{"paper_id":"102a6d1e-8cb5-4d45-87d4-06c5773aa5ea","body_text":"Received\n 08/26/2023 \nReview began\n 08/28/2023 \nReview ended\n 10/31/2023 \nPublished\n 11/03/2023\n© Copyright \n2023\nMuneeba et al. This is an open access\narticle distributed under the terms of the\nCreative Commons Attribution License CC-\nBY 4.0., which permits unrestricted use,\ndistribution, and reproduction in any\nmedium, provided the original author and\nsource are credited.\nDOI:\n 10.7759/cureus.48194\nThe Role of Dydrogesterone in the Management\nof Luteal Phase Defect: A Comprehensive Review\nShaikh Muneeba Jr. \n, \nNeema Acharya \n, \nShazia Mohammad \n1.\n Obstetrics and Gynecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and\nResearch, Wardha, IND\nCorresponding author: \nShaikh Muneeba Jr., \nskmuneeba@gmail.com\nAbstract\nThe luteal phase of the menstrual cycle is a pivotal period characterized by hormonal intricacies that lay the\nfoundation for successful embryo implantation and early pregnancy development. Luteal phase defect\n(LPD), marked by abnormalities in luteal function, presents challenges that can impede reproductive\noutcomes. This comprehensive review article explores the role of dydrogesterone in LPD management,\nelucidating its mechanisms of action, evidence of efficacy, safety profile, and potential in combination\ntherapies. Dydrogesterone, a synthetic progestogen, closely mirrors natural progesterone's actions,\neffectively supplementing the luteal phase and enhancing endometrial receptivity. Clinical studies\ndemonstrate improved pregnancy rates, extended luteal phase support, and enhanced reproductive\noutcomes with dydrogesterone supplementation. Its favorable safety profile, minimal side effects, and\nreduced risk of unwanted hormonal effects contribute to its appeal. Furthermore, dydrogesterone's inclusion\nin international guidelines solidifies its importance in LPD management. Combination therapies, leveraging\nsynergistic effects, offer a comprehensive approach. As gaps in knowledge persist, future research directions\nand personalized treatment strategies pave the way for a future where dydrogesterone stands as a beacon of\nhope in conquering the challenges of LPD and achieving successful reproductive outcomes.\nCategories:\n Public Health, Medical Education, Medical Simulation\nKeywords:\n endometrial receptivity, combination therapy, progestogen, reproductive outcomes, luteal phase defect,\ndydrogesterone\nIntroduction And Background\nThe luteal phase, a critical component of the menstrual cycle, ensures successful reproduction by creating an\noptimal environment for embryo implantation and early pregnancy development. Disruptions in this phase\ncan lead to a condition known as luteal phase defect (LPD), which has garnered significant attention within\nthe realm of reproductive health. This review article delves into the multifaceted aspects of LPD and its\nmanagement, focusing on the promising role of dydrogesterone as a therapeutic intervention \n[1,2]\n.\nLuteal phase defect, characterized by inadequate progesterone production and a shortened luteal phase\nduration, has emerged as a noteworthy concern in reproductive medicine. It is associated with compromised\nendometrial receptivity, hampered embryo implantation, and an increased risk of early pregnancy loss. LPD\nis a potential culprit behind unexplained infertility and recurrent miscarriages, prompting researchers and\nclinicians to investigate effective management strategies \n[3]\n.\nThe luteal phase follows ovulation and is governed by the corpus luteum, a temporary endocrine structure\nformed from the remains of the ovarian follicle. Progesterone, the hormone predominantly produced during\nthis phase, is pivotal in preparing the uterine lining for embryo attachment and nurturing the early stages of\npregnancy. Imbalances or defects in this phase can result in an inadequate uterine environment, hindering\nthe embryo's ability to implant successfully and leading to pregnancy complications \n[4]\n.\nDydrogesterone, a synthetic progestogen with unique pharmacological properties, has garnered considerable\nattention as a potential solution for LPD management. Unlike other progestogens, dydrogesterone has\nstructural similarities to natural progesterone, making it a more biologically compatible option for luteal\nphase support. Its selective progestogenic activity, combined with minimal androgenic, glucocorticoid, and\nmineralocorticoid effects, positions dydrogesterone as an attractive candidate for improving pregnancy\noutcomes in individuals with LPD \n[5]\n.\nThis review article aims to comprehensively explore the intricate relationship between luteal phase defect\nand reproductive health, highlighting the crucial role of dydrogesterone as a potential therapeutic agent. By\nsynthesizing existing literature, clinical studies, and guidelines, we seek to provide a comprehensive\noverview of dydrogesterone's mechanism of action, efficacy, safety profile, and potential combination\ntherapies. Additionally, this article will emphasize the implications of dydrogesterone use in LPD\nmanagement and its contribution to enhancing reproductive outcomes.\n1\n1\n1\n \nOpen Access Review Article\nPublished via DMIHER School of\nEpidemiology and Public Health\nHow to cite this article\nMuneeba S, Acharya N, Mohammad S (November 03, 2023) The Role of Dydrogesterone in the Management of Luteal Phase Defect: A\nComprehensive Review. Cureus 15(11): e48194. \nDOI 10.7759/cureus.48194\n\nReview\nPhysiology of the luteal phase\nThe luteal phase of the menstrual cycle plays a vital role in preparing the body for a potential pregnancy. It\nunfolds as a complex sequence of events orchestrated by a delicate interplay of hormones and physiological\nchanges. This phase follows ovulation, the release of a mature egg from the ovarian follicle, and sets the\nstage for the critical early stages of pregnancy \n[6]\n. During the luteal phase, the once-released ovarian follicle\ntransforms into a structure known as the corpus luteum. This transformation is accompanied by a cascade of\nhormonal shifts and molecular adaptations that work in concert to create an environment highly conducive\nto supporting a developing embryo. The corpus luteum becomes a temporary endocrine gland, producing\nprogesterone, a hormone that holds paramount importance in establishing and maintaining the uterine\nlining, also known as the endometrium. This endometrial preparation is crucial for the successful\nimplantation of a fertilized egg \n[7]\n.\nThe hormonal shifts during this phase are orchestrated primarily by two essential hormones: progesterone\nand estrogen. These hormones work in tandem to stimulate the development and maintenance of the\nendometrial lining, making it receptive to a fertilized egg. Additionally, the increased production of\nprogesterone acts to suppress further ovulation, preventing the release of more eggs while the body prepares\nfor a potential pregnancy \n[8]\n. Molecular adaptations further enhance the endometrial environment for\nsuccessful embryo implantation. The endometrial cells undergo changes that increase their receptivity to an\nembryo, facilitating attachment to the uterine wall. Blood vessels in the endometrium grow and become\nmore permeable, nourishing the developing embryo \n[9]\n.\nThe luteal phase represents a choreographed symphony of hormonal shifts and molecular changes. Its\nculmination in establishing the corpus luteum and the subsequent rise in progesterone levels transforms the\nuterus into an optimal environment for embryo implantation. This period of preparation and anticipation\nlays the foundation for early pregnancy development, making the luteal phase a critical juncture in the\nmenstrual cycle \n[4]\n.\nRegular Hormonal Changes During the Luteal Phase\nThe luteal phase, a pivotal stage in the menstrual cycle, is distinguished by a cascade of hormonal events\nthat orchestrate the conditions necessary for successful embryo implantation and the early stages of\npregnancy. The hormone progesterone is at the heart of this phase, whose dynamic secretion is mainly\norchestrated by a small but significant structure known as the corpus luteum \n[4]\n. The initiation of the luteal\nphase hinges on a sequence of hormonal events that begins with the release of follicle-stimulating hormone\n(FSH) from the anterior pituitary gland. FSH stimulates the development of a mature follicle in the ovary,\neventually culminating in ovulation. This released egg is then encapsulated within the corpus luteum, a\ntemporary endocrine gland formed from the remnants of the ruptured follicle \n[10]\n. The subsequent surge in\nluteinizing hormone (LH), another crucial pituitary hormone, follows the surge of FSH. LH's surge catalyzes\nthe transformation of the follicular remnants into the corpus luteum. This event is pivotal because the\ncorpus luteum produces progesterone, a hormone essential to sustain the uterine environment and facilitate\nembryo implantation.\nAs the corpus luteum assumes its role, it secretes progesterone in increasing amounts. This rise in\nprogesterone levels serves a dual purpose: it prepares the uterine lining, or endometrium, for the possible\narrival of an embryo, and it also feeds back to the anterior pituitary and hypothalamus to inhibit further\nsecretion of FSH and LH. This self-regulatory mechanism is crucial in preventing the development of new\novarian follicles and maintaining the corpus luteum's integrity and functionality \n[11]\n. Suppressing FSH and\nLH through progesterone's feedback loop has far-reaching implications. Firstly, it prevents the ovaries from\nproducing additional follicles, ensuring that only one dominant follicle is released during each menstrual\ncycle. Secondly, this suppression supports the corpus luteum's longevity, a prerequisite for producing\nadequate progesterone levels \n[12]\n.