Review Article Luteal Phase Support: Why, When and How

To cite: Nigam A. Luteal Aruna Nigam Phase Support: Why, When and How. Pan Asian J Obs Professor, Department of Obstetrics and Gynecology, Hamdard Institute of Medical Sciences Gyn 2018;1(2):79-83. and Research, Jamia Hamdard, New Delhi, India Received on: 01-08-2018

Accepted on: 15-10-2018 ABSTRACT Luteal phase support (LPS) is a known intervention for preventing the pregnancy loss. It is most commonly used in the artificial reproduction cycles. Most common agent used for the LPS is progesterone. Current review discusses the reasons of LPD in stimulated and unstimulated cycles and also analyses the utility of various drugs in the treatment of the same. Keywords: Corpus luteum, Luteal phase support, Progesterone, Artificial reproduction cycle.

Introduction secreted by the developing blastocyst to maintain the corpus luteum.Progesterone levels at conception Luteal phase support (LPS) is a known intervention for have been found linearly associated with miscarriage, preventing the pregnancy loss for last many decades and preterm birth, intrauterine growth retardation, and is a common practice among obstetricians. This is more eutrophic term birth.1 evident in the field of infertility, recurrent pregnancy For the adequate secretion of progesterone, the loss and preterm labour. This review has been done corpus luteum requires continuous stimulation by with an intend of finding the evidences and reasons of luteinizing hormone (LH) which has a pulsatile secretion use of various agents for LPS. Reviews, original articles, from the pituitary under the influence of hCG. Basically, guidelines have been searched in PUBMED from 1995- hCG is secreted from developing syncytio-trophoblasts 2018 using the key words ‘LPS’,‘recurrent pregnancy of placenta from week 2 of implantation. It also interacts loss’, ‘progesterone’, ‘infertility’ and ‘threatened with L-hCG receptor of the ovary to maintain the corpus miscarriage’. luteum so that corpus luteum continues to secrete To understand the concept of LPS, one must the progesterone for the support of pregnancy in the understand the physiology of the luteal phase. first trimester. Corpus luteal cells develop from the follicular cells surrounding the ovarian follicle. These Normal physiology of follicular cells are either theca cells or luteal cells. After luteal phase ovulation theca cells luteinize into small luteal cells and Natural menstrual cycle is divided into follicular phase granulosa cells luteinize into large luteal cells. Both (proliferative phase) and Luteal phase (secretory these cells secrete progesterone but the small luteal phase). Follicular phase starts from menstruation cells synthesize androgens besides progesterone due to and ends with ovulation. Luteal phase extends from the lack of aromatase enzyme whereas large luteal cells ovulation to the establishment of pregnancy or start secrete estrogen and inhibin A besides progesterone. of menses. This phase is governed by corpus luteum The studies have shown that although the progesterone which secretes progesterone and estradiol. If the patient conceives, embryo implantation occurs on around Address for Correspondence 6th day after fertilization. This embryo implantation Aruna Nigam Professor process is complicated and largely depends on the local Flat No. 6, Type 4 Quarters, Bangla Sahib Road environment supported by progesterone mainly and LHMC Campus, New Delhi-110001, India [email protected] the human chorionic gonadotropin (hCG) hormone

Pan Asian Journal of Obstetrics & Gynecology, September-December 2018;1(2):79-83 79 Aruna Nigam

