Ameet S. Patki1, 2, 3, 4 and Alok Sharma5
(1)
Fertility Associates, Mumbai, India
(2)
K.J. Somaiya Medical College and Hospital, Mumbai, India
(3)
Hinduja Surgical Hospitals, Mumbai, India
(4)
The Mumbai Obstetrics and Gynaecological Society (2014–15), Mumbai, India
(5)
Clinical Fellow Fertility Associates, Mumbai, India
Ameet S. Patki
Email: aspaap@hotmail.com
Email: ameetpatki@fertilityassociates.in
1 Introduction
The physiological role of progesterone is to prepare the endometrium for implantation and to support pregnancy. In fact, the name progesterone is derived from the Latin word ‘Gestare’ meaning to bear or carry. It is also believed that the name progesterone is derived from progestational steroidal ketone [1]. Progesterone is secreted primarily from the corpus luteum of the ovary during the second half of the menstrual cycle and from the placenta during pregnancy. Progesterone’s role in mammalian reproduction is well described and undisputed. After ovulation, progesterone, secreted by the corpus luteum induces transformation of the proliferative endometrium into the secretory type required for implantation. The endometrium then undergoes specific morphological changes, which are termed ‘decidualization’. All cellular types and structures localized in the functional layer are targets for progesterone action, namely, stromal cells, epithelial glands, and spiral arteries. However, in addition to the endocrine effects, progesterone has numerous immuno-modulatory effects.
In 1976 Georgeanmna Seegar Jones first described luteal deficiency (also known as luteal phase defect or luteal insufficiency), as a condition in which the corpus luteum produces inadequate amounts of progesterone for implantation, or placentation, or a lack of an adequate endometrial response [2], due to a suboptimal number of receptors. In these conditions progesterone or progestogen supplementation has been used. Luteal phase deficiency has been claimed to be responsible for: subfertility, implantation failure, and recurrent miscarriage. However, the whole concept of luteal deficiency has been controversial since its inception, with many doubting the existence of the condition. Similarly progesterone supplementation has also been controversial, with numerous workers doubting any beneficial effects. This chapter will examine the role of luteal deficiency in clinical infertility practice in general, and assisted reproduction in particular.
2 Role of Progesterone in Endometrial Ripening
In the proliferative phase of the cycle, estrogen induces endometrial proliferation. In the luteal phase, progesterone induces changes in endometrial morphology converting the proliferative endometrium to a secretory endometrium. In the secretory phase, the endometrial glands and blood vessels become more tortuous. Glycogen accumulates in vacuoles within the glandular cells, leading to secretion of glycoproteins and peptides into the endometrial cavity, and the stroma becomes edematous. Under the influence of progesterone, stromal cells are transformed into decidual cells, with accompanying infiltration of natural killer (NK) cells, T cells, and macrophages. Pinopode formation coincides with increased progesterone levels and down-regulation of progesterone receptors during the window of implantation Pinopodes may extract fluid from the uterus, facilitating closer contact between blastocyst and endometrium. Progesterone increases osteopontin (OPN, a ligand for integrin αvβ3 secretion) a bridging molecule between the embryo and endometrium. In the mid luteal phase, Leukemia inhibitory factor (LIF, a cytokine which is essential for implantation in muridae) is upregulated. In fact, antiprogestin treatment results in reduced LIF expression. HOXA-10 and 11 genes are up-regulated by estrogen and progesterone. HOXA-10 mediates integrin involvement in early embryo–endometrial interactions. HOXA-10 expression is required for pinopode formation in the mouse.
3 Role of Progesterone in Implantation
Normal luteal function is essential for initiating pregnancy. After adequate estrogen priming, progesterone induces secretory transformation of the endometrium which improves endometrial receptivity [3, 4]. In the “window of implantation” the endometrial epithelium acquires a functional and transient ovarian steroid-dependent status, which allows blastocyst adhesion [5]. The complex molecular interactions between the hormonally-primed uterus and an activated blastocyst results in successful implantation. Progesterone induces the proliferation and differentiation of stromal cells [6]. Progesterone receptor synthesis is controlled by estrogens through estrogen receptors during the proliferative phase. If the synthesis of the estrogen receptors is inhibited then progesterone leads to a fall of both estrogen and progesterone receptors. Various experimental studies have reported down regulation of progesterone receptor epithelial cell expression during the luteal phase of the menstrual cycle [7].