\nEstablishment and Maintenance of the Corpus Luteum\nAfter ovulation, a remarkable transformation takes place within the female reproductive system. This\ntransformation involves the dynamic interplay between the granulosa and theca cells that were once a part\nof the mature follicle, creating a temporary endocrine structure known as the corpus luteum. This process,\nscientifically termed \"luteinization,\" marks a crucial shift in hormonal function and lays the groundwork for\npotential pregnancy \n[13]\n.\nThe granulosa and theca cells, instrumental in nurturing the maturing egg within the follicle, undergo a\nprofound metamorphosis. Once the egg is released during ovulation, these cells change their role and\nstructure to become luteal cells. This transformation is not merely superficial; it involves a complex\nbiochemical cascade that fundamentally alters the cellular machinery \n[14]\n.\nAs luteal cells, they primarily aim to secrete progesterone, a hormone of paramount importance in\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n2\n of \n15\n\nreproductive processes. Progesterone serves as a linchpin in orchestrating the events that lead to embryo\nimplantation and the establishment of early pregnancy. Moreover, the corpus luteum is not a one-trick\nwonder; it produces progesterone and smaller quantities of estrogen, albeit in comparison to its larger\ncounterpart, the follicle \n[15]\n.\nThese hormonal outputs are far from trivial. Progesterone, the flagship hormone of this phase, undertakes\nmultiple roles. It transforms the uterine lining, the endometrium, into a receptive and nurturing\nenvironment for a potential embryo. This transformation involves thickening the endometrial lining,\nfostering the growth of blood vessels, and promoting the secretion of nourishing substances. Essentially, the\nendometrium is prepared like fertile soil, ready to embrace and nourish the seed of new life \n[16]\n. Estrogen,\nthough in smaller amounts, plays a supportive role. It helps maintain the health of the endometrial lining\nand ensures a harmonious environment for embryo implantation \n[17]\n.\nIn this intricate dance of hormones, the corpus luteum holds the spotlight during the first crucial weeks of\npregnancy. Its progesterone production sustains the endometrium, keeping it intact and supporting embryo\nattachment. However, if pregnancy does not occur, the corpus luteum's lifespan is limited. Without the\nsignal of pregnancy, it eventually degenerates, causing progesterone levels to decline. This decline triggers\nthe shedding of the endometrial lining, resulting in menstruation, and the cycle starts anew \n[3]\n.\nTransforming granulosa and theca cells into the corpus luteum showcases nature's elegant preparation for a\npotential pregnancy. Progesterone production and modest estrogen levels by the corpus luteum set the stage\nfor the intricate symphony of embryo implantation and early pregnancy. It is a biological performance that\nunderscores the remarkable precision and coordination of the female reproductive system \n[13]\n.\nRole of Progesterone in Endometrial Preparation and Embryo Implantation\nProgesterone, an essential hormone in the menstrual cycle and early pregnancy, exerts many effects on the\nendometrium, orchestrating a finely tuned sequence of changes crucial for optimizing its receptivity to an\nembryo. Under the influence of progesterone, the endometrium undergoes a complex decidualization\nprocess. During decidualization, the endometrial stromal cells transform into specialized decidual cells. This\ntransformation is fundamental, creating a supportive environment well-equipped to accommodate and\nnurture an implanting embryo \n[18]\n. This intricate process involves various structural and functional\nalterations within the endometrium. The decidual cells produce a range of factors, including growth factors\nand cytokines, which play pivotal roles in creating a welcoming milieu for embryo implantation. The\nheightened secretory activity of the uterine glands and the establishment of an enhanced vascular network\nwithin the endometrium are among the orchestrated changes that optimize the implantation process \n[19]\n.\nProgesterone's influence extends beyond structural adjustments. It acts as a natural regulator of uterine\ncontractions, effectively suppressing them. This function is critical to prevent premature expulsion of the\nembryo before it has securely implanted into the endometrium. This dual role of supporting implantation\nand safeguarding its success by controlling uterine contractility underscores the significance of\nprogesterone in early pregnancy \n[20]\n. Furthermore, progesterone orchestrates an intricate dance with the\nimmune system within the uterus. It promotes a unique state of immune tolerance conducive to embryo\nimplantation. This immunomodulatory function is pivotal, as it prevents the immune system from\nrecognizing the embryo as a foreign entity and mounting a response that could potentially hinder\nimplantation.\nLuteal phase defect (LPD)\nLuteal phase defect (LPD) represents a complex reproductive condition characterized by abnormalities in the\nduration and function of the luteal phase of the menstrual cycle. LPD has gained significant attention due to\nits potential impact on fertility outcomes and early pregnancy loss. This section delves into the nuances of\nLPD, including its definition, classification, underlying causes, and clinical consequences \n[21]\n.\nDefinition and Classification of LPD\nA luteal phase defect is an insufficient or inadequately maintained luteal phase, resulting in inadequate\nprogesterone levels and impaired endometrial receptivity. This defect can manifest in different ways, such as\na shortened luteal phase duration, suboptimal progesterone levels, or a combination of both. LPD can be\nclassified into primary and secondary forms. Primary LPD occurs without any apparent underlying cause,\nwhile secondary LPD is often associated with specific conditions, such as polycystic ovary syndrome (PCOS)\nor thyroid disorders \n[22]\n.\nCauses of and Contributing Factors to LPD\nThe etiology of luteal phase defect (LPD) is intricate and multifaceted, with various factors contributing to\nits development. These factors collectively lead to disruptions in the delicate hormonal balance essential for\nnormal luteal phase function. Common causes of LPD encompass the following: hormonal\nimbalances, ovarian dysfunction, stress and lifestyle factors, thyroid dysfunction, polycystic ovary syndrome\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n3\n of \n15\n\n(PCOS), and uterine abnormalities.\nHormonal imbalances: The orchestration of hormonal signals between the hypothalamus, pituitary gland,\nand ovaries is critical for successfully progressing the luteal phase. Insufficient luteinizing hormone (LH)\nsurge, inadequate progesterone production, or impaired communication among these endocrine players can\ndisturb the intricate hormonal interplay. Such imbalances thwart the timely formation and maintenance of\nthe corpus luteum, a fundamental structure responsible for progesterone secretion \n[23]\n.\nOvarian dysfunction: The process of follicular development and ovulation is complex, involving precise\nsynchronization of hormonal cues. Irregularities in these processes can result in compromised corpus\nluteum formation, leading to reduced progesterone secretion. As progesterone is central to the endometrial\npreparation necessary for embryo implantation, diminished secretion can negatively impact the uterine\nenvironment's receptivity \n[24]\n.\nStress and lifestyle factors: Chronic stress, excessive exercise, and maintaining a low body weight influence\nthe hypothalamic-pituitary-ovarian axis, affecting hormonal equilibrium. These factors disrupt the finely\ntuned hormonal orchestration required for optimal luteal phase function. Stress-related alterations in\nhormone secretion, particularly cortisol, can indirectly hinder the formation and function of the corpus\nluteum \n[25]\n.\nThyroid dysfunction: The thyroid gland plays a crucial role in hormonal regulation and metabolic processes.\nAbnormal thyroid function, specifically hypothyroidism, can disrupt the intricate hormonal cascade\nrequired for proper luteal phase development. Thyroid hormones influence LH and follicle-stimulating\nhormone (FSH) secretion, impacting ovarian function and progesterone production \n[26]\n.\nPolycystic ovary syndrome (PCOS): PCOS is characterized by hormonal imbalances, notably elevated\nandrogens, and disrupted ovulation. The hormonal irregularities associated with PCOS, including elevated\nLH levels and reduced FSH levels, can adversely affect the establishment and maintenance of the corpus\nluteum, leading to insufficient progesterone secretion and compromised luteal phase function \n[27]\n.\nUterine abnormalities: The uterus plays a pivotal role in successful embryo implantation. Structural\nabnormalities within the uterus, such as fibroids, adhesions, or congenital anomalies, can impede the\nestablishment of a receptive endometrium. These abnormalities compromise the uterine environment's\nability to support embryo implantation, regardless of the corpus luteum's function \n[28]\n.\nClinical Manifestations and Impact on Fertility\nShortened menstrual cycle: A hallmark feature of LPD is a luteal phase duration that falls below the normal\nrange, often shorter than 10 days. This abbreviated time frame poses a significant challenge to the\nendometrium's ability to achieve the optimal receptivity necessary for successful embryo implantation.\nInadequate progesterone secretion during this limited luteal phase window impairs the transformation of\nthe endometrium into a suitable environment for embryo attachment and growth, thus hindering the\nestablishment of pregnancy \n[29]\n.