is the most important component for the luteal support 1. It is said that the removal large amount of granulosa but the estrogen should also be given importance as cells during oocyte retrieval diminishes the source of evidenced by the studies1,2 where the better results have progesterone. been obtained on stimulating the follicular phase only 2. Multifollicular development in the IVF cycle leads to optimize the luteal phase producing higher estrogen to supraphysiological levels of steroids due to high and progesterone. Estradiol metabolites from corpus number of corpora lutea. This directly inhibits the luteum may play role in angiogenesis and its lifespan LH release via pituitary through negative feedback and regression.2 leading to LPD.7 It is important to remember that corpus luteum 3. GnRH agonist supplementation to prevent requires continuous LH stimulation for adequate spontaneous LH rise may also delay the pituitary steroidogenic activity (progesterone secretion) and recovery to stimulate the corpus luteum. in the event of LH withdrawal, premature luteolysis 4. Another reason of LPD in IVF cycles is the suppression occurs. It has been observed that if corpus luteum of LH production in the final stages of oocyte is removed prior to 7 weeks of gestation, it leads to maturation because of hCG administaration. pregnancy loss. This pregnancy can be supported by 5. In the GnRH antagonist treated IVF cycles, premature high dose of progesterone supplementation. luteolysis causes LPD and decreases the chances of pregnacncy. Luteal phase defect (LPD) In ARTcycles, depending upon the type of stimulation, Any problems with the progesterone secretion during LPD can be of 4 types the secretary phase leads to defective luteal phase • Luteal phase of monofollicular cycle: There is which is clinically observed by the early menses in a less impairment of luteal phase because of milder stimulated cycle. LPD is usually observed in cases of stimulation. polycystic ovarian disease, recurrent pregnancy loss • Luteal phase after controlled ovarian hyper­ and stimulated/invitro fertilization (IVF) cycles. LPD stimulation (COH) in which GnRH analogs have has also been observed around 8% of normo-ovulatory been used: Intense ovarian stimulation protocols patients who present with infertility.3 need high progesterone support for reasons It is said the half of the LPD occurs due to the discussed above. defect in gonadotropin releasing hormone (GnRH) • Luteal phase where GnRH antagonists have been pulse generation. With the more understanding of the used with GnRh agonist used as trigger leading to corpus luteum function the subclassification of the premature luteolysis: Here stimulation is intense LPD of ovarian origin has been given according to the but lesser than above and needs LP support. dysfunction of small/large luteal cells.4 As the small • Artificial cycle where ovulation is suppressed and luteal cells are LH responsive, if there is improper thawed embryo has been implanted: Due to the development of these cells, these cells will not secrete absence of corpus luteum, endometrial receptivity progesterone under the influence of normal LH pulses is totally dependent on exogenously supported this is known as small luteal cell defect. Large cell luteal sex steroids. These cycles have also helped us to defect results in decrease in basal level of progesterone understand the efficacy of different LPS preparations, levels in presence of normally secreted progesterone doses, regimens, and routes of administration.8 under the influence of LH.This subclassification is important as the treatment varies in different defects. TREATMENT FOR LUTEAL In case of LH responsive large cells corpus luteum PHASE DEFECT defect hCG and GnRH pulses will be beneficial but in Progesterone is the main stay of the treatment but case of LH unresponsive small cell defect, progesterone there is still controversy regarding the type and supplementation is needed. route of progesterone preparations. Most common It is well proven that IVF cycles are almost always progesterone used is micronized progesterone followed associated with LPD because of varied reason as by dydrogesterone. Former can be given by various discussed below:5,6 routes but the latter can be used by oral route only.

80 AIM Publications www.pajog.com Luteal Phase Support: Why, When and How

Role of Progesterone having a good oral bioavailability. It induces secretory Besides maintenance of pregnancy, transformation of the endometrium through its 1. It also improves the endometrial receptivity in antiestrogenic effect. It has also been shown in the adequately estrogenized endometrium. studies that dydrogesterone has immunological effects 13 2. It maintains stabilizes lysosomal membranes leading which are associated with higher rates of pregnancy. to quiescent uterus. Natural micronized progesterone14,15: The problem 3. It blocks the chemokines - transcription factor, of lesser bioavailability have been overcome by the NF-kB leading to inhibition of prostaglandin synthesis invent of sustained released preparations of the NMP causing uterine relaxation. This is also supported by in last decade. This preparation is provided in a methyl- the reduced intracellular calcium concentration and cellulose base which hydrates in the gastrointestinal lowered amount of phosphorylated myosin. tract causing a slow release of progesterone. Oral NMP 4. It causes uterine relaxation by causing nitric oxide have high protein binding with long half-life (18 hours) synthesis. leading to once a dosage benefit. The ‘Smooth’ release 5. It increases endometrial vascularity and promotes pattern of the drug helps in maintenance of the steady secretory transformation of endometrium. drug levels in blood because of decreased hepatic 6. Progesterone along with hCG and cortisol inhibits metabolism. the tissue rejection and protect the conceptus by its Both dydrogesterone and NMP are associated with immunomodulatory action. similar rates of successful pregnancies (24.1% versus 7. Progesterone positively regulates‘Progesterone 22.8% respectively).16,17 Induced Blocking Factor’, ‘Natural Killer cells’, HOX-10, trophoblast HLA gene leading to positive Vaginal Preparations of the Progesterones shift towards Th2 type.9 These are available in the form of the gel and pessaries. The advantage of vaginally progesterone is that they have Various Routes of Progesterone first uterine pass effect and a better bio-availability in Supplementation and Doses the uterus. This causes adequate secretary endometrial Currently available formulations of progesterone transformation despite lower serum progesterone include oral, vaginal, rectal and intramuscular. There concentrations.18,19 The side effects of oral absorption is still a controversy regarding the optimal route of are also minimal. Studies have shown similar clinical progesterone administration for LPS in ART cycles.10 pregnancy rates with significantly higher implantation Literature is full of studies which shows no difference rate in the vaginal progesterone groups in ART cycles. in efficacy between intramuscular/vaginal/ oral route It has also been recommended by authors that low of progesterone supplementation but the compliance dose vaginal micronized progesterone administration with oral sustained release preparations have been is simple, easy and well tolerated, so it can be the found to be better.11,12 method of choice for LPS especially for high responder patients at risk of ovarian hyperstimulation syndrome (OHSS).6 Studies have clearly shown that vaginal Oral Progesterone Preparations micronized progesterone is significantly more effective The two oral progesterone preparations available in creating an ‘in phase’ secretory endometrium than with us are Dydrogesterone and Natural Micronized oral dydrogesterone.18,19 Progesterone (NMP). These preparations are known to Patient compliance with vaginal progesterone is poor undergo fifirst pass prehepatic and hepatic metabolism because of side effects like vaginal discharge, pruritus, which results in progesterone degradation to its 5a- vaginal messiness and irritation. and 5b-reduced metabolites and this reduces there bioavailability. Thus oral drugs require more doses but Injectable Preparations of Progesterone these are the easiest and acceptable routes. This comes in the form of oil based intramuscular Dydrogesterone: This is a retroprogesterone and is a injections and aqueous solution subcutaneous biologically active metabolite of progesterone, thus injections. Subcutaneous administration avoids the