Local vasodilatation and uterine musculature quiescence is also promoted by progesterone by inducing nitric oxide synthesis in the decidua [8]. Fanchin et al. [9] investigated the consequences of uterine contractions at the time of embryo transfer. The authors reported that on the day of embryo transfer, a high frequency of uterine contractions hindered the transfer outcome, possibly by expelling the embryos from the uterine cavity. Additionally, there was a negative correlation between the frequency of contractions and progesterone concentrations [3].
Decreased endometrial receptivity is the main factor responsible for the low implantation rates in IVF [10].
3.1 Cytokines Acting in Implantation
Numerous cytokines are active in implantation, in order to modulate the inflammatory response, remodel tissues, and to induce endocrine effects. The entire picture is far from complete, but some of the cytokine effects are listed below. Cytokines such as Interleukin (IL)-3, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and Epidermal Growth Factor (EGF) stimulate placental cell proliferation [11] in vitro, and may enable the trophoblast to secrete hCG and hPL [12]. Interferon γ (IFNγ) leads to remodelling of the spiral arteries to utero-placental arteriies [13]. Interleukin-1 (IL-1) has many effects, both proinflammatory and anti-inflammatory. IL-1 stimulates IL-6, IL-8, LIF, TNFα, PGE2, PGF production. IL-1 induce COX-2 gene expression which mediates prostaglandin synthesis, induces MMP-1 production and increases the activity of MMP-9, which are involved in implantation. IL-1 modulates hCG and CRH synthesis and attenuates progesterone production by granulosa cells Additionally in animal models, blocking IL-1 reduced the number of implanted blastocysts. Interleukin-6 (IL-6) is associated with hCG release, and increases MMP9.
Leukemia inhibitory factor (LIF) is essential for implantation. LIF mRNA is induced by estrogen. Female mice with no LIF gene, have normal blastocysts which fail to implant. Injecting LIF−/− mice with LIF causes viable pregnancies. In humans, LIF causes cytotrophoblast differentiation to an anchoring phenotype due to increased fibronectin synthesis. Infertile patients with multiple implantation failure have been reported to have dysfunctional LIF production compared to fertile women [14]. Interleukin-15 (IL-15) increases trophoblast invasion, modulates MMP-1 and maintains uterine natural killer (NK) cells.
3.2 Action of Progesterone on Cytokines
Progesterone has been shown to induce changes in the functions of a number of immune-competent cells by different molecular and cellular mechanisms. Progesterone stimulates the activity of some specific enzyme matrix metalloproteinases [15]. and adhesion molecules [16], inhibits antibody production and suppresses T-cell activation and cytotoxicity [17] and directly or indirectly modifies the activity of NK cells, which are the most numerous lymphoid cells locally [18].
Progesterone is associated with decreased IFNγ and increased IL-10 in endocervical fluid [19]. Progesterone up regulates LIF mRNA expression in vitro [20]. Progesterone inhibits NK activity at the feto-maternal interface, inhibits the release of arachidonic acid, and favours the production of asymmetric, pregnancy-protecting antibodies. The cytokine effects of the progestogen dydrogesterone have been investigated more than progesterone itself. Dydrogesterone, inhibits IFNγ and TNFα production [21]. Dydrogesterone increases the levels of IL-4 and IL-6 [21]. Dydrogesterone Inhibits NK activity at the feto-maternal interface, and in preterm labour, dydrogesterone is associated with significantly higher serum levels of IL-10, and lower concentrations of IFNγ than controls [22].
4 Luteal Phase Insufficiency
4.1 Formation of the Corpus Luteum
The CL contains a heterogeneous population of cells including steroidogenic cells, fibroblasts, immune cells, and endothelial cells. The steroidogenic cells are the large and the small luteal cells that are derived from the granulosa and theca cells of the ruptured follicle, respectively [23]. The granulosa cells of the pre-ovulatory follicle are not vascularized, the blood supply stops at the basement membrane. Following ovulation, basement membrane integrity is lost, tissue re-modeling takes place and vessels, originating from the thecal vasculature, invade the granulosa-luteal cells [24]. Over the next few days, intensive angiogenesis takes place and a capillary network extends throughout the fully differentiated CL tissue. In humans, both vascular density and endothelial area of each vessel increase markedly from the luteinized granulosa cells of the early CL to the mid-luteal stage [25]. Neoangiogenesis is important for CL function and is controlled by various angiogenic factors, such as vascular endothelial growth (VEGF), fibroblast growth factor, angiopoietins, and insulin-like growth factors.