\nIrregular menstrual cycles: LPD can introduce irregularities in the menstrual cycle, causing variations in the\nlength of the cycle, the timing of ovulation, and the overall predictability of fertility windows. The\ninconsistency in the timing of ovulation and fertile days makes it difficult for individuals to time intercourse\nfor conception accurately. This unpredictability further challenges family planning efforts and reduces the\nchances of a successful pregnancy \n[30]\n.\nRecurrent miscarriages: LPD is associated with an elevated risk of recurrent early pregnancy loss. The\ncompromised endometrial support resulting from inadequate luteal phase function creates an unfavorable\nenvironment for embryo implantation and subsequent development. This deficiency in sustaining the\npregnancy leads to frequent miscarriages during the early stages of gestation, causing significant emotional\ndistress and reproductive setbacks for affected individuals \n[31]\n.\nUnexplained infertility: LPD can contribute to unexplained infertility, a perplexing scenario in which\nindividuals experience difficulty achieving pregnancy despite regular ovulation and sperm parameters. The\nrole of the luteal phase becomes apparent in such cases, as even with successful fertilization, insufficient\nluteal phase support can prevent the embryo from implanting and progressing \n[32]\n.\nImplantation failure: The ramifications of LPD extend to assisted reproductive techniques (ARTs), where\nrepeated embryo implantation failure occurs. The inadequate endometrial receptivity stemming from LPD\nposes a formidable obstacle to successful procedures such as in vitro fertilization (IVF). Despite the\nsuccessful creation of embryos, the compromised uterine environment diminishes the prospects of\nimplantation, leading to repeated disappointments for individuals undergoing ART \n[33]\n.\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n4\n of \n15\n\nDydrogesterone: Mechanism of action\nDydrogesterone, a synthetic progestogen, has gained significant recognition for its pivotal role in managing\nluteal phase defects (LPD) and addressing various reproductive conditions. Its mechanism of action is\ngrounded in its distinctive pharmacological attributes, which distinguish it from other progestogens,\nrendering it an attractive choice for optimizing luteal phase function and ultimately enhancing reproductive\noutcomes \n[34]\n.\nUnique Pharmacological Characteristics\nDydrogesterone stands out due to its structural similarity to endogenous progesterone, the hormone crucial\nfor maintaining the uterine environment during the luteal phase. Unlike some other progestogens,\ndydrogesterone closely mirrors the molecular structure of natural progesterone. This similarity enables\ndydrogesterone to interact with progesterone receptors selectively, specifically, those involved in uterine\nfunction, while minimizing interactions with other hormonal pathways \n[35]\n.\nEnhancing Luteal Phase Function\nDydrogesterone's primary mode of action revolves around providing exogenous progesterone-like support\nduring the luteal phase of the menstrual cycle. By mimicking the actions of endogenous progesterone,\ndydrogesterone bolsters the crucial processes that occur during this phase, such as promoting\ndecidualization and fostering a receptive endometrial lining. These actions create an environment\nconducive to successful embryo implantation and early pregnancy maintenance \n[34]\n.\nCompared with other progestogens, dydrogesterone's uniqueness stems from its selective binding and\nminimal interference with other hormonal receptors. In contrast, other progestogens might have\nnonspecific effects on androgen, glucocorticoid, or mineralocorticoid receptors, leading to potential side\neffects that could impact reproductive outcomes. Dydrogesterone's specificity and affinity for progesterone\nreceptors make it an appealing option, particularly in scenarios where targeted progestogenic actions are\ndesired without the risk of undesirable hormonal effects \n[36]\n.\nImproved Reproductive Outcomes\nDydrogesterone is critical in optimizing luteal phase function by offering tailored progestogenic support that\nclosely mirrors natural progesterone's actions. This optimization, in turn, contributes to better endometrial\nreceptivity, creating an environment conducive to embryo implantation and early pregnancy development.\nThe enhanced reproductive outcomes observed in clinical studies underscore the significance of\ndydrogesterone's mechanism of action in LPD management \n[37]\n.\nBrief Overview of Dydrogesterone as a Progestogen\nDydrogesterone is a synthetic derivative of naturally occurring progesterone. Unlike other progestogens,\ndydrogesterone closely mimics endogenous progesterone's molecular structure and biological actions. This\nstructural similarity contributes to its selectivity and efficacy in exerting progestogenic effects without\nsignificant androgenic, glucocorticoid, or mineralocorticoid activity \n[38]\n.\nExplanation of How Dydrogesterone Supports the Luteal Phase\nDydrogesterone's role in supporting the luteal phase is rooted in its ability to mimic the actions of\nprogesterone, an essential hormone for sustaining early pregnancy. The luteal phase, characterized by the\ncorpus luteum's formation after ovulation, requires optimal progesterone levels to prepare the uterine lining\nfor embryo implantation and maintain a nurturing environment for the developing pregnancy \n[37]\n. As a\nsynthetic progestogen, dydrogesterone is an exogenous source of progesterone-like support during this\ncritical phase. By providing additional progesterone-like activity, dydrogesterone ensures that the\nendometrium becomes adequately receptive for successful embryo attachment. This is achieved through\nmultiple mechanisms \n[39]\n.\nFirstly, dydrogesterone supports the process of decidualization, which involves the transformation of the\nuterine lining into a specialized tissue that is well-suited to support embryo implantation. This process\nrequires an orchestrated interplay of hormonal signals, with progesterone playing a central role.\nDydrogesterone's ability to replicate this progesterone-driven signal ensures that the endometrium is\nadequately prepared to receive the embryo \n[40]\n. Secondly, dydrogesterone enhances endometrial receptivity\nby promoting the growth and development of uterine glands and blood vessels. This fosters an environment\nconducive to embryo implantation, allowing for successful interaction between the embryo and the uterine\nlining \n[8]\n. Furthermore, dydrogesterone addresses potential luteal phase insufficiencies that may arise due to\nvarious underlying factors. It ensures that the progesterone levels necessary for a supportive luteal phase are\nmaintained, preventing premature shedding of the uterine lining and increasing the chances of embryo\nimplantation.\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n5\n of \n15\n\nA notable advantage of dydrogesterone is its selectivity for progesterone receptors, which minimizes\ninterference with other hormonal pathways. Unlike some progestogens, dydrogesterone's actions target\nprogesterone-related processes without significantly activating androgenic, glucocorticoid, or\nmineralocorticoid receptors. This selectivity preserves the hormone's desired effects on the endometrium\nand reduces the risk of unwanted side effects \n[36]\n.\nComparison of Dydrogesterone With Other Progestogens\nDydrogesterone distinguishes itself from other progestogens through its remarkable structural similarity to\nnatural progesterone. This unique feature sets the stage for a profound impact on its mode of action and\nclinical implications. By closely emulating the biological actions of endogenous progesterone,\ndydrogesterone becomes a standout option for luteal phase support, addressing the intricacies of\nreproductive health with precision \n[41]\n.\nThe structural resemblance between dydrogesterone and natural progesterone endows it with a heightened\nability to interact with progesterone receptors in a manner akin to the body's hormonal processes. This\nenables dydrogesterone to exert targeted progestogenic effects, fostering endometrial receptivity and\nfacilitating a suitable environment for embryo implantation and early pregnancy development. Its\ncompatibility with the body's natural hormonal pathways ensures seamless integration of its actions,\nenhancing its efficacy in managing luteal phase defects \n[42]\n.\nIn contrast, certain other progestogens may carry the risk of nonspecific effects on various hormonal\nreceptors, such as androgen, glucocorticoid, or mineralocorticoid receptors. This nonspecificity can give rise\nto potential side effects that affect reproductive outcomes. For instance, androgenic side effects could\ndisrupt hormonal balance and hinder the delicate processes for successful conception and pregnancy \n[42]\n.\nThis comparison underscores dydrogesterone's pharmacological superiority, especially when precise,\ntargeted progestogenic effects are desired without interfering with other hormonal pathways.\nDydrogesterone's potential to offer fewer side effects and a more favorable tolerability profile makes it an\nappealing and prudent choice for managing luteal phase defects. This advantage can have far-reaching\nimplications, optimizing reproductive success and enriching the quality of care for individuals navigating\nthe complexities of fertility and pregnancy \n[43]\n.\nEvidence of Dydrogesterone Efficacy\nThe efficacy of dydrogesterone in managing luteal phase defect (LPD) has been extensively investigated\nthrough clinical studies and trials. This section comprehensively reviews the evidence, highlighting critical\nfindings on pregnancy rates, luteal phase support, and overall reproductive outcomes \n[39]\n.\nNumerous clinical studies and randomized controlled trials (RCTs) have explored dydrogesterone's role in\nLPD management. These trials have evaluated its effectiveness in diverse patient populations, including\nthose undergoing assisted reproductive techniques (ART) and those with idiopathic infertility. Studies have\nemployed various routes of administration, such as oral and vaginal, to investigate the optimal way to\ndeliver dydrogesterone for luteal phase support \n[44]\n.