Pan Asian Journal of Obstetrics & Gynecology, September-December 2018;1(2):79-83 81 Aruna Nigam

concerns regarding vaginal administration and, unlike to the fact that the timing and duration of implantation IM injections that are known to cause significant is not precisely known. Some have recommended the adverse reactions, the subcutaneous injections in the start of progesterone dose from the day of retrieval, studies have been well tolerated. The doses of injectable others the day after retrieval or 2 days after retrieval. But progesterone used for LPS may vary between 25 and so far no impact on treatment effect has been known. 100 mg per day without any significant difference There are differing reports regarding the duration of concerning the outcome. support but it has been suggested that LPD support Side effects of injectable progesterones are pain and can be stopped any time after positive pregnancy test rashes at the injection site which are more commonly or ultrasound detection of pregnancy.28 The withdrawal observed with intramuscular preparations. of support after the confirmation of pregnancy has been suggested by the studies on pregnancies where the Progesterone + Estrogen conception has occurred after donor oocyte. As discussed above the corpus luteum secretes not only progesterone, but also estrogens and other steroid Conclusion hormones, thus authors debated the need of adding The embryo implantation and the LPS is a complicated estrogen to progesterone for LPD20 and suggested that event. Whatever may be the reason, the progesterone it would improve the implantation rates.21,22 However, is the mainstay of the treatment for the LPS. All the in a meta-analysis it has been shown that routine use routes of progesterone administration has almost equal of estrogen is not justified in progesterone supported efficacy and it remains the woman’s choice to choose luteal phase in IVF cycles.16 the type and route of administration. hCG Increased hyperstimulation rates have been observed Source of Support when the hCG is being used for luteal support.23 Luteal Nil support with hCG should be avoided if oestradiol concentrations are above 2500–2700 pg/mL on the day Conflict of Interest of hCG administration in IVF cycles or if there are more There are no conflict of interest. than 10 follicles.24,25 Cochrane review clearly states that hCG with or without progesterone is associated with higher risk of ovarian hyperstimulation syndrome, References therefore should be avoided.26,27 1. Siklósi GS, Bánhidy FG, Ács N. Fundamental role of folliculo-luteal function in recurrent miscarriage. Arch Gynecol Obstet 2012;286:1299-1305. GnRH Agonist 2. Devoto L, Henríquez S, Kohen P, Strauss JF. The significance of estradiol metabolites in human corpus GnRH agonists have been suggested as a novel LPS luteum physiology. Steroids 2017;123:50-54. that act at three levels i.e. pituitary, endometrium and 3. Rosenberg SM, Luciano AA, Riddick DH. The luteal the embryo itself.28 It may also support the corpus phase defect: the relative frequency of, and encouraging response to, treatment with vaginal progesterone. Fertil luteum by stimulating the secretion of LH by pituitary Steril 1980;34:17-20. or act directly on the endometrium through the locally 4. Wuttke W, Pitzel L, Seidlová-Wuttke D, Hinney B. expressed GnRH receptors. Prospective trials have LH pulses and the corpus luteum: the luteal phase deficiency LPD. Vitam Horm 2001;63:131-158. shown opposing effects of GnRH agonist with low 5. Kolibianakis EM, Albano C, Camus M, Tournaye H, Van quality of evidence in its support.29 Steirteghem AC, Devroey P. Initiation of gonadotropin- releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and Duration of Luteal Phase Support follicular development in in vitro fertilization cycles. J Clin Endocrinol Metab 2003;88(12):5632-5637. As far as opinion regarding the progesterone initiation, 6. Leth-Moller K, Hammer Jagd S, Humaidan P. The Luteal dose and duration of treatment is concerned, there is Phase after GnRH Trigger-Understanding An Enigma. still no consensus in the literature. This might be due Int J Fertil Steril. 2014;8(3):227-234.

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