The process of neovascularization is regulated by pituitary LH [26]. Luteinizing hormone activates matrix metalloproteinases that degrade extracellular matrix associated with the blood vessels. The CL produces progesterone, estrogens, and non-steroidal substances, such as inhibin A. Apart from the pituitary gonadotropins, different local substances may also regulate the CL life span and function. Such substances include growth factors, peptides, steroids, and prostaglandins [26].
Normal luteal function requires optimal pre-ovulatory follicular development, luteinization of the granulosa cells to produce progesterone, continued tonic lutenizing hormone (LH) support, vascularization of the corpus luteum (CL), and estrogen to induce progesterone (P4) receptors in the endometrium [27]. The normal luteal life span is 14 days unless the life span is prolonged by human chorionic gonadotropin (hCG). hCG is secreted by the developing blastocyst after implantation [28]. By inducing secretory changes, following adequate estrogen priming, progesterone induces normal endometrial receptivity.
4.2 Evaluation of the Luteal Phase
Luteal phase insufficiency generally stems from an insufficiency of estrogen and progesterone production after ovulation. At mid-cycle, the gonadotropin surge has important physiological roles, including induction of luteinization of the granulosa cells, resumption of oocyte meiosis, rupture of the pre-ovulatory follicle, and formation of the CL. Among other events, post-LH surge changes include a shift in steroidogenesis within the follicle with a marked decrease in estradiol (E2) concentrations and a gradual increase in serum progesterone concentrations [29, 30]. Additional alterations involve uncoupling of gap junctions between granulosa cells and the plasma membrane of the oocyte, a process that seems to be important for the resumption of meiosis [31]. For the transfer of cholesterol from the outer to the inner surface of the mitochondrial membrane steroidogenic acute regulatory protein (StAR) is important [32]. The StAR protein is absent from the granulosa cells before the onset of the LH surge and this explains the inability of these cells to produce progesterone [33].
Various investigations have been suggested to assess luteal insufficiency. The original method was by endometrial biopsy taken 2 days prior to menstruation and histologically dated according to Noyes et al.’s [34] criteria. Luteal deficiency is thought to occur if the dating lags more than 2 days behind the chronological age. This technique has produced a positive diagnosis in 26–35 % of cases [35, 36]. However, if the dating is accurately determined by ultrasonic monitoring of follicular size and biopsy timed to 12 days later, the incidence is only 4 % [37]. However, biopsy is taken in a non pregnancy cycle and assumed to reflect the situation in a pregnancy cycle. Plasma progesterone levels are an unreliable test of luteal function as progesterone is secreted in a pulsatile fashion, and blood may be drawn at a pulse peak or nadir. These may differ tenfold [38]. There may also be normal hormone levels in the presence of abnormal histology may also be due to a deficiency of progesterone receptors rather than a deficiency in progesterone itself.
4.3 Luteal Insufficiency in Stimulated Cycles
Luteal insufficiency is due to the inhibition of the LH secretion in the early luteal phase by steroids secreted in supra-physiologic doses in stimulated cycles [39]. If luteal phase hormonal support is not present in assisted reproduction technique (ART) cycles, the serum estrogen and P4 levels drop, thus leading to a decrease in the implantation rates and pregnancy rates [40]. There may be two types of luteal phase defect: one is associated with the presence of immature follicles, and the other where the follicles are mature. In both types, supplemental therapy with progesterone is effective in creating a healthy uterine environment [41].