\nPregnancy rates: Clinical evidence suggests that dydrogesterone supplementation positively impacts\npregnancy rates in individuals with LPD. Studies have reported improved implantation rates and higher\nclinical pregnancy rates among patients receiving dydrogesterone compared to placebo or other\nprogestogens. This indicates that dydrogesterone's support of the luteal phase contributes to a more\nconducive environment for embryo implantation and early pregnancy development \n[45]\n.\nLuteal phase support: Dydrogesterone effectively extends the luteal phase, thereby addressing one of the\ncritical abnormalities in LPD. The hormone's progestogenic actions support the endometrium during this\ncritical period, enhancing endometrial receptivity and preventing premature shedding. This is particularly\nimportant for individuals with LPD, as an adequately maintained luteal phase is essential for sustaining\npregnancy \n[37]\n.\nReproductive outcomes: Studies have shown that dydrogesterone supplementation improves reproductive\noutcomes, especially in patients with LPD. These outcomes include increased live birth rates and decreased\nmiscarriage rates. Dydrogesterone enhances overall reproductive success by optimizing the uterine\nenvironment and fostering embryo implantation \n[45]\n.\nAdministration and dosage\nDydrogesterone's efficacy in managing luteal phase defect (LPD) extends to its various forms of\nadministration and dosage regimens. This section explores the different available forms of dydrogesterone,\noutlines recommended dosage regimens for LPD treatment, and emphasizes the importance of considering\npatient preferences and clinical scenarios when choosing the administration route \n[46]\n.\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n6\n of \n15\n\nDifferent Forms of Dydrogesterone Available\nOral tablets: The availability of oral dydrogesterone tablets offers a convenient and widely adopted option\nfor LPD management. These tablets can be easily administered and absorbed through the digestive system,\nenabling efficient hormone delivery. This systemic approach ensures that the necessary levels of\ndydrogesterone are reached in the bloodstream, facilitating its actions in supporting the luteal phase and\nenhancing endometrial receptivity. The ease of use and familiarity associated with oral administration\ncontribute to the popularity of this form of dydrogesterone, making it a practical choice for patients and\nhealthcare providers alike \n[40]\n.\nVaginal suppositories or tablets: Vaginal administration of dydrogesterone introduces a distinct approach\nthat capitalizes on the local route for hormone delivery. Using suppositories or tablets placed directly into\nthe vagina, dydrogesterone can exert its effects locally within the uterine environment. This method allows\nfor direct endometrial exposure, which could enhance the hormone's impact on endometrial receptivity.\nFurthermore, the local delivery might lead to decreased systemic side effects, as the hormone's systemic\ncirculation might be limited. This approach is particularly relevant for individuals seeking to minimize\npotential systemic effects or with specific medical conditions that warrant a more localized intervention \n[5]\n.\nSublingual tablets: Sublingual administration introduces another avenue for dydrogesterone delivery.\nSublingual tablets are placed under the tongue, where they rapidly dissolve and are absorbed directly into\nthe bloodstream through the rich network of blood vessels in the area. This approach offers a potential\nbalance between systemic and local effects. The quick absorption into the bloodstream allows for efficient\nsystemic distribution of dydrogesterone while avoiding the digestive system, which could reduce the risk of\nmetabolism or degradation. Sublingual administration could be especially beneficial for individuals who\nrequire precise and rapid control over their hormone levels during the luteal phase \n[47]\n.\nRecommended Dosage Regimens for LPD Treatment\nOral tablets: In the context of oral administration, standard dosage ranges typically span from 10 to 40 mg\nof dydrogesterone daily. This dosage is often divided into two or more doses to maintain stable progesterone\nlevels throughout the luteal phase. The treatment regimen generally encompasses the second half of the\nmenstrual cycle, corresponding to the luteal phase. This approach ensures continuous progestogenic support\nduring the critical period for embryo implantation and early pregnancy establishment \n[5]\n.\nVaginal suppositories or tablets: Vaginal administration offers a targeted route for delivering dydrogesterone\ndirectly to the uterine environment. Dosage recommendations for vaginal suppositories or tablets typically\nrange from 200 to 400 mg per day. This dosage is distributed into two separate doses to ensure sustained\nprogesterone exposure to the endometrium. By delivering dydrogesterone locally, this approach optimizes\nendometrial receptivity and enhances support for embryo implantation and pregnancy maintenance \n[5]\n.\nSublingual tablets: Sublingual administration involves placing dydrogesterone tablets under the tongue for\nrapid absorption into the bloodstream. Sublingual dosage regimens often mirror oral administration,\nranging from 10 to 40 mg per day. Like oral dosing, sublingual doses can be divided to maintain consistent\nprogesterone levels during the luteal phase. This approach offers an alternative systemic delivery method\nwhile minimizing potential gastrointestinal effects \n[39]\n.\nConsideration of Patient Preferences and Clinical Scenarios\nChoosing the optimal administration route of dydrogesterone involves carefully evaluating various factors,\nincluding patient preferences, clinical situations, and potential side effects. The individual's comfort and\ntreatment adherence are pivotal in this decision-making process. Patients often have unique preferences\nregarding the method of administration, and taking these preferences into account can significantly\nenhance their commitment to the treatment plan. Moreover, the presence of specific clinical conditions\nfurther shapes the choice of administration route \n[48]\n.\nIn assisted reproductive techniques (ARTs), the administration route can be tailored to the specific treatment\nplan and the clinician's expertise. In scenarios where optimizing endometrial receptivity is paramount, such\nas in vitro fertilization (IVF) cycles, the choice of administration route gains even more significance. The\nvaginal route, for instance, can be favored in these cases due to its direct access to the uterine environment.\nThis approach aims to enhance the interaction between dydrogesterone and the endometrium, promoting\noptimal endometrial conditions for successful embryo implantation \n[49]\n.\nUltimately, the decision regarding the administration route of dydrogesterone is nuanced, shaped by a\ndelicate balance of patient preferences, clinical considerations, and the overarching treatment strategy.\nTailoring the route to suit individual needs can enhance treatment adherence and contribute to the overall\nsuccess of LPD management and reproductive outcomes \n[50]\n.\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n7\n of \n15\n\nSafety and tolerability\nIn reproductive medicine, the careful balance between therapeutic effectiveness and patient well-being\ntakes center stage. The paramount significance of safety and tolerability cannot be understated, particularly\nwhen addressing conditions such as luteal phase defect (LPD). As a potential solution in LPD management,\ndydrogesterone undergoes a rigorous evaluation of its safety profile and side effects, serving as a linchpin in\nits utilization \n[51]\n.\nUnderstanding Safety and Side Effects\nThe safety profile of dydrogesterone is a cornerstone of its acceptance in clinical practice. Identifying and\nquantifying potential side effects are essential in making informed treatment decisions. These side effects,\noften transient and mild, can include gastrointestinal discomfort, breast tenderness, and occasional\nheadaches. Dydrogesterone's profile sets it apart from other progestogens, demonstrating a minimal risk of\nunwanted hormonal effects, including androgenic or glucocorticoid-related complications \n[35]\n.\nComparative Evaluation\nThe comparative analysis of dydrogesterone with other progestogens brings forth its unique attributes.\nUnlike certain progestogens associated with undesirable side effects, dydrogesterone's structural\nresemblance to natural progesterone engenders a more favorable tolerability profile. The selective targeting\nof progestogenic actions minimizes potential disruptions in other hormonal pathways. This comparative\nadvantage positions dydrogesterone as an appealing option, particularly when considering patient comfort\nand treatment adherence \n[52]\n.\nTailoring to Special Patient Populations\nThe essence of personalized medicine resonates in the tailored attention required for special patient\npopulations. Individuals who are pregnant or breastfeeding or possess specific medical conditions\nnecessitate a nuanced approach to dydrogesterone treatment. While its safety remains, special care ensures\nthat treatment aligns with individual circumstances. Addressing the needs of these specific groups enhances\nthe overall therapeutic experience and optimizes treatment outcomes \n[53]\n.\nOverview of Safety Profile and Side Effects\nAs a therapeutic option for luteal phase defect (LPD) management, dydrogesterone boasts a reassuring\nsafety profile that is generally well-tolerated by patients. Individuals undergoing dydrogesterone treatment\ncommonly experience mild and transient side effects, which, if present, tend to be manageable \n[43]\n.