of progesterone was higher in uteri during the luteal phase (280 ± 156 ng/100 mg of endometrial tissue) than during the proliferative phase of the menstrual cycle (74 ± 28 ng/100 mg of endometrial tissue). These data demonstrate that a first uterine pass effect occurs when drugs are delivered vaginally, accounting for the unusually high uterine concentrations relative to the low serum concentration observed after vaginal administration. Thus, the vaginal route allows targeted drug delivery to the uterus, thereby maximizing the desired effects while minimizing the potential for adverse systemic effects.

However, therapeutic options have been limited to a few synthetic formulations of progesterone. These progestins have been effective in endometrial protection and menstrual regulation, but often cause unwanted adverse effects that reduce patient satisfaction and compliance.12

In 1998, the United States Food and Drug Administration (FDA) approved oral micronized progesterone for use in secondary amenorrhea. This product is derived from the yam plant and is chemically identical to the human hormone, thus offering distinct advantages over synthetic progestins. It provides similar therapeutic benefits as the synthetic compounds, but unlike them, is generally well-tolerated and does not produce unacceptable adverse effects.12

Micronized progesterone is absorbed after oral or vaginal administration. It induces endometrial maturation and leads to pregnancies following IVF – embryo transfer or during cycles of oocyte donation.5   Given orally, micronized progesterone increases the surface area of contact between the steroid molecule and the mucosa.12

Clinical studies on micronized progesterone for luteal support

Various clinical studies have found different formulations of micronized progesterone to be effective in luteal phase support.

Study: The effects of vaginal micronized progesterone on bleeding patterns and pregnancy outcomes after in vitro   fertilization and intracytoplasmic sperm injection (IVF-ICSI) were studied in 149 consecutive women who had undergone IVF-ICSI using ‘long-protocol’ stimulation with buserelin-human menopausal gonadotrophin (HMG).13   Vaginal progesterone (200 mg three times daily) was started the day before oocyte retrieval and continued for a minimum of 16-19 days following human chorionic gonadotrophin (hCG) administration. The length of luteal phase in these women was found to be normal (day of hCG minus day of onset of bleeding). In the absence of pregnancy, bleeding occurred after 19.2 ± 3.9 days (mean ± SD). Out of the pregnant group only three women bled within 19 days of hCG administration: two had biochemical pregnancies which spontaneously vanished and one evolved to term.

Conclusion: These results indicate that use of vaginal progesterone for luteal support in IVF and embryo transfer does not alter either the bleeding pattern or the luteal phase length.

Study: In a study by Miles et al,14   20 women with ovarian failure and 4 with normal ovulatory cycles were given either micronized progesterone vaginally or twice daily IM injections of progesterone. Endometrial progesterone concentrations were observed to be higher with vaginally administered progesterone than endometrial concentrations observed in normal ovulatory women or women who consistently had the highest serum progesterone after IM administration. After 7 days of progesterone, no differences between either treatment regimen and control groups were detected by histologic, ultrasonographic, or immunocytochemical receptor analyses.

Conclusion: The investigators concluded that vaginal micronized progesterone enhances progesterone delivery to the uterus compared with a standard IM regimen and results in a synchronous secretory endometrial histology in agonadal women preparing for embryo donation.

Study: A prospective randomized study15   evaluated the luteal phase hormone profiles in patients stimulated with recombinant FSH and GnRH antagonist for IVF under two different modes of luteal support: progesterone and progesterone with estradiol. In the study, 103 patients undergoing ovarian stimulation with a fixed dose of 200 IU recombinant FSH and GnRH antagonist were randomized to receive luteal phase supplementation with either progesterone vaginally (n = 49) or progesterone and 4 mg estradiol orally (n = 54). Hormonal assessment during the luteal phase on days 1, 4, 7, and 10 after the administration of hCG revealed no difference in hormone levels during the luteal phase between the two groups, except that estradiol concentration on day 10 after hCG was significantly higher in the estradiol-supplemented group compared with the progesterone only group (median 760 pg/mL, range 2,496 vs. median 589.50 pg/mL, range 2,098).