In women undergoing ovulation induction, multiple follicles of different size might ovulate at different times, thus expanding the fertilization window. It can be expected that sex steroid concentrations, both estradiol (E2 and progesterone), after multiple ovulation will be significantly higher [42]. These high concentrations may not only influence the receptivity of the endometrium, but may also cause luteal insufficiency [43] as high concentrations of steroids through negative feedback on the pituitary-hypothalamic axis, inhibit the production of luteal LH, which is mandatory for luteal progesterone production. A significant negative correlation has been reported between both pre-ovulatory estradiol concentrations and day 16 progesterone levels and the concentration of cytosolic progesterone receptor (Cpr) [44], while advanced endometrial maturity tends to be associated with low concentrations of cPR. Furthermore, natural cycles have been characterized by low cytosolic E-2 receptors (cER) and high cPR, whereas the concentration of both receptors was greatly reduced in stimulated cycles. Due to receptor abnormalities, the endometrium can be progesterone deficient even if plasma progesterone levels are normal [45]. According to one study it has been suggested that in approximately 25 % of women with recurrent miscarriage, the spatial expression of progesterone receptors in the endometrium is different from that in normal controls. Impaired reproductive function and early abortions may be caused by mutations in the progesterone receptor gene [46]. Polymorphism within the coding sequence of the human progesterone receptor gene hs been reported to be significantly higher in patients with recurrent miscarriages than in controls.
5 Hormone Supplementation in Infertility
In normal ovulatory sub-fertile women, with primary or secondary infertility, 92 % of cycles show normal luteal function. Therefore, luteal support seems to be unnecessary [47]. However, latrogenic LPD is seen with the use of controlled ovarian stimulation, and gonadotropin-releasing hormone (GnRH) analogues for in vitro fertilization (IVF), and intrauterine insemination (IUI) cycles. Latrogenic LPD has provided an opportunity to study the endocrine and endometrial abnormalities during the luteal phase and the impact of any pharmacological intervention. Various regimens of hormone supplementation have been used. These are discussed below.
5.1 Human Chorionic Gonadotropin (hCG)
Of the various mechanisms by which hCG may rescue the corpus luteum, an increase in both E2 and progesterone levels appears to be the most likely [48]. The usual dose is 1,500–2,500 IU twice a week from the day of embryo transfer (ET) continued until the day of the pregnancy test or until 8–10 weeks of gestation. Meta-analyses comparing hCG with progesterone have shown it to be associated with either better or at least similar pregnancy rates to that seen with progesterone [49, 50]. Recently, Van der Linden et al. [51] published the results of a metaanalysis to assess luteal phase support (progestogen, hCG or GnRH agonists) in the Cochrane database. The review comprised 69 studies of 16,327 women. The results are summarised in Table 3.1. hCG administration did not improve the pregnancy rate significantly when compared to placebo (OR = 1.30 95 % CI 0.09–1.88). and showed similar results to progesterone supplementation [51]. However, the risk of ovarian hyper-stimulation syndrome (OHSS) associated with hCG in stimulated IVF cycles limits its use for luteal support [52]. The results of luteal phase dynamics differ after GnRHa trigger in GnRH antagonist-treated cycles, the luteal phase being short or inadequate. Whether hCG offers a safe and effective luteal support in this group of women without the risk of OHSS is yet to be fully understood [53].
Table 3.1
Progestogens in luteal phase support
|
OR |
Side effects |
Studies (women) |
|
|
hCG vs. Placebo or No Rx |
1.30 (0.09–1.88) |
OHSS |
5 (746) |
|
Progestin/placebo, No Rx |
1.83 (1.29–2.61) |
7 (741) |
|
|
Progestin vs. hCG |
1.14 (0.90–1.45) |
OHSS |
10 (2,117) |
|
Progestin/progestin, GnRHa |
1.36 (1.11–1.66) |
6 (1,646) |
|
|
Micronised vs. DYD |
0.79 (0.65–0.96) |
32 (9,839) |
Adapted from Van der Linden et al. [51]
Results refer to clinical pregnancy rates
5.2 Micronized Progesterone
Micronized progesterone is to-day the most widely used form of luteal support. Micronized progesterone can be administered orally, rectally or vaginally. However, the bioavailability of micronized progesterone following oral administration is variable as progesterone is metabolised in the liver to pregnenolone and pregnanediol and thereby inactivated. Hence, endometrial changes are inconsistent [54]. In addition, side effects such as nausea, abdominal bloatedness, drowsiness are common with oral administration. The rectal route is rarely used. The vaginal route of administration is widely used, due to ease of administration and high bioavailability as hepatic degradation is avoided. Intra-vaginal administration results in a high uterine concentration of progesterone with relatively low levels in the peripheral circulation. Vaginal micronised progesterone is available in both capsule and gel forms. The daily dose is 600–800 mg/day in 2–3 divided doses, although no dosage finding study has been performed; and 90 mg of gel (8 %) once daily. Pregnancy rates are similar with both forms of vaginal preparations [55, 56]. The disadvantages of vaginal micronized progesterone include local irritation in some women, discharge from the gel or capsule, and staining of the clothes. The divided dose may also be inconvenient, as daily routines need to be interrupted in the middle of the day. Additionally, vaginal administration is unacceptable in some societies.