\nOne of the potential side effects associated with dydrogesterone treatment is gastrointestinal upset. Some\nindividuals might encounter minor disturbances in the gastrointestinal tract, such as bouts of nausea or\nbloating. These effects, while noticeable, are often temporary and generally do not escalate into severe\ndiscomfort \n[35]\n.\nBreast tenderness is another noteworthy side effect that could arise during dydrogesterone treatment. This\noccurrence is attributed to the hormone's progestogenic activity. Dydrogesterone's action on progesterone\nreceptors in breast tissue can increase sensitivity and mild breast discomfort. It is important to note that\nthis symptom is typically manageable and tends to diminish over time as the body adapts to the hormonal\nchanges \n[54]\n.\nReports of headaches have been sporadically associated with dydrogesterone use, although their frequency\nis generally low. These headaches are usually mild and infrequent and tend to abate as treatment progresses.\nIt is important to differentiate between incidental headaches and those directly linked to dydrogesterone\nuse, as headaches can stem from various factors \n[55]\n.\nIts favorable progestogenic selectivity is an important differentiating factor that sets dydrogesterone apart\nfrom certain other progestogens. This means that dydrogesterone's mechanism of action is primarily\ntargeted at progesterone receptors, minimizing the risk of triggering androgenic, glucocorticoid, or\nmineralocorticoid side effects commonly observed with other progestogens. This selectivity contributes to a\nmore comfortable experience for patients undergoing dydrogesterone treatment \n[36]\n.\nComparison of Dydrogesterone's Safety With Other Progestogens\nDydrogesterone's safety profile stands out due to its structural similarity to natural progesterone. Unlike\nother progestogens, dydrogesterone's unique chemical structure minimizes the risk of androgenic or other\nunwanted hormonal effects. This reduced risk of side effects positions dydrogesterone as an appealing\noption for individuals seeking luteal phase support with minimal disruptions to their overall well-being \n[56]\n.\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n8\n of \n15\n\nSpecial Considerations for Specific Patient Populations\nPregnancy: Dydrogesterone plays a significant role in supporting the luteal phase during the early stages of\npregnancy, particularly in cases where a history of recurrent miscarriages or threatened abortion exists.\nThese situations are often associated with inadequate progesterone levels, essential for maintaining the\nuterine environment conducive to embryo implantation and sustaining pregnancy. Dydrogesterone's safety\nprofile makes it a suitable choice for this purpose. Its structural resemblance to natural progesterone allows\nit to provide supplemental support to the corpus luteum, ensuring sustained progesterone levels critical for\npreserving endometrial receptivity and early pregnancy support. By maintaining a nurturing uterine\nenvironment, dydrogesterone offers a potential solution to the challenges faced by individuals with a history\nof pregnancy loss or threatened abortion \n[57]\n.\nBreastfeeding: Dydrogesterone's compatibility with breastfeeding is essential for individuals seeking LPD\nmanagement postpartum. The minimal transfer of dydrogesterone into breast milk makes it generally safe\nfor use during lactation. This characteristic suggests that the potential impact on breastfeeding infants is\nlimited, minimizing any concerns about exposure to the medication. However, it is important to note that\nindividual circumstances can vary, and medical advice should guide treatment decisions. Healthcare\nprofessionals should evaluate the overall health of both the mother and the breastfeeding infant before\nrecommending dydrogesterone. This cautious approach ensures that treatment choices prioritize the well-\nbeing of both mother and child \n[58]\n.\nMedical conditions: Patients with specific medical conditions require careful consideration when using\ndydrogesterone for LPD management. Conditions such as liver dysfunction or a history of thromboembolic\ndisorders can influence the body's metabolism and medication response. In these cases, physicians should\nexercise vigilance and thorough evaluation before prescribing dydrogesterone. Liver function tests may be\nrecommended to assess the drug's potential impact on hepatic health. Additionally, individuals with a\nhistory of thromboembolic disorders, which involve the formation of blood clots, need close monitoring due\nto the potential interaction of dydrogesterone with the body's coagulation system. These precautions\nunderscore the importance of tailoring treatment to each patient's unique medical history, ensuring that the\nbenefits of dydrogesterone outweigh any potential risks associated with underlying medical conditions \n[59]\n.\nCombination therapies\nThe intricacies of managing luteal phase defects (LPD) call for a comprehensive strategy that addresses the\nmultifaceted challenges posed by this condition. Recognizing that LPD arises from a complex interplay of\nhormonal dysregulation, endometrial abnormalities, and other contributing factors, the approach to\ntreatment goes beyond a single intervention. Combination therapies, which involve the simultaneous use of\ndifferent medications, emerge as a strategic avenue to tackle LPD's complexities and optimize reproductive\noutcomes \n[60]\n.\nDydrogesterone's Role in Combination Therapies\nDydrogesterone, as a powerful player in LPD management, can synergize with other medications to create a\nmore effective and holistic treatment approach. This might involve the integration of dydrogesterone with\nother interventions commonly employed in fertility treatments, such as gonadotropins and gonadotropin-\nreleasing hormone (GnRH) agonists \n[61]\n.\nRationale Behind Combination Therapies\nThe rationale for combination therapies stems from the need to target LPD from various angles, each aligned\nwith its underlying mechanisms. While dydrogesterone provides luteal support and enhances endometrial\nreceptivity, medications such as gonadotropins stimulate follicular development, and GnRH agonists control\nhormonal surges. By combining these interventions, clinicians aim to create a harmonious hormonal\nenvironment that optimizes the chances of successful embryo implantation and early pregnancy\nmaintenance \n[62]\n.\nSynergistic Effects\nThe real power of combination therapies lies in the potential for synergistic effects. Dydrogesterone's ability\nto enhance endometrial receptivity can work with gonadotropin-induced follicular growth, ensuring that a\nwell-prepared endometrium welcomes a healthy embryo. Similarly, GnRH agonists can prevent premature\nluteolysis, extending the supportive environment for the developing pregnancy. When these interventions\nare strategically combined, the outcomes can be greater than the sum of their individual effects \n[63]\n.\nClinical Customization\nCombination therapies are not one-size-fits-all but tailored to each patient's unique circumstances. The\nchoice of medications, dosages, and timing is guided by factors such as the severity of LPD, the patient's\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n9\n of \n15\n\nmedical history, and the specifics of the treatment plan. This customization ensures that the therapy aligns\nperfectly with the patient's needs, optimizing the chances of achieving a successful pregnancy \n[64]\n.\nExploration of Combination Therapies\nCombination therapies involving dydrogesterone are strategic approaches that harness the distinct\ncharacteristics of different interventions to enhance luteal phase support and optimize reproductive success\nsynergistically. In reproductive medicine, the luteal phase is pivotal in creating a receptive uterine\nenvironment for embryo implantation and early pregnancy establishment. Luteal phase defect (LPD),\nmarked by inadequate progesterone levels and compromised endometrial receptivity, can impede these\ncrucial processes \n[40]\n.\nTo address the multifaceted challenges of LPD, researchers and clinicians have explored the potential\nbenefits of combining dydrogesterone with other treatment modalities. These combination therapies\ncapitalize on the strengths of each intervention to create a harmonious and supportive reproductive\nenvironment \n[65]\n.\nOne such combination involves integrating dydrogesterone with gonadotropins within the context of\nassisted reproductive techniques (ARTs). Gonadotropin stimulation is routinely employed to induce\nfollicular development, ensuring the availability of mature eggs for fertilization. However, this process could\ndisrupt the natural hormonal balance of the luteal phase, jeopardizing the endometrial environment\nrequired for successful implantation. By supplementing dydrogesterone during the luteal phase,\npractitioners aim to provide essential support that sustains the endometrium and maintains the hormonal\nmilieu conducive to embryo attachment and development \n[66]\n.\nAnother promising combination involves the integration of dydrogesterone with gonadotropin-releasing\nhormone (GnRH) agonists. GnRH agonists are utilized in controlled ovarian stimulation to prevent\npremature luteinizing hormone (LH) surges that could result in the premature release of eggs. While this\nstrategy optimizes follicular development, it may inadvertently compromise the luteal phase by suppressing\nendogenous LH surges required for corpus luteum function. By supplementing with dydrogesterone, which\nexhibits progestogenic support, the goal is to ensure a sustained and adequate luteal phase that maintains\nendometrial receptivity and prevents early luteolysis \n[67]\n.