Treatment Of Luteal Phase Defect Research Articles

Luteal Phase Defects and Progesterone Supplementation

Importance: Luteal phase defects (LPDs), or an insufficiency of progesterone production during the luteal phase of the menstrual cycle, have been identified as a potential cause of recurrent pregnancy loss (RPL), but its exact contribution to RPL is not well-defined. In addition, the role of exogenous progesterone supplementation during pregnancy remains controversial. Objective: The goal of this review is to provide an updated, evidence-based summary of LPD, including prevalence and potential pathophysiologic mechanisms, and to explore the current controversies regarding progesterone supplementation for management and treatment of RPL. Evidence Acquisition: A literature review identified relevant research using a PubMed search, Cochrane summaries, review articles, textbook chapters, databases, and society guidelines. Results: Endogenous progesterone plays a crucial role in the first trimester of pregnancy, and therefore, insufficiency may contribute to RPL. However, the precise relationship between LPD and RPL remains unclear. LPD is primarily a clinical diagnosis based on a luteal phase less than 10 days. Although there may be a possibility of incorporating a combined clinical and biochemical approach in defining LPD, the current lack of validated diagnostic criteria creates a challenge for its routine incorporation in the workup of infertility. Moreover, no treatment modality has demonstrated efficacy in improving fertility outcomes for LPD patients, including progesterone supplementation, whose inconsistent data do not sufficiently support its routine use, despite its minimal risk. It is imperative that women diagnosed with LPD should be worked up for other potential conditions that may contribute to a shortened luteal phase. Future work needs to focus on identifying a reproducible diagnostic test for LPD to guide treatment. Conclusions and Relevance: Currently, the perceived relationship between LPD and RPL is challenged by conflicting data. Therefore, patients with an abnormal luteal phase should undergo a thorough workup to address any other potential etiologies. Although supplemental progesterone is commonly used for treatment of LPD and RPL, inconsistent supporting data call for exogenous hormone therapy to be only used in a research setting or after a thorough discussion of its shortcomings.

Luteal Phase Defect (LPD): A necessary tool in assisted reproductive techniques

In Luteal Phase Defect (LPD), endogenous progesterone is insufficient to maintain a functional secretory endometrium and also inhibit embryo growth and implant. In 1960, it was estimated that 20 million pregnancies were exposed to Dydrogesterone in utero. LOTUS I and LOTUS II two major multicenter Phase III studies were conducted on patients who were planning to undergo Fertilization (IVF) with or without Intracytoplasmic Sperm Injection (ICSI). The result of both studies shows that Dydrogesterone was non-inferior to micronized vaginal progesterone, which was the presence of fetal heartbeats at 12 weeks of gestation. Progesterone which can be administered either by oral preparation, vaginal administration along with optimal use of estrogen and Gonadotropin-Releasing Hormon (GnRH) agonist drugs is used in the treatment of LPD. Studies have suggested the use of Dydrogesterone in fresh IVF cycles and Luteal Phase Support (LPS) is continued till 10–12 weeks. However, it may be stopped at the time of β-hCG becoming positive or visualization of a fetal heartbeat.

Treatment of Luteal Phase Defects in Assisted Reproduction

Abnormal luteal function is a common issue in assisted reproduction techniques associated with ovarian stimulation probably due to low levels of LH in the middle and in the late luteal phase. This defect seems to be associated with supraphysiological steroid levels at the end of follicular phase. The luteal phase insufficiency has not got a diagnostic test which has proven reliable in a clinical setting. Luteal phase after ovarian stimulation becomes shorter and insufficient, resulting in lower pregnancy rates. Luteal phase support with progesterone or hCG improves pregnancy outcomes and no differences are found among different routes of administration. However, hCG increases the risk of ovarian hyperstimulation syndrome. In relation to the length of luteal support, the day of starting it remains controversial and it does not seem necessary to continue once a pregnancy has been established. After GnRHa triggering ovulation, intensive luteal support or hCG bolus can overcome the defect in luteal phase, but more studies are needed to show the LH utility as support.

Luteal-phase defect: the role of Georgeanna Seegar Jones

The study and treatment of luteal phase defect since the late 1940s, particularly the work of Georgeanna Seegar Jones, are summarized.

