Abstract
The corpus luteum (CL) is a transitory endocrine gland that develops from the postovulatory ruptured follicle during the luteal phase. Human chorionic gonadotropin (hCG), produced by the embryo, maintains the secretory activity of the CL due to its structural similarity to luteinizing hormone (LH) and subsequent activation of the same receptor. It maintains and stimulates the CL to produce estradiol (E2) and progesterone (P4). Luteal P4 is involved in the transition of the endometrium from a proliferative to a secretory type, with increasing decidualization – an essential facilitator of implantation [1] – and relaxation of the uterine muscle. Preparation of the endometrium lining the uterus for implantation of the embryo begins toward the end of a proliferative phase and extends throughout the luteal phase. This is important for the implantation process and maintenance of pregnancy until the placenta takes over steroid hormone production at approximately 7 weeks.
The corpus luteum (CL) is a transitory endocrine gland that develops from the postovulatory ruptured follicle during the luteal phase. Human chorionic gonadotropin (hCG), produced by the embryo, maintains the secretory activity of the CL due to its structural similarity to luteinizing hormone (LH) and subsequent activation of the same receptor. It maintains and stimulates the CL to produce estradiol (E2) and progesterone (P4). Luteal P4 is involved in the transition of the endometrium from a proliferative to a secretory type, with increasing decidualization – an essential facilitator of implantation [1] – and relaxation of the uterine muscle. Preparation of the endometrium lining the uterus for implantation of the embryo begins toward the end of a proliferative phase and extends throughout the luteal phase. This is important for the implantation process and maintenance of pregnancy until the placenta takes over steroid hormone production at approximately 7 weeks.
The Luteal Phase in Stimulated Cycles
The luteal phase is distinctly abnormal following ovarian stimulation. This was already reported by Professor Robert Edwards in the 1970s when he attempted to develop in vitro fertilization (IVF) using clomiphene citrate (CC) stimulation. Changes in the endocrine environment brought on by the gonadotropins used for ovarian stimulation are thought to underlie the CL dysfunction associated with IVF cycles.
The etiology of luteal phase defects in stimulated IVF cycles has been debated for decades. Initially, it was thought that the removal of large quantities of granulosa cells during oocyte retrieval might diminish the most important source of P4 synthesis, leading to inadequate CL formation and function [2] and subfertility. Others suggested that the prolonged pituitary recovery that follows the gonadotropin-releasing hormone (GnRH) agonist co-treatment designed to prevent spontaneous LH rise in stimulated cycles results in luteal phase defects. The introduction of GnRH antagonists in IVF raised speculations that the rapid recovery of the pituitary function would obviate the need for luteal phase supplementation. However, studies have confirmed that luteolysis is also initiated prematurely in antagonist-co-treated IVF cycles, compromising the chances for pregnancy. Despite the rapid recovery of pituitary function in GnRH antagonist protocols, luteal phase supplementation remains mandatory [3].
For many years, hCG administration was the standard form of luteal phase support. The disadvantage is the risk of ovarian hyperstimulation syndrome (OHSS), particularly in patients who respond well to stimulation. The pregnancy rate has been found to increase when excess hCG was administered during the luteal phase in which embryo transfer took place [4].
Luteal Progesterone Supplementation
The CL secretes more P4 than is required for fertility, and there is no definite evidence that P4 replacement in a natural cycle would improve the chances of conception. As a defective luteal phase has also been reported in hyperstimulated cycles, the optimal dose of P4 is not known.
The ideal time of an inadequate luteal function is during the resumption of gonadotropins secretion. Women who are breastfeeding, or who have pathological elevations of prolactin, have inhibited LH concentrations and, as such, are less capable of generating a sufficient LH surge. Similarly, women with recovering hypogonadotropic hypogonadism, secondary to low body fat as seen in anorexia, overexercise, or chronic illness, are also less likely to be able to generate an adequate LH surge [5]. In contrast, women with polycystic ovary syndrome tend to have higher baseline LH concentration and pulsatility, with a reduced area under the curve for the LH surge; the same is true in the perimenopausal state, where basal LH concentrations are elevated [5–6]. Also, women taking 5-day courses of antiestrogen fertility drugs, such as CC, tamoxifen, or letrozole, in the early follicular phase, may have reduced estrogen-regulated positive feedback to generate the LH surge, particularly if follicular growth is rapid [6] and the proliferation index in glands and stroma of endometrium during early luteal phase is low. These endometrial alterations may adversely affect implantation.
After ovulation in a stimulated cycle, the patient is advised to take medication to promote implantation. Commonly prescribed medications include P4, which is delivered in the form of oral, vaginal, rectal, subcutaneous (SC), and intramuscular (IM) preparations. In frozen–thawed embryo transfer cycles, P4 intake is proposed on the theoretical day of oocyte retrieval [7].
Although P4 alone can promote implantation and maintain pregnancy, there is evidence that the addition of E2 may have a synergistic effect [8]. E2 has been shown to upregulate the P4 receptor and may play a role in further promoting P4 action [1]. In clinical practice, it is now routine to replace both P4 and E2 for the first 10–12 weeks of gestation in artificial embryo replacement cycles.
Oral P4.
Orally administered natural micronized P4 undergoes first-pass prehepatic and hepatic metabolism. Thus, oral administration of P4 leads to variable levels of absorption and poorly sustained plasma P4 concentrations, and its use as luteal phase support in IVF yields inferior results. Parenteral administration (vaginal, rectal, SC, and IM) of P4 overcomes the metabolic challenges of oral P4 administration. The efficacy of oral dydrogesterone 30 mg daily (10 mg, three times daily) was demonstrated in two large randomized control trials and proved non-inferior to micronized vaginal P4 (MVP) 600 mg daily (200 mg three times daily) and to P4 gel (Crinone 8%; 90 mg) for luteal support in IVF [9–12]. Due to the more patient-friendly route of administration, and its high tolerability and efficacy, oral dydrogesterone may replace MVP as the standard of care for luteal phase support in IVF [13].
Subcutaneous and intramuscular P4.
P4 is rapidly absorbed after IM injection, with peak concentrations achieved after approximately 8 hours. However, the IM application of P4 may be painful and is often not the patient’s first choice. SC P4 is well tolerated and comparable in efficacy to vaginal administration [14].
Rectal and vaginal P4.
Rectal P4 administration yields improved uterine P4 levels compared with the oral route. Vaginal administration is associated with high uterine levels of P4 with low systemic exposure [15]. Following vaginal application (a vaginal gel or vaginal capsules), serum P4 concentrations reach maximal levels after 3–8 hours and then fall continuously over the next 8 hours. In the majority of cases, 300–600 mg vaginal P4 is administered daily, divided into two or three doses. Independent of the measured serum P4 levels, adequate secretory endometrial transformation is achieved following vaginal P4 use. Also, endometrial P4 levels are higher after vaginal compared with IM P4 administration [16]. Vaginally administered P4 exerts a direct local effect on the endometrium and myometrium before entering the systemic circulation.
hCG or P4 administration during the luteal phase of assisted reproductive technology (ART) cycles has been suggested to yield higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is still inconclusive [17]. hCG may increase the risk of OHSS and administration with or without P4 is associated with higher rates of OHSS than P4 alone. Neither the addition of E2 nor the route of P4 administration appears to be associated with improved pregnancy rates.
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