\nIn both scenarios, the synergy of dydrogesterone with other interventions aims to address the unique\nchallenges posed by LPD and assisted reproductive techniques. By strategically combining treatments,\nclinicians seek to create a holistic approach that encompasses both follicular and luteal phase support,\nultimately enhancing the chances of successful embryo implantation, pregnancy establishment, and overall\nreproductive success. As research continues to illuminate the intricacies of combination therapies, the\npotential for further refining LPD management grows, offering renewed hope to individuals navigating the\ncomplexities of fertility challenges.\nRationale for combined treatments and potential synergistic effects\nElaboration on Combination Therapies and Rationale\nThe rationale behind combining therapies in managing luteal phase defect (LPD) is deeply rooted in this\ncomplex and multifaceted condition. LPD can arise from a convergence of various factors, ranging from\nhormonal imbalances to disruptions in endometrial receptivity. Recognizing this intricate interplay,\ncombination therapies harness different interventions' strengths to create a synergistic effect that yields\nimproved treatment outcomes \n[62]\n.\nComprehensive luteal phase support: Combination therapies aim to provide comprehensive support to the\nluteal phase of the menstrual cycle, a critical period for successful embryo implantation and early pregnancy\ndevelopment. By addressing multiple aspects of this phase, such as progesterone levels and endometrial\nreceptivity, these therapies create an environment conducive to optimal reproductive outcomes. This\nmultifaceted approach ensures that all elements necessary for successful embryo implantation are nurtured,\nenhancing the chances of a viable pregnancy \n[68]\n.\nMinimized risks of luteal phase insufficiency: The multifactorial nature of LPD means that various\nmechanisms can be at play leading to inadequate luteal phase function. Combination therapies take a\nholistic stance by targeting these diverse mechanisms simultaneously. These therapies reduce the risk of\nluteal phase insufficiency by addressing the contributing factors comprehensively. This, in turn, minimizes\nthe chances of implantation failure and early pregnancy loss, allowing for more successful reproductive\noutcomes \n[62]\n.\nClinical guidelines and recommendations\nIncluding dydrogesterone in international fertility and gynecology guidelines represents a significant\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n10\n of \n15\n\nmilestone in recognizing its role as an effective intervention for managing luteal phase defects (LPD). These\nguidelines serve as authoritative references that offer clinicians evidence-based recommendations,\nproviding valuable insights and strategies to enhance LPD management \n[49]\n.\nDydrogesterone, a synthetic progestogen with structural similarities to natural progesterone, has garnered\nthe attention of leading organizations and societies in fertility and gynecology. These respected bodies have\nmeticulously evaluated the available scientific evidence and clinical data surrounding dydrogesterone's\nefficacy in addressing LPD. As a result, they have acknowledged its utility and explicitly endorsed its use in\nmanaging this reproductive condition \n[5]\n.\nThese guidelines are developed collaboratively by experts in the field, often involving rigorous reviews of\nrelevant research, clinical trials, and expert consensus. The endorsement of dydrogesterone within these\nguidelines signifies a consensus within the medical community regarding its value as a treatment option for\nLPD. Such recognition lends credibility to dydrogesterone's effectiveness and encourages its integration into\nclinical practice \n[69]\n.\nFor healthcare practitioners, these guidelines offer a structured framework for LPD management, with clear\nrecommendations on when and how to consider dydrogesterone as part of the treatment plan. They help\nguide decisions about administration routes, dosage regimens, and patient selection. Clinicians can feel\nconfident choosing to include dydrogesterone in their therapeutic approach, knowing their decision aligns\nwith the latest evidence-based guidelines established by authoritative organizations.\nFurthermore, these guidelines serve as a valuable educational resource for medical professionals, providing\na consolidated and up-to-date summary of the current understanding of LPD and its management. They\nempower clinicians to make informed decisions, tailor treatment plans to individual patient needs, and\noptimize outcomes for those seeking to overcome the challenges posed by luteal phase defects \n[70]\n. In\nessence, including dydrogesterone in international fertility and gynecology guidelines signifies the\nculmination of rigorous scientific evaluation, consensus-building, and expert endorsement. This recognition\nunderscores dydrogesterone's significance as a valuable tool in the arsenal of treatments for LPD, reassuring\nclinicians and patients that the highest standards of medical practice support its use.\nRecommended Approaches to LPD Management With Dydrogesterone\nDiagnosis: Accurate diagnosis of luteal phase defect (LPD) forms the foundation of effective management.\nThis involves a comprehensive clinical assessment, including evaluating menstrual cycle characteristics,\nhormonal levels (particularly progesterone), and potential contributing factors. In cases where clarity is\nrequired, an endometrial biopsy might be performed to assess endometrial receptivity and luteal phase\nadequacy. This thorough diagnosis enables tailored interventions to address the specific challenges of LPD\n[71]\n.\nAdministration route and dosage: Once diagnosed, the choice of administration route and dosage regimen of\ndydrogesterone is crucial. Patient preferences, clinical considerations, and the severity of LPD influence this\ndecision. The administration routes, such as oral, vaginal, or sublingual, offer different benefits and\nconsiderations. Similarly, the appropriate dosage depends on factors such as the individual's hormonal\nprofile, the desired luteal phase length, and the treatment context \n[72]\n.\nMonotherapy or combination: The decision to use dydrogesterone as monotherapy or in combination with\nother interventions depends on individual patient needs and treatment plans. Dydrogesterone's versatile\nrole as a progestogen allows it to be integrated into various therapeutic strategies. For instance, assisted\nreproductive techniques (ARTs) might be combined with gonadotropins or GnRH agonists to provide\ncomprehensive luteal phase support and enhance the success of embryo implantation \n[73]\n.\nAssisted reproductive techniques (ARTs): Dydrogesterone's significance in ART protocols is particularly\nnotable. Integrating dydrogesterone into these protocols helps create an optimal environment for embryo\nimplantation and early pregnancy development. By extending and supporting the luteal phase,\ndydrogesterone is critical in maintaining endometrial receptivity, a pivotal factor in ART success \n[74]\n.\nMonitoring and adjustments: The response to dydrogesterone treatment should be closely monitored\nthrough regular hormonal levels and clinical outcomes assessments. Adjustments to the treatment plan\nmight be necessary based on individual variations in response, ensuring that the luteal phase remains\nadequately supported throughout the treatment cycle \n[75]\n.\nPatient education: Educating patients about the rationale behind dydrogesterone treatment is essential for\nfostering understanding and adherence. Patients should be informed about the potential benefits, possible\nside effects (generally mild and transient), and the importance of adhering to the prescribed treatment\nregimen. Patient education empowers individuals to participate in their care actively and enhances\ntreatment outcomes \n[76]\n.\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n11\n of \n15\n\nFuture directions and research needs\nLong-Term Outcomes\nThe need for further investigation into the long-term effects of dydrogesterone on reproductive outcomes,\nencompassing parameters such as live birth rates and pregnancy complications, arises as a crucial gap in\ncurrent knowledge. Understanding the sustained impact of dydrogesterone treatment beyond the immediate\nluteal phase could provide valuable insights into its role in ensuring successful pregnancies \n[38]\n.\nOptimal Administration Route and Dosage\nDetermining the most effective administration route and dosage regimen for different patient populations\nand varying clinical scenarios is another gap. Tailoring treatment approaches based on individual\ncharacteristics and LPD severity is imperative for optimizing outcomes, and research in this area could yield\npersonalized and precise interventions \n[77]\n.\nCombination Therapies\nWhile dydrogesterone has been established as effective, more research is warranted to explore its potential\nsynergistic effects when combined with other interventions. Investigating the ideal combinations of\ndydrogesterone with treatments such as gonadotropins or GnRH agonists could offer a comprehensive\napproach to LPD management, enhancing treatment outcomes \n[35]\n.\nUnderlying Mechanisms\nThe mechanisms through which dydrogesterone exerts its beneficial effects on luteal phase function and\nendometrial receptivity remain partially understood. In-depth research into the underlying mechanisms\ncould unveil the pathways through which dydrogesterone contributes to successful embryo implantation\nand early pregnancy support \n[37]\n.\nSuggestions for Future Research Directions\nRandomized controlled trials (RCTs): To strengthen the evidence base, conducting large-scale RCTs with\nrobust methodologies is recommended. These trials could provide a more definitive understanding of\ndydrogesterone's efficacy, particularly in comparison to other progestogens or alternative interventions.\nComparative studies: Comparative studies that evaluate different administration routes of dydrogesterone\nand compare them with other progestogens could help delineate the optimal treatment approach. Such\nstudies would guide clinicians in selecting the most effective and patient-friendly options.