Treatment of luteal phase defect by ovarian stimulation

Dr Tin-Chiu Li (Jessop Hospital for Women, Sheffield, UK) and colleagues report in the February issue of Fertility and Sterility the use of controlled ovarian stimulation as a means for treating a defect in the luteal phase that is associated with unexplained recurrent pregnancy loss. The team used intramuscular injections of urinary-derived human menopausal follicle-stimulating hormone and luteinizing hormone, administered daily or on alternate days, to control ovarian stimulation. When plasma estradiol concentration reached 2000–3000 pmol l−1, or when there were two follicles that were at least 16-mm wide, an ovulatory dose of human chorionic gonadotropin was given.

Endocrinology: Observations on the use of purified follicle-stimulating hormone in the treatment of luteal phase defects

We treated 18 infertile patients affected by histologically confirmed luteal phase deficiency with 75 IU of purified follicle-stimulating hormone (FSH) daily during the first 5 days of the cycle. Patients who were not pregnant after the first cycle of treatment underwent a second cycle. In the second cycle the daily doses of purified FSH were doubled if luteal phase deficiency had persisted during the first cycle. During the two cycles before treatment and during treatment, patients underwent an endometrial biopsy 1-3 days before the expected onset of menses. An assessment of progesterone serum concentrations was also performed on days 8, 6 and 4 before the expected onset of menses. Treatment was administered in a total of 33 cycles resulting in 30 ovulatory cycles. Six pregnancies were achieved. Among non-conception ovulatory cycles, 13 presented delayed endometrial dating and 11 normal endometrium. The mean +/- SD of the sum of the three progesterone determinations was 14.7 +/- 1.4 ng/ml in pretreatment cycles, 14.6 +/- 1.6 ng/ml in cycles with normalization of endometrial dating, 14.8 +/- 1.7 ng/ml in cycles with persistence of luteal phase deficiency and 30.4 +/- 3.0 ng/ml in conception cycles (P < 0.05 versus other groups). We conclude that purified FSH, if effective in the treatment of luteal phase deficiency, does not act through an increase in progesterone concentrations.

Corpus luteal insufficiency

The corpus luteum is controlled by luteinizing hormone (LH) and intraovarian morphofunctional specialization and autocrine/paracrine mechanisms. Corpus luteal insufficiency produces luteal phase defects (LPD). The poor precision and validation of endometrial histologic dating and single or random multiple serum progesterone measurements produce widely variable diagnoses. The true prevalence rate of LPD may be only 3-5% similar to that due to chance. The role of LPD in causing infertility can be challenged because the diagnosis is not predictive of recurrence in subsequent cycles, and other causes of infertility are not controlled for. Intraobserver and interobserver variability, uterine site of biopsy, luteal phase length, time of ovulation, and luteal phase timing of biopsy have been examined and have confirmed the imprecision of dating as a sensitive and reliable assessment of luteal insufficiency. There is support for either early or late luteal phase biopsy. Endometrial dating using LH timing as a reference point is relatively more reliable. Integrated luteal progesterone is the only currently accurate assessment of luteal sufficiency. Clomiphene does not increase LPD but increases serum progesterone, integrated progesterone, corpus luteum LH/human chorionic gonadotropin (hCG), and insulin-like growth factor-1 (IGF-1) receptors, all of which promote increased progesterone production and do not affect endometrial estrogen and progesterone receptors. hCG is more likely to stimulate progesterone production if given at the mid rather than early luteal phase corresponding to the phase with highest total and available (unoccupied) corpus luteal LH receptors. Careful analysis of published studies on treatment of LPD revealed only one randomized controlled study, and, statistically, all studies revealed no better outcome with progesterone treatment.

Efficacy of clomiphene citrate in the treatment of luteal phase deficiency: quantity versus quality of preovulatory follicles

We tested the hypothesis that the efficacy of clomiphene citrate (CC) in the treatment of luteal phase defect (LPD) is related more to the number of ovulatory follicles than to the quality of a single follicle. Eighteen ovulatory women with LPD as defined by endometrial biopsies that lagged behind chronological dates by at least 3 days on two separate menstrual cycles were studied. During the menstrual cycle before treatment and also during a treatment cycle (100 mg of CC, on days 5 to 9), we obtained an endometrial biopsy 9 to 12 days after ovulation. All biopsies were read in a blinded fashion by the same gynecological pathologist. During the treatment cycle, 10 women had more than one preovulatory follicle (greater than 15 mm, mean of three dimensions), while 8 had one preovulatory follicle. Luteal phase defect was corrected according to biopsy in 8 of the 10 women with more than one preovulatory follicle, but in only 2 of the 8 women with a single preovulatory follicle.