When all progestogens were compared to placebo or no treatment in Van der Linden et al.’s [51] metaanalysis, progestogens were found to give a significantly better pregnancy rate than placebo or no treatment (OR = 1.83 95 % CI 1.29–2.61).
5.3 Intramuscular Progesterone
Progesterone in oil, 50–100 mg daily as an intramuscular injection is another form of luteal support. With the availability of vaginal progesterone, the intramuscular route is less often used than previously. Pain, rash and abscess at the injection site and the need for daily visits for intramuscular injection by trained staff, are important factors precluding routine use. Occasional occurrence of eosinophilic pneumonia has been reported in otherwise healthy women. However, if the vaginal route of administration is unacceptable or if there is severe local irritation, the i.m. route of administration may be preferred to the vaginal route. More recent evidence has found both routes to be equally effective [51, 57].
5.4 Estradiol Plus Progesterone
Luteal estradiol supplementation has been used in addition to progesterone support in an attempt to improve IVF outcomes, both in women with low luteal estrogen levels or electively in all treatment cycles. Transdermal estradiol patches delivering a dose of 100 μg/day or oral or vaginal estradiol 4–6 mg/day together with progesterone have all been used with variable results. The current evidence of benefit is limited to a higher implantation rate seen in one single study [58]. The addition of estradiol to progesterone support has not been shown to improve the pregnancy rate [51, 59].
5.5 Progesterone with Gonadotrophin-Releasing Hormone
Small bolus doses of GnRH have been used in an attempt to improve pregnancy rates in antagonist-treated cycles where GnRHa is used to trigger ovulation. Triptorelin 0.1 mg has been administered on the day of oocyte pick-up, embryo transfer and 3 days afterwards. The original reports suggested an improvement in both pregnancy and live birth rates [51, 60, 61]. GnRHa may support the CL by stimulating the secretion of LH by pituitary gonadotroph cells by acting directly on the endometrium through locally expressed GnRH receptors. Luteal-Phase GnRHa administration increases luteal phase serum hGC, estradiol and progesterone concentrations. The beneficial effect could possibly be due to a combination of effects on the embryo and the CL.
5.6 Synthetic Progestogens
Synthetic progestogens derived from 19-nor testosterone have stimulatory effects on the androgen receptors. Therefore, although effective, these preparations are not recommended in infertility practice for the fear of inducing androgenic side effects on a female fetus. Androgenization of a female embryo has been seen in laboratory rats, but has never been reported in humans.
Dydrogesterone is a stereoisomer of progesterone, manufactured by conversion of progesterone with ultra violet light. It has been extensively used in over 90 million women, in 90 countries over 40 years and has been found safe for use in pregnancy [62]. Dydrogesterone has a 50 % higher affinity for the progesterone receptor than progesterone itself [63], and has no stimulatory or inhibitory effect on the androgen receptor. Chakravarty et al. [64], have compared oral dydrogesterone to micronised progesterone and found them to be equally effective. Two studies have reported dydrogesterone to have a superior effect to progesterone itself. Iwase et al. [65], has found dydrogesterone to be associated with a significantly higher Live Birth Rate. Patki and Pawar [66] have found a statistically significant increase in pregnancy rates with use of 30 mg dydrogesterone as compared to vaginal micronised progesterone in ART cycles. The Cochrane review of Van der Linden et al. [51] also found a significant effect in favour of dydrogesterone over progesterone itself in terms of pregnancy rates.