\nImpact on IVF outcomes: Given the prevalence of assisted reproductive techniques, focusing research on\ndydrogesterone's impact on outcomes in vitro fertilization (IVF) cycles is warranted. Investigating\nparameters such as implantation, pregnancy, and live birth rates could shed light on its role in optimizing\nIVF success.\nPotential Areas of Improvement\nPatient education: Enhancing patient education regarding LPD and the benefits of dydrogesterone could\nsubstantially improve treatment adherence and outcomes. Educated patients are more likely to actively\nparticipate in their treatment plans, leading to more successful management.\nPersonalized treatment: The development of predictive models that consider patient characteristics and\nrelevant biomarkers holds the potential to guide personalized dydrogesterone treatment approaches.\nTailoring treatments to individual needs could maximize the chances of success.\nLong-term safety: Investigating the long-term safety of dydrogesterone is crucial, particularly its potential\neffects on maternal and fetal health. A comprehensive assessment of its risk-benefit profile over extended\nperiods would provide valuable insights into its role in LPD management.\nConclusions\nIn the intricate landscape of reproductive health, the luteal phase is a critical period that orchestrates the\ndelicate interplay between hormonal dynamics and endometrial receptivity. Luteal phase defect (LPD) casts\na shadow on this harmonious process, introducing complexities that can compromise embryo implantation,\nearly pregnancy development, and overall reproductive success. This comprehensive review article has\ndelved into the multifaceted world of LPD, exploring its definition, pathophysiology, clinical manifestations,\nand impact on fertility. Within this context, dydrogesterone emerges as a beacon of hope, offering a\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n12\n of \n15\n\nsolution that addresses the underlying deficiencies of the luteal phase. Its structural similarity to natural\nprogesterone, selectivity, and favorable pharmacological profile have positioned it as a frontline contender\nin LPD management. We have traversed the landscape of dydrogesterone's mechanism of action,\nunderstanding how its progestogenic support enhances endometrial receptivity and sustains early\npregnancy. The evidence from clinical studies underscores its efficacy, with improved pregnancy rates,\nextended luteal phase support, and enhanced reproductive outcomes. Safety and tolerability are paramount\nin any therapeutic journey, and dydrogesterone also shines here, with minimal side effects and a reduced\nrisk of unwanted hormonal effects. Patient preferences and special considerations for unique populations\nprovide a personalized touch to its administration, enhancing patient experience and outcomes. As\ndydrogesterone finds its place within international guidelines, its role in LPD management is validated.\nCombination therapies, guided by the wisdom of synergistic effects, hold the potential to usher in a new era\nof comprehensive care, addressing the multifaceted challenges of LPD with precision.\nAdditional Information\nDisclosures\nConflicts of interest:\n In compliance with the ICMJE uniform disclosure form, all authors declare the\nfollowing: \nPayment/services info:\n All authors have declared that no financial support was received from\nany organization for the submitted work. \nFinancial relationships:\n All authors have declared that they have\nno financial relationships at present or within the previous three years with any organizations that might\nhave an interest in the submitted work. \nOther relationships:\n All authors have declared that there are no\nother relationships or activities that could appear to have influenced the submitted work.\nReferences\n1\n. \nDashti S, Eftekhar M: \nLuteal-phase support in assisted reproductive technology: an ongoing challenge\n. Int J\nReprod Biomed. 2021, 19:761-72. \n10.18502/ijrm.v19i9.9708\n2\n. \nShah D, Nagarajan N: \nLuteal insufficiency in first trimester\n. Indian J Endocrinol Metab. 2013, 17:44-9.\n10.4103/2230-8210.107834\n3\n. \nPalomba S, Santagni S, La Sala GB: \nProgesterone administration for luteal phase deficiency in human\nreproduction: an old or new issue?\n. J Ovarian Res. 2015, 8:77. \n10.1186/s13048-015-0205-8\n4\n. \nMesen TB, Young SL: \nProgesterone and the luteal phase: a requisite to reproduction\n. Obstet Gynecol Clin\nNorth Am. 2015, 42:135-51. \n10.1016/j.ogc.2014.10.003\n5\n. \nSalehpour S, Tamimi M, Saharkhiz N: \nComparison of oral dydrogesterone with suppository vaginal\nprogesterone for luteal-phase support in in vitro fertilization (IVF): a randomized clinical trial\n. Iran J\nReprod Med. 2013, 11:913-8.\n6\n. \nThiyagarajan DK, Basit H, Jeanmonod R: \nPhysiology, menstrual cycle\n. StatPearls Publishing, Treasure Island,\nFL; 2023.\n7\n. \nInstitute of Medicine (US) and National Research Council (US) Committee on the Basic Science Foundations\nof Medically Assisted Conception: \nMedically assisted conception: an agenda for research\n. National\nAcademies Press, Washington, DC; 1989.\n8\n. \nBlanco-Breindel MF, Singh M, Kahn J: \nEndometrial receptivity\n. StatPearls Publishing, Treasure Island, FL;\n2023.\n9\n. \nHeger A, Sator M, Pietrowski D: \nEndometrial receptivity and its predictive value for IVF/ICSI-outcome\n.\nGeburtshilfe Frauenheilkd. 2012, 72:710-5. \n10.1055/s-0032-1315059\n10\n. \nThe menstrual cycle\n. (2023). Accessed: August 25, 2023: \nhttps://www.ucsfhealth.org/education/the-\nmenstrual-cycle\n.\n11\n. \nCable JK, Grider MH: \nPhysiology, progesterone\n. StatPearls Publishing, Treasure Island, FL; 2023.\n12\n. \nBaerwald AR, Pierson RA: \nOvarian follicular development during the use of oral contraception: a review\n. J\nObstet Gynaecol Can. 2004, 26:19-24. \n10.1016/s1701-2163(16)30692-2\n13\n. \nDuffy DM, Ko C, Jo M, Brannstrom M, Curry TE: \nOvulation: parallels with inflammatory processes\n. Endocr\nRev. 2019, 40:369-416. \n10.1210/er.2018-00075\n14\n. \nCavalcanti GS, Carvalho KC, Ferreira CD, Alvarez PA, Monteleone PA, Baracat EC, Soares Júnior JM:\nGranulosa cells and follicular development: a brief review\n. Rev Assoc Med Bras (1992). 2023, 69:e20230175.\n10.1590/1806-9282.20230175\n15\n. \nWhat is a corpus luteum?\n. (2017). Accessed: August 25, 2023:\nhttps://www.medicalnewstoday.com/articles/320433\n.\n16\n. \nYoung SL: \nOestrogen and progesterone action on endometrium: a translational approach to understanding\nendometrial receptivity\n. Reprod Biomed Online. 2013, 27:497-505. \n10.1016/j.rbmo.2013.06.010\n17\n. \nMarquardt RM, Kim TH, Shin JH, Jeong JW: \nProgesterone and estrogen signaling in the endometrium: what\ngoes wrong in endometriosis?\n. Int J Mol Sci. 2019, 20:\n10.3390/ijms20153822\n18\n. \nOchoa-Bernal MA, Fazleabas AT: \nPhysiologic events of embryo implantation and decidualization in human\nand non-human primates\n. Int J Mol Sci. 2020, 21:\n10.3390/ijms21061973\n19\n. \nOkada H, Tsuzuki T, Murata H: \nDecidualization of the human endometrium\n. Reprod Med Biol. 2018, 17:220-\n7. \n10.1002/rmb2.12088\n20\n. \nBhurke AS, Bagchi IC, Bagchi MK: \nProgesterone-regulated endometrial factors controlling implantation\n. Am\nJ Reprod Immunol. 2016, 75:237-45. \n10.1111/aji.12473\n21\n. \nSoules MR, McLachlan RI, Ek M, Dahl KD, Cohen NL, Bremner WJ: \nLuteal phase deficiency: characterization\nof reproductive hormones over the menstrual cycle\n. J Clin Endocrinol Metab. 1989, 69:804-12. \n10.1210/jcem-\n69-4-804\n22\n. \nBopp B, Shoupe D: \nLuteal phase defects\n. J Reprod Med. 1993, 38:348-56.\n23\n. \nKumar P, Sait SF: \nLuteinizing hormone and its dilemma in ovulation induction\n. J Hum Reprod Sci. 2011, 4:2-\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n13\n of \n15\n\n7. \n10.4103/0974-1208.82351\n24\n. \nOliver R, Pillarisetty LS: \nAnatomy, abdomen and pelvis, ovary corpus luteum\n. StatPearls Publishing,\nTreasure Island, FL; 2023.\n25\n. \nToufexis D, Rivarola MA, Lara H, Viau V: \nStress and the reproductive axis\n. J Neuroendocrinol. 2014, 26:573-\n86. \n10.1111/jne.12179\n26\n. \nShahid MA, Ashraf MA, Sharma S: \nPhysiology, thyroid hormone\n. StatPearls Publishing, Treasure Island, FL;\n2023.\n27\n. \nRosenfield RL, Ehrmann DA: \nThe pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of\nPCOS as functional ovarian hyperandrogenism revisited\n. Endocr Rev. 2016, 37:467-520. \n10.1210/er.2015-\n1104\n28\n. \nSimon A, Laufer N: \nAssessment and treatment of repeated implantation failure (RIF)\n. J Assist Reprod Genet.\n2012, 29:1227-39. \n10.1007/s10815-012-9861-4\n29\n. \nSchliep KC, Mumford SL, Hammoud AO, et al.: \nLuteal phase deficiency in regularly menstruating women:\nprevalence and overlap in identification based on clinical and biochemical diagnostic criteria\n. J Clin\nEndocrinol Metab. 2014, 99:E1007-14. \n10.1210/jc.2013-3534\n30\n. \nWilcox AJ, Dunson D, Baird DD: \nThe timing of the \"fertile window\" in the menstrual cycle: day specific\nestimates from a prospective study\n. BMJ. 2000, 321:1259-62. \n10.1136/bmj.321.7271.1259\n31\n. \nEl Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE: \nRecurrent pregnancy loss:\ncurrent perspectives\n. Int J Womens Health. 2017, 9:331-45. \n10.2147/IJWH.S100817\n32\n. \nQuaas A, Dokras A: \nDiagnosis and treatment of unexplained infertility\n. Rev Obstet Gynecol. 2008, 1:69-76.\n33\n. \nCakmak H, Taylor HS: \nImplantation failure: molecular mechanisms and clinical treatment\n. Hum Reprod\nUpdate. 2011, 17:242-53. \n10.1093/humupd/dmq037\n34\n. \nGriesinger G, Tournaye H, Macklon N, et al.: \nDydrogesterone: pharmacological profile and mechanism of\naction as luteal phase support in assisted reproduction\n. Reprod Biomed Online. 2019, 38:249-59.\n10.1016/j.rbmo.2018.11.017\n35\n. \nPeng C, Huang Y, Zhou Y: \nDydrogesterone in the treatment of endometriosis: evidence mapping and meta-\nanalysis\n. Arch Gynecol Obstet. 