The treatment of luteal phase defects with pulsatile infusion of gonadotropin-releasing hormone

Because pulsatile administration of gonadotropin-releasing hormone (GnRH) can initiate normal follicular maturation and corpus luteum function in women with hypothalamic amenorrhea, the authors attempted to treat five women with inadequate and one with short luteal phase with GnRH therapy. Pulsatile administration of GnRH (5 micrograms intravenously every 90 minutes) was begun on days 1 to 4 and continued throughout the cycle. Blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, and progesterone were monitored daily throughout the control and treatment cycles. There were 12 GnRH treatment cycles, all of them ovulatory. The length of the induced luteal phases varied from 11 to 17 days in all patients. Mean progesterone levels during GnRH treatment were significantly increased over those of the matched control cycles (control cycle 3.5 +/- 0.5 ng/ml; treatment cycle 8.2 +/- 1.45 ng/ml [mean +/- standard error]). Endometrial biopsies obtained during the luteal phase (days 25 to 27) in five women were in phase during the GnRH treatment cycle, in contrast to the control cycle in which they were two or more days out of phase. One patient achieved pregnancy during the treatment cycle, but aborted spontaneously at 8 1/2 weeks. The data demonstrate that pulsatile GnRH infusion, when initiated in the early follicular phase, can restore normal corpus luteum function in women with luteal phase defects.

Prolactin Production by Explants of Normal, Luteal Phase Defective, and Corrected Luteal Phase Defective Late Secretory Endometrium

The production of prolactin by explants of late secretory endometrium has been correlated with the extent of decidual differentiation. This correlation is strengthened by the observation that luteal phase defective endometrium produces less prolactin than normal control endometrium in a 24-hour in vitro culture system. In the present study the prolactin production by explants of normal, luteal phase defective, progesterone-corrected luteal phase defective, and clomiphene- or follicle-stimulating hormone/luteinizing hormone-corrected luteal phase defective late secretory endometrium was measured over 96 hours at 24-hour intervals. Progesterone in physiologic concentrations was added to the culture medium to maintain tissue integrity and prolactin synthesis. The prolactin production of normal late secretory endometrium rose over 96 hours under progesterone stimulation. The luteal phase defective endometrium produced significantly less prolactin under the same conditions. Histologically proven corrected luteal phase defective endometrium, regardless of treatment method, produced prolactin not different from the normal controls of the same dates. From these results it is concluded that histologic correction of luteal phase defective endometrium is associated with a corresponding biochemical correction with use of prolactin as a metabolic marker. The findings also strongly support timed endometrial biopsy as the method of diagnosis and evaluation of treatment of luteal phase defect.

The endometrial biopsy as a guide to the management of luteal phase defect.

The endometrial biopsy serves as a useful and valuable tool in the diagnosis and treatment of luteal phase defect (LPD). Eighty patients were diagnosed as having an LPD by endometrial biopsy. The subjects were divided into four equal groups, and different treatment protocols were introduced according to the histologic pattern found in the endometrial biopsy specimen. Patients in group I had glandular stromal asynchrony and were treated with clomiphene citrate therapy. Progesterone suppositories were administered to those patients in group II who showed glandular stromal synchrony. Groups III and IV had the same histologic pattern as groups I and II, but a reversal of the treatment protocol was made. The raw pregnancy rate was 85% and 80% for groups I and II, respectively. Groups III and IV had a raw pregnancy rate of 40% and 30%, respectively. Life-table analysis projected the pregnancy rate based on the protocol of therapy administered. This confirmed our findings and strengthened our belief that the endometrial biopsy is an invaluable guide in the treatment of LPD. This article addresses two distinct endometrial patterns within the framework of LPD and proposes a structured therapeutic regimen to treat this defect.

Prolactin production by explants of normal, luteal phase defective, and corrected luteal phase defective late secretory endometrium

The production of prolactin by explants of late secretory endometrium has been correlated with the extent of decidual differentiation. This correlation is strengthened by the observation that luteal phase defective endometrium produces less prolactin than normal control endometrium in a 24-hour in vitro culture system. In the present study the prolactin production by explants of normal, luteal phase defective, progesterone-corrected luteal phase defective, and clomiphene- or follicle-stimulating hormone/luteinizing hormone-corrected luteal phase defective late secretory endometrium was measured over 96 hours at 24-hour intervals. Progesterone in physiologic concentrations was added to the culture medium to maintain tissue integrity and prolactin synthesis. The prolactin production of normal late secretory endometrium rose over 96 hours under progesterone stimulation. The luteal phase defective endometrium produced significantly less prolactin under the same conditions. Histologically proven corrected luteal phase defective endometrium, regardless of treatment method, produced prolactin not different from the normal controls of the same dates. From these results it is concluded that histologic correction of luteal phase defective endometrium is associated with a corresponding biochemical correction with use of prolactin as a metabolic marker. The findings also strongly support timed endometrial biopsy as the method of diagnosis and evaluation of treatment of luteal phase defect.

