[Abstract] Luteal defect is a relatively common problem in clinical work in obstetrics and gynecology, and it is thought to be associated with infertility, early miscarriage, short cycles, premenstrual bleeding, abnormal thyroid function, hyperprolactinemia, and ovulation promotion therapy with assisted reproductive technology. Given that the diagnosis of luteal defects still lacks reliable means, the treatment of luteal support is mostly empirical based on the theory and clinical practice of lutogenesis. In this article, we will discuss the clinical issues related to luteal defects and luteal support. Luteal defects, also known as luteal phase defect (LPD), are a common clinical problem. Clinical observations and animal studies in the 1960s revealed that luteal defects can lead to a shortened luteal phase, low progesterone levels, or luteal bleeding that can cause difficulty in embryo implantation and affect pregnancy, or miscarriage or even infertility. [qw1] However, after more than 20 years of clinical research and practice, there are still a lot of controversies about luteal defects and luteal support treatment for luteal defects [1], this paper will discuss the clinical issues related to luteal defects and luteal support from definition, diagnosis to treatment. I. Definition of luteal defect Luteal defect was described by Jones GE as early as 1949, and its importance for early pregnancy maintenance was clarified especially after Csapo AI reported in 1971 that patients with surgical removal of the corpus luteum would not be able to maintain pregnancy. Luteal defect is considered in most of the literature to be a phenomenon in which the patient’s progesterone production during the luteal phase is reduced and insufficient to maintain the secretory phase function of the endometrium, thus affecting embryo implantation and growth. [O2] Insufficient luteal phase progesterone secretion may be associated with abnormal hypothalamic GnRH secretion in patients. In fact, the corpus luteum not only secretes progesterone but also estrogen, and estrogen is also considered important for the maintenance of early pregnancy; therefore, luteal insufficiency should be considered in addition to inadequate progesterone secretion and inadequate estrogen secretion. Furthermore, even if peripheral blood progesterone levels are normal and the endometrium itself has abnormal estrogen and progesterone receptors, resulting in inadequate function of the secretory phase of the endometrium, this has been considered by some authors as a luteal defect at the receptor level. Some authors have also attributed the lack of progesterone-induced blocking factor (PIBF, Progesterone Induced Blocking Factor) on the surface of endometrial lymphocytes and even the abnormalities of related cytokines to localized luteal phase function defects in the endometrium. Diagnosis of luteal defects Although there is no controversy about the importance of normal luteal function for early pregnancy maintenance, the clinical diagnosis of luteal defects has been controversial. In clinical work, there are three commonly used methods for the diagnosis of luteal defects, one is the basal body temperature measurement, the second is the observation of the temporal phase of the endometrium, and the third is the measurement of progesterone hormone after ovulation. The method of basal body temperature measurement is derived from the knowledge of the normal luteal phase, which is usually considered to be 12-14 days, then shorter than 12 days is usually diagnosed as luteal defect. However, based on basal body temperature, it is often difficult to determine the day of ovulation, and therefore the length of the luteal phase becomes difficult to determine. Of course, LH measurement can be helpful in determining the day of ovulation and can provide a more accurate picture of the length of the luteal phase. However, it is important to note that the luteal phase can be shorter than 12 days in healthy women. Progesterone levels in peripheral blood are also considered to be an indicator of luteal function. In an unpregnant cycle, progesterone levels usually peak 6-8 days after ovulation, but progesterone production is influenced by LH pulses that are equally pulsatile and can fluctuate even up to 8 times in 90 minutes, so the progesterone level obtained from a single blood sample is not necessarily an absolute criterion for luteal insufficiency. Therefore, although the recommended method for the diagnosis of luteal deficiency is a mid-luteal progesterone level of less than 10 ng/ml or a total of three progesterone levels in the luteal phase of less than 30 ng/ml [2], this view is not widely accepted. It is also because of the wide fluctuation range of progesterone levels in the luteal phase that it has been difficult to determine the absolute standard of progesterone levels in normal women in the luteal phase and to describe the standard characteristics of progesterone level changes in normal women after ovulation [2]. [O4] Moreover, once a patient obtains a pregnancy, the corpus luteum of pregnancy will be stimulated by HCG secreted by the embryo, so progesterone at this time can only respond to the survival of the embryo [O5], and cannot be used as an indicator of the need for antifetus. Biopsy of the endometrium for pathomorphological observation of the phase of endometrial secretion was once considered the gold standard for the diagnosis of luteal defects, and a difference of more than 2 days was usually considered to be diagnostic of luteal defects. However, in recent years, prospective, double-blind, randomized controlled studies have found that histopathological analysis of the endometrium is also an inconclusive diagnostic method. 