2021, 304:231-52. \n10.1007/s00404-020-05900-z\n36\n. \nRižner TL, Brožič P, Doucette C, et al.: \nSelectivity and potency of the retroprogesterone dydrogesterone in\nvitro\n. Steroids. 2011, 76:607-15. \n10.1016/j.steroids.2011.02.043\n37\n. \nVidal A, Dhakal C, Werth N, Weiss JM, Lehnick D, Kohl Schwartz AS: \nSupplementary dydrogesterone is\nbeneficial as luteal phase support in artificial frozen-thawed embryo transfer cycles compared to\nmicronized progesterone alone\n. Front Endocrinol (Lausanne). 2023, 14:1128564.\n10.3389/fendo.2023.1128564\n38\n. \nLou C, Wang C, Zhao Q, Jin F: \nEffect of dydrogesterone and progesterone on threatened miscarriage due to\ncorpus luteum insufficiency\n. Am J Transl Res. 2021, 13:4544-52.\n39\n. \nGriesinger G, Blockeel C, Kahler E, Pexman-Fieth C, Olofsson JI, Driessen S, Tournaye H: \nDydrogesterone as\nan oral alternative to vaginal progesterone for IVF luteal phase support: a systematic review and individual\nparticipant data meta-analysis\n. PLoS One. 2020, 15:e0241044. \n10.1371/journal.pone.0241044\n40\n. \nGriesinger G, Blockeel C, Tournaye H: \nOral dydrogesterone for luteal phase support in fresh in vitro\nfertilization cycles: a new standard?\n. Fertil Steril. 2018, 109:756-62. \n10.1016/j.fertnstert.2018.03.034\n41\n. \nStute P: \nDydrogesterone indications beyond menopausal hormone therapy: an evidence review and\nwoman's journey\n. Gynecol Endocrinol. 2021, 37:683-8. \n10.1080/09513590.2021.1908252\n42\n. \nSchindler AE: \nProgestational effects of dydrogesterone in vitro, in vivo and on the human endometrium\n.\nMaturitas. 2009, 65 Suppl 1:S3-11. \n10.1016/j.maturitas.2009.10.011\n43\n. \nTournaye H, Sukhikh GT, Kahler E, Griesinger G: \nA phase III randomized controlled trial comparing the\nefficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal\nsupport in in vitro fertilization\n. Hum Reprod. 2017, 32:1019-27. \n10.1093/humrep/dex023\n44\n. \nBarbosa MW, Valadares NP, Barbosa AC, et al.: \nOral dydrogesterone vs. vaginal progesterone capsules for\nluteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis\n. JBRA\nAssist Reprod. 2018, 22:148-56. \n10.5935/1518-0557.20180018\n45\n. \nBashiri A, Galperin G, Zeadna A, Baumfeld Y, Wainstock T: \nIncreased live birth rate with dydrogesterone\namong patients with recurrent pregnancy loss regardless of other treatments\n. J Clin Med. 2023,\n12:\n10.3390/jcm12051967\n46\n. \nBarbosa MW, Silva LR, Navarro PA, Ferriani RA, Nastri CO, Martins WP: \nDydrogesterone vs progesterone for\nluteal-phase support: systematic review and meta-analysis of randomized controlled trials\n. Ultrasound\nObstet Gynecol. 2016, 48:161-70. \n10.1002/uog.15814\n47\n. \nHua S: \nAdvances in nanoparticulate drug delivery approaches for sublingual and buccal administration\n.\nFront Pharmacol. 2019, 10:1328. \n10.3389/fphar.2019.01328\n48\n. \nBrennan PF, Strombom I: \nImproving health care by understanding patient preferences: the role of computer\ntechnology\n. J Am Med Inform Assoc. 1998, 5:257-62. \n10.1136/jamia.1998.0050257\n49\n. \nZhang Y, Fu X, Gao S, Gao S, Gao S, Ma J, Chen ZJ: \nPreparation of the endometrium for frozen embryo\ntransfer: an update on clinical practices\n. Reprod Biol Endocrinol. 2023, 21:52. \n10.1186/s12958-023-01106-5\n50\n. \nDurand C, Eldoma M, Marshall DA, Bansback N, Hazlewood GS: \nPatient preferences for disease-modifying\nantirheumatic drug treatment in rheumatoid arthritis: a systematic review\n. J Rheumatol. 2020, 47:176-87.\n10.3899/jrheum.181165\n51\n. \nVaiarelli A, Cimadomo D, Conforti A, et al.: \nLuteal phase after conventional stimulation in the same ovarian\ncycle might improve the management of poor responder patients fulfilling the Bologna criteria: a case\nseries\n. Fertil Steril. 2020, 113:121-30. \n10.1016/j.fertnstert.2019.09.012\n52\n. \nSaharkhiz N, Zamaniyan M, Salehpour S, et al.: \nA comparative study of dydrogesterone and micronized\nprogesterone for luteal phase support during in vitro fertilization (IVF) cycles\n. Gynecol Endocrinol. 2016,\n32:213-7. \n10.3109/09513590.2015.1110136\n53\n. \nGoetz LH, Schork NJ: \nPersonalized medicine: motivation, challenges, and progress\n. Fertil Steril. 2018,\n109:952-63. \n10.1016/j.fertnstert.2018.05.006\n54\n. \nReis FM, Coutinho LM, Vannuccini S, Batteux F, Chapron C, Petraglia F: \nProgesterone receptor ligands for\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n14\n of \n15\n\nthe treatment of endometriosis: the mechanisms behind therapeutic success and failure\n. Hum Reprod\nUpdate. 2020, 26:565-85. \n10.1093/humupd/dmaa009\n55\n. \nEller M, Gelfand AA, Riggins NY, Shiboski S, Schankin C, Goadsby PJ: \nExacerbation of headache during\ndihydroergotamine for chronic migraine does not alter outcome\n. Neurology. 2016, 86:856-9.\n10.1212/WNL.0000000000002406\n56\n. \nOtt J, Egarter C, Aguilera A: \nDydrogesterone after 60 years: a glance at the safety profile\n. Gynecol\nEndocrinol. 2022, 38:279-87. \n10.1080/09513590.2021.2016692\n57\n. \nOmar MH, Mashita MK, Lim PS, Jamil MA: \nDydrogesterone in threatened abortion: pregnancy outcome\n. J\nSteroid Biochem Mol Biol. 2005, 97:421-5. \n10.1016/j.jsbmb.2005.08.013\n58\n. \nStanton TA, Blumenthal PD: \nPostpartum hormonal contraception in breastfeeding women\n. Curr Opin\nObstet Gynecol. 2019, 31:441-6. \n10.1097/GCO.0000000000000571\n59\n. \nMalherbe JA, Garas G, Khor TS, MacQuillan GC: \nDelayed fulminant hepatic failure from dydrogesterone-\nrelated in vitro fertilization therapy requiring liver transplantation during pregnancy\n. Am J Case Rep. 2020,\n21:e925690. \n10.12659/AJCR.925690\n60\n. \nGinsburg KA: \nLuteal phase defect. Etiology, diagnosis, and management\n. Endocrinol Metab Clin North Am.\n1992, 21:85-104.\n61\n. \nHossein Rashidi B, Tarafdari A, Ghazimirsaeed ST, et al.: \nComparison of dydrogesterone and GnRH\nantagonists for prevention of premature LH surge in IVF/ICSI cycles: a randomized controlled trial\n. J Family\nReprod Health. 2020, 14:14-20.\n62\n. \nOrazov MR, Radzinskiy VE, Nosenko EN, et al.: \nCombination therapeutic options in the treatment of the\nluteal phase deficiency\n. Gynecol Endocrinol. 2017, 33:1-4. \n10.1080/09513590.2017.1399695\n63\n. \nPan D, Yang J, Zhang N, Wang L, Li N, Shi J, Zhou H: \nGonadotropin-releasing hormone agonist\ndownregulation combined with hormone replacement therapy improves the reproductive outcome in\nfrozen-thawed embryo transfer cycles for patients of advanced reproductive age with idiopathic recurrent\nimplantation failure\n. Reprod Biol Endocrinol. 2022, 20:26. \n10.1186/s12958-022-00897-3\n64\n. \nTorreggiani M, Fois A, Njandjo L, et al.: \nToward an individualized determination of dialysis adequacy: a\nnarrative review with special emphasis on incremental hemodialysis\n. Expert Rev Mol Diagn. 2021, 21:1119-\n37. \n10.1080/14737159.2021.1987216\n65\n. \nTetruashvili N, Domar A, Bashiri A: \nPrevention of pregnancy loss: combining progestogen treatment and\npsychological support\n. J Clin Med. 2023, 12:\n10.3390/jcm12051827\n66\n. \nLeão Rde B, Esteves SC: \nGonadotropin therapy in assisted reproduction: an evolutionary perspective from\nbiologics to biotech\n. Clinics (Sao Paulo). 2014, 69:279-93. \n10.6061/clinics/2014(04)10\n67\n. \nEngmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C: \nThe use of gonadotropin-releasing\nhormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk\npatients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a\nprospective randomized controlled study\n. Fertil Steril. 2008, 89:84-91. \n10.1016/j.fertnstert.2007.02.002\n68\n. \nGreenbaum S, Athavale A, Hershko Klement A, Bentov Y: \nLuteal phase support in fresh and frozen embryo\ntransfers\n. Front Reprod Health. 2022, 4:919948. \n10.3389/frph.2022.919948\n69\n. \nWang L, Guan HY, Xia HX, Chen XY, Zhang W: \nDydrogesterone treatment for menstrual-cycle\nregularization in abnormal uterine bleeding - ovulation dysfunction patients\n. World J Clin Cases. 2020,\n8:3259-66. \n10.12998/wjcc.v8.i15.3259\n70\n. \nGopalakrishnan S, Udayshankar PM, Rama R: \nStandard treatment guidelines in primary healthcare practice\n.\nJ Family Med Prim Care. 2014, 3:424-9. \n10.4103/2249-4863.148134\n71\n. \nDiagnosis and treatment of luteal phase deficiency: a committee opinion\n. Fertil Steril. 2021, 115:1416-23.\n10.1016/j.fertnstert.2021.02.010\n72\n. \nKim J, De Jesus O: \nMedication routes of administration\n. StatPearls Publishing, Treasure Island, FL; 2023.\n73\n. \nChakravarty BN, Shirazee HH, Dam P, Goswami SK, Chatterjee R, Ghosh S: \nOral dydrogesterone versus\nintravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART)\ncycles: results of a randomised study\n. J Steroid Biochem Mol Biol. 2005, 97:416-20.\n10.1016/j.jsbmb.2005.08.012\n74\n. \nJeschke L, Santamaria CG, Meyer N, Zenclussen AC, Bartley J, Schumacher A: \nEarly-pregnancy\ndydrogesterone supplementation mimicking luteal-phase support in art patients did not provoke major\nreproductive disorders in pregnant mice and their progeny\n. Int J Mol Sci. 2021, 22:\n10.3390/ijms22105403\n75\n. \nMumusoglu S, Polat M, Ozbek IY, et al.: \nPreparation of the endometrium for frozen embryo transfer: a\nsystematic review\n. Front Endocrinol (Lausanne). 2021, 12:688237. \n10.3389/fendo.2021.688237\n76\n. \nTaibanguay N, Chaiamnuay S, Asavatanabodee P, Narongroeknawin P: \nEffect of patient education on\nmedication adherence of patients with rheumatoid arthritis: a randomized controlled trial\n. Patient Prefer\nAdherence. 2019, 13:119-29. \n10.2147/PPA.S192008\n77\n. \nJin JF, Zhu LL, Chen M, et al.: \nThe optimal choice of medication administration route regarding intravenous,\nintramuscular, and subcutaneous injection\n. Patient Prefer Adherence. 2015, 9:923-42. \n10.2147/PPA.S87271\n \nPublished via DMIHER School of\nEpidemiology and Public Health\n2023 Muneeba et al. Cureus 15(11): e48194. DOI 10.7759/cureus.48194\n15\n of \n15","source_license":"CC0","license_restricted":false}