Dydrogesterone also has other advantages. It is available as an oral preparation. Although metabolised in the liver, the metabolite dihydrodydrogesterone, is active on the progesterone receptor, unlike the metabolites of progesterone itself.
References
1.
Allen WM. The isolation of crystalline progestin. Science. 1935;82:89–93.CrossRefPubMed
2.
Jones GES. The luteal phase defect. Fertil Steril. 1976;27:351–6.PubMed
3.
Kolibianakis EM, Devroey P. The luteal phase after ovarian stimulation. Reprod Biomed Online. 2002;5 Suppl 1:26–35.CrossRefPubMed
4.
Kolibianks EM, Devroey P. Blastocyst culture: facts and fiction. Reprod Biomed Online. 2002;5:285–93.CrossRef
5.
Martin J, Dominguez F, Avila S, et al. Human endometrial receptivity gene regulation. J Reprod Immunol. 2002;55:131–9.CrossRefPubMed
6.
Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345:1400–8.CrossRefPubMed
7.
Tuckerman E, Laird SM, Steward R, et al. Markers of endometrial function in women with unexplained recurrent pregnancy loss: a comparison between morphologically normal and retarded endometrium. Hum Reprod. 2004;19:196–205.PubMed
8.
Bulletti C, de Ziegler D. Uterine contractility and embryo implantation. Curr Opin Obstet Gynecol. 2005;7:265–76.CrossRef
9.
Fanchin R, Righini C, Olivennes F, et al. Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization. Hum Reprod. 1998;13:1968–74.CrossRefPubMed
10.
Paulson RJ, Sauer MV, Lobo RA. Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil Steril. 1990;53:870–4.PubMed
11.
Chaouat G, Menu E, Wegmann TG. Role of lymphokines of the CSF family and of TNF, gamma interferon and IL-2 in placental growth and fetal survival studied in two murine models of spontaneous resorptions. In: Chaouat G, Mowbray JF, editors. Cellular and molecular biology of the maternal-fetal relationship. Paris: INSERM/John Libbey Eurotext; 1991. p. 91.
12.
Garcia-Lloret MI, Morrish DW, Wegmann TG, Honore L, Turner AR, Guilbert LJ. Demonstration of functional cytokine-placental interactions: CSF-1 and GM-CSF stimulate human cytotrophoblast differentiation and peptide hormone secretion. Exp Cell Res. 1994;214:46–54.CrossRefPubMed
13.
Ashkar AA, Di Santo JP, Croy AB. Interferon γ contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med. 2000;192:259–70.PubMedCentralCrossRefPubMed
14.
Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am J Reprod Immunol. 1998;39:137–43.CrossRefPubMed
15.
Curry TE, Osteen KG. The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev. 2003;24:428–65.CrossRefPubMed
16.
Aplin JD. Adhesion molecules in implantation. Rev Reprod. 1997;2:84–112.CrossRefPubMed
17.
Lin H, Mosmannn TR, Guilbert L, et al. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993;151:4562–73.PubMed
18.
Dosiou C, Giudice L. Neural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocr Rev. 2005;261:44–62.CrossRef
19.
Alimohamadi S, Javadian P, Gharedaghi MH, Javadian N, Alinia H, Khazardoust S, Borna S, Hantoushzadeh S. Progesterone and threatened abortion: a randomized clinical trial on endocervical cytokine concentrations. J Reprod Immunol. 2013;98:52–60.CrossRefPubMed
20.
Aisemberg J, Vercelli CA, Bariani MV, Billi SC, Wolfson ML, Franchi AM. Progesterone is essential for protecting against LPS-induced pregnancy loss. LIF as a potential mediator of the anti-inflammatory effect of progesterone. PLoS One. 2013;8(2):e56161. doi:10.1371/journal.pone.0056161.PubMedCentralCrossRefPubMed
21.
Raghupathy R, Al Mutawa E, Makhseed M, Azizieh F, Szekeres-Bartho J. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. BJOG. 2005;112(8):1096–101.CrossRefPubMed
22.
Hudić I, Szekeres-Bartho J, Fatušić Z, Stray-Pedersen B, Dizdarević-Hudić L, Latifagić A, Hotić N, Kamerić L, Mandžić A. Dydrogesterone supplementation in women with threatened preterm delivery–the impact on cytokine profile, hormone profile, and progesterone-induced blocking factor. J Reprod Immunol. 2011;92(1–2):103–7.PubMed
23.