Conclusion: This led to the conclusion that addition of 4 mg estradiol for luteal support after stimulation with recombinant FSH and GnRH antagonist does not significantly alter the endocrine profile of the luteal phase until day 7 after hCG. At day 10 after hCG, the estradiol levels are significantly higher after estradiol supplementation.

Study: Mitwally and colleagues16   compared the effects of luteal support with 1) vaginal micronized progesterone and 2) IM progesterone in oil. In a cohort of 544 women, vaginal progesterone was used in 145 women, and the IM preparation in 399 women for luteal support. The primary outcome was ongoing pregnancy rate. Secondary outcomes included other IVF-ET outcomes, i.e., rates of clinical pregnancy and pregnancy loss (chemical and miscarriage) and serum progesterone levels during the luteal phase and early pregnancy.

Conclusion: It was found that the two routes of administration were not statistically different from each other as regards the treatment outcomes.

Study: A study by Frishman et al   17   evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects. In this study, 7 women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg three times a day). Endometrial biopsies were taken to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation.

Conclusion: Oral micronized progesterone was noted to be as efficacious as the vaginal route in the treatment of luteal phase defects, and was preferred by most of the patients over the vaginal route.

Study: In one study,  18   oral progesterone tablets 300 mg/day were compared with a vaginal application of 90 mg progesterone per day for luteal phase support in 283 patients undergoing an in IVF procedure. The patients were randomly assigned to either treatment within 24 hours of the embryo transfer procedure and continued until day 30 in cases of implantation.

No statistically significant difference was seen in the pregnancy rate per transfer between the groups at days 12, 30, and 90. Nor were the spontaneous abortion rates any different thereafter. There was also no statistically significant difference in the delivery rate as well as the ratio of new-born per transferred embryo. Safety parameters were also almost similar in both groups, with no serious adverse events being reported.

Conclusion: The investigators concluded that although the vaginal route of administering micronized progesterone is as effective as the oral route, it has the additional advantage of avoiding metabolic inactivation of progesterone during its first liver pass.

Study: The efficacy and the tolerability of two different vaginal formulations of micronized progesterone for luteal phase support after an IVF cycle were compared in a cohort study.19   One hundred and twenty-three women who underwent IVF/intracytoplasmic sperm injection (ICSI) stimulated cycles and who had at least six follicles of ≥   14 mm on the day of hCG administration, were randomly allocated to either vaginal progesterone (200 mg twice a day) or oral progesterone capsules (2 x 100-mg capsules, twice a day). This treatment was administered from the day of oocyte pickup (day 0) until periods or up to 10 weeks in pregnant patients.

Conclusion: The progesterone levels on days 0, 9 and 16 were not statistically different between the two formulations. The pregnancy rates were similar in the two groups (25.5% vs. 18.6%), whereas tolerance was significantly better in the vaginal group versus the oral group (vaginal discharge: 43% vs. 82%).

Study: To investigate the efficacy and safety of intravaginal micronized progesterone versus IM progesterone for luteal phase support after IVF-ET, a prospective open trial20   assigned 206 women to either of these treatments. The main outcome measures were pregnancy and miscarriage rates, and midluteal serum progesterone levels.

Both the groups showed similar positive beta-hCG pregnancy rates, clinical pregnancy rates per transfer, and ongoing pregnancy rates. The intravaginal preparation was associated with higher rates of biochemical pregnancy loss but lower rates of clinical pregnancy loss (i.e., spontaneous abortion) than IM progesterone. Midluteal serum progesterone concentrations were significantly higher in the IM progesterone group (94.3 ± 8.8 ng/mL versus 57.7 ± 7.4 ng/mL).

Conclusion: The results of this study support the use of intravaginal micronized progesterone as an acceptable therapeutic option for luteal support after IVF-ET.