Induction of luteal phase defect with clomiphene citrate

The effect of clomiphene citrate and progesterone on luteal function in infertile women was studied. Endometrial biopsies were performed in 103 women immediately prior to menstruation. Group 1 (n = 62) had secretory endometrium with a histologic lag time of ≥48 hours with respect to the subsequent menses, that is, luteal phase defect. Group 2 (n = 10) had normal histologic characteristics of the secretory phase. Group 3 (n = 31) had anovulatory endometrium. The last group was subdivided into those with polycystic ovary syndrome (n = 9) and those without the characteristic gonadotropin pattern of polycystic ovary syndrome (n = 22). Clomiphene citrate at doses of 50 to 250 mg daily for 5 days was administered for induction of ovulation, timing of ovulation, or treatment of luteal phase defect. An endometrial biopsy was obtained after three ovulatory treatment cycles. Only one fourth of the women with prior luteal phase defect had normalization of the biopsy specimen with clomiphene citrate, while one half of those treated with progesterone had normal specimens. Half of the normally ovulating women had induction of a luteal phase defect with clomiphene citrate. Only women with polycystic ovary syndrome had consistently well-timed endometrial histologic features with clomiphene citrate therapy. Despite successful induction of ovulation, 16 of the other 22 previously anovulatory women had endometrial histologic findings compatible with luteal phase defect. Increasing the clomiphene citrate dosage was unsuccessful in improving endometrial maturation. These results suggest that the use of clomiphene citrate may be associated with a high rate of luteal phase defect induction, except among women with polycystic ovary syndrome. Clomiphene citrate, even at high doses, appears to be ineffective therapy for luteal phase defect.

Endometrial biopsy during treatment of luteal phase defects is predictive of therapeutic outcome

Luteal phase deficiency (LPD), as diagnosed by endometrial biopsy, is not a single disorder but rather a spectrum of dysfunction that reflects both endometrial cycle and ovarian cycle abnormalities. Forty-three patients were diagnosed as having LPD by two consecutive abnormal cycles. Seven patients (16%) with hyperprolactinemia received bromocriptine, and one hypothyroid patient received thyroid replacement. The remaining patients were treated sequentially with progesterone suppositories, clomiphene, the combination, and follicle-stimulating hormone and luteinizing hormone. If no conception occurred in 6 months on a given type of therapy, treatment was advanced. Patients were rebiopsied on each medication. In all, 33 of 41 (81%) compliant patients conceived. No viable pregnancies occurred without normal endometrial maturation, regardless of the treatment modality employed. When compared with time-life table projections, pregnancies occurred at rates comparable to those of a normal population once normal endometrial maturation was obtained with therapy. The endometrial biopsy accurately reflects the functional state of both the ovarian cycle and the endometrial cycle and can be used to determine adequacy of therapy, thereby improving conception rates in patients with LPD and eliminating the need for therapeutic trials.

Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency

Forty-four infertile patients with inadequate luteal phase histologically documented in at least two separate cycles and normal plasma levels of progesterone (P), estradiol (E2), and prolactin (PRL) were entered into treatment plans on a random basis involving at least 3 months of each of the following: P vaginal suppositories, dehydrogesterone, and no treatment. Success rates were similar for P (62.5%) and dehydrogesterone (68.7%), based on a corrected endometrial defect during the fourth treated cycle or when a term pregnancy was achieved. However, these figures are significantly different (P less than 0.001) when compared with 16.6% of the control group. In ten additional infertile patients with normal luteal function as assessed by endometrial histologic study and hormone measurements, a second biopsy was performed in a consecutive cycle under dehydrogesterone administration. In no case was the normal secretory pattern impaired. It is concluded that (1) both P and dehydrogesterone can be used to advantage in the treatment of luteal phase defects, and (2) therapy with dehydrogesterone does not alter the normal pattern of endometrial secretion.

Clomiphene Citrate in the Treatment of Luteal Phase Defects

Clomiphene Citrate in the Treatment of Luteal Phase Defects