Retamales I, Carrasco I, Troncoso JL, Las Heras J, Devoto L, Vega M. Morpho-functional study of human luteal cell subpopulations. Hum Reprod. 1994;9:591–6.PubMed
24.
Fraser HM, Lunn SF. Regulation and manipulation of angiogenesis in the primate corpus luteum. Reproduction. 2001;121:3554–62.CrossRef
25.
Suzuki T, Sasano H, Takaya R, et al. Cyclic changes of vasculature and vascular phenotypes in normal human ovaries. Hum Reprod. 1988;13:953–9.CrossRef
26.
Schams D, Berisha B. Regulation of corpus luteum function in cattle-an overview. Reprod Domest Anim. 2004;39:241–51.CrossRefPubMed
27.
Fatemi HM, Bourgain C, Donoso P, et al. Effect of oral administration of dydrogesterone versus vaginal administration of natural micronized progesterone on thee secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept. Hum Reprod. 2007;22:1260–3.CrossRefPubMed
28.
Poenzias AS. Luteal phase support. Fertil Steril. 2002;77:318–23.CrossRef
29.
McNatty KP, Smith DM, Makris A, et al. The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro. J Clin Endocrinol Metab. 1979;49:851–60.CrossRefPubMed
30.
McNatty KP, Makris A, DeGrazia C, et al. The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro. J Clin Endocrinol Metab. 1979;49:687–99.CrossRefPubMed
31.
Norris RP, Freudzon M, Mehlmann LM, et al. Luteinizing hormone causes MAP minase-dependent phosphorylation and closure of connexin 43 gap junctions in mouse ovarian follicles: one of two paths to meiotic resumption. Development. 2008;135:3229–38.PubMedCentralCrossRefPubMed
32.
Miller WL. Mechanizm of StAR’s regulation of mitochondrial cholesterol import. Mol Cell Endocrinol. 2007;265–6:46–50.CrossRef
33.
Kiriakidou M, McAllister JM, Sugawara T, Strauss 3rd JF. Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. J Clin Endocrinol Metab. 1986;81:4122–8.
34.
Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–10.
35.
McNeely MJ, Soules MR. The diagnosis of luteal phase deficiency: a critical review. Fertil Steril. 1989;51:582–7.
36.
Noyes RW, Haman JO. Accuracy of endometrial dating: correlation of endometrial dating with basal body temperature and menses. Fertil Steril. 1953;4:504–9.PubMed
37.
Peters AJ, Lloyd RP, Coulam CB. Prevalence of out-of-phase endometrial biopsy specimens. Am J Obstet Gynecol. 1992;166:1738–41.CrossRefPubMed
38.
Abraham GE, Maroulis GB, Marshall JR. Evaluation of ovulation and corpus luteum function using measurements of plasma progesterone. Obstet Gynecol. 1974;44:522–7.PubMed
39.
Huybayter ZR, Muasher SJ. Luteal supplementation in vitro fertilization: more questions than answers. Fertil Steril. 2008;89:749–58.CrossRef
40.
Huytchinson-Williams KA, Lunefeld B, Diamond MP, et al. Human chorionic gonadotropin, estradiol, and progesterone profiles in conception and non-conception cycles in an in vitro fertilization program. Fertil Steril. 1989;52:441–5.
41.
Check JH. Progesterone therapy versus follicle maturing drugs possible opposite effects on embryo implantation. Clin Exp Obstet Gynecol. 2002;29:5–10.PubMed
42.
Macklon NS, Fauser BC. Impact of ovarian hyper-stimulation on the luteal phase. J Reprod Fertil Suppl. 2000;55:101–8.PubMed
43.
Erdem A, Erdem M, Atmaca S, Guler I. Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles; a prospective randomized study. Fertil Steril. 2009;91:2508–13.CrossRefPubMed
44.
Forman RG, Eychenne B, Nessmann C, et al. Assessing the early luteal phase in-vitro fertilization cycles: relationships between plasma steroids, endometrial receptors, and endometrial histology. Fertil Steril. 1989;51:310–6.PubMed
45.