Conclusion

  • Luteal phase defect is a threat to embryo implantation and hence, supplementation with a variety of steroid hormones is necessary after ovarian stimulation cycles.
  • Different types of luteal phase support strategies are available, including natural oral and vaginal progesterone supplementation, intramuscular progesterone and IM hCG.
  • Clinical studies have yielded variable results regarding the best type of luteal phase support.
  • Use of micronized progesterone as luteal phase support results in a significantly higher pregnancy rate compared to unsupported IVF-ET cycles.

References

  1. Lewis R. Luteal Phase Defect. Available at http://www.acuforconception.com/Conditions/Articles/Article_Luteal_Phase_Defect.htm. Accessed on Dec 18, 2010.
  2. O’Hara K. Miscarriage Prevention: Treating Luteal Phase Defect with Progesterone Supplements. Available at http://www.suite101.com/content/miscarriage-prevention-a55607. Accessed on Dec 18, 2010.
  3. Luteal Phase Defect. Available at http://www.fertilityfactor.com/infertility_luteal_phase_defect. Accessed on Dec 18, 2010.
  4. Al Inizi ST, Asaad M, Schick J. Luteal phase support in in-vitro fertilization. Middle East Fertility Society Journal 2006;11(1):64-69.
  5. Friedler S, Raziel A, Schachter M, Strassburger D, Bukovsky I, Ron-El R. Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration. Hum Reprod. 1999 Aug;14(8):1944-8.
  6. Nosarka S, Kruger T, Siebert I, Grové D. Luteal phase support in in vitro fertilization: meta-analysis of randomized trials. Gynecol Obstet Invest. 2005;60(2):67-74.
  7. Post-IVF Luteal Phase Support: Progesterone vs. hCG Hormonal Supplementation. Available at http://www.ivfauthority.com/2009/10/post-ivf-luteal-phase-support.html. Accessed on Dec 18, 2010.
  8. Ludwig M, Diedrich K. Evaluation of an optimal luteal phase support protocol in IVF. Acta Obstet Gynecol Scand. 2001 May;80(5):452-66.
  9. Cooper A., Spencer C., Whitehead MI et al. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet. 1998;351:1255-1256.
  10. Penzias AS, Alper MM. Luteal support with vaginal micronized progesterone gel in assisted reproduction. Reprod Biomed Online. 2003 Apr-May;6(3):287-95.
  11. Bulletti C, de Ziegler D, Flamigni C, Giacomucci E, Polli V, Bolelli G, Franceschetti F. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod. 1997 May;12(5):1073-9.
  12. Wendel W. Micronized progesterone: A new option for women’s health care. Nurse Practitioner, 1999. Available at http://findarticles.com/p/articles/mi_qa3958/is_199905/ai_n8834881/. Accessed on Dec 18, 2010.
  13. Roman E, Aytoz A, Smitz JE, Faguer B, Camus M, Van Steirteghem AC, Devroey P. Analysis of the bleeding pattern in assisted reproduction cycles with luteal phase supplementation using vaginal micronized progesterone. Hum Reprod. 2000 Jul;15(7):1435-9.
  14. Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994 Sep;62(3):485-90.
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  16. Mitwally MF, Diamond MP, Abuzeid M. Vaginal micronized progesterone versus intramuscular progesterone for luteal support in women undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2010 Feb;93(2):554-69.
  17. Frishman GN, Klock SC, Luciano AA, Nulsen JC. Efficacy of oral micronized progesterone in the treatment of luteal phase defects. J Reprod Med. 1995 Jul;40(7):521-4.
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  19. Germond M, Capelli P, Bruno G, Vesnaver S, Senn A, Rouge N, Biollaz J. Comparison of the efficacy and safety of two formulations of micronized progesterone (Ellios and Utrogestan) used as luteal phase support after in vitro fertilization. Fertil Steril. 2002 Feb;77(2):313-7.
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