2004 saw the publication of several RCT studies in fertility and sterility that reported diagnostic endometrial biopsy pathology observations between cycles in the same patient, between observers, and O6] [3], and studies have found no association between pathological findings of endometrial biopsy and history of infertility [O7] [4]. All of these reported findings question the significance of endometrial histopathological biopsy findings for the diagnosis of infertility and luteal defects. Given the uncertainty of endometrial histopathological diagnosis, recent studies on endometrial receptivity in the luteal phase have focused on molecular markers [5], and it was also hoped that these molecularological markers would provide a diagnosis of luteal defects; however, these molecular markers are still in the research phase and lack definitive and reliable conclusions. III. Treatment of luteal defects Due to the inconclusive results obtained from the clinical diagnostic means of luteal defects, the luteal support treatment for patients with luteal defects is currently mostly empirical. Luteal defects are thought to be associated with infertility, early miscarriage, short cycles, premenstrual bleeding, anorexia nervosa, starvation, excessive exercise, stress, obesity, endometriosis, advanced age, abnormal thyroid function, hyperprolactinemia, ovulation and assisted reproductive technologies and PCOS, among others, [qw8] therefore empirical treatment is derived from two sources, one being the already relatively clear presence of abnormalities or diseases of luteal insufficiency, such as abnormal thyroid function and hyperprolactinemia resulting in abnormal pituitary hypothalamic function affecting LH secretion, and inadequate LH secretion in patients with hypogonadotropic amenorrhea. Second, a large number of clinical observational studies suggest that luteal support will help improve pregnancy outcomes, leading to speculation about the presence of luteal insufficiency in populations such as patients with unexplained recurrent miscarriage [6] and patients treated with assisted reproductive technologies. The possible reasons for the presence of luteal insufficiency in patients after assisted reproductive technology treatment are currently considered to be twofold: first, the use of down-regulating drugs including GnRH agonists and antagonists, both of which may affect the level and frequency of LH secretion, leading to abnormal progesterone secretion; second, the negative feedback of high estrogen levels after ovulation promotion affects LH secretion leading to luteal insufficiency. However, the literature reports that luteal function was not affected in intrauterine insemination cycles with the ovulation-promoting drug clomiphene [7], presumably related to the low mean estrogen levels after clomiphene ovulation promotion in that study. The main drugs for luteal support include HCG, progesterone and estrogen. Clinical observations suggest that ovulation promotion seems to help in the treatment of patients with luteal defects, but it remains unclear whether the efficacy of their treatment stems from the development of multiple follicles or from the improved quality of the eggs themselves. Progesterone is available in oral, intramuscular and topical vaginal formulations. Oral progesterone preparations are absorbed orally, are poorly utilized, and are generally used more sparingly. Oral micronized progesterone was used for IVF-ET luteal support in the late 1980s, and subsequent studies found that oral micronized progesterone reduced the biological activity of the hormone and had slightly poorer pregnancy outcomes. Oral micronized progesterone in patients with premature ovarian failure also had a less pronounced endocrine phase conversion. Dydrogesterone is a trans structure of natural progesterone and has significantly higher oral absorption and utilization than natural progesterone, but peripheral blood drug levels are difficult to detect. In contrast, the use of dydrogesterone was first reported in 1987 for luteal support in stimulated cycles of IVF-ET, and the expected endosomal secretory phase conversion was achieved after oral administration. The solvent of the intramuscular formulation is oil, which is difficult to be absorbed in the muscle and is prone to form hard nodules. 1985 Leeton et al first demonstrated the use of 50 mg intramuscular progesterone to prolong the luteal phase of In Vitro Fertilization and Embryo Transfer (IVF-ET) stimulated cycles. Luteal phase. The literature reports no difference in IVF-ET pregnancy outcomes with 50-100 mg/day of inotropic progesterone. Common side effects of intramuscular progesterone are injection site pain, rash, inflammation and edema, and rare side effects include eosinophilic pneumonia or lipofuscinosis [8]. In contrast, vaginal preparations are better absorbed and utilized and are gradually becoming more widely used clinically. Progesterone used by the vaginal route is not metabolized by the liver and has a vaginal (uterine) first-pass effect, so it is widely used in higher local concentrations in the uterus. Some scholars have also used progesterone through the rectal route, and it should be noted that when comparing the serum progesterone concentration by sublingual, oral, vaginal and rectal administration with 50-100 mg, the serum concentration of progesterone in the first 8 hours was twice as high as that of other administration methods. There is a lack of results from prospective controlled studies with other dosing methods in large samples. The addition of HCG during the luteal phase can rescue luteal insufficiency and has been used as a standard luteal support drug since the 1980s. However, HCG should be used with caution for luteal support as estrogen levels above 2500-2700 pg/ml or follicle counts above 10 can easily induce ovarian hyperstimulation. Since the corpus luteum produces two important hormones, progesterone and estrogen, the role of progesterone in embryo implantation is relatively well understood, while the role of estrogen in luteal support is unknown. Since 1993, there has been a steady stream of prospective clinical studies confirming that estrogen added to IVF-ET stimulation cycles would be beneficial in improving pregnancy rates. However, there is still controversy regarding the addition of estrogen or not, as well as the timing and dosage of addition [9]. There is also a small amount of literature reporting the use of agonists of GnRH for luteal support, but it is not widely accepted and used. Due to the results of research on endometrial receptive molecular markers, local or systemic application of colony cell stimulating factor, interleukins and immune cells, and growth hormone, etc. into the uterine cavity for luteal support has also been reported, but these methods are not as effective as the use of progesterone [10]. In conclusion, the clinical diagnosis and treatment of luteal defects have clear factual basis for our reference, but there are also unclear data and reports that deserve more in-depth study.