Li TC, Tuckerman EM, Laird SM. Endometrial factors in recurrent miscarriage. Hum Reprod Update. 2002;1:43–52.CrossRef
46.
Schweikert A, Rau T, Berkholz A, et al. Association of progesterone receptor polymorphism with recurrent abortions. Eur J Obstet Gynecol Reprod Biol. 2004;113:67–72.CrossRefPubMed
47.
Resenberg SM, Luciano AA, Riddick DH. The luteal phase defect: the relative frequency of, and encouraging response to, treatment with vaginal progesterone. Fertil Steril. 1980;34:17–20.
48.
Hutchinson-Williams KA, DeCherney AH, Lavy G, et al. Luteal rescue in vitro fertilization-embryo transfer. Fertil Steril. 1990;53:495–500.PubMed
49.
Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod. 2002;17:2287–99.CrossRefPubMed
50.
Nosarka S, Kruger T, Siebert I, Grove D. Luteal phase support in in vitro fertilization: meta-analysis of randomized trials. Gynecol Obstet Invest. 2005;60:67–74.CrossRefPubMed
51.
van der Linden M, Buckingham K, Farquhar C, et al. Luteal phase support for assisted reproduction cycles. Cochrane Data base Syst rev 2011;5:CD009154.
52.
Ludwig M, Diedrich K. Evaluation of an optimal luteal phase support protocol in IVF. Acta Obstet Gynecol Scand. 2001;80:452–66.CrossRefPubMed
53.
Kol S, Humaidan P, Itskovitz-Eldor J. GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study. Hum Reprod. 2011;26:2874–7.CrossRefPubMed
54.
Devroey P, Palermo G, Bourgain C, et al. Progesterone administration in patients with absent ovaries. Int J Fertil. 1989;34:188–93.PubMed
55.
Ludwig M, Schwartz P, Babahan B, et al. Luteal phase support using either Crinone 8% or Utrogest: results of a prospective randomized study. Eur J Obstet Gynecol Reprod Biol. 2002;103:48–52.CrossRefPubMed
56.
Polyzos NP, Cl M, Papanikolau EG, et al. Vaginal progesterone gel for luteal phase support in IVF/ICSI cycles: a meta-analysis. Fertil Steril. 2010;94:2083–7.CrossRefPubMed
57.
Silverberg KM, Vaughn TC, Hansard LJ, et al. Vaginal (Crinone 8%) gel vs. intramuscular pro progesterone in oil for luteal phase support in in vitro fertilization: a large prospective trial. Fertil Steril. 2012;97:344–8.CrossRefPubMed
58.
Gorkemli H, Ak D, Akyurek C, et al. Comparison of pregnancy outcomes, of progesterone or progesterone + estradiol for luteal phase support in IFSI-ET cycles. Gynecol Obstet Invest. 2004;58:140–4.CrossRefPubMed
59.
Kolibianakis EM, Venetis CA, Papanikolau EG, et al. Estrogen addition to progesterone for luteal phase support in cycles stimulated with GnRH analogues and gonadotrophins for IVF: a systematic review and meta-analysis. Hum Reprod. 2008;23:1346–54.CrossRefPubMed
60.
Pirard C, Donnez J, Loumaye E. GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study. Hum Reprod. 2006;21:1894–900.CrossRefPubMed
61.
Kykrou D, Kolibianakis EM, Fatemi HM, et al. Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis. Hum Reprod Update. 2011;17:734–40.CrossRef
62.
Queisser-Luft A. Dydrogesterone use during pregnancy: overview of birth defects reported since 1977. Early Hum Dev. 2009;85:375–7.CrossRefPubMed
63.
King RJ, Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertil Steril. 1986;46:1062–6.PubMed
64.
Chakravarty BN, Shirazee HH, Dam P, et al. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomized study. J Steroid Biochem Mol Biol. 2005;97:416–20.CrossRefPubMed
65.
Iwase A, Ando H, Toda S, et al. Oral progestogen versus intramuscular progesterone for luteal support after assisted reproductive technology treatment: a prospective randomized study. Arch Gynecol Obstet. 2008;277:319–24.CrossRefPubMed
66.
Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 Suppl 1:68–72.